tRF-His-GTG-1 enhances NETs formation and interferon-α production in lupus by extracellular vesicle.

BACKGROUND: Hyperactive neutrophil extracellular traps (NETs) formation plays a crucial role in active severe systemic lupus erythematosus (SLE). However, what triggers the imbalance in dysregulated NETs formation in SLE is elusive. Transfer RNA-derived small RNAs (tsRNAs) are novel non-coding RNAs, which participate in various cellular processes. We explore the role of tsRNAs on NETs formation in SLE. METHODS: We analyzed the levels of NETs DNA and platelet-derived extracellular vesicles (pEVs) from 50 SLE patients and 20 healthy control subjects. The effects of pEVs on NETs formation were evaluated by using immunofluorescence assay and myeloperoxidase-DNA PicoGreen assay. The regulatory mechanism of pEVs on NETs formation and inflammatory cytokines production were investigated using an in vitro cell-based assay. RESULTS: Increased circulating NETs DNA and pEVs were shown in SLE patients and were associated with disease activity (P < 0.005). We demonstrated that SLE patient-derived immune complexes (ICs) induced platelet activation, followed by pEVs release. ICs-triggered NETs formation was significantly enhanced in the presence of pEVs through Toll-like receptor (TLR) 8 activation. Increased levels of tRF-His-GTG-1 in pEVs and neutrophils of SLE patients were associated with disease activity. tRF-His-GTG-1 interacted with TLR8 to prime p47phox phosphorylation in neutrophils, resulting in reactive oxygen species production and NETs formation. Additionally, tRF-His-GTG-1 modulated NF-κB and IRF7 activation in neutrophils upon TLR8 engagement, resulting IL-1ß, IL-8, and interferon-α upregulation, respectively. CONCLUSIONS: The level of tRF-His-GTG-1 was positively correlated with NETs formation in SLE patients; tRF-His-GTG-1 inhibitor could efficiently suppress ICs-triggered NETs formation/hyperactivation, which may become a potential therapeutic target.

Neutrophils and platelets are key members in the immunopathogenesis of SLE. EVs play a key role in intercellular communication. Abnormal NETs formation promotes vascular complications and organ damage in SLE patients. tsRNA is a novel regulatory small non-coding RNA and participates in diverse pathological processes. Herein, we showed that SLE patient-derived ICs activates platelets directly, followed by intracellular tRF-His-GTG-1 upregulation, which is loaded into pEVs. The pEV-carried tRF-His-GTG-1 could interact with TLR8 in neutrophils, followed by activation of the downstream signaling pathway, including p47phox-NOX2-ROS, which causes NETs enhancement, while IRF7 promotes the expression of IFN-α. The tRF-His-GTG-1 inhibitor could suppress efficiently SLE ICs-induced NETs formation and pEVs primed NETs enhancement. This study offers new molecular machinery to explain the association between the platelets-derived tsRNAs, pEVs, and hyperactive NETs formation in lupus. tRF-His-GTG-1 may serve as a potential therapeutic target and help to advance our understanding of tsRNAs in SLE pathogenesis.

Genomic architecture underlying morphological and physiological adaptation to high elevation in a songbird.

Organisms often acquire physiological and morphological modifications to conquer ecological challenges when colonizing new environments which lead to their adaptive evolution. However, deciphering the genomic mechanism of ecological adaptation is difficult because ecological environments are often too complex for straightforward interpretation. Thus, we examined the adaptation of a widespread songbird-the rufous-capped babbler (Cyanoderma ruficeps)-to a relatively simple system: distinct environments across elevational gradients on the mountainous island of Taiwan. We focused on the genomic sequences of 43 birds from five populations to show that the Taiwan group split from its sister group in mainland China around 1-2 million years ago (Ma) and colonized the montane habitats of Taiwan at least twice around 0.03-0.22 Ma. The montane and lowland Taiwan populations diverged with gene flow between them, suggesting strong selection associated with different elevations. We found that the montane babblers had smaller beaks than the lowland ones, consistent with Allen's rule, and identified candidate genes-COL9A1 and SOX11-underlying the beak size changes. We also found that altitudinally divergent mutations were mostly located in noncoding regions and tended to accumulate in chromosomal inversions and autosomes. The altitudinally divergent mutations might regulate genes related to haematopoietic, metabolic, immune, auditory and vision functions, as well as cerebrum morphology and plumage development. The results reveal the genomic bases of morphological and physiological adaptation in this species to the low temperature, hypoxia and high UV light environment at high elevation. These findings improve our understanding of how ecological adaptation drives population divergence from the perspective of genomic architecture.

Gender Differences in microRNA Expressions as Related to Long-Term Graft Function in Kidney Transplant Patients.

In recent studies, much has been discussed about biomarkers used in the evaluation of the transplanted graft function. However, there remains a lack of research regarding the long-term effects of microRNAs (miRNAs) on the different genders for kidney transplant (KTx) patients. In this study, we aim to assess the functions of miRNAs on long term outcomes of KTx patients by extracting differently expressed miRNAs between patients of normal graft function and graft dysfunction, while further analyzing their impact on the different genders. We analyzed the data of 40 patients who had received KTx for a period of more than ten years and included data regarding renal function, immuno-related markers and plasma miRNAs. Data were classified by gender for further studies. Twelve out of 17 females and 8 out of 23 males had undergone graft dysfunction. Renal function analysis showed significantly worse outcomes in the female patients. There were five differently expressed miRNAs between the female control group and female dysfunction group: miR-128-3p, miR-21-5p, miR-150-5p, miR-92a-3p and miR-15a-5p, and five between the male control group and male dysfunction group: miR-23a-3p, miR-126-3p, miR-142-3p, miR-223-3p and miR-26a-5p. Gender differences exist in incidences of kidney graft dysfunction, with male patients displaying better preservation in graft functions. Overall, these differently expressed miRNAs either enhance or suppress host immune responses. They can be predictive markers for graft survival and can also be important factors that lead to worse long term kidney graft function in females when compared to males.

Pneumococcal pneumonia in adult hospitalised solid organ transplant recipients: Nationwide, population-based surveillance.

BACKGROUND: Pneumococcal disease poses a burden to the community in high risk population. Most early studies focused on invasive pneumococcal disease. However, the epidemiology of pneumococcal pneumonia (PP) requiring hospitalisation in solid organ transplant recipients (SOTRs) is poorly defined. METHODS: We conducted a retrospective cohort study (January 1, 2000 and December 31, 2012) to evaluate the risk of PP requiring hospitalisation in SOTRs. SOTRs and non-SOT cohorts, propensity score-matched at a 1:1 ratio for age, sex, index date and underlying comorbidities, were identified from the National Health Insurance Research Database. RESULTS: Each cohort consisted of 7507 patients. In the SOT cohort, 26 episodes of PP requiring hospitalisation were identified (incidence rate of 52.4 per 100,000 person-years). The risk of PP requiring hospitalisation in the SOT cohort was 1.50 times greater than in the non-SOT cohort [adjusted hazard ratio: 1.50, 95% confidence interval = 1.31-1.71, P < .001]. The nested case control study identified older age, kidney transplant, and concomitant chronic obstructive pulmonary disease, chronic kidney disease and heart failure as predictors of PP requiring hospitalisation in the SOT cohort. The highest risk period for PP requiring hospitalisation occurred within the first year of transplantation (36.47 per 1000 patients). Amongst kidney transplant recipients, patients with PP requiring hospitalisation exhibited higher cumulative incidences of graft failure than those without PP (log-rank test: P value = .004). CONCLUSIONS: SOTRs are at risk of PP requiring hospitalisation with its attendant morbidity. Strategies to reduce risk of PP requiring hospitalisation using preventive vaccinations warrant further study.

Treatment of chronic active antibody-mediated rejection in renal transplant recipients - a single center retrospective study.

BACKGROUND: Chronic active antibody-mediated rejection is a major etiology of graft loss in renal transplant recipients. However, there is no consensus on the optimal treatment strategies. METHODS: Computerized records from Taichung Veterans General Hospital were collected to identify renal transplant biopsies performed in the past 7 years with a diagnosis of chronic active antibody-mediated rejection. The patients were divided into two groups according to treatment strategy: Group 1 received aggressive treatment (double filtration plasmapheresis and one of the followings: rituximab, intravenous immunoglobulin, antithymogycte globulin, bortezomib, or methylprednisolone pulse therapy); and group 2 received supportive treatment. RESULTS: From February 2009 to December 2017, a total of 82 patients with biopsy-proven chronic antibody mediated rejection were identified. Kaplan-Meier analysis of death-censored graft survival showed a worse survival in group 2 (P = 0.015 by log-rank test). Adverse event-free survival was lower in group 1, whereas patient survival was not significantly different. Proteinuria and supportive treatment were independent risk factors for graft loss in multivariate analysis. CONCLUSIONS: Aggressive treatment was associated with better graft outcome. However, higher incidence of adverse events merit personalized treatment, especially for those with higher risk of infection. Appropriate prophylactic antibiotics are recommended for patients undergoing aggressive treatment.

Long-term statin adherence in patients after hospital discharge for new onset of atherosclerotic cardiovascular disease: a population-based study of real world prescriptions in Taiwan.

BACKGROUND: Despite the recommendations of statins treatment for secondary prevention of atherosclerotic cardiovascular disease (ASCVD), treatment adherence and persistence are still a concern. This study examined the real world practice of long-term adherence and persistence to statins treatment initiated after hospital discharge for ASCVD, and their associated factors in a nationwide cohort. METHODS: Post discharge statin prescriptions between 2006 and 2012 were extracted from the Taiwan National Health Insurance claims database. Good adherence, defined as proportion of days covered (PDC) ≥0.8 and mean medication possession ratio (MPR), was measured every 180-day period. Non-persistence was defined on the date patients failed to refill statin for 90 days after the end of the last prescription. Their associations with influential factors were analyzed using a generalized estimating equation and Cox's proportional hazard model. RESULTS: There was a total of 185,252 post-discharge statin initiations (from 169,624 patients) and followed for 467,398 patient-years in the study cohort. Percentage of good adherence (mean MPR) was 71% (0.87) at 6-months; declined to 54% (0.68), 47% (0.59), and 42% (0.50) at end of year 1, 2, and 7, respectively. Persistence in statin treatment was 86, 67, 50, and 25% at 6-month, 1-, 2-, and 7-year, respectively. Comparing the statin-cohort initiated from year 2006 to 2012, 1-year persistence increased from 58 to 73%, and 1-year good adherence improved from 45 to 61%. Factors associated with sub-optimal adherence and non-persistence included: prescription by primary care clinics or non-cardiology specialties; patients' age > 75 years; no history of previous statin use; ASCVD events with ischemic stroke diagnosis; comorbidities of renal disease, liver disease, depression, and chronic obstructive pulmonary disease. CONCLUSIONS: Despite the improving trends, long-term adherence and persistence of statin treatment were suboptimal in Taiwan. Strategies to maintain statin treatment adherence and persistence need to be implemented to further enhance the positive trend.

Renal complications and subsequent mortality in acute critically ill patients without pre-existing renal disease.

BACKGROUND: Most studies of long-term renal outcomes after acute critical illness have enrolled patients with pre-existing renal dysfunction. We assessed renal outcomes in patients who did not have pre-existing renal disease and who were admitted to hospital for acute critical illness. METHODS: We identified adults who did not have pre-existing renal disease and who were admitted to hospital for acute critical illness between 2000 and 2011, from the Taiwan National Health Insurance Research Database. Each patient was matched 1:2 with controls without acute critical illness, according to age, sex and index date. A subset was further matched 1:1 with controls using propensity scores. Outcomes included acute kidney injury, chronic kidney disease and end-stage renal disease. RESULTS: We evaluated 33 613 patients with acute critical illness matched to 63 148 controls, of whom 14 218 were propensity matched to 14 218 controls. Patients with acute critical illness had incidence rates per 10 000 person-years of 9.45 for acute kidney injury, 78.3 for chronic kidney disease and 21.0 for end-stage renal disease. In the propensity-matched cohort, patients with acute critical illness had significantly higher risks of acute kidney injury (adjusted hazard ratio [aHR] 2.92, 95% confidence interval [CI] 1.78-4.77), chronic kidney disease (aHR 1.81, 95% CI 1.57-2.08), and end-stage renal disease (aHR 3.60, 95% CI 2.50-5.18). Acute critical illness conferred higher mortality risk among patients who subsequently developed end-stage renal disease (aHR 3.37, 95% CI 2.07-5.49) or chronic kidney disease (aHR 2.16, 95% CI 1.67-2.80). INTERPRETATION: Patients with acute critical illness and without pre-existing renal disease have a higher risk of adverse renal outcomes and subsequent mortality. A resolved episode of critical illness has implications for future renal function surveillance, even in patients without pre-existing renal disease.

Risk of cancer in patients with polycystic kidney disease: a propensity-score matched analysis of a nationwide, population-based cohort study.

BACKGROUND: Data for the risk of any solid cancer in patients with polycystic kidney disease are scarce. Therefore, we did a nationwide cohort study in Taiwan to establish the risk of cancer in patients with polycystic kidney disease without either chronic kidney disease or end-stage renal disease. METHODS: From inpatient claims of the Taiwan National Health Insurance Research Database, we included patients aged 20 years and older and diagnosed with polycystic kidney disease between January, 1998 and December, 2010, in the polycystic kidney disease cohort. Patients with a history of cancer, a history of chronic kidney disease or of end-stage renal disease (recorded from the Registry of Catastrophic Illness Patient Database) were excluded. For each patient with polycystic kidney disease, one patient aged older than 20 years with no history of polycystic kidney disease or cancer was randomly selected from the National Health Insurance Research Database, matched 1:1 on the basis of the propensity score calculated by logistic regression, and was included in the control non-polycystic kidney disease cohort. The follow-up period for each patient was estimated from the index date to the date of diagnosis of cancer, or the patient was censored due to withdrawal from the insurance programme (eg, death, immigration, or imprisonment) or on Dec 31, 2011. The primary outcome of interest was a diagnosis of cancer during a 14-year follow-up period. The risk of cancer was represented as a hazard ratio (HR) calculated in Cox proportional hazard regression models. FINDINGS: 4346 patients with polycystic kidney disease and 4346 without were enrolled in the study. The median follow-up period in the polycystic kidney disease cohort was 3·72 years (IQR 1·25-7·31) and in the non-polycystic kidney disease cohort was 4·96 years (2·29-8·38). The overall incidence of cancer was higher in the polycystic kidney disease cohort than in the control cohort (20·1 [95% CI 18·3-21·9] per 1000 person-years vs 10·9 [10·1-11·8] per 1000 person-years; crude hazard ratio (HR) 1·77 [95% CI 1·52-2·07]; HR adjusted for age, sex, frequency of medical visits, and comorbidities was 1·83 [1·57-2·15]). The specific risks (adjusted subhazard ratios) were significantly higher in the polycystic kidney disease cohort than that in the non-polycystic kidney disease cohort for liver cancer (1·49 [95% CI 1·04-2·13]; p=0·030), colon cancer (1·63 [1·15-2·30]; p=0·006), and kidney cancer (2·45 [1·29-4·65]; p=0·006). INTERPRETATION: To our knowledge, this is the first report of the association of polycystic kidney disease without end-stage renal disease with the risk of liver, colon, and kidney cancer. Health-care professionals should be aware of this risk, when treating patients with polycystic kidney disease. FUNDING: Taiwan Ministry of Health and Welfare Clinical Trial and Research Center of Excellence, Academia Sinica Taiwan Biobank, Stroke Biosignature Project, NRPB Stroke Clinical Trial Consortium, Tseng-Lien Lin Foundation, Taiwan Brain Disease Foundation, Katsuzo and Kiyo Aoshima Memorial Funds, China Medical University Hospital, and Taiwan Ministry of Education.

Nature-inspired design of tetraindoles: Optimization of the core structure and evaluation of structure-activity relationship.

Building on the initial successful optimization of a novel series of tetraindoles, a second generation of the compounds with changes in the core phenyl ring was synthesized to improve anticancer properties. 17 new compounds with different rigidity, planarity, symmetry and degree of conjugation of their core structures to 5-hydroxyindole units were synthesized. All the compounds were fully characterized and tested against breast cancer cell line (MDA-MB-231). The results revealed that the core structure is required for activity and it should be aromatic, rigid, planar, symmetrical and conjugated for optimal activity. Compound 29, which has strong anticancer activity against various tumor-derived cell lines, including Mahlavu (hepatocellular), SK-HEP-1 (hepatic), HCT116 (colon), MIA PaCa-2 (pancreatic), H441 (lung papillary), A549 (lung), H460 (non-small cell lung) and CL1-5 (lung carcinoma) with IC50 values ranging from 0.19 to 3.50µM, was generated after series of successive optimizations. It was found to induce cell cycle arrest and apoptosis in vitro and inhibit tumor growth in the non-obese diabetic-severe combined immunodeficiency (NOD/SCID) mice bearing xenografted MIA PaCa-2 human pancreatic cancer.

The interleukin-15 system suppresses T cell-mediated autoimmunity by regulating negative selection and nT(H)17 cell homeostasis in the thymus.

The interleukin-15 (IL-15) system is important for regulating both innate and adaptive immune responses, however, its role in autoimmune disease remained unclear. Here we found that Il15(-/-) and Il15ra(-/-) mice spontaneously developed late-onset autoimmune phenotypes. CD4(+) T cells of the knockout mice showed elevated autoreactivity as demonstrated by the induction of lymphocyte infiltration in the lacrimal and salivary glands when transferred into nude mice. The antigen-presenting cells in the thymic medullary regions expressed IL-15 and IL-15Rα, whose deficiency resulted in insufficient negative selection and elevated number of natural IL-17A-producing CD4(+) thymocytes. These findings reveal previously unknown functions of the IL-15 system in thymocyte development, and thus a new layer of regulation in T cell-mediated autoimmunity.

Pneumococcal pneumonia infection is associated with end-stage renal disease in adult hospitalized patients.

Pneumococcal disease leads to renal complications ranging from persistent proteinuria to end-stage renal disease (ESRD) in pediatric patients. However, long-term renal effects after pneumococcal pneumonia infection in adult patients remains largely unknown. To evaluate this we conducted a population-based retrospective cohort study consisting of 18,733 adult patients at the time of pneumococcal pneumonia diagnosis, using claims data from Taiwan's National Health Insurance Research Database (NHIRD) with a comparison cohort of 73,409 age- and gender-matched patients without pneumococcal pneumonia. The overall incidence rate ratio of ESRD was 23% higher in those with pneumococcal pneumonia than in those without pneumococcal pneumonia (5.26 vs. 3.10 per 1000 person-years), with an adjusted hazard ratio of 1.14 (95% confidence interval 1.01-1.29). In addition, the risk of developing ESRD was associated with covariates including age, gender, chronic kidney disease, diabetes mellitus, hypertension, hyperlipidemia, chronic obstructive pulmonary disease, and heart failure. The ESRD cumulative incidence curve showed a considerably higher risk of ESRD in those with pneumococcal pneumonia than in those without pneumococcal pneumonia (significant by log-rank test). Thus, pneumococcal pneumonia may be associated with an increased risk of ESRD in adult patients. A long-term follow-up of renal function is recommended for adult hospitalized patients with pneumococcal pneumonia infection.

IL-15 modulates the balance between Bcl-2 and Bim via a Jak3/1-PI3K-Akt-ERK pathway to promote CD8αα+ intestinal intraepithelial lymphocyte survival.

IL-15 is an essential survival factor for CD8αα(+) intestinal intraepithelial lymphocytes (iIELs) in vitro and in vivo. However, the IL-15-induced survival signals in primary CD8αα(+) iIELs remains elusive. Although Bcl-2 level in CD8αα(+) iIELs positively correlates with IL-15Rα expression in the intestinal epithelial cells, overexpression of Bcl-2 only moderately restores CD8αα(+) γδ iIELs in Il15(-/-) mice. Here, we found that IL-15 promptly activated a Jak3-Jak1-PI3K-Akt pathway that led to the upregulation of Bcl-2 and Mcl-1. This pathway also induced a delayed but sustained ERK1/2 activation, which not only was necessary for the maintenance of Bcl-2 but also resulted in the phosphorylation of extra-long Bim at Ser(65) . The latter event facilitated the dissociation of Bim from Bcl-2 without affecting Bim abundance in IL-15-treated CD8αα(+) iIELs. Using an adoptive cell transfer approach, we found that either overexpression of Bcl-2 or removal of Bim from CD8αα(+) iIELs promoted their survival in Il15ra(-/-) mice. Taken together, IL-15 promotes CD8αα(+) iIEL survival by both increasing Bcl-2 levels and dissociating Bim from Bcl-2 through activation of a Jak3-Jak1-PI3K-Akt-ERK1/2 pathway, which differs from a previously reported IL-15-induced survival signal.

Risk of Diabetic Retinopathy in Patients With Type 2 Diabetes After SGLT-2 Inhibitors: A Nationwide Population Cohort Study.

Diabetic retinopathy (DR) accounts for 80% of cases of vision loss in patients with type 2 diabetes mellitus (T2DM). Interventional treatments are only indicated in advanced DR and are ineffective in some patients. Sodium-glucose cotransporter 2 inhibitors (SGLT2is) are used to attenuate T2DM-associated cardiovascular complications. We conducted the cohort study to investigate the effect of SGLT2is on DR development. Data (May 2016-December 2018) obtained from the Taiwan National Health Insurance Research Database were analyzed in this nationwide retrospective cohort study. After propensity score matching, a total of 31,764 patients receiving SGLT2is and another 31,764 patients receiving dipeptidyl peptidase 4 inhibitors (DPP4is) were included in this study. Multiple Cox proportional-hazards regression models were used to evaluate DR risk. Overall DR incidence among SGLT2i or DPP4i users was 10.9 or 15.6 per 10,000 patient-years, respectively. After covariate adjustment, DR (both early and late stage) risk was substantially lower in SGLT2i users (adjusted hazard ratio: 0.68, 95% confidence interval: 0.6-0.78) than in DPP4i users. DR risk appears to be considerably lower in SGLT2i users than in DPP4i users. Glycemic control measurement with HbA1C level was unavailable in this claim database.

Predictors for Failed Removal of Nasogastric Tube in Patients With Brain Insult.

OBJECTIVE: To construct a prognostic model for unsuccessful removal of nasogastric tube (NGT) was the aim of our study. METHODS: This study examined patients with swallowing disorders receiving NGT feeding due to stroke or traumatic brain injury in a regional hospital. Clinical data was collected, such as age, sex, body mass index (BMI), level of activities of daily living (ADLs) dependence. Additionally, gather information regarding the enhancement in Functional Oral Intake Scale (FOIS) levels and the increase in food types according to the International Dysphagia Diet Standardization Initiative (IDDSI) after one month of swallowing training. A stepwise logistic regression analysis model was employed to predict NGT removal failure using these parameters. RESULTS: Out of 203 patients, 53 patients (26.1%) had experienced a failed removal of NGT after six months of follow-up. The strongest predictors for failed removal were age over 60 years, underweight BMI, total dependence in ADLs, and ischemic stroke. The admission prediction model categorized patients into high, moderate, and low-risk groups for removal failure. The failure rate of NGT removal was high not only in the high-risk group but also in the moderate-risk groups when there was no improvement in FOIS levels and IDDSI food types. CONCLUSION: Our predictive model categorizes patients with brain insults into risk groups for swallowing disorders, enabling advanced interventions such as percutaneous endoscopic gastrostomy for high-risk patients struggling with NGT removal, while follow-up assessments using FOIS and IDDSI aid in guiding rehabilitation decisions for those at moderate risk.

Regulation of Enhancers by SUMOylation Through TFAP2C Binding and Recruitment of HDAC Complex to the Chromatin.

Enhancers are fundamental to gene regulation. Post-translational modifications by the small ubiquitin-like modifiers (SUMO) modify chromatin regulation enzymes, including histone acetylases and deacetylases. However, it remains unclear whether SUMOylation regulates enhancer marks, acetylation at the 27th lysine residue of the histone H3 protein (H3K27Ac). To investigate whether SUMOylation regulates H3K27Ac, we performed genome-wide ChIP-seq analyses and discovered that knockdown (KD) of the SUMO activating enzyme catalytic subunit UBA2 reduced H3K27Ac at most enhancers. Bioinformatic analysis revealed that TFAP2C-binding sites are enriched in enhancers whose H3K27Ac was reduced by UBA2 KD. ChIP-seq analysis in combination with molecular biological methods showed that TFAP2C binding to enhancers increased upon UBA2 KD or inhibition of SUMOylation by a small molecule SUMOylation inhibitor. However, this is not due to the SUMOylation of TFAP2C itself. Proteomics analysis of TFAP2C interactome on the chromatin identified histone deacetylation (HDAC) and RNA splicing machineries that contain many SUMOylation targets. TFAP2C KD reduced HDAC1 binding to chromatin and increased H3K27Ac marks at enhancer regions, suggesting that TFAP2C is important in recruiting HDAC machinery. Taken together, our findings provide insights into the regulation of enhancer marks by SUMOylation and TFAP2C and suggest that SUMOylation of proteins in the HDAC machinery regulates their recruitments to enhancers.

Effect of different hemodialyzers on serum levels of interleukin-6, interleukin-10 and interleukin-18.

BACKGROUND: The blood and membrane contact during dialysis may elicit an immune reaction. The current study looked at the impact of different dialyzers on blood levels of cytokines. METHODS: During the first month, randomly selected patients were treated with one dialyzer (PF-170H) and then crossed over to another dialyzer (FLX-18GW) during the next month. Pre- and postdialysis blood samples were assayed for interleukin (IL)-6, IL-10 and IL-18. RESULTS: A significant drop of postdialysis systolic blood pressure (pre vs. post 156.4 ± 31.8 vs. 143.1 ± 24.8 mm Hg, p = 0.014) and diastolic pressure (80.7 ± 12.7 vs. 73.4 ± 10.9 mm Hg, p = 0.002) were found when patients were dialyzed with PF-170H. A significant increase of postdialysis IL-18 levels was found in both groups (pre vs. post 605.5 ± 278.6 vs. 690.6 ± 315.3 pg/ml, p = 0.016, for PF-170H and 556.4 ± 231.0 vs. 647.3 ± 282.6 pg/ml, p = 0.067, for FLX-18GW). There was a positive correlation between IL-6 and IL-10 levels (p < 0.0001). CONCLUSION: We demonstrated a significant increase of postdialysis serum IL-18 level when either dialyzer was used. There is a strong correlation between serum levels of IL-6 and IL-10.

Clinical outcome of elderly peritoneal dialysis patients with assisted care in a single medical centre: a 25 year experience.

AIM: Peritoneal dialysis (PD) is an alternative treatment for elderly patients with end-stage renal disease (ESRD). In Taiwan, non-professional personnel are employed to provide assisted care for elderly patients. Whether assisted care is appropriate for elderly patients is unknown. The aim of this paper is to evaluate the outcomes of assisted care in a single centre. METHODS: This is a retrospective cohort study in a single medical centre. The outcomes were derived from the assessment of patient survival, technique survival and peritonitis incidence between self-care patients and assisted-care patients. RESULTS: From 1984 to 2010, there were 138 elderly PD patients at Taichung Veterans General Hospital, of which 70% were assisted-care patients and 30% self-care patients. The mean duration of PD survival was 49.2 months in self-care patients, which was significantly longer than the 17.0 months of assisted-care patients (P < 0.05). Using the multivariate Cox proportion regression model to adjust for risk factors, it was found that self-care patients had a lower risk in both patient survival (Hazard Ratio 0.15; 95% confidence interval (CI) 0.2-0.94, P < 0.05) and technique survival (Hazard ratio; 0.11, 95% CI 0.1-0.9, P < 0.05). Fluid overloading was the major cause of technique failure in assisted-care patients. Type of assistance was not a risk factor for PD-related peritonitis. CONCLUSION: Our elderly assisted care had patients had a poorer survival and technique survival rates than those of the self-care patients. We argue that this is because early recognition of medical deterioration and early medical intervention are necessary for a better outcome for elderly PD patients.

In-hospital mortality risk estimation in patients with acute nonvariceal upper gastrointestinal bleeding undergoing hemodialysis: a retrospective cohort study.

BACKGROUND: Upper gastrointestinal bleeding (UGIB) is a major cause of clinical bleeding among patients with end-stage renal disease (ESRD). This study aimed to investigate the association between mortality and UGIB in patients with uremia. METHODS: From 2004 to 2010, a tertiary hospital-based retrospective cohort comprising 322 patients undergoing hemodialysis was investigated. All the patients were diagnosed with UGIB according to the International Classification of Diseases, 9th Revision (ICD-9) that included peptic ulcer bleeding, duodenal ulcer bleeding, and other symptoms. UGIB was required to be one of the first three discharge diagnoses. Rehospitalization within 3 days after discharge was regarded as the same course. Exclusion criteria were age <20 years, previous gastric resection or vagotomy, esophageal and gastric variceal bleeding, or gastric cancer within the first 2 years of the index hospitalization. RESULTS: The all-cause in-hospital mortality rate of patients with UGIB undergoing hemodialysis was high, with the first-month mortality rate of 13.7%, sixth-month mortality rate of 26.7%, and first-year mortality rate of 27.0%. Using Cox regression models, we found that the high mortality rate of the UGIB group was significantly correlated with older age [adjusted hazard ratio (HR) = 1.02, 95% confidence interval (CI) = 1.01-1.04], female sex (adjusted HR = 1.62, 95% CI = 1.05-2.51), infection during hospitalization (adjusted HR = 1.85, 95% CI = 1.13-3.03), single episodic UGIB (adjusted HR = 2.00, 95% CI = 1.08-3.70), abnormal white blood cell (WBC) count (adjusted HR = 1.59, 95% CI = 1.03-2.45), and albumin level ≤3 g/dL (adjusted HR = 2.67, 95% CI = 1.51-4.72). CONCLUSION: In conclusion, patients with ESRD who are admitted with primary UGIB have a profoundly increased risk of all-cause in-hospital mortality during the follow-up period.

Risk of Severe Alphaherpesvirus Infection after Solid Organ Transplantation: A Nationwide Population-Based Cohort Study.

Patients after solid organ transplantation (SOT) are more susceptible to various viral infections, including alphaherpesviruses. Therefore, the aim of our study was to investigate the risk of alphaherpesvirus infections, including herpes simplex and herpes zoster, after solid organ transplantation. Inpatient records from the Taiwan National Health Insurance Research Database (NHIRD) defined solid organ recipients, including heart, liver, lung, and kidney, hospitalized for alphaherpesvirus infections as a severe case group of transplants and matched them with a nontransplant cohort. We enrolled 18,064 individuals, of whom 9032 were in each group. A higher risk of severe alphaherpesvirus infection was noted in solid organ recipients (aHR = 9.19; p < 0.001) than in the general population. In addition, solid organ transplant recipients had the highest risk of alphaherpesvirus infection within 1 year after transplantation (aHR = 25.18). The comparison found a higher risk of herpes zoster and herpes simplex infections in recipients of kidney (aHR = 9.13; aHR = 12.13), heart (aHR = 14.34; aHR = 18.54), and liver (aHR = 5.90; aHR = 8.28) transplants. Patients who underwent solid organ transplantation had a significantly higher risk of alphaherpesvirus infection than the general population.

Outcome of Brain Lymphoma in a High Epstein-Barr Virus-Prevalence Country After Kidney Transplantation.

BACKGROUND: The incidence of post-transplant lymphoproliferative disorder (PTLD) in adult kidney transplant (KTx) recipients is less common in Taiwan. In our institute, we observed that brain lymphoma was the most notorious type. METHODS: The study describes the clinical, histologic, and radiological features of primary central nervous lymphoma (PCNSL) and the outcomes and associations with Epstein-Barr virus (EBV) infection in our center. RESULTS: Among 1470 KTx recipients, 5 patients had tissue-proven brain lymphoma (0.34%). The brain pathology disclosed diffuse large B-cell lymphoma in all patients. EBV was detected through in situ hybridization for Epstein-Barr encoding region (EBER) to disclose the EBV inclusion in the nuclei of lymphoma cells. The first treatment step was the reduction of immunosuppressants; 4 patients received whole-brain radiotherapy after complete resection of PCNSL, and 1 received concurrent chemoradiotherapy. Only one patient had poor performance status at the time of diagnosis and had a poor response to treatment with steroids. Four patients survived (mean 36.5 months, range 8.6 to 57.6 months), but one died after rapid neurologic deterioration. CONCLUSION: Epstein-Barr virus inclusion was found in PCNSL in our patients; however, the role of EBV in PCNSL remains to be clarified. Post-transplant lymphoproliferative disorder is a rare malignancy after KTx with a predilection of brain involvement in Taiwan. We report a successful care experience in a patient with primary CNS lymphoma with better survival.