bluuebunny/crossref_metadata_2025_split huggingface dataset:
Fluid–particle dynamics in canalithiasis
Authors: Obrist Dominik , Hegemann Stefan 
Published: March 2008

The semicircular canals (SCCs; located in the inner ear) are the primary sensors for angular motion. Angular head movements induce a fluid flow in the SCCs. This flow is detected by afferent hair cells inside the SCCs. Canalithiasis is a condition where small particles disturb this flow, which leads to benign paroxysmal positional vertigo (top-shelf vertigo).The present work investigates the interaction between the fluid flow and the particles on the basis of an idealized analytical model. Numerical solutions of the full model and a thorough analytical study of the linearized model reveal the principal mechanisms of canalithiasis. We propose a set of dimensionless numbers to characterize canalithiasis and derive explicit expressions connecting these dimensionless numbers directly to the typical clinical symptoms.
Measurement of tracheal wall pressure: a comparison of three different in vitro techniques
Authors: Horisberger T. , Gerber S. , Bernet V. , Weiss M. 
Published: March 2008

SummaryWe compared three different tracheal wall pressure measuring techniques in vitro. Using a high‐volume, low‐pressure, cuffed tracheal tube with an internal diameter of 7.5 mm and a model trachea, the pressure difference technique, the wall pressure membrane technique and the microchip sensor probe technique with and without lubrication were studied. Wall pressures were measured after sequential injections of 0.5 ml of air into the cuff at cuff pressures ranging from 0 to 50 mmHg. The coefficient of variance was largest for the microchip sensor probe technique with lubrication (29%) and without lubrication (214%), and was lower for the wall pressure membrane technique (22%) and the pressure difference technique (19%). The wall pressure membrane and pressure difference techniques provided comparable results. The microchip sensor probe technique considerably underestimated wall pressure. These findings have an impact on the interpretation of published data on tracheal or pharyngeal wall pressure using the microchip sensor probe technique.
Influence of the CYP2D6*4 polymorphism on dose, switching and discontinuation of antidepressants
Authors: Bijl Monique J. , Visser Loes E. , Hofman Albert , Vulto Arnold G. , Van Gelder Teun , Stricker Bruno H. Ch. , Van Schaik Ron H. N. 
Published: March 2008

What is already known about this subject • Most antidepressants are metabolized by CYP2D6. The variant allele CYP2D6*4 is the main polymorphism resulting in reduced enzyme activity in Caucasians.• Reduced enzyme activity potentially leads to increased toxicity of antidepressants, but the relevance of genotyping for clinical practice is unclear. Most clinical studies suffer from small numbers of patients. What this study adds • This large population‐based cohort study in 1198 elderly Dutch patients examines the influence of the CYP2D6*4 polymorphism on intolerability of antidepressants.• The risk of switching to another antidepressant in tricyclic antidepressant users is higher in poor metabolizers (PMs), but not in SSRI users. PMs require a lower maintenance dose of antidepressants compared with extensive metabolizers (EMs).• Antidepressants were initiated in a relatively low dose, with gradual dose increments thereafter, reducing the risk of adverse drug reactions. Therefore, the question remains whether genotyping prior to the start of antidepressant therapy contributes substantially to the optimization of pharmacotherapy.AimsTo study the effect of CYP2D6*4 on antidepressant dose, switching and discontinuation of therapy.MethodsThe study consisted of all subjects in the Rotterdam Study, who received a first antidepressant prescription between April 1st 1991 and July 1st 2005 and for whom data on CYP2D6 genotype were available. Binary logistic regression was performed to study the association between CYP2D6*4 and switching to any other antidepressant or discontinuation of therapy within 45 days. The difference in mean antidepressant dose was compared between CYP2D6 genotypes using t‐tests and repeated measurements analyses.ResultsIn users of tricyclic antidepressants (TCAs) the risk of switching to another antidepressant was significantly higher in poor metabolizers (PMs:*4/*4) compared with extensive metabolizers (EMs:*1/*1), with an adjusted OR of 5.77 (95% CI 1.59, 21.03; P = 0.01). In SSRI users there was no significant difference (OR 0.91; 95% CI 0.20, 4.15; P = 0.90). Heterozygous patients did not have an increased risk of switching in both TCA and SSRI users. The mean TCA dose was significantly lower in PMs than in EMs at the third and fourth prescription (difference 0.11 DDD, P = 0.03). In SSRI users the difference in mean dose between PMs and EMs was significant at the third prescription (0.17 DDD; P = 0.02).ConclusionsThe risk of switching to another antidepressant in TCA users is higher in PMs than in EMs. The maintenance doses of antidepressants were significantly lower in PMs. However, the question whether genotyping prior to the start of antidepressant therapy contributes substantially to the optimization of pharmacotherapy, requires further study.
Determinants of chronic benzodiazepine use in the elderly: A longitudinal study
Authors: Luijendijk Hendrika J. , Tiemeier Henning , Hofman Albert , Heeringa Jan , Stricker Bruno H. Ch. 
Published: March 2008

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • The risk of adverse events due to chronic benzodiazepine use is high in the elderly.• Cross‐sectional studies have shown that increasing age, female gender and poor physical and mental health are associated with benzodiazepine use.• When users were re‐examined some years later, chronic somatic disease, pain and stress seemed to contribute to the continuation of benzodiazepine use. WHAT THIS STUDY ADDS • This is the first longitudinal study that analyzed the determinants of new‐onset chronic benzodiazepine use in community‐dwelling elderly.• Symptoms of depression, hypertension, pain related joint complaints and the perception of poor physical health predicted new‐onset chronic use. Living alone was found to decrease the risk of chronic use.AIMSThe risk of adverse events due to chronic benzodiazepine use is high in the elderly. Clinicians need to be able to identify those persons who are at risk of chronic benzodiazepine use, but little is known about the determinants. This study determined social and health related factors that predict new‐onset chronic benzodiazepine use in community‐dwelling elderly.METHODSThis study was embedded in an ongoing cohort study among 5364 persons aged ≥57 years. Drug‐dispensing medication records were available for the period between 1991 and 2003. We defined chronic benzodiazepine use as use during at least 180 days in a period of 365 consecutive days. The association of various social, psychiatric and somatic variables with new‐onset chronic benzodiazepine use was studied with a Cox proportional hazards analysis.RESULTSSymptoms of depression, hypertension, pain related joint complaints and the perception of poor physical health predicted new‐onset chronic use. In the subsample of participants who had filled at least one prescription in the follow‐up period, of these variables only pain related joint complaints increased the risk of new‐onset chronic use. Living alone protected against chronic benzodiazepine use.CONCLUSIONSThe elderly with poor mental and physical health are at an increased risk of chronic benzodiazepine use. Living alone was found to decrease the risk of chronic use, which suggests that social factors may determine drug usage patterns. Very few characteristics predicted chronic benzodiazepine use once patients had received their first prescription. For clinicians, identification of patients at high risk is therefore not straightforward.
Incidence of fatal adverse drug reactions: a population based study
Authors: Wester Karin , Jönsson Anna K. , Spigset Olav , Druid Henrik , Hägg Staffan 
Published: March 2008

What is already known about this subject • Although drugs generally are safe and effective therapies for numerous diseases, adverse drug reactions do occur and may even be fatal.• The incidence of fatal adverse drug reactions in hospitalized patients has been estimated to be approximately 5%.• In previous studies the incidence of fatal adverse drug reactions in hospitalized patients has been reported, but the incidence of fatal adverse drug reactions in the general population is largely unknown. What this study adds • Fatal adverse drug reactions account for approximately 3% of all deaths in the general population.• Haemorrhages amount to almost two‐thirds of the fatal adverse drug reactions and antithrombotic agents are implicated in more than half of the suspected fatal adverse drug reactions.• Fatal adverse drug reactions are estimated to be the seventh most common cause of death in Sweden.AimsTo determine the incidence of fatal adverse drug reactions (FADRs) in a Swedish population.MethodsEvery seventh randomly selected deceased in three counties in South‐east Sweden during 1 January 2001–31 December 2001 was identified in the Cause of Death Register. Relevant case records (hospitals and/or primary care centres and medicolegal files) were reviewed to identify suspected drug‐related fatalities.ResultsOf 1574 deceased study subjects, 49 (3.1%; 95% CI 2.2%, 4.0%) were suspected to have died from FADRs. The most common suspected FADRs were gastrointestinal haemorrhages (n = 18; 37%), central nervous system haemorrhages (n = 14; 29%), cardiovascular disorders (n = 5; 10%), other haemorrhages (n = 4; 8%) and renal dysfunction (n = 3; 6%). The drugs most commonly implicated in FADRs were antithrombotic drugs (n = 31; 63%), followed by nonsteroidal anti‐inflammatory drugs (NSAIDs) (n = 9; 18%), antidepressants (n = 7; 14%) and cardiovascular drugs (n = 4; 8%). Of all the 639 fatalities in hospital 41 (6.4%; 95% CI 4.5%, 8.3%) were suspected to be due to FADRs.ConclusionsThe medical burden of FADRs is significant. Haemorrhages were seen in a majority of the FADRs; antithrombotic agents or NSAIDs were implicated in most of these events. These results suggest that preventive measures should be taken to reduce the number of deaths caused by drugs.
Effect of maraviroc on the pharmacokinetics of midazolam, lamivudine/ zidovudine, and ethinyloestradiol/ levonorgestrel in healthy volunteers
Authors: Abel Samantha , Russell Deborah , Whitlock Lyndsey A. , Ridgway Caroline E. , Muirhead Gary J. 
Published: March 2008

AIMSTo assess the effect of maraviroc on the pharmacokinetics of midazolam, a sensitive probe CYP3A4 substrate; lamivudine/zidovudine, a combination of nucleoside reverse transcriptase inhibitors (NRTIs); and ethinyloestradiol/levonorgestrel, a combination oral contraceptive.METHODSThree randomized, double‐blind, placebo‐controlled studies were conducted in healthy subjects to assess the effect of maraviroc on pharmacokinetics of other drugs. Two, two‐period crossover studies were conducted to assess (i) the effect of steady‐state maraviroc (300 mg b.i.d.) on pharmacokinetics of midazolam; and (ii) the effect of steady‐state maraviroc (300 mg b.i.d.) on the pharmacokinetics of lamivudine/zidovudine. A third two‐way crossover study was conducted to evaluate the effect of steady‐state maraviroc (100 mg b.i.d.) on the pharmacokinetics of 30 μg ethinyloestradiol/150 μg levonorgestrel (Microgynon®).RESULTSThe geometric mean ratios for Cmax and AUC for each of the compounds tested in the presence and absence of maraviroc were between 92% and 121%. There were no notable differences in Tmax, t1/2 or CLR (where measured) for any of the compounds.CONCLUSIONSMaraviroc had no clinically relevant effects on the pharmacokinetics of the CYP3A4 substrate midazolam, the NRTIs zidovudine/lamivudine, or the oral contraceptive steroids ethinyloestradiol and levonorgestrel.
A novel probe drug interaction study to investigate the effect of selected antiretroviral combinations on the pharmacokinetics of a single oral dose of maraviroc in HIV‐positive subjects
Authors: Pozniak Anton L. , Boffito Marta , Russell Deborah , Ridgway Caroline E. , Muirhead Gary J. 
Published: March 2008

AIMSMaraviroc (UK‐427 857), an antagonist of the CCR5 receptor with potent anti‐HIV activity, was recently approved for use in treatment‐experienced patients infected with CCR5‐tropic HIV‐1. The aim of this study was to evaluate the effect of selected commonly used antiretroviral therapy (ART) combinations on the pharmacokinetics of a single oral dose of maraviroc 300 mg in HIV‐positive subjects compared with historical controls.METHODSIn this study, four cohorts of HIV‐positive patients (n = 8 each) receiving one of the following combination therapies were recruited: cohort 1 – efavirenz + Combivir® (lamivudine/zidovudine); cohort 2 – efavirenz + didanosine + tenofovir; cohort 3 – nevirapine + lamivudine + tenofovir; cohort 4 – Kaletra® (lopinavir/ritonavir) + stavudine + lamivudine. Subjects continued on their prescribed ART and also received a single oral dose of maraviroc 300 mg. Serial blood samples and urine for determination of maraviroc pharmacokinetics were collected over 12 h postdose. Plasma pharmacokinetic parameters from this study were compared with historical data generated in HIV‐positive subjects receiving maraviroc monotherapy in a Phase IIa study.RESULTSA total of 29 subjects were recruited (eight each in cohorts 1–3, and five in cohort 4). The geometric mean ratios for AUC12 and Cmax for each treatment group compared with maraviroc monotherapy were: 47% and 67% (cohort 1); 48% and 76% (cohort 2); 101% and 154% (cohort 3); and 265% and 180% (cohort 4), respectively. Tmax was similar in all treatment groups. Mean values for renal clearance ranged from 8.2 l h−1 (cohort 1) to 13.2 l h−1 (cohort 4). There were no renal clearance data collected in the comparator study.CONCLUSIONSThe results of this study support those previously seen in healthy volunteer studies that showed that efavirenz reduces maraviroc exposure, whereas lopinavir/ritonavir increases maraviroc exposure. These data also suggest that nevirapine does not lead to a clinically significant effect on maraviroc pharmacokinetics.
Short‐period hypoxia increases mouse embryonic stem cell proliferation through cooperation of arachidonic acid and PI3K/Akt signalling pathways
Authors: Lee S. H. , Lee M. Y. , Han H. J. 
Published: March 2008

Abstract.  Hypoxia plays important roles in some early stages of mammalian embryonic development and in various physiological functions. This study examined the effect of arachidonic acid on short‐period hypoxia‐induced regulation of G1 phase cell‐cycle progression and inter‐relationships among possible signalling molecules in mouse embryonic stem cells. Hypoxia increased the level of hypoxia‐inducible factor‐1α (HIF‐1α) expression and H2O2 generation in a time‐dependent manner. In addition, hypoxia increased the levels of cell‐cycle regulatory proteins (cyclin D1, cyclin E, cyclin‐dependent kinase 2 (CDK2) and CDK4). Maximum increases in the level of these proteins and retinoblastoma phosphorylation were observed after 12–24 h of exposure to hypoxic conditions, and then decreased. Alternatively, the level of the CDK inhibitors, p21Cip1 and p27Kip1 were decreased. These results were consistent with the results of [3H]‐thymidine incorporation and cell counting. Hypoxia also increased the level of [3H]‐arachidonic acid release and inhibition of cPLA2 reduced hypoxia‐induced increase in levels of the cell‐cycle regulatory proteins and [3H]‐thymidine incorporation. The level of cyclooxygenase‐2 (COX‐2) was also increased by hypoxia and inhibition of COX‐2 decreased the levels of cell‐cycle regulatory proteins and [3H]‐thymidine incorporation. Indeed, the percentage of cells in S phase, levels of cell cycle regulatory proteins, and [3H]‐thymidine incorporation were further increased in hypoxic conditions with arachidonic acid treatment compared to normoxic conditions. Hypoxia‐induced Akt and mitogen‐activated protein kinase (MAPK) phosphorylation was inhibited by vitamin C (antioxidant, 10−3 M). In addition, hypoxia‐induced increase of cell‐cycle regulatory protein expression and [3H]‐thymidine incorporation were attenuated by LY294002 (PI3K inhibitor, 10−6 M), Akt inhibitor (10−6 M), rapamycin (mTOR inhibitor, 10−9 M), PD98059 (p44/42 inhibitor, 10−5 M), and SB203580 (p38 MAPK inhibitor, 10−6 M). Furthermore, hypoxia‐induced increase of [3H]‐arachidonic acid release was blocked by PD98059 or SB203580, but not by LY294002 or Akt inhibitor. In conclusion, arachidonic acid up‐regulates short time‐period hypoxia‐induced G1 phase cyclins D1 and E, and CDK 2 and 4, in mouse embryonic stem cells through the cooperation of PI3K/Akt/mTOR, MAPK and cPLA2‐mediated signal pathways.
Peroxisome proliferator‐activated receptor gamma agonism modifies the effects of growth hormone on lipolysis and insulin sensitivity
Authors: Krag Morten B. , Nielsen Søren , Guo ZengKui , Pedersen Steen B. , Schmitz Ole , Christiansen Jens S. , Jørgensen Jens O. L. 
Published: March 2008

SummaryContext  Peroxisome proliferator‐activated receptor gamma (PPAR‐γ) agonists such as thiazolidinediones (TZDs) improve insulin sensitivity in type 2 diabetes mellitus (T2DM) through effects on fat metabolism whereas GH stimulates lipolysis and induces insulin resistance.Objective  To evaluate the impact of TZDs on fat metabolism and insulin sensitivity in subjects exposed to stable GH levels.Design  A randomized, placebo‐controlled, double‐blind parallel‐group study including 20 GH‐deficient patients on continued GH replacement therapy. The patients were studied before and after 12 weeks.Intervention  Patients received either pioglitazone 30 mg (N = 10) or placebo (N = 10) once daily for 12 weeks.Results  Adiponectin levels almost doubled during pioglitazone treatment (P = 0·0001). Pioglitazone significantly decreased basal free fatty acid (FFA) levels (P = 0·02) and lipid oxidation (P = 0·02). Basal glucose oxidation rate (P = 0·004) and insulin sensitivity (P = 0·03) improved in the patients who received pioglitazone treatment. The change in insulin‐stimulated adiponectin level after pioglitazone treatment was positively correlated to the change in insulin‐stimulated total glucose disposal (R = 0·69, P = 0·04).Conclusion  The impact of GH on lipolysis and insulin sensitivity can be modified by administration of TZDs.
Association of race, body fat and season with vitamin D status among young women: a cross‐sectional study
Authors: McKinney Kevin , Breitkopf Carmen Radecki , Berenson Abbey B. 
Published: March 2008

SummaryObjective  The purpose of this study was to provide an estimate of vitamin D status in young women residing in south‐east Texas and to determine factors that predict 25‐hydroxyvitamin D (25‐OHD) concentration.Design  A cross‐sectional study was conducted on 800 non‐Hispanic white, non‐Hispanic black, and Hispanic women 16–33 years of age, who were seen in an outpatient clinic.Measurements  Information was obtained on race, smoking, exercise and dietary intake of vitamin D. Percentage total body fat (%TBF) was assessed using dual‐energy X‐ray absorptiometry (DXA). Exposure to sunlight was estimated by examining national records of temperature, hours of daylight and UV index for the latitude of the study site. To determine the relationship between 25‐OHD and %TBF, season, race, body mass index (BMI), dietary vitamin D, age and smoking in a multivariate context, stepwise linear regression analysis was performed.Results  Serum 25‐OHD levels differed among the racial groups (all pairwise differences P < 0·001), with the lowest value among non‐Hispanic blacks (37·7 nmol/l) and the highest value among non‐Hispanic whites (71·8 nmol/l). Among Hispanics, mean serum 25‐OHD was 47·9 nmol/l. Serum 25‐OHD was negatively associated with %TBF (r = –0·28), BMF (r = –0·36) and TBF (r = –0·33), all P < 0·001, and positively associated with dietary vitamin D (r = 0·10) and pack years of smoking (r = 0·11), both P < 0·01. In the summer months, serum 25‐OHD values were higher (55·4 nmol/l) than in the winter months (48·1 nmol/l), P < 0·001. The final regression model predicting serum 25‐OHD levels included race, %TBF and season (all P < 0·05) and explained 36% of the variance in 25‐OHD.Conclusions  Favourable environmental conditions do not result in sufficient vitamin D status for young women, especially non‐Hispanic blacks, Hispanics and the obese.
Acylated ghrelin and leptin in adolescent athletes with amenorrhea, eumenorrheic athletes and controls: a cross‐sectional study
Authors: Christo Karla , Cord Jennalee , Mendes Nara , Miller Karen K. , Goldstein Mark A. , Klibanski Anne , Misra Madhusmita 
Published: March 2008

SummaryObjectives  Neuroendocrine factors may predict which athletes develop amenorrhea and which athletes remain eugonadal. Specifically, ghrelin and leptin have been implicated in regulation of GnRH secretion, with ghrelin having inhibitory and leptin, facilitatory effects. We hypothesized that adolescent athletes with amenorrhea (AA) would have higher ghrelin and lower leptin levels than eumenorrheic athletes (EA) and would predict levels of gonadal steroids.Design  Cross‐sectionalSubjects and measurements  We enrolled 58 girls, 21 AA, 19 EA and 18 nonathletic controls 12–18 years old. Fasting blood was drawn for active ghrelin, leptin, E2 and testosterone. Athletes were > 85% of ideal body weight for age based on body mass index (BMI).Results  AA girls had lower BMI than EA and controls (P = 0·003). Log ghrelin was higher in AA than in EA and controls (P < 0·0001), and remained higher after controlling for BMI Z‐scores. Leptin was lower in AA than in the other groups (P < 0·0001), however, the differences did not persist after controlling for BMI Z‐scores. Testosterone was lower in AA than in EA and controls (P = 0·002) and log E2 trended lower in AA (P = 0·07). We observed inverse associations of log active ghrelin with testosterone (P = 0·01), and positive associations of leptin with testosterone and log E2 (P = 0·02 and 0·009).Conclusion  Higher ghrelin levels, even after controlling for BMI, and lower leptin in AA compared with EA and controls, and their inverse and positive associations, respectively, with gonadal steroids suggest endocrine perturbations that may explain why hypogonadism occurs in some but not all athletes.