Genetic contributions to female gout and hyperuricaemia using genome-wide association study and polygenic risk score analyses.

OBJECTIVES: To identify genetic variants and polygenic risk score (PRS) relating to female gout and asymptomatic hyperuricaemia (AH) in a genome-wide association study (GWAS). METHODS: Gout, AH and normouricemia controls were included from Taiwan biobank and China Medical University Hospital. All participants were divided into discovery and replication cohorts for GWAS. PRS was estimated according to whether the variant exhibited a protective effect on the phenotypes or not. Each cohort was separated into two groups by the age of 50 years old. RESULTS: A total of 59 472 females were enrolled, and gout and AH occupied 1.60% and 19.59%, respectively. Six variants located in genes SLC2A9, C5orf22, CNTNAP2 and GLRX5 were significantly predictors of female gout in those aged ≥50. For those aged <50 years old, only the variant rs147750368 (SPANXN1) on chromosome X was found. Most variants located in genes SLC2A9, ZNF518B, PKD2 and ABCG2 were found to be significantly related to AH in both age groups. The PRS could explain ∼0.59% to 0.89% of variance of gout in variants with protective effects, which showed 6.2 times of mean PRS in the risk variants, but only 1.2 times in the AH phenotype. Moreover, the PRS also revealed a dose-response trend between AH rates and quartile scores. CONCLUSION: The variants in gene SLC2A9 are the major genetic factors for females associated with gout in those aged ≥50. PRS can provide a more robust prediction of the gout/AH under a homogeneous selection of variants that show effects on the traits.

The Role of Macrophages in Connective Tissue Disease-Associated Interstitial Lung Disease: Focusing on Molecular Mechanisms and Potential Treatment Strategies.

Connective tissue disease-associated interstitial lung disease (CTD-ILD) is a severe manifestation of CTD that leads to significant morbidity and mortality. Clinically, ILD can occur in diverse CTDs. Pathologically, CTD-ILD is characterized by various histologic patterns, such as nonspecific interstitial pneumonia, organizing pneumonia, and usual interstitial pneumonia. Abnormal immune system responses have traditionally been instrumental in its pathophysiology, and various changes in immune cells have been described, especially in macrophages. This article first briefly overviews the epidemiology, clinical characteristics, impacts, and histopathologic changes associated with CTD-ILD. Next, it summarizes the roles of various signaling pathways in macrophages or products of macrophages in ILD, helped by insights gained from animal models. In the following sections, this review returns to studies of macrophages in CTD-ILD in humans for an overall picture of the current understanding. Finally, we direct attention to potential therapies targeting macrophages in CTD-ILD in investigation or in clinical trials, as well as the future directions regarding macrophages in the context of CTD-ILD. Although the field of macrophages in CTD-ILD is still in its infancy, several lines of evidence suggest the potential of this area.

Genetic and epigenetic alterations of cyclic AMP response element modulator in rheumatoid arthritis.

BACKGROUND: Genetic and epigenetic factors are strongly associated with the autoimmune disease rheumatoid arthritis (RA). Cyclic AMP response element modulator (CREM), a gene related to immune system regulation, has been implicated in various immune-mediated inflammatory processes, although it remains unknown whether CREM is involved in RA. METHODS: This study enrolled 278 RA patients and 262 controls. Three variants [rs12765063, rs17499247, rs1213386] were identified through linkage disequilibrium and expression quantitative trait locus analysis, and CREM transcript abundance was determined by quantitative real-time polymerase chain reaction. The identified variants were genotyped using the TaqMan Allelic Discrimination assay, and CREM promoter methylation was assessed by bisulphite sequencing. Differences between groups and correlations between variables were assessed with Student's t-tests and Pearson's correlation coefficients. Associations between phenotypes and genotypes were evaluated with logistic regression. RESULTS: Rheumatoid arthritis patients exhibited increased CREM expression (p < .0001), which was decreased by methotrexate (p = .0223) and biologics (p = .0001), but could not be attributed to CREM variants. Interestingly, rs17499247 displayed a significant association with serositis (p = .0377), and rs1213386 increased the risk of lymphadenopathy (p = .0398). Furthermore, seven CpG sites showed decreased methylation in RA (p = .0477~ p < .0001). CONCLUSIONS: Collectively, our results indicate that CREM hypomethylation and CREM upregulation occur in RA and that CREM variants are involved in the development of serositis and lymphadenopathy in RA. This study highlights the novel roles of CREM in RA pathophysiology.

APOE and KLF14 genetic variants are sex-specific for low high-density lipoprotein cholesterol identified by a genome-wide association study.

To demonstrate the loci that relate to high-density lipoprotein cholesterol (HDL-C) levels and genetic sex heterogeneity, we enrolled 41,526 participants aged between 30 and 70 years old from the Taiwan Biobank in a genome-wide association study. We applied the Manhattan plot to display the p-values estimated for the relationships between loci and low HDL-C. A total of 160 variants were significantly associated with low HDL-C. The genotype TT of rs1364422 located in the KLF14 gene has 1.30 (95% CI=1.20 - 1.42) times the risk for low-HDL compared to genotype CC in females (log(-p) =8.98). Moreover, the genes APOC1, APOE, PVRL2, and TOMM40 were associated significantly with low-HDL-C in males only. Excluding the variants with high linkage disequilibrium, we revealed the rs429358 located in APOE as the major genetic variant for lowering HDL-C, in which genotype CT has 1.24 (95% CI= 1.16 - 1.32) times the risk. In addition, we also examine 12 genes related to HDL-C in both sexes, including LPL, ABCA1, APOA5, BUD13, ZPR1, ALDH1A2, LIPC, CETP, HERPUD1, LIPG, ANGPTL8, and DOCK6. In conclusion, low-HDL-C is a genetic and sex-specific phenotype, and we discovered that the APOE and KLF14 are specific to low-HDL-C for men and women, respectively.

Genetic Variants in Transcription Factor Binding Sites in Humans: Triggered by Natural Selection and Triggers of Diseases.

Variants of transcription factor binding sites (TFBSs) constitute an important part of the human genome. Current evidence demonstrates close links between nucleotides within TFBSs and gene expression. There are multiple pathways through which genomic sequences located in TFBSs regulate gene expression, and recent genome-wide association studies have shown the biological significance of TFBS variation in human phenotypes. However, numerous challenges remain in the study of TFBS polymorphisms. This article aims to cover the current state of understanding as regards the genomic features of TFBSs and TFBS variants; the mechanisms through which TFBS variants regulate gene expression; the approaches to studying the effects of nucleotide changes that create or disrupt TFBSs; the challenges faced in studies of TFBS sequence variations; the effects of natural selection on collections of TFBSs; in addition to the insights gained from the study of TFBS alleles related to gout, its associated comorbidities (increased body mass index, chronic kidney disease, diabetes, dyslipidemia, coronary artery disease, ischemic heart disease, hypertension, hyperuricemia, osteoporosis, and prostate cancer), and the treatment responses of patients.

Systemic Investigation of Promoter-wide Methylome and Genome Variations in Gout.

Current knowledge of gout centers on hyperuricemia. Relatively little is known regarding the pathogenesis of gouty inflammation. To investigate the epigenetic background of gouty inflammation independent of hyperuricemia and its relationship to genetics, 69 gout patients and 1455 non-gout controls were included. Promoter-wide methylation was profiled with EPIC array. Whole-genome sequencing data were included for genetic and methylation quantitative trait loci (meQTL) analyses and causal inference tests. Identified loci were subjected to co-methylation analysis and functional localization with DNase hypersensitivity and histone marks analysis. An expression database was queried to clarify biologic functions of identified loci. A transcription factor dataset was integrated to identify transcription factors coordinating respective expression. In total, seven CpG loci involved in interleukin-1ß production survived genetic/meQTL analyses, or causal inference tests. None had a significant relationship with various metabolic traits. Additional analysis suggested gouty inflammation, instead of hyperuricemia, provides the link between these CpG sites and gout. Six (PGGT1B, INSIG1, ANGPTL2, JNK1, UBAP1, and RAPTOR) were novel genes in the field of gout. One (CNTN5) was previously associated with gouty inflammation. Transcription factor mapping identified several potential transcription factors implicated in the link between differential methylation, interleukin-1ß production, and gouty inflammation. In conclusion, this study revealed several novel genes specific to gouty inflammation and provided enhanced insight into the biological basis of gouty inflammation.

Sex differential association of dermatomyositis with Sjögren syndrome.

BACKGROUND: Although dermatomyositis and Sjögren syndrome share serologic autoantibodies and genetic polymorphisms, population data about the incidence of Sjögren syndrome in patients with dermatomyositis is unavailable. We performed a nationwide cohort study to explore the potential relation between dermatomyositis and Sjögren syndrome and, if an association exists, to elucidate whether it varies by sex. METHODS: We identified all patients with newly diagnosed dermatomyositis from the Registry of Catastrophic Illness Database in Taiwan between Jan. 1, 1998, and Dec. 31, 2011. Each patient was matched to, at most, 5 control patients from the National Health Insurance Research Database by age, sex and entry date. Cox regression was used to calculate the hazard ratio (HR) and 95% confidence interval (CI) of Sjögren syndrome after adjusting for age, sex, rheumatoid arthritis, systemic lupus erythematosus and systemic sclerosis. RESULTS: A total of 1602 patients with dermatomyositis and 7981 control patients were enrolled in the study. There was a positive association of having Sjögren syndrome among patients with dermatomyositis after adjusting for age, sex, rheumatoid arthritis, systemic lupus erythematosus and systemic sclerosis (HR 2.67, 95% CI 2.01-3.54). The association was more pronounced in the male cohort (HR 2.69, 95% CI 1.19-6.09). INTERPRETATION: We found a sex differential association of Sjögren syndrome among patients with dermatomyositis independent of age and concomitant autoimmune disease. Further studies are required to determine the clinical importance of this association for both outcomes and therapeutic options.

Simultaneous detection of respiratory syncytial virus and human metapneumovirus by one-step multiplex real-time RT-PCR in patients with respiratory symptoms.

BACKGROUND: Both respiratory syncytial virus (RSV) and human metapneumovirus (hMPV) are important viral pathogens causing respiratory tract infection (RTI) in the pediatric population. However, the clinical manifestations of RSV and hMPV infections are similar. Therefore, a reliable and rapid diagnostic tool is needed for diagnostic performance. METHODS: In order to optimize diagnosis efficiency of RTI, the aim of this study is to establish a rapid and advanced method for simultaneous detecting RSV and hMPV in nasopharyngeal aspirates specimens from patients. We designed a one-step triplex real-time RT-PCR (qRT-PCR) protocol using TaqMan probes for detecting RSV and hMPV. The plasmid clones containing RSV nucleoprotein gene and hMPV fusion gene were established as reference standards. We used virus culture supernatants from 86 known pediatric RTI patient to test the specificity and sensitivity of our assay. Then we used total 222 nasopharyngeal aspirates specimens from pediatric patients hospitalized with respiratory symptoms to evaluate our assay. RESULTS: Our one-step triplex qRT-PCR assay showed 100% sensitivity and specificity in testing RSV and hMPV in 86 known virus culture supernatants, with excellent linearity (R2 > 0.99) and reliable reproducibility (CV lower than 1.04%). This assay has a wide dynamic range 102-109copies/reaction (limit of detection; LOD = 100 copies/reaction). A total of 222 patients hospitalized with respiratory symptoms were enrolled for clinical evaluation. In these samples, our qRT-PCR assay detected 68 RSV positive and 18 hMPV positive cases. However, standard virus culture only detected 8 RSV positive cases and 0 hMPV cases. Based on this improved triplex qRT-PCR assay, we found that RSV infection was associated with severe inflammation by chest X-ray and occurrence of pneumonia which were not observed previously. CONCLUSIONS: In summary, we have developed a highly specific and sensitive one-step triplex qRT-PCR assay to detect hMPV and RSV simultaneously. This assay offers a valuable tool for routine diagnosis.

Increased incidence of multiple sclerosis in systemic sclerosis: A nationwide cohort study.

OBJECTIVE: Previous studies showed inconsistent results on the association of systemic sclerosis (SSc) with multiple sclerosis (MS), and are limited by a lack of adjustment for sex and age. The goals of this retrospective cohort study were to evaluate whether SSc is associated with increased incident MS independent of sex and age. METHODS: We enrolled patients with SSc from Taiwan's Registry of Catastrophic Illness Database and referent subjects from the National Health Insurance Research Database. Each SSc patient was matched to at most three referent subjects by sex, age, month and year of initial diagnosis of SSc. Incidence of MS in SSc patients and corresponding 95% confidence interval (95% CI) were calculated. Cox hazard regression was used to calculate the hazard ratio (HR) of MS. RESULTS: The study enrolled 1171 patients with SSc and 3409 referent subjects. Patients with SSc had higher incidence of MS than referent subjects (9.35 per 1000 person-years, 95% CI=6.86-11.85; 0.13 per 1000 person-years, 95% CI=0.03-0.37, respectively). Similar results also occurred in both men and women. SSc was associated with increased incidence of MS after adjusting for sex and age (HR: 69.48, 95% CI=21.69-222.54). CONCLUSION: SSc is associated with increased incidence of MS, independent of sex and age of the patients. Multidisciplinary teams should guide the assessment, treatment, and holistic care of SSc patients to reduce its morbidity.

Reduced incidence of Crohn's disease in systemic sclerosis: a nationwide population study.

BACKGROUND: To date, there has been no studies to evaluate the incidence of Crohn's disease in systemic sclerosis patients. The goals of this study were to evaluate the incidence of Crohn's disease and its relationship with sex and age in patients with systemic sclerosis. METHODS: We enrolled patients with systemic sclerosis and controls from Taiwan's Registry of Catastrophic Illness Database and National Health Insurance Research Database. Every systemic sclerosis patient was matched to at most three controls by sex, age, month and year of initial diagnosis of systemic sclerosis. The standardized incidence ratio (SIR) of Crohn's disease in systemic sclerosis patients, and 95% confidence interval (95% CI) were calculated. Cox hazard regression was used to calculate the hazard ratio (HR). RESULTS: The study enrolled 2,829 patients with systemic sclerosis and 8,257 controls. Male and female patients with systemic sclerosis both had lower rates of incident Crohn's disease (SIR: 0.18, 95% CI = 0.05-0.62; SIR: 0.10, 95% CI = 0.05-0.21, respectively). The risk of incident Crohn's disease in systemic sclerosis was still lower than in controls when we stratified the patients according to their ages. In Cox hazard regression, the hazard rates of Crohn's disease were lower in systemic sclerosis patients after adjusting for genders and ages (HR: 0.12, 95% CI = 0.06-0.21, p < 0.001). CONCLUSIONS: Systemic sclerosis is associated with decreased incidence of, irrespective of sex and age of the patients.

Metabolic syndrome, diabetes, and hyperuricemia.

PURPOSE OF REVIEW: To explore the causal relationship between metabolic syndrome, type 2 diabetes and hyperuricemia. RECENT FINDINGS: The prevalence of hyperuricemia in male adults with metabolic syndrome was increased and a large difference in prevalence of metabolic syndrome also existed in those with hyperuricemia compared with normouricemia. Even in those with normouricemia, higher serum uric acid levels were associated with metabolic syndrome. Serum uric acid was an independent risk factor for incident diabetes, and evidence showed that the patients with both gout and type 2 diabetes exhibited a mutual inter-dependent effect on higher incidences. Furthermore, obese patients often demonstrated insulin resistance and adipose tissue macrophage with low-grade inflammation, which is suggested to be the major contributor. Although alcohol intake is considered a risk for developing hyperuricemia, moderate alcohol intake showed a lower risk for developing type 2 diabetes and insulin resistance. Hyperinsulinemia reduces renal excretion of uric acid on the proximal tubular of the kidney leading to hyperuricemia, which has deleterious effects on endothelial function and on nitric oxide bioavailability, thus causing hyperinsulinemia. SUMMARY: We found evidence to suggest that insulin resistance plays a potentially key role in the causal relationship between metabolic syndrome, type 2 diabetes and hyperuricemia. Furthermore, it is likely that hyperuricemia and insulin resistance share a bidirectional causal effect.

Uncorrected visual acuity and noncycloplegic autorefraction predict significant refractive errors in Taiwanese preschool children.

PURPOSE: To investigate the accuracy of uncorrected visual acuity (UCVA), stereopsis, and noncycloplegic autorefraction (NCAR) tests performed by vision-screening technicians and to determine the best referral criteria when using these methods to screen for significant refractive errors in preschool children. DESIGN: Retrospective, case-control, and cross-sectional study. PARTICIPANTS: We reviewed 1000 records for a population-based preschool vision-screening program. The target conditions were defined as myopia ≤-3.0 diopters (D), hyperopia ≥ 4.5 D, astigmatism ≥ 2.0 D, and anisometropia ≥ 2.0 D. METHODS: Receiver operating characteristic (ROC) curve was used to calculate optimal referral cutoff values. The examination results obtained by the vision-screening technicians were compared with those obtained by a pediatric ophthalmologist, which were considered the gold standard. MAIN OUTCOME MEASURES: The efficacies (sensitivity, specificity, positive predictive value, and negative predictive value) of different tests were evaluated. RESULTS: In 7.0% (95% confidence interval [CI], 5.3-8.7) of the children, at least 1 eye showed 1 of the target conditions. If only the right eyes were considered, the prevalence of target conditions was 4.2% (95% CI, 2.9-5.5). The ROC curve analysis indicated that the NCAR cylinder test (cutoff value ≥ 0.875 D) was the best test for screening target conditions. With regard to age groups, UCVA ≤ 0.75 (Snellen equivalent) and ≤ 0.85 were the best referral criteria for ages ≤ 4 years and ≥ 5 years, respectively. Combining the UCVA test with the NCAR test (the child was referred after failing both tests) increased specificity without significantly decreasing sensitivity. CONCLUSIONS: The UCVA and NCAR tests performed by vision-screening technicians are adequately sensitive and specific for preschool vision screening. The ROC curve analysis was used for determining the appropriate screening criteria for these tests, and combining the tests increased their accuracy. The screening criteria should be age dependent. When analyzing the test accuracy in ophthalmic problems, if the disease of interest does not symmetrically (in terms of disease severity and prevalence) involve both eyes, the prevalence based on only 1 eye should be interpreted with caution.

RAS, BRAF, and TP53 gene mutations in Taiwanese colorectal cancer patients.

BACKGROUND: Colorectal cancer (CRC) plays an important role in cancer mortality and morbidity. This study examined colorectal tissues for RAS, BRAF, and TP53 gene mutations to assess their value as indicators of outcomes of CRC therapy. MATERIAL AND METHODS: DNA was extracted from tissues taken from 165 patients with CRC. RAS gene mutations (exons 2 and 3) were detected by primer extension analysis. BRAF gene mutations (V600E) were detected by high resolution melting (HRM) analysis. TP53 gene mutations (exons 5-8) were detected by direct sequencing. RESULTS: RAS, BRAF, and TP53 mutations occurred in 36.97% (61/165), 4.24% (7/165), and 37.58% (62/165), respectively. The KRAS mutation is a predictor for poor 5-year survival (p = 0.05), and the co-presence of KRAS and TP53 mutations correlates with lymph node involvement (p = 0.029), tumor stage (p = 0.029), and poor survival (p = 0.021). Multivariate analysis adjusted for tumor size, histologic grade, lymph node metastasis, sex, and age also indicated that KRAS mutations correlate significantly with overall survival (p = 0.036). CONCLUSION: The KRAS mutation is not present in about one-third of CRC patients, and therefore other gene mutations need to be investigated to better understand the molecular mechanisms of CRC and its treatment.

Efforts to improve the surgical outcome for exotropia and investigation of the insertion locations of the extraocular muscles.

In our previous retrospective study, we found that using the strabismus surgery dosages established by western strabismus mentors tends to result in undercorrection of Taiwanese exotropia (XT) patients compared with those in western populations. We also discovered that the location of extraocular muscle (EOM) insertion could vary by ethnicity. In this study, using a generalized estimation equation model, we compared the XT surgery outcome between augmented and original strabismus surgery dosages in Taiwanese patients. We also conducted an observational study to investigate the horizontal EOM insertion location in a Taiwanese population and compared the data with Dr. Apt L.'s study. For Taiwanese XT patients, augmented surgical dosages resulted in significantly better outcome at 6 months and 1 year postoperatively compared with original surgical dosages (p = 0.003 and p < 0.001, respectively). The distance from the lateral recuts muscle (LR) insertion location to the limbus was significantly shorter in Taiwanese than in white Americans (6.5 vs. 6.9 mm, respectively, p = 0.0001). Furthermore, the medial rectus muscle and LR insertion locations differed significantly between males and females (p < 0.001 and p = 0.023, respectively). The patients' sex did not affect the surgery outcome. Augmented surgery doses modified from western strabismus mentors produce better surgery outcome for Taiwanese XT patients. Surgeons may require country-specific guidelines for strabismus surgery dosage. We also demonstrated a simple method for young ophthalmologists to establish their own normograms to improve their surgical success rate. Our study confirms that LR insertion locations differ between Taiwanese and White Americans.

Cancer carrier screening in the general population using whole-genome sequencing.

BACKGROUND: Cancer is a major cause of death, and its early identification and intervention have potential for clinical actionability and benefits for human health. The studies using whole-genome sequencing (WGS) and large samples analysis of cancer-related genes have been rarely done. METHODS: We performed WGS to explore germline mutations in coding and non-coding areas of cancer-related genes and non-coding driver genes and regulatory areas. Structural variants (SVs) was also analyzed. We used several tools and a subgrouping method to analyze the variants in 1491 healthy participants. Moreover, 275 cancer-related genes sequencing was carried out in 125 cancer patients. RESULTS: The incidence of familial cancer in the Taiwanese general population is 8.79% (131/1491). Cancer carrier rate of cancer-related genes is about 7.04% (105/1491) for pathogenic/likely pathogenic variants (P/LP) on ClinVar database only, and 28.24% (421/1491) for P/LP and loss of function variants. The carrier frequencies of cancer-related genes P/LP on ClinVar database were as follows: 8.40% (11/131), 7.11% (28/394), and 6.83% (66/966) in FC, 1MC, and nMC, respectively. The SVs and non-coding driver gene variants are uncommon. There are 1.54% (23/1491) of actionable cancer genes in American College of Medical Genetics and Genomics (ACMG), and the germline mutation rate of 275 cancer-related genes is 7.2% (9/125) in cancer patients including 4.0% (5/125) of actionable cancer genes in ACMG. After analyzing the frequencies of P/LP variants on GJB2 and SLC25A13 genes, we suggest that these two genes may not be cancer-related genes and need be re-evaluated. CONCLUSIONS: WGS analysis can completely detect germline mutations in cancer carriers. This study use subgrouping approach for samples provides a strategy to study whether a gene or variant is a cancer-related gene or variant in the future studies.

Gout and type 2 diabetes have a mutual inter-dependent effect on genetic risk factors and higher incidences.

OBJECTIVE: To explore the causal relationship between gout and Type 2 diabetes based on genetic evidence and national outpatient database. METHODS: Twenty male gout patients with early-onset, gout family history, without a habit of alcohol consumption or obesity before the first attack of gout were selected from hospital in 2010; and 42 unrelated male Chinese subjects were selected from HapMap as controls for genome-wide analysis study (GWAS). The comorbid diseases with gout were revealed by applying the significant single nucleotide polymorphisms (SNPs) to MetaCore platform, and the comorbid relationship was analysed by standardized incidence ratio (SIR) from outpatient database. RESULTS: A total of 334 SNPs were significantly related to gout in GWAS (P < 10(-7)), and Type 2 diabetes was the most significantly associated disease with gout as recognized by 36 gene symbols correspondent to the above significant SNPs. The analysis of national outpatient database showed that the overall incident Type 2 diabetes was 1.50 cases per 1000 person-months among gout patients, which was higher than the overall incident gout (1.06 cases) among Type 2 diabetes. The age-adjusted SIR of incident Type 2 diabetes among gout was 2.59 (95% CI 2.42, 2.78), whereas the age-adjusted SIR for incident gout among Type 2 diabetes was 1.61 (95% CI 1.48, 1.74). CONCLUSION: After excluding obesity and alcohol consumption behaviour, this study showed that patients with gout and Type 2 diabetes shared the common genetic factors most, and that there existed a mutual inter-dependent effect on higher incidences.

Visit-to-visit variability in blood pressure strongly predicts all-cause mortality in patients with type 2 diabetes: a 5·5-year prospective analysis.

BACKGROUND: Elevations in blood pressure and visit-to-visit variability have been found to significantly increase the risk of cardiovascular morbidity and mortality in nondiabetic individuals. This study has assessed the association between all-cause mortality and blood pressure parameters [systolic blood pressure (SBP), diastolic blood pressure (DBP), pulse pressure (PP), mean arterial pressure (MAP) and visit-to-visit variability] in patients with type 2 diabetes. MATERIALS AND METHODS: A longitudinal cohort study of 2161 patients with type 2 diabetes and a mean follow-up period of 66·7 ± 7·5 months. Using Cox regression models, blood pressure parameters were related to the risk of all-cause mortality. RESULTS: Visit-to-visit variability in SBP [HR: 1·048 (95% CI: 1·005-1·092; P = 0·03)], DBP [HR: 1·090 (95% CI: 1·021-1·163; P = 0·01)] and MAP [HR: 1·099 (95% CI: 1·033-1·170; P = 0·003)] significantly predicted all-cause mortality in patients with type 2 diabetes after adjusting for baseline data, mean follow-up blood pressure profiles and HbA1c. Visit-to-visit variability in PP [HR: 1·139 (95% CI: 1·030-1·258; P = 0·01)] significantly predicted cardiovascular mortality. Neither baseline nor follow-up SBP, DBP, PP nor MAP was significantly associated with all-cause and cardiovascular mortality after adjusting for blood pressure variability. The risk of all-cause mortality with a mean follow-up SBP has a U-shaped distribution. Patients with a mean follow-up DBP > 90 mmHg were at higher risk of mortality than those with DBP < 90 mmHg. CONCLUSIONS: Visit-to-visit variability in blood pressure was significantly associated with all-cause mortality independent of mean BP in patients with type 2 diabetes. The data for blood pressure variability might be regarded as a potentially important therapeutic target in the management of type 2 diabetes.

A observational study of the efficacy and safety of capecitabine versus bolus infusional 5-fluorouracil in pre-operative chemoradiotherapy for locally advanced rectal cancer.

BACKGROUND AND OBJECTIVES: This study is to evaluate the safety and efficacy of preoperative radiotherapy (RT) combined with bolus infusional 5-fluorouracil (5-FU) or oral capecitabine in patients with locally advanced rectal cancer (LARC). MATERIALS AND METHODS: Seventy-four patients were retrospectively analyzed. Twenty-seven patients were treated with 5-FU (350 mg/m(2) i.v. bolus) and leucovorin (20 mg/m(2) i.v. bolus) for 5 days/week during week 1 and 5 of RT. Forty-seven patients were treated with capecitabine (850 mg/m(2), twice daily for 5 days/week). Both groups received the same RT course (45-50.4 Gy/25 fractions, 5 days/week, for 5 weeks). Patients underwent surgery in 6 weeks after completion of the chemoradiotherapy. Data of the observational study were collected. RESULTS: Grade 3 or 4 toxicities occurred in 40.7% (5-FU) and 19.1% (capecitabine) of the patients (P = 0.044). Six patients in the 5-FU group (22.2%) and six patients in the capecitabine group (14%) achieved complete response. Primary tumor (T) downstaging were achieved in 51.9% (5-FU) and 69.8% (capecitabine) of the patients. The pathological ypT0-2 stage was 40.7% (5-FU) and 67.4% (capecitabine) (P = 0.028). CONCLUSIONS: In consideration of the better ypT0-2 downstaging rate, less severe toxicities, and no need for indwelling intravenous device on oral capecitabine regimen, the administration of oral capecitabine with RT may be a more favorable option in the neoadjuvant treatment for LARC.

Working memory deficit in premenstrual dysphoric disorder and its associations with difficulty in concentrating and irritability.

OBJECTIVE: This study evaluates working memory deficit among women with premenstrual dysphoric disorder (PMDD) and whether such a deficit and its premenstrual aggravation is associated with difficulty in concentrating, irritability, and impaired daily function or not. METHOD: Sixty women with PMDD (PMDD group) and 60 women without PMDD (control group) completed the assessment. Severity of irritability, difficulty concentrating, total symptoms, and functional impairment of PMDD were evaluated by the Premenstrual Symptoms Screening Tool. All participants performed N2 and N3 back tasks to assess working memory in both luteal and follicular phases. RESULTS: The PMDD group had significantly poorer performance on N2 and N3 back tasks than the control group did in the luteal phase but not in the follicular phase. Compared to the control group, the PMDD group also exhibited more deterioration in performance of N3 back task in the luteal phase. Performance of N2 and N3 back tasks in luteal phase was significantly associated with irritability, symptom severity, and functional impairment by PMDD. CONCLUSIONS: Working memory deficit is aggravated in the luteal phase among women with PMDD. Appropriate interventions are needed to prevent negative consequences of working memory deficit.

Comparison of needlescopic and conventional video-assisted thoracic surgery for primary spontaneous pneumothorax.

Whether the outcome of primary spontaneous pneumothorax (PSP) when treated with needlescopic video-assisted thoracic surgery is positive is still under scrutiny. The present study was conducted to compare the needlescopic approach with the conventional approach. One-hundred and six patients with primary spontaneous pneumothorax who had undergone needlescopic video-assisted thoracic surgery (NVATS) between May 2006 and August 2008 were reviewed. Their age, gender, smoking status, BMI, side of attack, operative indications, operative time, intraoperative blood loss, postoperative length of stay, postoperative pain in visual analog scale (VAS), postoperative recurrence and follow-up period were recorded. These data were compared with those of 89 patients with PSP who had undergone conventional video-assisted thoracic surgery (CVATS) between June 2002 and April 2006. The operative time was shorter (NVATS: 82.36 ± 35.58 min, CVATS: 99.78 ± 35.74 min; p = 0.008) and intraoperative blood loss was less (NVATS: 16.67 ± 25.90 ml, CVATS: 24.36 ± 26.86 ml; p = 0.04) for the NVATS group. The postoperative pain in VAS was significantly less in NVATS. No major complication or mortality was found in either group. For treatment of primary spontaneous pneumothorax, NVATS is a safe and effective option. Further, it has the added benefit of less pain and improved cosmetics.