bluuebunny/crossref_metadata_2025_split huggingface dataset:
Driving forces behind increasing cardiovascular drug utilization: a dynamic pharmacoepidemiological model
Authors: Kildemoes Helle Wallach , Støvring Henrik , Andersen Morten 
Published: August 2008

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Several studies indicate that switch to more expensive drugs and increasing treatment intensity, rather than population ageing have been responsible for rising drug expenditures during the 1990s.• Little is known about the driving forces behind the increasing treatment intensity with cardiovascular drugs. WHAT THIS STUDY ADDS • This study provides a new pharmacoepidemiological method to analyse drug utilization trends, applying dispensing data at the individual level.• The suggested semi‐Markov model allows for quantification of the influence of changing incidence, discontinuation and user mortality on rising treatment prevalence.• Increasing treatment incidence was the main driver behind rising treatment prevalence for most cardiovascular drug categories.• Whereas declining discontinuation drove some of the growth, declining mortality among drug users had little influence.AIMSTo investigate the driving forces behind increasing utilization of cardiovascular drugs.METHODSUsing register data, all Danish residents as of 1 January 1996 were followed until 2006. Cohort members were censored at death or emigration. Cardiovascular drug utilization on the individual level was traced, applying registered out‐of‐hospital dispensing. The impact of population ageing on cardiovascular drug utilization was investigated using standardized intensities and prevalences. Based on a three‐state (untreated, treated and dead) semi‐Markov model, we explored to what extent increasing treatment prevalence was driven by changing incidence, discontinuation and mortality. Expected treatment prevalences were modelled, applying stratum‐specific cohort prevalence in 1996 along with incidence, discontinuation and drug user mortality either throughout 1996–2004 or at fixed 1996 levels.RESULTSTreatment prevalence (ages ≥20 years) with cardiovascular drugs increased by 39% during 1996–2005 from 192.4 to 256.9 per 1000 inhabitants (95% confidence interval 256.5, 257.3). Treatment intensity grew by 109% from 272 to 569 defined daily doses 1000−1 day−1. Population ‘middle‐ageing’ accounted for 11.5 and 20.3%, respectively. Increasing treatment incidence was the main driver of the rising treatment prevalence in most drug categories. Declining discontinuation drove some of the growth, declining drug user mortality less. Even with fixed incidence in the model, treatment prevalence continued to increase.CONCLUSIONSAge‐related increases in treatment intensity and prevalence, rather than population ageing, drove the increasing treatment intensity with cardiovascular drugs. Increasing treatment prevalence in subgroups was primarily caused by increasing incidence. Due to pharmacoepidemiological disequilibrium, treatment prevalence will continue to grow even with unchanged incidence.
Characterization of PRF1, STX11 and UNC13D genotype‐phenotype correlations in familial hemophagocytic lymphohistiocytosis
Authors: Horne AnnaCarin , Ramme Kim Göransdotter , Rudd Eva , Zheng Chengyun , Wali Yasser , Al‐Lamki Zakia , Gürgey Aytemiz , Yalman Nevin , Nordenskjöld Magnus , Henter Jan‐Inge 
Published: August 2008

SummaryFamilial hemophagocytic lymphohistiocytosis (FHL) is a rare autosomal recessive lethal condition characterized by fever, cytopenia, hepatosplenomegaly and hemophagocytosis. The hallmark of FHL is defect apoptosis triggering and lymphocyte cellular cytotoxicity. Thus far three disease‐causing genes (PRF1, UNC13D, STX11) have been identified. We performed a genotype‐phenotype study in a large, multi‐ethnic cohort of 76 FHL patients originating from 65 unrelated families. Biallelic mutations in PRF1, UNC13D and STX11 were demonstrated in 13/74 (18%), 6/61 (10%) and 14/70 (20%) patients, respectively. In 27/60 (45%) patients analyzed for all three genes, no molecular diagnosis was established. STX11 mutations were most common in Turkish families (7/28, 25%), whereas in Middle East families, PRF1 mutations were most frequent (6/13, 46%). No biallelic mutation was identified in most families of Nordic origin (13/14, 93%). Patients carrying PRF1 mutations had higher risk of early onset (age <6 months) compared to patients carrying STX11 mutations [adjusted odds ratio 8·23 (95% confidence interval [CI] = 1·20–56·40), P = 0·032]. Moreover, patients without identified mutations had increased risk of pathological cerebrospinal fluid (CSF) at diagnosis compared to patients with STX11 mutations [adjusted odds ratio 26·37 (CI = 1·90–366·82), P = 0·015]. These results indicate that the disease‐causing mutations in FHL have different phenotypes with regard to ethnic origin, age at onset, and pathological CSF at diagnosis.
Serum autotaxin measurement in haematological malignancies: a promising marker for follicular lymphoma
Authors: Masuda Akiko , Nakamura Kazuhiro , Izutsu Koji , Igarashi Koji , Ohkawa Ryunosuke , Jona Masahiro , Higashi Katsumi , Yokota Hiromitsu , Okudaira Shinichi , Kishimoto Tatsuya , Watanabe Takuro , Koike Yukako , Ikeda Hitoshi , Kozai Yasushi , Kurokawa Mineo , Aoki Junken , Yatomi Yutaka 
Published: August 2008

SummaryAutotaxin (ATX) is a tumour cell motility‐stimulating factor originally isolated from melanoma cell supernatants. ATX is identical to lysophospholipase D, which produces a bioactive lipid mediator, lysophosphatidic acid (LPA), from lysophosphatidylcholine. ATX is overexpressed in various malignancies, including Hodgkin lymphoma, and ATX may stimulate tumour progression via LPA production. The present study measured the serum ATX antigen levels in patients with haematological malignancies using a recently developed automated enzyme immunoassay. The serum ATX antigen levels in patients with B‐cell neoplasms, especially follicular lymphoma (FL), were higher than those in healthy subjects. Serum ATX antigen levels in FL patients were associated with tumour burden and changed in parallel with the patients’ clinical courses. The serum ATX antigen levels were little affected by inflammation, unlike the soluble interleukin‐2 receptor and β2‐microglobulin levels. As expected, the plasma LPA levels in FL patients were correlated with the serum ATX antigen levels. Given that leukaemic tumour cells from FL patients expressed ATX, the shedding of ATX from lymphoma cells probably leads to the elevation of serum ATX antigen levels. Our results suggest that the serum ATX antigen level may be a promising and novel marker for FL.
Polymorphisms of the Z protein protease inhibitor and risk of venous thromboembolism: a meta‐analysis
Authors: Dentali Francesco , Gianni Monica , Lussana Federico , Squizzato Alessandro , Cattaneo Marco , Ageno Walter 
Published: August 2008

SummaryTwo nonsense polymorphisms of Z‐dependent protease inhibitor (ZPI; Serpina10) have been identified. To assess the risk of venous thromboembolism (VTE) associated with W303x and R67X Serpina10 mutations, we performed a meta‐analysis of studies comparing the prevalence of these two mutations in VTE patients and in controls Odds Ratios (ORs) and 95% confidence intervals (CIs) were calculated for each trial and pooled using a random‐effects model. Five studies involving 5000 patients were included. R67X and W303X mutations of Serpina10 were not associated with increased VTE risk (OR 1·63; 95% CI 0·84, 3·16 and OR 1·21; 95% CI 0·29, 4·98 respectively).
Duffy (Fy), DARC, and neutropenia among women from the United States, Europe and the Caribbean
Authors: Grann Victor R. , Ziv Elad , Joseph Cecil K. , Neugut Alfred I. , Wei Ying , Jacobson Judith S. , Horwitz Marshall S. , Bowman Natalie , Beckmann Kenneth , Hershman Dawn L. 
Published: August 2008

SummaryNeutropenia associated with race/ethnicity has essentially been unexplained and, although thought to be benign, may affect therapy for cancer or other illnesses. A recent study linked a single nucleotide polymorphism (SNP) (rs2814778) in the Duffy antigen/receptor chemokine gene (DARC) with white blood cell count. We therefore analysed the association of the rs2814778 CC, TC and TT genotypes with absolute neutrophil count (ANC) among asymptomatic women from the Caribbean, Europe and the United States. Among 261 study participants, 33/47 women from Barbados/Trinidad‐Tobago, 34/49 from Haiti, 26/37 from Jamaica, and 29/38 US‐born black women, but only 4/50 from the Dominican Republic and 0/40 US‐ or European‐born whites (P = 0·0001) had the CC genotype. In a linear regression model that included percentage African ancestry, national origin, cytokines, socio‐economic factors and the ELA2 rs57834246 SNP, only the DARC rs2814778 genotype and C‐reactive protein were associated with ANC (P < 0·0001). Women with the CC genotype had lower ANC than other women. Further research is needed on the associations of rs2814778 genotype with neutropenia and treatment delay in the setting of cancer. A better understanding of these associations may help to improve cancer outcomes among individuals of African ancestry.
Reduction of B cell turnover in chronic lymphocytic leukaemia
Authors: Defoiche Julien , Debacq Christophe , Asquith Becca , Zhang Yan , Burny Arsène , Bron Dominique , Lagneaux Laurence , Macallan Derek , Willems Luc 
Published: August 2008

SummaryWhether chronic lymphocytic leukaemia (CLL) is a latent or a proliferating disease has been intensively debated. Whilst the dogma that CLL results from accumulation of dormant lymphocytes is supported by the unresponsiveness of leukaemic cells to antigens and polyclonal activators, recent in vivo kinetic measurements indicate that B lymphocytes do divide at significant rates in CLL. However, an important and still unanswered question is whether CLL cells proliferate faster or slower compared with their normal counterparts. This report addressed directly this point and compared B‐cell kinetics in CLL subjects and healthy controls, using a pulse‐chase approach based on incorporation of deuterium from 6,6‐2H2‐glucose into DNA. We confirmed that B cells proliferated at significant levels in CLL but found that the proliferation rates were reduced compared with healthy subjects (mean 0·47 vs. 1·31%/d respectively, P = 0·007), equivalent to an extended doubling time of circulating B cells (147 d vs. 53 d). In conclusion, CLL B cells proliferate at reduced levels compared with healthy controls. CLL is thus characterized by an aberrant B‐cell kinetics with a decrease in cell turnover, an observation that may impact on elaboration of efficient therapeutic strategies.
Status of minimal residual disease testing in childhood haematological malignancies
Authors: Campana Dario 
Published: August 2008

SummaryIn children with acute leukaemia, measurements of minimal residual disease (MRD) provide unique information on treatment response and have become a crucial component of contemporary treatment protocols. In acute lymphoblastic leukaemia (ALL), the most useful MRD assays are based on polymerase chain reaction (PCR) amplification of antigen‐receptor genes, and on flow cytometric detection of abnormal immunophenotypes. The latter is the only MRD assay available for most patients with acute myeloid leukaemia (AML). PCR amplification of chromosomal breakpoints and fusion transcripts can also be used to track MRD in a minority of patients with ALL or AML. Because of the strong correlation between MRD levels and risk of relapse, several ongoing regimens include treatment intensification for children with higher MRD. Treatment de‐intensification for patients with early MRD clearance is also being tested. In addition to their direct clinical application, MRD measurements can be used to better understand the molecular and cellular mechanisms of drug resistance in vivo. The identification of new markers of leukaemia and the use of increasingly sophisticated technologies for detection of rare cells should further facilitate routine monitoring of MRD and elucidate the features of drug‐resistant leukaemic cells.
Effect of exercise training on A‐FABP, lipocalin‐2 and RBP4 levels in obese women
Authors: Choi K. M. , Kim T. N. , Yoo H. J. , Lee K. W. , Cho G. J. , Hwang T. G. , Baik S. H. , Choi D. S. , Kim S. M. 
Published: August 2008

SummaryObjective  Lipocalin family proteins, including adipocyte fatty acid‐binding protein (A‐FABP), lipocalin‐2 and retinol‐binding protein 4 (RBP4), have recently been identified as novel adipokines associated with obesity, type 2 diabetes and the metabolic syndrome. We have evaluated the effect of exercise training on lipocalin family proteins and inflammatory markers.Study subjects  Thirty obese Korean women and 15 age‐matched nonobese control subjects were studied.Design  Concentrations of the lipocalin family proteins were compared between obese and nonobese women and were evaluated before and 3 months after an exercise programme consisting of aerobic exercise (45 min/session, 300 kcal/day) and muscle strength training (20 min/session, 100 kcal/day) five times a week.Results  Obese women exhibited higher A‐FABP levels compared to nonobese women (21·4 ± 6·4 µg/l vs. 13·6 ± 4·4 µg/l, P < 0·001). However, neither lipocalin‐2 nor RBP4 levels were significantly different between the two groups, although the difference in lipocalin‐2 was marginally significant (P = 0·054). Circulating A‐FABP levels were significantly associated with body mass index (BMI), waist circumference, triglyceride, alanine aminotransferase (ALT), lipocalin‐2 and high‐sensitivity C‐reactive protein (hsCRP) levels. After 3 months of the exercise training programme, serum A‐FABP levels decreased significantly from 21·4 ± 6·4 µg/l to 19·3 ± 6·8 µg/l (P = 0·038), along with a reduction in weight, BMI, waist circumference, fasting glucose and total cholesterol levels. There was no significant change in the lipocalin‐2 and RBP4 levels, although IL‐6 levels increased after the exercise programme.Conclusion  Exercise training with weight loss induced a significant reduction in circulating A‐FABP levels in obese Korean women.
Resistin gene variation is associated with systemic inflammation but not plasma adipokine levels, metabolic syndrome or coronary atherosclerosis in nondiabetic Caucasians
Authors: Qasim Atif N. , Metkus Thomas S. , Tadesse Mahlet , Lehrke Michael , Restine Stephanie , Wolfe Megan L. , Hannenhalli Sridhar , Cappola Thomas , Rader Daniel J. , Reilly Muredach P. 
Published: August 2008

SummaryObjective  Resistin causes insulin resistance and diabetes in mice whereas in humans it is linked to inflammation and atherosclerosis. Few human genetic studies of resistin in inflammation and atherosclerosis have been performed. We hypothesized that the –420C>G putative gain‐of‐function resistin variant would be associated with inflammatory markers and atherosclerosis but not with metabolic syndrome or adipokines in humans.Design and methods  We examined the association of three resistin polymorphisms, –852A>G, –420C>G and +157C>T, and related haplotypes with plasma resistin, cytokines, C‐reactive protein (CRP), adipokines, plasma lipoproteins, metabolic syndrome and coronary artery calcification (CAC) in nondiabetic Caucasians (n = 851).Results  Resistin levels were higher, dose‐dependently, with the –420G allele (CC 5·9 ± 2·7 ng/ml, GC 6·5 ± 4·0 ng/ml and GG 7·2 ± 4·8 ng/ml, trend P = 0·04) after age and gender adjustment [fold higher for GC + GG vs. CC; 1·07 (1·00–1·15), P < 0·05)]. The –852A>G single nucleotide polymorphism (SNP) was associated with higher soluble tumour necrosis factor‐receptor 2 (sol‐TNFR2) levels in fully adjusted models [1·06 (95% CI 1·01–1·11), P = 0·01)]. The estimated resistin haplotype (GGT) was associated with sol‐TNFR2 (P = 0·04) and the AGT haplotype was related to CRP (P = 0·04) in the fully adjusted models. Resistin SNPs and haplotypes were not associated with body mass index (BMI), fasting glucose, insulin resistance, metabolic syndrome, adipokines or CAC scores.Conclusions  Despite modest associations with plasma resistin and inflammatory biomarkers, resistin 5′ variants were not associated with metabolic parameters or coronary calcification. This suggests that resistin is an inflammatory cytokine in humans but has little influence on adiposity, metabolic syndrome or atherosclerosis.
Prevalence and functional analysis of the S107P polymorphism (rs6647476) of the monocarboxylate transporter 8 (SLC16A2) gene in the male population of north‐west Spain (Galicia)
Authors: Lago‐Lestón Ramón , Iglesias María‐José , San‐José Esther , Areal Carlos , Eiras Adolfo , Araújo‐Vilar David , Lado‐Abeal Joaquín , Domínguez‐Gerpe Lourdes 
Published: August 2008

SummaryObjective  Mutations in SLC16A2, the gene encoding the thyroid hormone (TH)‐specific transporter monocarboxylate transporter 8 (MCT8), result in a thyroid phenotype and severe mental retardation caused by neuronal TH deficiency. These mutational effects raise the question of whether polymorphic variation in SLC16A2 may also be associated with differences in serum levels of TH and/or TSH.Design  This is the first major study of the frequency of the SLC16A2 rs6647476 single nucleotide polymorphism (SNP) (amino acid change Ser107Pro). We also studied the relationships of SLC16A2 genetic variants with serum levels of TSH, T4 and T3, with their mRNA expression and with expression of the TH‐responsive genes ZAKI‐4 and BTEB in white blood cells. Experiments in cultured fibroblasts were carried out to ascertain the dynamics of the T3 response.Methods  A total of 276 men were studied. Genotyping of the S107P SNP was carried out using polymerase chain reaction restriction fragment length polymorphism (PCR‐RFLP); serum hormone levels were determined by chemiluminescence; expression of mRNA was quantified by real‐time PCR.Results  The SLC16A2 S107P SNP was found in 36% of Galician males. With the present sample size we did not find any association of this polymorphism with variability in serum levels of TSH, free T4 (fT4) or fT3, or with basal expression of mRNA for SLC16A2 or the two TH‐responsive genes ZAKI‐4 and BTEB, either in white blood cells or in cultured human fibroblasts from either Ser107 or Pro107 genotypes under T3 stimulation.Conclusions  The S107P change in MCT8 is frequent in the male population in Galicia. In the population studied in this report an association with a thyroid phenotype was not demonstrated, even though the S107P SNP causes an important amino acid change.
Effects of rehabilitation treatment on thyroid function
Authors: Aprile Irene , Romitelli Federica , Piazzini Diana Barbara , Padua Luca , Lancellotti Stefano , Maggi Loredana , Zuppi Cecilia , Bertolini Carlo , Di Stasio Enrico 
Published: August 2008

SummaryObjective  The aim of the study was to evaluate the effects of an intensive rehabilitation programme on thyroid metabolism, the relationship between disability and thyroid hormone level, and the occurrence of nonthyroidal illness syndrome (NTIS) before and after rehabilitation.Design, subjects and measurements  This was a clinical prospective study. Orthopaedic surgery patients (n = 82) were classified into two groups: patients in whom early active mobilization and walking were possible (walking group, WG, n = 45), and patients in whom these were not recommended (nonwalking group, NWG, n = 37). Levels of free T3 (fT3), fT4, TSH and rT3 were measured before and after surgery, and then at 1, 3, 7, 14 and 30 days from the beginning of rehabilitation. Personal, nutritional and clinical data were acquired for all patients. The Barthel Index (BI) was used to assess disability before and after rehabilitation.Results  Immediately after surgery, both groups of patients showed a significant decrease in mean fT3 concentrations and a significant increase in rT3; mean fT4 values decreased significantly only in NWG patients. Once rehabilitation had been completed, fT3 and rT3 levels returned to baseline values in WG patients. In NWG patients mean fT3 and fT4 levels continued to decrease significantly and rT3 values remained significantly high until the end of rehabilitation. NTIS occurred in 38% of the NWG patients. No significant changes in TSH levels were observed in either group. Finally, we observed a direct correlation between fT3 levels and the BI in WG patients.Conclusions  Our data suggest that early patient mobilization and physical activity during an active and intensive rehabilitation programme induce recovery of thyroid function and avoid occurrence of NTIS.
The tryptophan 620 allele of the lymphoid tyrosine phosphatase (PTPN22) gene predisposes to autoimmune Addison's disease
Authors: Roycroft Matthew , Fichna Marta , McDonald David , Owen Kate , Żurawek Magdalena , Gryczyńska Maria , Januszkiewicz‐Lewandowska Danuta , Fichna Piotr , Cordell Heather , Donaldson Peter , Nowak Jerzy , Pearce Simon 
Published: August 2008

SummaryObjective  Previous studies of the association between autoimmune Addison's disease (AAD) and a nonsynonymous single nucleotide polymorphism (SNP) in the PTPN22 gene (C1858T, pR620W; SNP ID no. rs2476601) have shown conflicting results. We aimed to examine this association using additional cohorts of AAD subjects from the UK and Poland.Design  DNA samples were obtained from UK and Polish AAD subjects (n = 251 and 87, respectively) and ethnically matched healthy controls (n = 429 and 236, respectively). Genotyping for the C1858T PTPN22 marker was performed by polymerase chain reaction restriction fragment length polymorphism (PCR‐RFLP) assay. Meta‐analysis of the results, together with those from three other populations, was performed using RevMan v5·0 software.Results  In 251 UK AAD subjects the frequency of the PTPN22 1858T allele was 12·2% compared to 7·8% in healthy UK controls; P = 0·008. Similarly, in 87 Polish AAD subjects the PTPN22 1858T allele was found in 19·5% of alleles compared to 11·7% in healthy Polish subjects; P = 0·010. A meta‐analysis, combining these result with published data for three other populations, involving 797 AAD subjects and 2032 controls in total, showed that the 1858T allele was associated with AAD susceptibility with a pooled odds ratio (OR) of 1·44 [95% confidence interval (CI) 1·21–1·72; P = 5·6 × 10−5], under a fixed‐effects model.Conclusion  This study confirms the association between the PTPN22 1858T allele and AAD in an expanded UK cohort and in the previously unstudied Polish population. This meta‐analysis allows for the first time a reliable estimate of the strength of effect of this autoimmune disease susceptibility allele across different European Caucasian populations.