bluuebunny/crossref_metadata_2025 huggingface dataset:
Variation in nitrogen‐use traits within and between five Carex species growing in the lowland mires of northern Japan
Authors: Nakamura T. , Uemura S. , Yabe K.
Published: March 2003

Theory suggests that there should be a trade‐off between nitrogen productivity (A) and mean residence time of nitrogen in plant tissues (MRT), and that this trade‐off depends on the N availability of the habitats. To test this, we studied A, MRT and nitrogen‐use efficiency (NUE, reciprocal of N concentration in the dead shoot) in wetland Carex species sampled from seven lowland mires in Japan.

The NUE and MRT of unproductive species that usually grow in acidic and N‐poor habitats exceeded those of productive species that are abundant in weakly acidic and N‐rich habitats. Except for the most productive species, C. lyngbyei, interspecific differences in A were small, irrespective of productivity.

Intraspecific variation in A was relatively large in contrast to those in NUE and MRT. Within each species, no parameter correlated with the concentration of total dissolved nitrogen (TDN) in the soil water.

 Although NUE and MRT of the plants growing in the weakly acidic habitats correlated negatively with TDN, they were constantly high in the acidic habitats regardless of the TDN concentration. Responses of A did not correlate with TDN concentration of soil water in either acidic or weakly acidic habitats.

 A trade‐off between A and MRT in the five Carex species was not detected in relation to habitat N richness. We suggest that soil water acidity dominates the ecological performance of the Carex species, and that the trade‐off between A and MRT does not necessarily apply to wetland vegetation.
Classical and nonclassical 21‐hydroxylase deficiency: a molecular study of Argentine patients
Authors: Dain Liliana B. , Buzzalino Noemí D. , Oneto Adriana , Belli Susana , Stivel Mirta , Pasqualini Titania , Minutolo Carolina , Charreau Eduardo H. , Alba Liliana G.
Published: March 2003

objective

To characterize the molecular basis of the 21‐hydroxylase deficiency in a group of Argentine patients presenting the classical and nonclassical forms of the disease.

DESIGN

To analyse the frequency of point mutations in the CYP21 gene by DNA amplification and mutation detection.

patients

Forty‐one patients from 36 nonrelated families: 25 nonclassical (NC), 11 salt‐wasting (SW) and five simple virilising (SV). A total of 27 parents and 13 nonaffected siblings were also analysed.

MEASUREMENTS Basal steroid hormones and 17‐hydroxyprogesterone levels following adrenal stimulation with adrenocorticotrophic hormone were measured, together with an analysis of 10 point mutations in the CYP21 gene.

results A total of 83% and 74·4% classical and nonclassical chromosomes, respectively, were characterized. The intron 2 mutation was the most prevalent among classical alleles. In addition, a high frequency for R356W was observed in both groups (13·3 and 6·9%, respectively), while V281L was the most frequent mutation among the nonclassical patients with a frequency of 39·5%. No alleles containing P30L were observed, and one de novo mutation (R356W) was found. A total of 68·3% patients were fully genotyped, and all but one showed no genotype/phenotype discrepancy. Though the cut‐off value for post‐ACTH 17‐hydroxyprogesterone stimulation was 30·25 nmol/l (10·00 µg/l), the lowest value observed in the fully genotyped nonclassical group was 42·35 nmol/l (14·00 µg/l).

conclusions The high number of unidentified alleles in the nonclassical group suggests that less frequent mutations, or the presence of new ones, might be the cause of the disease in the Argentine population. Alternatively, the cut‐off value in the ACTH‐stimulated 17‐hydroxyprogesterone test might overestimate the diagnosis of the nonclassical form by including some patients with heterozygous status.
Incidence of adverse drug reactions in paediatric in/out‐patients: a systematic review and meta‐analysis of prospective studies
Authors: Impicciatore Piero , Choonara Imti , Clarkson Amanda , Provasi Davide , Pandolfini Chiara , Bonati Maurizio
Published: March 2003

Aims  To explore the usefulness of data derived from observational studies on adverse drug reactions (ADRs) in defining and preventing the risk of pharmacological interventions in children in different health care settings.

Methods  A systematic review of studies on ADRs in hospitalized children, in outpatient children, and on ADRs causing paediatric hospital admissions was performed. Studies were identified through a search of the MEDLINE and EMBASE databases. The inclusion criteria required that the population was not selected for particular conditions or drug exposure and prospective monitoring was used for identifying ADRs. Data were analysed by a random‐effects model.

Results  Seventeen prospective studies were included. In hospitalized children, the overall incidence of ADRs was 9.53% (95% confidence interval [CI], 6.81,12.26); severe reactions accounted for 12.29% (95%CI, 8.43,16.17) of the total. The overall rate of paediatric hospital admissions due to ADRs was 2.09% (95%CI, 1.02,3.77); 39.3% (95%CI, 30.7,47.9) of the ADRs causing hospital admissions were life threatening reactions. For outpatient children the overall incidence of ADRs was 1.46% (95%CI, 0.7,3.03).

Conclusions  The results show that ADRs in children are a significant public health issue. The completeness and accuracy of prescription reporting as well as clinical information from studies was a rarity, making it difficult for health practitioners to implement evidence based preventive strategies. Further, methodologically sound drug surveillance studies are necessary for an effective promotion of a safer use of drugs in children.
Pharmacokinetic–pharmacodynamic model for perindoprilat regional haemodynamic effects in healthy volunteers and in congestive heart failure patients
Authors: Bellissant Eric , Giudicelli Jean‐François
Published: March 2003

Aims  We compared the relationships between the plasma concentrations (C) of perindoprilat, active metabolite of the angiotensin I‐converting enzyme inhibitor (ACEI) perindopril, and the effects (E) induced on plasma converting enzyme activity (PCEA) and brachial vascular resistance (BVR) in healthy volunteers (HV) and in congestive heart failure (CHF) patients after single oral doses of perindopril.

Methods
 Six HV received three doses of perindopril (4, 8, 16 mg) in a placebo‐controlled, randomized, double‐blind, crossover study whereas 10 CHF patients received one dose (4 mg) in an open study. Each variable was determined before and 6–12 times after drug intake. E (% variations from baseline) were individually related to C (ng ml−1) by the Hill model E=Emax.Cγ/(CE50γ + Cγ). When data showed a hysteresis loop, an effect compartment was used.

Results
 (means±s.d.) In HV, relationships between C and E were direct whereas in CHF patients, they showed hysteresis loops with optimal ke0 values of 0.13 ± 0.16 and 0.13 ± 0.07 h−1 for PCEA and BVR, respectively. For PCEA, with Emax set to −100%, CE50 = 1.87 ± 0.60 and 1.36 ± 1.33 ng ml−1 (P = 0.34) and γ = 0.90 ± 0.13 and 1.11 ± 0.47 (P = 0.23) in HV and CHF patients, respectively. For BVR, Emax=−41 ± 14% and −60 ± 7% (P = 0.02), CE50 = 4.95 ± 2.62 and 1.38 ± 0.85 ng ml−1 (P = 0.02), and γ = 2.25 ± 1.54 and 3.06 ± 1.37 (P = 0.32) in HV and CHF patients, respectively.

Conclusions
 Whereas concentration‐effect relationships were similar in HV and CHF patients for PCEA blockade, they strongly differed for regional haemodynamics. This result probably expresses the different involvements, in HV and CHF patients, of angiotensinergic and nonangiotensinergic mechanisms in the haemodynamic effects of ACEIs.
Endothelin‐A receptor antagonist inhibits angiotensin II and noradrenaline in man
Authors: Wenzel R. R. , Rüthemann J. , Bruck H. , Schäfers R. F. , Michel M. C. , Philipp Th.
Published: March 2003

Aims  Endothelin‐1 (ET‐1) is a potent vasoconstrictor produced by the vascular endothelium. The interactions of ET with the mediators of the sympathetic nervous system and the renin‐angiotensin‐system in humans are unclear.

Methods  We studied the effects of the ETA‐selective antagonist BQ‐123 and the ETB‐selective antagonist BQ‐788 (both 10−10−10−8m) on ET‐1 (10−16−10−10m), angiotensin II (AT, 10−16−10−10m) and noradrenaline (NA, 10−16−10−10m) induced vasoconstriction in the human skin microcirculation in vivo in 25 healthy male volunteers using laser Doppler flowmetry and double injection technique.

Results  BQ‐123 caused a dose‐dependent vasodilatation (maximum effect: + 949 ± 84 AUC‐PU, P < 0.001), whereas BQ‐788 induced mild vasoconstriction (maximum effect: −388 ± 96 AUC‐PU, P < 0.01). In the presence of BQ‐123, but not BQ‐788, ET‐1, AT and NA caused markedly less vasoconstriction at any tested agonist dose; the effect was most pronounced on ET‐1 (maximum effect at 10−14m: + 814 ± 93 AUC‐PU vs ET alone, P < 0.001), followed by noradrenaline (maximim effect at 10−16m: + 580 ± 107 AUC‐PU vs NA alone, P < 0.01) and angiotensin II (maximim effect at 10−14m: + 493 ± 111 AUC‐PU vs AT alone, P < 0.001).

Conclusions  ETA‐selective antagonism inhibits vasoconstriction to AT and NA in vivo in healthy subjects. This beneficial effect may be useful for the treatment of patients with cardiovascular disease including hypertension especially in combination therapy with sympatholytic agents and inhibitors of the renin‐angiotensin system.
Effects of anticancer drugs on the metabolism of the anticancer drug 5,6‐dimethylxanthenone‐4‐acetic (DMXAA) by human liver microsomes
Authors: Zhou Shufeng , Chin Rebecca , Kestell Philip , Tingle Malcolm D. , Paxton James W.
Published: March 2003

Aims  To investigate the effects of various anticancer drugs on the major metabolic pathways (glucuronidation and 6‐methylhydroxylation) of DMXAA in human liver microsomes.

Methods  The effects of various anticancer drugs at 100 and 500 µm on the formation of DMXAA acyl glucuronide (DMXAA‐G) and 6‐hydroxymethyl‐5‐methylxanthenone‐4‐acetic acid (6‐OH‐MXAA) in human liver microsomes were determined by high performance liquid chromatography (h.p.l.c.). For those anticancer drugs showing significant inhibition of DMXAA metabolism, the inhibition constants (Ki) were determined. The resulting in vitro data were extrapolated to predict in vivo changes in DMXAA pharmacokinetics.

Results
Vinblastine, vincristine and amsacrine at 500 µm significantly (P < 0.05) inhibited DMXAA glucuronidation (Ki = 319, 350 and 230 µm, respectively), but not 6‐methylhydroxylation in human liver microsomes. Daunorubicin and N‐[2‐(dimethylamino)‐ethyl]acridine‐4‐carboxamide (DACA) at 100 and 500 µm showed significant (P < 0.05) inhibition of DMXAA 6‐methylhydroxylation (Ki = 131 and 0.59 µm, respectively), but not glucuronidation. Other drugs such as 5‐fluoroucacil, paclitaxel, tirapazamine and methotrexate exhibited little or negligible inhibition of the metabolism of DMXAA. Pre‐incubation of microsomes with the anticancer drugs (100 and 500 µm) did not enhance their inhibitory effects on DMXAA metabolism. Prediction of DMXAA–drug interactions in vivo based on these in vitro data indicated that all the anticancer drugs investigated except DACA appear unlikely to alter the pharmacokinetics of DMXAA, whereas DACA may increase the plasma AUC of DMXAA by 6%.

Conclusions
These results indicate that alteration of the pharmacokinetics of DMXAA appears unlikely when used in combination with other common anticancer drugs. However, this does not rule out the possibility of pharmacokinetic interactions with other drugs used concurrently with this combination of anticancer drugs.
Repeated local administration of noradrenaline or saline inhibits thermal hyperalgesia in pain‐sensitized human skin
Authors: Drummond Peter D. , Lipnicki Darren M.
Published: March 2003

Aims  Noradrenaline increases thermal hyperalgesia in skin sensitized to heat by the topical application of capsaicin. The aim of this study was to determine whether desensitization to the hyperalgesic effects of noradrenaline would develop after repeated local administrations of noradrenaline in the skin of the forearm.

Methods  Noradrenaline and saline were administered to the forearm by iontophoresis (200 µA, 2 min, over a surface area of 3.1 cm2) two times per day for 4–10 days in 19 healthy subjects. The adequacy of the desensitization procedure was evaluated by measuring noradrenaline‐induced vasoconstriction with laser Doppler fluxmetry. Thresholds and pain ratings to heat were then investigated at treated and control sites before and after the topical application of capsaicin, and after the iontophoresis of noradrenaline.

Results  At previously untreated sites blood flow was 49 ± 14% (± 95% confidence intervals) lower than flow at reference sites after the iontophoresis of noradrenaline. Vascular signs of adrenergic desensitization developed after 4–5 days of repeated local administration of noradrenaline in the majority of subjects. In those whose vessels constricted after the acute administration of noradrenaline, the adrenergic response averaged 23 ± 15% at the desensitized site compared with 61 ± 9% at previously untreated sites (P < 0.001). However, similar signs developed after repeated iontophoreses of saline (adrenergic response 7 ± 16% compared with 58 ± 15% at previously untreated sites, P < 0.001). Both the noradrenaline and saline treatments inhibited thermal hyperalgesia after the topical application of capsaicin. Heat‐pain thresholds averaged 43.2 ± 2.5 °C and 43.0 ± 2.3 °C at the noradrenaline and saline pretreated sites compared with 41.4 ± 2.7 °C at the control site (P < 0.05 and P < 0.06, respectively). On a 0–10 scale, heat‐pain ratings to a 7 s, 45 °C stimulus averaged 3.8 ± 1.6 and 3.5 ± 1.7 at the noradrenaline and saline pretreated sites compared with 5.3 ± 1.6 at the control site (P < 0.05). After the iontophoresis of noradrenaline heat‐pain ratings increased 1.6 ± 1.4 at the site pretreated with saline (P < 0.05) compared with only 0.4 ± 1.0 at the site pretreated with noradrenaline (not significant), consistent with local adrenergic desensitization.

Conclusions  We conclude that repeated iontophoreses of noradrenaline or saline inhibit vasoconstriction to noradrenaline, and also inhibit increases in thermal hyperalgesia evoked by capsaicin. The release of endogenous stores of noradrenaline by iontophoretic currents might contribute to these effects.
Pharmacodynamic characterization of the interaction between abciximab or tirofiban with unfractionated or a low molecular weight heparin in healthy subjects
Authors: Klinkhardt Ute , Graff Jochen , Westrup Dagmar , Kirchmaier Carl M. , Esslinger Hans‐Ulrich , Breddin Hans Klaus , Harder Sebastian
Published: March 2003

Aims  The objective of our study was to define the interaction between either unfractionated heparin (UFH) or a low molecular weight heparin, reviparin (REV), and the pharmacodynamic profile of the GPIIb/IIIa‐antagonists abciximab (ABC) or tirofiban (T).

Methods  Two studies each containing 18 healthy subjects were performed, and all were pretreated with aspirin (ASA) for 3 days. Volunteers then received UFH (5000 IU bolus/infusion 7 IU kg−1 h−1 for 7 h, n = 6), REV (4200‐anti‐Xa‐IU s.c., n = 6) or placebo (n = 6). One hour later, ABC (study I) or T (study II) were given by i.v. infusion for 6 h. The pharmacodynamic effects measured were bleeding time (BT), fibrinogen‐binding at the GPIIb/IIIa‐receptor (FIB), expression of the platelet secretion marker CD62, and ADP (20 µm)‐ and collagen (5 µg ml−1)‐induced platelet aggregation.

Results  After treatment with both GPIIb/IIIa‐antagonists, prolongation of BT occurred to a similar magnitude (approximately 25–30 min) and was not affected by UFH or REV‐comedication. ABC or T with ASA alone resulted in nearly the same magnitude of reduction in FIB and platelet aggregation. After coadministration with UFH, FIB was significantly higher (thus less inhibited) than after after T + ASA alone (19 ± 16% vs 55 ± 36%) or ABC + ASA alone (8 ± 9% vs 32 ± 11%). This attenuation of FIB was not seen with REV. Inhibition of ADP‐and collagen‐induced aggregation tended to be attenuated by treatment with UFH (e.g. ADP‐induced aggregation at 0.25 h after ABC + ASA alone =13 ± 4%; after coadministration with UFH = 40 ± 26%). No such changes were noted with REV. Minor reductions in CD62‐expression were seen in subjects given ABC or T alone, but expression was not affected by UFH or REV.

Conclusions  Co‐medication with UFH attenuated platelet inhibition during treatment with GPIIb/IIIa‐antagonists, but these effects were not seen with the low molecular weight heparin reviparin. The results show that administration of reviparin together with abciximab or tirofiban did not adversely affect the pharmacodynamic profile of these GPIIb/IIIa‐antagonists.
Random and systematic medication errors in routine clinical practice: a multicentre study of infusions, using acetylcysteine as an example
Authors: Ferner R. E. , Langford N. J. , Anton C. , Hutchings A. , Bateman D. N. , Routledge P. A.
Published: March 2003

Aims  The nature and incidence of errors in prescribing and giving medicines have previously been estimated by trained observers, or by retrospective analysis of incidents in which patients have come to harm. We have examined prospectively in routine clinical practice the concentrations of intravenous infusions of a drug (acetylcysteine) which is given according to a complicated dosing schedule.

Methods  We prospectively collected samples before and, where possible, after the infusion of acetylcysteine in 66 anonymous patients requiring treatment for acetaminophen (paracetamol) overdose in four centres in the United Kingdom. We measured the concentration in each infusion bag, and deduced from the weight of the patient the percentage of the anticipated dose that had actually been given.

Results  The experimentally determined dose was within 10% of the anticipated dose in 68 of 184 individual bags (37%), and within 20% of the anticipated dose in 112 bags (61%). Doses in 17 bags were more than 50% from the anticipated doses. In three patients, values in all three bags appeared to be systematically wrong by 50% or more; in a further seven cases, individual bags differed by 50% or more from the anticipated value. The median difference between pre‐ and post‐infusion samples was 0% [interquartile range −5.2% to +14.6%], but 9% showed a disparity of greater than ± 50%.

Conclusions  Our data suggest that there is large random variation in administered dosage of intravenous infusions. Systematic calculation errors occur in about 5% [95% confidence interval 2, 8%] of cases, and major errors in drawing up in a further 3% [1, 7%], with inadequate mixing in 9% [4, 14%]. While we have no evidence that patients were adversely affected, and while the regime of administration of the drug studied (acetylcysteine) is complicated, these data suggest that the delivered dose often deviates from the intended dose, and that methods of quality control are needed.
Pharmacokinetics and systemic activity of fluticasone via Diskus® and pMDI, and of budesonide via Turbuhaler®
Authors: Thorsson Lars , Edsbäcker Staffan , Källén Anders , Löfdahl Claes‐Göran
Published: March 2003

Aims To determine the basal pharmacokinetics, lung uptake and plasma cortisol suppression for two commonly prescribed inhaled corticosteroids.

Methods
 Twenty‐one subjects (13 healthy and 8 mild asthmatic patients) received fluticasone propionate via a chlorofluorocarbon‐propelled pressurized metered‐dose inhaler (pMDI) (healthy subjects only) and Diskus® and budesonide via Turbuhaler®, 1000 µg twice daily for 7 days. Intravenous doses (200 µg) of both compounds were used as references. Plasma concentrations of fluticasone and budesonide were determined during 48 h by liquid chromatography plus tandem mass spectrometry (LC‐MS‐MS). Plasma concentrations of cortisol were determined by LC‐MS every second hour for 24 h at baseline, and following each treatment.

Results
 The volume of distribution was found to be larger and the elimination half‐life and mean absorption time longer for fluticasone than for budesonide. The systemic availability of budesonide via Turbuhaler (39%) was significantly higher than that of fluticasone via Diskus (13%) (ratio 3.0 [2.5, 3.6] with 95% confidence interval [CI]), and via pMDI (21%) (ratio 1.8 [1.3, 2.3]). In addition, at steady state the systemic availability of fluticasone via pMDI was significantly higher than via Diskus (ratio 1.6 [1.1, 2.2]). The lung deposition of budesonide via Turbuhaler was 2.2‐fold [1.7, 2.9] higher than that of fluticasone pMDI and 3.4‐fold [2.8, 4.0] higher than that of fluticasone Diskus. In addition, the lung deposition of fluticasone via pMDI was 1.5‐fold [1.1, 2.9] higher than that via the Diskus inhaler. Plasma cortisol (24 h) was significantly reduced vs baseline for all three treatments. The cortisol concentration vs baseline was 12% for fluticasone pMDI, which was significantly lower (ratio 0.32 [0.24, 0.42]) than that for fluticasone Diskus (39%), and for budesonide Turbuhaler (46%) (ratio 0.27 [0.21, 0.37]). The plasma cortisol concentration did not differ significantly between treatments with fluticasone Diskus and budesonide Turbuhaler (ratio 0.87 [0.65; 1.15]).

Conclusions
 Budesonide and fluticasone differ in their pharmacokinetic properties in that although clearance is the same, the rate of uptake and elimination is slower for fluticasone. Despite a significantly higher pulmonary availability of budesonide via Turbuhaler, the plasma cortisol suppression is less than that of fluticasone via pMDI and similar to that of fluticasone via Diskus. There is no indication of any difference between healthy subjects and mild asthmatic patients in the pharmacokinetics and plasma cortisol suppression of fluticasone and budesonide.
Opioid analgesic prescribing and use – an audit of analgesic prescribing by general practitioners and The Multidisciplinary Pain Centre at Royal Brisbane Hospital
Authors: Nissen L. M. , Tett S. E. , Cramond T. , Williams B. , Smith M. T.
Published: March 2003

Aims  This study evaluated the use of and need for opioids in patients attending the Multidisciplinary Pain Centre at the Royal Brisbane Hospital (RBH).

Methods  All consecutive in‐patient admissions in 1998 were reviewed. A 10‐point scoring system based on the World Health Organization (WHO) analgesic ladder was devised to facilitate comparison of analgesic prescribing on admission and at the time of discharge. A conversion table was used to standardize opioid analgesic doses to an oral morphine equivalent.

Results  Of the 370 patients reviewed, 233 (81%) were by their general practitioners. Records of 288 (78%) were available for full review and 270 (94%) of these had noncancer pain. On admission, 239 (83%) were taking an opioid analgesic, with 135 (47%) taking strong opioids (e.g. morphine, oxycodone, methadone). There was a significant decrease in the mean total daily oral morphine equivalent prescribed on discharge 36.9 mg (95% CI: 33.4, 40.4) compared with that on admission 88.7 mg (95% CI: 77.6, 99.8) (P < 0.001). There was a significant decrease (P < 0.05) in the proportion of patients taking a primary opioid on discharge 153 (58%) compared with admission 239 (83%), although the proportion of patients taking a strong opioid on discharge 150 (52%) compared with admission 135 (47%) was not significantly different (P > 0.05). The proportion of patients taking a laxative showed a significant increase on discharge 110 (73%) compared with admission 38 (28%) (P < 0.05).

Conclusions  Our analgesic prescribing scoring system and opioid conversion table have the potential to be developed further as tools for assessing opioid analgesic prescribing. The significant decrease in total daily oral morphine equivalents signifies the value of prescribing in accordance with the WHO analgesic ladder, and the necessity of general practitioner education. The management of chronic pain is complex, and it requires interventions additional to pharmacological therapy. Evaluation by a multidisciplinary team, coupled with experience in and an understanding of analgesic prescribing and rehabilitation provides an effective basis for improving the management of patients with chronic pain.
Allometric plasticity in a polyphenic beetle
Authors: Moczek Armin P.
Published: March 2003

Abstract1. Environmental conditions, such as variation in nutrition, commonly contribute to morphological variation among individuals by affecting body size and the expression of certain morphological traits; however the scaling relationship between a morphological trait and body size over a range of body sizes is generally assumed not to change in response to environmental fluctuation (allometric plasticity), but instead to be constant and diagnostic for a particular trait and species or population. The work reported here examined diet‐induced allometric plasticity in the polyphenic beetleOnthophagus taurusSchreber (1759) (Coleoptera: Scarabaeidae).

2. MaleO. taurusvary in body size depending on larval nutrition. Only males above a critical body size threshold express fully developed horns; males smaller than this threshold develop only rudimentary horns or no horns at all.

3. Field populations that naturally utilise two different resources for feeding larvae (horse dung vs. cow manure) exhibited significant differences in the average scaling relationship between body size and male horn length over the same range of body sizes. Males collected from cow manure populations expressed consistently longer horns for a given body size than males collected from horse dung populations.

4. Males reared in the laboratory on horse dung or cow manure also exhibited significant differences in the average scaling relationship between body size and horn length. Differences between laboratory populations reared on horse dung or cow manure were of the same kind and magnitude as differences between field populations that utilise these different resources naturally.

5. These findings suggest that between‐population differences in scaling relationships between horn length and body size can be the product of differences in the quality of resources available to developing larvae. Results are discussed in the context of onthophagine mating systems and recent insights in the developmental and endocrine control of horn polyphenisms.
Brain natriuretic peptide increases urinary albumin and alpha‐1 microglobulin excretion in Type 1 diabetes mellitus
Authors: McKenna K. , Smith D. , Moore K. , Glen A. , Tormey W. , Thompson C. J.
Published: March 2003

Atrial natriuretic peptide (ANP) increases urinary albumin excretion in Type 1 diabetes mellitus (DM). Brain natriuretic peptide (BNP) is structurally and functionally related to ANP, but its effect on urine albumin excretion rate (UAER) is unknown.

Aims  To compare the albuminuric effects of intravenous infusion of ANP and BNP, and to assess the effect of both peptides on tubular protein excretion.

Methods  Eight subjects with Type 1 DM were randomised to a three leg, double blind, and placebo controlled study. On each study day, subjects were euglycaemic clamped and subsequently water loaded (20 mL/kg orally, plus urine losses) to steady state diuresis. When in steady state, creatinine clearance was estimated in three separate 1 hour periods. At the end of the first period, a 1 hour intravenous infusion of either placebo, ANP 0.025 μg/kg/min, or BNP 0.025 μg/kg/min was administered. There followed a 1 hour recovery period. Urine was collected at 15 min intervals for estimation of urine albumin (ACR) and α1 microglobulin creatinine ratio (MCR). Results were analysed by anova.

Results  Creatinine clearance was similar on the three study days, and was unaltered by any infusion. ACR was unaltered by placebo (1.3 ± 0.5–1.2 ± 0.4 mg/mmol, mean ± SD, p = 0.81), but increased compared to placebo with infusion of both ANP (1.2 ± 0.4–9.8 ± 8.4 mg/mmol, P = 0.0004), and BNP (1.1 ± 0.4–13.4 ± 8.6 mg/mmol, P = 0.0001). The MCR was unaltered by placebo infusion (P = 0.89), but increased compared with placebo after infusion of ANP (5.4 ± 0.9–12.3 ± 4.2 mg/mmol, P < 0.0001), and BNP (5.4 ± 0.8–12.1 ± 2.5 mg/mmol, P < 0.0001).

Conclusions  Intravenous infusion of BNP and ANP both increase the urine excretion of albumin and the tubular protein α1 microglobulin, independent of creatinine clearance.

Diabet. Med. 18, 973–978 (2001)
Double‐blind, randomised study of the effect of combined treatment with vitamin C and E on albuminuria in Type 2 diabetic patients
Authors: Gæde P. , Poulsen H. E. , Parving H.‐H. , Pedersen O.
Published: March 2003

Aims  Elevated levels of urinary albumin excretion rate (AER) predict high risk for progressing to end‐stage renal disease. In streptozotocin‐induced diabetes, supplementation with vitamin C or E reduces albuminuria and glomerular hypertrophy. We tested the hypothesis that supplementation of both vitamin C and E in pharmacological doses lowers AER in Type 2 diabetic patients with persistent micro/macroalbuminuria.

Methods  Thirty Type 2 diabetic patients with AER 30–300 mg/24 h were included in a double‐blind randomised, cross‐over trial. Patients received vitamin C (1250 mg) and vitamin E (680 IU) per day or matching placebo for 4 weeks with a 3‐week wash‐out period between treatment periods in random order.

Results  Combined treatment with vitamin C and E reduced AER by 19% (95% CI 6–34%) (p = 0.04), geometric mean 197 mg/24 h (95% CI 114–341 mg/24 h) vs. 243 mg/24 h (146–404 mg/24 h). No changes were seen in serum creatinine, haemoglobin A1C or blood pressure. Fasting plasma concentrations of vitamin C and E increased in all patients during active treatment (mean vitamin C 79.4 μmol/L (SD 27.8) vs. 41.9 μmol/L (18.4) and vitamin E 47.0 μmol/L (19.8) vs. 29.5 μmol/L (15.3), P < 0.000001). Except for two patients that started additional blood pressure lowering treatment during the run‐in period, no changes in medication, food and exercise habits or in the number of smokers occurred during the study.

Conclusion  Short‐term treatment with vitamin C and E in pharmacological doses lowers AER in Type 2 diabetic patients with micro/macroalbuminuria. Further long‐term, large‐scale studies of this albuminuria reducing treatment modality are warranted.

Diabet. Med. 18, 756–760 (2001)
Control of secretion by mitochondria depends on the size of the local [Ca2+] after chromaffin cell stimulation
Authors: Montero Mayte , Alonso Maria Teresa , Albillos Almudena , Cuchillo‐Ibáñez Inmaculada , Olivares Román , G. García Antonio , García‐Sancho Javier , Alvarez Javier
Published: March 2003

In chromaffin cells, plasma membrane calcium (Ca2+) channels and mitochondria constitute defined functional units controlling the availability of Ca2+ nearby exocytotic sites. We show here that, when L‐/N‐type Ca2+ channels were inhibited with nisoldipine and ω‐conotoxin GVIA, cytosolic [Ca2+] ([Ca2+]c) peaks measured in fura‐4F‐loaded cells were reduced by 36%; however, mitochondrial Ca2+ uptake was unaffected and secretion was potentiated by protonophores as in control cells. By contrast, when non L‐type Ca2+ channels were inhibited with ω‐conotoxin MVIIC, [Ca2+]c peaks induced by high K+ were reduced by 73%, mitochondrial Ca2+ uptake was abolished, and secretion was not modified by protonophores. However, if Ca2+ entered only through L‐type channels activated by FPL64176, high K+ stimulation induced fast mitochondrial Ca2+ uptake and catecholamine secretion was strongly increased and potentiated by protonophores. These results confirm the close association of catecholamine secretion to mitochondrial Ca2+ uptake, and indicate the sharp threshold of local [Ca2+]c (about 5 µm) required for triggering fast mitochondrial Ca2+ uptake that is able to modulate secretion. The entry of Ca2+ through L‐type channels generated local [Ca2+]c increases just below that, inducing little mitochondrial Ca2+ uptake unless FPL64176 was present. By contrast, Ca2+ entry through P/Q‐type channels fully activated mitochondrial Ca2+ uptake. Control of secretion by mitochondria therefore depends critically on the ability of the stimulus to create large local [Ca2+]c microdomains.
Effects of post‐inhalation treatment with interleukin‐12 on airway hyper‐reactivity, eosinophilia and interleukin‐18 receptor expression in a mouse model of asthma
Authors: Kuribayashi K , Kodama T , Okamura H , Sugita M , Matsuyama T
Published: March 2003

Background  Correcting Th1/Th2 imbalance with administration of IL‐12 before and during antigen challenge holds therapeutic promise in asthma. However, the effects of IL‐12 on the established asthmatic responses have not fully been examined.

Objective  We investigated whether IL‐12 administered after antigen challenge could diminish airway hyper‐reactivity (AHR) and eosinophilia in mice actively sensitized to ovalbumin. We also have investigated the ability of administered IL‐12 to induce IL‐18 receptor (IL‐18R) expression that may lead possible synergic action of IL‐12 with endogenous IL‐18.

Methods  C57BL/6 mice immunized to ovalbumin (OVA) by intraperitoneal (i.p.) injection, were challenged three times with an aerosol of OVA every second day for 8 days. Recombinant IL‐12 (500 ng) was intravenously administered on a single occasion 1 h after the final challenge of mice. Mice were analysed for effects of IL‐12 on AHR, inflammatory cell infiltration and cytokine levels in lung tissue as well as serum immunoglobulin (Ig) E levels. Immunohistochemistry for IL‐18R was performed using rat monoclonal antibody specific for murine IL‐18Rα (IL‐1 receptor related protein; IL‐1Rrp).

Results  An intravenous IL‐12 administration diminished AHR, pulmonary eosinophilia and T lymphocyte infiltration, serum IgE, IL‐4 and IL‐13 in lung tissue. Expression of IL‐18R was induced in the mononuclear cells in the lung of mice exposed to OVA. IL‐12 administration enhanced the IL‐18R expression compared with the control.

Conclusion  These data indicate that IL‐12 can attenuate established antigen‐induced AHR and inflammation. In this mechanism it would be interpreted as follows: IL‐12 administration in OVA‐challenged mice decreased IL‐4 production and IgE production thereafter through direct effect on inhibiting the activation of established Th2 cells response and also combined effect with up‐regulation of IL‐18R expression by inflammatory cells in the lung.
Depth distribution of earthquakes in the Baikal rift system and its implications for the rheology of the lithosphere
Authors: Déverchère Jacques , Petit Carole , Gileva Nadejda , Radziminovitch Natalia , Melnikova Valentina , San'Kov Vladimir
Published: March 2003

The correspondence between the predicted brittle–plastic transition within the crust and the maximum depth of earthquakes is examined in the case of the Baikal rift, Siberia. Although little accurate information on depths is available through large- and moderate-size earthquakes, there are frequent indications of foci at 20 km depth and more. We have relocated 632 events recorded at nearby stations that occurred between 1971 and 1997, with depth and epicentral uncertainties less than 5 km, over the eastern and southern parts of the Baikal rift. We have compared these results with other depth distributions obtained in previous studies from background seismicity in the NE rift (1365 events in the Kalar-Chara zone and 704 events in the Muya region). The relative abundance of earthquakes is generally low at depths between 0 and 10 km (7–15 per cent) and high between 15 and 25 km (∼50 per cent). Earthquake activity is still significant between 25 and 30 km (9–15 per cent) and persists between 30 and 40 km (7–13 per cent). Very few earthquakes are below the Moho. We use empirical constitutive laws to obtain the yield-stress limits of several layers made of dominant lithologies and to examine whether the observed distribution of earthquakes at depth (519 events controlled by a close station and located within the extensional domain of the Baikal rift system) can match the predicted crustal strength proportion with depth and the deeper brittle–ductile transition in the crust. A good fit is obtained by using a quartz rheology at 0–10 km depth and a diabase rheology at 10–45 km depth with a moderate temperature field which corresponds to a ∼100 Myr thermal lithosphere. No dioritic composition of the crust is found necessary. In any case, earthquakes occur at deep crustal levels, where the crust is supposed to be ductile, in a way very similar to what is found in the East African Rift System. From these results we conclude that the seismogenic thickness is ∼35–40 km in the Baikal rift system and that the depth distribution of earthquakes is at first order proportional to the strength profile found in a rheologically layered crust dominated by a mafic composition in the ∼10–45 km depth range. An upper mantle core with high strength, however, generally prevents it from reaching stress failure at greater depth.
Cell cycle distribution of primitive haematopoietic cells stimulated in vitro and in vivo
Authors: Zhang X.‐W. , Audet J. , Piret J. M. , Li Y.‐X.
Published: March 2003

A novel approach is used to study the proliferating behaviour of primitive haematopoietic cell populations in response to different stimuli. A mathematical model based on the average proportion of apoptotic, dividing and quiescent cells in primitive haematopoietic cell populations is developed to describe the mitotic history of 5‐ (and 6‐) carboxyfluorescein diacetate succinimidyl ester‐labelled cells. The cell cycle distributions in different cytokine‐supplemented cultures of primitive human and mouse bone marrow cells are determined and compared with those found in vivo. The results indicate that a combination of flt‐3 ligand, Steel factor and interleukin‐11 or hyper‐interleukin‐6 provide a level of mitogenic stimulation similar to that existing in vivo after a myeloablative radiation dose. The comparison of the cell cycle distribution obtained for different cultures of human bone marrow CD34+(45RA/71)− cells demonstrates that the addition of flt‐3 ligand in these cultures decreases apoptosis significantly but does not reduce quiescence. In addition, in vivo and in vitro, it was found that more than 3 days of stimulation are required to recruit a maximum number of quiescent cells into active cell cycle. These kinetics of cell cycle activation are found to be similar to those identified for the haematopoietic stem cells compartment in the same cultures. This mathematical analysis provides a useful tool for the development of haematopoietic stem cell culture processes for clinical applications.
High sensitivity of human epidermal keratinocytes (HaCaT) to topoisomerase inhibitors
Authors: Pessina A. , Raimondi A. , Cerri A. , Piccirillo M. , Neri M. G. , Croera C. , Foti P. , Berti E.
Published: March 2003

In the panorama of the numerous established cell lines, the human keratinocyte line HaCaT has a very interesting feature, having a close similarity in functional competence to normal keratinocytes. This cell line has been used in many studies as a paradigm for epidermal cells and therefore we selected HaCaT as a cell model for investigating the activity of three antitopoisomerase drugs (Camptothecin, Doxorubicin, Ciprofloxacin) on in vitro cell growth. The effect was evaluated both by a 24‐h cytotoxicity test and by a 7‐day antiproliferation assay, in which the cell viability was assessed by an MTT (3‐(4,5‐dimethyl‐2‐thiazolyl) 2,5‐diphenil‐2‐H‐tetrazolium bromide) test. DNA topoisomerase I was also partially purified from a nuclear extract of HaCaT cells, the level of topo I catalytic activity was measured by a pBR322 DNA relaxation assay and then the in vitro effect of antitopoisomerase drugs on the target enzyme was also assessed.

The results indicated that the in vitro sensitivity of human epidermal HaCaT cells to antitopoisomerase drugs is comparable to that of many human tumour cell lines. HaCaT cells express a high level of topoisomerase I activity that is significantly inhibited by both Camptothecin and Doxorubicin and to a minor degree by Ciprofloxacin. A high correlation between the cell sensitivity to the antitopoisomerase I drug measured by the MTT test and the in vitro direct inhibition of HaCaT topoisomerase I was observed, suggesting that HaCaT cells can represent a very interesting model both for studying cellular pharmacokinetics of antineoplastic drugs on keratinocytes and for predicting possible secondary effects, exerted by these drugs on cutaneous cells, during treatment with chemotherapy.
Ultrasonic scalpel in laparoscopic gynaecological surgery: an observational study in 354 cases
Authors: Jansen Frank W. , Trimbos‐Kemper Trudy , Baptist Trimbos J.
Published: March 2003

Objective To evaluate the ultrasonically activated scalpel (UAS) and laparoscopic coagulating shears (LCS) for gynaecological laparoscopic procedures.

Main outcome measures  Data were evaluated regarding type of procedure, duration of surgery, blood loss, complications and cost‐effectiveness of the technique.

Design  Prospective observational study.

Setting  All patients who underwent a laparoscopic procedure in which the UAS or LCS was used, between 1993 and 2001 at the Leiden University Medical Center.

Results  A total of 354 consecutive women underwent a laparoscopic procedure with the UAS or LCS. One major complication occurred (bleeding) for which a laparotomy was necessary. The results showed that these instruments are effective tools for cutting and coagulating.

Conclusions  Additionally to bipolar electrosurgery, the UAS is a safe instrument and is especially useful for extirpative laparoscopic procedures in gynaecology. Due to the cavitational effect, it is not, in our opinion, a good instrument for delicate reconstructive surgery for fertility.
Seasonality in surface‐layer net zooplankton communities in Prince William Sound, Alaska
Authors: Cooney R. T. , Coyle K. O. , Stockmar E. , Stark C.
Published: March 2003

The upper‐layer net‐zooplankton community in Prince William Sound, Alaska, is characterized by strong seasonality. Abundance and wet‐weight biomass in the upper 50 m drop to fewer than 100 individuals and 10 mg m−3 in February before rebounding to 5000 individuals and 600 mg m−3 in June. Copepods dominate in all months, but are augmented by other prominent taxa, particularly pteropods and larvaceans during the late spring, summer and fall. The small copepods Pseudocalanus, Acartia and Oithona are common. Though much less abundant, larger calanoids like Neocalanus, Calanus and Metridia contribute substantially to the biomass in spring and early summer. Meroplankters like barnacle nauplii are also occasionally very abundant. Neocalanus, Calanus and Pseudocalanus all exhibit ontogenetic vertical displacement of populations when stage 5 copepodites (C5) leave the surface in late May and early June for deep water. This seasonality has implications for food‐webs supporting juvenile pink salmon (Oncorhynchus gorbuscha) and Pacific herring (Clupea pallasi) in Prince William Sound.
Helicobacter pylori Eradication in Patients on Long‐ Term H2 Receptor Antagonists. Economic and Symptomatic Benefits. A Large Prospective Study in Primary Care
Authors: Verma Sumita , Giaffer Mustafa H.
Published: March 2003

Background. A large proportion of patients in primary care are still being maintained on long‐term acid suppression, without any attempts to identify Helicobacter pylori status and to treat those that test positive.

Objectives. To assess the prevalence and economic and symptomatic benefits of H. pylori eradication in patients maintained on long‐term H2 receptor antagonists (H2RA) in primary care.

Patients and Methods. Patients on long‐term (i.e. 6 months or longer) H2RA were identified from the computerised records of six practices in north England. Helicobacter pylori status was identified using serology and H. pylori positive patients were then offered standard 7‐day proton pump based triple therapy, followed by a urea breath test (UBT) to confirm H. pylori eradication. Those who had a positive UBT were offered a second line course of H. pylori eradication therapy. Follow up period was 1 year. The main outcome measures were improvement in dyspepsia symptom scores, amount of H2RA being consumed, and economic benefits after H. pylori eradication.

Results. One thousand and seven patients (1.5%) were identified on long‐term H2RA, of whom 471 (46%) ultimately had their H. pylori serology assessed. Sixty‐three (297) percent of the patients tested had a positive serology for H. pylori, the majority of whom (58%, 172) had prior evidence of peptic ulcer disease. The mean duration of therapy and mean time since endoscopy/barium studies was significantly longer in patients with peptic ulcer disease compared to their counterparts with nonulcer dyspepsia and gastro‐oesophageal reflux disease, p= .0002 and .0001, respectively. After successful H. pylori eradication (which was possible in 84% of the patients), at the end of the 1‐year study period, on an intention to treat basis 62% of the patients could either stop or significantly reduce dosage of their H2RA. There was also significant reduction in the mean dose of H2RA being consumed and severity of symptoms at the end of the study period (p < .00001).

Conclusion. Almost two‐thirds of patients on long‐term H2RA in primary care will have a positive serology for H. pylori; the majority of these will have peptic ulcer disease. In over 60% of cases H. pylori eradication led to significant improvement in symptom scores and reduction in dosage of H2RA being consumed. Cessation or reduction in long‐term H2RA prescribing is cost effective.
Quantitative study of the optic nerve in buffaloes (Bos bubalis)
Authors: KASSAB Ahmed , AOYAMA Masato , SUGITA Shoei
Published: March 2003

The total number, distribution and size of the optic axons of the buffalo (Bos bubalis) were studied in five optic nerves using light and transmission electron microscopes. Semithin sections were cut at 0.40 μm with an ultramicrotome and stained with 0.3% toluidine blue for light microscopic analysis. The ultrathin sections were cut at 70 nm, mounted on copper mesh grids (No. 200) and stained with saturated solution of uranyl acetate dihydrate and examined with the transmission electron microscope. The optic axons were assessed in 10 regions of roughly equal area. The total number of optic fibers was estimated on semithin and ultrathin sections. The measurements of the axonal diameters were made on electron micrographs taken from various regions across the optic nerve. The mean value of the total number of optic axons calculated was 1 397 099 ± 10 995 and 1 584 255 by light and electron microscopes, respectively. There was very little difference in the density of the optic fibers between the 10 regions of the optic nerve. The optic nerve area ranged from 18.2 to 22.4 mm2 (mean, 21.3 mm2). The diameters of the optic axons ranged from 0.5 to 12.3 μm (mean, 3.3 μm).
Dietary conjugated linoleic acids alleviate early inflammatory response caused by lipopolysaccharide injection in male broiler chicks
Authors: TAKAHASHI Kazuaki , AKIBA Yukio , IWATA Toshio , KASAI Masaaki
Published: March 2003

An experiment was undertaken to determine if dietary conjugated linoleic acid (CLA) influences the early stage of the inflammatory response caused by a single injection of Salmonella enteritidisi lipopolysaccharide (LPS) in male broiler chicks. Chicks (7 days old) were fed either 0 or 10 g CLA/kg in their diet for 21 days. At 28 days old, birds were injected intraperitoneally with 1.5 mg LPS/kg body weight after 12 h fasting. Changes in feed intake, rectal temperature and plasma α‐1 acid glycoprotein and ceruloplasmin concentrations were measured during 24 h after LPS injection. Chicks fed the CLA diet were fed more feed for 24 h, had a lower rectal temperature at 9 and 24 h and a lower plasma α‐1 acid glycoprotein concentration at 24 h after LPS injection than chicks fed the basal diet. Plasma ceruloplasmin concentration tended to be lower in chicks fed the CLA diet than in chicks fed the basal diet. The results suggest that dietary CLA alleviate undesirable early inflammatory response due to LPS injection in male broiler chicks.