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Showing papers by "Erasmus University Medical Center published in 2007"


Journal ArticleDOI
TL;DR: Most consistent positive correlates of PA were father's PA, time spent outdoors and school PA‐related policies, and support from significant others, mother’s education level, family income, and non‐vocational school attendance (in adolescents).
Abstract: Obesogenic environments are thought to underlie the increased obesity prevalence observed in youth during the past decades. Understanding the environmental factors that are associated with physical activity (PA) in youth is needed to better inform the development of effective intervention strategies attempting to halt the obesity epidemic. We conducted a systematic semi-quantitative review of 150 studies on environmental correlates of youth PA published in the past 25 years. The ANalysis Grid for Environments Linked to Obesity (ANGELO) framework was used to classify the environmental correlates studied. Most studies retrieved used cross-sectional designs and subjective measures of environmental factors and PA. Variables of the home and school environments were especially associated with children's PA. Most consistent positive correlates of PA were father's PA, time spent outdoors and school PA-related policies (in children), and support from significant others, mother's education level, family income, and non-vocational school attendance (in adolescents). Low crime incidence (in adolescents) was characteristic of the neighbourhood environment associated with higher PA. Convincing evidence of an important role for many other environmental factors was, however, not found. Further research should aim at longitudinal and intervention studies, and use more objective measures of PA and its potential (environmental) determinants.

956 citations


Journal ArticleDOI
TL;DR: Current thinking about how gene conversion occurs is assessed, the key part it has played in fashioning extant human genes is explored, and a meta-analysis of gene-conversion events that are known to have caused human genetic disease is carried out.
Abstract: Gene conversion, one of the two mechanisms of homologous recombination, involves the unidirectional transfer of genetic material from a 'donor' sequence to a highly homologous 'acceptor'. Considerable progress has been made in understanding the molecular mechanisms that underlie gene conversion, its formative role in human genome evolution and its implications for human inherited disease. Here we assess current thinking about how gene conversion occurs, explore the key part it has played in fashioning extant human genes, and carry out a meta-analysis of gene-conversion events that are known to have caused human genetic disease.

609 citations


Journal ArticleDOI
TL;DR: All the cardinal features of asthma, including eosinophilic airway inflammation, Th2 cytokine production and bronchial hyper-reactivity, were abrogated when lung ATP levels were locally neutralized using apyrase or when mice were treated with broad-spectrum P2-receptor antagonists.
Abstract: Extracellular ATP serves as a danger signal to alert the immune system of tissue damage by acting on P2X or P2Y receptors. Here we show that allergen challenge causes acute accumulation of ATP in the airways of asthmatic subjects and mice with experimentally induced asthma. All the cardinal features of asthma, including eosinophilic airway inflammation, Th2 cytokine production and bronchial hyper-reactivity, were abrogated when lung ATP levels were locally neutralized using apyrase or when mice were treated with broad-spectrum P2-receptor antagonists. In addition to these effects of ATP in established inflammation, Th2 sensitization to inhaled antigen was enhanced by endogenous or exogenous ATP. The adjuvant effects of ATP were due to the recruitment and activation of lung myeloid dendritic cells that induced Th2 responses in the mediastinal nodes. Together these data show that purinergic signaling has a key role in allergen-driven lung inflammation that is likely to be amenable to therapeutic intervention.

581 citations



Journal ArticleDOI
TL;DR: In this paper, the authors reported mutations in the gene encoding RANKL (receptor activator of nuclear factor-KB ligand) in six individuals with SRO whose bone biopsy specimens lacked osteoclasts.
Abstract: Autosomal recessive osteopetrosis is usually associated with normal or elevated numbers of nonfunctional osteoclasts. Here we report mutations in the gene encoding RANKL (receptor activator of nuclear factor-KB ligand) in six individuals with autosomal recessive osteopetrosis whose bone biopsy specimens lacked osteoclasts. These individuals did not show any obvious defects in immunological parameters and could not be cured by hematopoietic stem cell transplantation; however, exogenous RANKL induced formation of functional osteoclasts from their monocytes, suggesting that they could, theoretically, benefit from exogenous RANKL administration.

358 citations


Journal ArticleDOI
TL;DR: Initial support for the taxonomic generalizability of the 8-syndrome model across very diverse societies, both genders, and 2 age groups is provided.
Abstract: As a basis for theories of psychopathology, clinical psychology and related disciplines need sound taxonomies that are generalizable across diverse populations. To test the generalizability of a statistically derived 8-syndrome taxonomic model for youth psychopathology, confirmatory factor analyses (CFAs) were performed on the Youth Self-Report (T. M. Achenbach & L. A. Rescorla, 2001) completed by 30,243 youths 11-18 years old from 23 societies. The 8-syndrome taxonomic model met criteria for good fit to the data from each society. This was consistent with findings for the parent-completed Child Behavior Checklist (Achenbach & Rescorla, 2001) and the teacher-completed Teacher's Report Form (Achenbach & Rescorla, 2001) from many societies. Separate CFAs by gender and age group supported the 8-syndrome model for boys and girls and for younger and older youths within individual societies. The findings provide initial support for the taxonomic generalizability of the 8-syndrome model across very diverse societies, both genders, and 2 age groups.

306 citations


Journal ArticleDOI
TL;DR: Mirror therapy combined with a conventional stroke rehabilitation program enhances lower-extremity motor recovery and motor functioning in subacute stroke patients.

291 citations


Journal ArticleDOI
TL;DR: Intervention programs in search of amendable factors to prevent SSI should focus on timely administration of antibiotic prophylaxis, according to this study.
Abstract: Background. Surgical site infections (SSIs) following total hip arthroplasty can lead to prolonged hospitalization, increased morbidity and mortality, and high costs. This article analyzes the effect of various parameters of surgical antibiotic prophylaxis on the risk of SSI following total hip arthroplasty. Methods. Data about SSI and potential prophylaxis-, patient-, and procedure-related risk factors were prospectively collected for 1922 patients who underwent elective total hip arthroplasty in 11 hospitals that participated in the Dutch intervention project, Surgical Prophylaxis and Surveillance. Multivariate logistic regression analysis was performed to correct for random variation among hospitals. Results. SSIs (superficial and deep) occurred in 50 patients (2.6%). The highest odds ratios for SSI were found in patients who received prophylaxis after incision (2.8, 95% confidence interval [CI], 0.9-8.6; P = .07), had an American Society of Anesthesiology score that was >2 (2.8, 95% CI, 0.8-9.2; P = .09), and experienced a duration of surgery that was >75th percentile (2.5; 95% CI, 1.1-5.8; P = .04). Prolonged prophylaxis after the end of surgery and the use of antibiotic-impregnated cement did not contribute to fewer SSIs in this study. Conclusions. This study suggests that intervention programs in search of amendable factors to prevent SSI should focus on timely administration of antibiotic prophylaxis.

264 citations


Journal ArticleDOI
TL;DR: A robust method for the isolation of IgG subclasses using protein A (binds IgG1, IgG2, and IgG4) and protein G ( binds additionally IgG3) at the 96‐well plate level, which is suitable for automation is described and revealed distinct differences in N‐glycosylation between the four IgGSubclasses.
Abstract: All four subclasses of human serum IgG contain a single N-glycosylation site in the constant region of their heavy chain, which is occupied by biantennary, largely core-fucosylated and partially truncated oligosaccharides, that may carry a bisecting N-acetylglucosamine and sialic acid residues. IgG glycosylation has been shown to be altered under various physiological and pathological circumstances. IgG N-glycan profiles vary with age, and galactosylation for example is enhanced during pregnancy. Several diseases including rheumatoid arthritis are associated with a reduction in galactosylation of the IgG N-glycans. Here, we describe a robust method for the isolation of IgG subclasses using protein A (binds IgG1, IgG2, and IgG4) and protein G (binds additionally IgG3) at the 96-well plate level, which is suitable for automation. Isolated IgGs were digested with trypsin, and obtained glycopeptides were analyzed by nano-LC-MS. Glycopeptides were characterized by CID as well as electron transfer dissociation (ETD). The method provided glycosylation profiles for IgG1, IgG2, IgG3, and IgG4 and revealed distinct differences in N-glycosylation between the four IgG subclasses. The changes in galactosylation associated with rheumatoid arthritis could readily be monitored. This method is suitable for the subclass-specific analysis of IgG glycosylation from clinical samples.

261 citations


Journal ArticleDOI
05 Dec 2007-PLOS ONE
TL;DR: This study considers a situation when study participants are genetically related and proposes a fast two-step method called Genome-wide Association using Mixed Model and Regression (GRAMMAR) for the analysis of pedigree-based quantitative traits.
Abstract: textBackground. Feasibility of genotyping of hundreds and thousands of single nucleoticle polymorphisms (SNPs) in thousands of study subjects have triggered the need for fast, powerful, and reliable methods for genome-wide association analysis. Here we consider a situation when study participants are genetically related (e.g. due to systematic sampling of families or because a study was performed in a genetically isolated population). Of the available methods that account for relatedness, the Measured Genotype (MG) approach is considered the 'gold standard'. However, MG is not efficient with respect to time taken for the analysis of genome-wide data. In this context we proposed a fast two-step method called Genome-wide Association using Mixed Model and Regression (GRAMMAR) for the analysis of pedigree-based quantitative traits. This method certainly overcomes the drawback of time limitation of the measured genotype (MG) approach, but pays in power. One of the major drawbacks of both MG and GRAMMAR, is that they crucially depend on the availability of complete and correct pedigree data, which is rarely available. Methodology. In this study we first explore type 1 error and relative power of MG, GRAMMAR, and Genomic Control (GCC) approaches for genetic association analysis. Secondly, we propose an extension to GRAMMAR i.e. GRAMMAR-GC. Finally, we propose application of GRAMMAR-GC using the kinship matrix estimated through genomic marker data, instead of (possibly missing and/or incorrect) genealogy. Conclusion. Through simulations we show that MG approach maintains high power across a range of heritabilities and possible pedigree structures, and always outperforms other contemporary methods. We also show that the power of our proposed GRAMMAR-GC approaches to that of the 'gold standard' MG for all models and pedigrees studied. We show that this method is both feasible and powerful and has correct type 1 error in the context of genome-wide association analysis in related individuals.

251 citations


Journal ArticleDOI
TL;DR: It is shown that the availability of thyroid hormone within the hypothalamus is a key determinant of seasonal transitions, and a pivotal role for hypothalamic DIO3 and T(3) catabolism in seasonal cycles of body weight and reproduction in mammals.
Abstract: Seasonal adaptations in physiology exhibited by many animals involve an interface between biological timing and specific neuroendocrine systems, but the molecular basis of this interface is unknown. In this study of Siberian hamsters, we show that the availability of thyroid hormone within the hypothalamus is a key determinant of seasonal transitions. The expression of the gene encoding type III deiodinase (Dio3) and Dio3 activity in vivo (catabolism of T4 and T3) is dynamically and temporally regulated by photoperiod, consistent with the loss of hypothalamic T3 concentrations under short photoperiods. Chronic replacement of T3 in the hypothalamus of male hamsters exposed to short photoperiods, thus bypassing synthetic or catabolic deiodinase enzymes located in cells of the ependyma of the third ventricle, prevented the onset of short-day physiology: hamsters maintained a long-day body weight phenotype and failed to undergo testicular and epididymal regression. However, pelage moult to a winter coat was n...

Journal ArticleDOI
TL;DR: Ducks may maintain influenza virus from 1 year to the next as long as the duck population does not change significantly.
Abstract: We conducted large-scale, systematic sampling of influenza type A virus in migratory waterfowl (mostly mallards [Anas platyrhynchos]) at Ottenby Bird Observatory, southeast Sweden. As with previous studies, we found a higher prevalence in fall than spring, and among juveniles compared with adults. However, in contrast to other studies, we found that prevalence in spring was sometimes high (mean 4.0%, highest 9.5%). This finding raises the possibility that ducks are capable of perpetuating influenza A virus of different subtypes and subtype combinations throughout the year and from 1 year to the next. Isolation of the H5 and H7 subtypes was common, which suggests risk for transmission to sensitive domestic animals such as poultry. We argue that wild bird screening can function as a sentinel system, and we give an example of how it could have been used to forecast a remote and deadly outbreak of influenza A in poultry.

Journal ArticleDOI
TL;DR: Results indicate considerable consistency across 24 countries in adolescents' self-reported problems but less consistency for positive qualities.
Abstract: In this study, the authors compared ratings of behavioral and emotional problems and positive qualities on the Youth Self-Report (T. M. Achenbach & L. A. Rescorla, 2001) by adolescents in general population samples from 24 countries (N = 27,206). For problem scales, country effect sizes (ESs) ranged from 3% to 9%, whereas those for gender and age ranged from less than 1% to 2%. Scores were significantly higher for girls than for boys on Internalizing Problems and significantly higher for boys than for girls on Externalizing Problems. Bicountry correlations for mean problem item scores averaged .69. For Total Problems, 17 of 24 countries scored within one standard deviation of the overall mean of 35.3. In the 19 countries for which parent ratings were also available, the mean of 20.5 for parent ratings was far lower than the self-report mean of 34.0 in the same 19 countries (d = 2.5). Results indicate considerable consistency across 24 countries in adolescents' self-reported problems but less consistency for positive qualities.

Journal ArticleDOI
TL;DR: As a number of VDAs are now being tested in clinical studies, their mechanism of action and the results obtained in preclinical studies are discussed and data from clinical studies will be reviewed and some considerations with regard to the future development are given.
Abstract: Growth of human tumours depends on the supply of oxygen and nutrients via the surrounding vasculature. Therefore tumour vasculature is an attractive target for anticancer therapy. Apart from angiogenesis inhibitors that compromise the formation of new blood vessels, a second class of specific anticancer drugs has been developed. These so-called vascular disrupting agents (VDAs) target the established tumour vasculature and cause an acute and pronounced shutdown of blood vessels resulting in an almost complete stop of blood flow, ultimately leading to selective tumour necrosis. As a number of VDAs are now being tested in clinical studies, we will discuss their mechanism of action and the results obtained in preclinical studies. Also data from clinical studies will be reviewed and some considerations with regard to the future development are given.

Journal ArticleDOI
TL;DR: It is concluded that dialysis patients have a lower quality of life than RTx patients, but this difference can partly be explained by differences in age and prevalence of diabetes.

Journal ArticleDOI
15 Nov 2007-Blood
TL;DR: It is found that in these leukemias, the CEBPA gene was silenced, which was associated with frequent promoter hypermethylation, and the enhanced expression of TRIB2, which is identified here as a direct target of the T-cell commitment factor NOTCH1, suggested aberrantly activated Notch signaling.

Journal ArticleDOI
TL;DR: Gender differences in sedentary and physical exercise behaviors and their association with overweight status in children from nine European countries are described and differences between boys and girls regarding the behaviors and risks for overweight are noteworthy.
Abstract: Before starting interventions addressing energy-balance related behaviors, knowledge is needed about the prevalence of sedentary behaviors and low physical exercise, their interrelationships, possible gender differences. Therefore this study aimed to describe gender differences in sedentary and physical exercise behaviors and their association with overweight status in children from nine European countries. Additionally, to identify clusters of children sharing the same pattern regarding sedentary and physical exercise behavior and compare these groups regarding overweight status. Cross-sectional study among 11-year-old children in nine countries (n = 12538). Self-administered questionnaires assessed the time spent on TV viewing during dinner and during the day, PC use and on physical exercise. The parents reported children's weight and height. Descriptive statistics, cluster analyses, and logistic regression analyses were used for data analyses. Boys spent more time on sedentary behaviors but also more on physical exercise than girls. High TV viewing and low exercise behavior independently increased the risk of being overweight. Based on the behaviors, five clusters were identified. Among boys, clear associations with being overweight were found, with the most unhealthy behavior pattern having the highest risks of being overweight. Among girls, high TV viewers and high PC users had increased risk of being overweight. In girls sedentary behaviors seemed more important than physical exercise with regard to overweight status. Despite selective non-response on BMI and reliance on self-reports, the associations between clusters and overweight in boys were clear, and differences between boys and girls regarding the behaviors and risks for overweight are noteworthy. These differences need to be considered when developing tailored intervention strategies for prevention of overweight.

Journal ArticleDOI
TL;DR: Withdrawal of fall-risk-increasing drugs appears to be effective as a single intervention for falls prevention in a geriatric outpatient setting, and the effect was greatest for withdrawal of cardiovascular drugs.
Abstract: Aims: Falling in older persons is a frequent and serious clinical problem. Several drugs have been associated with increased fall risk. The objective of this study was to identify differences in the incidence of falls after withdrawal (discontinuation or dose reduction) of fall-risk-increasing drugs as a single intervention in older fallers. Methods: In a prospective cohort study of geriatric outpatients, we included 139 patients presenting with one or more falls during the previous year. Fall-risk-increasing drugs were withdrawn, if possible. The incidence of falls was assessed within 2 months of follow-up after a set 1 month period of drug withdrawal. Multivariate adjustment for potential confounders was performed with a Cox proportional hazards model. Results: In 67 patients, we were able to discontinue a fall-risk-increasing drug, and in eight patients to reduce its dose. The total number of fall incidents during follow-up was significantly lower in these 75 patients, than in those who continued treatment (mean number of falls: 0.3 vs. 3.6; P value 0.025). The hazard ratio of a fall during follow-up was 0.48 (95% confidence interval (CI) 0.23, 0.99) for overall drug withdrawal, 0.35 (95% CI 0.15, 0.82) for cardiovascular drug withdrawal and 0.56 (95% CI 0.23, 1.38) for psychotropic drug withdrawal, after adjustment for age, gender, use of fall-risk-increasing drugs, baseline falls frequency, comorbidity, Mini-Mental State Examination score, and reason for referral. Conclusions: Withdrawal of fall-risk-increasing drugs appears to be effective as a single intervention for falls prevention in a geriatric outpatient setting. The effect was greatest for withdrawal of cardiovascular drugs.

Journal ArticleDOI
TL;DR: A proper understanding of CPOE as a collaborative effort and the transformation of the health care activities into integrated care programs requires an understanding of how orders are created and processed, how C POE as part of an integrated system can support the workflow, and how risks affecting patient care can be identified and reduced.

Journal ArticleDOI
TL;DR: It is concluded that the survival advantage for Dutch PD compared with HD patients decreases over time, with age and in the presence of diabetes as primary disease.

Journal ArticleDOI
TL;DR: Therapeutic administration of recombinant Opn during pulmonary secondary antigenic challenge decreased established TH2 responses and protected mice from allergic disease and suggest that Opn-s is an important therapeutic target and provide new insight into its role in immunity.
Abstract: Osteopontin (Opn) is important for T helper type 1 (TH1) immunity and autoimmunity. However, the role of this cytokine in TH2-mediated allergic disease as well as its effects on primary versus secondary antigenic encounters remain unclear. Here we demonstrate that OPN is expressed in the lungs of asthmatic individuals and that Opn-s, the secreted form of Opn, exerts opposing effects on mouse TH2 effector responses and subsequent allergic airway disease: pro-inflammatory at primary systemic sensitization, and anti-inflammatory during secondary pulmonary antigenic challenge. These effects of Opn-s are mainly mediated by the regulation of TH2-suppressing plasmacytoid dendritic cells (DCs) during primary sensitization and TH2-promoting conventional DCs during secondary antigenic challenge. Therapeutic administration of recombinant Opn during pulmonary secondary antigenic challenge decreased established TH2 responses and protected mice from allergic disease. These effects on TH2 allergic responses suggest that Opn-s is an important therapeutic target and provide new insight into its role in immunity.

Journal ArticleDOI
TL;DR: A model that could explain gender-related differences in health care utilization among women was developed and found gender related differences in the strength of the relations between mental distress, other mediating variables and utilization were not found.

Journal ArticleDOI
TL;DR: Sugammadex (2.0, 4.2 mg/kg rocuronium bromide) or placebo (0.9% saline) was then administered 5 min after the administration of rocuroneurium, which reduced the mean recovery time from 122 min to less than 2 min in a dose-dependent manner.
Abstract: BACKGROUND: Reversal of rocuronium-induced neuromuscular blockade can be accomplished by chemical encapsulation of rocuronium by sugammadex, a modified gamma-cyclodextrin derivative. This study investigated the efficacy and safety of sugammadex in reversing rocuronium-induced profound neuromuscular blockade at 5 min in American Society of Anesthesiologists physical status I and II patients. METHODS: Forty-five American Society of Anesthesiologists physical status I and II patients (aged 18-64 yr) scheduled to undergo surgical procedures (anticipated anesthesia duration >/= 90 min) were randomly assigned to a phase II, multicenter, assessor-blinded, placebo-controlled, parallel, dose-finding study. Anesthesia was induced and maintained with propofol and an opioid. Profound neuromuscular blockade was induced with 1.2 mg/kg rocuronium bromide. Sugammadex (2.0, 4.0, 8.0, 12.0, or 16.0 mg/kg) or placebo (0.9% saline) was then administered 5 min after the administration of rocuronium. Neuromuscular function was monitored by acceleromyography, using train-of-four nerve stimulation. Recovery time was the time from the start of administration of sugammadex or placebo, to recovery of the train-of-four ratio to 0.9. Safety assessments were performed on the day of the operation and during the postoperative and follow-up period. RESULTS: A total of 43 patients received either sugammadex or placebo. Increasing doses of sugammadex reduced the mean recovery time from 122 min (spontaneous recovery) to less than 2 min in a dose-dependent manner. Signs of recurrence of blockade were not observed. No serious adverse events related to sugammadex were reported. Two adverse events possibly related to sugammadex were reported in two patients (diarrhea and light anesthesia); however, both patients recovered without sequelae. CONCLUSIONS: Sugammadex rapidly and effectively reversed profound rocuronium-induced neuromuscular blockade in humans and was well tolerated.

Journal ArticleDOI
TL;DR: Compared with traditional scoring methods, the ASM can be used more precisely to quantify the deforming effect of OA on the proximal femur and to identify, at an earlier stage of disease, those subjects at highest risk of developing radiographic OA or needing a total hip replacement.
Abstract: Objective Few methods exist to measure the progression of osteoarthritis (OA) or to identify people at high risk of developing OA. Striking radiographic changes include deformation of the femoral head and osteophyte growth, which are usually measured semiquantitatively following visual assessment. In this study, an active shape model (ASM) of the proximal femur was used to determine whether morphologic changes to the bone could be quantified and used as a marker of hip OA. Methods One hundred ten subjects who had no signs of radiographic hip OA at baseline (Kellgren/Lawrence [K/L] scores 0–1) were selected from the Rotterdam Study cohort of subjects ages ≥55 years. To measure the progression of OA, subjects were followed up with radiographic assessment after 6 years. At the 6-year followup, 55 subjects had established OA (K/L score 3), and in 12 of these OA subjects, the progression of the disease required a total hip replacement (THR). Age- and sex-matched control subjects had a K/L score of 0 at followup. Using the ASM, subjects were assessed for shape changes in the femoral head and neck before, during, and after the development of radiographic OA. Scores of shape variance, or mode scores, were assigned for 10 modes of variation in each subject, and differences in mode scores were determined. Results During followup, significant changes in shape of the proximal femur occurred within the OA group from baseline to followup (P < 0.0001 for mode 1 and P = 0.002 for mode 6) but not within the control group. At baseline (all subjects having K/L scores 0–1), there were significant differences in mode 6 between the OA group and the control group (P = 0.020), and in modes 3 and 6 between the OA subjects who underwent THR and the remaining OA subjects (P = 0.012 and P = 0.019, respectively). Conclusion Compared with traditional scoring methods, the ASM can be used more precisely to quantify the deforming effect of OA on the proximal femur and to identify, at an earlier stage of disease, those subjects at highest risk of developing radiographic OA or needing a THR. The ASM may therefore be useful as an imaging biomarker in the assessment of patients with hip OA.

Journal ArticleDOI
TL;DR: Offering self‐sampling for hrHPV testing in nonresponders is an attractive adjunct to effectively increase population coverage of screening without the adverse effect of markedly increased costs per detected CIN2+ lesion.
Abstract: Women not attending cervical screening programs are at increased risk of cervical cancer. We investigated in these nonresponders to what extent offering self-sampling devices for cervicovaginal brushes for high-risk human papillomavirus (hrHPV) testing would induce participation and, if so, what the yield of precursor (i.e. CIN2 or worse) lesions following self-sampling would be. In addition, we assessed screening history of participants and costs per detected high-grade CIN2 or worse (‘‘CIN21’’) lesion in comparison to the regular program in the Netherlands. Nonresponders received a device for hrHPV testing (self-sampling group, n 5 2,546) or an extra recall for conventional cytology (control group, n 5 284). The percentage of self-sampling responders were compared with responders in the recall group. hrHPV positive selfsampling responders were invited for cytology and colposcopy. CIN21 yield and costs per detected CIN21 were evaluated. Active response was higher in the self-sampling than in the control group (34.2 vs. 17.6%; p < 0.001). hrHPV positive self-sampling responders were less likely to have a prior screening history than screening participants (p < 0.001), indicating that they are regular nonresponders. hrHPV prevalence was similar (8.0 vs. 6.8%; p 5 0.11), but CIN21 yield was higher in self-sampling responders compared to screening participants (1.67 vs. 0.97%; OR 5 2.93, 95% CI 1.48–5.80; p 5 0.0013). Costs per CIN21 lesion detected via self-sampling were in the same range as those calculated for conventional cytological screening (€8,836 vs. €7,599). Offering self-sampling for hrHPV testing in nonresponders is an attractive adjunct to effectively increase population coverage of screening without the adverse effect of markedly increased costs per detected CIN21 lesion. ' 2006 Wiley-Liss, Inc.

Journal ArticleDOI
TL;DR: Random inactivation of one of the two female X chromosomes establishes dosage compensation between XY males and XX females in placental mammals and is implicated in the mechanism of random choice.

Journal ArticleDOI
TL;DR: This study suggests that the presence of the ABCC2*2 haplotype is associated with less irinotecan‐related diarrhea, maybe as a consequence of reduced hepatobiliary secretion of irinOTecan.
Abstract: Interindividual pharmacokinetic variability of the anticancer agent irinotecan is high. Life-threatening diarrhea is observed in up to 25% of patients receiving irinotecan and has been related with irinotecan pharmacokinetics and UGT1A1 genotype status. Here, we explore the association of ABCC2 (MRP2) polymorphisms and haplotypes with irinotecan disposition and diarrhea. A cohort of 167 Caucasian cancer patients who were previously assessed for irinotecan pharmacokinetics (90-min infusion given every 21 days), toxicity, and UGT1A1*28 genotype were genotyped for polymorphisms in ABCC2 using Pyrosequencing. Fifteen ABCC2 haplotypes were identified in the studied patients. The haplotype ABCC2*2 was associated with lower irinotecan clearance (28.3 versus 31.6 l/h; P=0.020). In patients who did not carry a UGT1A1*28 allele, a significant reduction of severe diarrhea was noted in patients with the ABCC2*2 haplotype (10 versus 44%; odds ratio, 0.15; 95% confidence interval, 0.04-0.61; P=0.005). This effect was not observed in patients with at least one UGT1A1*28 allele (32 versus 20%; odds ratio, 1.87; 95% confidence interval, 0.49-7.05; P=0.354). This study suggests that the presence of the ABCC2*2 haplotype is associated with less irinotecan-related diarrhea, maybe as a consequence of reduced hepatobiliary secretion of irinotecan. As the association was seen in patients not genetically predisposed at risk for diarrhea due to UGT1A1*28, confirmatory studies of the relationships of ABCC2 genotypes and irinotecan disposition and toxicity are warranted.

Journal ArticleDOI
TL;DR: Interaction with genetic factors that control energy metabolism could provide even more powerful pharmacological tools for effective drugs used in ischemic heart disease and heart failure.
Abstract: Proper heart function relies on high efficiency of energy conversion. Mitochondrial oxygen-dependent processes transfer most of the chemical energy from metabolic substrates into ATP. Healthy myocardium uses mainly fatty acids as its major energy source, with little contribution of glucose. However, lactate, ketone bodies, amino acids or even acetate can be oxidized under certain circumstances. A complex interplay exists between various substrates responding to energy needs and substrate availability. The relative substrate concentration is the prime factor defining preference and utilization rate. Allosteric enzyme regulation and protein phosphorylation cascades, partially controlled by hormones such as insulin, modulate the concentration effect; together they provide short-term adjustments of cardiac energy metabolism. The expression of metabolic machinery genes is also dynamically regulated in response to developmental and (patho)physiological conditions, leading to long-term adjustments. Specific nuclear receptor transcription factors and co-activators regulate the expression of these genes. These include peroxisome proliferator-activated receptors and their nuclear receptor co-activator, estrogen-related receptor and hypoxia-inducible transcription factor 1. Increasing glucose and reducing fatty acid oxidation by metabolic regulation is already a target for effective drugs used in ischemic heart disease and heart failure. Interaction with genetic factors that control energy metabolism could provide even more powerful pharmacological tools.

Journal ArticleDOI
TL;DR: In this article, the authors show that monocarboxylate transporter 8 (MCT8) shows particularly high activity towards thyroid uptake and release of thyroid hormone, and that MCT8 is the only transporter with high thyroid activity.
Abstract: Background: Cellular uptake and release of thyroid hormone are mediated by transporters. Among these, monocarboxylate transporter 8 (MCT8) shows particularly high activity towards t

Journal ArticleDOI
TL;DR: Results indicated that the policy of reserving capacity for emergency surgery in all elective ORs led to an improvement in waiting times forEmergency surgery from 74 minutes to 8 minutes, which led to closing of the Emergency OR in the Erasmus MC (Rotterdam, The Netherlands).
Abstract: Long waiting times for emergency operations increase a patient's risk of postoperative complications and morbidity. Reserving Operating Room (OR) capacity is a common technique to maximize the responsiveness of an OR in case of arrival of an emergency patient. This study determines the best way to reserve OR time for emergency surgery. In this study two approaches of reserving capacity were compared: (1) concentrating all reserved OR capacity in dedicated emergency ORs, and (2) evenly reserving capacity in all elective ORs. By using a discrete event simulation model the real situation was modelled. Main outcome measures were: (1) waiting time, (2) staff overtime, and (3) OR utilisation were evaluated for the two approaches. Results indicated that the policy of reserving capacity for emergency surgery in all elective ORs led to an improvement in waiting times for emergency surgery from 74 (±4.4) minutes to 8 (±0.5) min. Working in overtime was reduced by 20%, and overall OR utilisation can increase by around 3%. Emergency patients are operated upon more efficiently on elective Operating Rooms instead of a dedicated Emergency OR. The results of this study led to closing of the Emergency OR in the Erasmus MC (Rotterdam, The Netherlands).