Clustering of comorbidities and associated outcomes in people with osteoarthritis - A UK Clinical Practice Research Datalink study.

OBJECTIVE: To examine the clusters of chronic conditions present in people with osteoarthritis and the associated risk factors and health outcomes. METHODS: Clinical Practice Research Datalink (CPRD) GOLD was used to identify people diagnosed with incident osteoarthritis (n = 221,807) between 1997 and 2017 and age (±2 years), gender, and practice matched controls (no osteoarthritis, n = 221,807) from UK primary care. Clustering of people was examined for 49 conditions using latent class analysis. The associations between cluster membership and covariates were quantified by odds ratios (OR) using multinomial logistic regression. General practice (GP) consultations, hospitalisations, and all-cause mortality rates were compared across the clusters identified at the time of first diagnosis of osteoarthritis (index date). RESULTS: In both groups, conditions largely grouped around five clusters: relatively healthy; cardiovascular (CV), musculoskeletal-mental health (MSK-MH), CV-musculoskeletal (CV-MSK) and metabolic (MB). In the osteoarthritis group, compared to the relatively healthy cluster, strong associations were seen for 1) age with all clusters; 2) women with the MB cluster (OR 5.55: 5.14-5.99); 3) obesity with the CV-MSK (OR 2.11: 2.03-2.20) and CV clusters (OR 2.03: 1.97-2.09). The CV-MSK cluster in the osteoarthritis group had the highest number of GP consultations and hospitalisations, and the mortality risk was 2.45 (2.33-2.58) times higher compared to the relatively healthy cluster. CONCLUSIONS: Of the five identified clusters, CV-MSK, CV, and MSK-MH are more common in OA and CV-MSK cluster had higher health utilisation. Further research is warranted to better understand the mechanistic pathways and clinical implications.

Risk of cancer in patients with ankylosing spondylitis: a nationwide cohort study in Taiwan.

Objective: To estimate the incidence of cancer among patients with ankylosing spondylitis (AS) and compare this risk with that of the general population.Method: We obtained data from Taiwan's National Health Insurance database on 19 289 patients with a first diagnosis of AS registered between 2000 and 2012 with no history of cancer before the diagnosis of AS. Standardized incidence ratios (SIRs) for all cancers and for site-specific cancers were used to assess whether AS was associated with an increased risk of cancer.Results: During the follow-up period, 485 patients developed cancer. The incidence rate was therefore 256.3 per 100 000 person-years. Compared with the general population, patients with AS had an increased risk of cancer [SIR 1.33, 95% confidence interval (CI) 1.20-1.47]. The SIR of cancer was higher in older patients; the risk increased from 8 years after initial diagnosis. Among solid tumours, the risk of melanoma was the highest (SIR 4.64, 95% CI 1.93-11.15), followed by prostate (SIR 2.53, 95% CI 2.01-3.19), thyroid (SIR 2.09, 95% CI 1.45-3.00), and bone cancer (SIR 2.00, 95% CI 1.01-3.99). Among haematological cancers, the risk of leukaemia was the highest (SIR 1.94, 95% CI 1.21-3.12). By contrast, the risks of oesophageal and oral cancers decreased in patients with AS.Conclusion: This nationwide population-based cohort study demonstrated that patients with AS in Taiwan are at an increased risk of cancer, particularly melanoma; prostate, thyroid, and bone cancers; and haematological malignancies.

Trends in incidence and prevalence of osteoarthritis in the United Kingdom: findings from the Clinical Practice Research Datalink (CPRD).

OBJECTIVE: This study aimed to explore the incidence and prevalence of OA in the UK in 2017 and their trends from 1997 to 2017 using a large nationally representative primary care database. DESIGN: The UK Clinical Practice Research Datalink (CPRD) comprising data on nearly 17.5 million patients was used for the study. The incidence and prevalence of general practitioner diagnosed OA over a 20 years period (1997-2017) were estimated and age-sex and length of data contribution standardized using the 2017 CPRD population structure. Cohort effects were examined through Age-period-cohort analysis. RESULTS: During 1997-2017, there were 494,716 incident OA cases aged ≥20 years. The standardised incidence of any OA in 2017 was 6.8 per 1000 person-years (95% CI 6.7 to 6.9) and prevalence was 10.7% (95% CI 10.7-10.8%). Both incidence and prevalence were higher in women than men. The incidence of any-OA decreased gradually in the past 20 years at an annual rate of -1.6% (95%CI -2.0 to -1.1%), and the reduction speeded up for people born after 1960. The prevalence of any-OA increased gradually at an annual rate of 1.4% (95% CI 1.3-1.6%). Although the prevalence was highest in Scotland and Northern Ireland, incidence was highest in the East Midlands. Both incidence and prevalence reported highest in the knee followed by hip, wrist/hand and ankle/foot. CONCLUSION: In the UK approximately one in 10 adults have symptomatic clinically diagnosed OA, the knee being the commonest. While prevalence has increased and become static after 2008, incidence is slowly declining. Further research is required to understand these changes.

Comorbidity in multiple sclerosis: its temporal relationships with disease onset and dose effect on mortality.

BACKGROUND AND PURPOSE: We aimed to determine the burden of comorbidities at the time of diagnosis of multiple sclerosis (MS), the risk of developing new comorbidities after diagnosis and the effect of comorbidities on mortality in patients with MS. METHODS: This study used data from 2526 patients with incident MS and 9980 age-, sex- and physician-matched controls without MS identified from the UK Clinical Practice Research Datalink. RESULTS: Before the MS diagnosis, the adjusted odds ratio for the association between MS and a Charlson comorbidity index score of 1-2, 3-4 or ≥5 was 131 [95% confidence interval (CI), 1.17-1.47], 1.65 (95% CI, 1.20-2.26) or 3.26 (95% CI, 1.58-6.70), respectively. MS was associated with increased risks of cardiovascular and neurological/mental diseases. After diagnosis, the adjusted hazard ratio for the association between MS and an increased risk of developing comorbidities was 1.13 (95% CI, 1.00-1.29). The risk of developing any comorbidity in terms of neoplasms, musculoskeletal/connective tissue diseases or neurological/mental diseases was higher in MS. Patients with MS had a higher mortality risk compared with controls, with a hazard ratio of 2.29 (95% CI, 1.81-2.73) after adjusting for comorbidities. There was a dose effect of pre-existing comorbidities on mortality. CONCLUSIONS: Patients with MS have an increased risk of developing multiple comorbidities both before and after diagnosis and pre-existing comorbidities have an impact on survival.

Epilepsy and associated mortality in patients with multiple sclerosis.

BACKGROUND AND PURPOSE: We aimed to determine the prevalence of epilepsy in patients with multiple sclerosis (MS) at diagnosis, the risk of developing epilepsy after the diagnosis of MS and the relative risk of mortality associated with epilepsy. METHODS: We used the UK Clinical Practice Research Data-link to identify 2526 patients with incident MS and 9980 age-, sex- and index year-matched non-MS controls from 1997 to 2006. Logistic regression was used to estimate odds ratios [95% confidence interval (CI)] for epilepsy and Cox regression was used to estimate hazard ratios (HRs) (95% CI) for epilepsy and mortality. RESULTS: Patients with incident MS were on average 45 years old and 70.9% were female. At diagnosis, the prevalence of epilepsy in patients with MS was 1.30% compared with 0.57% in non-MS controls. At diagnosis, MS was associated with an adjusted odds ratio (95% CI) of 2.11 (1.36-3.27) for pre-existing epilepsy. Among epilepsy-free patients, the cumulative probabilities of developing epilepsy, first recorded within 10 years of the index date, were 2.77% for patients with MS and 0.90% for controls. MS was associated with an adjusted HR (95% CI) of 6.01 (2.94-12.29) for epilepsy. Among patients with MS, epilepsy was associated with an HR (95% CI) of 2.23 (1.02-4.84) for all-cause mortality. CONCLUSIONS: This population-based study found an increased prevalence of epilepsy in patients with MS at diagnosis when compared with non-MS controls and the risk of developing epilepsy was also higher following the MS diagnosis. Patients with MS with epilepsy had a higher risk of mortality compared with those without.

Increased risk of varicella zoster virus infection in inflammatory bowel disease in an Asian population: a nationwide population-based cohort study.

PURPOSE: Whether patients with inflammatory bowel disease (IBD) exhibit a high risk of developing varicella zoster virus (VZV) infection in Asian populations remains inconclusive. We investigated the causal relationship between two diseases by analysing the Taiwan National Health Insurance Research Database. PATIENTS AND METHODS: Based on a universal insurance claims database, we enrolled 7055 IBD patients and 28,220 age- and sex-matched controls. We calculated the hazard ratios (HRs) and 95% confidence intervals (CIs) of the herpes zoster virus (HZV) in the IBD and comparison cohorts, using the Cox proportional hazards regression model. RESULTS: Patients with IBD exhibited significantly higher risk of the HZV compared with the controls (adjusted HRs, 1.42; 95% CI, 1.27-1.60). Further analysis indicated that male patients (adjusted HRs, 1.61; 95% CI, 1.35-1.92), aged 35-44 (adjusted HRs, 1.47; 95% CI, 1.08-2.01) and aged 65 years and older (adjusted HRs, 1.47; 95% CI, 1.19-1.80), and patients without comorbidities (adjusted HRs, 1.44; 95% CI, 1.26-1.66), exhibited excessive risks of VZV infection. Moreover, our findings show that the overall risk of developing VZV infection increased risk from 1.03 (95% CI, 0.90-1.18) (≤ 2 visits) to 9.76 (95% CI, 7.60-12.5) (> 4 visits), which correlates positively with the frequency of medical visits (trend test p < 0.0001). CONCLUSION: Patients with IBD, particularly men aged 35-44/65 years and over, and patients without comorbidities, are associated with a long-term risk of VZV infection. The excessive risk of VZV infection should be considered for administering vaccines to IBD patients.

Klebsiella pneumoniae sepsis with unusual cutaneous presentation of generalized pustulosis.

Klebsiella pneumoniae is a well-known Gram-negative pyogenic pathogen that can cause various types of infection. Liver abscesses caused by community-acquired K. pneumoniae infection are commonly reported in Taiwan, especially in people with diabetes mellitus. Meningococcal bacteraemia can present as disseminated pustules and leucocytoclastic vasculitis, but it has rarely been seen in patients with K. pneumoniae infection. To date, there are only two reports in the English literature about K. pneumoniae bacteraemia presenting as generalized pustulosis. We report a third case, occurring in a Taiwanese woman with a community-acquired K. pneumoniae liver abscess leading to sepsis and generalized pustules, complicated by cutaneous leucocytoclastic vasculitis.

Cancer risk among patients with systemic sclerosis: a nationwide population study in Taiwan.

OBJECTIVES: Systemic sclerosis (SSc) has been associated with high cancer risk. We compared the cancer risk among SSc patients with that among the general Taiwanese population. METHODS: The catastrophic illness registry of the Taiwan National Health Insurance Research Dataset (NHIRD) was used to identify patients diagnosed with SSc and cancer in Taiwan during 1996-2008. The standardized incidence ratio (SIR) for cancer was calculated, and mortality was ascertained using the data from the National Death Registry. RESULTS: Data analysis revealed that 2053 (472 men, 1581 women) Taiwanese individuals were diagnosed with SSc during the study period and 83 (30 men, 53 women) had cancer. The incidence of cancer was 6.9/1000 person-years. The most common cancer sites in male SSc patients were the lung (n = 10), oral cavity and pharynx (n = 8), and gastrointestinal tract (n = 4), and those in female patients were the breast (n = 11), lungs (n = 11), and blood (n = 6). Compared to the Taiwanese population of 1996, the all-cancer SIR for SSc was 1.63 [95% confidence interval (CI) 1.31-2.01]. Cancer risk was elevated for cancers of the lung (SIR 4.20), oral cavity and pharynx (SIR 3.67), and blood (SIR 3.50). A cancer diagnosis in SSc patients was associated with a hazard ratio (HR) of 2.15 (95% CI 1.30-3.53). Among cancer patients, a diagnosis of SSc was not associated with increased mortality. CONCLUSIONS: SSc patients are at high risk of developing cancer, especially of the lung, oral cavity and pharynx, and blood.

Incidence, cancer risk and mortality of dermatomyositis and polymyositis in Taiwan: a nationwide population study.

BACKGROUND: Nationwide data on the epidemiology of dermatomyositis (DM) and polymyositis (PM) were limited. OBJECTIVES: This study was to estimate the incidence, occurrence of cancer and mortality of DM and PM in Taiwan. METHODS: Both the register of critical illness of the Taiwan National Health Insurance Research Dataset and the National Death Registry of Taiwan were used to calculate estimates of the incidence, cancer association, and mortality of DM and PM between 2003 and 2007. RESULTS: A total of 803 DM and 500 PM cases were identified between 2003 and 2007. Mean age at diagnosis was 44·0 ± 18·3 years for DM and 49·2 ± 15·9 years for PM. The overall annual incidences of DM and PM were 7·1 (95% CI 6·6-7·6) and 4·4 (95% CI 4·0-4·8) cases per million population. The incidence of both DM and PM increased with age and reached a peak at age 50-59 years. One hundred and eleven (13·8%) patients with DM and 31 (6·2%) patients with PM had cancers. The diagnosis of most cancers was made after the diagnoses of DM (n = 71; 64·0%) and PM (n = 21; 67·7%). Overall, the standardized incidence ratios (SIR) for cancer were 5·36 (4·12-6·87) and 1·80 (1·10-2·79) among patients with DM and PM; however, during the first year, SIRs for cancer were 24·55 (95% CI 18·62-31·79) and 9·17 (95% CI 14·82-15·93) in patients with DM and PM, respectively. The most common types of cancer were nasopharyngeal cancer for men and breast cancer for women. Patients with DM and PM had standardized mortality ratios of 7·68 (6·41-9·01) and 5·29 (4·28-6·48). CONCLUSION: This study reports robust estimates of important aspects of the epidemiology of both DM and PM in Taiwan. This highlights the rarity of these diseases, and their associated cancer risks and increased mortality.

Filaggrin polymorphism P478S, IgE level, and atopic phenotypes.

BACKGROUND: Whether environmental exposures may modulate the effect of the skin barrier gene on atopic dermatitis (AD) remains to be elucidated. OBJECTIVES: To determine whether filaggrin (FLG) variants can serve as a predictor for atopic disorders in Chinese individuals and if allergen exposures may modify the effect of FLG variants on AD by total IgE levels. METHODS: In total, 116 children aged 2-5years with AD and 212 control subjects were analysed for the FLG variants using DNA sequencing. Multiple logistic regression models were performed to estimate the association among FLG polymorphisms and atopic phenotypes. Serum total IgE level, standing for the degree of allergen exposures, was later stratified to determine the effects of FLG polymorphisms on AD. RESULTS: A significant difference in genotype frequency was found among AD cases and controls in FLG P478S polymorphism. FLG P478S GG genotype significantly increased the risk of AD [odds ratio (OR) 4·60, 95% confidence interval (CI) 1·88-11·24]. In addition, among subjects with AD, GG genotypes also significantly increased the risk of developing asthma (OR 4·68, 95% CI 1·37-16·03). Further, a similar result was obtained for allergic rhinitis (OR 3·23, 95% CI 1·01-10·30). Interestingly, the P478S GG genotype was significantly related to AD (OR 5·67, 95% CI 1·93-16·60) in children with IgE level ≥100 kU L(-1) . However, the association was not evident when IgE level was < 100 kU L(-1) . CONCLUSIONS: Our results suggest that the FLG P478S polymorphism may confer susceptibility to the development of AD among Chinese individuals and may be modified by IgE levels.

Hyperuricaemia and accelerated reduction in renal function.

OBJECTIVES: Hyperuricaemia has been linked to reduced renal function, and evidence indicates that it may be associated with acceleration of the decline in glomerular filtration rate (GFR) and progression of chronic kidney disease (CKD). METHODS: We analysed a population of subjects who had undergone serum uric acid (SUA) and serum creatinine measurements in a hospital-based cohort. Initial and final serum creatinine measurements were used to calculate the estimated glomerular filtration rate (eGFR) and the annual decline in eGFR. Cox regression was used to investigate the relationship between SUA and CKD progression. RESULTS: A total of 63,785 subjects were enrolled in the study during a 12-year follow-up period. The mean age at the time of initial serum creatinine measurement was 50.0 ± 14.9 years. Hyperuricaemic subjects had a significantly larger annual eGFR decline, both in absolute terms (2.5 ± 9.5 mL/min/1.73 m(2) per year) and as a percentage (2.8 ± 11.6% per year), as compared to the normouricaemia group (1.3 ± 9.6 mL/min/1.73 m(2) per year, 1.1 ± 11.1% per year, p < 0.001). After adjustment for age, sex, status of diabetes mellitus (DM) and hypertension, baseline eGFR, azotaemia, hypercholesterolaemia, and hyperglycaemia, hyperuricaemia was associated with a hazard ratio (HR) of 1.28 [95% confidence interval (CI) 1.23-1.33, p < 0.001] for an accelerated eGFR decline ≥ 3 mL/min/1.73 m(2) per year and an HR of 1.52 (95% CI 1.46-1.59) for CKD progression at the end of follow-up. CONCLUSION: Hyperuricaemia was associated with an accelerated decline in eGFR and higher risk of CKD progression. Therefore, renal function should be monitored closely in patients with hyperuricaemia.

Antinuclear antibody status and risk of death in children and adolescents.

OBJECTIVES: The association between the presence of antinuclear antibodies (ANA) and mortality has been rarely reported. The present study explored the value of ANA as a predictor of overall survival in children and adolescents. METHODS: Patients younger than 20 years who underwent ANA testing in Chang Gung Memorial Hospital (CGMH) from 2000 to 2008 were enrolled in this study. Mortality was ascertained by using the National Death Registry of Taiwan. Positive ANA titres were categorized as low (1:40 to 1:80), medium (1:160 to 1:320), and high (≥ 1:640). RESULTS: A total of 13 345 subjects (6579 males, 6766 females) were enrolled during the 9-year study period. The overall prevalence of low, medium, and high ANA titres was 20.8% (n = 2774), 6.0% (n = 804), and 2.5% (n = 338), respectively. During 45,140 person-years of follow-up, 146 deaths were identified and the crude mortality rates were 3.8 and 3.0 per 1000 person-years for subjects with positive and negative ANA test results, respectively (p = 0.130). Compared with ANA-negative subjects, the adjusted hazard ratio (HR) for all-cause mortality among those with a high ANA titre was 5.18 [95% confidence interval (CI) 3.13-8.57]. A low-to-medium ANA titre was not associated with increased mortality. Among the 18 deaths in individuals with a high ANA titre, 14 were due to systemic lupus erythematosus (SLE). In comparison, five out of 34 deaths among those with low-to-medium titres of ANA and none of those with negative ANA were related to SLE. CONCLUSIONS: Children and adolescents with high ANA titres should receive greater attention and monitoring to prevent unfavourable outcomes because they have a higher mortality risk than those with negative ANA results.

Epidemiology and mortality of systemic sclerosis: a nationwide population study in Taiwan.

OBJECTIVES: There have been few nationwide population studies of systemic sclerosis (SSc). We describe the epidemiological features of SSc in Taiwan. METHODS: The catastrophic illness registry of the Taiwan National Health Insurance Research Dataset (NHIRD) and the National Death Registry of Taiwan were used to calculate estimates of the incidence, prevalence, and mortality of SSc. RESULTS: A total of 1479 persons (325 males, 1154 females) with incident SSc were enrolled in the study. The annual incidence of SSc in Taiwan was found to be 10.9 cases (4.7 males, 17.4 females) per million population. During 2002-2007, the mean prevalence was 56.3 cases per million population. There were 204 deaths (70 males, 134 females) during the study period; 1-, 2-, and 5-year survival rates were 94.9, 92.0, and 83.2%, respectively. SSc patients had a standardized mortality ratio (SMR) of 3.24 [95% confidence interval (CI) 2.82-3.71] for all-cause mortality, as compared with the national population in 2002. There was excess mortality from neoplasms (SMR 1.50, 95% CI 1.03-2.11), cardiovascular diseases (2.23, 1.52-3.16), kidney disease (4.67, 2.66-7.64), gastrointestinal diseases (2.50, 1.27-4.46), and pulmonary diseases (3.20, 1.89-5.09). In addition to male sex and older age, cancer and end-stage renal disease (ESRD) diagnosis were risk factors for death, with hazard ratios (HRs) of 2.71 (95% CI 1.27-5.76) and 2.59 (1.14-5.90), respectively. CONCLUSION: SSc patients had a threefold greater risk of all-cause mortality than the general population of Taiwan. Male sex, older age, diagnosis of cancer, and ESRD were risk factors for death.

Gout and risk of non-alcoholic fatty liver disease.

OBJECTIVES: To investigate the association between gout and non-alcoholic fatty liver disease (NAFLD). METHODS: The study subjects were participants in a health-screening programme at Chang Gung Memorial Hospital from 2000 to 2006. Subjects were classified into eight groups based on serum urate (SU) level and gout status (≤ 4.9, 5.0-6.9, 7.0-8.9, and ≥ 9.0 mg/dL, without and with gout). The association between gout and NAFLD was assessed by multiple logistic regression. RESULTS: Among a total of 54 325 subjects, 1930 (3.6%) had gout and 6169 (11.3%) had NAFLD. The prevalence of NAFLD was significantly higher in subjects with gout (23.1%, n = 445) than in those without gout (10.9%, n = 5724, p < 0.001). Among subjects with NAFLD, the severity of NAFLD was higher in gout patients. Gout was associated with an increased risk for NAFLD [odds ratio (OR) 1.42, 95% confidence interval (CI) 1.25-1.60, p < 0.001], after adjustment for age, sex, presence of metabolic syndrome, and low estimated glomerular filtration rate (eGFR). With SU ≤ 4.9 mg/dL in the absence of gout as reference, the ORs (95% CI) for NAFLD, after adjustment for age, sex, presence of metabolic syndrome, and low eGFR, were, respectively, 2.16 (1.94-2.41), 3.98 (3.55-4.46), and 5.99 (5.19-6.90) for SU levels 2-4 in those without gout and 2.61 (1.39-4.91), 2.87 (2.04-4.04), 4.53 (3.70-5.56), and 6.31 (5.12-7.77) for SU levels 1-4 in those with gout. CONCLUSIONS: There was an independent association between gout and the risk for NAFLD. In addition, there was a dose-response relationship between SU and NAFLD in subjects with and without gout.

Inhibition of group A streptococcal infection by Melaleuca alternifolia (tea tree) oil concentrate in the murine model.

AIMS: To investigate the effect of a water-soluble Melaleuca alternifolia concentrate (MAC) on group A streptococcus (GAS; Streptococcus pyogenes)-induced necrotizing fasciitis. METHODS AND RESULTS: MAC pretreatment (1% and 2% v/v) was able to protect mice from GAS infection in an air pouch model. GAS-induced mouse death and skin injury were inhibited dose dependently by MAC. Administration of MAC at 6 h post-GAS infection partially delayed mouse death. Surveys of the exudates of the air pouch of MAC-treated mice revealed that the survival of infiltrating cells was prolonged, the bacteria were eliminated, and the production of inflammatory cytokines was inhibited. MAC could directly inhibit the growth of GAS in vitro, and the minimal inhibitory concentration (MIC) of MAC for GAS was determined as 0.05% v/v using the time-kill assay. Furthermore, a sub-MIC dose of MAC not only enhanced the bactericidal activity of RAW264.7 macrophage cells against GAS but also increased susceptibility of GAS for blood clearance. CONCLUSIONS: These results suggest that MAC may inhibit GAS-induced skin damage and mouse death by directly inhibiting GAS growth and enhancing the bactericidal activity of macrophages. SIGNIFICANCE AND IMPACT OF THE STUDY: Our results provide scientific data on the use of MAC for the treatment of GAS-induced necrotizing fasciitis in the murine model.

Atomic structure of the DNA repair [4Fe-4S] enzyme endonuclease III.

The crystal structure of the DNA repair enzyme endonuclease III, which recognizes and cleaves DNA at damaged bases, has been solved to 2.0 angstrom resolution with an R factor of 0.185. This iron-sulfur [4Fe-4S] enzyme is elongated and bilobal with a deep cleft separating two similarly sized domains: a novel, sequence-continuous, six-helix domain (residues 22 to 132) and a Greek-key, four-helix domain formed by the amino-terminal and three carboxyl-terminal helices (residues 1 to 21 and 133 to 211) together with the [4Fe-4S] cluster. The cluster is bound entirely within the carboxyl-terminal loop with a ligation pattern (Cys-X6-Cys-X2-Cys-X5-Cys) distinct from all other known [4Fe-4S] proteins. Sequence conservation and the positive electrostatic potential of conserved regions identify a surface suitable for binding duplex B-DNA across the long axis of the enzyme, matching a 46 angstrom length of protected DNA. The primary role of the [4Fe-4S] cluster appears to involve positioning conserved basic residues for interaction with the DNA phosphate backbone. The crystallographically identified inhibitor binding region, which recognizes the damaged base thymine glycol, is a seven-residue beta-hairpin (residues 113 to 119). Location and side chain orientation at the base of the inhibitor binding site implicate Glu112 in the N-glycosylase mechanism and Lys120 in the beta-elimination mechanism. Overall, the structure reveals an unusual fold and a new biological function for [4Fe-4S] clusters and provides a structural basis for studying recognition of damaged DNA and the N-glycosylase and apurinic/apyrimidinic-lyase mechanisms.

Preventing arteriovenous shunt failure in hemodialysis patients: a population-based cohort study.

Essentials Uncertainty remains about antiplatelets for vascular access patency in hemodialysis patients. 95 971 people under hemodialysis were followed in a claims database in Taiwan. Aspirin reduced vascular access failure rate and did not increase major bleeding rate. Clopidogrel, Aggrenox, and warfarin might increase major bleeding rate. SUMMARY: Background Dialysis adequacy is a major determinant of survival for patients with end-stage renal disease. Good vascular access is essential to achieve adequate dialysis. Objectives This study evaluated the impacts of different drugs on the vascular access failure rate of an arteriovenous fistula or an arteriovenous graft and the rate of major bleeding in hemodialysis patients. Patients and methods We studied patients with end-stage renal disease registered in the Taiwan National Health Insurance program from 1 January 1997 to 31 December 2012. A total of 95 971 patients were enrolled in our study. Vascular access dysfunction was defined as the need for thrombectomy or percutaneous angioplasty. Major bleeding was defined as emergency department visits or hospitalization with a primary diagnosis of gastrointestinal bleeding or intracerebral hemorrhage. The adjusted odds ratios between person-quarters with or without antiplatelet or oral anticoagulant use were calculated using a generalized estimating equation. Results The odds ratio of vascular access failure was 0.21 (0.11-0.39) for aspirin, 0.76 (0.74-0.79) for clopidogrel, 0.67 (0.59-0.77) for dipyridamole, 0.67 (0.53-0.86) for Aggrenox and 0.96 (0.90-1.03) for warfarin. The highest odds ratio for intracerebral hemorrhage was 5.33 (1.25-22.72) in younger patients using Aggrenox. The highest odds ratio for gastrointestinal bleeding was 1.34 (1.10-1.64) for clopidogrel. Conclusion Antiplatelet agents, but not warfarin, might reduce the vascular access thrombosis rate. The gastrointestinal bleeding rate was increased in the group using clopidogrel. Aggrenox should be used with caution in young individuals because it might increase the rate of intracerebral hemorrhage.

Positional and developmental regulation of glutamine synthetase expression in mouse liver.

In situ hybridization showed that all fetal hepatocytes contain glutamine synthetase (GS) mRNA but that in adult mouse liver, only a single cell layer surrounding the central veins contains GS mRNA. A shift from the fetal to the adult pattern begins within a few days of birth and is complete within 12 days of birth. Since the total GS mRNA and the transcription rate of the single GS gene are similar at birth and in adults, we conclude that there is a generalized reduction in GS transcription for most hepatocytes and a sharp rise in GS transcription for the immediate pericentral cells. This may be a case of positional regulation of specific gene transcription in apparently a single cell lineage.

Expression of the yes proto-oncogene in cerebellar Purkinje cells.

To identify the kinds of cells in the brain that express the yes proto-oncogene, we examined chicken brains by using immunofluorescent staining and in situ hybridization. Both approaches showed that the highest level of the yes gene product was in cerebellar Purkinje cells. In addition, we analyzed Purkinje cell degeneration (pcd) mutant mice. The level of yes mRNA in cerebella of pcd mutants was four times lower than that found in cerebella of normal littermates. Our studies point to Purkinje cells as an attractive model for functional studies of the yes protein.

Antagonism between apolipoprotein AI regulatory protein 1, Ear3/COUP-TF, and hepatocyte nuclear factor 4 modulates apolipoprotein CIII gene expression in liver and intestinal cells.

Apolipoprotein CIII (apoCIII), a lipid-binding protein involved in the transport of triglycerides and cholesterol in the plasma, is synthesized primarily in the liver and the intestine. A cis-acting regulatory element, C3P, located at -90 to -66 upstream from the apoCIII gene transcriptional start site (+1), is necessary for maximal expression of the apoCIII gene in human hepatoma (HepG2) and intestinal carcinoma (Caco2) cells. This report shows that three members of the steroid receptor superfamily of transcription factors, hepatocyte nuclear factor 4 (HNF-4), apolipoprotein AI regulatory protein 1 (ARP-1), and Ear3/COUP-TF, act at the C3P site. HNF-4 activates apoCIII gene expression in HepG2 and Caco2 cells, while ARP-1 and Ear3/COUP-TF repress its expression in the same cells. HNF-4 activation is abolished by increasing amounts of ARP-1 or Ear3/COUP-TF, and repression by ARP-1 or Ear3/COUP-TF is alleviated by increasing amounts of HNF-4. HNF-4 and ARP-1 bind with similar affinities to the C3P site, suggesting that their opposing transcriptional effects may be mediated by direct competition for DNA binding. HNF-4 and ARP-1 mRNAs are present within the same cells in the liver and intestine, and protein extracts from hepatic tissue, HepG2, and Caco2 cells contain significantly more HNF-4 than ARP-1 or Ear3/COUP-TF binding activities. These findings suggest that the transcription of the apoCIII gene in vivo is dependent, at least in part, upon the intracellular balance of these positive and negative regulatory factors.