bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of ipriflavone on pain due to recent osteoporotic vertebral crush fracture
Authors: Rahman Mohammad M. , Haq Syed A. , Alam Mohammad N. , Chowdhury Mohammad A. J.
Published: March 2003

Aim: Ipriflavone conserves bone mass in postmenopausal osteoporosis. Salmon calcitonin and alendronate, two other anti‐resorptive drugs, have been found to have analgesic effects in osteoporotic acute vertebral fracture. This study aimed to determine if ipriflavone also possesses such an effect.

Methods: Thirty‐two women with recent osteoporotic vertebral fractures were randomly assigned to ipriflavone treatment or placebo groups. Ipriflavone was given at the dose of 200 mg three times a day. Non‐steroidal anti‐inflammatory drugs were given ad libitum in both groups. Calcium carbonate (1 g daily) was administered to all subjects. Intensity of pain at rest, on movement and on pressure, pain rating on a 10‐point visual analogue scale, degree of mobility impairment, and supplementary analgesic were assessed at the end of a 3‐month period in both groups to assess the analgesic effect of ipriflavone.

Results: Fourteen subjects in the ipriflavone group and 12 in the placebo group completed the trial. After 3 months, all pain variables had decreased significantly in both groups. Intensity of pain at rest and on pressure and supplementary analgesic use were significantly lower in the ipriflavone group compared to the placebo group.

Conclusion: The study shows that ipriflavone has an analgesic adjuvant effect in acute osteoporotic vertebral fracture.
Growth conditions are more important than species origin in determining leaf pigment content of British plant species
Authors: Rosevear M. J. , Young A. J. , Johnson G. N.
Published: March 2003

This paper describes a study of 23 plant species native to the British Isles, to investigate the relative importance of growth conditions and ecological origin in determining the content and composition of the photosynthetic pigments (chlorophylls and carotenoids) within leaves.

 The species studied reflected a range of ecological types, from deep shade to full sun.

 Plants were grown in two light environments: high light (HL), filtered through a clear filter; and low light (LL), filtered through a neutral density filter which reduced total irradiance with enhanced far‐red.

 Plants grown at high irradiance contained more carotenoid per unit chlorophyll and showed a marked increase in xanthophyll cycle pigments relative to other carotenoids.

 Deep‐shade plants were slightly less responsive to changes in growth light conditions than plants native to less shaded locations. Intermediate sun/shade plants were slightly more responsive; however these differences were small compared with the extent of the response of all species to HL vs LL.

 The main conclusion is that that the light conditions to which the plants are exposed are more important than the genetic predisposition of those plants in determining the pigment content and composition of leaves.
Strategy shifts in leaf physiology, structure and nutrient content between species of high‐ and low‐rainfall and high‐ and low‐nutrient habitats
Authors: Wright I. J. , Reich P. B. , Westoby M.
Published: March 2003

Relationships were examined among photosynthetic capacity (Amass and Aarea), foliar dark respiration rate (Rd‐mass and Rd‐area), stomatal conductance to water (Gs), specific leaf area (SLA), and leaf nitrogen (N) and phosphorus (P) across 79 perennial species occurring at four sites with contrasting rainfall levels and soil nutrients in eastern Australia. We hypothesized that the slope of log–log ‘scaling’ relationships between these traits would be positive and would not differ between sites, although slope elevations might shift between habitat types.

 Amass, Rd‐mass, SLA, Nmass and Pmass were positively associated in common slopes fitted across sites or rainfall zones, although rather weakly within individual sites in some cases. The relationships between Amass (and Rd‐mass) with each of Nmass and SLA were partially independent of each other, with Amass (or Rd‐mass) increasing with SLA at a given Nmass, or with Nmass at a given SLA (only weakly in the case of Amass). These results improve the quantification and extend the generalization of reported patterns to floras largely unlike those studied previously, with the additional contribution of including phosphorus data.

 Species from drier sites differed in several important respects. They had (i) higher leaf N and P (per dry mass or area); (ii) lower photosynthetic capacity at a given leaf N or P; (iii) higher Rd‐mass at a given SLA or Amass; and (iv) lower Gs at a given Aarea (implying lower internal CO2 concentration).

 These trends can be interpreted as part of a previously undocumented water conservation strategy in species from dry habitats. By investing heavily in photosynthetic enzymes, a larger drawdown of internal CO2 concentration is achieved, and a given photosynthetic rate is possible at a lower stomatal conductance. Transpirational water use is similar, however, due to the lower‐humidity air in dry sites. The benefit of the strategy is that dry‐site species reduce water loss at a given Aarea, down to levels similar to wet‐site species, despite occurring in lower‐humidity environments. The cost of high leaf N is reflected in higher dark respiration rates and, presumably, additional costs incurred by N acquisition and increased herbivory risk.
Growth‐enhanced fish can be competitive in the wild
Authors: Johnsson J. I. , Björnsson B. TH.
Published: March 2003

The widespread commercial interest in producing growth‐enhanced organisms has raised concerns about ecological consequences, emphasizing the need to understand the costs and benefits associated with accelerated growth in nature. Here, sustained‐release growth hormone (GH) implants were used to estimate the competitive ability of growth‐enhanced fish in the wild. Growth rate, movements and survival over winter were compared between GH‐implanted and control Brown Trout in a natural stream. The study was repeated over two consecutive years.

 GH treatment had no effect on recapture rates, indicating that mortality rates did not differ between GH‐treated and control fish. More GH‐treated trout (63%) than control fish (41%) were recaptured within their 10 m section of release. Thus, GH‐treated fish were more stationary than control fish over winter.

 GH‐treated fish grew about 20% faster than control fish. This was mainly because of a three‐fold growth rate increase in GH‐treated fish in late summer, whereas growth rates over winter did not differ significantly between treatment groups. These results were consistent over both replicate years.

 This first study of growth‐enhanced fish in the wild shows that they can survive well and therefore may out‐compete normal fish with lower growth rates. Although selection against rapid growth may be more intense at other life‐history stages and/or during periods of extreme climate conditions, our findings raise concerns that released or escaped growth‐enhanced salmonids may compete successfully with resident fish. It is clear that the potential ecological risks associated with growth‐enhanced fish should not be ignored.
Body size, locomotor speed and antipredator behaviour in a tropical snake (Tropidonophis mairii, Colubridae): the influence of incubation environments and genetic factors
Authors: Webb J. K. , Brown G. P. , Shine R.
Published: March 2003

The physical conditions experienced by reptile embryos inside natural nests can influence the size, shape and behaviour of the resultant hatchlings. Although most reptiles are tropical, the effects of incubation temperatures on offspring phenotypes have received little attention in tropical species.

 The consequences of differences in thermal variance during incubation on offspring were studied in a tropical natricine snake (the Keelback Tropidonophismairii), which lays eggs in soil cracks of varying depths. Some 253 eggs from 19 clutches were incubated under two thermal regimes with identical mean temperatures (25·6 °C), but temperatures in the ‘variable’ treatment fluctuated more (21·8–29·6 °C) than those in the ‘constant’ temperature treatment (25·2–26·5 °C). These thermal regimes were similar to those of shallow (20 cm deep) and deep (40 cm deep) soil cracks, respectively, and represent thermal conditions inside natural nests and potential nest sites.

 Incubation temperatures affected body size, shape and antipredator behaviour of hatchling snakes. Snakes from constant temperature incubation were longer and thinner than snakes from high variance incubation. Clutch effects influenced all offspring traits, with significant interactions between clutch of origin and incubation treatment for body size, but not swimming speed or behaviour.

 There was a significant interaction between incubation treatment and offspring sex on neonate swimming speed. Incubation under cycling thermal regimes significantly increased swimming speeds of females, but had little effect on males. Such sex differences in phenotypic responses of hatchling snakes support a major assumption of the Charnov–Bull hypothesis for the evolution of temperature‐dependent sex determination.
Photosynthetic adaptation and acclimation to exploit seasonal periods of direct irradiance in three temperate, deciduous‐forest herbs
Authors: ROTHSTEIN D. E. , ZAK D. R.
Published: March 2003

We evaluated the potential for three species of deciduous‐forest herbs to exploit seasonal periods of direct irradiance. In particular, we investigated the importance of photosynthetic acclimation as a mechanism for shade‐tolerant herbs to utilize direct light reaching the forest floor before canopy expansion in the spring and after canopy leaf drop in the autumn.

 We measured the photosynthetic and growth characteristics of three co‐occurring herbs of a northern hardwood forest: the spring ephemeral Allium tricoccum Ait., the summer‐green Viola pubescens Ait., and the semi‐evergreen Tiarella cordifolia L.

 Leaf CO2 exchange, leaf mass per area, and leaf biochemistry differed among species and seasonally within species to match the changing light environment below the forest canopy. From spring to summer, as irradiance dropped with the expansion of the overstorey canopy, Viola leaves exhibited reduction of both photosynthetic capacity and light compensation point. Weaker acclimation of less magnitude occurred in Tiarella leaves over the spring–summer light transition; this was followed by further acclimation to the stronger autumn irradiance.

 Viola’s greater range of photosynthetic acclimation was associated with shifts in allocation between Rubisco and chlorophyll, as well as changes in total leaf nitrogen (N) concentration and leaf mass per area (LMA). In contrast, Tiarella’s narrow range of acclimation was associated solely with changes in allocation to Rubisco versus chlorophyll, with no changes in total leaf N or LMA.

 Seasonal changes in leaf chemistry and structure in Viola suggest a stepwise ontogeny whereby individual leaves are able to function as ‘sun leaves’ for 3–5 weeks in the spring, and then as ‘shade leaves’ for up to 3 months in the summer.

 Whole‐plant biomass accumulation showed that all three species accumulated most of their annual biomass increment during periods of direct irradiance. These results demonstrate the importance of brief seasonal periods of strong irradiance to the growth of deciduous forest herbs, even shade‐tolerant, summer and evergreen species.
Clinical experience of amiodarone‐induced thyrotoxicosis over a 3‐year period: role of colour‐flow Doppler sonography*
Authors: Eaton S. E. M. , Euinton H. A. , Newman C. M. , Weetman A. P. , Bennet W. M.
Published: March 2003

objective Current thinking is that amiodarone‐induced thyrotoxicosis (AIT) might be either iodine‐induced thyrotoxicosis in latent hyperthyroidism (Type 1) or destructive thyroiditis (Type 2), and also that colour‐flow Doppler sonography (CFDS) of the thyroid and serum interleukin 6 (IL‐6) are tools that can classify AIT and direct treatment. To assess the validity of this thinking, our objective was to determine whether CFDS and IL‐6 identified AIT subgroups with distinct features.

design Retrospective case‐note audit of all patients presenting with AIT to the Endocrine Department of a UK teaching hospital over a 3‐year period. To assess proportions of Type 1 vs. Type 2 AIT and to compare and contrast their clinical features.

patients 37 patients were identified with AIT (mean age 65, range 20–86 years). In 30 patients in whom AIT persisted, 25 underwent CFDS.

results In 25 patients who underwent CFDS, 10 (40%) were classified as Type 1, 10 (40%) as Type 2 and 5 (20%) as indeterminate type. In the patients classified by CFDS in whom AIT persisted, 40% of Type 1 patients were male vs. 90% of Type 2 patients. Also, free T4 tended to be lower in patients presenting with Type 1 AIT (52·1 ± 7·5 pmol/l) compared to Type 2 (74·8 ± 8·1 pmol/l, P = 0·08), free T3 was lower (8·8 ± 0·9 vs. 15·6 ± 3·0 pmol/l, P = 0·03) and the cumulative amiodarone dose was lower (66 ± 20 vs. 186 ± 28 g, P = 0·002). We used less prednisolone to achieve euthyroidism in patients with Type 1 AIT whereas carbimazole doses were not different and the time to euthyroidism was the same in both groups (81 ± 21 vs. 88 ± 13 days). IL‐6 was raised in two patients with Type 1 and in one patient with Type 2 AIT.

conclusions CFDS could characterize two distinct subtypes in patients with AIT. Conversely, IL‐6 seemed to be an unhelpful test in this context.
The effects of cimetidine and antacid on the pharmacokinetic profile of sildenafil citrate in healthy male volunteers
Authors: Wilner Keith , Laboy Lucia , LeBel Marc
Published: March 2003

Aims  To examine the effect of concomitant cimetidine or antacid administration on the pharmacokinetic profile of sildenafil citrate in healthy male volunteers in two open‐label, randomized studies.

Methods  The first study was a parallel‐group design in which 22 healthy male volunteers received sildenafil (50 mg) on days 1 and 5 and cimetidine (800 mg) or placebo on days 3, 4, 5, and 6. Blood samples were collected predose and at specified times up to 48 h postdose on days 1 and 5 to determine plasma levels of sildenafil and its metabolite, UK‐103,320. The second study was a two‐way crossover design in which 12 volunteers received sildenafil with or without a 30‐ml dose of a magnesium hydroxide/aluminium hydroxide antacid. Blood samples were collected and analysed as in the first study. The two study periods were separated by at least 14 days.

Results  Coadministration of cimetidine had no statistically significant effect on the tmax or kel of sildenafil but caused a statistically significant increase in sildenafil AUCt and Cmax of 56% and 54%, respectively (P<0.01). Differences between the two treatment groups were smaller for the metabolite than for sildenafil, although cimetidine treatment did significantly (P<0.05) increase the AUCt for UK‐103,320 by 30%. Antacid coadministration had no statistically significant effect on any pharmacokinetic parameter of sildenafil or UK‐103,320. Whether taken alone, with cimetidine, or with an antacid, sildenafil was well tolerated. Most adverse events were mild in nature, and no subject withdrew from either study for any reason related to the drug.

Conclusions  Cimetidine co‐administration produced an increase in sildenafil plasma levels; however, this increase is not sufficient to warrant dosage adjustment of either drug. Antacid coadministration had no effect on the pharmacokinetic profile of sildenafil.
Drug therapy in the elderly: what doctors believe and patients actually do
Authors: Barat I. , Andreasen F. , Damsgaard E. M. S.
Published: March 2003

Aims  To examine the medication adherence among old persons living in their own homes, to assess their knowledge of their medication, and to indicate target areas for intervention.

Methods  A cross‐sectional study of data collected from randomly selected samples of 348 persons, aged 75 years recruited from a population‐based register in the municipality of Aarhus, Denmark. Information on all drugs was collected from the subjects during a home visit, and their drug storage was examined. Information was collected from the general practitioners (GP). The measures of adherence were scores of agreements between the GPs' lists and the subjects' actual drug consumption.

Results  We found disagreement between the drug information collected from the study population and from the GPs: concerning drugs in 22% of the study‐population, concerning doses in 71%, and concerning regimens prescribed by the GP in 66%. Twenty‐four percent stated that they did not always follow prescriptions. Most of the deviations from prescriptions were toward lower doses and less frequent drug intake. The drugs most often involved in deviations were hypnotics, analgesics, bronchodilators and diuretics. Sixty percent of the participants knew the purpose of medication, and 21% knew the consequences of omission of the drugs. Less than 6% of the subjects knew about the toxic risks, side‐effects, or potential drug interactions. The participants' knowledge of the drugs was positively associated with their adherence. We found a correlation between an increased number of prescribed frequency of drug intake per day and deviation from the regimen (r = 0.25, P = 0.01). There was a positive association between nonadherence and the use of three or more drugs (odds ratio (OR) 2.5; 95% confidence interval (CI) 1.5,4.1), prescriptions from more than one doctor (OR 2.5; 95% CI 1.3,4.8), and probability of dementia (OR 9.0; 95% CI 1.1,72.5). Moreover compliance aids facilitated adherence (OR 4.4; 95% CI 1.6,12.3). Persons living alone were more prone to medication errors (OR 2.0; 95% CI 1.1,3.5).

Conclusions  A differentiated evaluation of adherence by considering the drug, the dose, and the regimen separately produced quantifiable data concerning the subjects' medication habits. Non‐adherence ranged from 20 to 70% depending on the measuring method. The participants' knowledge of the treatment was poor. Our results suggest that better information on medication and the use of compliance aids may prevent nonadherence. Special attention should be paid to persons receiving three or more drugs, living alone, receiving drugs from other doctors, and to persons with predementia symptoms, as they are at higher risk of nonadherence.
Effect of the CYP2C19 oxidation polymorphism on fluoxetine metabolism in Chinese healthy subjects
Authors: Liu Zhao‐Qian , Cheng Ze‐Neng , Huang Song‐Lin , Chen Xiao‐Ping , Ou‐Yang Dong‐Sheng , Jiang Chang‐Hong , Zhou Hong‐Hao
Published: March 2003

Aims  The study was designed to investigate whether genetically determined CYP2C19 activity affects the metabolism of fluoxetine in healthy subjects.

Methods  A single oral dose of fluoxetine (40 mg) was administrated successively to 14 healthy young men with high (extensive metabolizers, n=8) and low (poor metabolizers, n = 6) CYP2C19 activity. Blood samples were collected for 5–7 half‐lives and fluoxetine, and norfluoxetine were determined by reversed‐phase high performance liquid chromatography.

Results  Poor metabolizers (PMs) showed a mean 46% increase in fluoxetine peak plasma concentrations (Cmax, P < 0.001), 128% increase in area under the concentration vs time curve (AUC(0,∞), P < 0.001), 113% increase in terminal elimination half‐life (t½) (P < 0.001), and 55% decrease in CLo (P < 0.001) compared with extensive metabolizers (EMs). Mean ± (s.d) norfluoxetine AUC(0,192 h) was significantly lower in PMs than that in EMs (1343 ± 277 vs 2935 ± 311, P < 0.001). Mean fluoxetine Cmax and AUC(0,∞) in wild‐type homozygotes (CYP2C19*1/CYP2C19*1) were significantly lower than that in PMs (22.4 ± 3.9 vs 36.7 ± 8.9, P < 0.001; 732 ± 42 vs 2152 ± 492, P < 0.001, respectively). Mean oral clearance in individuals with the wild type homozygous genotype was significantly higher than that in heterozygotes and that in PMs (54.7 ± 3.4 vs 36.0 ± 8.7, P < 0.01; 54.7 ± 3.4 vs 20.6 ± 6.2, P < 0.001, respectively). Mean norfluoxetine AUC(0,192 h) in PMs was significantly lower than that in wild type homozygotes (1343 ± 277 vs 3163 ± 121, P < 0.05) and that in heterozygotes (1343 ± 277 vs 2706 ± 273, P < 0.001), respectively.

Conclusions  The results indicated that CYP2C19 appears to play a major role in the metabolism of fluoxetine, and in particular its N‐demethylation among Chinese healthy subjects.
Plasma concentrations of haloperidol are related to CYP2D6 genotype at low, but not high doses of haloperidol in Korean schizophrenic patients
Authors: Roh Hyung‐Keun , Chung Jea‐Yon , Oh Dong‐Yul , Park Chang‐Shin , Svensson Jan‐Olof , Dahl Marja‐Liisa , Bertilsson Leif
Published: March 2003

Aims  This study was carried out to evaluate the influence of CYP2D6 genotype on the steady state plasma concentrations of haloperidol and reduced haloperidol in Korean schizophrenic patients.

Methods  One hundred and twenty Korean schizophrenic patients treated with various, clinically determined, doses of haloperidol (range 3–60, median 20 mg day−1) during monotherapy were recruited. CYP2D6 genotypes were determined by analysis of the CYP2D6*10 allele using allele‐specific PCR and the CYP2D6*5 allele by long‐PCR. Steady state plasma concentrations of haloperidol and reduced haloperidol were analysed by h.p.l.c.

Results  Twenty‐three (19.2%), 60 (50.0%), 1 (0.8%), 33 (27.5%) and 3 patients (2.5%) possessed the CYP2D6 genotypes *1/*1, *1/*10, *1/*5, *10/*10 and *10/*5, respectively. The allele frequencies of CYP2D6*1, *10 and *5 were 44.6%, 53.8% and 1.7%, respectively. Significant relationships between dose and plasma concentrations of haloperidol (linear; r2 = 0.60, P < 0.0001) and reduced haloperidol (quadratic equation; r2 = 0.67) were observed. Overall, the concentrations normalized for dose (C/D) of haloperidol were significantly different between the CYP2D6*1/*1, *1/*10 and*10/*10 genotype groups (one‐way anova; P = 0.028). No significant differences between the genotype groups were found with respect to the C/D of reduced haloperidol (P = 0.755). However, in patients with daily doses less than 20 mg, significant differences in the C/D of haloperidol (P = 0.003), but not of reduced haloperidol, were found between the three major genotype groups. In patients with doses higher than 20 mg, no differences were found between the genotype groups for either haloperidol or reduced haloperidol. 68 patients (57%) used benztropine, an antimuscarinic agent. All four patients with a *5 allele (one together with *1 and three with *10) were found to use benztropine. The patients homozygous for the *1 allele seemed to need less benztropine than the patients with one or two mutated alleles (Fisher's exact test; P = 0.036).

Conclusions  The dose‐corrected steady state plasma concentrations of haloperidol, but not of reduced haloperidol, were significantly different between the CYP2D6*1/*1, *1/*10 and *10/*10 genotype groups when doses lower than 20 mg haloperidol were given. No differences were found at higher doses. These results suggest the involvement of CYP2D6 in the metabolism of haloperidol at low doses of haloperidol (< 20 mg daily), while another enzyme, probably CYP3A4, contributes at higher doses.
Curtailing unnecessary vancomycin usage in a hospital with high rates of methicillin resistant Staphylococcus aureus infections
Authors: Kumana Cyrus R. , Ching Tai Yin , Kong Yvonne , Ma Evelyn C. W. , Kou Maybelle , Lee Rodney A. , Cheng Vincent C. C. , Chiu Susan S. , Seto Wing‐Hong
Published: March 2003

Aims  To implement and monitor the effectiveness of a strategy to curb unnecessary use of vancomycin and teicoplanin for inpatients in a teaching hospital/tertiary referral centre where 33% of S. aureus isolates (72% from ICU patients) were methicillin resistant.

Methods  A sample of 182 vancomycin/teicoplanin inpatient prescriptions surveyed, revealed that only 31 (17%) conformed with Centre for Disease Control (CDC) guidelines. Following education (ward‐rounds, bulletins) on appropriate CDC based guidelines for prescribing glycopeptides directed at relevant clinicians, ‘Immediate Concurrent Feedback’ (ICF) was gradually deployed throughout the hospital. This entailed review of respective inpatient records on the next working day. If the indication was deemed not to conform with our guidelines, the prescriber was issued a memo (copied to the supervising doctor). Each memo detailed the ‘errant’ incident, listed appropriate indications and explicitly advised desisting from such prescribing and suggested alternative therapy if necessary. Corresponding glycopeptide usage data for our hospital and others in Hong Kong were retrieved and analysed as were samples of records of our inpatients with staphylococcal septicaemia (pre and during ICF).

Results  Compared with baseline values, during 2 years of ICF, inpatient prescribing of vancomycin and teicoplanin deemed to conform increased to 71% (773/1086); difference 54% (P < 0.0001, 95% CIs 47–62%). Corresponding average monthly usage (DDDs/1000 admissions) decreased from 76 (pre‐ICF) to 45; mean difference 31 (P < 0.0001, 95% CIs 24, 38). Mortality from staphylococcal bacteraemia remained unchanged. No comparable changes in glycopeptide usage ensued in comparator hospitals.

Conclusions  ICF can be used safely to curb irrational overuse of vancomycin and teicoplanin in a hospital with high methicillin resistant S. aureus infection rates.
Population pharmacokinetics and pharmacodynamics of oral etoposide
Authors: Toffoli Giuseppe , Corona Giuseppe , Sorio Roberto , Robieux Isabelle , Basso Barbara , Colussi Anna Maria , Boiocchi Mauro
Published: March 2003

Aims  To study the population pharmacokinetics and pharmacodynamics of oral etoposide in patients with solid tumours.

Methods  A prospective, open label, cross‐over, bioavailability study was performed in 50 adult patients with miscellaneous, advanced stage solid tumours, who were receiving oral (100 mg capsules) etoposide for 14 days and i.v. (50 mg) etoposide on day 1 or day 7 in randomised order during the first cycle treatment. Total and unbound etoposide concentration were assayed by h.p.l.c. Population PK parameters estimation was done by using the P‐Pharm software (Simed). Haematological toxicity and tumour response were the main pharmacodynamic endpoints.

Results  Mean clearance was 1.14 l h−1 (CV 25%). Creatinine clearance was the only covariable to significantly reduce clearance variability (residual CV 18%). (CL = 0.74 + 0.0057 CLCR; r2 = 0.32). Mean bioavailability was 45% (CV 22%) and mean protein binding 91.5% (CV 5%). Exposure to free, pharmacologically active etoposide (free AUC p.o.) was highly variable (mean value 2.8 mg l−1 h; CV 64%; range 0.4–9.5). It decreased with increased creatinine clearance and increased with age which accounted for 9% of the CV. Mean free AUC p.o. was the best predictor of neutropenia. Free AUC50 (exposure producing a 50% reduction in absolute neutrophil count) was 1.80 mg l−1 h. In patients with lung cancer, the free AUC p.o. was higher in the two patients with responsive tumour (5.9 mg l−1 h) than in patients with stable (2.1 mg l−1 h) or progressive disease (2.3 mg l−1 h) (P = 0.01).

Conclusions  Exposure to free etoposide during prolonged oral treatment is highly variable and is the main determinant of pharmacodynamic effects. The population PK model based on creatinine clearance is poorly predictive of exposure. Therapeutic drug monitoring would be necessary for dose individualization or to study the relationship between exposure and antitumour effect.
A rapid screening method for a single nucleotide polymorphism (SNP) in the human MOR gene
Authors: Grösch Sabine , Niederberger Ellen , Lötsch Jörn , Skarke Carsten , Geisslinger Gerd
Published: March 2003

Aims  Genetic association studies have suggested that the single nucleotide polymorphism (SNP) at position 118 of the human µ‐opioid receptor (MOR) gene could be a potential risk factor for drug treatment variability in patients. Therefore, we wanted to develop a fast and reliable detection method for this SNP which is applicable in a clinical setting.

Methods  To detect the polymorphism at position A118→G in the human MOR gene we used the fluorescence resonance energy transfer (FRET)‐PCR technique with subsequent melting curve analysis.

Results  The polymorphism at position A118→G in the human MOR gene could be clearly discriminated with melting peak temperatures of 69.8 ° C and 63.8 ° C, corresponding to the wild type and mutated MOR allele, respectively. The results from FRET‐PCR were validated by sequencing and restriction‐fragment length polymorphism (RFLP). Screening of blood samples from 100 subjects showed an allelic distribution for the human MOR alleles of 79% (homozygous wild type), 20% (heterozygous) and 0.9% (homozygous mutated).

Conclusions  The FRET‐PCR protocol for detection of the human MOR gene polymorphism at position 118 offers a rapid and reliable method which could be used for population screening of this and other genes.
Activated charcoal alone or after gastric lavage: a simulated large paracetamol intoxication
Authors: Christophersen A. B. , Levin D. , Hoegberg L. C. G. , Angelo H. R. , Kampmann J. P.
Published: March 2003

Aims  Activated charcoal is now being recommended for patients who have ingested potentially toxic amounts of a poison, where the ingested substance adsorbs to charcoal. Combination therapy with gastric lavage and activated charcoal is widely used, although clinical studies to date have not provided evidence of additional efficacy compared with the use of activated charcoal alone. There are also doubts regarding the efficacy of activated charcoal, when administered more than 1 h after the overdose. The aim of this study was to examine if there was a difference in the effect of the two interventions 1 h post ingestion, and to determine if activated charcoal was effective in reducing the systemic absorption of a drug, when administered 2 h post ingestion.

Methods  We performed a four‐limbed randomized cross‐over study in 12 volunteers, who 1 h after a standard meal ingested paracetamol 50 mg kg−1 in 125 mg tablets to mimic real‐life, where several factors, such as food, interfere with gastric emptying and thus treatment. The interventions were activated charcoal after 1 h, combination therapy of gastric lavage followed by activated charcoal after 1 h, or activated charcoal after 2 h. Serum paracetamol concentrations were determined by h.p.l.c. Percentage reductions in the area under the curve (AUC) were used to estimate the efficacy of each intervention (paired observations).

Results  There was a significant (P<0.005) reduction in the paracetamol AUC with activated charcoal at 1 h (median reduction 66%, 95% confidence intervals 49, 76) compared with controls, and a significant (P<0.01) reduction for gastric lavage followed by activated charcoal at 1 h (median reduction 48.2%, 95% confidence interval 32.4, 63.7) compared with controls. There was no significant difference between the two interventions (95% confidence interval for the difference −3.8, 34.0). Furthermore, we found a significant (P<0.01) reduction in the paracetamol AUC when activated charcoal was administered 2 h after tablet ingestion when compared with controls (median 22.7%, 95% confidence intervals 13.6–34.4).

Conclusions  These results suggest that combination treatment may be no better than activated charcoal alone in patients presenting early after large overdoses. The effect of activated charcoal given 2 h post ingestion is substantially less than at 1 h, emphasizing the importance of early intervention.
Classification of Headaches
Authors: Göbel H
Published: March 2003

It was not until 1962 that the Ad-Hoc Committee of the National Institute of Health first published a classification of headache syndromes by brief glossary definitions. The general disadvantage of such glossary definitions is that they require subjective interpretation. Therefore under the chairmanship of Prof. Jes Olesen, Copenhagen, the International Headache Society published in 1988 on the basis of empirical findings a first ever headache classification using operationalized criteria. The headache classification of the International Headache Society was immediately translated into the world’s major languages and was adopted by all national headache societies represented in the International Headache Society, the World Health Organisation and the World Federation of Neurology. The new classification proved so successful and enjoyed such rapid international acceptance that no revision was undertaken until 1999. The second edition, again under the chairmanship of Prof. Jes Olesen, will probably be completed in 2002. The classification produced such a high degree of inspiration and motivation of pathophysiological and epidemiological research work that knowledge in the field of headache has displayed growth unparalleled in any other field of neurological research. This development was made possible by the determined work of the Chairman of the Headache Classification Committee, Prof. Jes Olesen. He succeeded in bringing together international researchers, motivating them and jointly turning the current fund of knowledge into a evidence-based classification. Prof. Jes Olesen thus performed the decisive pioneering work for all those who have to do with headaches–patients, doctors and scientists. The IHS classification is the most frequently cited text and one of the most important milestones in the history of the scientific study of headaches.
Chronic Tension-Type Headache in Children and Adolescents
Authors: Abu-Arafeh Ishaq
Published: March 2003

In this study, the causes, predisposing factors and clinical features of chronic daily headache in children and adolescents were studied within the population of patients attending a specialist headache. The International Headache Society's (IHS) criteria for the diagnosis of chronic tension type headache (CTTH) were assessed for their applicability in the paediatric age group. Over a period of three years, demographic and clinical data were collected prospectively on all children who attended the clinic and suffered from daily attacks of headache.

One hundred and fifteen children and adolescents (32% of all clinic population) had chronic daily headache, of whom 93 patients (81%) fulfilled the IHS criteria for the diagnosis of CTTH. They were between 3-15 years of age (mean: 11.1, SD: 2.3) and their female to male ratio was 1.2: 1. Around one third of the patients also suffered from migraine (mainly migraine without aura).

The headache was described as mild in 60.9%, moderate 36.5% and severe 2.6%. Headache was located at the forehead in 53% or over the whole of the head in 29.6%. Pain was described as ‘just sore’ or dull by 73.9%. During attacks of headache, at least half the patients reported light intolerance, noise intolerance, anorexia or nausea. Thirty-two percent of patients had at least one underlying chronic disease that may have contributed to the pathogenesis of the CTTH. Eleven percent had serious stressful events related to family illnesses and in four patients headaches were triggered by family bereavement. Fourteen percent were investigated with neuroimaging and 22% were referred for clinical psychology assessment and management.

In conclusion, CTTH is a common cause of headache in children attending a specialist headache clinic. The clinical features closely match those of adult population and the IHS criteria for the diagnosis of CTTH can be adapted for use in children. Predisposing stressful risk factors, physical or emotional, are present in a large proportion.
Global motion integration in the cat's lateral posterior‐pulvinar complex
Authors: Dumbrava Daniela , Faubert Jocelyn , Casanova Christian
Published: March 2003

Our laboratory previously showed that thalamic neurons in an extrageniculate nucleus, the lateral posterior‐pulvinar complex (LP‐pulvinar) could perform higher‐order neuronal operations that had until then only been attributed to higher‐level cortical areas. To further assess the role of the thalamus in the analysis of complex percepts, we have investigated whether neurons in the LP‐pulvinar complex can signal the direction of motion of random‐dot kinematograms wherein the individual elements of the pattern do not provide coherent motion cues. Our results indicate that a subset of LP‐pulvinar cells can integrate the displacement of individual elements into a global motion percept and that their large receptive fields permit the integration of motion for elements separated by large spatial intervals. We also found that almost all of the global motion‐sensitive neurons were not systematically pattern‐motion‐selective when tested with plaid patterns. The results indicate that LP‐pulvinar cells can perform the higher‐level spatio‐temporal integration required to detect the global displacement of objects in a complex visual scene, further supporting the notion that extrageniculate thalamic cells are involved in higher‐order motion processing. Furthermore, these results provide some evidence that there may be specialized mechanisms for processing different types of complex motion within the LP‐pulvinar complex.
Feeding suppression by fibroblast growth factor‐1 is accompanied by selective induction of heat shock protein 27 in hypothalamic astrocytes
Authors: Suzuki Seigo , Li Ai‐Jun , Ishisaki Akira , Hou Xiaogang , Hasegawa Mamoru , Fukumura Masayuki , Akaike Toshihiro , Imamura Toru
Published: March 2003

It has been suggested that fibroblast growth factor (FGF)‐1 serves as a physiological satiety factor in the hypothalamus, although the molecular mechanism underlying such a function is poorly understood. To gain additional insight into this issue, we used a Sendai virus (SeV) gene expression system in rats to explore genes differentially expressed subsequent to expression of FGF‐1. Using cDNA arrays, we determined that infusion of FGF‐1/SeV into one lateral ventricle induced selective expression of heat shock protein (HSP) 27 in the hypothalamus. Whereas FGF‐1 expression was restricted to the ependymal cell layer of the cerebral ventricles, HSP27 was more widely expressed in astrocytes residing in the surrounding periventricular region. Similarly, infusion of FGF‐1 polypeptide into a lateral ventricle induced dose‐dependent HSP27 expression in periventricular astrocytes surrounding the third ventricle, with maximum mRNA levels being attained 6 h after infusion. This induction of HSP27 was accompanied by a significant suppression of feeding behaviour. Interestingly, suppression of feeding caused by intracerebro ventricular infusion of ciliary neurotrophic factor was also accompanied by induction of HSP27 in periventricular astrocytes, but suppression of feeding caused by infusion of leptin was not. It therefore appears that suppression of feeding by FGF‐1 is accompanied by selective induction of HSP27 expression in hypothalamic astrocytes surrounding the third ventricle, and that this response may be a key component of the mechanism by which appetite is regulated by FGF‐1.
Survival from out‐of‐hospital cardiac arrest in the Geelong region of Victoria, Australia
Authors: Jennings Paul , Pasco John
Published: March 2003

Objective:

To study the outcome from prehospital cardiac arrest managed by ambulance personnel, and to examine overall survival rates from successful resuscitation.

Methods:

A retrospective analysis was made of 115 patient care records of prehospital cardiac arrests with attempted resuscitation between July 1996 and September 1999. All cases had a presumed primary cardiac cause for their cardiac arrest.

Results:

Overall survival, defined as admitted to hospital alive, was 22 subjects (19.1%), with five subjects (4.3%) being discharged from hospital neurologically intact. Of the patients who survived to the emergency department, six (5%) had initially presented in pulseless electrical activity and 16 (14%) presented with ventricular fibrillation. No patients prsented with ventricular tachycardia and no survivors presented in asystole. Median response interval from time of call to arrival of initial crew at patient’s side was 9 min. No patients survived when response interval was greater than 14 min. Bystander cardiopulmonary resuscitation was being performed on 55 patients (48%) on arrival of initial ambulance crew; 68.2% of patients surviving to hospital having had bystander cardiopulmonary resuscitation.

Conclusion:

Decreasing time delays in accessing the patient is crucial to improving outcome in out‐of‐hospital cardiac arrest.
Ethical relationships in paediatric emergency medicine: Moving beyond the dyad
Authors: Bridges John , Hanson Ralph , Little Miles , Flannigan Alison Choy , Fairley Michael , Haywood Leigh
Published: March 2003

Most areas of health‐services research concentrate on a dyadic relationship between doctor and patient. In paediatric emergency medicine it may be necessary to focus on a more complicated relationship because the parents of the child play an important role in the delivery of medical services. This paper discusses the ethical principles in paediatric emergency medicine from the perspective of five disciplines: health economics, paediatrics, medical ethics, law and mental health. The general consensus is that the traditional dyadic model is inadequate and that a more complicated relationship is needed for the paediatric emergency setting, such as triadic, multiple‐dyadic or polyadic. Such models allow the inclusion of the parents and possibly other family members, medical providers and community members. If the paediatric setting is considered in such a framework, it may be possible to deliver a more socially beneficial medical service.
Acute opioid withdrawal in the emergency department: Inadvertent naltrexone abuse?
Authors: Bristow Katherine , Meek Robert , Clark Nicholas
Published: March 2003

From July 1999 it became evident that a rising number of heroin users were presenting to the Dandenong Hospital Emergency Department with a rapid onset, florid opioid withdrawal syndrome following the intravenous injection of what they had believed to be heroin. We suspect that the injected substance was in fact naltrexone. This paper describes two such cases and reviews the literature on naltrexone. Recommendations regarding the management of the acute opioid withdrawal syndrome are made.
Effects of intravenous injection of Salmonella antigen on the distribution of major histocompatibility complex class II positive cells in the ovarian follicles of hens
Authors: YOSHIMURA Yukinori , TAKATA Tomomasa
Published: March 2003

The goal of this study was to determine whether the distribution of major histocompatibility complex class II positive (MHC class II+) cells was affected by foreign agents in the blood circulation. White Leghorn layers were injected intravenously with or without formalin fixed Salmonella paratyphi, and the area of MHC class II+ cells in the ovarian follicles, which included the largest (F1) and third largest follicles (F3), white follicles (WF) and cortical follicles, was examined by immunocytochemistry. The immunoreaction products for MHC class II were observed in cells of the thecal layer of all follicles in both treated and control birds. Salmonella paratyphi antigen caused a significant increase in the area of MHC class II+ cells in the theca of the F1, F3 and WF, but not in the cortical follicles. The results suggest that the MHC class II+ cells in the theca increase in response to circulating foreign agents, and play a significant role in ovarian local immunity.
Comparison of the antioxidant activities of 22 commonly used culinary herbs and spices on the lipid oxidation of pork meat
Authors: TANABE Hisako , YOSHIDA Masami , TOMITA Nanae
Published: March 2003

The antioxidant activities of 22 selected culinary herbs and spices (i.e. ginger, cinnamon, clove, bay, sage, rosemary, thyme, savory, oregano, sweet basil, parsley, coriander, tarragon, sansho, allspice, cumin, black and white peppercorns, nutmeg, caraway, dill and fennel) when they were added to pork homogenate were measured and expressed as a thiobarbituric acid (TBA) value. The addition of liquid extracts of all the herbs and spices significantly suppressed lipid oxidation of the pork, especially the extracts of sansho, sage and ginger, which showed the strongest inhibition of lipid oxidation.
Fat depot‐specific differences in leptin mRNA expression and its relation to adipocyte size in steers
Authors: YANG Seung Hak , MATSUI Tohru , KAWACHI Hiroyuki , YAMADA Tomoya , NAKANISHI Naoto , YANO Hideo
Published: March 2003

ABSTRACT This experiment was conducted to investigate leptin mRNA expression, adipocyte size, and their relationship in several adipose tissues of fattening steers. Subcutaneous, perirenal, intermuscular and intramuscular adipose tissues were collected from three crossbred steers (Japanese Black cattle X Holstein) aged 21 months. The mRNA level and adipocyte diameter were determined in these adipose tissues. The intramuscular adipose tissue had a lower leptin mRNA level than the intermuscular and perirenal adipose tissues (P < 0.05). Leptin mRNA level was lower in the subcutaneous depot than in the intermuscular depot (P < 0.05). Adipocyte diameter was larger in the intermuscular adipose tissue than in the subcutaneous and intramuscular adipose tissues (P < 0.05). Leptin mRNA level was positively correlated with adipocyte diameter (r2 = 0.81, P < 0.05). These results suggest that the cattle have fat depot‐specific differences in leptin gene expression, which are a result of a difference in adipocyte size.
Assessment of criteria for improvement in Theileria orientalis sergenti infection tolerance
Authors: FUKASAWA Michiru , KIKUCHI Tadashi , KONASHI Shigeru , NISHIDA Akira , YAMAGISHI Toshihiro
Published: March 2003

We examined the relationships between calf productivity, anemia and Theileria orientalis sergenti infection from records of 109 Japanese shorthorn calves during a grazing period and we quantified the relative importance of the T. orientalis sergenti infection‐resistance criteria used. A decrease in average parasitemia (AvePara) and an increase in average packed cell volume (AvePCV) would cause a decrease in the number of drug treatments. An increase in AvePCV would decrease the number of drug treatments more efficiently than a decrease in AvePara. An increase in AvePCV would cause an increase in dairy gain, while a decrease in AvePara would cause a decrease in dairy gain. Therefore, an improvement in the capacity to control anemia development would improve T. orientalis sergenti infection resistance more efficiently than an improvement in the capacity to control parasitemia development.