AtMPK6-induced phosphorylation of AtERF72 enhances its DNA binding activity and interaction with TGA4/OBF4 in Arabidopsis.

The ethylene-responsive element binding factor (ERF) family is a large family of transcription factors involved in plant development and environmental stress responses. We previously reported the identification of 29 putative substrates of Mitogen-activated Protein Kinase3 (AtMPK3), AtMPK4 and AtMPK6, based on a solid-phase phosphorylation screening using a lambda phage expression library in Arabidopsis thaliana. In this study, a putative MPK substrate, AtERF72 (At3g16770), was strongly phosphorylated by AtMPK6 on the serine residue at position 151 (Ser151). AtERF72 binds to the GCC box (AGCCGCC) in the promoters of several pathogenesis-related (PR) genes and activates their transcription. We also show that the DNA-binding activity of AtERF72 is enhanced upon phosphorylation by AtMPK6 in vitro. In addition, transient co-expression experiments in Arabidopsis protoplasts revealed that effector constructs expressing a mutant variant of AtERF72, AtERF72S151D (carrying a Ser to aspartic acid [Asp] substitution at amino acid position 151) showed higher expression of the ß-glucuronidase (GUS) reporter gene driven by the GCC box element than effector constructs expressing the wild-type AtERF72. Furthermore, yeast two-hybrid assays revealed that the interaction between AtERF72S151D and TGA4/OBF4 was stronger than that between wild-type AtERF72 and TGA4/OBF4. Since AtERF72S151D is equivalent to AtERF72 phosphorylated by AtMPK6 at Ser151, these results suggest that the phosphorylation of AtERF72 by AtMPK6 triggers an event of transcriptional regulation from defence signalling in Arabidopsis.

Functional characterisation of two phytochelatin synthases in rice (Oryza sativa cv. Milyang 117) that respond to cadmium stress.

Cadmium (Cd) is one of the most toxic heavy metals and a non-essential element to all organisms, including plants; however, the genes involved in Cd resistance in plants remain poorly characterised. To identify Cd resistance genes in rice, we screened a rice cDNA expression library treated with CdCl2 using a yeast (Saccharomyces cerevisiae) mutant ycf1 strain (DTY167) and isolated two rice phytochelatin synthases (OsPCS5 and OsPCS15). The genes were strongly induced by Cd treatment and conferred increased resistance to Cd when expressed in the ycf1 mutant strain. In addition, the Cd concentration was twofold higher in yeast expressing OsPCS5 and OsPCS15 than in vector-transformed yeast, and OsPCS5 and OsPCS15 localised in the cytoplasm. Arabidopsis thaliana plants overexpressing OsPCS5/-15 paradoxically exhibited increased sensitivity to Cd, suggesting that overexpression of OsPCS5/-15 resulted in toxicity due to excess phytochelatin production in A. thaliana. These data indicate that OsPCS5 and OsPCS15 are involved in Cd tolerance, which may be related to the relative abundances of phytochelatins synthesised by these phytochelatin synthases.

Real-world evidence of improved healthcare utilization in patients with schizophrenia or schizoaffective disorder after early treatment of paliperidone palmitate once-monthly treatment in Hong Kong.

BACKGROUND: Very few data are available to demonstrate the economic benefit of early paliperidone palmitate once-monthly long-acting injectable (PP1M) treatment in patients with schizophrenia or schizoaffective disorder. METHODS AND MATERIALS: This study has retrospectively compared the healthcare utilization and associated costs of pre- and post-PPIM treatment in 413 patients with schizophrenia or schizoaffective disorder recruited from three major public hospitals providing psychiatric services in Hong Kong. Patients were categorized into early treatment (≤3 years since diagnosis) and chronic (>3 years) groups, and also whether they were receiving polypharmacy (POP). RESULTS: It was found that patients who were started on early therapy with no POP had the most favourable outcomes. Overall results of the entire cohort, including both early and late treatments, indicate that there was a slight increase in annual in-patient days (IP) per patient and outpatient visit (OP) by 3.18 and 1.87, respectively, and a decrease in emergency room visit (ER) of 0.9 (p < 0.05). For non-polypharmacy (NP) patients receiving early PP1M therapy, there was a significant decrease in IP and ER of 21.56 (p < 0.05) and 1.15 (p < 0.05), respectively, but an increase in OP of 1.88 (p < 0.05). For patients with POP, there was an all-across increase in IP and all-across decrease in OP and ER. In monetary terms, a NP patient receiving early therapy may have an overall saving of HKD40,878 (USD5,241, 1USD = 7.8HKD) per year compared to HKD6,224 (USD798) in patients where therapy was given after 3 years. For patients with POP, there was an all-across increase in overall spending despite reductions in OP and ER. CONCLUSIONS: From the 413 patients studied, potential annual savings is higher by early administration of PPIM in patients with NP. Analysis using multivariate linear regression based on generalized estimating equations and sensitivity analysis using a linear mixed model supported the findings.

Blood profile and meat quality of Holstein-Friesian steers finished on total mixed ration or flaxseed oil-supplemented pellet mixed with reed canary grass haylage.

Holstein-Friesian steer beef production is renowned globally as a secondary product of the milk industry. Grass feeding is a common practice in raising Holstein steers because of its low cost. Furthermore, grass feeding is an alternative way to produce beef with a balanced n-6 to n-3 fatty acids (FAs) ratio. However, the performance and meat quality of Holstein-Friesian cattle is more likely to depend on a high-quality diet. The aim of this study was to observe whether feeding two mixed diets; a corn-based total mixed ration (TMR) with winter ryegrass (Lolium perenne) or flaxseed oil-supplemented pellets with reed canary grass haylage (n-3 mix) provided benefits on carcass weight, meat quality and FA composition compared with cattle fed with reed canary grass (Phalaris arundinacea) haylage alone. In all, 15 21-month-old Holstein-Friesian steers were randomly assigned to three group pens, were allowed free access to water and were fed different experimental diets for 150 days. Blood samples were taken a week before slaughter. Carcass weight and meat quality were evaluated after slaughter. Plasma lipid levels and aspartate aminotransferase (AST), γ-glutamyl transpeptidase (GGT), creatine kinase (CK) and alkaline phosphatase (ALP) activities were determined. Diet did not affect plasma triglyceride levels and GGT activity. Plasma cholesterol levels, including low-density and high-density lipoproteins, were higher in both mixed-diet groups than in the haylae group. The highest activities of plasma AST, CK and ALP were observed in the haylage group, followed by n-3 mix and TMR groups, respectively. Carcass weight was lower in the haylage group than in the other groups and no differences were found between the TMR and n-3 mix groups. Although the n-3 mix-fed and haylage-fed beef provided lower n-6 to n-3 FAs ratio than TMR-fed beef, the roasted beef obtained from the TMR group was more acceptable with better overall meat physicochemical properties and sensory scores. According to daily cost, carcass weight and n-6 to n-3 FAs ratio, the finishing diet containing flaxseed oil-supplemented pellets and reed canary grass haylage at the as-fed ratio of 40 : 60 could be beneficial for the production of n-3-enriched beef.

Increased risk of stroke in patients with osteoarthritis: a population-based cohort study.

OBJECTIVES: Osteoarthritis (OA) is related to carotid atherosclerosis. Few studies have investigated the incidence of cerebrovascular diseases in patients with OA. Therefore, we conducted a population-based cohort study to determine the incidence and risk of stroke in patients with OA. METHODS: We used data from Taiwan's Longitudinal Health Insurance Database 2000 (LHID2000) to investigate the incidence of stroke in 43,635 patients with OA newly diagnosed between 2002 and 2003. The non-osteoarthritis (non-OA) cohort comprised 43,635 people from the general population. The follow-up period was from the index date of OA to the date of censoring date or stroke diagnosis, or to the end of 2010. RESULTS: The overall incidence of stroke was 36% higher in the OA cohort than in the non-OA cohort, with an adjusted hazard ratio (aHR) of 1.10 (95% confidence interval [CI] = 1.06-1.14) after adjustment for covariates. Men, age, comorbidity, non-selective nonsteroidal anti-inflammatory drugs (NSAIDs), and Cox-2 selective NSAIDs are independent risk factors of stroke. The OA adults with mild to moderate OA (aHR = 1.97, 95% CI = 1.70-2.28 for young adults; aHR = 1.33, 95% CI = 1.25-1.42 for middle-aged adults; aHR = 1.16, 95% CI = 1.12-1.21 for older adults) and severe OA (aHR = 3.78, 95% CI = 2.50-5.70 for young adults; aHR = 1.34, 95% CI = 1.16-1.56 for middle-aged adults; and aHR = 1.01, 95% CI = 0.92-1.10 for older adults) exhibited increased risks of stroke compared with their counterparts without OA. CONCLUSION: OA may be associated with a slightly increased risk of stroke.

Unprovoked venous thromboembolism and subsequent cancer risk: a population-based cohort study.

UNLABELLED: ESSENTIALS: A relationship between unprovoked venous thromboembolism (VTE) and cancer risk was investigated. We collected 27,751 VTE patients and compared them with 110,409 frequency-matched people without VTE. This cohort study showed significantly higher risks of overall and site-specific cancers in the VTE group. There is an increased risk in the first 6 months after VTE, and VTE can be an indicator of occult cancer. BACKGROUND: We investigated the relationship between unprovoked venous thromboembolism (VTE) and subsequent cancer risk in Taiwan, focusing on both short-term and long-term cancer development. METHODS: For the case group, we obtained data on 27,751 patients diagnosed with unprovoked VTE between 1 January 1998, and 31 December 2008. For the comparison group, four people without unprovoked VTE were frequency-matched with each unprovoked VTE patient according to age, sex, and index year. Cox proportional hazards regression models were employed to determine the effects of unprovoked VTE on cancer risk. RESULTS: Overall cancer risk was significantly higher in the unprovoked VTE group than in the comparison group (adjusted hazard ratio = 2.26, 95% confidence interval = 2.16-2.37). The increased risk was observed in both men and women in various age groups. The patients in the unprovoked VTE group showed a significantly increased risk of cancer at all site-specific cancer sites. Analyses stratified according to follow-up duration revealed that significant differences were more evident between the two groups over a follow-up duration of < 0.5 years than over a follow-up duration of ≥ 3 years. Furthermore, the 1-year mortality risk of cancer patients with unprovoked VTE was significantly higher than that for cancer patients in the non-VTE group. CONCLUSION: The results of this study show that unprovoked VTE is associated with a consistently high risk of subsequent cancer diagnosis. This is particularly true in the first 6 months after VTE. It suggests that unprovoked VTE can be an indicator of occult malignancy.

Association of systemic lupus erythematosus and sleep disorders: a nationwide population-based cohort study.

OBJECTIVE: Using a population-based cohort study, we investigated whether sleep disorders (SDs) increase the risk of systemic lupus erythematosus (SLE). PATIENTS AND METHODS: We identified patients with SDs and a control cohort from 1998-2001 by using the Taiwan Longitudinal Health Insurance Database 2000. Two controls for each patient with an SD were selected and randomly frequency-matched according to age, gender, and index year. The follow-up person-years were estimated for the patients from the index date to SLE diagnosis, loss to follow-up, or the end of 31 December 2011. We used the Cox proportional hazards models to evaluate how SDs influence the risk of SLE after adjustments for demographic factors and comorbidities. RESULTS: A total of 144,396 subjects (48,132 SD cases and 96,264 controls) were followed for 1,477,055 person-years. The patients with SDs displayed higher incidence density rate of developing SLE than did the controls (1.03 vs. 0.46 per 10,000 person-years). After adjustment for covariates, the patients with SDs exhibited a 2.20-fold higher adjusted hazard ratio (aHR) of developing SLE than the controls (95% confidence interval (CI) = 1.44-3.36). Women exhibited a greater prevalence of SDs and SLE compared to men. Patients with SDs aged 49 years and younger exhibited a significantly increased risk of SLE compared to the controls (aHR=2.30, 95% CI = 1.33-3.98). Patients with SDs living in urban areas exhibited a significantly increased risk of SLE. CONCLUSION: This large population-based cohort study revealed that SDs increase the risk of SLE development.

Increased risk of lung cancer among patients with bronchiectasis: a nationwide cohort study.

BACKGROUND: We conducted a longitudinal nationwide cohort study in Taiwan to determine whether patients with bronchiectasis are at an increased risk of developing lung cancer. METHODS: This study investigated the incidence and risk for lung cancer in 57 576 patients newly hospitalized with bronchiectasis between 1998 and 2010 from the Taiwan National Health Insurance Research Database. The comparison cohort comprised 230 304 individuals from the general population without bronchiectasis. The follow-up period was from the time of the initial hospitalization for bronchiectasis to the date of a lung cancer diagnosis, censoring, or 31 December 2011. We used Cox proportional hazard regression models to analyse the risk of lung cancer by including the variables of sex, age and comorbidities. RESULTS: The incidence of lung cancer was higher in patients with bronchiectasis than in the comparison cohort (4.58 vs. 2.02 per 1000 person-years). The bronchiectasis patients exhibited a 2.36-fold increased risk of lung cancer compared with the comparison cohort after adjustment for age, sex and comorbidities (adjusted hazard ratio [aHR] = 2.36, 95% confidence interval [CI] = 2.19-2.55). The sex-specific bronchiectasis cohort to comparison cohort revealed that the aHR was 2.41 (95% CI = 2.11-2.76) for the women and 2.33 (95% CI = 2.12-2.56) for the men. The incidence rate of lung cancer increased as age increased in both cohorts. CONCLUSION: This nationwide study determined that the patients with bronchiectasis exhibited an increased risk of lung cancer compared with the general population.

Comorbid risks of deep vein thrombosis and pulmonary thromboembolism in patients with chronic pancreatitis: a nationwide cohort study.

UNLABELLED: ESSENTIALS: Risks of deep vein thrombosis (DVT) and pulmonary embolism (PE) in chronic pancreatitis (CP) are unclear. We conducted a nationwide cohort study to evaluate the risks of DVT and PE in CP patients. 17 778 patients with CP and 71 106 without CP were followed for 86 740 and 429 116 person-years, respectively. Patients with CP had a 2.95-fold increased rate of DVT and a 4.51-fold increased rate of PE. BACKGROUND: Studies on the association between chronic pancreatitis (CP) and cardiovascular diseases are scarce. We conducted a nationwide cohort study to evaluate the risks of deep vein thrombosis (DVT) and pulmonary embolism (PE) in CP patients. METHODS: Using the data from the Taiwan National Health Insurance Research Database, we randomly selected a non-CP cohort from insurants without a history of CP, and frequency-matched them at a ratio of 4 : 1 according to age, sex and index year with each patient newly diagnosed with CP between 2000 and 2010. The follow-up period ranged from the index date of new CP diagnosis to the diagnosis of DVT or PE, censoring, or the end of 2011. We used univariable and multivariable Cox proportional hazard regression models to determine the risks of DVT and PE. RESULTS: In total, 17 778 patients in the CP cohort (82.6% men; mean age of 48.6 years) and 71 106 persons in the non-CP cohort were observed for 86 740 and 429 116 person-years, respectively. The CP cohort showed a 2.95-fold greater adjusted hazard ratio (aHR) for DVT (95% confidence interval [CI] 2.06-4.22) and a 4.51-fold greater aHR for PE (95% CI 2.86-7.11) than the non-CP cohort. Substantial risks of DVT and PE were evident in patients with CP aged < 55 years. The CP cohort with comorbidities showed increased risks of DVT and PE as compared with the non-CP cohort with no comorbidities. CONCLUSIONS: The risks of DVT and PE are significantly higher in CP patients than in the general population.

Increased risk of coronary heart disease in patients with hip fracture: a nationwide cohort study.

UNLABELLED: The study indicates that hip fracture is independently associated with increased risk of coronary heart disease. In addition, the highest risk of coronary heart disease following hip fracture appeared within the first year after hip fracture, indicating the need for multidisciplinary care for the patients. INTRODUCTION: Bone and vasculature are modulated through numerous common pathways. However, data on the risk of coronary heart disease (CHD) after hip fracture are scarce. Therefore, we investigated whether hip fracture increased the risk of CHD by conducting a large nationwide cohort study. METHODS: Using universal insurance claims data from 2000 to 2010, we identified a study cohort of 6013 participants newly diagnosed with hip fracture and a control cohort of 23,802 participants. Both cohorts were followed up to the end of 2011 to evaluate the risk of CHD. RESULTS: The overall incidence of CHD was 1.69-fold higher in the hip fracture cohort than it was in the control cohort (29.2 vs. 17.1 per 1000 person-years) with an adjusted hazard ratio of 1.51 (95 % confidence interval [CI] = 1.39-1.65). Sex-, age-, and comorbidity-specific analyses showed a higher relative risk of CHD for both women and men, all age groups, those with and without comorbidities, and patients with hip fracture compared with the control cohort. The highest risk of CHD was within the first year after hip fracture (adjusted HR = 1.72, 95 % CI = 1.45-2.04), and the risk remained high in the following years. CONCLUSION: Hip fracture was independently associated with a subsequent risk of CHD.

Increased risk of erectile dysfunction among patients with sleep disorders: a nationwide population-based cohort study.

AIMS: Few studies have investigated the relationship between sleep disorders (SD) and erectile dysfunction (ED). Therefore, this study explored whether patients with SD in an Asian population are at an increased risk of developing ED. METHODS: This longitudinal nationwide population-based cohort study investigated the incidence and risk of developing ED in 34,548 men newly diagnosed with SD between 2002 and 2008 from the National Health Insurance Research Database. A total of 138,192 controls without SD were randomly recruited from the general population and frequency matched according to age and sex. The follow-up period began from the date of entering the study cohort until the date of an ED event, censoring, or 31 December 2010. We conducted Cox proportional hazard regression analyses to estimate the effects of SD on the risk of ED. RESULTS: The SD cohort had a 2.11-fold adjusted hazard ratio (HR) of subsequent ED development compared with the non-SD cohort [95% confidence interval (CI) = 1.89-2.37]. The incidence of ED increased with age for both cohorts and was higher for the patients in the SD cohort. Compared with the participants without SD or comorbidities, the patients without SD with any comorbidity exhibited a 1.79-fold risk of developing ED (95% CI = 1.54-2.09); the highest risk was for those with both SD and any comorbidity (HR = 3.34, 95% CI = 2.82-3.95). Furthermore, SD patients who had a particular number of comorbidities showed the dose-response effect of developing ED. CONCLUSION: This nationwide cohort study determined that ED risk evidently increased in SD patients compared with the general population.

Mycoplasma pneumonia increases the risk of acute coronary syndrome: a nationwide population-based cohort study.

BACKGROUND: Studies investigating the epidemiological relationship between Mycoplasma pneumonia (MP) and the subsequent development of acute coronary syndrome (ACS) are scant. We conducted a nationwide longitudinal cohort study in Taiwan to explore whether MP patients are at an increased risk of developing ACS. METHODS: This study investigated the incidence and risk factors for ACS in 12 152 newly diagnosed MP patients from the Taiwan National Health Insurance Research Database between 2004 and 2011. The control group consisted of 48 600 individuals without MP. The follow-up period ran from the time of initial MP diagnosis to the date of an ACS event, censoring, or 31 December 2011. We analyzed the risk of ACS by using Cox proportional hazard regression models, including variables for sex, age and comorbidities. RESULTS: The incidence of ACS was higher in MP patients than in comparison cohort (3.08 vs. 2.42 per 1000 person-years). The hazard ratio of developing ACS increased 37% in MP patients compared with that in the comparison cohort after adjustment for covariates. The effect of MP on subsequent ACS development appeared to 12 months after infection. CONCLUSION: This nationwide study determined that compared with the general population, MP patients exhibited a 37% increase in the risk of subsequently developing ACS. Clinicians should be aware of this risk in MP patients and provide appropriate cardiovascular management in addition to MP treatment.

Bronchiectasis and the risk of cancer: a nationwide retrospective cohort study.

BACKGROUND: Studies that have investigated the epidemiological relationship between bronchiectasis and cancers are scarce. METHODS: In this study, we investigated the incidence and risk of cancer in 53,755 patients newly hospitalized with bronchiectasis between 1998 and 2010 using data from the Taiwan National Health Insurance Research Database. The comparison cohort comprised 215,020 people from the general population without bronchiectasis. The follow-up period extended from the initial hospitalization date for bronchiectasis to the date of a cancer diagnosis, censoring, or 31 December 2011. We used Cox proportional hazard regression models to analyze the risks of cancer by including the variables of sex, age, and comorbidities. RESULTS: The overall cancer incidence was higher in patients with bronchiectasis than in the comparison cohort (17.0 vs. 12.2 per 1000 person-years). The bronchiectasis patients exhibited a 1.46-fold greater risk of cancer than did the comparison cohort after we adjusted for age, sex and comorbidities [adjusted hazard ratio (aHR) = 1.46, 95% CI = 1.41-1.52]. Although the cancer incidence increased with age in both cohorts, the younger patients with bronchiectasis exhibited the greatest risk of cancer compared with the comparison cohort. Patients with bronchiectasis had a considerably higher risk of lung cancer (aHR = 2.40, 95% CI = 2.22-2.60), oesophageal cancer (aHR = 2.06, 95% CI = 1.61-2.64), and hematologic malignancy (aHR = 2.02, 95% CI = 1.72-2.37) than did the comparison cohort. CONCLUSION: This nationwide cohort study suggested the patients with bronchiectasis exhibited increased substantial risks of certain cancer compared with the general population.

Increased risk of stroke among hip fracture patients: a nationwide cohort study.

SUMMARY: Our study indicates that hip fracture is independently associated with increased risk of developing stroke. In addition, the risk of stroke following the incidence of hip fracture is more prominent in younger patients, men, those with cardiovascular comorbidities, and in patients using specific medication, such as diuretics and ABRs. INTRODUCTION: Hip fractures are associated with increased risk of major morbidity. However, few data are available on the risk of stroke after hip fracture. Therefore, we investigated whether hip fracture increases the risk of stroke in a large nationwide cohort study. METHODS: Using universal insurance claims data, we identified a study cohort comprising of 6013 newly diagnosed with hip fracture patients from 2000 to 2010 and a non-hip fracture cohort of 23,802 participants. Incidence and risk of stroke were estimated for both cohorts until the end of 2011. RESULTS: Stroke incidence was 1.69-fold (95% confidence interval [CI]=1.56-1.83) higher in the hip fracture cohort than in the comparison cohort with an adjusted hazard ratio (HR) of 1.54 (95% CI=1.42-1.67) for the hip fracture cohort. The hip fracture patients were at higher risk of developing ischemic stroke (HR=1.55, 95% CI=1.42-1.69) and hemorrhagic stroke (HR=1.55, 95% CI=1.16-1.89), respectively. At an incidence of 64.6 per 1000 person-years, the adjusted HR of stroke increases to 3.10 (95% CI=2.47-3.90) for patients with coexisting diabetes, hypertension, and heart failure compared with those without these three conditions. At an incidence of 60.4 per 1000 person-years, the adjusted HR of stroke increases to 2.92 (95% CI=2.43-3.51) for hip fracture patients prescribed with diuretics and angiotensin II receptor blockers (ARBs) compared with those without hip fracture or prescriptions for diuretics or ARBs. CONCLUSIONS: Hip fracture is independently associated with a subsequent risk of stroke.

Effect of levitra on sustenance of erection (EROS): an open-label, prospective, multicenter, single-arm study to investigate erection duration measured by stopwatch with flexible dose vardenafil administered for 8 weeks in subjects with erectile dysfunction.

To investigate the change of erection duration measured by stopwatch with flexible dose vardenafil administered for 8 weeks in subjects with erectile dysfunction (ED). Effect of levitra on sustenance of erection was an open-label, prospective, multicenter and single-arm study designed to measure the duration of erection in men with ED receiving a flexible dose of vardenafil over an 8-week treatment period. Patients were instructed to take vardenafil 10 mg 60 min before attempting the intercourse. Vardenfil could be increased to 20 mg or decreased to 5 mg concerning patients' efficacy and safety. Following the initial screening, patients entered a 4-week treatment-free run-in phase and 8-week treatment period, during which they were instructed to attempt intercourse at least four times on four separate days. A total of 95 men were enrolled in 10 centers. After the 8 weeks treatment, the mean duration of erection leading to successful intercourse was statistically superior when patients were treated with vardenafil. After an 8-week treatment, the duration of erection leading to successful intercourse was 9.39 min. There were significant benefits with vardenafil in all domains of International Index of Erectile Function. Secondary efficacy end points included success rate of penetration, maintaining erection, ejaculation and satisfaction were superior when patients were treated with vardenafil. There was a significant correlation between duration of erection with other sexual factors. Also partner's sexual satisfaction was increased with vardenafil. Most adverse events were mild or moderate in severity. Vardenafil was safe and well tolerated. Vardenafil therapy provided a statistically superior duration of erection leading to successful intercourse in men with ED with female partner.

Genomic aberrations of myeloproliferative and myelodysplastic/myeloproliferative neoplasms in chronic phase and during disease progression.

INTRODUCTION: Myeloproliferative neoplasms (MPN) and myelodysplastic/myeloproliferative neoplasms (MDS/MPN) may transform into secondary myelofibrosis (MF) or evolve into acute myeloid leukemia (AML). The genetic mechanisms underlying disease progression in MPN and MDS/MPN patients remain unclear. The purpose of this study was to investigate sequential genomic aberrations identified by single nucleotide polymorphism array (SNP-A)-based karyotyping that can detect cryptic aberrations or copy neutral loss of heterozygosity (CN-LOH) in the chronic phase and during disease progression of MPN and MDS/MPN patients. METHODS: The study group included 13 MPN and four MDS/MPN patients (seven polycythemia vera (PV); four essential thrombocythemia (ET); two MPN-unclassifiable (MPN-U); one chronic myelomonocytic leukemia (CMML); one atypical chronic myeloid leukemia, BCR-ABL1 negative (aCML); and two MDS/MPN-unclassifiable (MDS/MPN-U)). Among them, five patients (two PV, two MPN-U, and one MDS/MPN-U) progressed to MF and three patients (one CMML, one aCML, and one MDS/MPN-U) transformed to AML. The median follow-up period was 70 months (range, 7-152). Whole-genome SNP-A (SNP 6.0; Affymetrix, Santa Clara, CA, USA)-based karyotyping and JAK2 mutation analysis were performed according to the manufacturer's instructions. RESULTS: SNP-A showed 19 kinds of genomic aberrations, including seven gains, eight deletions, and four CN-LOH. CN-LOH of 9p involving JAK2 was the most common aberration, followed by 5q deletion and 9p gain. The incidence of genomic changes identified by SNP was not different in patients with disease progression (75%), compared with those without disease progression (56%) (P = 0.4). However, when excluding 9p CN-LOH, the incidence of genomic changes was significantly higher in patients with disease progression than in patients without disease progression (63% and 0%, respectively, P = 0.01). Among eight patients with disease progression, two patients (two MPN-U) showed abnormal SNP-A results, whereas metaphase cytogenetics (MC) analysis showed normal results at diagnosis and during follow-up. In nine patients without disease progression, SNP-A did not show any genomic aberrations except for 9p CN-LOH. In three patients (one PV, one aCML, and one MDS/MPN-U), clonal evolutions were identified by both MC and SNP-A according to disease progression. One PV patient who progressed to MF at 45 months after diagnosis showed sequential genomic changes from 9p CN-LOH to 9p gain by SNP-A. Results of JAK2 mutation analysis were variable depending on the patient. Most of the patients with 9p CN-LOH or 9p gain showed more than 50% of the JAK2 mutant alleles. In one patient (MDS/MPN-U) evolving to AML, the number of JAK2 mutant alleles decreased according to disease progression. CONCLUSION: This study suggests sequential genomic changes identified by SNP-A may be associated with disease progression.

Consensus statements on adherence issues in schizophrenia for Hong Kong.

AIM: In view of the clinical importance of the adherence issues in schizophrenia management, a consensus group of experienced local psychiatrists and nurse specialists gathered to outline a number of consensus statements for clinicians to consider enhancing adherence in their patients. PROCESS: Prior to the consensus group meeting, three core members drafted eight statements on the issue of adherence in schizophrenia. Using a modified Delphi method, published literature and published guidelines regarding the management of schizophrenia were reviewed by the full panel during the group meeting. After discussion and reflection from each individual member of the consensus group, the eight statements were reworded and electronically voted on anonymously in two steps: acceptance on quality of evidence and practicability in implementation. RESULTS: After modifications of the original statements, there was very high overall level of agreement and acceptance (reaching international standard) on all the five areas of adherence within the eight statements of the finalised statement. CONCLUSIONS: The present consensus statements are the first in Hong Kong to address systematically adherence issues in schizophrenia management. They include areas on adherence assessment and definition, treatment strategies in enhancing adherence, and treatment considerations at specific phases of schizophrenia. They are tailored to be of practical utility in the local Hong Kong setting.

Inhaled corticosteroids and the increased risk of pulmonary tuberculosis: a population-based case-control study.

AIMS: The association between inhaled corticosteroid (ICS) use and pulmonary tuberculosis (TB) development is uncertain. We conducted a population-based case-control study to investigate whether ICS use increases the risk of developing TB. METHODS: Tuberculosis patients aged 18 years and older were identified using the National Health Insurance Research Database (NHIRD) in Taiwan between 2002 and 2010. Each TB patient was frequency matched to four control patients according to age, sex and index year. We retrospectively followed up the medications and comorbid medical conditions for the 5 years prior to the index date. We calculated the odds ratios (ORs) and 95% confidence intervals (CIs) of TB development using multiple logistic regression models. RESULTS: Most of the study participants were men (68.7%), and the mean age among the 8091 TB patients and 32,364 comparison participants was 61.3 ± 18.6 years. After adjusting for potential covariates, ICS use caused a 2.04-fold increased risk of developing TB (adjusted OR: 2.04, 95% CI: 1.78-2.33). When considering dose-response and adjusting for potential covariates, ICS and oral corticosteroids (OCS) use remained independent risk factors and exhibited a dose-response relationship of TB development. The multiplicative increased risk of TB was also significant in patients using ICS and OCS compared with patients not using ICS and OCS (adjusted OR: 4.31, 95% CI: 3.39-5.49). Previous TB history exhibited the greatest risk of TB development among the comorbidities (adjusted OR: 8.50, 95% CI: 7.52-9.61). CONCLUSION: Long-term ICS use may increase the risk of TB.