bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evaluation of nevirapine dosing recommendations in HIV‐infected children
Authors: Foissac Frantz , Bouazza Naïm , Frange Pierre , Blanche Stéphane , Faye Albert , Lachassinne Eric , Dollfus Catherine , Hirt Déborah , Benaboud Sihem , Treluyer Jean‐Marc , Urien Saïk 
Published: December 2012

AimsNevirapine (NVP) is a non‐nucleoside reverse transcriptase inhibitor used for chronic human immunodeficiency virus infections in adults and children. The aims of this study were to investigate the population pharmacokinetics of NVP in children, establish factors that influence NVP pharmacokinetics and evaluate the current dosing recommendations.MethodsConcentrations were measured on a routine basis in 94 children aged from 2 months to 17 years. A total of 390 NVP plasma concentrations were retrospectively collected, and a population pharmacokinetic model was developed with Monolix 4.0.ResultsNevirapine pharmacokinetics was best described by a one‐compartment model with first‐order absorption and elimination. After standardization to a 70 kg adult using allometry, postmenstrual age had a significant effect on the bioavailability. Estimates of apparent clearance and volume of distribution were 3.9 l h−1 (70 kg)−1 and 140 l (70 kg)−1, respectively. Based on simulations of European Medicines Agency (EMA) and World Health Organization (WHO) dosing recommendations, the probability of observing minimal concentrations below the efficacy target of 3 mg l−1 is higher following the EMA recommendations than the WHO recommendations. However, NVP underdosing persists for the 3–6 and 6–10 kg weight ranges following the WHO recommendations.ConclusionsIt is suggested to increase doses to 75 and 100 mg twice daily for the 3–6 and 6–10 kg weight ranges, respectively, in order to obtain more than 95% of children with concentrations above 3 mg l−1.
Iron chelation: a potential therapeutic strategy in oesophageal cancer
Authors: Keeler BD , Brookes MJ 
Published: December 2012

Raised intracellular iron has been identified as a potential aetiological factor in the development of several epithelial malignancies, including those of the gastrointestinal tract. The mechanism behind this increase is thought to include disorders of iron uptake and storage. Several iron chelators have been identified as potential anti‐tumour agents, with much work undertaken to ascertain the exact mode of action. Despite this, there is little known about the role that these drugs play in the cellular iron metabolism of oesophageal cancer. Consequently, the present study looks to review the relationship of two clinically important iron‐chelating agents, deferoxamine and deferasirox, on cellular iron uptake and storage in oesophageal squamous and adenocarcinoma. This provides important evidence for the debate about the role these agents have in the clinical management of such tumours.Linked ArticleThis article is a commentary on Ford et al., pp. 1316–1328 of this issue. To view this paper visit http://dx.doi.org/10.1111/bph.12045
Olesoxime protects embryonic cortical neurons from camptothecin intoxication by a mechanism distinct from BDNF
Authors: Gouarné Caroline , Giraudon‐Paoli Marc , Seimandi Mathieu , Biscarrat Clotilde , Tardif Gwenaëlle , Pruss Rebecca M , Bordet Thierry 
Published: December 2012

Background and PurposeOlesoxime is a small cholesterol–oxime promoting rat embryonic motor neurons survival in the absence of trophic factors. Because olesoxime can substitute for neurotrophic factors in many situations, and to gain further understanding of its mechanism of action, we wondered if it could prevent neuronal death induced by camptothecin (CPT) and compared its effects with those of brain‐derived neurotrophic factor (BDNF).Experimental ApproachE17 rat embryonic cortical neurons were treated with olesoxime, BDNF or vehicle and intoxicated with CPT. Caspase‐dependent and caspase‐independent death pathways along with pro‐survival pathways activation were explored.Key ResultsAs previously reported for BDNF, olesoxime dose‐dependently delayed CPT‐induced cell death. Both compounds acted downstream of p53 activation preventing cytochrome c release and caspases activation. When caspase activation was blocked, both olesoxime and BDNF provided additional neuroprotective effect, potentially through the prevention of apoptosis‐inducing factor release from mitochondria. While BDNF activates both the PI3K/Akt and the ERK pathway, olesoxime induced only a late activation of the ERK pathways, which did not seem to play a major role in its neuroprotection against CPT. Rather, our results favour preserved mitochondrial membrane integrity by olesoxime.Conclusions and ImplicationsAlbeit different, olesoxime and BDNF mechanisms for neuroprotection converge to preserve mitochondrial function. These findings emphasize the importance of targeting the mitochondria in the process of neurodegeneration. Importantly olesoxime, by mimicking neurotrophin pro‐survival activities without impacting PI3K/Akt and ERK signalling, may have greater therapeutic potential in many diseases where neurotrophins were considered as a therapeutic solution.
Characterization and Prediction of Natriuretic Peptide “Nonresponse” During Heart Failure Management: Results From the ProBNP Outpatient Tailored Chronic Heart Failure (PROTECT) and the NT‐proBNP–Assisted Treatment to Lessen Serial Cardiac Readmissions and Death (BATTLESCARRED) Study
Authors: Gaggin Hanna K. , Truong Quynh A. , Rehman Shafiq U. , Mohammed Asim A. , Bhardwaj Anju , Parks Kimberly A. , Sullivan Dorothy A. , Chen‐Tournoux Annabel , Moore Stephanie A. , Richards A. Mark , Troughton Richard W. , Lainchbury John G. , Weiner Rory B. , Baggish Aaron L. , Semigran Marc J. , Januzzi James L. 
Published: December 2012

Many proven heart failure (HF) therapies decrease N‐terminal pro B‐type natriuretic peptide (NT‐proBNP) values over time, yet some patients have an NT‐proBNP >1000 pg/mL following treatment, which is associated with poor outcomes. A total of 151 patients with left ventricular systolic dysfunction were treated with aggressive HF therapy in the ProBNP Outpatient Tailored Chronic Heart Failure (PROTECT) study. Clinical characteristics and NT‐proBNP were measured at each visit during 10 months. In this post hoc analysis, biomarker nonresponse was defined as an NT‐proBNP >1000 pg/mL and its relationship with echocardiographic and clinical characteristics and outcomes were explored. A risk model predictive of nonresponse was derived and externally validated. A rising NT‐proBNP over time was associated with increased cardiovascular event rates while a decreasing NT‐proBNP was associated with better clinical outcomes (58.2% vs 27.6%, P=.001). A higher percentage of time in biomarker response was associated with lower event rates (P<.001). Importantly, responders showed improved left ventricular remodeling parameters (all P<.001), while nonresponders did not. A risk model for predicting nonresponse had a C statistic of 0.82 (P<.001) and predicted outcomes well. Using data from the NT‐proBNP–Assisted Treatment to Lessen Serial Cardiac Readmissions and Death (BATTLESCARRED) cohort, the risk score was validated for its ability to predict nonresponse (C statistic 0.73, P<.001). Serial changes in NT‐proBNP inform risk for adverse outcome and are associated with prognostically meaningful metrics. Prediction of future NT‐proBNP nonresponse to HF therapy is possible.
Remote Care Costs for Congestive Heart Failure: A Systematic Review and Meta‐Analysis of Randomized Controlled Trials in the United States Comparing Remote Versus More Intensive Care Settings
Authors: Voigt Jeffrey , Mosier Michael 
Published: December 2012

It has been assumed that less intense levels of care for managing heart failure result in a lowering of the overall costs for this care in the United States. The objective of this review was to determine whether this assumption is correct. A systematic review was performed using Medline, technology assessment Web sites, and relevant cardiovascular and heart failure journals from the year 2000 to the present. US randomized controlled trials where costs were evaluated as one of the endpoints were included. Data were collected using Cochrane Review characteristics of included studies and risk of bias assessment forms. Cost data from each trial were converted to a uniform cost definition and year. Meta‐analysis was performed where appropriate. Ten trials were identified evaluating costs at various time points (3, 6, and 12 months). Meta‐analysis of trials demonstrated no difference in costs for care, no matter the patient condition or settings. In high‐quality trials examining costs, there may be a shifting in costs from more expensive care settings to less expensive care settings without savings to the healthcare system. Larger and longer‐term trials should be undertaken to understand this issue.
A combined test of acetylcholine‐mediated vasodilation of both the forearm resistance vessels and the radial artery
Authors: Lind Lars 
Published: December 2012

SummaryObjectiveTo evaluate a new combined test of endothelium‐dependent vasodilation (EDV) in the forearm resistance vessel and the radial artery.MethodsAcetylcholine (ACh) and sodium nitroprusside (SNP) infusion in the brachial artery were used to simultaneous evaluate EDV and endothelium‐independent vasodilation (EIDV) in forearm resistance vessels (plethysmography) and in the radial artery (ultrasound) in 76 healthy subjects. Brachial artery ultrasound was used to assess flow‐mediated vasodilation (FMD).ResultsAcetylcholine induced a 4·5% (median value, P = 0·0010) increase in the radial artery diameter, while SNP induced a 31·2% increase in diameter (P<0·0001). While no increase in radial artery blood flow was induced by ACh (P = 0·69), an increase by 181% in radial blood flow was induced by SNP (P<0·0001).When relating the radial artery diameter data to FMD, the change in radial artery diameter induced by ACh was significantly correlated with FMD (r = 0·35, P = 0·013). No such relationship was seen for the diameter change induced by SNP (r = −0·03, P = 0·81).When relating the radial artery blood flow data to EDV and EIDV, the change in radial artery blood flow induced by ACh was significantly correlated with EDV in an inverse fashion (r = −0·42, P = 0·0032). No such relationship was seen for the blood flow change induced by SNP when related to EIDV (r = −0·07, P = 0·63).ConclusionSimultaneous measurements of blood flow in forearm vessels by plethysmography and in the radial artery by ultrasound during ACh infusion is a new way to assess EDV in both resistance and conduit arteries during one investigation.
High readmission rates are associated with a significant economic burden and poor outcome in patients with grade III/IV acute GvHD
Authors: Dignan Fiona L. , Potter Mike N. , Ethell Mark E. , Taylor Matthew , Lewis Lily , Brennan Joy , McNamara Louise , Evans Steve O. , Riley Unell , Davies Faith E. , Dearden Claire E. , Morgan Gareth J. , Shaw Bronwen E. 
Published: December 2012

AbstractGraft‐versus‐host disease (GvHD) is a common complication following haematopoietic stem cell transplant but little is published about the impact of this condition on hospital readmission rates. We report a retrospective analysis of readmission rates and associated costs in 187 consecutive allogeneic transplant patients to assess the impact of GvHD. The overall readmission rate was higher in patients with GvHD (86% (101/118) vs. 59% (41/69), p < 0.001). The readmission rate was higher both in the first 100 d from transplant (p = 0.02) and in the first year following transplant (p < 0.001). 151/455 (33%) of all readmission episodes occurred within 100 d of transplant. The mean number of inpatient days was significantly higher in patients with grade III/IV acute GvHD (101 d) compared with those with grade I/II GvHD (70 d; p = 0.003). The mean cost of readmission was higher in patients with GvHD (£28 860) than in non‐GvHD patients (£13 405; p = 0.002) and in patients with grade III/IV GvHD (£40 012) compared with those patients with grade I/II GvHD (£24 560; p = 0.038). Survival was higher in those with grade I/II GvHD (55%) compared to grade III/IV GvHD (14%; p < 0.001). This study shows the high economic burden and poor overall survival associated with grade III/IV GvHD.
Gastric bypass in Type 2 diabetes with BMI < 30: weight and weight loss have a major influence on outcomes
Authors: Dixon J. B. , Hur K.‐Y. , Lee W.‐J. , Kim M.‐J. , Chong K. , Chen S.‐C. , Straznicky N. E. , Zimmet P. 
Published: December 2012

AbstractAimTo assess factors influencing glycaemic control following gastric bypass surgery in patients with Type 2 diabetes and BMI< 30 kg/m2.MethodsProspective longitudinal study of 103 patients with inadequate glycaemic control who underwent gastric bypass surgery at Soonchunhyang University, Seoul, Korea (n = 66) and Min‐Sheng General Hospital, Taipei, Taiwan (n = 37). Procedures were performed August 2009 to January 2011. Key outcome measures were excellent glycaemic control of Type 2 diabetes defined as HbA1c < 42 mmol/mol (≤6%); inadequate response defined as HbA1c > 53 mmol/mol (> 7%). Analysis was conducted using binary logistic regression, and cut‐points obtained from receiver operator characteristics.ResultsExcellent glycaemic control was achieved in 31 (30%) at 1 year. Diabetes duration of < 7 years and BMI > 27 kg/m2 provided independent predictors and useful cut‐points. Likelihood of excellent glycaemic control for an individual could be estimated using loge (Odds) = –6.7 + (0.26 × BMI) + (–1.2 × diabetes duration). Baseline BMI of < 27 kg/m2 and baseline C‐peptide of < 2.0ng/ml, best predicted a poor glycaemic response. In those with favourable baseline characteristics percentage weight loss (%WL) had a dominant influence on glycaemic outcomes. Baseline C‐peptide (> 2.4 ng/ml) and subsequent percentage weight loss (> 16%) were associated with excellent glycaemic control. Higher BMI was associated with greater percentage weight loss.ConclusionIn patients with Type 2 diabetes and BMI < 30 kg/m2, glycaemic response to gastric bypass is predicted by higher baseline BMI, shorter disease duration and higher fasting C‐peptide. Post‐surgery weight loss has a dominant effect. Baseline BMI and weight loss have a major influence on outcomes.
Slow cortical potentials capture decision processes during temporal discounting
Authors: Oswald Felix , Sailer Uta 
Published: December 2012

AbstractVarious neuroimaging studies have detected brain regions involved in discounting the value of temporally delayed rewards. This study used slow cortical potentials (SCPs) to elaborate the time course of cognitive processing during temporal discounting. Depending on their strength of discounting, subjects were categorised as low and high impulsive. Low impulsives, but not high impulsives, showed faster reaction times for making decisions when the delayed reward was of high amount than when it was of low amount. Both low impulsives and high impulsives chose the delayed reward more often when its amount was high than when it was low, but this behavior was more pronounced for low impulsives. Moreover, only low impulsives showed more negative SCPs for low than for high amounts. All three measures indicated that only low impulsives experienced extended conflict for delayed low amounts than for high amounts. Additionally, the SCPs of low impulsives were more sensitive to the delay of the delayed reward than those of high impulsives, extending seconds after the response. This indicates that they continued evaluating their choices even after the decision. Altogether, the present study demonstrated that SCPs are sensitive to decision‐related resource allocation during inter‐temporal decision‐making. Resource allocation depended both on the choice situation and on impulsivity. Furthermore, the time course of SCPs suggested that decision‐related processes occurred both prior to and after the response.
Ceramides stimulate caspase‐14 expression in human keratinocytes
Authors: Jiang Yan J. , Kim Peggy , Uchida Yoshikazu , Elias Peter M. , Bikle Daniel D. , Grunfeld Carl , Feingold Kenneth R. 
Published: December 2012

AbstractCaspase‐14 is an enzyme that is expressed predominantly in cornifying epithelia and catalyses the degradation of profilaggrin. Additionally, caspase‐14 plays an important role in the terminal differentiation of keratinocytes. However, how caspase‐14 expression is regulated remains largely unknown. Here we demonstrate that ceramides (C2‐Cer and C6‐Cer), but not other sphingolipids (C8‐glucosylceramides, sphinganine, sphingosine‐1‐phosphate or ceramide‐1‐phosphate), increase caspase‐14 expression (mRNA and protein) in cultured human keratinocytes in a dose‐ and time‐dependent manner. Inhibitors of glucosylceramide synthase and ceramidase increase endogenous ceramide levels and also increase caspase‐14 expression, indicating an important regulatory role for ceramides and suggesting that the conversion of ceramides to other metabolites is not required. The increase in caspase‐14 expression induced by ceramides is first seen at 16 h and requires new protein synthesis, suggesting that the ceramide‐induced increase is likely an indirect effect. Furthermore, ceramides increase caspase‐14 gene expression primarily by increasing transcription. Blocking de novo synthesis of ceramides does not affect caspase‐14 expression, suggesting that basal expression is not dependent on ceramide levels. These studies show that ceramides, an important structural lipid, stimulate caspase‐14 expression providing a mechanism for coordinately regulating the formation of lipid lamellar membranes with the formation of corneocytes.
In vivo imaging reveals selective PPAR activity in the skin of peroxisome proliferator‐activated receptor responsive element‐luciferase reporter mice
Authors: El‐Jamal Noura , Dubuquoy Laurent , Auwerx Johan , Bertin Benjamin , Desreumaux Pierre 
Published: December 2012

AbstractPeroxisome proliferator‐activated receptors (PPARs) have been revealed as key regulators of several skin disorders. This has led to a growing interest in the development of drugs targeting PPARs as therapeutics for skin diseases. To evaluate skin PPAR activity, we developed peroxisome proliferator responsive element‐luciferase (PPRE‐Luc) mice, a mouse model in which the luciferase gene expression is under the control of a PPAR‐inducible promoter in all organs. Our aim was to define and validate experimental conditions to establish PPRE‐Luc mice as a valuable tool for in vivo non‐invasive evaluation of PPARs activation in the skin. We demonstrated by optical imaging that topical application of 40 mm of Luciferin for 10 min was enough to reveal the optimal luciferase activity in mice skin. The treatment of mice skin with the PPARγ and PPARα agonists, pioglitazone and WY14643, was associated with significant increase in photons emission reaching maximal signalling at 6 h. We have performed dose response studies by testing a large range of pioglitazone and WY14643 concentrations on mouse skin. The specificity of bioluminescence signal induced by pioglitazone and WY14643 was assessed using PPARγ and PPARα antagonists, GW9662 and GW6471, respectively. This approach revealed that the isoform specificity of PPARs agonists decreased when high ligand concentrations were applied on mouse skin. These results were further confirmed by in vitro measurement of luciferase activity in skin extracts. Overall, our results demonstrated that PPRE‐Luc mice represent a valuable reporter mouse model for the in vivo pharmacological profiling of drugs targeting PPARs in the skin.
Analysis of moment structures for assessing relationships among perceived chewing ability, dentition status, muscle strength, and balance in community‐dwelling older adults
Authors: Moriya Shingo , Notani Kenji , Murata Ayumi , Inoue Nobuo , Miura Hiroko 
Published: December 2012

ObjectiveThe aim of this study was to assess relationships among perceived chewing ability, dentition status, muscle strength and balance in community‐dwelling older adults using analysis of moment structures (Amos).BackgroundPhysical performance parameters such as muscle strength and balance can predict the future onset of disabilities in activities of daily living among older adults. In this context, elucidation of the relationships among oral conditions and physical performance parameters is necessary.Materials and methodsData on occlusal contact patterns of natural teeth (OPNT), self‐assessed masticatory ability (mastication), body mass index (BMI), handgrip strength (HG) and one‐leg standing time with eyes open (OLST) were collected from 501 independently living adults aged 65–74 years. The relationships among these parameters were analysed using Spearman's rank correlation coefficients and Amos.ResultsSubjects of both genders showed significant correlations among OPNT, mastication, HG and OLST, evaluated using Spearman's rank correlation coefficients. For each Amos model, the goodness‐of‐fit statistic indicated a good level of fit. In both men and women, OPNT was significantly related to mastication, and mastication was related to HG but not to OLST. OPNT was related to neither HG nor OLST in women and was related to OLST but not HG in men.ConclusionThe findings observed in this study present a possible importance of dental status and perceived chewing ability for the onset of disability by influencing physical performance in community‐dwelling older adults.
Measuring excreta patch distribution in grazed pasture through low‐cost image analysis
Authors: Dennis S.J. , Moir J.L. , Cameron K.C. , Edwards G.R. , Di H.J. 
Published: December 2012

AbstractNutrient losses from grazed pasture are an important non‐point source of water pollution. The distribution of animal urine patches on pasture is an important factor in determining nitrate losses and influencing pasture growth, nutritive value and pasture acceptability to livestock, as a high amount of nitrogen (N) is deposited onto a small area of soil under a urine patch. Urine distribution may be recorded during or post‐grazing. Measurements during grazing have been automated, but post‐grazing measurement currently relies on manual observations that are time consuming and cannot be subsequently verified. To automate post‐grazing measurements, aerial photographs were taken of grazed pasture approximately 14 d post‐grazing using a standard digital camera. Pasture response areas were successfully identified by analysing the hue of the images using readily available software, yielding comparable results to manual counts. The majority of dung patches did not produce observable pasture responses, with only 14% of the visible response areas being associated with dung, so although this method cannot distinguish between urine and dung response areas, it is primarily influenced by urine. Provided photographs are taken in full sunlight with a high‐quality camera, excreta patch numbers, areas and spatial distribution can be measured with a high degree of precision. Furthermore, the method is relatively inexpensive and applicable to a wide range of situations. A permanent photographic record of the pasture is also established, which allows verification of the analysis in future.