bluuebunny/crossref_metadata_2025_split huggingface dataset:
Development of population PK model with enterohepatic circulation for mycophenolic acid in patients with childhood‐onset systemic lupus erythematosus
Authors: Sherwin Catherine M. T. , Sagcal‐Gironella Anna Carmela P. , Fukuda Tsuyoshi , Brunner Hermine I. , Vinks Alexander A. 
Published: November 2011

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Despite its increased use, the pharmacokinetics (PK) of mycophenolic acid (MPA) and the relationship between dose, plasma concentration and exposure are poorly understood, especially in children.• The PK of MPA are associated with high inter‐ and intra‐individual variability.• MPA and its metabolites, like the inactive 7‐O‐MPA‐β‐glucuronide (MPAG) undergo enterohepatic circulation (EHC), which can contribute to an increase in exposure to MPA of 40% (range 10–60%).WHAT THIS STUDY ADDS• Thisis the first report of MPA PK in adolescents with childhood‐onset systemic lupus erythematosus (cSLE).• The proposed final population PK model successfully incorporates the physiological aspects associated with MPA disposition, which includes MPA and its main metabolite MPAG, and adequately reflects the complex processes of absorption and enterohepatic circulation associated with mycophenolate mofetil (MMF) oral dosing in patients with cSLE.• This model provides a basis for further development of a model‐based Bayesian estimator for individualized MPA dosing in paediatric patients treated for cSLE.AIMThis study aimed to develop a population pharmacokinetic (PK) enterohepatic recycling model for MPA in patients with childhood‐onset systemic lupus erythematosus (cSLE).METHODSMPA concentration–time data were from outpatients on stable oral mycophenolate mofetil (MMF) and collected under fasting conditions, with standardized meals (1 and 4 h post‐dose). Sampling times were pre‐dose, 20, 40 min, 1, 1.5, 2, 3, 4, 6 and 9 h, post dose. The population PK analysis simultaneously modelled MPA and 7‐O‐MPA‐β‐glucuronide (MPAG) concentrations using nonlinear mixed effect modelling.RESULTSPK analysis included 186 MPA and MPAG concentrations (mg l–1) from 19 patients. cSLE patients, age range 10–28 years, median 16.5 years were included. Mean ± SD disease duration was 3.8 ± 3.7 years. The final PK model included a gallbladder compartment for enterohepatic recycling and bile release time related to meal times, with first order absorption and single series of transit compartments. The PK estimates for MPA were CL1/F 25.3 l h–1, V3/F 20.9 l, V4/F 234 l and CL2/F 19.8 l h–1.CONCLUSIONThe final model fitted the complex processes of absorption and enterohepatic circulation (EHC) in those treated with MMF for cSLE and could be applied in Bayesian dose optimization algorithms.
Impact of moderate vs stringent TSH suppression on survival in advanced differentiated thyroid carcinoma
Authors: Diessl Stefanie , Holzberger Barbara , Mäder Uwe , Grelle Inge , Smit Johannes W. A. , Buck Andreas K. , Reiners Christoph , Verburg Frederik A. 
Published: November 2011

SummaryObjectives  To assess (i) the influence of Thyrotropin (TSH) suppression at a level of <0·1 mU/l and (ii) whether FT3 and FT4 levels have a prognostic significance independently of TSH values with regard to survival in patients with differentiated thyroid carcinoma (DTC) and distant metastases.Patients and methods  In a retrospective patient chart study, we reviewed survival in 157 DTC patients with distant metastases treated between September 1985 and 1 July 2010. Patients with at least three available FT3 and FT4 values during TSH suppression were eligible.Results  Fifty‐three of 157 patients died from DTC. DTC‐specific survival was significantly better in patients with a median TSH level ≤0·1 mU/l (median survival 15·8 years) than those with a non‐suppressed TSH level (median survival 7·1 years; P < 0·001). However, there was no further improvement in survival caused by TSH suppression to a level ≤0·03 mU/l (P = 0·24). FT3 and FT4 levels were also significantly associated with poorer survival; of these, only the prognostic value of FT3 was independent from that of TSH levels.Conclusion  The care of patients with DTC and distant metastases is like walking an endocrinological tightrope: non‐suppressed TSH levels, that is, >0·1 mU/l, are associated with an impaired prognosis. There is, however, no prognostic benefit from suppressing TSH to levels lower than 0·1 mU/l. On the contrary, an improvement in prognosis might be achieved by keeping FT3 levels as low as possible.
Two small RNAs, CrcY and CrcZ, act in concert to sequester the Crc global regulator in Pseudomonas putida, modulating catabolite repression
Authors: Moreno Renata , Fonseca Pilar , Rojo Fernando 
Published: November 2011

SummaryThe Crc protein is a translational repressor that recognizes a specific target at some mRNAs, controlling catabolite repression and co‐ordinating carbon metabolism in pseudomonads. In Pseudomonas aeruginosa, the levels of free Crc protein are controlled by CrcZ, a sRNA that sequesters Crc, acting as an antagonist. We show that, in Pseudomonas putida, the levels of free Crc are controlled by CrcZ and by a novel 368 nt sRNA named CrcY. CrcZ and CrcY, which contain six potential targets for Crc, were able to bind Crc specifically in vitro. The levels of CrcZ and CrcY were low under conditions generating a strong catabolite repression, and increased strongly when catabolite repression was absent. Deletion of either crcZ or crcY had no effect on catabolite repression, but the simultaneous absence of both sRNAs led to constitutive catabolite repression that compromised growth on some carbon sources. Overproduction of CrcZ or CrcY significantly reduced repression. We propose that CrcZ and CrcY act in concert, sequestering and modulating the levels of free Crc according to metabolic conditions. The CbrA/CbrB two‐component system activated crcZ transcription, but had little effect on crcY. CrcY was detected in P. putida, Pseudomonas fluorescens and Pseudomonas syringae, but not in P. aeruginosa.
Nitrate and ammonium lead to distinct global dynamic phosphorylation patterns when resupplied to nitrogen‐starved Arabidopsis seedlings
Authors: Engelsberger Wolfgang R. , Schulze Waltraud X. 
Published: November 2011

SummaryNitrogen is an essential macronutrient for plant growth and development. Inorganic nitrogen and its assimilation products control various metabolic, physiological and developmental processes. Although the transcriptional responses induced by nitrogen have been extensively studied in the past, our work here focused on the discovery of candidate proteins for regulatory events that are complementary to transcriptional changes. Most signaling pathways involve modulation of protein abundance and/or activity by protein phosphorylation. Therefore, we analyzed the dynamic changes in protein phosphorylation in membrane and soluble proteins from plants exposed to rapid changes in nutrient availability over a time course of 30 min. Plants were starved of nitrogen and subsequently resupplied with nitrogen in the form of nitrate or ammonium. Proteins with maximum change in their phosphorylation level at up to 5 min after nitrogen resupply (fast responses) included GPI‐anchored proteins, receptor kinases and transcription factors, while proteins with maximum change in their phosphorylation level after 10 min of nitrogen resupply (late responses) included proteins involved in protein synthesis and degradation, as well as proteins with functions in central metabolism and hormone metabolism. Resupply of nitrogen in the form of nitrate or ammonium resulted in distinct phosphorylation patterns, mainly of proteins with signaling functions, transcription factors and transporters.
A PORR domain protein required for rpl2 and ccmFC intron splicing and for the biogenesis of c‐type cytochromes in Arabidopsis mitochondria
Authors: des Francs‐Small Catherine Colas , Kroeger Tiffany , Zmudjak Michal , Ostersetzer‐Biran Oren , Rahimi Nima , Small Ian , Barkan Alice 
Published: November 2011

SummaryAngiosperm mitochondria encode approximately 20 group II introns, which interrupt genes involved in the biogenesis and function of the respiratory chain. Nucleus‐encoded splicing factors have been identified for approximately half of these introns. The splicing factors derive from several protein families defined by atypical RNA binding domains that function primarily in organelles. We show here that the Arabidopsis protein WTF9 is essential for the splicing of group II introns in two mitochondrial genes for which splicing factors had not previously been identified: rpl2 and ccmFC. WTF9 harbors a recently recognized RNA binding domain, the PORR domain, which was originally characterized in the chloroplast splicing factor WTF1. These findings show that the PORR domain family also functions in plant mitochondria, and highlight the parallels between the machineries for group II intron splicing in plant mitochondria and chloroplasts. In addition, we used the splicing defects in wtf9 mutants as a means to functionally characterize the mitochondrial rpl2 and ccmFC genes. Loss of ccmFC expression correlates with the loss of cytochromes c and c1, confirming a role for ccmFC in cytochrome biogenesis. By contrast, our results strongly suggest that splicing is not essential for the function of the mitochondrial rpl2 gene, and imply that the Rpl2 fragment encoded by rpl2 exon 1 functions in concert with a nuclear gene product that provides the remainder of this essential ribosomal protein in trans.
Effect of Staining and Freezing Media on Sortability of Stallion Spermatozoa and their Post‐thaw Viability After Sex‐sorting and Cryopreservation
Authors: Clulow JR , Buss H , Evans G , Sieme H , Rath D , Morris LHA , Maxwell WMC 
Published: November 2011

ContentsSex‐sorted, frozen–thawed stallion spermatozoa remain out of reach of commercial horse breeders because of the low efficiency of the sex‐sorting process and unacceptable fertility rates after insemination. Two experiments were designed to test the effects of alternative staining and freezing media to improve the viability of sex‐sorted frozen–thawed stallion spermatozoa. Experiment 1 compared two freezing media, INRA 82® and a modified lactose‐ethylenediaminetetraacetic acid (EDTA), for the cryopreservation of sex‐sorted stallion spermatozoa. No significant differences between the two freezing media could be identified, suggesting that both cryodiluents would be suitable for incorporation into a sex‐preselection protocol for stallion spermatozoa. Experiment 2 compared Kenney’s modified Tyrode’s (KMT) and Sperm TALP (Sp‐TALP) as the staining and incubation medium for stallion spermatozoa prior to sex‐sorting. A significant increase in the percentage of acrosome‐reacted spermatozoa occurred after staining and incubation in the clarified Sp‐TALP compared with KMT. As no improvements in sorting rates were achieved using Sp‐TALP, it was concluded that stallion sorting protocols could include KMT as the staining and incubation medium while either INRA 82® or lactose‐EDTA could be employed as a cryodiluents.
Influences of Metabolic Traits on Subclinical Endometritis at Different Intervals Postpartum in High Milking Cows
Authors: Senosy WS , Izaike Y , Osawa T 
Published: November 2011

ContentsSeventy pluriparous high‐yielding cows were used to investigate the impact of metabolic traits and body condition score (BCS) during early lactation on subclinical endometritis diagnosed at weeks 5, 6 and 7 postpartum (pp). Blood samples were collected from animals with no peripartum problems from the second (W2) to seventh (W7) weeks pp to estimate some blood metabolites including non‐esterified fatty acids (NEFA), β‐hydroxybutyric acid (BHBA), blood glucose, total cholesterol (T‐chol) and blood urea nitrogen (BUN). Reproductive tract examination was carried out at weeks 5, 6 and 7 pp by endometrial cytology (percentage of polymorphonuclear cells; PMN%). Based on PMN%, animals having <5% were defined as subclinical endometritis group (ENDM group) while animals unaffected by endometritis were defined as no subclinical endometritis group (NOENDM group). Animals with endometritis during week 5 were identified as ENDM5, during week 6 identified as ENDM6 and during week 7 identified as ENDM7 or animals with no endometritis during weeks 5 (NOENDM5), 6 (NOENDM6) and 7 (NOENDM7) pp. Animals diagnosed at week 5; BUN and BCS were lower p < 0.05 in ENDM 5 than NOENDM5 group at W2, W4, W6 and W7. Cows diagnosed at week 6; T‐chol was significantly higher (p = 0.05) in ENDM6 group (279.2 ± 12.5 mg/dl) than NOENDM6 group (246 ± 9.5 mg/dl) at W7. Moreover, blood glucose was significantly low (p < 0.05) in ENDM6 group when compared to NOENDM group at W4 pp (49.2 ± 1.8 vs 53.8 ± 1.3 mg/dl). BCS was significantly lower (p < 0.001) in animals suffered from endometritis during week 7 when compared to NOENDM7 cows at W3, W4, W5, W6 and W7. In conclusion, lower blood glucose, BUN and BCS could be a risk factor for cytologically diagnosed endometritis at weeks 5, 6 and 7 pp.
Effect of the antipsychotic agent amisulpride on glucose lowering and insulin secretion
Authors: Roix J. J. , DeCrescenzo G. A. , Cheung P. H. , Ciallella J. R. , Sulpice T. , Saha S. , Halse R. 
Published: November 2011

Aims: To investigate the effects of the second generation antipsychotic (R/S)‐amisulpride, and the chirally purified enantiomers, on glucose homeostasis in diet‐induced obese (DIO) mice.Methods: Normal and DIO mice were treated with pharmacologically relevant doses of amisulpride prior to oral glucose tolerance tests (OGTTs). Blood glucose, insulin, glucagon‐like peptide‐1, prolactin and amisulpride drug levels were determined.Results: Racemic amisulpride significantly reduced glucose excursions during OGTT in both normal and DIO mice. This potent effect was preserved with the ‘off‐isomer’, R‐amisulpride (ED50 1 mg/kg). Insulin secretion was significantly increased with R‐amisulpride with only a minor increase in prolactin levels.Conclusions: Amisulpride has antidiabetic actions in DIO mice resulting from increased insulin secretion. This provides some explanation for why amisulpride, unlike other atypical antipsychotics, is not diabetogenic in man. Furthermore, the observation that R‐amisulpride is also antidiabetic and has minimal impact on prolactin levels presents the opportunity for development of this isomer as an antidiabetic agent.
The rs553668 polymorphism of the ADRA2A gene predicts the worsening of fasting glucose values in a cohort of subjects without diabetes. A population‐based study
Authors: Bo S. , Cassader M. , Cavallo‐Perin P. , Durazzo M. , Rosato R. , Gambino R. 
Published: November 2011

Diabet. Med. 29, 549–552 (2012)AbstractAims  Single‐nucleotide polymorphisms in the human ADRA2A gene have been associated with increased risk of Type 2 diabetes. The associations between the rs553668 polymorphism and fasting glucose concentrations both cross‐sectionally and longitudinally after 6‐year follow‐up were evaluated in an adult Caucasian population‐based cohort.Methods  From a cohort of 1658 individuals, after excluding patients with diabetes, those who died and those whose blood samples were not available for genotyping, data of 1345 individuals were analysed.Results  Subjects homozygous for the A allele showed significantly increased baseline fasting glucose values and a significant worsening of fasting glucose (β = 0.48; 95% CI 0.10–0.86) and insulin secretion (β = −20.75; −32.67 to −8.82 for homeostasis model assessment for β‐cell function) at follow‐up by using generalized estimating equations. Incidence of impaired fasting glucose and diabetes was almost twofold higher in subjects homozygous for the A allele (respectively: incident impaired fasting glucose 7.6–8.2, 16.1%, incident diabetes 1.7–2.3, 3.2% in GG, AG, AA carriers).Conclusions  Our results suggested that the rs553668 polymorphism is associated with glucose worsening in subjects without diabetes at baseline.
Introducing personalised care planning into Newham: outcomes of a pilot project
Authors: Walker R. , Davison C. , Maher A‐M. , Law J. , Reilly P. , Fordjour G. 
Published: November 2011

AbstractDiabet. Med. 29, 1074–1078 (2012)Aim  To explore the feasibility and acceptability of implementing a personalised care planning approach for diabetes care in general practice.Methods  A four‐stage care planning process was introduced for diabetes annual review, involving patients (1) being made aware of the new process, (2) attending an appointment to gather clinical data, (3) receiving and reviewing their results and (4) attending a care planning consultation. The latter is a collaborative discussion with the health professional about their response to their results, their goals and desired action plan. Health professionals received specialist training in personalised care planning, including practice observations and feedback.Results  Sixty‐six per cent of patients eligible to participate in the project attended both appointments and received an annual review. Of these, 89% also agreed a personalised care plan. Staff reported greater engagement among patients who had read and understood their results. Fourteen per cent of patients reported that they had not agreed a care plan but would have liked one. Patients reported increased confidence in managing their condition with 75% feeling that their ideas and goals were discussed completely.Conclusions  Introducing personalised care planning to general practice diabetes care is possible and well received. Our model for implementation of personalised care planning, which includes specialist training for practice teams and ongoing support from local colleagues and health organizations, can help to meet national recommendations for the provision of personalised care plans for people with long‐term conditions. When implementing personalised care planning, efficient administration is vital and behaviour change is necessary for both staff and patients.
Assessment of D216H DYT1 polymorphism in a Chinese primary dystonia patient cohort
Authors: Chen Y. , Burgunder J.‐M. , Song W. , Huang R. , Shang H.‐F. 
Published: November 2011

Background:  The D216H single‐nucleotide polymorphism (SNP) (rs1801968) in DYT1 exon 4 has been suggested to be a genetic modifier in primary dystonia.Methods:  To further explore this question, we assessed rs1801968 variations in a cohort of 210 Chinese patients with primary dystonia devoid of DYT1 mutations.Results:  We found that focal dystonia, specifically cervical dystonia, was the most common form of dystonia, with 8.1% of all the patients having a positive family history of dystonia. No association of the D216H SNP with primary dystonia was identified. In a subsequent subgroup analysis, the 216H allele was found to occur more frequently in patients with writer’s cramp, but no correlation was found between the allele and other forms of dystonia or age of onset.Conclusions:  Our findings do not confirm that the allele contributes to the risk of D216H SNP primary dystonia.
Associations Between Cytomegalovirus Infection and Functional Impairment and Frailty in the BELFRAIL Cohort
Authors: Matheï Catharina , Vaes Bert , Wallemacq Pierre , Degryse Jan 
Published: November 2011

ObjectivesTo investigate whether an observed association between cytomegalovirus (CMV) exposure and functional impairment and frailty in older adults is reproducible in a cohort of individuals aged 80 and older.DesignThe baseline results of the BELFRAIL study, a prospective observational cohort study, were analyzed.SettingThree well‐circumscribed areas of Belgium.ParticipantsFive hundred sixty‐seven persons aged 80 and older recruited by 29 general practitioners.MeasurementsSerum samples were assayed for levels of CMV immunoglobulin (Ig)G antibodies, interleukin (IL)‐6, and C‐reactive protein. Measures of functional impairment were the Physical Performance Battery, Activities of Daily Living, and the Mini‐Mental State Examination. Frailty was assessed using the Fried criteria.ResultsPositive CMV serology was found in 74% of the population, 61% of whom had a high anti‐CMV IgG titer (>250 IU/mL). CMV infection was not associated with functional or cognitive impairment. Positive CMV serology was negatively associated with prevalent frailty after adjusting for age, sex, level of education, comorbidity, smoking status, body mass index, and IL‐6 level. High levels of anti‐CMV IgG were associated with functional impairment. In the adjusted models, this relationship was no longer statistically significant. There was no association between prevalent frailty or cognitive impairment and high anti‐CMV IgG titers.ConclusionThe findings of previous studies could not be confirmed. Moreover, positive CMV serology was found to be negatively associated with frailty. These apparently contradictory results may reflect a survival effect because the current study population was considerably older than the populations of older adults in previous studies.
Precursors of adrenomedullin, endothelin and atrial natriuretic peptide as diagnostic markers of neonatal infection
Authors: Cao Yun , Xia Qing , Chen Chao , Yang Yi 
Published: November 2011

AbstractAim:  To evaluate the serum levels of three precursors of vasoactive peptide as diagnostic markers for neonatal infections.Methods:  Overall, 356 neonates (160 without infection, 114 with mild infections and 82 with severe infections) were enrolled in this study. Their serum levels of mid‐regional pro‐adrenomedullin (MR‐pro‐ADM), C‐terminal pro‐endothelin‐1 (CT‐pro‐ET‐1) and mid‐regional pro‐atrial natriuretic peptide (MR‐pro‐ANP) were measured by immunoassay, and receiver operating curve analysis was performed for each biomarker to evaluate their diagnostic values for neonatal infection.Results:  The serum levels of MR‐pro‐ADM (2.079 ± 1.195 nm), CT‐pro‐ET‐1 (109.4 ± 62.9 pm) and MR‐pro‐ANP (1221.4 ± 725.0 pm) in the severe infection group were significantly higher than those in the mild infection group (1.025 ± 0.421 nm, 86.7 ± 51.8 pm, and 687.6 ± 575.7 pm, respectively) and in the non‐infection group (0.853 ± 0.488 nm, 51.3 ± 40.6 pm, and 943.3 ± 847.3 pm, respectively) (p < 0.01–0.001). Their areas under the curve were 0.72, 0.76 and 0.61, respectively. Among them, CT‐pro‐ET‐1 had the highest sensitivity (82.65%), whereas MR‐pro‐ADM had the highest specificity (86.25%).Conclusions:  MR‐pro‐ADM, CT‐pro‐ET‐1 and MR‐pro‐ANP may serve as useful laboratory markers to indicate bacterial infection in neonates.
Sleep architecture in healthy 5‐year‐old preschool children: associations between sleep schedule and quality variables
Authors: Iwata Sachiko , Iwata Osuke , Iemura Akiko , Iwasaki Mizue , Matsuishi Toyojiro 
Published: November 2011

AbstractAim:  Although disturbed sleep quality such as night awakenings and difficulties in falling asleep are common symptoms during sleep in preschool children, relationships between sleep quality and sleep schedule are mostly unknown. This study aimed to evaluate the relationships between sleep schedule and quality variables in preschool children.Methods:  Sleep‐wake patterns of 48 healthy 5‐year‐old children were assessed over 7 consecutive days using actigraphy.Results:  Children with longer sleep latency had a lower sleep quality, a later bedtime, a later sleep onset time, a shorter nocturnal sleep period and a longer daytime nap. Children with a longer nocturnal sleep period on weekends compared with weekdays had longer sleep latency and a later sleep onset time on weekdays, resulting in a lower sleep quality on weekends. An irregular bedtime on weekdays was associated with a later sleep onset time and a shorter sleep period on weekends.Conclusion:  Sleep quality and schedule were linked with each other, whiche may explain why sleep problems tend to aggregate and form a wider syndrome of disturbed sleep even in young children. Strategies solely targeting the improvement of sleep quantity may not promote ideal sleep; simultaneous considerations for the sleep rhythm and quality may be required.