[Clinicopathological Features of Primary Small Cell Neuroendocrine Carcinoma of the Bladder].

Objective To investigate the clinicopathological features,immunohistochemical features,diagnosis,and relationship with sporadic prostate cancer in primary small cell neuroendocrine carcinoma of the bladder. Methods We retrospectively analyzed the clinical characteristics of 12 patients with primary small cell neuroendocrine carcinoma of the bladder diagnosed at Beijing Chao-Yang Hospital affiliated to Capital Medical University from January 2013 to September 2022.The histological features of primary small cell neuroendocrine carcinoma of the bladder were re-evaluated by two pathologists according to the 2022 revision of the World Health Organization Classification of Tumors of the Urinary System and Male Genital Organs.Electronic medical records were retrieved,and telephone follow-up was conducted from the time of histopathological diagnosis to the death or the end of the last follow-up until January 31,2023. Results The 12 patients include 7 patients in pT3 stage and 1 patient in pT4 stage.Eight patients were complicated with other types of tumors,such as high-grade urothelial carcinoma of the bladder and squamous cell carcinoma.Five patients had sporadic prostate cancer.Immunohistochemical staining showed that 12 (100.0%),10 (83.3%),and 8 (66.7%) patients were tested positive for CD56,Syn,and CgA,respectively.The Ki67 proliferation index ranged from 80% to 90%.Five patients with urothelial carcinoma were tested positive for CK20,GATA3,and CK7.P504S was positive in all the 5 patients with prostate cancer,while P63 and 34ßE12 were negative.The follow-up of the 12 patients lasted for 3-60 months.Eight of these patients died during follow-up,with the median survival of 15.5 months.Four patients survived. Conclusions Primary small cell neuroendocrine carcinoma of the bladder is a rare urological tumor with high aggressiveness and poor prognosis.In male patients with bladder prostatectomy,all prostate tissue should be sampled.If prostate cancer is detected,the prostate-specific antigen level should be monitored.

Clinical and Pathological Characteristics and Prognosis of Lung Adenocarcinoma With High-Grade Fetal Features: A Retrospective Analysis.

Fetal adenocarcinoma of the lung is a rare tumor. The clinical and pathological characteristics, treatment, and prognosis of patients with lung adenocarcinoma with fetal lung-like morphology were retrospectively investigated. The tumors of 9 patients with lung adenocarcinoma contained fetal lung-like morphology. One patient had pure-type high-grade fetal adenocarcinoma. Two patients had more than 50% high-grade fetal adenocarcinoma. Six specimens accounted for < 50% of the high-grade fetal features. It occurred in 7 men and 2 women. The median age at diagnosis was 62.0 years. Thyroid transcription factor-1 was frequently expressed in 8 specimens. All 9 specimens showed high rates of immunopositivity for ß-catenin and E-cadherin. Three specimens showed nuclear ß-catenin staining. Some patients showed immune expression of CDX2, α-fetoprotein (AFP), SALL4, and Glypican-3. Three of these specimens were diffusely strongly positive for p53, including 1 mixed-type high-grade fetal adenocarcinoma and 2 lung adenocarcinomas with high-grade fetal features. However, the other 6 patients had wild-type p53, including 1 pure-type high-grade fetal adenocarcinoma. PD-L1 was not expressed in all patients. Epidermal growth factor receptor mutations were detected in 1 patient. All patients were diagnosed using surgical samples. During the follow-up period of 36 months (range: 1-92 months), 3 patients received chemotherapy. One patient underwent radiotherapy. Two patients experienced recurrences. No patient died. PD-L1 expression status suggests a poor response to immune checkpoint therapy. The prognosis of the patient was relatively good.

Predicting survival for patients with mesothelioma: development of the PLACE prognostic model.

INTRODUCTION: The overall survival of patients with mesothelioma is poor and heterogeneous. At present, the prediction model for Chinese patients needs to be improved. We sought to investigate predictors of survival in malignant pleural mesothelioma and develop prognostic prediction models. METHODS: This Two-center retrospective cohort study recruited patients with pathologically diagnosed mesothelioma at Beijing Chao-Yang Hospital and Beijing Tong-Ren Hospital. We developed a new prognostic prediction model based on COX multivariable analysis using data from patients who were recruited from June 1, 2010 to July 1, 2021 in Beijing Chao-Yang Hospital (n = 95, development cohort) and validated this model using data from patients recruited from July 18, 2014 to May 9, 2022 in Beijing Tong-Ren Hospital (n = 23, validation cohort). Receiver operating characteristic analysis was used to estimate model accuracy. RESULTS: The parameters in this new model included PLT > 289.5(10^9/L) (1 point), Lymphocyte > 1.785(10^9/L) (-1point), Age > 73 years old (1 point), Calcium > 2.145(mmol/L) (-1point), Eastern Cooperative Oncology Group performance status (ECOG PS) > 2 (2 points). When the sum of scores < 0, it is recognized as a low-risk group; when the score is 0 ~ 3, it is recognized as a high-risk group. The survival rate of patients in the high-risk group was significantly lower than that in the low-risk group (hazard ratio [HR], 3.878; 95% confidence interval [CI], 2.226-6.755; P < 0.001). The validation group had similar results (HR,3.574; 95%CI,1.064-12.001; P = 0.039). Furthermore, the areas under the curve 6 months after diagnosis in the two cohorts were 0.900 (95% CI: 0.839-0.962) and 0.761 (95% CI: 0.568-0.954) for development and validation cohorts, respectively. CONCLUSION: We developed a simple, clinically relevant prognostic prediction model for PLACE by evaluating five variables routinely tested at the time of diagnosis. The predictive model can differentiate patients of Chinese ethnicity into different risk groups and further guide prognosis.

KMT2D links TGF-ß signaling to noncanonical activin pathway and regulates pancreatic cancer cell plasticity.

Although KMT2D, also known as MLL2, is known to play an essential role in development, differentiation, and tumor suppression, its role in pancreatic cancer development is not well understood. Here, we discovered a novel signaling axis mediated by KMT2D, which links TGF-ß to the activin A pathway. We found that TGF-ß upregulates a microRNA, miR-147b, which in turn leads to post-transcriptional silencing of KMT2D. Loss of KMT2D induces the expression and secretion of activin A, which activates a noncanonical p38 MAPK-mediated pathway to modulate cancer cell plasticity, promote a mesenchymal phenotype, and enhance tumor invasion and metastasis in mice. We observed a decreased KMT2D expression in human primary and metastatic pancreatic cancer. Furthermore, inhibition or knockdown of activin A reversed the protumoral role of KMT2D loss. These findings support a tumor-suppressive role of KMT2D in pancreatic cancer and identify miR-147b and activin A as novel therapeutic targets.

Repurposing a Cyclin-Dependent Kinase 1 (CDK1) Mitotic Regulatory Network to Complete Terminal Differentiation in Lens Fiber Cells.

Purpose: During lens fiber cell differentiation, organelles are removed in an ordered manner to ensure lens clarity. A critical step in this process is removal of the cell nucleus, but the mechanisms by which this occurs are unclear. In this study, we investigate the role of a cyclin-dependent kinase 1 (CDK1) regulatory loop in controlling lens fiber cell denucleation (LFCD). Methods: We examined lens differentiation histologically in two different vertebrate models. An embryonic chick lens culture system was used to test the role of CDK1, cell division cycle 25 (CDC25), WEE1, and PP2A in LFCD. Additionally, we used three mouse models that express high levels of the CDK inhibitor p27 to test whether increased p27 levels affect LFCD. Results: Using chick lens organ cultures, small-molecule inhibitors of CDK1 and CDC25 inhibit LFCD, while inhibiting the CDK1 inhibitory kinase WEE1 potentiates LFCD. Additionally, treatment with an inhibitor of PP2A, which indirectly inhibits CDK1 activity, also increased LFCD. Three different mouse models that express increased levels of p27 through different mechanisms show impaired LFCD. Conclusions: Here we define a conserved nonmitotic role for CDK1 and its upstream regulators in controlling LFCD. We find that CDK1 functionally interacts with WEE1, a nuclear kinase that inhibits CDK1 activity, and CDC25 activating phosphatases in cells where CDK1 activity must be exquisitely regulated to allow for LFCD. We also provide genetic evidence in multiple in vivo models that p27, a CDK1 inhibitor, inhibits lens growth and LFCD.

Clinical, laboratory, pathological, and radiological characteristics and prognosis of patients with pulmonary salivary gland-type tumors.

PURPOSE: Primary pulmonary salivary gland-type tumor (PSGT) included two main subtypes, pulmonary adenoid cystic carcinoma (PACC) and pulmonary mucoepidermoid carcinoma (PMEC). The purpose of this study was to compare the similarities and differences between these two subtypes and to identify independent risk factors for the prognosis of PSGT patients. METHODS: This study screened patients with a pathological diagnosis of PSGT in Beijing Chaoyang Hospital between 2010 and 2021. The clinical, pathological, radiological, laboratory test, and other characteristics were collected, and t, nonparametric and chi-squared tests were used to compare the differences in clinical characteristics of the two subtypes. COX univariate and multivariate analyses were used to explore prognostic-related risk factors. RESULTS: A total of 62 patients with PSGT were included in our center over a 12-year period. There were 26 PMEC patients and 36 PACC patients. There were differences in the clinical, pathological, and radiological features of the two tumor subtypes. Univariate analysis showed that weight loss, chemotherapy, white blood cells, lymphocytes, red blood cells, total protein, and total bilirubin might be related to the prognosis in PSGT patients. Multivariate results showed that lymphocytes (p = 0.031), red blood cells (p = 0.047), total protein (p = 0.032), and total bilirubin (p = 0.010) were independent prognostic risk factors. Chemotherapy (HR 4.452; 95% CI 1.723-11.503; p = 0.002) might be associated with progression-free survival (PFS). CONCLUSION: The two subtypes of PSGT had significantly different clinical, laboratory, pathological, and radiological features. However, there was no significant difference in the prognosis of patients with PMEC and PACC subtypes. Cox univariate and multivariate analyses showed that levels of lymphocytes, erythrocytes, total protein and total bilirubin in the peripheral blood of PSGT patients might be related to patient overall survival. Chemotherapy might also be associated with PFS.

Clinical, Laboratory, Histological, Radiological, and Metabolic Features and Prognosis of Malignant Pleural Mesothelioma.

Background: Malignant pleural mesothelioma (MPM) is an aggressive and rare malignant pleural tumor. Methods: MPM patients diagnosed in Beijing Chaoyang Hospital and Beijing Tongren Hospital were the focus of this study. We collected and analyzed the histological, radiological, and metabolic features of MPM patients. At the same time, Cox univariable and multivariable analyses were used to explore the laboratory risk factors affecting the prognosis of MPM patients. Results: A total of 129 MPM patients were included in this study. MPM includes three main histological subtypes: epithelioid, sarcomatoid and biphasic. Among them, epithelial subtypes accounted for the highest proportion. Calretinin, Wilms' tumor gene (WT1), cytokeratin 5/6 (CK5/6), and D2-40 were the most useful mesothelial markers to support a MPM diagnosis. The imaging features of MPM patients are pleural thickening and pleural effusion. In PET-CT, the affected pleura showed obvious high uptake of tracer, and the degree was related to the specific subtype. The median follow-up time was 55.0 (30.0, 94.0) months. A total of 92 (71.3%) patients died during follow-up. The median survival time of patients was 21.0 (9.0, 48.0) months. The Cox multivariable analysis showed that age [hazard ratio (HR), 1.824; 95% confidence interval (CI) 1.159-2.872; p = 0.009; uncorrected], ESR (HR, 2.197; 95% CI 1.318-3.664; p = 0.003; with Bonferroni correction), lymphocytes (HR, 0.436; 95% CI 0.258-0.737; p = 0.002; with Bonferroni correction), platelets (HR, 1.802; 95% CI 1.084-2.997; p = 0.023; uncorrected) and total protein (HR, 0.625; 95% CI 0.394-0.990; p = 0.045; uncorrected) were independent risk factors for prognosis, after adjusting for confounding factors. Conclusions: Age, ESR, lymphocytes, platelets and total protein may be related to the prognosis of MPM patients. Summarizing the histological, radiological, and metabolic features of MPM patients in the two centers can increase clinicians' understanding of this rare tumor.

Increasing chemical oxygen demand and nitrogen removal efficiencies of surface-flow constructed wetlands in macrophyte-dominant seasons by adding artificial macrophytes.

The objective was to test the effectiveness of a new strategy, i.e., adding artificial macrophytes (AMs) to surface-flow constructed wetlands (SFCWs) planted with emergent macrophytes (EMs), to improve COD and N removal efficiencies (REs) at the pilot scale. During EM-dominant periods, the SFCWs with only EMs had REs of 78.2%, 59.8%, 50.8% and -54.2% for NH4+-N, NO3--N, TN, and COD, respectively, while the SFCWs with both AMs and EMs increased the REs to 85.1%, 72.2%, 73.8%, and 2.0%. The addition of AMs to SFCWs had no significant effect on EM growth (biomass or root activity). Mutual benefit was found between EMs and AMs, i.e., AMs reduced the secondary pollution caused by withered EMs, while EMs improved AM-attached biofilm functions of chemoheterotrophy, nitrate_reduction, and nitrification. Therefore, AM addition is a useful strategy to improve COD and N REs during EM-dominant periods when pollutant removal is a challenge for SFCWs.

KDM6A Regulates Cell Plasticity and Pancreatic Cancer Progression by Noncanonical Activin Pathway.

BACKGROUND & AIMS: Inactivating mutations of KDM6A, a histone demethylase, were frequently found in pancreatic ductal adenocarcinoma (PDAC). We investigated the role of KDM6A (lysine demethylase 6A) in PDAC development. METHODS: We performed a pancreatic tissue microarray analysis of KDM6A protein levels. We used human PDAC cell lines for KDM6A knockout and knockdown experiments. We performed bromouridine sequencing analysis to elucidate the effects of KDM6A loss on global transcription. We performed studies with Ptf1aCre; LSL-KrasG12D; Trp53R172H/+; Kdm6afl/fl or fl/Y, Ptf1aCre; Kdm6afl/fl or fl/Y, and orthotopic xenograft mice to investigate the impacts of Kdm6a deficiency on pancreatic tumorigenesis and pancreatitis. RESULTS: Loss of KDM6A was associated with metastasis in PDAC patients. Bromouridine sequencing analysis showed up-regulation of the epithelial-mesenchymal transition pathway in PDAC cells deficient in KDM6A. Loss of KDM6A promoted mesenchymal morphology, migration, and invasion in PDAC cells in vitro. Mechanistically, activin A and subsequent p38 activation likely mediated the role of KDM6A loss. Inhibiting either activin A or p38 reversed the effect. Pancreas-specific Kdm6a-knockout mice pancreata showed accelerated PDAC progression, developed a more aggressive undifferentiated type of PDAC, and increased metastases in the background of Kras and p53 mutations. Kdm6a-deficient pancreata in a pancreatitis model had a delayed recovery with increased PDAC precursor lesions compared with wild-type pancreata. CONCLUSIONS: Loss of KDM6A accelerates PDAC progression and metastasis, most likely by a noncanonical p38-dependent activin A pathway. KDM6A also promotes pancreatic tissue recovery from pancreatitis. Activin A might be used as a therapeutic target for KDM6A-deficient PDACs.

PEAR1 is not a major susceptibility gene for cardiovascular disease in a Flemish population.

BACKGROUND: Platelet Endothelial Aggregation Receptor 1 (PEAR1), a membrane protein highly expressed in platelets and endothelial cells, plays a role in platelet contact-induced activation, sustained platelet aggregation and endothelial function. Previous reports implicate PEAR1 rs12041331 as a variant influencing risk in patients with coronary heart disease. We investigated whether genetic variation in PEAR1 predicts cardiovascular outcome in a white population. METHODS: In 1938 participants enrolled in the Flemish Study on Environment, Genes and Health Outcomes (51.3% women; mean age 43.6 years), we genotyped 9 tagging SNPs in PEAR1, measured baseline cardiovascular risk factors, and recorded Cardiovascular disease incidence. For SNPs, we contrasted cardiovascular disease incidence of minor-allele heterozygotes and homozygotes (variant) vs. major-allele homozygotes (reference) and for haplotypes carriers vs. non-carriers. In adjusted analyses, we accounted for family clusters and baseline covariables, including sex, age, body mass index, mean arterial pressure, the total-to-HDL cholesterol ratio, smoking and drinking, antihypertensive drug treatment, and history of cardiovascular disease and diabetes mellitus. RESULTS: Over a median follow-up of 15.3 years, 238 died and 181 experienced a major cardiovascular endpoint. The multivariable-adjusted hazard ratios of eight PEAR1 SNPs, including rs12566888, ranged from 0.87 to 1.07 (P ≥0.35) and from 0.78 to 1.30 (P ≥0.15), respectively. The hazard ratios of three haplotypes with frequency ≥10% ranged from 0.93 to 1.11 (P ≥0.49) for mortality and from 0.84 to 1.03 (P ≥0.29) for a cardiovascular complications. These results were not influenced by intake of antiplatelet drugs, nonsteroidal anti-inflammatory drugs, or both (P-values for interaction ≥ 0.056). CONCLUSIONS: In a White population, we could not replicate previous reports from experimental studies or obtained in patients suggesting that PEAR1 might be a susceptibility gene for cardiovascular complications.

Retinal microvascular diameter, a hypertension-related trait, in ECG-gated vs. non-gated images analyzed by IVAN and SIVA.

The diameters of the retinal microvasculature reflect intermediate target organ damage and predict adverse health outcomes. In view of the pulsatility of the cerebral blood flow and refinement of software used for off-line analysis, we assessed the repeatability of retinal microvascular diameters in ECG-gated vs. non-gated images using nonmydriatic retinal photographs (Canon Cr-DGi visualization system) postprocessed by IVAN (Vasculomatic ala Nicola, version 1.1) or SIVA (Singapore I Vessel Assessment, version 3.6). Using these algorithms, we determined the central retinal arteriolar (CRAE) and venular (CRVE) equivalents and their ratio (arteriole-to-venule ratio (AVR)). The estimates of CRAE (mean, 158.5 µm), CRVE (222.5 µm) and AVR (0.71) in 10 volunteers were unaffected (P⩾0.059) by ECG gating. We assessed intragrader repeatability by the Bland and Altman approach in 30 participants with non-gated images and 30 with ECG-gated photographs. Repeatability, which was expressed as the percentage of near maximal variability (4-s.d. range), did not improve with ECG gating. Using SIVA, CRAE and CRVE were systematically larger (P⩽0.031), and the AVR estimates were similar (P⩾0.15) compared with IVAN. The differences (IVAN-SIVA) averaged -5.4 µm for CRAE, -3.9 µm for CRVE and -0.012 for AVR in the non-gated images and -3.3 µm, -6.9 µm and 0.006, respectively, in the ECG-gated photographs. In conclusion, ECG gating does not affect estimates of the retinal microvascular diameters or improve intragrader repeatability. SIVA yields slightly but significantly larger estimates of the retinal arteriolar and venular diameters. Combining historical readings analyzed by IVAN with more recent readings by SIVA is possible only for AVR and is not recommended for either CRAE or CRVE.

Conventional and Ambulatory Blood Pressure as Predictors of Retinal Arteriolar Narrowing.

At variance with the long established paradigm that retinal arteriolar narrowing trails hypertension, several longitudinal studies, all based on conventional blood pressure (CBP) measurement, proposed that retinal arteriolar narrowing indicates heightened microvascular resistance and precedes hypertension. In 783 randomly recruited Flemish (mean age, 38.2 years; 51.3% women), we investigated to what extent CBP and daytime (10 am to 8 pm) ambulatory blood pressure (ABP) measured at baseline (1989-2008) predicted the central retinal arteriolar equivalent (CRAE) in retinal photographs obtained at follow-up (2008-2015). Systolic/diastolic hypertension thresholds were 140/90 mm Hg for CBP and 135/85 mm Hg for ABP. In multivariable-adjusted models including both baseline CBP and ABP, CRAE after 10.3 years (median) of follow-up was unrelated to CBP (P≥0.14), whereas ABP predicted CRAE narrowing (P≤0.011). Per 1-SD increment in systolic/diastolic blood pressure, the association sizes were -0.95 µm (95% confidence interval, -2.20 to 0.30)/-0.75 µm (-1.93 to 0.42) for CBP and -1.76 µm (-2.95 to -0.58)/-1.48 µm (-2.61 to -0.34) for ABP. Patients with ambulatory hypertension at baseline (17.0%) had smaller CRAE (146.5 versus 152.6 µm; P<0.001) at follow-up. CRAE was not different (P≥0.31) between true normotension (normal CBP and ABP; prevalence, 77.6%) and white-coat hypertension (elevated CBP and normal ABP, 5.4%) and between masked hypertension (normal CBP and elevated ABP, 10.2%) and hypertension (elevated CBP and ABP, 6.8%). In conclusion, the paradigm that retinal arteriolar narrowing precedes hypertension can be explained by the limitations of CBP measurement, including nonidentification of masked and white-coat hypertension.

CXCL10 Is a Circulating Inflammatory Marker in Patients with Advanced Heart Failure: a Pilot Study.

Chemokines are involved in the remodeling of the heart; however, their significance as biomarkers in heart failure is unknown. We observed that circulating CXCR3 receptor chemokines CXCL9 and CXCL10 in a rat model of heart failure were increased 1 week after myocardial infarction. CXCL10 was also increased in both remote and infarcted regions of the heart and remained elevated at 16 weeks; CXCL9 was elevated in the remote area at 1 week. In humans, hierarchical clustering and principal component analysis revealed that circulating CXCL10, MIP-1α, and CD40 ligand were the best indicators for differentiating healthy and heart failure subjects. Serum CXCL10 levels were increased in patients with symptomatic heart failure as indexed by NYHA classification II through IV. The presence of CXCL10, MIP-1α, and CD40 ligand appears to be dominant in patients with advanced heart failure. These findings identify a distinct profile of inflammatory mediators in heart failure patients.

Urinary Proteomics Pilot Study for Biomarker Discovery and Diagnosis in Heart Failure with Reduced Ejection Fraction.

BACKGROUND: Biomarker discovery and new insights into the pathophysiology of heart failure with reduced ejection fraction (HFrEF) may emerge from recent advances in high-throughput urinary proteomics. This could lead to improved diagnosis, risk stratification and management of HFrEF. METHODS AND RESULTS: Urine samples were analyzed by on-line capillary electrophoresis coupled to electrospray ionization micro time-of-flight mass spectrometry (CE-MS) to generate individual urinary proteome profiles. In an initial biomarker discovery cohort, analysis of urinary proteome profiles from 33 HFrEF patients and 29 age- and sex-matched individuals without HFrEF resulted in identification of 103 peptides that were significantly differentially excreted in HFrEF. These 103 peptides were used to establish the support vector machine-based HFrEF classifier HFrEF103. In a subsequent validation cohort, HFrEF103 very accurately (area under the curve, AUC = 0.972) discriminated between HFrEF patients (N = 94, sensitivity = 93.6%) and control individuals with and without impaired renal function and hypertension (N = 552, specificity = 92.9%). Interestingly, HFrEF103 showed low sensitivity (12.6%) in individuals with diastolic left ventricular dysfunction (N = 176). The HFrEF-related peptide biomarkers mainly included fragments of fibrillar type I and III collagen but also, e.g., of fibrinogen beta and alpha-1-antitrypsin. CONCLUSION: CE-MS based urine proteome analysis served as a sensitive tool to determine a vast array of HFrEF-related urinary peptide biomarkers which might help improving our understanding and diagnosis of heart failure.

Vitamin K Dependent Protection of Renal Function in Multi-ethnic Population Studies.

BACKGROUND: Following activation by vitamin K (VK), matrix Gla protein (MGP) inhibits arterial calcification, but its role in preserving renal function remains unknown. METHODS: In 1166 white Flemish (mean age, 38.2 years) and 714 South Africans (49.2% black; 40.6 years), we correlated estimated glomerular filtration (eGFR [CKD-EPI formula]) and stage of chronic kidney disease (CKD [KDOQI stages 2-3]) with inactive desphospho-uncarboxylated MGP (dp-ucMGP), using multivariable linear and logistic regression. RESULTS: Among Flemish and white and black Africans, between-group differences in eGFR (90, 100 and 122 mL/min/1.73 m(2)), dp-ucMGP (3.7, 6.5 and 3.2 µg/L), and CKD prevalence (53.5, 28.7 and 10.5%) were significant, but associations of eGFR with dp-ucMGP did not differ among ethnicities (P ≥ 0.075). For a doubling of dp-ucMGP, eGFR decreased by 1.5 (P = 0.023), 1.0 (P = 0.56), 2.8 (P = 0.0012) and 2.1 (P < 0.0001) mL/min/1.73 m(2) in Flemish, white Africans, black Africans and all participants combined; the odds ratios for moving up one CKD stage were 1.17 (P = 0.033), 1.03 (P = 0.87), 1.29 (P = 0.12) and 1.17 (P = 0.011), respectively. INTERPRETATION: In the general population, eGFR decreases and CKD risk increases with higher dp-ucMGP, a marker of VK deficiency. These findings highlight the possibility that VK supplementation might promote renal health.

Unfolded-protein response-associated stabilization of p27(Cdkn1b) interferes with lens fiber cell denucleation, leading to cataract.

Failure of lens fiber cell denucleation (LFCD) is associated with congenital cataracts, but the pathobiology awaits elucidation. Recent work has suggested that mechanisms that direct the unidirectional process of LFCD are analogous to the cyclic processes associated with mitosis. We found that lens-specific mutations that elicit an unfolded-protein response (UPR) in vivo accumulate p27(Cdkn1b), show cyclin-dependent kinase (Cdk)-1 inhibition, retain their LFC nuclei, and are cataractous. Although a UPR was not detected in lenses expressing K6W-Ub, they also accumulated p27 and showed failed LFCD. Induction of a UPR in human lens epithelial cells (HLECs) also induced accumulation of p27 associated with decreased levels of S-phase kinase-associated protein (Skp)-2, a ubiquitin ligase that regulates mitosis. These cells also showed decreased lamin A/C phosphorylation and metaphase arrest. The suppression of lamin A/C phosphorylation and metaphase transition induced by the UPR was rescued by knockdown of p27. Taken together, these data indicate that accumulation of p27, whether related to the UPR or not, prevents the phosphorylation of lamin A/C and LFCD in maturing LFCs in vivo, as well as in dividing HLECs. The former leads to cataract and the latter to metaphase arrest. These results suggest that accumulation of p27 is a common mechanism underlying retention of LFC nuclei.

Renal glomerular dysfunction in relation to retinal arteriolar narrowing and high pulse pressure in seniors.

Retinal arteriolar narrowing and high pulse pressure (PP) are associated with macrovascular complications and microvascular renal disease. Few studies addressed whether in seniors (⩾60 years) estimated glomerular filtration rate (eGFR) is independently related to central retinal arteriolar equivalent (CRAE) and PP. In 292 randomly recruited seniors (49.3% women; mean, 68.2 years), we measured PP by standard sphygmomanometry, CRAE (IVAN software), eGFR (Chronic Kidney Disease Epidemiology Collaboration equation) and stage of chronic kidney disease (CKD (Kidney Disease Outcomes Quality Initiative guideline)). Statistical methods included linear and logistic regression. PP, CRAE and eGFR averaged 59.2 mm Hg, 146.3 µm and 79.9 ml min(-1) per 1.73 m(2). Decline in eGFR (-2.27 ml min(-1) per 1.73 m(2) per 15 µm; P=0.011) occurred in parallel with CRAE narrowing. CRAE (effect size per 1-s.d. increment, -1.85 µm; P=0.032) and eGFR (-2.68 ml min(-1) per 1.73 m(2); P=0.003) both declined with higher PP. With PP increasing from 63 to 73 mm Hg (threshold for macrovascular complications), CRAE dropped by -4.70 µm (P⩽0.037). A 70-mm Hg PP threshold corresponded with a 150-µm CRAE cutoff. The risk of CKD (stage ⩾2 vs. 1; n=203 vs. 89) rose with CRAE <150 µm (odds ratio, 2.81; P<0.0001), but not with PP ⩾70 mm Hg (1.47; P=0.20). Additionally, CRAE added to PP increased the area under the curve from 0.58 to 0.64 (P=0.047) for identifying stage ⩾2 CKD. In seniors, CRAE and eGFR decline in parallel with higher PP. CRAE <150 µm identifies early decline in eGFR.

Correlates of Peripheral Blood Mitochondrial DNA Content in a General Population.

Accumulation of mitochondrial DNA (mtDNA) mutations leads to alterations of mitochondrial biogenesis and function that might produce a decrease in mtDNA content within cells. This implies that mtDNA content might be a potential biomarker associated with oxidative stress and inflammation. However, data on correlates of mtDNA content in a general population are sparse. Our goal in the present study was to describe in a randomly recruited population sample the distribution and determinants of peripheral blood mtDNA content. From 2009 to 2013, we examined 689 persons (50.4% women; mean age = 54.4 years) randomly selected from a Flemish population (Flemish Study on Environment, Genes, and Health Outcomes). Relative mtDNA copy number as compared with nuclear DNA was measured by quantitative real-time polymerase chain reaction in peripheral blood. There was a curvilinear relationship between relative mtDNA copy number and age. mtDNA content slightly increased until the fifth decade of life and declined in older subjects (Page (2) = 0.0002). mtDNA content was significantly higher in women (P = 0.007) and increased with platelet count (P < 0.0001), whereas it was inversely associated with white blood cell count (P < 0.0001). We also observed lower mtDNA content in women using estroprogestogens (P = 0.044). This study demonstrated in a general population that peripheral blood mtDNA content is significantly associated with sex and age. Blood mtDNA content is also influenced by platelet and white blood cell counts and estroprogestogen intake. Further studies are required to clarify the impact of chronic inflammation and hormone therapy on mitochondrial function.

Incidence of nephrolithiasis in relation to environmental exposure to lead and cadmium in a population study.

Whether environmental exposure to nephrotoxic agents that potentially interfere with calcium homeostasis, such as lead and cadmium, contribute to the incidence of nephrolithiasis needs further clarification. We investigated the relation between nephrolithiasis incidence and environmental lead and cadmium exposure in a general population. In 1302 participants randomly recruited from a Flemish population (50.9% women; mean age, 47.9 years), we obtained baseline measurements (1985-2005) of blood lead (BPb), blood cadmium (BCd), 24-h urinary cadmium (UCd) and covariables. We monitored the incidence of kidney stones until October 6, 2014. We used Cox regression to calculate multivariable-adjusted hazard ratios for nephrolithiasis. At baseline, geometric mean BPb, BCd and UCd was 0.29µmol/L, 9.0nmol/L, and 8.5nmol per 24h, respectively. Over 11.5 years (median), nephrolithiasis occurred in 40 people. Contrasting the low and top tertiles of the distributions, the sex- and age-standardized rates of nephrolithiasis expressed as events per 1000 person-years were 0.68 vs. 3.36 (p=0.0016) for BPb, 1.80 vs. 3.28 (p=0.11) for BCd, and 1.65 vs. 2.95 (p=0.28) for UCd. In continuous analysis, with adjustments applied for sex, age, serum magnesium, and 24-h urinary volume and calcium, the hazard ratios expressing the risk associated with a doubling of the exposure biomarkers were 1.35 (p=0.015) for BPb, 1.13 (p=0.22) for BCd, and 1.23 (p=0.070) for UCd. In conclusion, our results suggest that environmental lead exposure is a risk factor for nephrolithiasis in the general population.