bluuebunny/crossref_metadata_2025_split huggingface dataset:
Resurgence in the use of physiologically based pharmacokinetic models in pediatric clinical pharmacology: parallel shift in incorporating the knowledge of biological elements and increased applicability to drug development and clinical practice
Authors: Johnson Trevor N. , Rostami‐Hodjegan Amin 
Published: May 2010

SummaryAims and Objectives: (i) To describe an example of the development work required for building a ‘pediatric physiologically based pharmacokinetic’ (P‐PBPK) model (Simcyp Pediatric ADME Simulator), (ii) to replicate pediatric clinical studies and undertake theoretical studies to show the potential applications of mechanistic PBPK in pediatric drug clinical investigation and practice, with emphasis on pediatric anesthesia.Background: PBPK models draw together the physiological and biochemical information that determine drug absorption, distribution, metabolism, and excretion and then link them in a physiologically realistic ‘systems’ model. Incorporating the emerging additional information on developmental physiology and biochemistry has resulted in the creation of P‐PBPK. There has been a renewed interest in the application of such modeling by the pharmaceutical industry to improve the efficiency of drug development, especially in populations where designing and conducting clinical studies is more challenging, such as pediatric patients.Methods: P‐PBPK was used to simulate a number of published clinical studies and clinical case scenarios with the aim of highlighting the potential applications.Results: Changing the P‐PBPK model parameters in a number of ‘what if’ simulations were used to explore the likely underlying reasons for observed pharmacokinetic (PK) behavior of drugs in critically ill children. In addition, the use of P‐PBPK models to predict complex drug–drug interactions (DDI) highlighted disparities with adult populations.Discussion: The examples highlight the use of prior knowledge ofin vitrodrug attributes and biology of the system (human body) to simulate PK and multiple DDI scenarios not infrequently encountered in critically ill pediatric patients.
In vitroandin vivorelaxation of urinary bladder smooth muscle by the selective myosin II inhibitor, blebbistatin
Authors: Zhang Xinhua , Kuppam Dwaraka Srinivasa R. , Melman Arnold , DiSanto Michael E. 
Published: May 2010

What’s known on the subject? and What does the study add?Various pathological conditions of the bladder, including overactive bladder syndrome (OAB), are associated with unregulated increases in bladder smooth muscle (SM) contraction. Although a number of new pre‐clinical pharmacological agents for OAB have been identified, they predominantly target at the neural or detrusor cell membrane level rather than the SM contractile apparatus itself. The current study provides the first demonstration that blebbistatin, a novel small cell permeable molecule with demonstrated high affinity and selectivity toward the myosin II contractile molecule, potently and efficiently relaxes both rat and human bladder SMin vitroand also significantly alters urodynamic parametersin vivoto values reflective of decreased bladder overactivity.OBJECTIVETo investigate thein vitroandin vivoeffects of blebbistatin (a small cell‐permeable molecule with high affinity and selectivity toward the myosin II contractile molecule) on bladder smooth muscle (SM) contractility, as antimuscarinic therapy is only 65–75% effective in treating overactive bladder (OAB) and is associated with considerable side‐effects, with a <25% continuation rate at 1 year.MATERIALS AND METHODSBladder and aortic strips from adult male rats, and human bladder strips obtained from open prostatectomy, were used for organ‐bath studies of blebbistatin. Awake cystometry was also used in rats in both the presence and absence of intravesically delivered blebbistatin.RESULTSBlebbistatin dose‐dependently and completely relaxed both KCl‐ and carbachol‐induced rat detrusor and endothelin‐1‐induced human bladder contraction. Pre‐incubation with 10 µmblebbistatin attenuated carbachol responsiveness by ≈65% while blocking electrical field stimulation‐induced bladder contraction reaching 50% inhibition at 32 Hz. The basal tone and amplitude of spontaneous contraction were also significantly diminished. Urodynamic variables were obviously altered by intravesical infusion with blebbistatin.CONCLUSIONOur novel data show that blebbistatin strongly relaxes both rat and human bladder contraction induced by various physiological stimuli. Coupled with ourin vivodata showing that nanomole doses of blebbistatin significantly alter urodynamic variables to produce a less active bladder, our results suggest the possibility of intravesically administered blebbistatin binding at myosin II being developed as a therapeutic treatment for OAB via a novel targeting of the SM contractile apparatus.
Location and number of positive surgical margins as prognostic factors of biochemical recurrence after salvage radiation therapy after radical prostatectomy
Authors: Bastide Cyrille , Savage Caroline , Cronin Angel , Zelefsky Michael J. , Eastham James A. , Touijer Karim , Scardino Peter T. , Guillonneau Bertrand D. 
Published: May 2010

Study Type – Prognosis (case series) Level of Evidence 4OBJECTIVETo determine if the location and number of positive surgical margins (PSMs) after radical prostatectomy (RP) are associated with recurrence after salvage external beam radiation therapy (sEBRT).PATIENTS AND METHODSWe retrospectively reviewed the medical records of 60 patients with PSMs who underwent three‐dimensional conformal sEBRT for biochemical recurrence (BCR) or clinically detected local recurrence after RP between 1996 and 2007. PSMs were categorized as present or absent at three locations, and patients were classified as having either one or more than one PSM. BCR after RP was defined as a prostate‐specific antigen (PSA) level of ≥0.1 ng/mL. BCR after sEBRT was defined as a serum PSA level of ≥0.1 ng/mL above the PSA nadir after sEBRT.RESULTSIn all, 24 (40%) patients had more than one PSM. Overall, the most common location of a PSM was the posterior prostate with 40 (66%) patients having a positive posterior margin. The location of PSMs was not significantly associated with secondary BCR (global P= 0.8). There was a borderline result between the number of PSMs and BCR: men with more than one PSM were less likely to recur compared with those with only one PSM (hazard ratio 0.42; P= 0.067).CONCLUSIONSThis is the first study to specifically analyse location and number of PSMs as prognostic factors for men who undergo sEBRT. There was no evidence to suggest that the location of a PSM predicted secondary BCR. Further research is needed to determine whether the number of PSMs is an important predictor of BCR after sEBRT.
The changing prevalence of diagnosed diabetes and its associated vascular complications in a large region of the UK*
Authors: Morgan C. L. , Peters J. R. , Currie C. J. 
Published: May 2010

Diabet. Med. 27, 673–678 (2010)AbstractAims  To characterize the prevalence of diabetes in a large health district in 2004 and compare it with a previous estimate made in 1996.Methods  The study population comprised the resident population of Cardiff and the Vale of Glamorgan. Routine record linkage was used to identify patients from various sources of hospital and mortality data. Patients with diabetes were identified according to biochemistry test results, coding on routine data or attendance at a diabetes‐related clinic. Diabetes‐related complications were ascribed according to coding on routine data.Results  It was possible to identify 17 088 people with diabetes alive on 1 January 2005. Of these patients, 9064 (53.0%) were male and 8024 (47.0%) were female. Mean age (± sd) was 59.6 ± 18.9 years for males and 61.2 ± 20.4 years for females. The crude prevalence of diabetes in 2005 was 3.9% (3.4% adjusted) compared with 2.5% in 1996 (2.3% adjusted). With the exception of females aged ≥ 75 years, the prevalence of diabetes increased in all age‐ and sex‐specific subgroups. Within the 2005 cohort, over two‐thirds has no recorded complications compared with approximately one half of the 1996 cohort. The prevalence of individual complications decreased, with the exception of renal complications.Conclusions  The prevalence of identified diabetes appears to have increased substantially over a relatively short period of 9 years to 2004. The increase in prevalence was 46%, with an increase in numbers of patients with diabetes of 53%. A number of factors are likely to have contributed to this, including an increase in case ascertainment.
Paediatric intensive care admissions for acute diabetes complications
Authors: Burns M. R. , Bodansky H. J. , Parslow R. C. 
Published: May 2010

Diabet. Med. 27, 705–708 (2010)AbstractAim  To describe the admission characteristics and outcomes of children admitted to paediatric intensive care because of acute diabetes complications in England and Wales.Methods  Retrospective review of children admitted to paediatric intensive care in England and Wales between April 2003 and March 2007 with acute diabetes complications using data from the Paediatric Intensive Care Audit Network (PICANet).Results  There were 341 admissions in 330 patients for acute diabetes complications, comprising 0.6% of all 56 322 intensive care admissions. There was a steady annual increase during this period from 0.54% to 0.67%. The majority of admissions were for ketoacidosis (87%), with more female admissions than males (56% vs. 44%). Forty per cent of the diabetes admissions were aged 11–15 years. There were five deaths (1.5%), all female.Conclusions  Acute diabetes complications are an increasing cause of admission to paediatric intensive care, particularly for teenage girls. The overall mortality rate was low for intensive care admissions for diabetes. Earlier diagnosis of new cases, heightened awareness of this condition and better management of existing diabetic patients may obviate the need for costly intensive care treatment.
Culturally appropriate health education for Type 2 diabetes in ethnic minority groups: a systematic and narrative review of randomized controlled trials
Authors: Hawthorne K. , Robles Y. , Cannings‐John R. , Edwards A. G. K. 
Published: May 2010

Diabet. Med. 27, 613–623 (2010)AbstractTo determine if culturally appropriate health education is more effective than ‘usual’ health education for people with diabetes from ethnic minority groups living in high‐ and upper‐middle‐income countries. A systematic review with meta‐analysis, following the methodology of the Cochrane Collaboration. Electronic literature searches of nine databases were made, with hand searching of three journals and 16 author contacts. The criteria for inclusion into the analysis were randomized controlled trials of a specified diabetes health education intervention, and a named ethnic minority group with Type 2 diabetes. Data were collected on HbA1c, blood pressure, and quality‐of‐life measures. A narrative review was also performed. Few studies fitted the selection criteria, and were heterogeneous in methodologies and outcome measures, making meta‐analysis difficult. HbA1c showed an improvement at 3 months [weighted mean difference (WMD) −0.32%, 95% confidence interval (CI) −0.63, −0.01] and 6 months post intervention (WMD −0.60%, 95% CI −0.85, −0.35). Knowledge scores also improved in the intervention groups at 6 months (standardized mean difference 0.46, 95% CI 0.27, 0.65). There was only one longer‐term follow‐up study, and one formal cost‐effectiveness analysis. Culturally appropriate health education was more effective than ‘usual’ health education in improving HbA1c and knowledge in the short to medium term. Due to poor standardization between studies, the data did not allow determination of the key elements of interventions across countries, ethnic groups and health systems, or a broad view of their cost‐effectiveness. The narrative review identifies learning points to direct future research.
Fatigue in multiple sclerosis: associations with health‐related quality of life and physical performance
Authors: Smedal T. , Beiske A. G. , Glad S. B. , Myhr K.‐M. , Aarseth J. H. , Svensson E. , Gjelsvik B. , Strand L. I. 
Published: May 2010

Background and purpose:  Fatigue is a common, but still one of the least understood symptoms in multiple sclerosis (MS). We aimed to investigate whether fatigue was associated with demographic‐, clinical‐, health‐related quality of life (HRQoL)‐ and physical performance variables, and whether change in fatigue after treatment was associated with changes in HRQoL and physical performance.Methods:  Sixty patients were included for inpatient physiotherapy. Fifty‐six patients completed the study and were available for analysis. Fatigue (Fatigue Severity Scale; FSS), HRQoL (Multiple Sclerosis Impact Scale; MSIS‐29) and physical performance (walking ability and balance) were assessed at screening, baseline, after treatment and at follow‐up after 3 and 6 months. We analysed possible associations between fatigue and other variables at baseline by regression models, and between change in fatigue versus changes in both HRQoL and physical performance variables after physiotherapy by correlation analysis.Results:  Fatigue at baseline was associated with HRQoL (explained 21.9% of variance), but not with the physical performance tests. Change in fatigue was correlated with change in HRQoL, but not with changes in physical performance. All measures were improved after treatment (P ≤ 0.001). While improvements in fatigue and HRQoL were lost at follow‐up, improvements in physical performance tests were maintained for at least 6 months (P ≤ 0.05).Conclusions:  Fatigue was associated with HRQoL at baseline. Improvement in fatigue seemed to be related to other factors than improvement in physical performance. A broader strategy including both physical and psychological dimensions seems to be needed to improve fatigue over the long‐term.
Loan Sales and Loan Market Competition*
Authors: AHN JUNG‐HYUN 
Published: May 2010

ABSTRACTIn this article, I suggest a theoretical explanation for the recent spectacular growth of the loan sales market in terms of both quantity and quality. I show that banks can use loan sales as a strategic tool in order to preserve their informational advantage in a competitive environment. I consider a two‐period competition model where banks acquire private information about their clientele during the lending relationship and where there is informational asymmetry in the loan sales market. In spite of the information dilution costs incurred in selling high‐quality loans, banks have an incentive to imitate low‐quality loan holders by selling their loans in order to avoid communicating negative signals about the quality of their clientele to potential competitors. As a result, loan market competition can lead to the emergence of a liquid loan sales market in which both low‐ and high‐quality loans coexist, thereby improving the quantity and quality of the loan sales market.
Super‐obesity and risk for early and late pre‐eclampsia
Authors: Mbah AK , Kornosky JL , Kristensen S , August EM , Alio AP , Marty PJ , Belogolovkin V , Bruder K , Salihu HM 
Published: May 2010

Please cite this paper as: Mbah A, Kornosky J, Kristensen S, August E, Alio A, Marty P, Belogolovkin V, Bruder K, Salihu H. Super‐obesity and risk for early and late pre‐eclampsia. BJOG 2010;117:997–1004.Objective  To examine the association between obesity subtypes and risk of early and late pre‐eclampsia.Design  Population‐based retrospective study.Setting  State of Missouri maternally linked birth cohort files.Population  All singleton live births in the state of Missouri from 1989 to 2005.Methods  The body mass index (BMI) was used to classify women as normal weight (BMI = 18.5–24.9 kg/m2), class I obesity (BMI = 30–34.9 kg/m2), class II obesity (BMI = 35–39.9 kg/m2), class III obesity (BMI = 40–49.9 kg/m2) or super‐obesity (BMI ≥ 50 kg/m2). Adjusted odds ratios (OR) and 95% confidence intervals (CI) for the association between obesity and the risk of pre‐eclampsia were obtained from logistic regression models with adjustment for intracluster correlation.Results  The rate of pre‐eclampsia increased with increasing BMI, with super‐obese women having the highest incidence (13.4%). Compared with normal weight women, obese women (BMI ≥ 30 kg/m2) had a higher risk for pre‐eclampsia (OR = 2.59, 95% CI = 2.87–3.01). This risk remained approximately the same for late‐onset pre‐eclampsia (pre‐eclampsia occurring at 34 weeks or more of gestation) and was slightly reduced for early‐onset pre‐eclampsia (pre‐eclampsia occurring at 34 weeks or less of gestation). Within each BMI category, the risk of pre‐eclampsia increased with the rate of weight gain. Compared with normal weight mothers with moderate weight gain, super‐obese women with a high rate of weight gain had the greatest risk for pre‐eclampsia (OR = 7.52, 95% CI = 2.70–21.0).Conclusion  BMI and rate of weight gain are synergistic risk factors that amplify the burden of pre‐eclampsia among super‐obese women.
The proton‐coupled amino acid transporter, SLC36A1 (hPAT1), transports Gly‐Gly, Gly‐Sar and other Gly‐Gly mimetics
Authors: Frølund S , Holm R , Brodin B , Nielsen CU 
Published: May 2010

BACKGROUND AND PURPOSE The intestinal proton‐coupled amino acid transporter, SLC36A1, transports zwitterionic α‐amino acids and drugs such as vigabatrin, gaboxadol and δ‐aminolevulinic acid. We hypothesize that SLC36A1 might also transport some dipeptides. The aim of the present study was to investigate SLC36A1‐mediated transport of Gly‐Gly and Gly‐Gly mimetics, and to investigate Gly‐Sar transport via SLC36A1 and the proton‐coupled dipeptide/tripeptide transporter, SLC15A1 in Caco‐2 cells.EXPERIMENTAL APPROACH Transport of a compound via SLC36A1 was determined by its ability to induce an increase in the inward current of two‐electrode voltage clamped SLC36A1 cRNA‐injected Xenopus laevis oocytes. SLC36A1‐mediated l‐[3H]Pro uptake in Caco‐2 cells was measured in the absence and presence of Gly‐Gly or Gly‐Sar. In addition, apical [14C]Gly‐Sar uptake was measured in the absence and presence of the SLC36A1 inhibitor 5‐hydroxy‐l‐tryptophan (5‐HTP) or the SLC15A1 inhibitor l‐4,4′‐biphenylalanyl‐l‐proline (Bip‐Pro).KEY RESULTS In SLC36A1‐expressing oocytes, an inward current was induced by Gly‐Sar, Gly‐Gly, δ‐aminolevulinic acid, β‐aminoethylglycine, δ‐aminopentanoic acid, GABA, Gly and Pro, whereas Val, Leu, mannitol, 5‐HTP and the dipeptides Gly‐Ala, Gly‐Pro and Gly‐Phe did not evoke currents. In Caco‐2 cell monolayers, the apical uptake of 30 mM Gly‐Sar was inhibited by 20 and 22% in the presence of 5‐HTP or Bip‐Pro, respectively, and by 48% in the presence of both.CONCLUSION AND IMPLICATIONS Our results suggest that whereas Gly‐Gly amid bond bioisosteres are widely accepted by the hPAT1 carrier, dipeptides in general are not; and therefore, Gly‐Sar might structurally define the size limit of dipeptide transport via SLC36A1.
Intraoral Registration Coping Formation Using an Interim Restoration as a Matrix
Authors: Stamoulis Kostas 
Published: May 2010

AbstractAn intraoral procedure for registration coping fabrication is described. The indirectly constructed shell of the interim fixed partial denture is used as a matrix, and a light‐cured resin is added directly to form the copings. The proposed technique reduces the total number of clinical sessions and can be useful in cases when tooth preparations and final impressions can be completed at the same appointment.
Effects of elevated CO2 associated with maize on multiple generations of the cotton bollworm, Helicoverpa armigera
Authors: Yin Jin , Sun Yucheng , Wu Gang , Ge Feng 
Published: May 2010

AbstractUnder elevated environmental carbon dioxide (CO2), leaf chewers tend to compensate for decreased leaf nutritional quality with increased consumption; mortality and development times also increase and cause a reduction in the fitness of leaf chewers. However, the effect of elevated CO2 on multiple successive generations of these and other insects is not well understood. Furthermore, information about the direct effects of increased environmental CO2 on developmental time and consumption of herbivores is lacking. In this paper, we tested the hypothesis that cascade effects of elevated CO2 through plants, rather than the direct effects of elevated CO2, are the main factors decreasing the fitness of cotton bollworm, Helicoverpa armigera Hübner (Lepidoptera: Noctuidae). We used two series of experiments to quantify the growth, development, and consumption of H. armigera fed on an artificial diet or C4 plants (maize) grown under two CO2 levels (ambient vs. double ambient). In the first series of experiments, elevated CO2 had no effect on the population abundance or individual consumption for three successive generations of cotton bollworms fed on an artificial diet. In the second series of experiments, elevated CO2 reduced population abundance of cotton bollworm larvae for two successive generations when they were fed maize milky grains. The specific effects were longer larval duration, lower fecundity, and decreased rm of cotton bollworms. Furthermore, elevated CO2 increased individual consumption when cotton bollworm was fed maize milky grains for two successive generations and decreased the population’s total consumption in the first generation but increased it in the second generation. The results from this study indicate that: (1) The effects of elevated CO2 on three successive generations of cotton bollworm fed on artificial diet were weak, or even non‐existent, and (2) elevated CO2 increased the consumption when cotton bollworm were fed maize. Our study also suggests that the damage inflicted by cotton bollworm on maize (a C4 plant) will be seriously affected by the increases in atmospheric CO2, which is unlike our previous results for spring wheat (a C3 plant).