Showing papers by "Erasmus University Medical Center published in 2004"

Long-term Follow-up of a Randomized Controlled Trial of Suture Versus Mesh Repair of Incisional Hernia

Abstract: OBJECTIVE: The objective of this study was to determine the best treatment of incisional hernia, taking into account recurrence, complications, discomfort, cosmetic result, and patient satisfaction. BACKGROUND: Long-term results of incisional hernia repair are lacking. Retrospective studies and the midterm results of this study indicate that mesh repair is superior to suture repair. However, many surgeons are still performing suture repair. METHODS: Between 1992 and 1998, a multicenter trial was performed, in which 181 eligible patients with a primary or first-time recurrent midline incisional hernia were randomly assigned to suture or mesh repair. In 2003, follow-up was updated. RESULTS: Median follow-up was 75 months for suture repair and 81 months for mesh repair patients. The 10-year cumulative rate of recurrence was 63% for suture repair and 32% for mesh repair (P < 0.001). Abdominal aneurysm (P = 0.01) and wound infection (P = 0.02) were identified as independent risk factors for recurrence. In patients with small incisional hernias, the recurrence rates were 67% after suture repair and 17% after mesh repair (P = 0.003). One hundred twenty-six patients completed long-term follow-up (median follow-up 98 months). In the mesh repair group, 17% suffered a complication, compared with 8% in the suture repair group (P = 0.17). Abdominal pain was more frequent in suture repair patients (P = 0.01), but there was no difference in scar pain, cosmetic result, and patient satisfaction. CONCLUSIONS: Mesh repair results in a lower recurrence rate and less abdominal pain and does not result in more complications than suture repair. Suture repair of incisional hernia should be abandoned.

Mortality after osteoporotic fractures

Abstract: The aim of this study was to examine the pattern of mortality following osteoporotic fractures at the spine, shoulder, hip, and forearm. We studied 2,847 patients with fractures at these sites identified from the radiology department in Malmo, Sweden. Poisson regression was used to compute mortality immediately after the fracture and with time. Mortality immediately after fracture was significantly higher in fracture cases than in the general population except for forearm fractures in both men and women. Mortality was higher in men than in women, but not different when adjusted for sex-specific population risks. For spine, shoulder, and hip fracture, mortality fell after the 1st year, an effect that was most marked for patients with spine fractures. The decrease in mortality risk with time was significant for hip, vertebral, and shoulder fracture. We conclude that the risk of death is increased in patients with osteoporotic fractures and that the highest risk is found immediately after the fracture event. The decreasing mortality with time after fracture may be due in part to a decrease in deaths causally related to the fracture. The extent to which early intervention for osteoporosis might avoid some of these deaths is unknown.

A meta-analysis of prior corticosteroid use and fracture risk.

Abstract: The relationship between use of corticosteroids and fracture risk was estimated in a meta-analysis of data from seven cohort studies of approximately 42,000 men and women. Current and past use of corticosteroids was an important predictor of fracture risk that was independent of prior fracture and BMD. INTRODUCTION: The aims of this study were to validate that corticosteroid use is a significant risk factor for fracture in an international setting and to explore the effects of age and sex on this risk. MATERIALS AND METHODS: We studied 42,500 men and women from seven prospectively studied cohorts followed for 176,000 patient-years. The cohorts comprised the EPOS/EVOS study, CaMos, the Rotterdam Study, Dubbo Osteoporosis Epidemiology Study (DOES), and prospective cohorts at Sheffield, Rochester, and Gothenburg. The effect of ever use of corticosteroids, BMD, age, and sex on all fracture, osteoporotic fracture, and hip fracture risk alone was examined using Poisson regression in each cohort and for each sex. The results of the different studies were merged from the weighted beta coefficients. RESULTS: Previous corticosteroid use was associated with a significantly increased risk of any fracture, osteoporotic fracture, and hip fracture when adjusted for BMD. Relative risk of any fracture ranged from 1.98 at the age of 50 years to 1.66 at the age of 85 years. For osteoporotic fracture, the range of relative risk was 2.63-1.71, and for hip fracture 4.42-2.48. The estimate of relative risk was higher at younger ages, but not significantly so. No significant difference in risk was seen between men and women. The risk was marginally and not significantly upwardly adjusted when BMD was excluded from the model. The risk was independent of prior fracture. In the three cohorts that documented current corticosteroid use, BMD was significantly reduced at the femoral neck, but fracture risk was still only partly explained by BMD. CONCLUSION: We conclude that prior and current exposure to corticosteroids confers an increased risk of fracture that is of substantial importance beyond that explained by the measurement of BMD. Its identification on an international basis validates the use of this risk factor in case-finding strategies.

Gene-Expression Patterns in Drug-Resistant Acute Lymphoblastic Leukemia Cells and Response to Treatment

Abstract: Background Childhood acute lymphoblastic leukemia (ALL) is curable with chemotherapy in approximately 80 percent of patients. However, the cause of treatment failure in the remaining 20 percent of patients is largely unknown. Methods We tested leukemia cells from 173 children for sensitivity in vitro to prednisolone, vincristine, asparaginase, and daunorubicin. The cells were then subjected to an assessment of gene expression with the use of 14,500 probe sets to identify differentially expressed genes in drug-sensitive and drug-resistant ALL. Gene-expression patterns that differed according to sensitivity or resistance to the four drugs were compared with treatment outcome in the original 173 patients and an independent cohort of 98 children treated with the same drugs at another institution. Results We identified sets of differentially expressed genes in B-lineage ALL that were sensitive or resistant to prednisolone (33 genes), vincristine (40 genes), asparaginase (35 genes), or daunorubicin (20 genes). ...

SARS risk perception, knowledge, precautions, and information sources, the Netherlands

Abstract: Severe acute respiratory syndrome (SARS)–related risk perceptions, knowledge, precautionary actions, and information sources were studied in the Netherlands during the 2003 SARS outbreak. Although respondents were highly aware of the SARS outbreak, the outbreak did not result in unnecessary precautionary actions or fears.

Proteomic Analysis of Exosomes Isolated from Human Malignant Pleural Effusions

Abstract: Exosomes are membrane vesicles from endosomal origin secreted by various cells such as hematopoietic, epithelial, and tumor cells. Exosomes secreted by tumor cells contain specific antigens potentially useful for immunotherapeutic purposes. Our aim was to determine if exosomes are present in human cancerous pleural effusions and to identify their proteomic content. Exosomes were purified by sucrose gradient ultracentrifugation, and electron microscopy was used to check both concentration and purity of exosomes. Proteins were separated by one-dimensional sodium dodecyl sulfate-polyacrylamide gel electrophoresis, and protein bands were identified by matrix-assisted laser desorption ionization time-of-flight mass spectrometry and Western blotting. Exosomes were present in pleural fluid obtained from patients suffering from mesothelioma (n = 4), lung cancer (n = 2), breast cancer (n = 2), and ovarian cancer (n = 1). As previously reported by others, antigen-presenting molecules, cytoskeletal proteins, and signal transduction-involved proteins were present. Proteins not previously reported were identified (SNX25, BTG1, PEDF, thrombospondin 2). Different types of immunoglobulins and complement factors were abundantly present in the sucrose fractions containing exosomes. Exosome-directed specificity of these immunoglobulins was not observed. In conclusion, sucrose gradient ultracentrifugation allows isolation of exosomes from malignant pleural effusions. However, pleural fluid proteins and especially immunoglobulins are coisolated and may hamper the use of exosomes isolated from malignant effusion for immunotherapy programs.

The active spatial organization of the β-globin locus requires the transcription factor EKLF

Abstract: Three-dimensional organization of a gene locus is important for its regulation, as recently demonstrated for the β-globin locus. When actively expressed, the cis-regulatory elements of the β-globin locus are in proximity in the nuclear space, forming a compartment termed the Active Chromatin Hub (ACH). However, it is unknown which proteins are involved in ACH formation. Here, we show that EKLF, an erythroid transcription factor required for adult β-globin gene transcription, is also required for ACH formation. We conclude that transcription factors can play an essential role in the three-dimensional organization of gene loci.

GATA-2 plays two functionally distinct roles during the ontogeny of hematopoietic stem cells.

Abstract: GATA-2 is an essential transcription factor in the hematopoietic system that is expressed in hematopoietic stem cells (HSCs) and progenitors. Complete deficiency of GATA-2 in the mouse leads to severe anemia and embryonic lethality. The role of GATA-2 and dosage effects of this transcription factor in HSC development within the embryo and adult are largely unexplored. Here we examined the effects of GATA-2 gene dosage on the generation and expansion of HSCs in several hematopoietic sites throughout mouse development. We show that a haploid dose of GATA-2 severely reduces production and expansion of HSCs specifically in the aorta-gonad-mesonephros region (which autonomously generates the first HSCs), whereas quantitative reduction of HSCs is minimal or unchanged in yolk sac, fetal liver, and adult bone marrow. However, HSCs in all these ontogenically distinct anatomical sites are qualitatively defective in serial or competitive transplantation assays. Also, cytotoxic drug-induced regeneration studies show a clear GATA-2 dose–related proliferation defect in adult bone marrow. Thus, GATA-2 plays at least two functionally distinct roles during ontogeny of HSCs: the production and expansion of HSCs in the aorta-gonad-mesonephros and the proliferation of HSCs in the adult bone marrow.

Iodothyronine levels in the human developing brain: major regulatory roles of iodothyronine deiodinases in different areas

Abstract: Thyroid hormones are required for human brain development, but data on local regulation are limited. We describe the ontogenic changes in T4, T3, and rT3 and in the activities of the types I, II, and III iodothyronine deiodinases (D1, D2, and D3) in different brain regions in normal fetuses (13–20 wk postmenstrual age) and premature infants (24–42 wk postmenstrual age). D1 activity was undetectable. The developmental changes in the concentrations of the iodothyronines and D2 and D3 activities showed spatial and temporal specificity but with divergence in the cerebral cortex and cerebellum. T3 increased in the cortex between 13 and 20 wk to levels higher than adults, unexpected given the low circulating T3. Considerable D2 activity was found in the cortex, which correlated positively with T4 (r = 0.65). Cortex D3 activity was very low, as was D3 activity in germinal eminence and choroid plexus. In contrast, cerebellar T3 was very low and increased only after midgestation. Cerebellum D3 activities were the ...

Angiogenesis inhibitors in clinical development; where are we now and where are we going?

Abstract: Angiogenesis is crucial for tumour growth and the formation of metastases. Various classes of angiogenesis inhibitors that are each able to inhibit one of the various steps of this complex process can be distinguished. Results from clinical studies with these agents are summarised. In general, it has been shown that most angiogenesis inhibitors can be safely administered, but that tumour regressions are rare. Combining angiogenesis inhibitors with cytotoxic chemotherapy can enhance anticancer activity. Recently, some promising data with regard to clinical efficacy have been presented. While performing clinical studies with angiogenesis inhibitors, defining biological activity is crucial, but thus far no validated techniques are available. It is conceivable that in the near future various classes of angiogenesis inhibitors will be combined in an attempt to further improve antiangiogenic and anticancer activity.

Multiple interactions between regulatory regions are required to stabilize an active chromatin hub

Abstract: The human beta-globin locus control region (LCR) is required for the maintenance of an open chromatin configuration of the locus. It interacts with the genes and the hypersensitive regions flanking the locus to form an active chromatin hub (ACH) transcribing the genes. Proper developmental control of globin genes is largely determined by gene proximal regulatory sequences. Here, we provide the first functional evidence of the role of the most active sites of the LCR and the promoter of the beta-globin gene in the maintenance of the ACH. When the human beta-globin gene promoter is deleted in the context of a full LCR, the ACH is maintained with the beta-globin gene remaining in proximity. Additional deletion of hypersensitive site HS3 or HS2 of the LCR shows that HS3, but not HS2, in combination with the beta-globin promoter is crucial for the maintenance of the ACH at the definitive stage. We conclude that multiple interactions between the LCR and the beta-globin gene are required to maintain the appropriate spatial configuration in vivo.

Developmental Trends in Cord and Postpartum Serum Thyroid Hormones in Preterm Infants

Abstract: The purpose of this study was first to clarify postnatal trends in sera T(4), free T(4) (FT(4)), T(4)-binding globulin, TSH, T(3), rT(3), and T(4) sulfate levels in cord and at 7, 14, and 28 d in groups of preterm infants at 23-27 wk (n = 101), 28-30 wk (n = 196), and 31-34 (n = 253) wk gestation, and second to compare these trends to those of term infants and also with cord sera levels of equivalent gestational ages (n = 812; 23-42 wk gestation). In all preterm groups, TSH and rT(3) decrease to below, T(4)-binding globulin increases to within, and T(3) and T(4) sulfate increase to above cord levels of equivalent gestational age. Term infants are hyperthyroxinemic relative to cord and nonpregnant adult levels of T(4). Postnatal T(4) increases are attenuated in 31- to 34-wk infants, absent in 28- to 30-wk infants (although levels are equivalent to gestational age), and crucially reversed in 23- to 27-wk infants. This immature group is hypothyroxinemic relative to other groups and to cord levels of equivalent gestational age. Compared with term infants, postnatal FT(4) increases are lower in 31- to 34-wk infants, attenuated in 28- to 30-wk infants, and absent in 23- to 27-wk infants. The 23- to 27-wk group is distinctive; they are hypothyroxinemic on T(4) levels, yet FT(4) levels are within the cord levels of equivalent gestational age.

Bivariate tail estimation: dependence in asymptotic independence

Abstract: In the classical setting of bivariate extreme value theory, the procedures for estimating the probability of an extreme event are not applicable if the componentwise maxima of the observations are asymptotically independent. To cope with this problem, Ledford and Tawn proposed a submodel in which the penultimate dependence is characterized by an additional parameter. We discuss the asymptotic properties of two estimators for this parameter in an extended model. Moreover, we develop an estimator for the probability of an extreme event that works in the case of asymptotic independence as well as in the case of asymptotic dependence, and prove its consistency.

Annual revaccination against influenza and mortality risk in community-dwelling elderly persons.

Abstract: ContextAlthough large-scale observational studies have demonstrated the effectiveness of influenza vaccination, no large studies have systematically addressed the clinical benefit of annual revaccinations.ObjectiveTo investigate the effect of annual influenza revaccination on mortality in community-dwelling elderly persons.Design, Setting, and ParticipantsA population-based cohort study using the computerized Integrated Primary Care Information (IPCI) database in the Netherlands including community-dwelling individuals aged 65 years or older from 1996 through 2002. For each year, we computed the individual cumulative exposure to influenza vaccination since study start.Main Outcome MeasureAssociation between the number of consecutive influenza vaccinations and all-cause mortality vs no vaccination after adjusting for age, sex, chronic respiratory and cardiovascular disease, hypertension, diabetes mellitus, renal failure, and cancer.ResultsThe study population included 26 071 individuals, of whom 3485 died during follow-up. Overall, a first vaccination was associated with a nonsignificant annual reduction of mortality risk of 10% (hazard ratio [HR], 0.90; 95% confidence interval [CI], 0.78-1.03) while revaccination was associated with a reduced mortality risk of 24% (HR, 0.76; 95% CI, 0.70-0.83). Compared with a first vaccination, revaccination was associated with a reduced annual mortality risk of 15% (HR, 0.85; 95% CI, 0.75-0.96). During the epidemic periods this reduction was 28% (HR, 0.72; 95% CI, 0.53-0.96). Similar estimates were obtained for persons with and without chronic comorbidity and those aged 70 years or older at baseline. Overall, influenza vaccination is estimated to prevent 1 death for every 302 vaccinees at a vaccination coverage that varied between 64% and 74%.ConclusionAnnual influenza vaccination is associated with a reduction in all-cause mortality risk in a population of community-dwelling elderly persons, particularly in older individuals.

APC dosage effects in tumorigenesis and stem cell differentiation

Abstract: It is well established that concentration gradients of signaling molecules (the so-called "morphogens") organize and pattern tissues in developing animals. In particular, studies in Drosophila and different vertebrates have shown that gradients of the Wnt, Hedgehog (Hh) and transforming growth factor-beta (TGF-β) families of morphogens play critical roles in limb patterning. Morphogens are often expressed in organizing centres and can act over a long range to coordinate the patterning of an entire field of cells. These observations imply that exposure to different concentrations of these diffusible factors may trigger differential cellular responses. In order to study these dosage-dependent Wnt/β-catenin signaling effects, we have generated several hypomorphic mutant alleles at the mouse Apc locus and studied their cellular and phenotypic outcomes in stem cell renewal and differentiation, and in tumorigenesis. The results clearly show that Apc mutations differentially affect the capacity of stem cells to differentiate in a dosage-dependent fashion. Likewise, different Apc mutations (and the corresponding Wnt signaling dosages) confer different degrees of susceptibility to tumorigenesis in the corresponding mouse models. These results have implications for the understanding of the molecular and cellular basis of tumor initiation by defects in the Wnt pathway. We propose a model in which adult somatic stem cell compartments are characterized by tissue-specific β-catenin threshold levels for cell proliferation, differentiation and apoptosis. Different APC mutations will result in different levels of β-catenin signaling, thus conferring different degrees of tumor susceptibility in different tissues. Hence, β-catenin dosage - dependent effects may not only explain how a single pathway is involved in the development and homeostasis of different tissues, but also its pleiotrophic role in tumorigenesis.

Autologous peripheral retinal pigment epithelium translocation in patients with subfoveal neovascular membranes

Abstract: Aim: To evaluate the possibility of translocating autologous peripheral retinal pigment epithelial (RPE) cells and enhance their adhesion to improve functional outcome after choroidal neovascular membrane extraction in patients with subfoveal neovascular membranes. Methods: A prospective, non-controlled surgical study in eight consecutive patients operated between February and July 2001 with final data monitoring in July 2002. All patients had mixed subfoveal membranes of 2–4 disc diameters. Functional tests included Snellen vision and central fixation testing. During vitrectomy, after the extraction of the neovascular complex, 8×104–16×104 RPE cells were removed from the periphery and translocated under the macula following the submacular injection of 2 μg of poly-l-lysine to promote adhesion of the cells. Results: With a follow up ranging from 3 months to 16 months, a pigmented area was seen in the extraction bed of the neovascular membrane in only one patient. Fixation was at the edge of the extraction bed in three patients. Vision remained the same in five patients and deteriorated in three (all with retinal detachment). Retinal detachment due to proliferative vitreoretinopathy occurred in three patients. Conclusions: The translocation of autologous peripheral RPE cells after membrane extraction was technically possible in a sterile manner, but was associated with a high proliferative vitreoretinopathy rate and in the present series had no measurable positive effect on functional outcome.

Distribution of information in biomedical abstracts and full-text publications

Abstract: Motivation: Full-text documents potentially hold more information than their abstracts, but require more resources for processing. We investigated the added value of full text over abstracts in terms of information content and occurrences of gene symbol---gene name combinations that can resolve gene-symbol ambiguity. Results: We analyzed a set of 3902 biomedical full-text articles. Different keyword measures indicate that information density is highest in abstracts, but that the information coverage in full texts is much greater than in abstracts. Analysis of five different standard sections of articles shows that the highest information coverage is located in the results section. Still, 30--40% of the information mentioned in each section is unique to that section. Only 30% of the gene symbols in the abstract are accompanied by their corresponding names, and a further 8% of the gene names are found in the full text. In the full text, only 18% of the gene symbols are accompanied by their gene names.

Prediction of irinotecan pharmacokinetics by use of cytochrome P450 3A4 phenotyping probes.

Abstract: textBACKGROUND: Irinotecan is a topoisomerase I inhibitor that has been approved for use as a first- and second-line treatment for colorectal cancer. The response to irinotecan is variable, possibly because of interindividual variation in the expression of the enzymes that metabolize irinotecan, including cytochrome P450 3A4 (CYP3A4) and uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1). We prospectively explored the relationships between CYP3A phenotype, as assessed by erythromycin metabolism and midazolam clearance, and the metabolism of irinotecan and its active metabolite SN-38. METHODS: Of the 30 white cancer patients, 27 received at least two treatments with irinotecan administered as one 90-minute infusion (dose, 600 mg) with 3 weeks between treatments, and three received only one treatment. Before the first and second treatments, patients underwent an erythromycin breath test and a midazolam clearance test as phenotyping probes for CYP3A4. Erythromycin metabolism was assessed as the area under the curve for the flux of radioactivity in exhaled CO2 within 40 minutes after administration of [N-methyl-14C]erythromycin. Midazolam and irinotecan were measured by high-performance liquid chromatography. Genomic DNA was isolated from blood and screened for genetic variants in CYP3A4 and UGT1A1. All statistical tests were two-sided. RESULTS: CYP3A4 activity varied sevenfold (range = 0.223%-1.53% of dose) among patients, whereas midazolam clearance varied fourfold (range = 262-1012 mL/min), although intraindividual variation was small. Erythromycin metabolism was not statistically significantly associated with irinotecan clearance (P = .090), whereas midazolam clearance was highly correlated with irinotecan clearance (r = .745, P<.001). In addition, the presence of a UGT1A1 variant with a (TA)7 repeat in the promoter (UGT1A1*28) was associated with increased exposure to SN-38 (435 ng x h/mL, 95% confidence interval [CI] = 339 to 531 ng x h/mL in patients who are homozygous for wild-type UGT1A1; 631 ng x h/mL, 95% CI = 499 to 762 ng . h/mL in heterozygous patients; and 1343 ng x h/mL, 95% CI = 0 to 4181 ng x h/mL in patients who are homozygous for UGT1A1*28) (P = .006). CONCLUSION: CYP3A4 phenotype, as assessed by midazolam clearance, is statistically significantly associated with irinotecan pharmacokinetics. Evaluation of midazolam clearance combined with UGT1A1*28 genotyping may assist with optimization of irinotecan chemotherapy.