bluuebunny/crossref_metadata_2025 huggingface dataset:
Cigarette smoking in men and vascular responsiveness
Authors: Butler R. , Morris A. D. , Struthers A. D.
Published: March 2003

Aims  Smoking is a major risk factor for developing atherosclerosis. In order to understand the vascular abnormalities observed in smokers, we investigated vascular responsiveness in cigarette smokers.

Methods  We performed two consecutive matched group comparative studies to investigate vascular responsiveness using venous occlusion plethysmography. The mean effects of three incremental doses of each vasoactive agent are presented. Both studies compared smokers with nonsmokers.

Results  The first investigated 68 subjects (smokers = 29; mean ± s.d. ages; 24 ± 6 vs 25 ± 5 years; P = NS) and found smoking was associated with a significant blunting of the flow ratio between treated and untreated arms to endothelium‐dependent vasodilatation to acetylcholine (mean ± s.d., nonsmokers vs smokers) 4.07 ± 2.18 vs 3.42 ± 1.79 (P = 0.04, 95% CI 0.02, 1.12). By contrast, there was no significant difference in the responses to the endothelium‐independent vasodilators sodium nitroprusside and verapamil. Smoking was also associated with a significant impairment in endothelium‐dependent vasoconstriction induced by monomethyl‐l‐arginine (L‐NMMA) 0.78 ± 0.22 vs 0.87 ± 0.21 (P = 0.006, 95% CI −0.14, −0.02) and a trend to blunted endothelium‐independent vasoconstrictor responses to noradrenaline. In the second study we investigated the response to angiotensin I and II in 23 subjects (smokers=12; mean ± s.d. ages; 34 ± 10 vs 32 ± 11 years). There was significant impairment in smokers of the mean vasoconstrictor response to angiotensin I 0.51 ± 0.15 vs 0.59 ± 0.16 (nonsmokers vs smokers; P = 0.003, 95% CI −0.13, −0.03) and a nonsignificant trend towards impairment of the response to angiotensin II.

Conclusions  Cigarette smoking in male volunteers is associated with blunted basal and stimulated nitric oxide bioactivity. Endothelial independent vasodilator responses (to nitroprusside and verapamil) were unaltered in smokers. A defect in the vasoconstrictor response to angiotensin I was also seen.
Multiple dose study of interactions between artesunate and artemisinin in healthy volunteers
Authors: Zhang Shu‐Qiu , Hai Trinh Ngoc , Ilett Kenneth F. , Huong Dinh Xuan , Davis Timothy M. E. , Ashton Michael
Published: March 2003

Aims  To investigate whether coadministration of the antimalarials artesunate and artemisinin alters the clearance of either drug.

Methods  Ten healthy Vietnamese males (Group AS) were randomized to receive a single dose of 100 mg oral artesunate (pro‐drug of dihydroartemisinin) on day −5 and then once daily for 5 consecutive days (days 1–5). Oral artemisinin (500 mg) was coadministered on days 1 and 5. Another 10 subjects (Group AM) were given 500 mg oral artemisinin on day −5 and then further doses on days 1–5. Artesunate 100 mg was given on days 1 and 5. Artemisinin and dihydroartemisinin plasma concentrations on days −5, 1 and 5 were quantified by h.p.l.c. with on‐line postcolumn derivatization and u.v. detection.

Results  In Group AS, dihydroartemisinin oral clearance values (mean (95% CI)) were similar on day 1 (32 (22, 47)) l h−1 and day 5 (38 (28, 51)) l h−1 of daily artesunate administration but these mean values were approximately three fold higher compared with day −5 after a single dose (95 (56, 159)). In this group, artemisinin oral clearance increased from 196 (165, 232) l h−1 on day 1–315 (241, 410) l h−1 on day 5. In Group AM, dihydroartemisinin oral clearance on day 1 was 39 (34, 46) l h−1 and increased 1.6 fold to 64 (48, 85) l h−1 on day 5. In this group, artemisinin oral clearance increased sequentially (1.5 and 4.7 fold, respectively) from 207 (151, 285) l h−1 on day −5–308 (257, 368) l h−1 on day 1 and to 981 (678, 1420) l h−1 on day 5. The increase in artemisinin oral clearance between days −5 and 1 (in the absence of artesunate) was similar to that between days 1 and 5 in Group AS subjects who took daily artesunate. Dihydroartemisinin was not a significant metabolite of artemisinin.

Conclusions  Artesunate (dihydroartemisinin) did not alter the elimination of artemisinin. However, dihydroartemisinin elimination was inhibited by artemisinin. Artemisinin induced its own elimination even 5 days after a single oral dose. There was no evidence for the formation of dihydroartemisinin from artemisinin.
In vitro evaluation of valproic acid as an inhibitor of human cytochrome P450 isoforms: preferential inhibition of cytochrome P450 2C9 (CYP2C9)
Authors: Wen Xia , Wang Jun‐Sheng , Kivistö Kari T. , Neuvonen Pertti J. , Backman Janne T.
Published: March 2003

Aims  To evaluate the potency and specificity of valproic acid as an inhibitor of the activity of different human CYP isoforms in liver microsomes.

Methods  Using pooled human liver microsomes, the effects of valproic acid on seven CYP isoform specific marker reactions were measured: phenacetin O‐deethylase (CYP1A2), coumarin 7‐hydroxylase (CYP2A6), tolbutamide hydroxylase (CYP2C9), S‐mephenytoin 4′‐hydroxylase (CYP2C19), dextromethorphan O‐demethylase (CYP2D6), chlorzoxazone 6‐hydroxylase (CYP2E1) and midazolam 1′‐hydroxylase (CYP3A4).

Results 
Valproic acid competitively inhibited CYP2C9 activity with a Ki value of 600 µm. In addition, valproic acid slightly inhibited CYP2C19 activity (Ki = 8553 µm, mixed inhibition) and CYP3A4 activity (Ki = 7975 µm, competitive inhibition). The inhibition of CYP2A6 activity by valproic acid was time‐, concentration‐ and NADPH‐dependent (KI = 9150 µm, Kinact=0.048 min−1), consistent with mechanism‐based inhibition of CYP2A6. However, minimal inhibition of CYP1A2, CYP2D6 and CYP2E1 activities was observed.

Conclusions 
Valproic acid inhibits the activity of CYP2C9 at clinically relevant concentrations in human liver microsomes. Inhibition of CYP2C9 can explain some of the effects of valproic acid on the pharmacokinetics of other drugs, such as phenytoin. Co‐administration of high doses of valproic acid with drugs that are primarily metabolized by CYP2C9 may result in significant drug interactions.
Population pharmacokinetics of the new antimalarial agent tafenoquine in Thai soldiers
Authors: Edstein Michael D. , Kocisko David A. , Brewer Thomas G. , Walsh Douglas S. , Eamsila Chirapa , Charles Bruce G.
Published: March 2003

Aims  To describe the population pharmacokinetics of tafenoquine in healthy volunteers after receiving tafenoquine for malaria prophylaxis.

Methods  The population consisted of 135 male Thai soldiers (mean age 28.9 years; weight 60.3 kg). All soldiers were presumptively treated with artesunate for 3 days plus doxycycline for 7 days to remove any pre‐existing malaria infections. After the treatment regime, 104 soldiers (drug group) received a loading dose of 400 mg tafenoquine base daily for 3 days followed by 400 mg tafenoquine monthly for 5 consecutive months. In the placebo group, 31 soldiers were infected with malaria during the study period. They were re‐treated with artesunate for 3 days plus doxycycline for 7 days followed by a loading dose of 400 mg tafenoquine daily for 3 days and then 400 mg tafenoquine weekly for prophylaxis. Blood samples were randomly collected from each soldier on monthly and weekly prophylaxis. Plasma tafenoquine concentrations were measured by h.p.l.c. Population pharmacokinetic modelling was performed using NONMEM.

Results  A one‐compartment model was found best to describe the pharmacokinetics of tafenoquine after oral administration. Age and weight influenced volume of distribution (V/F), and subjects who contracted malaria had higher clearance (CL/F), but none of these factors was considered to have sufficient impact to warrant change in dosing. The population estimates of the first‐order absorption rate constant (Ka), CL/F and V/F were 0.694 h−1, 3.20 l h−1 and 1820 l, respectively. The intersubject variability in these parameters (coefficient of variation, CV%) was 61.2%, 25.3% and 14.8%, respectively. The absorption and elimination half‐lives were 1.0 h and 16.4 days, respectively. The residual (unexplained) variability was 17.9%.

Conclusions  The population pharmacokinetics of orally administered tafenoquine have been determined in Thai soldiers under field conditions. This information, together with its known potent antimalarial activity, portends well for the application of tafenoquine as a useful prophylactic drug or for short‐term radical treatment of vivax malaria.
Effect of bile acids on absorption of nitrendipine in healthy subjects
Authors: Sasaki Masato , Maeda Akira , Sakamoto Ko‐ichi , Fujimura Akio
Published: March 2003

Aims  To examine whether bile acids such as ursodeoxycholic acid (UDCA) and chenodeoxycholic acid (CDCA) can influence the absorption of nitrendipine, a highly lipophilic calcium channel blocker.

Methods  Six healthy subjects received nitrendipine (10 mg) with and without UDCA (50 mg) and CDCA (200 and 600 mg) with an interval of 1∼2 weeks between study phases.

Results  Bile acids decreased the Cmax (ng ml−1) [control 10.9 ± 5.8 (mean± s.d.), UDCA 5.0 ± 4.7 (95% confidence interval for difference; 3.9, 7.8, P = 0.0006), CDCA (600 mg) 5.0 ± 3.9 (2.6, 9.2, P = 0.0059)] and AUC (ng ml−1 h) [(control; 60 ± 36, UDCA 15 ± 13 (20, 73, P = 0.0064), CDCA (600 mg) 19 ± 19 (21, 63, P = 0.0038)] of nitrendipine, while elimination half‐life remained unchanged.

Conclusions  These results suggest that the amount of nitrendipine absorbed was decreased when the drug was administered with UDCA and CDCA.
Human thiopurine methyltransferase activity varies with red blood cell age
Authors: Lennard L. , Chew T. S. , Lilleyman J. S.
Published: March 2003

Aims  Inherited differences in thiopurine methyltransferase (TPMT) activity are an important factor in the wide interindividual variations observed in the clinical response to thiopurine chemotherapy. The aim of this study was to establish a population range for red blood cell (RBC) TPMT activity in children with acute lymphoblastic leukaemia (ALL) at disease diagnosis. An additional aim was to investigate factors that can influence TPMT activity within the RBC.

Methods
 Blood samples were collected from children with ALL at disease diagnosis, prior to any blood transfusions, as part of the nationwide UK MRC ALL97 therapeutic trial. RBC TPMT activity was measured by h.p.l.c. RBCs were age‐fractionated on Percoll density gradients.

Results
 Pretreatment blood samples were received from 570 children within 3 days of venepuncture. TPMT activities at disease diagnosis ranged from 1.6 to 23.6 units/ml RBCs (median 7.9) compared with 0.654–18.8 units (median 12.9), in 111 healthy control children (median difference 4.5 units, 95% CI 3.9, 5.1 units, P < 0.001). A TPMT quality control sample, aliquots of which were assayed in 60 analytical runs over a 12 month period, contained a median of 11.98 units with a CV of 11.6%. Seven children had their RBCs age‐fractionated on density gradients. TPMT activities in the top gradient (young cells) ranged from 4.2 to 14.1 units (median 7.5) and in the bottom gradient (old cells) 1.5–12.6 units (median 4.7 units), median difference 2.3 units, 95% CI 0.7, 4.1, P = 0.035.

Conclusions
 Circulating RBCs do not constitute a homogeneous population. They have a life span of around 120 days and during that time undergo a progressive ageing process. The anaemia of ALL is due to deficient RBC production. The results of this study indicate that RBC TPMT activities are significantly lower in children with ALL at disease diagnosis. This may be due, at least in part, to a relative excess of older RBCs.
Pharmacodynamic effect of continuous vs intermittent dosing of dofetilide on QT interval
Authors: Allen Michael J. , Oliver Stuart D. , Newgreen Margaret W. , Nichols Donald J.
Published: March 2003

Aims  To investigate the pharmacokinetics and pharmacodynamics of dofetilide 1 mg twice daily continuously for 24 days compared with intermittent single dose treatments.

Methods  A randomized, single‐blinded, placebo‐controlled, parallel‐group, multiple‐dose study design was utilized. Healthy male volunteer subjects were randomized into three groups. Group 1 received dofetilide 1.0 mg twice daily for 23 days and once on day 24. Group 2 received matching placebo capsules under the same regimen as group 1. Group 3 received a single dose of dofetilide 1.0 mg on days 1, 5, 10, 17, and 24 with identical placebo capsules administered at all other times to match the dosing pattern of the other groups.

Results  Continuous administration of dofetilide resulted in the achievement of steady‐state concentrations by day 5. Pharmacokinetic parameters following intermittent treatment showed no accumulation. Maximum daily QTc interval (mean± s.e. mean) increased in response to continuous twice‐daily dofetilide from baseline (373 ± 5) to day 2 (453 ± 9) but thereafter decreased slightly, but not beyond day 5, by which time the mean maximum QTc was 440 ± 7 ms. In contrast, single doses of dofetilide in the intermittently treated group led to reproducible increases in QTc. Thus mean (± s.e. mean) maximum QTc increased from a baseline of 387 ± 7–467 ± 14, 467 ± 18, 469 ± 14 and 458 ± 10 ms on days 5, 10, 17 and 24, respectively. In view of the pharmacokinetic accumulation on continuous dosing, the attenuation of responsiveness is best represented by the slope of the QTc vs plasma concentration relationship. In the continuously treated group, an initial decrease in the value of the mean slope between day 1 (14.2 ± 1.7 ms/ng ml−1) and day 5 (9.1 ± 0.8 ms/ng ml−1) did not progress beyond day 5. The mean difference in slopes (95% CI) between the intermittent and continuously treated groups were 4.4 (1.3, 7.4) on day 5, 4.9 (1.6, 8.2) on day 10, 5.2 (1.1, 9.2) on day 17 and 4.4 (0.4, 8.4) on day 24.

Conclusions  With continuous twice‐daily administration the QT interval responsiveness to dofetilide is greater after the first dose than it is at steady state. After day 5 the relationship between dofetilide plasma concentration and its QT interval effect is predictable and stable over time.
Early clinical experience with the novel NMDA receptor antagonist CNS 5161
Authors: Walters M. R. , Bradford A. P. J. , Fischer J. , Lees K. R.
Published: March 2003

Aims  To investigate the safety, tolerability and pharmacokinetics of the novel NMDA antagonist CNS 5161 in humans. Excessive activation of glutamate receptors, especially of the N‐methyl‐d‐aspartate (NMDA) subtype has been associated with neuropathic pain, and brain damage caused by focal ischaemia in mature brain or hypoxia‐ischaemia (HI) in neonates. CNS 5161 is a novel NMDA ion‐channel antagonist that interacts with the NMDA receptor/ion channel site to produce a noncompetitive blockade of the actions of glutamate. Pre‐clinical studies have demonstrated neuroprotective effects of CNS 5161 in the adult rat model of focal cerebral ischaemia, as well as anticonvulsant and analgesic effects. This study reports the first administration of CNS 5161 to man. Its objectives were to investigate the haemodynamic effects of the compound, to assess its safety and tolerability in healthy male volunteers, and to provide some preliminary human pharmacokinetic data.

Methods  We performed a randomized, double‐blind placebo controlled phase 1 dose escalation study of CNS 5161. Volunteers were randomized to receive CNS 5161 or placebo in a ratio of 3 : 1. Twenty‐four of 32 healthy volunteers received intravenous infusion of CNS 5161 over 15 min, followed by serial measurements of plasma drug concentration and haemodynamic observations over 24 h. A dose escalation design was adopted and the volunteers were stratified into eight dosage groups, ranging from 30 µg to 2000 µg.

Results  The drug was well tolerated by recipients. Side‐effects were dose‐related, self limiting and comprised minor subjective sensory symptoms. A dose dependent rise in systolic, mean arterial and diastolic blood pressure was seen in subsequent dosage groups, reaching 23/19 mmHg. Maximal effects were seen between 60 and 120 min after commencement of infusion. All subjects returned to baseline haemodynamic values within 24 h. Putative neuroprotective concentrations of CNS 5161 were achieved transiently, although these levels were not sustained. The pharmacokinetic data were best described by a two compartment model. The mean half‐life was 2.95 h (s.d. 0.75). Mean clearance was 106 l h−1 (s.d. 17.8) mean volume of distribution was 296 l (s.d. 69). These parameters were not significantly affected by body weight.

Conclusions  This study suggests that CNS 5161 is well tolerated in healthy volunteers within the dose range studied. In addition, information concerning the pharmacokinetics of the compound has been acquired. Studies to investigate the efficacy of the compound in man may now be justified.
Local nitric oxide release does not affect tachyphylaxis to angiotensin II in dorsal hand veins in man in the presence of prostaglandin synthesis inhibition
Authors: de Haas S. L. , Wilkinson I. B. , Boyd J. L. , Webb D. J.
Published: March 2003

Aims  Local prostaglandin (PG) production contributes to tachyphylaxis to angiotensin II (ANGII) in veins. Our aim was to assess the hypothesis that local nitric oxide (NO) generation is also, in part, responsible for tachyphylaxis to ANGII in veins, using the Aellig dorsal hand vein technique.

Methods  Eight healthy male volunteers received 600 mg of aspirin (orally) to inhibit PG production. The venoconstrictor effects of ANGII and noradrenaline (NA) were then compared in dorsal hand veins during co‐infusion of the NO synthase inhibitor L‐NMMA or saline, on separate occasions.

Results  ANGII and NA produced a similar degree of initial venoconstriction. However, the response to ANGII was significantly attenuated by 12 min compared with NA (AUC 147 ± 38 vs 196 ± 40, respectively; [95% confidence interval for difference: 7, 92], P = 0.02). Infusion of L‐NMMA did not influence the response to ANGII or NA (P = 0.2 and P = 0.3, respectively).

Conclusions  Tachyphylaxis to ANGII in dorsal hand veins is not dependent on local NO release.
Comparative activity of cetirizine and mizolastine on histamine‐induced skin wheal and flare responses at 24 h
Authors: Purohit A. , Mélac M. , Pauli G. , Frossard N.
Published: March 2003

Aims  The aim of our study was to compare the activity of cetirizine 10 mg with that of mizolastine 10 mg vs placebo at 24 h after intake in healthy volunteers.

Methods  This was a double‐blind, randomized, placebo controlled, three‐way cross‐over study with a wash‐out period of 7±2 days between each period. The study included 36 healthy volunteers (18–50 years, mean age = 32 years; 9 males). The objective measurement was the cutaneous reactivity to increasing concentrations of histamine (0, 5, 10, 20, 40, 80, 160 mg ml−1) administered by prick tests. The reactivity was evaluated by the wheal and flare areas (mm2). The AUC (area under curves) values of the wheal and flare areas as a function of the log2 transformed histamine concentration were calculated for each subject and treatment, and compared.

Results  A highly significant treatment effect was evidenced both for wheal and flare responses (P = 0.0001). This indicates the good activity of both cetirizine 10 mg and mizolastine 10 mg in inhibiting skin wheal and flare reactions to histamine. In addition, the mean AUC values significantly differed between cetirizine and mizolastine (64.8 and 117.8 log2 (mg ml−1) × mm2 for wheal, and 939.4 and 2340.8 for flare, respectively; P = 0.0001), with a superior activity of cetirizine than mizolastine at 24 h after intake both on wheal and flare responses. The tolerance of cetirizine and mizolastine was good. The severity of the adverse events was never more than ‘moderate’, ‘fatigue’ being the most frequent reported symptom [cetirizine (6 subjects), placebo (3), mizolastine (5)], followed by ‘somnolence’[cetirizine (0), placebo (1), mizolastine (3)]. There was no serious adverse event.

Conclusions  This study shows that cetirizine (10 mg) suppresses skin reactivity to histamine more effectively than mizolastine (10 mg) 24 h after intake in healthy volunteers.
Flow‐mediated nitric oxide activity in the forearm vasculature of premenopausal women
Authors: Anumba Dilly O. C. , Robson Stephen C. , Ford Gary A.
Published: March 2003

Aims  Nitric oxide (NO) is involved in acute flow‐mediated vasodilatation in various vascular beds. We determined whether acutely increasing flow in the human forearm of premenopausal women increases vascular NO activity.

Methods  Forearm blood flow (FBF) was measured by venous occlusion plethysmography. Responses to brachial artery infusion of noradrenaline (a control vasoconstrictor, 20, 50, and 100 ng min−1, each for 5 min) and NG‐monomethyl l‐arginine (L‐NMMA), an NO synthase inhibitor (200, 400, and 800 µg min−1, each for 5 min), were determined in eight premenopausal women before and following elevation of basal FBF with glyceryl trinitrate (GTN) on two separate occasions.

Results  Flow elevation with GTN increased responses to L‐NMMA (summary measure 103±12 vs 65±12 arbitrary units, P<0.05), but not to noradrenaline (95±35 vs 74±12, P=0.50).

Conclusions  Acute elevation of FBF in nonpregnant women is associated with enhanced responses to NO synthase inhibition, consistent with flow‐mediated increased NO activity.
Pharmacokinetics and gamma scintigraphy evaluation of two enteric coated formulations of didanosine in healthy volunteers
Authors: Damle Bharat , Ullah Ismat , Doll Walter , Wiley Gary , Knupp Catherine
Published: March 2003

Aims
The aims of the study were to evaluate the bioavailability of didanosine from the encapsulated enteric coated beads (1 × 200 mg; enteric beads) and enteric coated mini‐tablets (4 × 50 mg; enteric tablet) formulations relative to the chewable/dispersible buffered tablets (2 × 100 mg; buffered tablet), and to study their rate of gastrointestinal transit.

Methods
This was a single‐dose, randomized, three‐way crossover study in 18 healthy male volunteers. A 200 mg dose of didanosine was given in each period and each formulation contained a gamma radiation–emitting isotope. Pharmacokinetic parameters determined were Cmax, tmax, AUC(0,∞) and t1/2. Bioequivalence was assessed using the confidence interval (CI) of 0.80, 1.25 for Cmax and AUC(0,∞). Scintigraphic images were recorded and gastrointestinal transit profiles were generated.

Results
The point estimate and 90% CI of the ratio of Cmax for the enteric beads and enteric tablet relative to the buffered tablet was 0.71 (0.59, 0.85) and 0.55 (0.46, 0.66), respectively. The tmax was significantly different for the enteric beads (median, 1.33 h) and the enteric tablet (median, 2.83 h) than for the buffered tablet (median, 0.67 h). The AUC(0,∞) satisfied the bioequivalence criteria, and the point estimate and 90% CI of the ratio were 1.02 (0.91, 1.15) and 0.92 (0.82, 1.04) for the enteric beads and enteric tablet, respectively. The AUC(0,∞) values appeared to be less variable with the enteric beads (% CV = 19%) than with the enteric tablet (% CV = 33%). The t1/2 values were not significantly different between formulations, and the mean values ranged from 1.82 to 1.92 h. Inspection of the individual scintigraphy profiles and concentration‐time curves suggested that didanosine was absorbed throughout the small intestine. Gastrointestinal transit parameters were higher for both enteric formulations than for the buffered tablet, indicating slower transit of the enteric formulations. Between the enteric formulations, gastric emptying was slower for the enteric beads than for the enteric tablet; however, plasma didanosine concentrations were observed sooner for the enteric beads, suggesting that the enteric coat for the beads dissolved more rapidly.

Conclusions
The enteric beads and enteric tablet formulations of didanosine were equivalent to the buffered tablet in their extent of absorption. Although the gastric emptying of the enteric tablet was faster, based on the rapid uncoating and the lower variability in AUC, the enteric beads were chosen for further clinical development.
Reflecting on part‐time private practice: Is it worth it?
Authors: Bates Merrelyn
Published: March 2003

Gradual, but not so subtle, changes in Australia's political and welfare cultures have meant that over the past 10 years social workers have been showing a greater interest in private practice as a legitimate aspect of the profession. This paper presents some of the major practical considerations required for a part‐time practice to be successfully initiated and maintained. The author uses her own experience as an example and explores the personal, professional and commercial decisions she has made in such a practice over the past 16 years.
Alternating Hemiplegia of Childhood: No Mutations in the Familial Hemiplegic Migraine CACNA1A Gene
Authors: Haan J , Kors EE , Terwindt GM , Vermeulen FLMG , Vergouwe MN , van den Maagdenberg AMJM , Gill DS , Pascual J , Ophoff RA , Frants RR , Ferrari MD
Published: March 2003

Introduction

Alternating hemiplegia of childhood (AHC) is a rare disorder mainly characterized by attacks of hemiplegia and mental retardation. It has been often associated with migraine. The CACNA1A gene on chromosome 19 is involved in familial hemiplegic migraine and other episodic cerebral disorders, but also with progressive neuronal damage.

Methods

We performed mutation analysis in this gene in four AHC patients, using single strand conformation polymorphism analysis.

Results

We found nine polymorphisms, but no mutations in any of the 47 exons.

Conclusions

Other cerebral ion channel genes remain candidate genes for AHC.
Relationship between β‐cell responsiveness and fasting plasma glucose in Caucasian subjects with newly presenting Type 2 diabetes
Authors: Hovorka R. , Albarrak A. , Chassin L. , Luzio S. D. , Playle R. , Owens D. R.
Published: March 2003

Aims  β‐cell responsiveness was related to fasting plasma glucose to gain further understanding of pathophysiology of Type 2 diabetes.

Methods  An insulin secretion model gave fasting β‐cell responsiveness M0 (ability of fasting glucose to stimulate β‐cell) and postprandial β‐cell responsiveness MI (ability of postprandial glucose to stimulate β‐cell) by analysing glucose and C‐peptide time‐concentration curves sampled every 10–30 min over 240 min during a meal tolerance test (MTT; 75 g CHO, 500 kcal). Caucasian subjects with newly presenting Type 2 diabetes according to WHO criteria (N = 83, male/female: 65 : 18, age: 54 ± 10 years, body mass index (BMI): 30.9 ± 5.2 kg/m2, fasting plasma glucose (FPG): 11.0 ± 3.2 mmol/L; mean ± SD) and Caucasian healthy subjects (N = 54, m/f: 21 : 33, age: 48 ± 9 years, BMI: 26.1 ± 3.7 kg/m2, FPG: 5.1 ± 0.4 mmol/L) were studied.

Results  A continuum inverse relationship between MI and FPG was observed. In the diabetes group, MI was closely related to FPG (rs = −0.74, P < 0.0001) and explained 60% intersubject FPG variability with the use of an exponential regression model.

Conclusions  In newly presenting Type 2 diabetes in Caucasian subjects a close inverse association exists between postprandial β‐cell responsiveness and FPG.

Diabet. Med. 18, 797–802 (2001)
Associations between apolipoprotein E phenotype, glucose metabolism and cognitive function in men. An explorative study in a population sample
Authors: Helkala E‐L. , Lakka T. , Vanhanen M. , Tuomainen T‐P. , Ehnholm C. , Kaplan G.A. , Salonen J.T.
Published: March 2003

Aims  To investigate the associations of the apolipoprotein E phenotype (apoE) and disturbed glucose metabolism with cognitive function in a random population sample.

Methods  A cross‐sectional study was conducted, in which 528 men aged 54 or 60 years were recruited randomly from a larger population‐based sample of 1516 men. A subject was defined as having abnormal glucose tolerance (AGT), if he had a clinical diagnosis of diabetes, with either dietary or oral antidiabetic treatment or showed impaired glucose tolerance in an oral glucose tolerance test. The subjects were divided into three groups according to apolipoprotein E phenotypes: (a) E2/4, E3/4 or E4/4 (apoE E4); (b) E 3/3 (apoE E3); and (c) E2/2 or E2/3 (apoE E2). Memory function was examined using a word‐list learning with Buschke's selective reminding method and test. Executive functions were assessed with the Trail Making Test A and B.

Results  Those subjects with apoE E2 and abnormal glucose metabolism demonstrated the worst cognitive executive control compared to other groups. Simple cognitive speed did not differ between the groups.

Conclusions  The exploratory analyses revealed that subjects with apoE E2 allele and AGT had worse glycaemic control and cognitive executive control compared to other groups. Different apolipoprotein phenotypes together with impaired glucose tolerance may have different cumulative adverse effects on age‐related cognitive performance. Some subgroups of subjects may be especially vulnerable to cognitive impairment.

Diabet. Med. 18, 991–997 (2001)
Appalachian basin stratigraphic response to convergent‐margin structural evolution
Authors: Castle J. W.
Published: March 2003

ABSTRACT From study of Palaeozoic formations in the Appalachian foreland basin, a predictive stratigraphic model is proposed based on facies tract development during convergent‐margin structural evolution. Five major facies tracts are recognized: shallow‐water carbonates that formed during interorogenic quiescence and initial foreland subsidence; deep‐water siliciclastics that accumulated in the proximal foreland basin during early collision; syn‐collisional shallow‐water siliciclastics; syn‐collisional, channellized fluvial sandstones that aggraded in the proximal foreland; and progradational shoreline sandstones that were deposited in response to filling of the proximal foreland. Two other facies tracts that occur are organic‐rich siliciclastics (‘black shales’), which accumulated in oxygen‐deficient areas of low clastic‐sediment influx, and incised valley‐fill deposits, which formed where subsidence rate was low.

Because the origin of each facies tract is dependent upon a unique combination of rate of accommodation change and rate of sediment supply, facies tract distribution is predictable from spatial and temporal patterns of subsidence and uplift associated with plate convergence. Alternating phases of thrust loading and quiescence caused fluctuations between underfilled and overfilled conditions during Palaeozoic evolution of the Appalachian basin. Along‐strike variations in stratigraphic thickness, facies tract distribution, and development of unconformities in the Appalachian basin reflect the influence of structural irregularities along the collisional margin. In distal parts of the Appalachian foreland and in areas of structural recesses, eustatic influence on stratigraphic patterns is expressed more clearly than in areas of higher subsidence rate.
Thermal history and exhumation of the Northern Apennines (Italy): evidence from combined apatite fission track and vitrinite reflectance data from foreland basin sediments
Authors: Ventura B. , Pini G. A. , Zuffa G. G.
Published: March 2003

ABSTRACT Apatite fission track ages of 20 samples collected from turbidite successions deposited in foreland basins adjacent to the Northern Apennines range between ∼3 and ∼10 Ma. The youngest fission track ages are concentrated in a NW–SE elongated belt, which approximately runs through the centre of the study area, while gradually increasing ages are distributed towards the south‐western and north‐eastern borders. Integration of apatite fission track data and published vitrinite reflectance values indicate this region of the Apennines experienced continuous but variable exhumation starting from ∼14 Ma. The extent of exhumation and uplift range between 5 and 6 km at the south‐western and north‐eastern borders of the study area, and ∼7 km in the central part. Exhumation was driven mainly by erosion, with minor faulting in response to structural readjustment related to differential exhumation. Regional exhumation and erosion are interpreted as the result of isostatic rebound following crustal thickening in the lower part of the orogen.
Modification of the pacemaker activity of vestibular neurons in brainstem slices during vestibular compensation in the guinea pig
Authors: Ris Laurence , Capron Brigitte , Vibert Nicolas , Vidal Pierre‐Paul , Godaux Emile
Published: March 2003

In the guinea pig, unilateral labyrinthectomy causes an immediate and severe depression of the spontaneous activity of the ipsilateral central vestibular neurons, which subsequently recovers completely within one week. A possible underlying mechanism could be an increase in the endogenous activity of the neurons deprived of their labyrinthine input. Here, we addressed this hypothesis. The endogenous activity of the neurons was assessed by their spontaneous activity recorded extracellularly in brainstem slices in the presence of a cocktail of neurotransmitter blockers (CNQX, d‐APV, bicuculline and strychnine) which freed them from their main synaptic influences. The left medial vestibular nucleus (MVN) was explored in a very systematic way and strict methodological precautions were taken in order to validate comparisons between the numbers of spontaneously active neurons recorded in the MVN of distinct slices. In the presence of neurotransmitter antagonists, the mean number of spontaneously active neurons detected in a single MVN increased dramatically from 9.5 in slices from control guinea pigs to 26.3 in slices from animals labyrinthectomized on the left side one week beforehand. The mean firing rate of the recorded neurons also increased from 7.5 ± 5.6 spikes/s in slices from control animals to 12.3 ± 7.6 spikes/s in slices from guinea pigs labyrinthectomized one week beforehand. These results show that deprivation of the vestibular neurons of their labyrinthine input caused a change in the deprived neurons themselves. They suggest that an increase in pacemaker activity might be a factor responsible for the restoration of spontaneous activity in the vestibular neurons after labyrinthectomy.
Cultural adaptation is associated with atopy and wheezing among children of Turkish origin living in Germany
Authors: Grüber C. , Illi S. , Plieth A. , Sommerfeld C. , Wahn U.
Published: March 2003

Background Turkish children have been found to suffer less from atopic diseases than their German peers. The underlying causes are unknown.

Objective To evaluate rates of sensitization and atopic disease among children in Germany with German or Turkish ethnicity and different degrees of cultural adaptation.

Methods This was a cross‐sectional study. The setting was screening for school eligibility in an inner‐city district of Berlin/Germany. The participants were preschool children born in Germany with double German or double Turkish parental citizenship. Cultural adaptation of Turkish children was assessed by the language parents used to communicate with their child: only Turkish (n = 60, group A); Turkish and German (n = 269, group B); and only German (n = 103, group C). Group D contained children from German parents (n = 383). The main outcome measures were specific sensitization to common aeroallergens (CAP‐System, Pharmacia Phadiatop ≥ 0.35 kU/L), and lifetime and 1‐year prevalences of allergic disease symptoms (ISAAC questionnaire in German and Turkish, Mantel‐Haenszel test for trend).

Results Sensitization rates for groups A, B, C and D were 8.0%, 6.8%, 18.9% and 18.3%, respectively (P = 0.004). The corresponding prevalence rates for wheeze ever were 6.7%, 9.3%, 12.6% and 21.3% (P < 0.001), wheeze in the past year 3.3%, 3.7%, 9.7% and 10.2% (P = 0.001), itchy rash ever 3.3%, 6.3%, 8.7% and 13.7% (P < 0.001), itchy rash in the past year 1.7%, 3.7%, 4.9% and 9.5% (P < 0.001), respectively. No significant differences were found for hay fever symptoms.

Conclusions Higher cultural adaptation is correlated with higher rates of allergic sensitization and disease among children of Turkish origin living in Berlin. This correlation suggests that environmental rather than genetic differences are responsible for the differences observed.
Two new polymorphisms in the human interferon gamma (IFN‐γ) promoter
Authors: Chevillard C. , Henri S. , Stefani F. , Parzy D. , Dessein A.
Published: March 2003

Two new single‐nucleotide polymorphisms are described within the human interferon gamma (IFN‐γ) promoter in a Sudanese population. One is a G to T transition at position −183 from the transcription start. The other is a A to G transition at position −155. Allelic frequency analysis indicated frequencies of 0.927 (G) and 0.073 (T) at position −183 and 0.977 (A) and 0.023 (G) at position −155. These two polymorphisms have not been detected in the Centre d’Etude du Polymorphisme Humain (CEPH) reference population. The polymorphism −183(G → T) may alter the AP‐1 binding domain and the regulation of transcription. The polymorphism −155(A → G) is located close to the nuclear factor‐activated T‐cell site (NFAT site) (−168 TAAAGGAAA‐160) and may affect the stability of this region.
Managing acute pain and anxiety in children undergoing procedures in the emergency department
Authors: Krauss Baruch
Published: March 2003

See Commentary, page 271.
Spontaneous splenic rupture in infectious mononucleosis
Authors: Rothwell Sean , McAuley Duncan
Published: March 2003

Spontaneous splenic rupture is a rare but life‐threatening complication of infectious mononucleosis. Abdominal pain and tachycardia are unusual in uncomplicated infectious mononucleosis and should alert a doctor to the possibility of spontaneous splenic rupture.
Current trends in the management of major paediatric trauma
Authors: Browne Gary J , Cocks Amanda J , McCaskill Mary E
Published: March 2003

See Commentary, page 405.
Physical variability in Prince William Sound during the SEA Study (1994–98)
Authors: Vaughan Shari L. , Mooers Christopher N. K. , Gay Shelton M.
Published: March 2003

From 1994 to 1998, a multidisciplinary ecosystem study (the Sound Ecosystem Assessment) examined the primary physical and biological factors that influence the production of pink salmon and Pacific herring in Prince William Sound (PWS), species that experienced population declines after the 1989 Exxon‐Valdez oil spill. Three physical processes are described that influence ecosystem processes: surface layer stratification; upper layer (<100 m) circulation; and exchange between PWS and the northern Gulf of Alaska (NGOA). Stratification formed first in the PWS nearshore regions in March, and subsequently in the northern central basin in April, primarily due to freshening. The northern stratified layer and the associated zonal density front persisted at least through June, but year‐to‐year differences occurred. In spring and summer, circulation in central PWS could be either cyclonic or anticyclonic. Drifter trajectories often linked central PWS to a nearshore bay or fjord, or one bay or fjord to another. September was characterized by a cyclonic circulation and isopycnal doming in central PWS, with little year‐to‐year variability. At Hinchinbrook Entrance, a main connection with the Gulf of Alaska, alternating inflows and outflows occurred in spring over all depths. In summer through early autumn (1995), in the absence of predominantly westward winds, the dominant exchange pattern was outflow above about 150 m and inflow below. In summer through early autumn (1996–98), there was also surface (<20 m) inflow at Montague Strait (the other main entrance). Northward transport at Hinchinbrook Entrance was maximum in late autumn through winter, with inflow above ~150 m and outflow below. Westward wind events over the shelf associated with the weather cycle drove inflow events at both Hinchinbrook Entrance and Montague Strait that may result in transport of zooplankton important to the PWS ecosystem.
Characterization of ammonia‐assimilating bacteria in a lagoon for wastewater from a paddock of dairy cattle
Authors: SASAKI Hiraku , MARUYAMA Gen , SUZUKI Hanatsu , NONAKA Jun , SATO Masaaki , SASAKI Takako , OHTA Minoru , NAKAI Yutaka
Published: March 2003

We investigated microorganisms that assimilated ammonia in lagoon treatment processes. Ammonia‐assimilating microorganisms were detected by nitrogen‐limited medium that contained ammonia as the sole nitrogen source. Numbers of ammonia‐assimilating aerobes (log CFU/g) were 3.4, 4.8, 5.0, 4.8 and 5.0 (log CFU/mL) on the culture plate incubated at 4°C, 10°C, 15°C, 20°C and 25°C, respectively. Many isolates used ammonia in high rates when they were purely cultivated in nitrogen‐limited medium added to sterilized lagoon extract. Many of them used ammonia even when they were cultivated in media containing viable microbial flora of the lagoon. Among them, enterobacteriaceae and Pseudomonas sp. were identified by analysis of 16S ribosomal DNA.
Influence of dietary phosphorus level on growth performance in chicks given corn‐soybean diet supplemented with amylase and acid protease
Authors: KOBAYASHI Tetsuya , MURAI Atsushi , OKADA Toru , OKUMURA Jun‐ichi
Published: March 2003

Two experiments were conducted to determine if dietary amylase and acid protease supplementation improves the nutritive value of corn‐soybean diet, and whether the dietary inorganic phosphorus (P) level affects the growth‐promoting effect induced by the enzyme supplementation in chicks. In the first experiment, 4‐day‐old Single Comb White Leghorn male chicks were given a corn‐soybean diet supplemented with amylase and acid protease for 10 days. Dietary amylase addition produced a significant improvement in growth and food efficiency, whereas acid protease had no effect on these parameters. Although there was no significant interaction between amylase and acid protease, the combination of the two enzymes produced the greatest improvement in growth performance. In contrast, neither enzyme influenced the metabolizable energy value or nitrogen balance. In the second experiment, chicks were given corn‐soybean diets having low, medium and high levels of inorganic P (3.5, 4.3 and 5.1 g/kg, respectively), supplemented with both enzymes. There were significant interactions between the dietary inorganic P level and enzyme supplementation on final bodyweight, bodyweight gain and food intake. Enzyme supplementation significantly improved chick growth at the medium inorganic P level, but not at the low or high levels. Although the thigh bone ash content and serum P concentration were improved as the dietary inorganic P level increased, enzyme supplementation had no influence on these parameters. In conclusion, the present results indicate that dietary amylase and acid protease have beneficial effects on growth performance in chicks given corn‐soybean diet. The dietary inorganic P level affects the growth response to dietary amylase and acid protease supplementation.
Electron paramagnetic resonance analysis of liver and serum in Sprague–Dawley rats exposed subchronically to coplanar pentachlorobiphenyl‐congener 3,3′,4,4′,5
Authors: YOSHIKAWA Hiroshi , MORITA Hidetoshi , TAKIZAWA Tatsuya , SHIRAI Mistuyuki , AKAHORI Fumikae , IMANO Noboru , NAKAAKI Kenji , SAKATA Roichi , YOSHIMURA Tetsuhiko
Published: March 2003

A unique electron paramagnetic resonance (EPR) signal was found at g = 2.49 at 77 K in the liver tissues or microsomes of Sprague–Dawley rats that were exposed to 3,3′,4,4′,5‐pentachlorobiphenyl (PCB126) or 2,3,7,8‐tetrachlorodibenzo‐p‐dioxin (TCDD) by the oral route. This unique EPR signal was not detected in the liver excised from rats treated with carbon tetrachloride or 3‐methyl‐cholanthrene. The EPR signal intensity increased in proportion to the dose; no gender‐specific difference was noted and the EPR signal at g = 2.49 may have originated from heme‐iron in cytochrome P450. Although, several serum parameters of the PCB126‐treated rats were slightly higher than those of the control, PCB126 does not induce hepatic dysfunction at the dose range used in this study. 3,3′,4,4′,5‐Pentachlorobiphenyl was given daily via the oral route to pregnant rats. The rats were reared until Day 22 of pregnancy, after which they were killed and EPR signals were obtained from the fetal livers. A signal at g = 2.49 was observed for each fetal liver. These results indicate that the EPR signal at g = 2.49 could be appropriate as a biomarker of exposure to PCB126 or TCDD in the situation where hepatic dysfunction is not detected.
Similarities and differences in meat consumption patterns in Asia and Pacific‐Rim countries
Authors: KOIZUMI Seiichi , KOBAYASHI Shinichi , PAN In‐Jen , TAKAKU Shinichi , BABA Masao , JUSSAUME Raymond A. , RIETHMULLER Paul , MORISON Julian , RYOO J. C. , LIN C. W. , LIN I. H. , ZHOU H. , RATANAWARAHA Apichai , NAGANO Minoru
Published: March 2003

This study investigated consumer behavior towards meat across Asia and Pacific‐Rim countries. Mail surveys were undertaken in 1994 and 1995. Data was obtained from 6197 households in Japan, the USA (mainland and Japanese–Americans in Hawaii), Australia, Thailand, Korea, Taiwan and China. The data were mainly analyzed using cluster analysis to determine the distance between each country and to classify countries into groups. Japanese respondents purchased beef more frequently than respondents from other countries. The average amount purchased on each occasion was far more for Australian respondents than for respondents from other countries, while Japanese purchased far less. Respondents in Japan, Korea, China and Australia thought beef was the most expensive meat, whereas lamb was thought to be the most expensive in the remaining countries. Chinese respondents indicated the highest consciousness of price indexes. The level of uneasiness about eating meat indicated by Asian respondents was relatively strong compared with respondents in Hawaii, the USA and Australia. Average ratings (semantic differential scale) on plans for future meat consumption were higher for beef than for other meats in Korea and China, whereas chicken was rated higher in the other countries. From the dendrogram, surveyed countries were classified into three groups: Japan, Taiwan and Korea; Thailand and China; and the USA, Japanese–Americans and Australia. Among them, the first and second clusters merged into a larger cluster, the ‘Asian’ group.
Rapid activation of Mac‐1(CD11b/CD18) molecules on macrophages by a new chemotactic factor ‘Gasserokine’ produced by Lactobacillus gasseri JCM1131T
Authors: KITAZAWA Haruki , INO Tomohiko , KAWAI Yasushi , ITOH Takatoshi , SAITO Tadao
Published: March 2003

The chemoattractant activity of a new chemotactic factor, ‘Gasserokine’ produced by Lactobacillus gasseri JCM1131T, has been proposed as a novel immunological function of probiotic lactic acid bacteria. The focus of the present study was to understand the mechanism of the chemotaxis induced by Gasserokine, using activation of an adhesion molecule, Mac‐1 (CD11b/CD18) on macrophages. The macrophage chemotaxis to Gasserokine was abolished by preincubation of macrophages with the anti‐Mac‐1 mAb. Gasserokine induced rapid serine phosphorylation of CD18 molecules within 1 min of stimulation, but the effect was short‐lived. Substantial tyrosine phosphorylation was observed in CD18‐associated protein of macrophages stimulated by Gasserokine. The tyrosine phosphorylation was confirmed in macrophages stimulated with Gasserokine and also serine/threonine phosphorylation was detected on CD18 molecules by laser microscopy using a double immunostaining method. These results suggest that selective activation of intracellular signaling cascades, such as the mitogen‐activated protein kinase pathway, are related to the macrophage chemotaxis induced by Gasserokine.