bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prescribing pattern of anti‐epileptic drugs in an Italian setting of elderly outpatients: a population‐based study during 2004–07
Authors: Oteri Alessandro , Trifirò Gianluca , Gagliostro Maria Silvia , Tari Daniele Ugo , Moretti Salvatore , Bramanti Placido , Spina Edoardo , Caputi Achille Patrizio , Arcoraci Vincenzo 
Published: January 2010

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• In the last years there has been a growing trend in anti‐epileptic drug (AED) use, particularly in elderly patients, but few data concerning indication of use are available in general practice.• Various AEDs, including newer agents, have been approved for indications other than epilepsy and are increasingly also used for unlicensed indications.• No data about the impact of re‐imbursement restrictions on the choice of anti‐epileptic drugs in general practice are available.WHAT THIS STUDY ADDS• In general practice, a rapid increase of AED prescriptions in the elderly was observed, principally due to the use of newer AEDs for indications other than epilepsy.• Re‐imbursement restrictions influenced newer AED use, particularly pregabalin and gabapentin prescriptions.• Phenobarbital, accounting for more than 50% of total AED volume, was the most prescribed medication during the entire study period. This finding should be considered in light of the potential risks associated with phenobarbital use in the geriatric population.AIMSThe aims of the study were to assess the trend of older and newer anti‐epileptic drugs (AEDs) in the elderly population and to analyze the effects of a health‐policy intervention with regard to AED use in general practice in a setting in Southern Italy.METHODSData were extracted from the ‘Caserta‐1’ Local‐Health‐Unit Arianna database in the years 2004–07. Patients aged over 65 years, receiving at least one AED prescription and registered in the lists of 88 general practitioners, were selected. The use of older and newer AEDs was calculated as 1 year prevalence and incidence of use and defined daily dose (DDD) per 1000 inhabitants day−1. Sub‐analyses by gender, age and indication of use were performed.RESULTSMost of AED users were treated because of neuropathic pain (64.8%). However, the main indication of use for older AEDs (57.8%) was epilepsy, whereas newer AEDs (79.5%) were used for neuropathic pain. Prevalence and incidence of newer AED use increased until 2006, followed by a reduction in 2007. Newer AEDs, particularly gabapentin and pregabalin, were used in the treatment of more patients than older AEDs. However phenobarbital, accounting for more than 50% of total AED volume, was the most prescribed medication during the entire study period.CONCLUSIONSAn increasing use of AEDs has been observed during 2004–07, mostly due to the prescription of newer compounds for neuropathic pain. The fall in the use of newer AEDs during 2007 coincides with revised re‐imbursement criteria for gabapentin and pregabalin. The large use of phenobarbital in the elderly should be considered in the light of a risk of adverse drug reactions.
Population pharmacokinetics of intravenously and orally administered docetaxel with or without co‐administration of ritonavir in patients with advanced cancer
Authors: Koolen Stijn L. W. , Oostendorp Roos L. , Beijnen Jos H. , Schellens Jan H. M. , Huitema Alwin D. R. 
Published: January 2010

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Docetaxel is an approved drug for the treatment of cancer of various primary origins.• An oral docetaxel regimen is warranted because of patient convenience and the opportunity to investigate more schedule intensive treatment regimens.• Co‐administration of ritonavir significantly enhanced the apparent oral bioavailability of docetaxel. WHAT THIS STUDY ADDS • This study demonstrates that ritonavir increased the absorption of docetaxel after oral administration.• Furthermore, we showed that the clearance of docetaxel was inhibited in a concentration dependent manner.• The developed model will be used for further development of an oral docetaxel regimen.AIM Docetaxel has a low oral bioavailability due to affinity for P‐glycoprotein and cytochrome P450 (CYP) 3A4 enzymes. Inhibition of the CYP3A4 enzymes by ritonavir resulted in increased oral bioavailability. The aim of this study was to develop a population pharmacokinetic (PK) model and to evaluate and quantify the influence of ritonavir on the PK of docetaxel.METHODS Data from two clinical trials were included in the data analysis, in which docetaxel (75 mg m−2 or 100 mg) had been administered intravenously or orally (10 mg or 100 mg) with or without co‐administration of oral ritonavir (100 mg). Population modelling was performed using non‐linear mixed effects modelling. A three‐compartment model was used to describe the i.v. data. PK data after oral administration, with or without co‐administration of ritonavir, were incorporated into the model.RESULTS Gut bioavailability of docetaxel increased approximately two‐fold from 19 to 39% (CV 13%) with ritonavir co‐administration. The hepatic extraction ratio and the elimination rate of docetaxel were best described by estimating the intrinsic clearance. Ritonavir was found to inhibit in a concentration dependent manner the intrinsic clearance of docetaxel, which was described by an inhibition constant of 0.028 µg ml−1 (CV 36%). A maximum inhibition of docetaxel clearance of more then 90% was reached.CONCLUSIONS A PK model describing both the PK of orally and intravenously administered docetaxel in combination with ritonavir, was successfully developed. Co‐administration of ritonavir lead to increased oral absorption and reduced elimination rate of docetaxel.
Risk of diarrhoea in a long‐term cohort of renal transplant patients given mycophenolate mofetil: the significant role of the UGT1A8*2 variant allele
Authors: Woillard Jean‐Baptiste , Rerolle Jean‐Philippe , Picard Nicolas , Rousseau Annick , Drouet Mireille , Munteanu Eliza , Essig Marie , Marquet Pierre , Le Meur Yann 
Published: January 2010

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Mycophenolate mofetil (MMF), the most widely used drug in allograft transplantation, is subject to hepatic and intestinal glucuronidation and entero‐hepatic cycling.• Diarrhoea is its most frequent adverse event leading to non‐compliance, treatment interruption and ultimately to an increased rate of acute rejection.• Cyclosporin reduces the biliary excretion of mycophenolate metabolites, presumably by inhibiting the efflux transporter MRP2.• When combined with MMF, cyclosporin reduces the incidence of diarrhoea, suggesting the role played by biliary excretion of mycophenolate glucuronides in this adverse event. WHAT THIS STUDY ADDS • In a long‐term cohort of renal transplant patients on MMF, the two factors significantly associated with a reduced incidence of diarrhoea were the co‐medication with cyclosporin (as opposed to tacrolimus or sirolimus) and the *2 variant allele of the intestinal UGT1A8.• Polymorphisms in the other UDP‐glucuronosyl‐transferases and MRP2 were not significant.AIM In renal transplant patients given mycophenolate mofetil (MMF), we investigated the relationship between the digestive adverse events and polymorphisms in the UGT genes involved in mycophenolic acid (MPA) intestinal metabolism and biliary excretion of its phase II metabolites.METHODS Clinical data and DNA from 256 patients transplanted between 1996 and 2006 and given MMF with cyclosporin (CsA, n = 185), tacrolimus (TAC, n = 49) or sirolimus (SIR, n = 22), were retrospectively analysed. The relationships between diarrhoea and polymorphisms in UGT1A8 (*2; 518C>G, *3; 830G>A), UGT1A7 (622C>T), UGT1A9 (−275T>A), UGT2B7 (−840G>A) and ABCC2 (−24C>T, 3972C>T) or the co‐administered immunosuppressant were investigated using the Cox proportional hazard model.RESULTS Multivariate analysis showed that patients on TAC or SIR had a 2.8 higher risk of diarrhoea than patients on CsA (HR = 2.809; 95%CI (1.730, 4.545); P < 0.0001) and that non‐carriers of the UGT1A8*2 allele (CC518 genotype) had a higher risk of diarrhoea than carriers (C518G and 518GG genotypes) (HR = 1.876; 95%CI (1.109, 3.175); P = 0.0192). When patients were divided according to the immunosuppressive co‐treatment, a significant effect of UGT1A8*2 was found in those co‐treated with CsA (HR = 2.414; 95%CI (1.089, 5.354); P = 0.0301) but not TAC or SIR (P = 0.4331).CONCLUSION These results suggest that a possible inhibition of biliary excretion of MPA metabolites by CsA and a decreased intestinal production of these metabolites in UGT1A8*2 carriers may be protective factors against MMF‐induced diarrhoea.
Current dosing of low‐molecular‐weight heparins does not reflect licensed product labels: an international survey
Authors: Barras Michael A. , Kirkpatrick Carl M. J. , Green Bruce 
Published: January 2010

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Low‐molecular‐weight heparins (LMWHs) are effective anti‐coagulants for the treatment of thromboembolic diseases.• LMWHs are hydrophilic drugs with clearance related to lean body weight and renal function.• Poor subject outcomes are linked to the inadequate dosing of LMWHs. WHAT THIS STUDY ADDS • Minimal adherence to the product label occured when dosing LMWHs.• Hospitals preferred to dose‐individualize using a variety of methods that included dose‐capping, post‐dose monitoring of anti‐Xa activity and the use of lean body size descriptors to calculate a starting dose and renal function.AIMS Low‐molecular‐weight heparins (LMWHs) are used globally to treat thromboembolic diseases; however, there is much debate on how to prescribe effectively for patients who have renal impairment and/or obesity. We aimed to investigate the strategies used to dose‐individualize LMWH therapy.METHODS We conducted an online survey of selected hospitals in Australia, New Zealand (NZ), United Kingdom (UK) and the United States (US). Outcome measures included: the percentage of hospitals which recommended that LMWHs were prescribed according to the product label (PL), the percentage of hospitals that dose‐individualized LMWHs outside the PL based on renal function, body weight and anti‐Xa activity and a summary of methods used to dose‐individualize therapy.RESULTS A total of 257 surveys were suitable for analysis: 84 (33%) from Australia, 79 (31%) from the UK, 73 (28%) from the US and 21 (8%) from NZ. Formal dosing protocols were used in 207 (81%) hospitals, of which 198 (96%) did not adhere to the PL. Of these 198 hospitals, 175 (87%) preferred to dose‐individualize based on renal function, 128 (62%) on body weight and 48 (23%) by monitoring anti‐Xa activity. All three of these variables were used in 29 (14%) hospitals, 98 (47%) used two variables and 71 (34%) used only one variable.CONCLUSIONS Dose‐individualization strategies for LMWHs, which contravene the PL, were present in 96% of surveyed hospitals. Common individualization methods included dose‐capping, use of lean body size descriptors to calculate renal function and the starting dose, followed by post dose anti‐Xa monitoring.
A facultative mutualism between aphids and an invasive ant increases plant reproduction
Authors: STYRSKY JOHN D. , EUBANKS MICKY D. 
Published: January 2010

1. The consequences to plants of ant–aphid mutualisms, particularly those involving invasive ants, are poorly studied. Ant–aphid mutualisms may increase or decrease plant fitness depending on the relative cost of herbivory by ant‐tended aphids versus the relative benefit of increased ant suppression of other (non‐aphid) herbivores.2. We conducted field and greenhouse experiments in which we manipulated the presence and absence of cotton aphids (Aphis gossypii) on cotton plants to test the hypothesis that a mutualism between cotton aphids and an invasive ant, the red imported fire ant (Solenopsis invicta), benefits cotton plants by increasing fire ant suppression of caterpillars. We also manipulated caterpillar abundance to test whether the benefit of the mutualism varied with caterpillar density.3. We found that more fire ants foraged on plants with cotton aphids than on plants without cotton aphids, which resulted in a significant reduction in caterpillar survival and caterpillar herbivory of leaves, flower buds, and bolls on plants with aphids. Consequently, cotton aphids indirectly increased cotton reproduction: plants with cotton aphids produced 16% more bolls, 25% more seeds, and 10% greater seedcotton mass than plants without aphids. The indirect benefit of cotton aphids, however, varied with caterpillar density: the number of bolls per plant at harvest was 32% greater on plants with aphids than on plants without aphids at high caterpillar density, versus just 3% greater at low caterpillar density.4. Our results highlight the potential benefit to plants that host ant–hemipteran mutualisms and provide the first experimental evidence that the consequences to plants of an ant–aphid mutualism vary at different densities of non‐aphid herbivores.
Isolation from a marching band increases haemocyte density in wild locusts (Chortoicetes terminifera)
Authors: MILLER GABRIEL A. , SIMPSON STEPHEN J. 
Published: January 2010

1. The density‐dependent prophylaxis hypothesis predicts that individuals in high‐density populations will invest more resources in immune defence than individuals at lower densities.2. However, recent work suggests that this prediction may not apply to all situations; solitarious species may paradoxically have higher scores than crowded counterparts in certain immune assays.3. To investigate the relationship between a key immune parameter and field population densities, the total haemocyte counts (THCs) of Australian plague locusts (Chortoicetes terminifera) from three population densities in Western Australia were compared.4. THCs were negatively correlated with field population densities, and locusts removed from a marching band and kept in isolation had increased THCs relative to group‐housed controls.5. These results demonstrate that immune investment can inversely relate to population density in field conditions.6. We suggest that isolated locusts increase their haemocyte densities relative to crowded conspecifics in response to potentially greater exposure to parasitoids and nematodes.
Diverse diet compositions among harpaline ground beetle species revealed by mixing model analyses of stable isotope ratios
Authors: IKEDA HIROSHI , KUBOTA KOHEI , KAGAWA AKIRA , SOTA TEIJI 
Published: January 2010

1. Species diversities of some insect lineages have been attributed to differentiation of feeding habits among species. Our objective was to determine variation in diet composition among harpaline ground beetle species occurring in a riverside grassland.2. We examined the diet compositions of 14 species from six genera in the spring and 10 species from two genera in the autumn. We performed measurements of nitrogen and carbon stable isotope ratios in consumers and in their potential food items, and estimated relative contributions of different food items with two mixing models, IsoSource and MixSIR.3. IsoSource and MixSIR software gave similar results, but IsoSource tended to calculate higher contributions of principal food items and smaller percentile ranges than MixSIR. Among harparine beetle species, there were diverse food utilisation patterns among four food categories (detritivorous invertebrates, herbivorous invertebrates, C3 plants, and C4 plants). Detritivores comprised the main diets of abundant harpaline species in the spring, whereas abundant harpaline species in the autumn were primarily herbivores feeding on C4 plants, or omnivores feeding on herbivorous invertebrates and C3 plants. Seasonal changes in food use were related to seasonal changes in the abundance of each food resource.4. Mixing model analysis of stable isotope ratios is a convenient and effective method for roughly estimating diets of many species with diverse food habits (such as ground beetles). This method can contribute to determining the trophic relationships of related insects in one ecosystem.
Temporal gene expression profiles in a palaearctic springtail as induced by desiccation, cold exposure and during recovery
Authors: Sørensen Jesper G. , Heckmann Lars‐Henrik , Holmstrup Martin 
Published: January 2010

Summary 1. Cryoprotective dehydration is a cold tolerance strategy used by small permeable invertebrates overwintering in frozen habitats. Even though an increasing number of species using this strategy have been described, little is known of the functional genomics of cryoprotective dehydration. 2. Megaphorura arctica is a northern palaearctic springtail (Collembola) which survives extreme low temperatures by cryoprotective dehydration. The massive loss of body water associated with this strategy requires a fine tuned physiological adaptation to both desiccation and cold exposure. 3. We investigated the temporal gene expression profile of six candidate genes, and compared gene expression responses to desiccation and cold separately, as well as both factors combined. 4. The major responses were found in Heat shock protein 70 (HSP70) and Trehalose‐6‐Phosphate‐Synthase (TPS). TPS expression followed water loss closely, while HSP70 was induced after considerable water loss. HSP70 transcript response in M. arctica was induced by desiccation and rehydration, but not by exposure to cold. 5. The data suggest that cold and water loss induce partly different responses and that temporal sampling is important for uncovering the dynamics of gene responses to cryoprotective dehydration.
Consequences of ‘load‐lightening’ for future indirect fitness gains by helpers in a cooperatively breeding bird
Authors: Meade Jessica , Nam Ki‐Baek , Beckerman Andrew P. , Hatchwell Ben J. 
Published: January 2010

Summary 1. Helpers that invest energy in provisioning the offspring of related individuals stand to gain indirect fitness benefits from doing so. First, if the helper’s effort is additional to that of the parents (additive) the productivity of the current breeding attempt can be increased. Secondly, if the parents reduce their workload (compensation) this can result in future indirect fitness gains to the helper via increased breeder survival; termed ‘load‐lightening’. 2. Long‐tailed tits (Aegithalos caudatus) have a cooperative breeding system in which helpers assist kin and parents exhibit both additive and compensatory reactions in the presence of helpers. Offspring from helped nests are heavier and more likely to recruit into the breeding population, thus helpers gain indirect fitness benefits from increasing the productivity of the current breeding attempt. Despite breeders’ reduction of feeding effort in the presence of helpers, previous investigations found no subsequent increase in breeder survival. 3. The aim of this study was to test the hypothesis that load‐lightening resulted in indirect fitness benefits for helpers. We used data from a 14‐year study to investigate the provisioning rate, survival and future fecundity of male and female long‐tailed tits that did and did not receive help at the nest. 4. We found an asymmetrical response to the presence of helpers at large brood sizes. Males reduced their feeding rate more than females, and this differential response was reflected in a significant increase in male survival when provisioning large broods assisted by helpers. We found no evidence of any increase in future fecundity for helped breeders. 5. The finding that males reduce their provisioning rate in the presence of helpers (at large brood sizes) to a greater degree than females, and that this is reflected in an increase in survival rate for males only, implies that the survival increase is caused by the reduction in work‐rate rather than a non‐specific benefit of a larger group size. 6. The marginal benefits of help for breeder survival are likely to be more difficult to identify than the increased productivity at helped nests, but should not be overlooked when investigating the potential indirect fitness gains that supernumeraries can accrue by helping.
Modulation of host innate and adaptive immune defenses by cytomegalovirus: timing is everything
Authors: Loewendorf A. , Benedict C. A. 
Published: January 2010

Abstract.  Loewendorf A, Benedict CA (La Jolla Institute for Allergy and Immunology, La Jolla, CA, USA). Modulation of host innate and adaptive immune defenses by cytomegalovirus: timing is everything (Symposium). J Intern Med 2010; 267: 483–501.Human cytomegalovirus (HCMV) (HHV‐5, a β‐herpesvirus) causes the vast majority of infection‐related congenital birth defects, and can trigger severe disease in immune suppressed individuals. The high prevalence of societal infection, the establishment of lifelong persistence and the growing number of immune‐related diseases where HCMV is touted as a potential promoter is slowly heightening public awareness to this virus. The millions of years of co‐evolution between CMV and the immune system of its host provides for a unique opportunity to study immune defense strategies, and pathogen counterstrategies. Dissecting the timing of the cellular and molecular processes that regulate innate and adaptive immunity to this persistent virus has revealed a complex defense network that is shaped by CMV immune modulation, resulting in a finely tuned host–pathogen relationship.
Cytokine production from sputum cells and blood leukocytes in asthmatics according to disease severity
Authors: Manise M. , Schleich F. , Gusbin N. , Godinas L. , Henket M. , Antoine N. , Corhay J. L. , Louis R. 
Published: January 2010

To cite this article: Manise M, Schleich F, Gusbin N, Godinas L, Henket M, Antoine N, Corhay JL, Louis R. Cytokine production from sputum cells and blood leukocytes in asthmatics according to disease severity. Allergy 2010; 65: 889–896.AbstractBackground:  Although mild to moderate asthma is known to be Th2 driven, cytokines produced in refractory asthma might not fit the classical Th2 pattern.Methods:  The aim of our study was to assess the cytokine production by sputum and blood cells from 15 refractory asthmatics (American Thoracic Society Criteria) compared to 15 mild untreated and 17 moderate treated asthmatics and 22 healthy subjects. Spontaneous production of interleukin (IL)‐4, IL‐6, IL‐10, interferon‐γ, and tumor necrosis factor α was measured by immunotrapping after 24 h sputum or blood cell culture.Results:  Moderate and refractory asthmatics were both characterized by a lower production of IL‐6 from their airway cells compared to healthy subjects. However, the difference was no longer significant when expressing the results per gram of sputum. No significant difference between the three groups was found regarding other cytokines. As for cytokine production from blood, the three groups of asthmatics exhibited raised production of IL‐4 when compared to healthy subjects, and this was true when results were expressed per blood volume or after normalization for total leukocyte cell count. Moderate asthmatics exhibited greater production of IL‐10 when compared to refractory asthmatics and healthy subjects when results were normalized for total leukocyte cell count.Conclusions:  Sputum cells from moderate and refractory asthmatics release less IL‐6. While the systemic overproduction of IL‐4 was observed through the all spectrum of asthma severity, moderate asthmatics exhibited greater systemic IL‐10 production compared to refractory asthmatics.