bluuebunny/crossref_metadata_2025 huggingface dataset:
Identification of syntaxin‐1A sites of phosphorylation by casein kinase I and casein kinase II
Authors: Dubois Thierry , Kerai Preeti , Learmonth Michele , Cronshaw Andy , Aitken Alastair
Published: March 2003

Casein kinases I (CKI) are serine/threonine protein kinases widely expressed in a range of eukaryotes including yeast, mammals and plants. They have been shown to play a role in diverse physiological events including membrane trafficking. CKIα is associated with synaptic vesicles and phosphorylates some synaptic vesicle associated proteins including SV2. In this report, we show that syntaxin‐1A is phosphorylated in vitro by CKI on Thr21. Casein kinase II (CKII) has been shown previously to phosphorylate syntaxin‐1A in␣vitro and we have identified Ser14 as the CKII phosphorylation site, which is known to be phosphorylated in vivo. As␣syntaxin‐1A plays a key role in the regulation of neurotransmitter release by forming part of the SNARE (soluble N‐ethylmaleimide‐sensitive factor attachment protein receptor) complex, we propose that CKI may play a role in synaptic vesicle exocytosis.
High pressure‐induced changes of biological membrane
Authors: Kato Michiko , Hayashi Rikimaru , Tsuda Takeo , Taniguchi Kazuya
Published: March 2003

In order to study the pressure‐induced changes of biological membrane, hydrostatic pressures of from 0.1 to 400 MPa were applied to membrane‐bound Na+/K+‐ATPase from pig kidney as a model system of protein and lipid membrane. The activity showed at least a three‐step change induced by pressures of 0.1–100 MPa, 100–220 MPa, and 220 MPa or higher. At pressures of 100 MPa or lower a decrease in the fluidity of lipid bilayer and a reversible conformational change in transmembrane protein is induced, leading to the functional disorder of membrane‐associated ATPase activity. A pressure of 100–220 MPa causes a reversible phase transition in parts of the lipid bilayer from the liquid crystalline to the gel phase and the dissociation of and/or conformational changes in the protein subunits. These changes could cause a separation of the interface between α and β subunits and between protein and the lipid bilayer to create transmembrane tunnels at the interface. Tunnels would be filled with water from the aqueous environment and take up tritiated water. A pressure of 220 MPa or higher irreversibly destroys and fragments the gross membrane structure, due to protein unfolding and interface separation, which is amplified by the increased pressure. These findings provide an explanation for the high pressure‐induced membrane‐damage to subcellular organelles.
A comparison of the urea‐induced unfolding of apoflavodoxin and flavodoxin from Desulfovibrio vulgaris
Authors: Nuallain Brian Ó , Mayhew Stephen G.
Published: March 2003

The kinetics and thermodynamics of the urea‐induced unfolding of flavodoxin and apoflavodoxin from Desulfovibrio vulgaris were investigated by measuring changes in flavin and protein fluorescence. The reaction of urea with flavodoxin is up to 5000 times slower than the reaction with the apoprotein (0.67 s−1 in 3 m urea in 25 mm sodium phosphate at 25 °C), and it results in the dissociation of FMN. The rate of unfolding of apoflavodoxin depends on the urea concentration, while the reaction with the holoprotein is independent of urea. The rates decrease in high salt with the greater effect occurring with apoprotein. The fluorescence changes fit two‐state models for unfolding, but they do not exclude the possibility of intermediates. Calculation suggests that 21% and 30% of the amino‐acid side chains become exposed to solvent during unfolding of flavodoxin and apoflavodoxin, respectively. The equilibrium unfolding curves move to greater concentrations of urea with increase of ionic strength. This effect is larger with phosphate than with chloride, and with apoflavodoxin than with flavodoxin. In low salt the conformational stability of the holoprotein is greater than that of apoflavodoxin, but in high salt the relative stabilities are reversed. It is calculated that two ions are released during unfolding of the apoprotein. It is concluded that the urea‐dependent unfolding of flavodoxin from D. vulgaris occurs because apoprotein in equilibrium with FMN and holoprotein unfolds and shifts the equilibrium so that flavodoxin dissociates. Small changes in flavin fluorescence occur at low concentrations of urea and these may reflect binding of urea to the holoprotein.
Time use and importance of instrumental activities of daily living
Authors: Fricke Janet , Unsworth Carolyn
Published: March 2003

This study investigated time use and the importance of instrumental activities of daily living (IADL) tasks to an older community‐dwelling population. In addition, the study compared occupational therapists’ and older people’s perception of importance of IADL tasks for maintaining community living. Thirty‐three subjects completed a time diary and an interview‐based questionnaire to ascertain their time use and the importance of IADL tasks. It was found that older people living in the community spent most of their time at home and alone, with nearly half the day being spent on IADL tasks. The subjects indicated that the three most important tasks were use of the telephone, use of transportation (including driving) and reading. Differences were found when the results from an earlier study of occupational therapists were compared with results from the present study of older people. The occupational therapists also considered use of the telephone as most important but then rated medication management and snack preparation as the most necessary activities for continued community living. These results emphasize the differences in the perception of ‘important’ between the two groups studied. The results from this research confirm the importance of IADL to both the occupational therapy profession and older people living at home in the community. Further, these results confirm the need for client‐centred practice and collaborative intervention planning for occupational therapy.
Habitat assessment for a rare, arboreal forest mammal, the tree hyrax Dendrohyrax arboreus
Authors: Gaylard A. , Kerley G. I. H.
Published: March 2003

Recent findings have suggested that there has been a change in the structural nature of forests in the Eastern Cape, South Africa, which explains decreases in forest fauna. One of these (rare) forest species is the tree hyrax Dendrohyrax arboreus, a nocturnal, arboreal folivore, which makes use of cavity‐bearing trees as dens. However, a conflict exists between the use of forest resources and in protecting habitats for the tree hyrax. In order to design appropriate management strategies, conservation authorities and forest managers require information regarding the specific habitat requirements of fauna in their forest, particularly those that are already threatened by resource use. The aims of this study were thus: (i) to characterise the den trees of D. arboreus, (ii) to determine whether D. arboreus selects for certain den tree characteristics (i.e. relative to the abundance of that characteristic); and (iii) to develop a habitat assessment model for D. arboreus. The tree hydrax was found to select for den trees with particular characteristics: seven tree species were selected as den trees, which were usually the tallest trees in the canopy (4–8 m). Den trees were usually only partly decayed, with multiple cavity entrances and trunk angles of between 45° and 68°. Cavity entrance and orientation did not appear to play a role in den tree selection by D. arboreus. A function which discriminated between den trees and non‐den trees was calculated, and can be used to determine the suitability of a tree as a den for a tree hyrax (and thus to prevent it from being removed during commercial logging operations), or to assess the suitability of an area for habitation by tree hyraxes. This model can therefore help to alleviate the conflict between forest conservation managers and resource users in the Eastern Cape.
Decline of the African lungfish (Protopterus aethiopicus) in Lake Victoria (East Africa)
Authors: Goudswaard Kees (P. C.) , Witte Frans , Chapman Lauren J.
Published: March 2003

Catch and effort data for the period 1973–1990 demonstrate a dramatic decline of lungfish in the Tanzanian waters of Lake Victoria. Bottom trawl catches in the Mwanza Gulf showed a decline in catch rates from 67.5 kg h−1 in 1973 to 5.5 kg h−1 in 1986. Trawling of commercial vessels in the Speke Gulf revealed a decline in lungfish catches from 1.3 kg h−1 in 1986 to 0.07 kg h−1 in 1990. The development of anoxia in the deeper waters of Lake Victoria, the algal blooms, and the decline of water transparency, all associated with eutrophication, are not likely to have contributed to the decreased catch rate. However, the lungfish decline may reflect the interaction of overexploitation by the fishery and a low level of Nile perch predation that restricts lungfish to wetland refugia. We suggest that this may have been reinforced over the past few decades by large‐scale conversion of wetlands to agricultural land and harvesting of nest‐guarding male lungfish leading to decreased recruitment of young.
Phenological influences on the utilization of woody plants by eland in semi‐arid shrubland
Authors: Watson Laurence H. , Owen‐Smith Norman
Published: March 2003

Our study monitored the acceptability, shoot phenology and chemical content of karoid woody species over the seasonal cycle. Species favoured by eland as long as they retained leaves, were classified as palatable, while those neglected for part of the seasonal cycle, even though they retained leaves, were classified as unpalatable. Changes in the acceptability of unpalatable species over the seasonal cycle appeared to be related to changes in the proportion of young shoots on plants, as influenced by rainfall and temperature. These species were typically only favoured when they offered relatively high proportions of young shoots. Our study identified total fibre as the most important chemical factor influencing the acceptability of woody species to eland. The shoots of palatable species contained low fibre concentrations, while the shoots of unpalatable species were more variable in fibre content. When favoured, the shoots of unpalatable species typically had similar levels of fibre to palatable species, but when neglected, the shoots of unpalatable species generally had increased fibre levels. Eland have thrived since being introduced into our study area, which is dominated by microphyllous and leptophyllous woody species. We suggest that this is because eland are able to select a diet sufficiently low in fibre content.
The small mammal community of a coastal site of south‐west Mauritania
Authors: Granjon L. , Bruderer C. , Cosson J. F. , Dia A. T. , Colas F.
Published: March 2003

The small mammal community of a coastal site of south‐western Mauritania was monitored using live trapping, owl pellet analysis and nocturnal visual censuses. Ten species of rodents and two shrews were recorded. Gerbillid rodents (Gerbillus nanus, G. gerbillus, G. tarabuli, G. nigeriae and Taterillus arenarius) were the most prevalent in traps, whereas a relatively large proportion of owl pellets were made up of a murid rodent, Mastomys huberti. The presence of two species of murids (M. huberti and Arvicanthis niloticus) in this presaharian environment is made possible by the presence of small patches of green vegetation associated with localized fresh water inputs. The contradiction of results from the sampling methods indicate potential biases in the determination of community composition and relative species abundance. Results are also discussed in estimating the potential role of predation and competition in this small mammal community.
Rapid cold hardening in Antarctic microarthropods
Authors: Worland M. R. , Convey P.
Published: March 2003

Rapid cold hardening was examined in three common Antarctic microarthropods using differential scanning calorimetry over timescales between 3 and 30 h, under field and controlled laboratory conditions.

In fresh field samples and cultures of the springtail, Cryptopygus antarcticus (Willem), and cultures of the mites, Alaskozetes antarcticus (Michael) and Halozetes belgicae (Michael), maintained under summer field‐simulating conditions, supercooling point (SCP) distributions tracked microhabitat temperature variation over the observation period.

 Controlled acclimation of samples of summer‐acclimatized C. antarcticus caused significant cold hardening after 12 h at temperatures around 0 °C (+3 to −2 °C). No response was obtained at higher or lower temperatures, or in field‐fresh winter‐acclimatized animals. The latter did not lose cold hardiness when held at positive temperatures for 12 h.

 Gradual cooling of C. antarcticus over 20 h from +5 to −5 °C caused a considerable increase in cold tolerance. Rewarming partially but non‐significantly reversed this effect. The greatest response occurred between +3 and +1 °C. Maximum faecal pellet production also occurred in this interval, but gut clearance alone was not sufficient to explain observed cold hardening.

 It is hypothesized that these species possess a hitherto unrecognized capacity to alter cold hardiness in summer in response to environmental temperature cues over a shorter timescale than previously thought, by a mechanism that relies on neither gut clearance nor concentration of body fluids via water loss. This ability may reduce the developmental costs of premature entry into an inactive, cold‐hardy state.
Metastatic tumours of the adrenal glands: a 30‐year experience in a teaching hospital
Authors: Lam K.‐Y. , Lo C.‐Y.
Published: March 2003

objective Adrenal metastases are frequently encountered during autopsy but uncommonly present clinically. The aim of this study was to evaluate the clinical and pathological impact of adrenal metastases in a large series of patients.

patients Four hundred and sixty‐four patients (288 men, 176 women) with metastatic disease in the adrenal glands over a 30‐year period were included in the study.

measurements The clinical records and pathological features were reviewed.

results The frequencies of adrenal metastases at autopsies, adrenalectomies and fine‐needle aspiration biopsies were 3·1%, 7·5% and 33%, respectively. The lesions were often seen in elderly patients (mean age, 62, SD = 13 years). Many of the metastatic lesions in the adrenal gland occurred shortly after the detection of a primary tumour (mean latent period = 7 months). Four per cent of the adrenal lesions (n = 20) were symptomatic. The symptomatic adrenal lesions, as compared with asymptomatic ones, were bigger and seen in younger patients. Five patients presented with adrenal insufficiency (Addison’s disease) and one had massive peritoneal haemorrhage because of metastatic carcinoma. Ninety per cent (n = 421) of the metastatic adrenal tumours were carcinomas and 56% of these were adenocarcinoma. Lung was the most common primary tumour site (35%), followed by the stomach (14%), the oesophagus (12%) and the liver/bile ducts (10%). The adrenal metastases were bilateral in approximately half of the patients (49%, n= 229). The mean diameter of the adrenal metastases was 2 cm (SD = 1·9 cm). The mean weight of the right adrenal gland harbouring the metastasis was 19 g, while that of the left 20 g. The median survival of the 20 patients with symptomatic adrenal lesions was 3 months (range, 0–75 months) after the detection of adrenal metastases. Patients with surgically removed adrenal metastases had slightly better survival rates than those without surgical resection.

conclusions  A variety of tumours may give rise to adrenal metastases. They are often asymptomatic and detected as part of multiorgan metastases. Symptomatic cases, albeit rare, may occur. Long‐term survival may be achieved in selected patients in whom an aggressive surgical approach may be adopted.
Leydig cell hypoplasia: cases with new mutations, new polymorphisms and cases without mutations in the luteinizing hormone receptor gene
Authors: Richter‐Unruh A. , Martens J. W. M. , Verhoef‐Post M. , Wessels H. T. , Kors W. A. , Sinnecker G. H. G. , Boehmer A. , Drop S. L. S. , Toledo S. P. A. , Brunner H. G. , Themmen A. P. N.
Published: March 2003

background Defective male sex differentiation in patients with hypoplasia of Leydig cells (LCH) is caused by deficient LH receptor signal transduction. To further investigate the variety of LH receptor gene mutations present in LCH patients and their influence on the phenotype, we examined 10 nonrelated patients with the clinical presentation of LCH.

patients and methods Ten patients with a clinical phenotype of LCH were analysed for mutations in the complete coding region of the LH receptor gene. Exons 1–10 and two overlapping fragments of exon 11 of the LH receptor gene including all intron–exon boundaries were amplified by polymerase chain reaction and sequenced. To screen for frequencies of DNA changes, mutation analysis was performed on 45–59 healthy persons using denaturation high‐performance liquid chromatography.

results Six new DNA alterations were identified. Three of them appear to be new polymorphisms. A G to C change at the 28th nucleotide of intron 1 on one allele and a heterozygous CGA to CAA transition at codon 124 (R124Q) were found. Both findings in these two patients are polymorphisms that occur with a frequency of 17% and 1·7%, respectively. A silent heterozygous CTA to TTA change at codon 204 was identified. In a patient with micropenis, the analysis revealed a homozygous missense mutation at codon 625 (I625K). As reported previously, this alteration significantly impaired signal transduction and explains the partial phenotype. Finally, in one compound heterozygous patient, two different mutations were discovered. At the polymorphic site in exon 1, a 27‐bp insertion (CTG)2 AAG (CTG)5 CAG and a premature stop codon in the transmembrane segment 4 (W491*) were found. Both mutations disrupt signal transduction and explain the complete phenotype of this patient. In five patients, no DNA alterations could be identified.

conclusions Three mutations (33 bp insertion in exon 1; W491* and I625K) were identified that explain the phenotype in two patients. In addition, most of the patients with the clinical phenotype of LCH did not have causative mutations, suggesting that changes in other regions of the LH receptor gene, such as the large introns or the promoter region, may be responsible for the majority of cases. Alternatively, the displayed phenotype may be the result of other genetic defects. Our work further underscores the importance of thorough clinical analysis of patients before molecular analysis of a particular gene is performed.
Normalized dyslipidaemia after parathyroidectomy in mild primary hyperparathyroidism: population‐based study over five years
Authors: Hagström Emil , Lundgren Ewa , Lithell Hans , Berglund Lars , Ljunghall Sverker , Hellman Per , Rastad Jonas
Published: March 2003

objective Postmenopausal women are at increased risk of primary hyperparathyroidism (pHPT). Secondary dyslipidaemia in pHPT has attracted little attention, although morbidity and mortality associated with cardiovascular diseases have been reported to be increased in these patients.

design A population‐based screening programme was used to recruit postmenopausal women with mild, asymptomatic pHPT (mean serum calcium 2·57 ± 0·12 mmol/l) and matched controls.

measurements and patients Serum lipids, lipoprotein fractions and influences of treatment for the parathyroid disease were studied in 87 case‐control pairs (mean age 67 years), 69 of whom completed a 5‐year follow‐up period.

results pHPT was characterized by decreased serum high‐density lipoprotein (HDL)‐cholesterol, increased total triglycerides, very‐low‐density lipoprotein (VLDL)‐triglycerides and VLDL‐cholesterol levels and an elevated atherogenic index. The differences were more pronounced in the cases with serum parathyroid hormone levels in the normal range and were inversely correlated to the serum parathyroid hormone level. Parathyroidectomy, with or without additive hormone replacement therapy, normalized the dyslipidaemia. Five‐year surveillance of pHPT without treatment was associated with a maintained increase in total triglycerides and the atherogenic index and a decrease in HDL‐cholesterol levels.

conclusion Proatherosclerotic dyslipidaemia characterizes mild pHPT and is effectively reversed by parathyroidectomy. As dyslipidaemia might contribute to the increased risk of cardiovascular diseases and death observed in pHPT, the findings favour operative intervention rather than conservative surveillance in mild, asymptomatic pHPT in postmenopausal females.
Differential cognitive effects of ebastine and (+)‐chlorpheniramine in healthy subjects: Correlation between cognitive impairment and plasma drug concentration
Authors: Tagawa Masaaki , Kano Michiko , Okamura Nobuyuki , Higuchi Makoto , Matsuda Michiaki , Mizuki Yasuyuki , Arai Hiroyuki , Fujii Toshihiko , Komemushi Sadao , Itoh Masatoshi , Sasaki Hidetada , Watanabe Takehiko , Yanai Kazuhiko
Published: March 2003

Aims  It has been widely recognized that classical antihistamines induce sedation as an adverse effect, while second‐generation antihistamines have few if any sedative effects. In order to evaluate the sedative properties of ebastine, a second‐generation antihistamine, its effect on cognitive performance in healthy subjects was compared with placebo and (+)‐chlorpheniramine.

Methods  Twelve healthy male subjects were instructed to perform six types of attention‐demanding cognitive tasks, and objective measurements of reaction times and accuracy was made before and after drug administration. Their sleepiness levels were also monitored. Test drugs were ebastine 10 mg, placebo and two doses of (+)‐chlorpheniramine 2 mg and 6 mg, as positive controls. Plasma drug concentrations at the end of the study were analysed.

Results  After treatments with (+)‐chlorpheniramine, the reaction times of the tasks were significantly prolonged (e.g. ratios of after/before dosing: placebo (0.998±0.113) vs (+)‐chlorpheniramine 2 mg (1.103±0.083; P<0.05) or (+)‐chlorpheniramine 6 mg (1.170±0.139; P<0.001) in a 7 ms visual discrimination time task) and the accuracy was significantly decreased (e.g. ratios: placebo (1.038±0.158) vs (+)‐chlorpheniramine 2 mg (0.792±0.202; P<0.01) or (+)‐chlorpheniramine 6 mg (0.837±0.222; P<0.05) in a 7 ms task). On the other hand, performance was not affected by ebastine or placebo treatment (e.g. ebastine 10 mg (reaction time ratio; 1.014±0.067 and accuracy ratio; 0.990±0.146) in a 7 ms task). Subjective sleepiness was also not affected by ebastine but (+)‐chlorpheniramine significantly increased sedation. With respect to the relationship between plasma drug concentrations and task performance, the latter deteriorated with an increase in plasma (+)‐chlorpheniramine concentration (e.g. r=0.439 (P=0.007) in a 5 ms and r= 0.352 (P=0.039) in a 7 ms task), but it did not correlate with the plasma concentration of carebastine, an active metabolite of ebastine.

Conclusions  Ebastine 10 mg did not cause any cognitive impairment or subjective sleepiness. On the other hand, (+)‐chlorpheniramine impaired cognitive function and induced sleepiness even at 2 mg, the recommended dose in over‐the‐counter medication. In addition, impaired CNS performance was significantly correlated with plasma (+)‐chlorpheniramine concentration.
6‐Thioguanine in children with acute lymphoblastic leukaemia: influence of food on parent drug pharmacokinetics and 6‐thioguanine nucleotide concentrations
Authors: Lancaster D. L. , Patel N. , Lennard L. , Lilleyman J. S.
Published: March 2003

Aims  Since relatively little is known about the pharmacokinetics of 6‐thioguanine (6TG) in children receiving 6‐thioguanine for maintenance therapy of acute lymphoblastic leukaemia (ALL), we studied plasma drug concentrations under standardized conditions and investigated the effect of food on parent drug pharmacokinetics and the accumulation of the active metabolites 6‐thioguanine nucleotides (6‐TGNs) in red cells.

Methods

 Single oral doses of 40 mg of 6‐TG were administered both in the fasting and fed state to children with ALL. Pharmacokinetic sampling was performed up to 6 h post dose. Daily oral doses of 40 mg m−2 of 6‐TG were administered both fasting and after food over two 4 week periods. Twice weekly samples were taken for metabolite concentrations. The study design was cross‐over with each child receiving dosing in either fasted or after food over a 4 week period in each phase.

Results

 Eleven patients were studied. A wide interindividual variation in Cmax (median 313 pmol ml−1, range 51–737) and AUC (median 586 pmol ml−1 h, range 156–1306) was observed in the fasted state. Concomitant food administration resulted in a significant reduction in Cmax (median 71 vs 313 pmol ml−1, P = 0.006, CI from 36 to 426), AUC (median 200 vs 586 pmol ml−1 h, P = 0.006, 95% CI from 109 to 692), and time to reach Cmax (median 1.5 vs 3 h, P = 0.013, 95% CI from 0.74 to 2.73). There was no difference in the steady state concentration of red cell 6‐TGNs observed after a 4 week period of 6‐TG administered fasting or after food.

Conclusions

 Children with ALL demonstrate significant interindividual variation in 6‐TG pharmacokinetics. Although there would appear to be a reduction in parent drug Cmax and AUC with food there was no difference in 6‐TGN concentrations after 4 weeks of 6‐TG. Taking the drug on an empty stomach may not be necessary.
First results from an intensified monitoring system to estimate drug related hospital admissions
Authors: Schneeweiss Sebastian , Göttler Martin , Hasford Joerg , Swoboda Walter , Hippius Marion , Hoffmann Anne‐Kathrin , Riethling Ann‐Katrin , Krappweis Jutta
Published: March 2003

Aims  An intensified monitoring system was set up to identify drug related hospital admissions and estimate population‐based incidences for commonly prescribed medications.

Methods  Pharmacovigilance‐centres systematically screened nonelective admissions to emergency rooms or departments of internal medicine for drug related hospitalizations (DRH). Clinical pharmacologists used standardized causality assessment. Service areas of each acute care hospital were defined by 5 digit postal codes that covered 60% of all admissions. Drug dispensing information was available through claims processed by regional pharmacy computing centres. Quarterly incidences were estimated by dividing the number of events by the number of treated patients.

Results  435 DRHs were reported during five quarters. The incidence of ADRs leading to admissions varied for specific drug groups from 1.5/10 000 treated patients to 24/10 000. Quarterly variation of incidences was moderate except for insulin and calcium antagonists. 95% confidence intervals overlap for all quarters within each group. Incidences are sensitive to changes in the definition of the source population.

Conclusions  Our pharmacovigilance monitoring system allows comparisons of population‐based incidences of drug‐related hospitalizations among drugs and over time. It provides important information for risk management and monitoring outcomes of pharmaceutical quality management programmes.
A pharmacoeconomic analysis of the impact of therapeutic drug monitoring in adult patients with generalized tonic‐clonic epilepsy
Authors: Rane C. T. , Dalvi S. S. , Gogtay N. J. , Shah P. U. , Kshirsagar N. A.
Published: March 2003

Aims  To carry out a retrospective pharmacoeconomic analysis of the impact of therapeutic drug monitoring (TDM) in adult patients with generalized tonic‐clonic epilepsy in an academic, non profit making organization.

Methods  Twenty‐five patients who had undergone TDM were compared with 25 age, disease and duration of drug therapy matched controls who had not undergone TDM. Only direct costs were calculated. These included cost to the hospital of providing the TDM service, cost to the hospital per seizure saved, and cost to the patient per seizure saved.

Results  Patients undergoing TDM had much more effective seizure control (P = 0.00032, OR 4.846, 95% confidence interval 1.29,18.3), fewer adverse events, better earning and were more likely to be married than the control group.

Conclusions  In patients with adult onset epilepsy, a minimum of two drug estimations per year offers significant benefit in terms of better seizure control, fewer adverse events and greater chances of remission.
Acute hyperhomocysteinaemia affects pulse pressure but not microvascular vasodilator function
Authors: Davis Karl R. , Pearson Helen , Moat Stuart , Bonham James R. , Donnelly Richard
Published: March 2003

Aims  Raised homocysteine (hcy) levels are associated with premature coronary artery disease, but the underlying vascular mechanism and the extent to which hcy affects small vessel vasodilator responses (especially non‐nitric oxide mediated pathways) are unclear.

Methods  This double‐blind, placebo‐controlled crossover study in 14 healthy male subjects evaluated the effects of single‐dose oral methionine 15 g (to induce acute hyperhomocysteinaemia) on cutaneous microvascular vasodilator responses to incremental‐dose iontophoretic administration of acetylcholine (Ach) and sodium nitroprusside (SNP) using laser Doppler fluximetry (LDF), and the effects on von Willibrand factor (vWF) levels and systemic haemodynamics.

Results  Methionine administration produced a three fold rise in plasma hcy levels at 8 h, which was accompanied by a significant increase in pulse pressure (53 vs 49 mmHg, P < 0.05) but no change in heart rate. Acute hyperhomocysteinaemia had no significant effect on incremental microvascular vasodilator dose–response curves to Ach and SNP, or circulating levels of vWF.

Conclusions  The present study shows that acute hyperhomocysteinaemia increases pulse pressure (a marker of large vessel stiffness) but has no effect on endothelial‐dependent (non‐NO‐mediated) microvascular vasodilation.
Association between aspirin and upper gastrointestinal complications: Systematic review of epidemiologic studies
Authors: Rodrı´guez Luis A. Garcı´a ,   Sonia Hernández‐Dı´az, De Abajo Francisco J.
Published: March 2003

Aims  Because of the widespread use of aspirin for prevention of cardiovascular diseases, side‐effects associated with thromboprophylactic doses are of interest. This study summarizes the relative risk (RR) for serious upper gastrointestinal complications (UGIC) associated with aspirin exposure in general and with specific aspirin doses and formulations in particular.

Methods  After a systematic review, 17 original epidemiologic studies published between 1990 and 2001 were selected according to predefined criteria. Heterogeneity of effects was explored. Pooled estimates were calculated according to different study characteristics and patterns of aspirin use.

Results  The overall relative risk of UGIC associated with aspirin use was 2.2 (95% confidence interval (CI): 2.1, 2.4) for cohort studies and nested case‐control studies and 3.1 (95% CI: 2.8, 3.3) for non‐nested case‐control studies. Original studies found a dose–response relationship between UGIC and aspirin, although the risk was still elevated for doses lower or up to 300 mg day−1. The summary RR was 2.6 (95% CI: 2.3, 2.9) for plain, 5.3 (95% CI: 3.0, 9.2) for buffered, and 2.4 (95% CI: 1.9, 2.9) for enteric‐coated aspirin formulations.

Conclusions  Aspirin was associated with UGIC even when used at low doses or in buffered or enteric‐coated formulations. The latter findings may be partially explained by channeling of susceptible patients to these formulations.
The promise of new antiepileptic drugs
Authors: Duncan John S.
Published: March 2003

Epilepsy is the most common serious disorder of the brain and comprises a wide range of different conditions with varying aetiologies. The long‐established antiepileptic drugs (AEDs) control seizures in 50% of patients developing partial seizures, and 60–70% of those developing generalized seizures. Several AEDs were made available in the 1990s. These drugs have efficacy, but have had only a modest impact on those with refractory epilepsies. A 50% seizure reduction, which is commonly used as an endpoint in clinical trials, confers little benefit to a patient. Of the newer AEDs, lamotrigine and oxcarbazepine are now licensed for use as monotherapy and vigabatrin has a monotherapy licence for infantile spasms. Careful and prolonged postmarketing surveillance is essential to detect adverse effects, which may not be evident in premarketing clinical trials. At this time, there are 10 AEDs currently in varying stages of clinical development. Current strategies for selecting an AED for a particular patient are crude. Magnetic resonance spectroscopic measures of cerebral neuro‐transmitters and genetic analysis may allow better prediction of which drug is most likely to be efficacious and to have low risk of adverse effects. Present AEDs suppress the occurrence of seizures. Agents that prevent the development of epilepsy and which protect the brain from the consequences of seizures would be of great value, but it will be difficult to prove their effectiveness. At present AEDs are given continually and systemically. Local drug delivery is feasible and could avoid the adverse effects of AEDs. The combination of local drug delivery with prediction of seizure occurrence could revolutionize the treatment of currently refractory epilepsies.
Extreme altitude mountaineering and Type 1 diabetes; the Diabetes Federation of Ireland Kilimanjaro Expedition
Authors: Moore K. , Vizzard N. , Coleman C. , McMahon J. , Hayes R. , Thompson C. J.
Published: March 2003

Aims To examine the effects of extreme altitude mountaineering on glycaemic control in Type 1 diabetes, and to establish whether diabetes predisposes to acute mountain sickness (AMS).

Methods  Fifteen people with Type 1 diabetes and 22 nondiabetic controls were studied during the Diabetes Federation of Ireland Expedition to Kilimanjaro. Daily insulin requirements, blood glucose estimations and hypoglycaemic attacks were recorded in diaries by the people with diabetes. The performance of blood glucose meters at altitude was assessed using standard glucose solutions. Symptoms of acute mountain sickness were recorded daily by people with diabetes and by the nondiabetic controls using the Lake Louise Scoring Charts. The expedition medical team recorded the incidence of complications of altitude and of diabetes. The final height attained for each individual was recorded by the expedition medical team and verified by the expedition guides.

Results  The final altitude ascended was lower in the diabetic than the nondiabetic group (5187 ± 514 vs. 5654 ± 307 m, P= 0.001). The mean daily insulin dose was reduced from 67.1 ± 28.3–32.9 ± 11.8 units (P < 0.001), but only 50% of recorded blood glucose readings were within the target range of 6–14 mmol/L. There were few hypoglycaemic attacks after the first two days of climbing. Both blood glucose meters tested showed readings as low as 60% of standard glucose concentrations at high altitude and low temperatures. The Lake Louise questionnaires showed that symptoms of AMS occurred equally in the diabetic and nondiabetic groups. There were two episodes of mild diabetic ketoacidosis; two of the diabetic group and three of the nondiabetic group developed retinal haemorrhages.

Conclusions  People with Type 1 diabetes can participate in extreme altitude mountaineering. However, there are significant risks associated with this activity, including hypoglycaemia, ketoacidosis and retinal haemorrhage, with the additional difficulties in assessing glycaemic control due to meter inaccuracy at high altitude. People with Type 1 diabetes must be carefully counselled before attempting extreme altitude mountaineering.

Diabet. Med. 18, 749–755 (2001)
H1‐antihistamines: inverse agonism, anti‐inflammatory actions and cardiac effects
Authors: Leurs R. , Church M. K. , Taglialatela M.
Published: March 2003

This review addresses novel concepts of histamine H1‐receptor function and attempts to relate them to the anti‐inflammatory effects of H1‐antihistamines. Furthermore, the molecular mechanisms underlying the cardiotoxic effects of H1‐antihistamines are discussed.

H1‐receptors are G‐protein‐coupled‐receptors (GPCRs), the inactive and active conformations of which coexist in equilibrium. The degree receptor activation in the absence of histamine is its ‘constitutive activity’. In this two‐state model, histamine acts as an agonist by combining with and stabilizing the activated conformation of the H1‐receptor to shift the equilibrium towards the activated state. Drugs classified previously as antagonists act as either inverse agonists or neutral antagonists. Inverse agonists combine with and stabilize the inactive conformation of the receptor to shift the equilibrium towards the inactive state. Thus, they may down‐regulate constitutive receptor activity, even in the absence of histamine. Neutral antagonists combine equally with both conformations of the receptor, do not affect basal receptor activity but do interfere with agonist binding. All H1‐antihistamines examined to date are inverse agonists. As the term ‘H1‐receptor antagonists’ is obviously erroneous, we suggest that it be replaced by ‘H1‐antihistamines’.

The observations that H1‐receptors modulate NF‐κB activation and that there are complex interactions between GPCRs, has allowed us to postulate receptor dependent‐mechanisms for some anti‐inflammatory effects of H1‐antihistamines, e.g. inhibition of ICAM‐1 expression and the effects of bradykinin.

Finally, the finding that blockade of HERG1 K+ channels is the mechanism by which some H1‐antihistamines may cause cardiac arrhythmias has allowed the development of preclinical tests to predict such activity.
Lactobacillus casei strain Shirota suppresses serum immunoglobulin E and immunoglobulin G1 responses and systemic anaphylaxis in a food allergy model
Authors: Shida K. , Takahashi R. , Iwadate E. , Takamizawa K. , Yasui H. , Sato T. , Habu S. , Hachimura S. , Kaminogawa S.
Published: March 2003

Background  Our previous study using allergen‐sensitized murine splenocyte cultures has shown that Lactobacillus casei strain Shirota (LcS), a lactic acid bacterium widely used as a starter for fermented milk products, suppresses IgE production through promoting a dominant Th1‐type response mediated by IL‐12 induction.

Objective  We tried to evaluate the ability of LcS to suppress both IgE response and allergic reactions in vivo using a food allergy model with ovalbumin‐specific T cell receptor transgenic (OVA‐TCR‐Tg) mice.

Methods  The ability of heat‐killed LcS to induce IL‐12 in serum was tested. OVA‐TCR‐Tg mice were fed a diet containing OVA for 4 weeks and injected with LcS intraperitoneally three times in the first week of this period. Cytokine and antibody secretion by splenocytes, and serum IgE and IgG1 responses were examined. The inhibitory effect of LcS on systemic anaphylaxis induced by intravenous challenge of OVA‐fed OVA‐TCR‐Tg mice with OVA was also tested.

Results  Intraperitoneal injection of LcS induced an IL‐12 response in the serum of OVA‐TCR‐Tg mice. In the food allergy model, LcS administration skewed the pattern of cytokine production by splenocytes toward Th1 dominance, and suppressed IgE and IgG1 secretion by splenocytes. The ability of LcS to modulate cytokine production was blocked by anti‐IL‐12 antibody treatment. LcS also inhibited serum OVA‐specific IgE and IgG1 responses and diminished systemic anaphylaxis.

Conclusion  LcS administration suppresses IgE and IgG1 responses and systemic allergic reactions in a food allergy model, suggesting a possible use of this lactic acid bacterium in preventing food allergy.
Minor H antigens: genes and peptides
Authors: Simpson E. , Scott D. , James E. , Lombardi G. , Cwynarski K. , Dazzi F. , Millrain M. , Dyson P. J.
Published: March 2003

In this review, we describe the evidence from which the existence of non‐MHC histocompatibility (H) antigens was deduced, the clinical setting of bone marrow transplantation in which they are important targets for T‐cell responses, and the current understanding of their molecular identity. We list the peptide epitopes of the human and murine minor H antigens now identified at the molecular level, their MHC restriction molecules and the genes encoding them. Identification of the peptide epitopes allows T‐cell responses to these antigens following transplantation of MHC‐matched, minor H‐mismatched tissues to be enumerated using tetramers and elispot assays. This will facilitate analysis of correlations with host‐versus‐graft (HVG), graft‐versus‐host (GVH) and graft‐versus‐leukaemia (GVL) reactions in vivo. The potential to use minor H peptides to modulate in vivo responses to minor H antigens is discussed. Factors controlling immunodominance of T‐cell responses to one or a few of many potential minor H antigens remain to be elucidated but are important for making predictions of in vivo HVG, GVH and GVL responses and tailoring therapy after HLA‐matched bone marrow transplantation and donor lymphocyte infusion.
The HLA Dictionary 2001: a summary of HLA‐A, ‐B, ‐C, ‐DRB1/3/4/5 and ‐DQB1 alleles and their association with serologically defined HLA‐A, ‐B, ‐C, ‐DR and ‐DQ antigens
Authors: Schreuder G. M. Th. , Hurley C. K. , Marsh S. G. E. , Lau M. , Maiers M. , Kollman C. , Noreen H. J.
Published: March 2003

This report presents the serological equivalents of 123 HLA‐A, 272 HLA‐B and 155 HLA‐DRB1 alleles. The equivalents cover over 64% of the presently identified HLA‐A, ‐B and ‐DRB1 alleles. The dictionary is an update of the one published in 1999 (<1>Schreuder et al., 1999, Tissue Antigens, 54, 409) and also includes equivalents for HLA‐C, DRB3, DRB4, DRB5 and DQB1 alleles. The data summarize information obtained by the WHO Nomenclature Committee for Factors of the HLA System, the International Cell Exchange (UCLA), the National Marrow Donor Program (NMDP) and individual laboratories. In addition, a listing is provided of alleles that are expressed as antigens with serological reaction patterns that differ from the well‐established HLA specificities. The equivalents provided will be useful in guiding searches for unrelated hematopoietic stem cell donors in which patients and/or potential donors are typed by either serology or DNA‐based methods. These equivalents will also serve typing and matching procedures for organ transplant programmes where HLA typings from donors and from recipients on waiting lists represent mixtures of serological and molecular typings. The tables with HLA equivalents and a questionnaire for submission of serological reaction patterns for poorly identified allelic products will also be available on the WMDA web page: www.worldmarrow.org
The efficacy of intracervical lidocaine in outpatient hysteroscopy
Authors: Esteve Marcelo , Schindler Sandra , Borges Machado Simone , Argollo Borges Silvana , Ramos Santos Claudia , Coutinho Elsimar
Published: March 2003

Objective Diagnostic hysteroscopy today is a fast procedure carried out on an outpatient basis but which still causes a certain degree of discomfort to patients. This randomized, double‐blind study in which lidocaine is compared to a placebo was designed to evaluate the efficacy of intracervical anaesthesia during this procedure.

Design Patients were allocated into two groups: group I consisting of 34 patients who were given lidocaine and group II consisting of 28 patients who were given a saline solution. Both groups of patients were asked to quantify their pain at four different times: T1, during hysteroscopy; T2, during the biopsy; T3, at the end of the procedure, and T4, 30 min after the end of the procedure.

Results During hysteroscopy (T1) there was a statistically significant difference between the two groups (a median of 2.5 cm vs. a median of 5.0 cm). There was no statistically significant difference between the two groups at T2, T3 or T4.

Conclusions These results suggest that intracervical anaesthesia can reduce cervical sensitivity, as shown by the difference found between the two groups at T1, but is insufficient to block the uterine stimuli resulting from distension and manipulation of the uterine cavity.
RURAL TRAINING AND THE STATE OF RURAL HEALTH SERVICES: EFFECT OF RURAL BACKGROUND ON THE PERCEPTION AND ATTITUDE OF FIRST‐YEAR MEDICAL STUDENTS AT THE UNIVERSITY OF MELBOURNE
Authors: Azer Samy A. , Simmons David , Elliott Susan L.
Published: March 2003

The aim of this project is to investigate the relationship between medical students’ background and their perception of the state of rural health services; willingness to undertake internship training or work as a doctor in a rural hospital; expected benefits and disadvantages of training or working as a doctor in a rural hospital; and factors interfering with acceptance of a job as a doctor in rural areas. A questionnaire‐based survey was distributed to 100 first‐year medical students attending the Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne at the end of semester 1. The response rate was 97%, including 44 males and 53 females. A strong relationship was found between rural background and an intention to undertake internship training in a rural hospital (86% of students from a rural background expressed this desire vs 30% of students from an urban background). Furthermore, all students from a rural background expressed a desire to work as a doctor in a rural hospital after completing postgraduate training. Compared to urban students, students from a rural background showed a more positive attitude towards health services in rural areas including public hospitals ( P= 0.02), private general practice (

P= 0.004), ambulance service (

P= 0.0002) and baby health centres (

P= 0.005). Citizenship or gender was not significantly related to the perception of any of these services. The ranking of factors interfering with acceptance of a job as a doctor in rural areas were different for rural and urban students. Students from rural backgrounds reported spouse/partner needs (76% vs 49%,

P= 0.038) and school availability for children (59% vs 30%,

P= 0.023) as barriers more frequently than urban students, respectively). On the other hand, urban students rated the following factors higher: personal factors (76% vs 53%, respectively), education opportunities (56% vs 24%), social/cultural facilities (50% vs 41%) and the need for frequent travel (29% vs 12%). None of these interfering factors were significantly different. Urban students were more likely than rural students to report that their views were a result of adverse media reports. In conclusion, students from a rural background were more willing to be trained or to work as doctors in rural areas. This was associated with a greater adverse influence by the media upon students.