Conformational surveillance of Orai1 by a rhomboid intramembrane protease prevents inappropriate CRAC channel activation.

Calcium influx through plasma membrane calcium release-activated calcium (CRAC) channels, which are formed of hexamers of Orai1, is a potent trigger for many important biological processes, most notably in T cell-mediated immunity. Through a bioinformatics-led cell biological screen, we have identified Orai1 as a substrate for the rhomboid intramembrane protease RHBDL2. We show that RHBDL2 prevents stochastic calcium signaling in unstimulated cells through conformational surveillance and cleavage of inappropriately activated Orai1. A conserved disease-linked proline residue is responsible for RHBDL2's recognizing the active conformation of Orai1, which is required to sharpen switch-like signaling triggered by store-operated calcium entry. Loss of RHBDL2 control of CRAC channel activity causes severe dysregulation of downstream CRAC channel effectors, including transcription factor activation, inflammatory cytokine expression, and T cell activation. We propose that this surveillance function may represent an ancient activity of rhomboid proteases in degrading unwanted signaling proteins.

Defect Induced Structural Transition and Lipase Immobilization in Mesoporous Aluminum Metal-Organic Frameworks.

The transition from disorder to order and structural transformation are distinctive metal-organic framework (MOF) features. How to adapt or control both behaviors in MOF has rarely been studied. In this case, we demonstrate that our successful synthesis of [Al(OH)(PDA)]n (AlPDA-53-DEF, AlPDA-53-H, and AlPDA-68) with H2PDA=4,4'-[1,4-phenylenebis(ethyne-2,1-diyl)]-di benzoic acid has shown the intricate world of Aluminum Metal-Organic Frameworks (Al-MOFs). It offers profound insights into defect structures to order and transformations. AlPDA-53-DEF, in particular, revealed a fascinating interplay of various pore sizes within both micro and mesoporous regions, unveiling a unique lattice rearrangement phenomenon upon solvent desorption. Defects and disorders emerged as crucial impacts of transforming AlPDA-53-DEF, with its initially imperfect crystallinity, into the highly crystalline, hierarchically porous AlPDA-53-H.

Predicting risk of dementia among the elderly with major depressive disorder in remission: A prospective study.

OBJECTIVES: Cognitive impairment and change are a focus of research into late-life depression. The aims of this 5-year prospective study were (1) to observe cognitive status change; (2) to investigate the rate and risk ratio of dementia or cognitive decline; and (3) to examine the cognitive domain predictors for conversion to dementia within 5 years among a clinical cohort with remitted major depressive disorder (MDD). METHODS: The study cohort included 130 elderly persons with late-life remitted MDD and 100 normal controls. Comprehensive neuropsychological tests were conducted to determine cognitive domain status. Diagnoses of mild cognitive impairment (MCI) and dementia were made at baseline and at a follow-up visit at the 5-year point. In total, 98 cases and 55 normal controls completed the 5-year follow-up assessment. RESULTS: Of the study cohort with late-life remitted MDD, 28.6% had MCI and 25.5% developed dementia within 5 years. Patients with late-life remitted MDD had an approximate 3 times higher risk of subsequent cognitive decline as compared with the normal controls. Information-processing speed (p = 0.009) and memory (p = 0.041) could predict subsequent progression to dementia within 5 years among patients with MDD. CONCLUSIONS: This study demonstrated that compared with the general elderly population, elderly patients with depression have more significant impairment in cognitive function after 5 years. Further, we found that in depressed patients, deficits in information-processing speed and memory domains were highly suggestive of progression to dementia within 5 years.

Single-nucleotide polymorphisms in Orai1 associated with atopic dermatitis inhibit protein turnover, decrease calcium entry and disrupt calcium-dependent gene expression.

Loss-of function mutations in Orai1 Ca2+ channels lead to a form of severe combined immunodeficiency, auto-immunity, muscle hypotonia and defects in dental enamel production and sweat gland function. Two single-nucleotide polymorphisms (SNPs) in Orai1 have been found and localize to the second extracellular loop. These polymorphisms associate with atopic dermatitis but how they affect Ca2+ signalling and cell function is unknown. Here, we find that Orai1-SNPs turnover considerably more slowly than wild type Orai1 and are more abundantly expressed in the plasma membrane. We show a central role for flotillin in the endocytotic recycling of Orai1 channels and that endocytosed wild type Orai1 is trafficked to Rab 7-positive late endosomes for lysosomal degradation. Orai1-SNPs escape the degradation pathway and instead enter Rab 11-positive recycling endosomes, where they are returned to the surface membrane through Arf6-dependent exocytosis. We find that Orai1-SNPs escape late endosomes through endosomal pH regulation of interaction between the channel and flotillin. We identify a pH-sensitive electrostatic interaction between positively charged arginine in extracellular loop 2 (K210) and a negatively charged aspartate (D112) in extracellular loop 1 that helps determine Orai1 turnover. The increase in membrane Orai1-SNP leads to a mis-match in Orai1-STIM stoichiometry, resulting in inhibition of Ca2+ entry and Ca2+-dependent gene expression. Our results identify new strategies for targeting atopic dermatitis.

Clinical Outcomes of Metastatic Breast Cancer in Patients Having Imaging Liver Pseudocirrhosis with or without Evident Varices.

BACKGROUND: Pseudocirrhosis is an imaging finding of malignancies with liver metastasis with or without clinical liver cirrhosis-related portal hypertension (pHTN). This study defined evident pHTN by the presence of esophageal or gastric varices and compared patients' outcomes of metastatic breast cancer with imaging-diagnosed pseudocirrhosis with or without varices. METHODS: The medical records from patients with metastatic breast cancer and pseudocirrhosis between 2005 and 2017 were retrospectively analyzed. Survival outcomes were compared based on endoscopic evidence of esophageal or gastric varices. RESULTS: Among 106 patients with pseudocirrhosis, 33 (31%) had de novo stage IV disease, and 66 (62%) had hormone receptor (HR)-positive and human epidermal growth factor receptor 2 (HER2)-negative breast cancer. Eighty-one (76%) had initial metastases in both hepatic lobes, and 32 (30%) had esophageal or gastric varices. The median overall survival (OS) was 5 and 13 months in patients with and without varices (P = .002). The median OS in patients with HER2-positive, HR-positive/HER2-negative, and triple-negative subtype was 16, 9, and 2 months, respectively (P = .001). Patients with varices usually had cirrhotic complications, including gastrointestinal bleeding, hyperbilirubinemia, hyperammonemia, and coagulopathy. Despite their challenging clinical conditions, 7 patients with varices had OS exceeding 1 year. In multivariate analysis, evident varices (P = .007) and triple-negative subtype (P = .013) were associated with poor OS. CONCLUSIONS: Patients with pseudocirrhosis and evident varices had a significantly shorter median OS, and were usually associated with clinical cirrhosis-related complications. To maximize OS, early identification and meticulous supportive care are warranted.

Neuropsychiatric symptoms and mortality among patients with mild cognitive impairment and dementia due to Alzheimer's disease.

BACKGROUND: Neuropsychiatric symptoms (NPS) could increase mortality risk in people with dementia due to Alzheimer's disease (AD). However, whether NPS affects mortality risk in people with mild cognitive impairment (MCI) and whether any specific syndrome of NPS influences this risk are still unclear. METHODS: In total, 984 participants with dementia due to AD, 338 with MCI, and 365 controls were enrolled. Over a mean of 5-year follow-up, cause of death data were obtained from the Ministry of Health and Welfare in Taiwan. NPS were assessed using Neuropsychiatric Inventory Questionnaire (NPI-Q), and psychosis, mood, and frontal domain scores were determined. Survival analyses were conducted to determine the hazard ratio (HR) of death. RESULTS: In controlled analyses, HR of death for AD was 2.19 (95% confidence interval [CI] = 1.29-3.71) compared with the control group, whereas no statistical significance was noted for the MCI group. A high NPI-Q score (above the median score) increased mortality risk for both the MCI and AD groups, with HRs of 2.32 (95% CI = 1.07-5.03) and 2.60 (95% CI = 1.51-4.47), respectively. Among NPI-Q domain scores, only high mood domain, but not psychosis or frontal domain, scores increased death risk for both the MCI (HR = 2.89, 95% CI = 1.00-8.51) and AD (HR = 2.59, 95% CI = 1.47-4.55) groups. CONCLUSION: Mortality risk is high for patients with AD. Not only for AD, patients with MCI presenting with NPS, particularly mood symptoms, have high death risk.

Associations of Endometriosis and Hormone Therapy With Risk of Hyperlipidemia.

Using claims data from the universal health insurance program of Taiwan, we conducted a retrospective cohort study to investigate whether endometriosis and hormone therapy are associated with the risk of developing hyperlipidemia. We selected 9,155 women aged 20-55 years with endometriosis diagnosed during the period 2000-2013 and 212,641 women without endometriosis with a median follow-up time of 7 years. Among patients with endometriosis, 86% of cases were identified on the basis of diagnosis codes with an ultrasound claim, and 14% were defined by diagnostic laparoscopy or surgical treatments. In a Cox proportional hazards model, the adjusted hazard ratio was 1.30 (95% confidence interval (CI): 1.19, 1.41) for all women, 1.04 (95% CI: 0.81, 1.32) for women under 35 years of age, 1.17 (95% CI: 1.03, 1.32) for women aged 35-44 years, and 1.34 (95% CI: 1.18, 1.52) for women aged 45-54 years. Hysterectomy and/or bilateral oophorectomy accounted for 46.9% of the association between endometriosis and hyperlipidemia, and hormone therapy accounted for 21.6%. Among women with endometriosis, the marginal structural model approach adjusting for time-varying hysterectomy/bilateral oophorectomy showed no association between use of hormone medications and risk of hyperlipidemia. We concluded that women with endometriosis are at increased risk of hyperlipidemia; use of hormone therapy by these women was not independently associated with the development of hyperlipidemia.

Comprehensive single-PCR 16S and 18S rRNA community analysis validated with mock communities, and estimation of sequencing bias against 18S.

Universal primers for SSU rRNA genes allow profiling of natural communities by simultaneously amplifying templates from Bacteria, Archaea, and Eukaryota in a single PCR reaction. Despite the potential to show relative abundance for all rRNA genes, universal primers are rarely used, due to various concerns including amplicon length variation and its effect on bioinformatic pipelines. We thus developed 16S and 18S rRNA mock communities and a bioinformatic pipeline to validate this approach. Using these mocks, we show that universal primers (515Y/926R) outperformed eukaryote-specific V4 primers in observed versus expected abundance correlations (slope = 0.88 vs. 0.67-0.79), and mock community members with single mismatches to the primer were strongly underestimated (threefold to eightfold). Using field samples, both primers yielded similar 18S beta-diversity patterns (Mantel test, p < 0.001) but differences in relative proportions of many rarer taxa. To test for length biases, we mixed mock communities (16S + 18S) before PCR and found a twofold underestimation of 18S sequences due to sequencing bias. Correcting for the twofold underestimation, we estimate that, in Southern California field samples (1.2-80 µm), there were averages of 35% 18S, 28% chloroplast 16S, and 37% prokaryote 16S rRNA genes. These data demonstrate the potential for universal primers to generate comprehensive microbiome profiles.

Network meta-analysis-based comparison of first-line steroid-sparing adjuvants in the treatment of pemphigus vulgaris and pemphigus foliaceus.

BACKGROUND: Steroid-sparing adjuvants may enhance oral glucocorticoid benefits in pemphigus treatment. Selecting the optimal therapeutic option among various first-line steroid-sparing adjuvants is often a clinical challenge due to the lack of head-to-head clinical trials. OBJECTIVE: To determine the best first-line steroid-sparing adjuvants for pemphigus treatment. METHODS: Randomized controlled trials comparing different steroid-sparing adjuvants in patients with pemphigus were identified through a systematic literature search and subjected to a network meta-analysis. The primary outcomes were the proportion of remission and the mean cumulative glucocorticoid dose. RESULTS: Ten trials involving 592 patients were analyzed. Among the 7 steroid-sparing adjuvants evaluated, rituximab was the most effective for achieving remission and was more effective than steroid alone (odds ratio, 14.35; 95% confidence interval [CI], 4.71-43.68). Rituximab, azathioprine, and cyclophosphamide pulse therapy enabled the reduction of the cumulative glucocorticoid doses compared to the use of steroid alone: mean differences, -11,830.5 mg (95% CI, -14,089.48 to -9571.52), -3032.48 mg (-4700.74 to -1364.22), and -2469.54 mg (-4128.42 to -810.66), respectively. LIMITATIONS: The results were driven primarily by a small number of studies, and the effect estimates are imprecise because of indirect comparisons. CONCLUSION: Network meta-analysis showed that rituximab appears to be an efficacious, well tolerated steroid-sparing adjuvant for pemphigus.

A novel 3D histotypic cartilage construct engineered by supercritical carbon dioxide decellularized porcine nasal cartilage graft and chondrocytes exhibited chondrogenic capability in vitro.

Augmentative and reconstructive rhinoplasty surgical procedures use autologous tissue grafts or synthetic grafts to repair the nasal defect and aesthetic reconstruction. Donor site trauma and morbidity are common in autologous grafts. The desperate need for the production of grafted 3D cartilage tissues as rhinoplasty grafts without the adverse effect is the need of the hour. In the present study, we developed a bioactive 3D histotypic construct engineered with the various ratio of adipose-derived stem cells (ADSC) and chondrocytes together with decellularized porcine nasal cartilage graft (dPNCG). We decellularized porcine nasal cartilage using supercritical carbon dioxide (SCCO2) extraction technology. dPNCG was characterized by H&E, DAPI, alcian blue staining, scanning electron microscopy and residual DNA content, which demonstrated complete decellularization. 3D histotypic constructs were engineered using dPNCG, rat ADSC and chondrocytes with different percentage of cells and cultured for 21 days. dPNCG together with 100% chondrocytes produced a solid mass of 3D histotypic cartilage with significant production of glycosaminoglycans. H&E and alcian blue staining showed an intact mass, with cartilage granules bound to one another by extracellular matrix and proteoglycan, to form a 3D structure. Besides, the expression of chondrogenic markers, type II collagen, aggrecan and SOX-9 were elevated indicating chondrocytes cultured on dPNCG substrate facilitates the synthesis of type II collagen along with extracellular matrix to produce 3D histotypic cartilage. To conclude, dPNCG is an excellent substrate scaffold that might offer a suitable environment for chondrocytes to produce 3D histotypic cartilage. This engineered 3D construct might serve as a promising future candidate for cartilage tissue engineering in rhinoplasty.

Comparison of clinicopathological features and treatment outcomes in aggressive primary intestinal B- and T/NK-cell lymphomas.

BACKGROUND: Primary intestinal lymphomas (PILs) are rare, and this study compared the clinical outcomes of aggressive primary intestinal B-cell lymphomas (aB-PILs) and T/natural killer-cell lymphomas (T/NK-PILs). METHODS: The clinical information of patients diagnosed with aggressive PILs at our institution between 1995 and 2015 were retrospectively investigated. Pathological subtypes were confirmed according to the 2016 revision of the World Health Organization classification. The correlation between clinicopathological features and overall survival (OS) was determined using univariate and multivariate analyses. RESULTS: Cases of T/NK-PILs had higher initial bowel perforation incidence (67% vs. 7%, P < 0.001) and lower complete response rate to first-line chemotherapy regimens (22% vs. 69%, P = 0.009) than aB-PILs. Patients with aB-PILs had a better 5-year event-free survival rate (55.8% vs. 13.9%, P = 0.026) and a 5-year OS rate (74.3% vs. 29.6%, P = 0.036) than those with T/NK-cell lymphomas. Multivariate analysis identified that female gender and stage III/IV were unfavorable prognostic factors. Among the 54 patients with diffuse large B-cell lymphoma (DLBCL), those with International Prognostic Index (IPI) scores of 0-2 had a better 5-year OS rate than those with scores of 3-5 (84.2% vs. 46.8%, P = 0.002). IPI scores of 3-5 (P = 0.026) and tumors located in the large intestine (P = 0.015) were poor prognostic factors based on the multivariate analysis. CONCLUSION: The prognosis of T/NK-PILs was less favorable than that of aB-PILs. Female gender, stage III/IV disease, DLBCL with IPI scores of 3-5, or tumors in the large intestine were poor prognostic factors.

The impact on incident tuberculosis by kidney function impairment status: analysis of severity relationship.

BACKGROUND: The risk of tuberculosis (TB) in patients with impaired kidney function remains unclear by different stages of renal function impairment. METHODS: We retrospectively recruited all patients with kidney function in a tertiary-care referral center from January 2008 to December 2013 and followed them till December 2016. We defined the primary outcome as active TB development and analyzed the impact of kidney function impairment. RESULTS: During the study period, a total of 289,579 patients were enrolled for analysis, and of them, 1012 patients had active TB events in an average of 4.13 years of follow-up. According to kidney function impairment, the incidence rate of TB was similar in patients with no chronic kidney disease (CKD) or stage 1 and stage 2, and it increased apparently at stage 3a (167.68 per 100,000 person-years) to stage 3b, stage 4 and stage 5 (229.25, 304.95 and 349.29 per 100,000 person-years, respectively). In a Cox proportional hazard regression model, the dose response of TB risk among different stages of kidney function impairment increased significantly from CKD stage 3a to stage 5. Patients with long-term dialysis had a hazard ratio of 2.041 (1.092-3.815, p = 0.0254), which is similar to that of stage 4 CKD but lower than that of stage 5. CONCLUSION: In patients with impaired kidney function, the risk of TB increases from CKD stage 3, and in stage 5, the risk is even higher than that of those receiving dialysis. Further strategies of TB control need to consider this high-risk group.

Role of novel protein kinase C in neuroendocrine-immune regulatory network in haemocytes of Litopenaeus vannamei: An in vitro approach.

Shrimp lack adaptive immune systems and mainly rely on the cellular and humoral defences, involving the haemocytes (functionally analogous to vertebrate leukocytes) in non-self matter recognition, elimination, and in downstream coagulation. Furthermore, the linkage between stress-induced catecholamine (CA), a class of biogenic amines (BAs), releasing and immunological responses has been detected in shrimp. Varied isotypes of protein kinase C (PKC) regulate multiple cellular processes following their specific location and distribution within the cells, and a novel PKC identified in Litopenaeus vannamei (termed as LvnPKC) is proposed to mediate signaling transduction of immunocompetence and BA biosynthesis. In the present study, we analyzed the effects of the LvnPKC-silenced haemocytes by co-incubating with its dsRNA on the immune responses specific to prophenoloxidase (proPO) and antioxidant systems as well as phagocytic activity. In addition, the capability of haemocytes to produce BAs was assessed. The results revealed that LvnPKC-silenced haemocytes can induce interference in phenoloxidase and superoxide dismutase activities, respiratory bursts, and phagocytic activity; meanwhile, the disturbed gene expressions of proPO activating enzyme, proPOII, lipopolysaccharide- and ß-1,3-glucan-binding protein, and cytosolic manganese superoxide dismutase were detected. The same deviated pattern was observed in tyrosine, dopamine, and norepinephrine levels, and in dopamine ß-hydroxylase (DBH) activity and gene expressions of tyrosine hydroxylase, DOPA decarboxylase, and DBH involving in BA biosynthesis. Taken together, these results suggest that the immunocompetence and BA biosynthesis of haemocytes can be mediated via LvPKC signaling transduction, which proved the presence of a neuroendocrine-immune regulatory network in haemocytes.

Genetics of neuropsychiatric symptoms in patients with Alzheimer's disease: A 1-year follow-up study.

AIM: The aim of this study was to investigate the associations between candidate gene variants and domains of neuropsychiatric symptoms (NPS) and the changes in these associations over a 1-year period. METHODS: Seven hundred and ninety-three Taiwanese participants (47.8% female) with Alzheimer's disease (AD) were enrolled. Genes associated with a risk of developing AD were selected as candidate genes. NPS were assessed using the Neuropsychiatric Inventory Questionnaire (NPI-Q), and the NPI-Q total score and sub-scores for the Psychosis, Mood, and Frontal Syndrome domains were calculated. RESULTS: Patients with AD and the APOE ε4 allele exhibited more obvious symptoms of psychosis. Mood symptoms were associated with CD33 rs3865444 and EPHA1 rs11767557, and frontal symptoms were associated with SORL1 rs3824968. A 1-year Time × Alleles interaction effect of CD33 rs3865444 on mood symptoms was discerned. CONCLUSION: Risk genes of AD, which are also associated with NPS, are APOE ε4 for psychosis, CD33 and EPHA1 for mood symptoms, and SORL1 for frontal symptoms. The association between CD33 and mood symptoms is dynamic and could change over 1 year; however, the results should be interpreted with caution because corrections for multiple comparisons were not performed.

Risk of Infective Endocarditis After Invasive Dental Treatments: Case-Only Study.

BACKGROUND: Invasive dental treatments (IDTs) can yield temporary bacteremia and have therefore been considered a potential risk factor of infective endocarditis (IE). It is hypothesized that, through the trauma caused by IDTs, bacteria gain entry to the bloodstream and may attach to abnormal heart valves or damaged heart tissue, giving rise to IE. However, the association between IDTs and IE remains controversial. The aim of this study is to estimate the association between IDTs and IE. METHODS: The data in this study were obtained from the Health Insurance Database in Taiwan. We selected 2 case-only study designs, case-crossover and self-controlled case series, to analyze the data. The advantage of these methods is that confounding factors that do not vary with time are adjusted for implicitly. In the case-crossover design, a conditional logistic regression model with exposure to IDTs was used to estimate the risks of IE following an IDT with 4, 8, 12, and 16 weeks delay, respectively. In the self-controlled case series design, a conditional Poisson regression model was used to estimate the risk of IE for the risk periods of 1 to 4, 5 to 8, 9 to 12, and 13 to 16 weeks following an IDT. RESULTS: In total, 9120 and 8181 patients with IE were included in case-crossover design and self-controlled case series design, respectively. In the case-crossover design, 277 cases and 249 controls received IDTs during the exposure period, and the odds ratio was 1.12 (95% confidence interval, 0.94-1.34) for 4 weeks. In the self-controlled case series design, we observed that 407 IEs occurred during the first 4 weeks after IDTs, and the age-adjusted incidence rate ratio was 1.14 (95% confidence interval, 1.02-1.26) for 1 to 4 weeks after IDTs. CONCLUSIONS: In both study designs, we did not observe a clinically larger risk for IE in the short periods after IDTs. We also found no association between IDTs and IE among patients with a high risk of IE. Therefore, antibiotic prophylaxis for the prevention of IE is not required for the Taiwanese population.

Multi-year dynamics of fine-scale marine cyanobacterial populations are more strongly explained by phage interactions than abiotic, bottom-up factors.

Currently defined ecotypes in marine cyanobacteria Prochlorococcus and Synechococcus likely contain subpopulations that themselves are ecologically distinct. We developed and applied high-throughput sequencing for the 16S-23S rRNA internally transcribed spacer (ITS) to examine ecotype and fine-scale genotypic community dynamics for monthly surface water samples spanning 5 years at the San Pedro Ocean Time-series site. Ecotype-level structure displayed regular seasonal patterns including succession, consistent with strong forcing by seasonally varying abiotic parameters (e.g. temperature, nutrients, light). We identified tens to thousands of amplicon sequence variants (ASVs) within ecotypes, many of which exhibited distinct patterns over time, suggesting ecologically distinct populations within ecotypes. Community structure within some ecotypes exhibited regular, seasonal patterns, but not for others, indicating other more irregular processes such as phage interactions are important. Network analysis including T4-like phage genotypic data revealed distinct viral variants correlated with different groups of cyanobacterial ASVs including time-lagged predator-prey relationships. Variation partitioning analysis indicated that phage community structure more strongly explains cyanobacterial community structure at the ASV level than the abiotic environmental factors. These results support a hierarchical model whereby abiotic environmental factors more strongly shape niche partitioning at the broader ecotype level while phage interactions are more important in shaping community structure of fine-scale variants within ecotypes.

Sleep Duration and Proteinuria Progression: A Population-Based Cohort Study.

BACKGROUND: Extensive studies have demonstrated that sleep is an important modulator of cardiovascular and metabolic diseases. However, its impact on renal function remains uncertain. METHODS: A total of 26,249 adults aged ≥20 years were recruited through voluntary health examinations in Taiwan. Sleep duration was self-reported by questionnaire. Proteinuria was graded semi-quantitatively by dipstick urine test. The associations of sleep duration with proteinuria and estimated glomerular filtration rate (eGFR) were analyzed. RESULTS: After an average follow-up period of 2.62 years, the crude hazard ratio (HR) for proteinuria progression were 1.92 (95% CI 1.22-3.03), 1.23 (95% CI 1.09-1.39), and 1.18 (95% CI 1.00-1.39) for those with sleep duration < 4, 4-6, and > 8 h compared to those with sleep duration of 6-8 h (the reference group), respectively. The HR remained significant for those with sleep duration < 4 h (adjusted HR 1.65 [95% CI 1.05-2.61]) and 4-6 h (adjusted HR 1.19 [95% CI 1.06-1.35]) after adjustment for age, sex, blood pressure, fasting glucose, body mass index, cholesterols, triglycerides, uric acids, physical activity, smoking, alcohol consumption, income/educational levels, and baseline eGFR. However, eGFR was not significantly different among different sleep duration groups. DISCUSSION: This result indicates short sleep duration is independently associated with the progression of proteinuria.

H. pylori isolates with amino acid sequence polymorphisms as presence of both HtrA-L171 & CagL-Y58/E59 increase the risk of gastric cancer.

BACKGROUND: H. pylori CagL-Y58/E59 increase gastric cancer risk by stronger binding with integrin to faciliate type IV secretory system (T4SS). H. pylori can secrete high temperature requirement A (HtrA) to mediate E-Cadherin cleavage for gastric epithelial junction disruption, so H. pylori CagL can adhere to integrin located on basolateral side of epithelium. The study test whether H. pylori HtrA amino acid polymorphisms can increase gastric cancer risk synergistically with CagL-Y58/E59. METHODS: One-hundred and sixty-four H. pylori-positive patients, including 71 with non-ulcer dyspepsia (NUD), 63 with peptic ulcers (PU), and 30 with gastric cancers (GC), were enrolled to receive upper gastrointestinal endoscopy to obtain gastric biopsies for H. pylori culture and histology by the updated Sydney system. Each isolate was screened for htrA & cagL genotype by polymerase chain reaction and HtrA & CagL-Y58/E59 amino acid sequence polymorphisms by sequencing. RESULTS: The prevalence rates of htrA & cagL gene were both 100%. The HtrA amino acid sequence polymorphisms were not different between NUD and PU. The H. pylori isolates of GC had higher rates of HtrA residue 171 as leucine than those of NUD (73.3% vs. 50.7%, P = 0.036, OR[95%CI] = 2.7[1.1-6.8]). The risk of the H. pylori-infected subjects to get gastric cancer was increased up to 15.4-fold, if the infected isolates had presence of both HtrA-L171 and CagL-Y58/E59 (P < 0.001). CONCLUSIONS: The H. pylori isolates of gastric cancer subjects had a higher rate of HtrA-L171. H. pylori isolates with presence of both HtrA-171 & CagL-Y58/E59 can synergistically increase the risk of gastric cancer.

Spasmolytic polypeptide-expressing metaplasia associated with higher expressions of miR-21, 155, and 223 can be regressed by Helicobacter pylori eradication in the gastric cancer familial relatives.

BACKGROUND AND AIMS: Spasmolytic polypeptide-expressing metaplasia (SPEM) is a preneoplastic gastric cancer lesion related to epigenetic microRNA (miRNA) expression. This study elucidated whether Helicobacter pylori-infected first-degree relatives of patients with gastric cancer (GCF) are susceptible to have SPEM and correlated with miR-21, 155, and 223 expressions. We also validated whether SPEM and these miRNAs can be regressed after H pylori eradication. METHODS: We prospectively enrolled 148 GCF and 148 nonulcer dyspepsia (NUD) subjects without gastric cancer familial history as controls. Each case had received a panendoscopy to determine H pylori status and gastric histology, including SPEM. The cases with SPEM were followed after H pylori eradication to determine SPEM regression. The total RNA was extracted to analyze tissues miR-21, 155, and 223 before and after eradication. RESULTS: GCF subjects had a higher prevalence of H pylori infection (73% vs 32%) and SPEM (42% vs 14%, P < 0.01) than controls. The tissue miR-21, 155, and 223 in antrum were higher in cases with SPEM than in those without SPEM (P <= 0.05). There was similar SPEM reversibility after H pylori eradication between GCF subjects and controls (72% vs 69%, P = 0.852). In the SPEM regressed cases, tissue miR-21, 155, and 223 decreased after H pylori eradication (P < 0.05). CONCLUSION: The H pylori-infected GCF subjects were prone to have SPEM with higher tissues miR-21, 155, and 223 expressions. H pylori eradication can result in a 70% SPEM regression, accompanied by a decline in miR-21, 155, and 233 expression levels.

Association of brain white matter lesions and atrophy with cognitive function in chronic kidney disease.

OBJECTIVES: Cognitive impairment is common in patients with chronic kidney disease (CKD), possibly leading to poor outcomes. However, the correlation between brain structural abnormalities and cognitive impairment remains unclear. The aim of this study was to investigate the impairment of specific cognitive domains and their association with brain structural abnormalities. METHODS: Patients with CKD of at least stage 3 who were not on hemodialysis were enrolled. All participants underwent comprehensive neuropsychological testing in five cognitive domains. Ventricular atrophy, sulcal atrophy, medial temporal atrophy, and white matter changes were assessed using brain magnetic resonance imaging according to standard protocols. RESULTS: Eighty-seven patients and 50 controls were enrolled. Patients with CKD exhibited decreased cognitive function relative to controls. Compared with patients with stage 3 CKD, those with advanced stage (stages 4 or 5) had poorer cognitive performance, more pronounced white matter hyperintensity (WMH) and more severe ventricular atrophy. Among CKD patients, executive function (ß = -.23, P = .043) and attention (ß = -.29, P = .004) were associated with WMH in controlled analyses. However, no cognitive impairment was associated with ventricular atrophy. CONCLUSION: Patients with CKD exhibited cognitive impairment and brain structural abnormalities including WMH and general brain atrophy. Impairment of attention and executive dysfunction were associated with WMH.