bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of CYP2C19 polymorphism on nelfinavir to M8 biotransformation in HIV patients
Authors: Hirt Déborah , Mentré France , Tran Agnès , Rey Elisabeth , Auleley Solange , Salmon Dominique , Duval Xavier , Tréluyer Jean‐Marc ,   The COPHAR2‐ ANRS Study Group
Published: October 2007

What is already known about this subject • Nelfinavir is an HIV protease inhibitor, substrate of the transporter P‐glycoprotein and metabolized via CYP2C19, CYP3A4 and CYP3A5 enzymes.• Pharmacokinetic studies have shown wide interindividual variability of nelfinavir concentrations, some of this variability perhaps caused by variant drug metabolism or transporter genes.• For CYP3A4*1B and CYP3A5*3 polymorphism, results from three studies are in agreement, showing no difference in nelfinavir concentrations between patients with these different genotypes.• However, for MDR1 and CYP2C19 polymorphism, there have been contradictory studies, showing either no impact on nelfinavir concentration or modified concentrations which could influence virological response. What this study adds • Patients with an *1/*2 or *2/*2 genotype for CYP2C19 had a nelfinavir to M8 biotransformation divided by 2 compared with *1/*1 patients.• No evidence of any influence of MDR1 polymorphism on nelfinavir absorption could be detected.AimsTo evaluate the effect of CYP2C19 polymorphism on nelfinavir and M8 pharmacokinetic variability in human immunodeficiency virus‐infected patients and to study the link between pharmacokinetic exposure and short‐term efficacy and toxicity.MethodsNelfinavir (n = 120) and M8 (n = 119) concentrations were measured in 34 protease inhibitor‐naïve patients. Two weeks after initiating the treatment, blood samples were taken before, 1, 3 and 6 h after drug administration. Genotyping for CYP3A4, 3A5, 2C19 and MDR1 was performed. A population pharmacokinetic model was developed to describe nelfinavir‐M8 concentration time‐courses and to estimate interpatient variability. The influence of individual characteristics and genotypes were tested using a likelihood ratio test. Estimated mean (Cmean), maximal (Cmax) and trough (Ctrough) nelfinavir and M8 concentrations were correlated to short‐term virological efficacy and tolerance using Spearman nonparametric correlation tests.ResultsA one‐compartment model with first‐order absorption, elimination and metabolism to M8 best described nelfinavir data. M8 was modelled by an additional compartment. Mean pharmacokinetic estimates and the corresponding intersubject variabilities were: absorption rate 0.17 h−1 (99%), absorption lag time 0.82 h, apparent nelfinavir total clearance 52 l h−1 (49%), apparent nelfinavir volume of distribution 191 l, M8 elimination rate constant 1.76 h−1 and nelfinavir to M8 0.39 h−1 (59%) in *1/*1 patients and 0.20 h−1 in *1/*2 or *2/*2 patients for CYP2C19*2. Nelfinavir Cmean was positively correlated to glycaemia and triglyceride increases (P = 0.02 and P = 0.04, respectively).ConclusionsThe rate of metabolism of nelfinavir to M8 was reduced by 50% in patients with *1/*2 or *2/*2 genotype for CYP2C19 compared with those with *1/*1 genotype.
Bioavailable testosterone is associated with a reduced risk of amnestic mild cognitive impairment in older men
Authors: Chu Leung‐Wing , Tam Sidney , Lee Peter W. H. , Wong Rachel L. C. , Yik Ping‐Yiu , Tsui Wilson , Song Youqiang , Cheung Bernard M. Y. , Morley John E. , Lam Karen S. L. 
Published: October 2007

SummaryObjective  We investigated the risk of amnestic mild cognitive impairment (aMCI) in relation to serum bioavailable (BT) and total testosterone (TT) levels in older men.Design, setting and subjects  A cross‐sectional study in an ambulatory setting, with older men aged 55–93 years with normal cognition, aMCI and Alzheimer's disease (AD).Measurements  Morning serum BT and TT levels were determined. AD was diagnosed by the Neurological and Communicative Disorders and Stroke/Alzheimer's Disease and Related Disorders Association (NINCDS‐ADRDA) criteria for probable AD and aMCI by the Petersen criteria.Results  We recruited 203 Chinese older men (48 aMCI, 66 AD and 89 with normal cognition). Mean serum BT, but not TT, levels were significantly lower in the aMCI (mean BT ± SEM 1·06 ± 0·10 nmol/l) and AD (0·99 ± 0·08 nmol/l) groups than in the normal controls (1·82 ± 0·12 nmol/l) (P < 0·001, one‐way anova) with no significant difference between the aMCI and AD groups. After adjustment for education, age and apolipoprotein E (apoE) genotype, logistic regression analyses showed that the serum BT level [adjusted odds ratio (OR) = 0·52, 95% confidence interval (CI) 0·32–0·85] was an independent protective factor for aMCI. For the combined outcome of aMCI and AD, the serum BT level was an independent protective factor but age and apoE ɛ4 were independent risk factors. There was no interaction between BT and age.Conclusions  In older men, serum BT, but not TT, levels were associated with a lower risk of aMCI and AD.
Leptin therapy for partial lipodystrophy linked to a PPAR‐γ mutation
Authors: Guettier Jean‐Marc , Park Jean Y. , Cochran Elaine K. , Poitou Christine , Basdevant Arnaud , Meier Muriel , Clément Karine , Magré Jocelyne , Gorden Phillip 
Published: October 2007

SummaryAims/hypothesis  Partial lipodystrophy (PL) is most commonly characterized by loss of subcutaneous fat in the extremities with preservation of truncal fat and is associated with insulin resistance, diabetes and hyperlipidaemia. Recombinant human leptin (r‐metHuLeptin) therapy has been shown to be effective in treating metabolic abnormalities associated with congenital or acquired generalized lipodystrophy and PL associated with lamin A/C (LMNA) gene mutations or highly active antiretroviral therapy (HAART). Our aim was to assess the effectiveness of leptin therapy in treating metabolic complications of PL associated with heterozygous peroxisome proliferator activated receptor gamma (PPARG) mutations. This is the first report to detail the clinical response of a patient with PL due to a PPARG mutation treated with r‐metHuLeptin.Methods  A 36‐year‐old female with PL associated with a heterozygous PPARG mutation complicated by poorly controlled diabetes and severe, refractory hypertriglyceridaemia was enrolled in a National Institutes of Health (NIH) protocol to evaluate the role of r‐metHuLeptin in lipodystrophy. The patient received escalating doses of r‐metHuLeptin until a dose 0·12 mg/kg/day was reached. Metabolic parameters, including serum chemistries, fasting blood glucose, glycated haemoglobin (HbA1c), lipid profile, an oral glucose tolerance test (OGTT), an insulin tolerance test (ITT), liver volume, percentage body fat and energy expenditure were followed at regular time intervals over 18 months of therapy.Results  Eighteen months of r‐MetHuLeptin therapy was associated with a marked improvement in glucose homeostasis as evidenced by normalization of the fasting blood glucose (baseline = 8·3 mmol/l; 18 months = 4·9 mmol/l), lowering of HbA1c (baseline = 9·9%; 18 months = 7·2%) and improved tolerance to an oral glucose load. In addition, a striking amelioration in the patient's refractory, severe hypertriglyceridaemia was observed (baseline = 21·15 mmol/l; 18 months = 5·96 mmol/l).Conclusion  r‐MetHuLeptin is effective in treating metabolic complications associated with PL due to PPARG mutations. In the context of previously published work, our findings suggest that the response to r‐MetHuLeptin is independent of the aetiology in lipodystrophy.
Radioiodine treatment for benign thyroid disorders: results of a nationwide survey of UK endocrinologists
Authors: Vaidya Bijay , Williams Graham R. , Abraham Prakash , Pearce Simon H. S. 
Published: October 2007

SummaryBackground  A survey of physicians’ practice relating to radioiodine administration for hyperthyroidism was carried out in the UK over 15 years ago and showed wide variations in patient management. This led to the development of national guidelines for the use of radioiodine in hyperthyroidism. As there have been significant advances in the field since that survey, we carried out another survey to study the prevalent practices relating to radioiodine therapy for benign thyroid disorders across the UK.Subjects and methods  We mailed 698 UK consultant endocrinologists a questionnaire on radioiodine treatment based on three patient scenarios: hyperthyroid Graves’ disease, subclinical hyperthyroidism and nontoxic goitre.Results  The response rate was 40%. For the scenario of an initial presentation of Graves’ disease, 80%, 19% and 0·4% of respondents preferred thionamide, radioiodine or thyroidectomy, respectively. There were inconsistencies in respondents’ recommendations on radioiodine dose, the use of pre‐ and post‐radioiodine supplementary treatments, timing of a repeat dose, and the use of radioiodine in thyroid eye disease. For the case of subclinical hyperthyroidism, one‐third of respondents would generally initiate treatment. The majority were more likely to treat subclinical hyperthyroidism in the presence of paroxysmal atrial fibrillation or osteoporosis. If a decision were made to treat subclinical hyperthyroidism, 63%, 35%, 1% and 0·4% would recommend radioiodine, thionamide, beta‐blocker and thyroidectomy, respectively. For the scenario of nontoxic goitre, 62%, 21%, 13% and 5% favoured observation, thyroidectomy, radioiodine and thyroxine, respectively.Conclusions  There remain significant differences in several aspects of clinical practice relating to the use of radioiodine treatment for benign thyroid disorders in the UK.
Evaluation of adrenal function using the human corticotrophin‐releasing hormone test, low dose Synacthen test and 9am cortisol level in children and adolescents with central adrenal insufficiency
Authors: Maguire Ann M. , Biesheuvel Cornelis J. , Ambler Geoffrey R. , Moore Bin , McLean Mark , Cowell Christopher T. 
Published: October 2007

SummaryBackground  The insulin tolerance test (ITT) has become less popular in paediatrics because of the risks associated with hypoglycaemia. Human corticotrophin‐releasing hormone (hCRH) test results correlate with the ITT and may be an acceptable method to test for central adrenal insufficiency (CAI). Simpler tests, such as the low dose Synacthen test (LDST) and 9am cortisol, have also been proposed.Objective  To compare the ability of the hCRH test, LDST, 9am cortisol level and 24‐h cortisol profiles to diagnose CAI in a paediatric population.Design and setting  A cross‐sectional study in a tertiary paediatric endocrine clinic.Participants  Thirty‐one children and adolescents (aged 2·3–18·3 years) with CAI risk factors had an hCRH test, LDST, 9am cortisol and 24‐h cortisol profile performed.Results  Of 23 patients with confirmed CAI (hCRH peak cortisol < 400 nmol/), 19 failed the LDST (peak cortisol < 267 nmol/l, i.e. 10th percentile for controls). Nineteen would have failed based on the 10th percentile cut point for 9am cortisol (< 140 nmol/l). Using receiver operating characteristic (ROC) curve coordinates, a 9am cortisol < 108 nmol/l was sensitive (83%) and specific (99%) for CAI. The 9am cortisol levels measured on two occasions were repeatable (94%) and correlated (r = 0·83, P = 0·01). All eight adrenally sufficient patients (hCRH peak cortisol ≥ 400 nmol/l) passed the LDST. Seven had normal 9am cortisol (≥ 140 nmol/l). The 24‐h cortisol area under the curve (AUC) for these patients was within the 10th–90th percentiles for control subjects’ AUC. The peak cortisol to hCRH and LDST were correlated (r = 0·88, P = 0·01), with no difference between the peaks (mean difference –5·3 nmol/l, P = 0·69).Conclusions  In children with CAI risk factors, the diagnosis can be made if unstressed 9am cortisol is < 108 nmol/l. As cortisol levels > 381 nmol/l are highly suggestive of normal hypothalamic–pituitary–adrenal (HPA) function, stimulation testing need only be performed if 9am cortisol is 108–381 nmol/l. The LDST should be interpreted cautiously because mild CAI may be missed. When stimulation results are marginal, 24‐h cortisol profiles can provide reassurance of normal cortisol status.
Identification of molecular mechanisms related to nonthyroidal illness syndrome in skeletal muscle and adipose tissue from patients with septic shock
Authors: Rodriguez‐Perez Alfonso , Palos‐Paz Fernando , Kaptein Ellen , Visser Theo J. , Dominguez‐Gerpe L. , Alvarez‐Escudero Julian , Lado‐Abeal Joaquin 
Published: October 2007

SummaryObjective  Septic shock is one of various causes of nonthyroidal illness syndrome (NTIS). In humans, the molecular mechanisms involved in NTIS are mostly unknown. The aim of this study was to investigate, in patients with NTIS secondary to septic shock, changes in the expression of genes involved in the actions of thyroid hormones and in the activity of deiodinase enzymes, in two tissues important for protein and energy metabolism, skeletal muscle (SM) and subcutaneous adipose tissue (SAT).Design  Hospitalized patients were divided into a control and a septic shock NTIS group.Measurement  Serum collection for biochemical measurements, and SM and SAT biopsies for mRNA expression analysis of thyroid hormone receptors (THRB1, THRA1), retinoid X receptors (RXRA, RXRB, RXRG), nuclear receptor corepressor (NCOR1), silencing mediator of retinoid and thyroid hormone receptor (SMRT), steroid receptor coactivator (SRC1), type 1 and 2 deiodinases (D1, D2), monocarboxylate transporter 8 (MCT8), SECIS binding protein 2 (SBP2) and uncoupling protein 3 (UCP3) as well as D1, D2 and D3 enzyme activity measurements.Results  The NTIS group had lower serum TSH, and free T3 and higher rT3 than controls. D1 and D3 were detected in SAT, with no differences found between the two groups; SM had very low D2 activity and again no differences were found between groups; D3 activity in SM was higher in NTIS than controls. SM expression of THRB1, RXRG and D2 was lower and RXRA higher in NTIS than controls. SAT from NTIS patients had lower MCT8, THRB1, THRA1, RXRG and SMRT, and higher UCP3 expression than controls.Conclusions  In patients with septic shock NTIS tissue responses are orientated to decrease production and increase degradation (muscle) or decrease uptake (adipose tissue) of T3, as well as to decrease thyroid hormone actions.
Association of ENPP1 (PC‐1) K121Q polymorphism with obesity‐related parameters in subjects with metabolic syndrome
Authors: González‐Sánchez José L. , Zabena Carina , Martínez‐Larrad María T. , Martínez‐Calatrava María J. , Pérez‐Barba Milagros , Serrano‐Ríos Manuel 
Published: October 2007

SummaryBackground  The metabolic syndrome (MS), a cluster of several metabolic disorders, is increasingly being recognized as a risk factor for cardiovascular disease. Ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1), originally described as a plasma cell allo‐antigen and named plasma cell membrane glycoprotein (PC‐1), is an inhibitor of insulin‐induced activation of the insulin receptor. The single nucleotide polymorphism (SNP) K121Q in the ENPP1 gene has been studied in relation to obesity, insulin resistance and other features of MS in several populations with conflicting results.We therefore investigate the role of the K121Q SNP in the ENPP1 gene in MS in Caucasians from the province of Segovia in Central Spain (Castille).Design and methods  We recruited 794 unrelated persons (46·5% males and 53·5% females), ages 35–74 years from a cross‐sectional population‐based epidemiological survey in the province of Segovia in Central Spain (Castille). Obesity‐related anthropometric measurements included BMI, waist circumference, blood pressure and lipid profile. MS was defined by International Diabetes Federation (IDF) guidelines. K121Q PC‐1 genotypes were determined by polymerase chain reaction‐restriction fragment length polymorphism (PCR‐RFLP).Results  The 121Q allele was associated with an increased BMI and waist circumference among subjects fulfilling the criteria for MS. These differences remained statistically significant even after the adjustment for sex, age and degree of glucose tolerance (β = 1·347, P = 0·017 and β = 2·824, P = 0·046; for BMI and waist circumference, respectively). Moreover, among type 2 diabetic patients those carrying the 121Q allele had higher BMI and higher leptin levels than subjects carrying the K121K genotype.Conclusions  Our results suggest that the ENPP1121Q allele might contribute to the genetic susceptibility to abdominal obesity among subjects with MS.
Adaptive differences in gene expression in European flounder (Platichthys flesus)
Authors: LARSEN PETER F. , NIELSEN EINAR E. , WILLIAMS TIMOTHY D. , HEMMER‐HANSEN JAKOB , CHIPMAN JAMES K. , KRUHØFFER MOGENS , GRØNKJÆR PETER , GEORGE STEPHEN G. , DYRSKJØT LARS , LOESCHCKE VOLKER 
Published: October 2007

AbstractPopulation structure was previously believed to be very limited or absent in classical marine fishes, but recently, evidence of weakly differentiated local populations has been accumulating using noncoding microsatellite markers. However, the evolutionary significance of such minute genetic differences remains unknown. Therefore, in order to elucidate the relationship between genetic markers and adaptive divergence among populations of marine fishes, we combined cDNA microarray and microsatellite analysis in European flounders (Platichthys flesus). We demonstrate that despite extremely low levels of neutral genetic divergence, a high number of genes were significantly differentially expressed between North Sea and Baltic Sea flounders maintained in a long‐term reciprocal transplantation experiment mimicking natural salinities. Several of the differentially regulated genes could be directly linked to fitness traits. These findings demonstrate that flounders, despite little neutral genetic divergence between populations, are differently adapted to local environmental conditions and imply that adaptation in gene expression could be common in other marine organisms with similar low levels of population subdivision.
Exhumation across the Indus Suture Zone: a record of back sliding of the hanging wall
Authors: Zeilinger Gerold , Seward Diane , Burg Jean‐Pierre 
Published: October 2007

AbstractThe Kohistan Arc Complex is an integral part of the NW Himalayan collision system and is bounded by two major suture zones, the Indus Suture Zone (ISZ) and the Northern Suture in the south and north respectively. Fission‐track analyses on samples collected along the Indus River across the arcuated ISZ in the Besham region are presented here. The footwall yields zircon and apatite fission‐track (FT) ages of ∼23 Ma and ∼3.7 Ma respectively; the hanging wall ages range from 24 to 42 Ma for zircon and ∼10 Ma for apatite. Thus, the change in ISZ kinematics from thrusting to normal faulting was not later than Oligocene and normal faulting on this ISZ segment was still active at least into early Pliocene times. At this time normal faulting had already ended at other ISZ segments, but it was still (or again) active across the ISZ in the Besham region most likely as a local phenomenon caused by the growth of the Indus Syntaxis, a transverse antiform parallel to the Nanga Parbat Syntaxis.
Sweet delivery – sugar translocators as ports of entry for antisense oligodeoxynucleotides in plant cells
Authors: Sun Chuanxin , Ridderstråle Karin , Höglund Anna‐Stina , Larsson Lars‐Gunnar , Jansson Christer 
Published: October 2007

SummaryAntisense oligodeoxynucleotides (ODNs) are short (12–25 nt long) stretches of single‐stranded DNA that may be delivered to a cell, where they hybridize to the cognate mRNA in a sequence‐specific manner, thereby inhibiting gene expression. Here we used confocal microscopy to monitor the uptake and trafficking of ODNs in barley tissues. We conclude that uptake of ODNs across the plant plasma membrane is mediated by active transport of mono‐ or disaccharides through sugar translocators. We demonstrate that sugar transport can deliver ODNs to barley seeds, and that this strategy may be employed to suppress gene activity in endosperm cells by antisense ODN inhibition. We further found that sucrose compared favorably with oligofectamine as a vehicle for ODN delivery to human cells in a low‐serum environment.
Effects of cumulus cells on rabbit oocyte in vitro maturation
Authors: Tao Y. , Cao C. , Zhang M. , Fang F. , Liu Y. , Zhang Y. , Ding J. , Zhang X. 
Published: October 2007

SummaryCumulus cells (CCs) are of great importance in oocyte development and maturation in many species, but detailed influence of CCs has not been extensively examined, especially on rabbit. The present study was designed to investigate the effects of CCs and the elongation of in vitro maturation (IVM) time on rabbit oocyte nuclear and ooplasmic maturation and survival. Cumulus oocyte complexes (COCs) and naked oocytes (NOs) were recovered directly from rabbits super‐ovulated with eCG. Corona‐enclosed oocytes (COs) and denuded oocytes (DOs) were obtained from COCs after removing a part or whole of CCs. The oocytes were cultured in the following seven groups. (i) Cumulus cell enclosed oocytes (CEOs) were cultured alone (CEOs); (ii) COs were cultured alone (COs); (iii) DOs were cultured alone (DOs); (iv) NOs were cultured alone; (v) DOs were co‐cultured with COCs [DOs(COCs)]; (vi) DOs were co‐cultured with CCs [DOs(CCs)]; (vii) NOs were co‐cultured with CCs [NOs(CCs)]. After the oocytes were cultured for 24 and 30 h, the nuclear maturation was evaluated by first polar body (PB1) extrusion while the ooplasmic maturation was evaluated by the cleavage rate after parthenogenetic activation. The results showed that the nuclear maturation rate of CEOs, COs, DOs(COCs) and DOs(CCs) after 24 h incubation were significantly different from each other (p ≤ 0.05), the rate of DOs(CCs) was similar to that of DOs (p ≥ 0.05). The cleavage rates in the first two groups were significantly higher than those of the others (p < 0.05). For oocytes cultured for 30 h, the nuclear maturation rates were significantly different for each culture model (p < 0.05). The cleavage rates in first two groups were significantly higher than those of others (p < 0.05). Both the nuclear and cleavage rates significantly increased when the culture time of DOs(COCs) was prolonged from 24 to 30 h. DOs(CCs) nuclear maturation was significantly improved when the culture time was prolonged from 24 to 30 h, but the ooplasmic maturation was not. Few NOs incubated with or without CCs accomplished nuclear maturation (approximately 2% both), even when the culture time was prolonged from 24 to 30 h. The oocyte degeneration rates were significantly different for each culture model after both 24 and 30 h incubation (p ≤ 0.05). There was no significant difference in oocyte degeneration in the same groups between 24 and 30 h incubation (p > 0.05). The results suggest that rabbit CCs affect oocyte nuclear and ooplasmic maturation, and their survival. The prolongation of the culture time of rabbit oocyte from 24 to 30 h improves the nuclear and ooplasmic maturation differently in the present system. Rabbit oocytes free of CCs, especially NOs, show weak meiotic resumption potential and compromised viability, which cannot be improved by co‐culture with dispersed CCs. The degeneration mostly happens at early time of IVM.