bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

Summarybackground 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

Summaryobjective 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.
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

AbstractAims 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

SummaryThis 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

SummaryBackground  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

SummaryIn 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.