Citations

ObjectiveTo examine trends in glucocorticoid (GC) use and dosing among patients diagnosed with rheumatoid arthritis (RA) over time.MethodsA population‐based inception cohort of RA patients diagnosed during 1980–2007 was followed longitudinally through their medical records until death, migration, or December 31, 2008. GC start and stop dates were collected, along with doses in prednisone equivalents.ResultsThe study population comprised 349 patients (68% women) diagnosed in 1980–1994 and 464 (69% women) diagnosed in 1995–2007, with a median followup of 15.3 and 5.7 years, respectively. A higher proportion of patients started GCs in their first year of disease in 1995–2007 (68% versus 36%; P < 0.001), but the starting dose (mean 8.7 versus 10.3 mg; P = 0.08) and cumulative dose in the first year of use (mean 1.8g [mean daily dose 4.9 mg] versus 2.1 gm [mean daily dose 5.8 mg]; P = 0.48) were not different. A higher proportion also discontinued GCs in their first year of disease in the 1995–2007 cohort (P < 0.001). These differences in GC initiation and discontinuation persisted throughout followup. Prevalence of GC use was higher in the 1995–2007 cohort for the first 3 years of disease.ConclusionMore patients are starting GCs early in their disease course now compared to previously, which is consistent with established treatment guidelines. A higher proportion are also discontinuing GCs, but the proportion of patients taking GCs at any given point of disease during the first 4 years is higher now than previously. Despite early addition of a disease‐modifying antirheumatic drug, some patients may not be able to discontinue GCs over the long term.

Abstract B7-H4 is a recently identified B7 family member that negatively regulates T cell immunity by the inhibition of T cell proliferation, cytokine production, and cell cycle progression. In this study, we report that the genomic DNA of human B7-H4 is mapped on chromosome 1 comprised of six exons and five introns spanning 66 kb, of which exon 6 is used for alternative splicing to generate two different transcripts. Similar B7-H4 structure is also found in mouse genomic DNA in chromosome 3. A human B7-H4 pseudogene is identified in chromosome 20p11.1 with a single exon and two stop codons in the coding region. Immunohistochemistry analysis using B7-H4-specific mAb demonstrates that B7-H4 is not expressed on the majority of normal human tissues. In contrast, up to 85% (22 of 26) of ovarian cancer and 31% (5 of 16) of lung cancer tissues constitutively express B7-H4. Our results indicate a tight regulation of B7-H4 expression in the translational level in normal peripheral tissues and a potential role of B7-H4 in the evasion of tumor immunity.

Background and Purpose— To address the increasing need to counsel patients about treatment indications for unruptured intracranial aneurysms (UIA), we endeavored to develop a consensus on assessment of UIAs among a group of specialists from diverse fields involved in research and treatment of UIAs. Methods— After composition of the research group, a Delphi consensus was initiated to identify and rate all features, which may be relevant to assess UIAs and their treatment by using ranking scales and analysis of inter-rater agreement (IRA) for each factor. IRA was categorized as very high, high, moderate, or low. Results— Ultimately, 39 specialists from 4 specialties agreed (high or very high IRAs) on the following key factors for or against UIA treatment decisions: (1) patient age, life expectancy, and comorbid diseases; (2) previous subarachnoid hemorrhage from a different aneurysm, family history for UIA or subarachnoid hemorrhage, nicotine use; (3) UIA size, location, and lobulation; (4) UIA growth or de novo formation on serial imaging; (5) clinical symptoms (cranial nerve deficit, mass effect, and thromboembolic events from UIAs); and (6) risk factors for UIA treatment (patient age and life expectancy, UIA size, and estimated risk of treatment). However, IRAs for features rated with low relevance were also generally low, which underlined the existing controversy about the natural history of UIAs. Conclusions— Our results highlight that neurovascular specialists currently consider many features as important when evaluating UIAs but also highlight that the appreciation of natural history of UIAs remains uncertain, even within a group of highly informed individuals.

Abstract Dihydropyrimidine dehydrogenase (DPD) is the initial and rate-limiting enzyme of the uracil catabolic pathway, being critically important for inactivation of the commonly prescribed anti-cancer drug 5-fluorouracil (5-FU). DPD impairment leads to increased exposure to 5-FU and, in turn, increased anabolism of 5-FU to cytotoxic nucleotides, resulting in more severe clinical adverse effects. Numerous variants within the gene coding for DPD, DPYD, have been described, although only a few have been demonstrated to reduce DPD enzyme activity. To identify DPYD variants that alter enzyme function, we expressed 80 protein-coding variants in an isogenic mammalian system and measured their capacities to convert 5-FU to dihydro-fluorouracil, the product of DPD catabolism. The M166V, E828K, K861R, and P1023T variants exhibited significantly higher enzyme activity than wild-type DPD (120%, P = 0.025; 116%, P = 0.049; 130%, P = 0.0077; 138%, P = 0.048, respectively). Consistent with clinical association studies of 5-FU toxicity, the D949V substitution reduced enzyme activity by 41% (P = 0.0031). Enzyme activity was also significantly reduced for 30 additional variants, 19 of which had &lt;25% activity. None of those 30 variants have been previously reported to associate with 5-FU toxicity in clinical association studies, which have been conducted primarily in populations of European ancestry. Using publicly available genotype databases, we confirmed the rarity of these variants in European populations but showed that they are detected at appreciable frequencies in other populations. These data strongly suggest that testing for the reported deficient DPYD variations could dramatically improve predictive genetic tests for 5-FU sensitivity, especially in individuals of non-European descent. Cancer Res; 74(9); 2545–54. ©2014 AACR.

ObjectiveLifestyle intervention can improve insulin sensitivity in obese youth, yet few studies have examined the molecular signatures associated with these improvements. Therefore, the purpose of this study was to explore gene expression changes in whole blood that are associated with intervention‐induced improvements in insulin sensitivity.MethodsFifteen (7M/8F) overweight/obese (BMI percentile = 96.3 ± 1.1) Latino adolescents (15.0 ± 0.9 years) completed a 12‐week lifestyle intervention that included weekly nutrition education and 180 minutes of moderate–vigorous exercise per week. Insulin sensitivity was estimated by an oral glucose tolerance test and the Matsuda Index. Global microarray analysis profiling from whole blood was performed to examine changes in gene expression and to explore biological pathways that were significantly changed in response to the intervention.ResultsA total of 1,459 probes corresponding to mRNA transcripts (717 up, 742 down) were differentially expressed with a fold change ≥1.2. These genes were mapped within eight significant pathways identified, including insulin signaling, type 1 diabetes, and glycerophospholipid metabolism. Participants with increased insulin sensitivity exhibited five times the number of significant genes altered compared with nonresponders (1,144 vs. 230).ConclusionsThese findings suggest that molecular signatures from whole blood are associated with lifestyle‐induced health improvements among high‐risk Latino youth.

Abstract Dihydropyrimidine dehydrogenase (DPD, encoded by DPYD) is the rate-limiting enzyme in the uracil catabolic pathway and has a pivotal role in the pharmacokinetics of the commonly prescribed anticancer drug 5-fluorouracil (5-FU). Deficiency of DPD, whether due to inadequate expression or deleterious variants in DPYD, has been linked to severe toxic responses to 5-FU. Little is known about the mechanisms governing DPD expression in the liver. In this report, we show increased accumulation of RNA-induced silencing complex (RISC) proteins on DPYD mRNA in cells overexpressing the highly homologous microRNAs (miRNA) miR-27a and miR-27b. These miRNAs were shown to repress DPD expression through two conserved recognition sites in DPYD. The IC50 of 5-FU for HCT116 cells overexpressing miR-27a or miR-27b was 4.4 μmol/L (both), significantly lower than that for cells expressing a nontargeting (scramble) control miRNA (14.3 μmol/L; P = 3.3 × 10−5 and P = 1.5 × 10−7, respectively). Mouse liver DPD enzyme activity was inversely correlated with expression levels of miR-27a (R2 = 0.49; P = 0.0012) and miR-27b (R2 = 0.29; P = 0.022). A common variant in the hairpin loop region of hsa-mir-27a (rs895819) was also shown to be associated with elevated expression of the miR-27a in a panel of cell lines (P = 0.029) and in a transgenic overexpression model (P = 0.0011). Furthermore, rs895819 was associated with reduced DPD enzyme activity (P = 0.028) in a cohort of 40 healthy volunteers. Taken together, these results suggest that miR-27a and miR-27b expression may be pharmacologically relevant modulators of DPD enzyme function in the liver. Furthermore, our data suggest that rs895819 may be a potential risk allele for 5-FU sensitivity. Mol Cancer Ther; 13(3); 742–51. ©2014 AACR.

Background and Purpose— Meta-analyses of extant genome-wide data illustrate the need to focus on subtypes of ischemic stroke for gene discovery. The National Institute of Neurological Disorders and Stroke SiGN (Stroke Genetics Network) contributes substantially to meta-analyses that focus on specific subtypes of stroke. Methods— The National Institute of Neurological Disorders and Stroke SiGN includes ischemic stroke cases from 24 genetic research centers: 13 from the United States and 11 from Europe. Investigators harmonize ischemic stroke phenotyping using the Web-based causative classification of stroke system, with data entered by trained and certified adjudicators at participating genetic research centers. Through the Center for Inherited Diseases Research, the Network plans to genotype 10 296 carefully phenotyped stroke cases using genome-wide single nucleotide polymorphism arrays and adds to these another 4253 previously genotyped cases, for a total of 14 549 cases. To maximize power for subtype analyses, the study allocates genotyping resources almost exclusively to cases. Publicly available studies provide most of the control genotypes. Center for Inherited Diseases Research–generated genotypes and corresponding phenotypes will be shared with the scientific community through the US National Center for Biotechnology Information database of Genotypes and Phenotypes, and brain MRI studies will be centrally archived. Conclusions— The Stroke Genetics Network, with its emphasis on careful and standardized phenotyping of ischemic stroke and stroke subtypes, provides an unprecedented opportunity to uncover genetic determinants of ischemic stroke.

ObjectiveTo determine whether the impact of aging on cardiovascular disease (CVD) risk in patients with rheumatoid arthritis (RA) differs from that in the general population (as estimated by the Framingham Risk Score [FRS]).MethodsA population‐based inception cohort of Olmsted County, Minnesota residents ages ≥30 years who fulfilled the American College of Rheumatology 1987 criteria for RA in 1988–2008 was assembled and followed up until death, migration, or July 1, 2012. Data on CVD events were collected by medical records review. The 10‐year FRS for CVD was calculated. Cox models adjusted for FRS were used to examine the influence of age on CVD risk.ResultsThe study included 563 patients with RA without prior CVD (mean age 55 years, 72% women, and 69% seropositive [i.e., rheumatoid factor and/or anti–citrullinated protein antibody positive]). During a mean followup of 8.2 years, 98 patients developed CVD (74 seropositive and 24 seronegative), but the FRS predicted only 59.7 events (35.4 seropositive and 24.3 seronegative). The gap between observed and predicted CVD risk increased exponentially across age, and the effect of age on CVD risk in seropositive RA was nearly double its effect in the general population, with additional log(age) coefficients of 2.91 for women (P = 0.002) and 2.06 for men (P = 0.027).ConclusionOur findings indicate that age exerts an exponentially increasing effect on CVD risk in seropositive RA, but no increased effect among seronegative patients. The causes of accelerated aging in patients with seropositive RA deserve further investigation.

ObjectiveTo examine lipid profiles among statin‐naive patients with rheumatoid arthritis (RA) and those without RA before and after the initiation of statins.MethodsInformation regarding lipid measures and statin use was gathered in a population‐based incident cohort of patients with RA (1987 American College of Rheumatology criteria first met between January 1, 1988 and January 1, 2008) and in a cohort of non‐RA subjects from the same underlying population. Only patients with no prior history of statin use were included.ResultsThe study included 161 patients with RA (mean age 56.3 years, 57% female) and 221 non‐RA subjects (mean age 56.0 years, 66% female). Prior to the start of statins, the levels of total cholesterol and low‐density lipoprotein (LDL) cholesterol were lower in the RA versus the non‐RA cohort (P < 0.001 and P = 0.003, respectively). The absolute and percentage change in LDL cholesterol after at least 90 days of statin use tended to be smaller in the RA versus the non‐RA cohort (P = 0.03 and P = 0.09, respectively). After at least 90 days of statin use, patients with RA were less likely to achieve therapeutic goals for LDL cholesterol than the non‐RA subjects (P = 0.046). Increased erythrocyte sedimentation rate (ESR) at baseline (odds ratio 0.47, 95% confidence interval 0.26–0.85) was associated with lower likelihood of achieving therapeutic LDL goals.ConclusionPatients with RA had lower total cholesterol and LDL cholesterol levels before statin initiation and lower likelihood of achieving therapeutic LDL goals following statin use than the non‐RA subjects. Some RA disease characteristics, in particular ESR at baseline, may have an adverse impact on achieving therapeutic LDL goals.