The generation of genuine quadripartite Einstein-Podolsky-Rosen steering in an optical superlattice.

Einstein-Podolsky-Rosen (EPR) steering is a quantum effect based on quantum entanglement and it is the key resource for building quantum networks because of its useful properties. Based on the criterion for genuine multipartite EPR steering, the genuine quadripartite EPR steering is confirmed and it can be generated by a spontaneous parametric down-conversion cascaded process with two sum-frequency generations in an optical superlattice. This occurs either below the oscillation threshold and without oscillation threshold. The influence of the parameters of cascaded nonlinear process on the quadripartite EPR steering among signal, idler, and two sum-frequency beams are also discussed. Choosing appropriate nonlinear parameters can achieve good quadripartite quantum steering. This scheme of the generation of genuine quadripartite EPR steering has potential applications in quantum communication and computing.

[A case of malignant peritoneal mesothelioma].

Malignant mesothelioma is a highly malignant disease that most often occurs in the pleural cavity, followed by the peritoneum and pericardium. Malignant peritoneal mesothelioma (MPM) accounts for 10%-15% of all mesothelioma. The most important risk factor for MPM is exposure to asbestos. MPM has no specific clinical symptoms, imaging and histopathology are critical for the diagnosis. There are currently no generally accepted guidelines for curative treatment of MPM. The patient mainly presented with abdominal pain, abdominal distension and discomfort. Due to extensive omentum metastasis, no further surgical treatment was performed. Pemetrexed combined with cisplatin chemotherapy was given for 2 cycles, and the patient is still alive.

Areca Nut and Oral Cancer: Evidence from Studies Conducted in Humans.

Areca nut chewing is one of the major risk factors for oral cancer, with large-magnitude risks reported in studies comparing betel quid chewers and never users, and it has been evaluated as a group 1 carcinogen by the International Agency for Research on Cancer. Data from a high-quality meta-analysis examining risk estimates are presented in summary form with additional information from more recent studies (pooled adjusted relative risk, 7.9; 95% CI, 7.1 to 8.7). The risk of oral cancer increases in a dose-response manner with the daily number of quids consumed and the number of years chewing. In the Indian subcontinent and in Taiwan, approximately half of oral cancers reported are attributed to betel quid chewing (population attributable fraction, 53.7% for residents in Taiwan and 49.5% for the Indian population), a disease burden that could be prevented. Oral leukoplakia and oral submucous fibrosis are 2 main oral potentially malignant disorders caused by areca nut chewing that can progress to oral cancer with continued use. Ex-chewers seem to demonstrate lower risks than current chewers, but the impact of areca nut cessation on oral cancer risk has not been scientifically evaluated on the basis of randomized controlled studies. These data strongly reconfirm that betel quid chewing, primarily areca nut use, should be taken into account in assessing the cancer risk of South Asian, East Asian populations and Pacific Islanders for the development of oral cancer.

[Blood pressure control and influencing factors in hypertension patients with metabolic syndrome].

Objective: To investigate the blood pressure control and its influencing factors in hypertension patients with MS. Methods: Between January 2017 and December 2018, more than 78 000 residents aged 35-75 years selected through convenient sampling were invited to participant in China Patient-Centered Evaluative Assessment of Cardiac Event Million Persons Project in Fujian province, physical and laboratory tests were conducted for them, and their basic information were recorded. A total of 5 281 hypertension patients with MS were included in the study. Results: The treatment rate of hypertension patients with MS was 55.5%, and the control rate was 7.2%. The control rate was higher in patients who were older, women, had advanced education level, had history or family history of cardiovascular disease. The results of multivariate analysis indicated that living area (urban or rural), cardiovascular history, diabetes, urine protein, BMI had impacts on both treatment and control of hypertension. Family history of cardiovascular disease, age, self-management of hypertension, dyslipidemia, waist circumference and drinking had impacts on the treatments, and gender had effects on the control. Conclusions: The treatment rate of hypertension patients with MS was unsatisfactory and the control rate was low. Intervention should be strengthened in rural area, males and young age groups, and activity of self-management group of hypertension should be conducted regularly.

Rheumatoid factor and immunoglobulin M mark hepatitis C-associated mixed cryoglobulinaemia: an 8-year prospective study.

OBJECTIVES: The prevalence and factors of hepatitis C virus (HCV) -associated mixed cryoglobulinaemia in Asia remain elusive, and we aimed to investigate these topics. METHODS: An 8-year prospective cohort study was conducted in 678 consecutive Taiwanese individuals with chronic HCV infection (438 completed an anti-HCV therapy course). RESULTS: Of 678 individuals, 437 (64.5%) had mixed cryoglobulinaemia and 20 (2.9%) had mixed cryoglobulinaemic syndrome. At baseline, IgM (cut-off >122 mg/dL), triglycerides and IgG levels, and HCV genotype 3 were independently associated with mixed cryoglobulinaemia. Rheumatoid factor (RF) levels were associated with mixed cryoglobulinaemic syndrome (cut-off >12.2 IU/mL). At 24 weeks post-therapy, the 362 individuals with a sustained virological response (SVR) had higher cured (106/362 (29.3%) versus 10/76 (13.2%), p = 0.003) and lower persistent (100/362 (27.6%) versus 33/76 (43.4%), p = 0.003) mixed cryoglobulinaemia rates than non-SVR patients. Among SVR patients, compared with baseline levels, RF, IgG and IgM levels decreased, except in individuals with new mixed cryoglobulinaemia. Pre-therapy IgM levels were associated with 24-week post-therapy new (95% CI of OR 1.002-1.023) and persistent (95% CI of OR 1.004-1.015) mixed cryoglobulinaemia in SVR patients. After up to 8 years, 24-week post-therapy IgM levels were associated with mixed cryoglobulinaemia in SVR patients (9/51; 17.64%; 95% CI of HR 1.004-1.011). Among 17 SVR patients with pre-therapy mixed cryoglobulinaemic syndrome, 5 (29.4%) had long-term mixed cryoglobulinaemia and 4 (23.5%) had mixed cryoglobulinaemic syndrome. CONCLUSIONS: Over 60% of chronic HCV-infected individuals had mixed cryoglobulinaemia, and 17.64% of SVR patients had mixed cryoglobulinaemia 8 years post-therapy. Pre-therapy RF and IgM levels marked HCV-associated mixed cryoglobulinaemic syndrome and mixed cryoglobulinaemia, respectively.

Impact of postoperative infective complications on long-term survival after liver resection for hepatocellular carcinoma.

BACKGROUND: Postoperative complications have a great impact on the postoperative course and oncological outcomes following major cancer surgery. Among them, infective complications play an important role. The aim of this study was to evaluate whether postoperative infective complications influence long-term survival after liver resection for hepatocellular carcinoma (HCC). METHODS: Patients who underwent resection with curative intent for HCC between July 2003 and June 2016 were identified from a multicentre database (8 institutions) and analysed retrospectively. Independent risk factors for postoperative infective complications were identified. After excluding patients who died 90 days or less after surgery, overall survival (OS) and recurrence-free survival (RFS) were compared between patients with and without postoperative infective complications within 30 days after resection. RESULTS: Among 2442 patients identified, 332 (13·6 per cent) had postoperative infective complications. Age over 60 years, diabetes mellitus, obesity, cirrhosis, intraoperative blood transfusion, duration of surgery exceeding 180 min and major hepatectomy were identified as independent risk factors for postoperative infective complications. Univariable analysis revealed that median OS and RFS were poorer among patients with postoperative infective complications than among patients without (54·3 versus 86·8 months, and 22·6 versus 43·2 months, respectively; both P < 0·001). After adjustment for other prognostic factors, multivariable Cox regression analyses identified postoperative infective complications as independently associated with decreased OS (hazard ratio (HR) 1·20, 95 per cent c.i. 1·02 to 1·41; P = 0·027) and RFS (HR 1·19, 1·03 to 1·37; P = 0·021). CONCLUSION: Postoperative infective complications decreased long-term OS and RFS in patients treated with liver resection for HCC.

Hydroxychloroquine was associated with reduced risk of new-onset diabetes mellitus in patients with Sjögren syndrome.

OBJECTIVES: To determine whether taking hydroxychloroquine (HCQ) could prevent the development of new-onset diabetes mellitus (DM) among patients with Sjögren syndrome (SS). METHODS: This is a nationwide, population-based, retrospective cohort study utilizing the Taiwan National Health Insurance Research Database (NHIRD). Data were collected from 1 January 1999, through 31 December 2013, using the International Classification of Diseases, Ninth Revision, Clinical Modification codes. In total, 7774 patients newly diagnosed with SS by at least three outpatient visits or one inpatient admission were selected from the NHIRD as participants. Patients who had previously been diagnosed with DM and whose follow-up durations shorter than 90 days were excluded. HCQ exposure group includes patients who had been diagnosed with SS no longer than 180 days previously, and had been prescribed HCQ for the first time for at least 90 days. The diagnosis of DM was defined as at least two outpatient visits or one inpatient admission with anti-diabetic medication prescription. RESULTS: Patients with SS treated with HCQ had a significantly lower cumulative incidence of new-onset DM than those not treated with HCQ (adjusted hazard ratio: 0.51, 95% confidence interval: 0.28-0.96, P < 0.05). HCQ use for 3 years or more had favorable protective effects (adjusted hazard ratio: 0.22, CI: 0.05-0.92). CONCLUSIONS: HCQ reduced the incidence of DM in a time and dose-dependent manner. Patients with SS who had taken HCQ for 3 years or more exhibited significant protective effects against developing new-onset DM.

Multicentre study of the prognostic impact of preoperative bodyweight on long-term prognosis of hepatocellular carcinoma.

BACKGROUND: Whether preoperative bodyweight is associated with long-term prognosis in patients after liver resection for hepatocellular carcinoma (HCC) is controversial. This study aimed to investigate the relationship of patient weight with long-term recurrence and overall survival (OS) after curative liver resection for HCC. METHODS: Data for patients with HCC who underwent curative liver resection between 2000 and 2015 in five centres in China were analysed retrospectively in three groups according to their preoperative BMI: underweight (BMI 18·4 kg/m2 or less), normal weight (BMI 18·5-24·9 kg/m2 ) and overweight (BMI 25·0 kg/m2 or above). Patients' baseline characteristics, operative variables and long-term survival outcomes were compared. Univariable and multivariable Cox regression analyses were performed to identify risk factors for OS and recurrence-free survival (RFS) after resection. RESULTS: Of 1524 patients, 107 (7·0 per cent) were underweight, 891 (58·5 per cent) were of normal weight and 526 (34·5 per cent) were overweight. Univariable analyses showed that underweight and overweight patients had poorer OS (both P < 0·001) and RFS (both P < 0·001) than patients of normal weight. Multivariable Cox regression analysis also identified both underweight and overweight to be independent risk factors for OS (hazard ratio (HR) 1·22, 95 per cent c.i. 1·19 to 1·56, P = 0·019; and HR 1·57, 1·36 to 1·81, P < 0·001, respectively) and RFS (HR 1·28, 1·16 to 1·53, P = 0·028; and HR 1·34, 1·17 to 1·54, P < 0·001). CONCLUSION: Underweight and overweight patients appear to have a worse prognosis than those of normal weight following liver resection for HCC.

Niacin Pretreatment Attenuates Ischemia and Reperfusion of Pancreas-induced Acute Pancreatitis and Remote Lung Injury Through Suppressing Oxidative Stress and Inflammation and Activation of SIRT1.

BACKGROUND: Lung injury subsequent to pancreatic ischemia and reperfusion (PIR) due to shock, revascularization, and pancreas transplantation is a major clinical problem. In addition to proteases, massive production and release of reactive oxygen species (ROS) and induction of inflammatory cytokines have been implicated in remote lung injury. Niacin, also known as vitamin B3, is both antioxidative and anti-inflammatory. In this study, we examined the protective effectiveness of niacin pretreatment against PIR-induced pancreatic and remote lung injury. METHODS: Male Sprague-Dawley rats were divided into a sham-operated group, a PIR group, and a PIR group pretreated with niacin; the niacin (300 mg/kg per day) was given on 4 consecutive days before the study. Pancreatic ischemia was established by occluding both the gastroduodenal and splenic arteries for 120 minutes, followed by 240 minutes of reperfusion. Lung injury was assessed by pulmonary barrier function via pulmonary filtration coefficient, Kfc, using an isolated-perfused rat lung preparation. Alveolar protein leakage was assessed by protein concentration in the bronchoalveolar lavage fluid (PCBAL). Lung water content was assessed by both wet-weight/dry-weight ratio (W/D) and lung-weight/body-weight ratio (LW/BW). Lung inflammation was evaluated by the lavage differential neutrophil cell count and tissue tumor necrosis-alpha (TNF-α) level. Oxidative stress was assessed by tissue malondialdehyde (MDA) level. Serum lactate dehydrogenase (LDH) and amylase were examined for lung and pancreas injury. We also evaluated lung tissue SIRT1 mRNA expression. RESULTS: Compared with the sham group, the PIR group had increased serum amylase and LDH, and impaired the pulmonary barrier dysfunction with marked increases in Kfc, PCBAL, W/D, and LW/BW, and augumented oxidative stress and inflammation with elevated tissue MDA and TNF-α and lavage neutrophil count, which correlated with decreased SIRT1 mRNA expression. Conversely, niacin pretreatment reduced pancreatic and remote lung injury and attenuated pulmonary oxidative stress and inflammation, and also protected against PIR-induced pulmonary barrier dysfunction while restoring SIRT1 mRNA expression. CONCLUSION: Niacin pretreatment reduced PIR-induced pancreatic and lung injury and protected against pulmonary barrier function impairment, which was associated with niacin's antioxidative and anti-inflammatory activity and its capacity to increase SIRT1 mRNA expression.

[Clinical effects of pediatric penetrating keratoplasty for congenital corneal opacity].

Objective: To report the clinical results of pediatric penetrating keratoplasty (PKP) in patients under 3 years old with congenital corneal opacity. Methods: Retrospective study. Sixteen eyes of 12 patients who were treated with PKP in Aier Eye Hospital Group from June 2009 to December 2016 were enrolled in this study. All the patients were diagnosed as congenital corneal opacities: 8 cases (11 eyes) with Peter's anomaly I, 2 cases (3 eyes) with sclerocornea, and 2 cases (2 eyes) with corneal dermoid tumor combined with iris synechia. Seven cases (7 eyes) were under 1 year old. Eight cases (10 eyes) could not follow the light. Only 1 case (2 eyes) received PKP with extracapsular cataract extraction, and the others only had PKP. Postoperative examinations were performed more frequently than in adults, and sometimes general anesthesia was needed. Results: The follow-up period was from 8 months to 6 years (33.17±22.60 months). The postoperative visual acuity improvement was found in all eyes from 1 week to 1 month after surgery except a 3-year-old patient with corneal dermoid tumor with serious esotropia. All the surgeries were successful without intraoperative complications. Graft rejection occurred in 4 cases (4 eyes). The graft of a 33-month-old patient became semitransparent. The grafts of 2 cases under 1 year old were clear after drug therapy. And the vision of a 3-year-old patient with Peter anomaly improved obviously, but immune rejection occurred 2 years after surgery. The second PKP was performed, but rejection occurred again. Secondary glaucoma was found in the other eye early after operation; anti-glaucoma surgery failed, and the graft became cloudy. Graft infection associated with loosened sutures was observed in one case (2 eyes) of sclerocornea, and the second PKP failed. Conclusions: For the patients with congenital corneal opacities, there is often a noticeable visual improvement after PKP. Good postoperative care, appropriate amblyopia treatment and timely examination are the keys to success. (Chin J Ophthalmol, 2017, 53: 941-946).

Calcitonin alleviates hyperalgesia in osteoporotic rats by modulating serotonin transporter activity.

Calcitonin may relieve pain by modulating central serotonin activity. Calcitonin partly reversed the hypersensitivity to pain induced by ovariectomy. This suggests that the anti-nociceptive effects of calcitonin in the treatment of osteoporosis may be mediated by alterations in neural serotonin transporter (SERT) activity. INTRODUCTION: This study used a rat model of osteoporosis to evaluate the role of the cerebral serotonin system in the anti-nociceptive effect of calcitonin, a drug used to treat post-menopausal osteoporosis. METHODS: Osteoporosis was induced in rats by ovariectomy (OVX). Rats were then randomized to the following four groups: sham operation, OVX, OVX plus calcitonin, or OVX plus alendronate. RESULTS: OVX led to alterations in bone micro-architecture; alendronate strongly reversed this effect, and calcitonin moderately reversed this effect. OVX increased hyperalgesia (determined as the time for hind paw withdrawal from a heat source); calcitonin reduced this effect, but alendronate had no effect. OVX increased the expression of c-Fos (a neuronal marker of pain) in the thalamus; calcitonin strongly reversed this effect, and alendronate moderately reversed this effect. OVX also reduced SERT but increased 5-HT1A receptor expression and activity; calcitonin aggravated this effect, but alendronate had no effect on recovery of SERT/5-HT1A activity and expression. CONCLUSIONS: Our study of a rat model of osteoporosis suggests that OVX-induced enhancement of the serotonergic system may protect against hyperalgesia. However, the anti-nociceptive effects of calcitonin in osteoporosis may be mediated by decreased neural SERT activity and increased activation of 5-HT1 receptors in the thalamus.

[Estimation of underreporting rate of death cases in disease surveillance system of Fujian province using propensity score weighting method, 2012-2014].

Objective: To understand the underreporting of death cases and related factors in disease surveillance system of Fujian province. Methods: We carried out a field underreporting survey in 20 disease surveillance sites selected through stratified cluster random sampling during 2012-2014. The related factors of underreporting were analyzed by using logistic regression method. Propensity score weighting method was used to calculate the underreporting rate in different groups classified by year, urban/rural areas, gender, age and death cause variables. Results: The overall underreporting rate was 9.21%(95%CI: 9.06%-9.39%) after adjusting by propensity score weighting method. The underreporting rate was higher in rural area (11.55%, 95%CI: 11.30%-11.81%) than in urban area (6.64%, 95%CI: 6.50%-6.78%). The underreporting rate was highest in age group 0-14 years (36.29%, 95% CI: 34.23%-38.67%) and lowest in age group ≥65 years (7.91%, 95% CI: 7.78%-8.03%). The underreporting rate was higher in people died of perinatal disease, congenital anomalies and injury. Conclusion: The underreporting rates were different between different groups classified by urban/rural areas, age and death cause variables. Propensity score weighting method can be used to adjust underreporting rate of death cases in mortality surveillance in Fujian.

The effects of cleanroom noise intensity and frequency on physiological measures and subjective responses.

BACKGROUND: Workplace noise exposure gains growing attention in high tech industry. OBJECTIVE: This study investigated the noise effect on physiological and subjective responses in semiconductor manufacturing clean room environment. METHODS: Twenty subjects including 10 males and 10 females completed all phases of the experiment. Each subject was asked to participate in four treatment combinations of two noise intensities [65 dB(A) and 80 dB(A)] × two frequency levels [high and low]. For each treatment condition, the subject was exposed to the specified noise condition in a sound proof cabin for one hour. The physiological measures included blood pressure and heart rate. The subjective measures included noise sensitivity, fatigue and annoyance. RESULTS: The ANOVA results indicate that long-time noise exposure caused significant increase in blood pressure (p< 0.001). Furthermore, the noise intensity by time interaction effect was found to be significant on annoyance and fatigue. CONCLUSIONS: The findings suggest that prolonged exposure to noise intensity at 80 dB(A) would result in a significant increase in physiological cost and subjective discomfort feeling. Thus, some countermeasures should be taken to reduce noise exposure and to promote health, and quality of working life.

Myeloid lineage skewing due to exacerbated NF-κB signaling facilitates osteopenia in Scurfy mice.

Immune surveillance through Foxp3+ regulatory T cells plays a crucial role in bone homeostasis. Scurfy, the mouse model of autoimmune IPEX syndrome, bears a loss-of-function mutation in Foxp3 that leads to multi-organ inflammation. Herein, we report that scurfy mice exhibit severe bone loss mediated by accelerated osteoclastogenesis. Mechanistically, Foxp3 deficiency results in the upregulation of NF-κB in T helper cells through the loss of repressive Foxp3/NEMO interaction, thereby unleashing NF-κB-mediated over-production of pro-osteoclastogenic cytokines. Flow cytometry analysis shows marked increase in lin-Sca-1+c-kit+ hematopoietic stem cells (LSK HSCs) and granulocyte/macrophage progenitors (GMPs) in bone marrow of scurfy mice with corresponding exacerbated osteoclastogenic potential, implying that osteoclast progenitors are affected at a very primitive stage in this disorder. Scurfy LSK HSCs exhibit greater sensitivity to M-CSF and contain abundant PU.1+ Sf LSK HSCs compared with WT. Accordingly, genetic or pharmacological inhibition of M-CSF or mTOR signaling, but not IL-17 signaling, attenuates osteoclastogenesis and osteopenia in scurfy. Thus, our study suggests that Foxp3 deficiency leads to osteopenia owing to dysregulated NF-κB activity and subsequent cytokine-mediated hyper-proliferation of myeloid precursors, and positions the NF-κB pathway as a potential target for therapeutic intervention for this disorder.

KLHL39 suppresses colon cancer metastasis by blocking KLHL20-mediated PML and DAPK ubiquitination.

Cullin 3 (Cul3)-family ubiquitin ligases use the BTB-domain-containing proteins for the recruitment of substrates, but the regulation of this family of ubiquitin ligases has not been completely understood. KLHL20 is a BTB-family protein and targets tumor suppressor promyelocytic leukemia protein (PML) and death-associated protein kinase (DAPK) to its kelch-repeat domain for ubiquitination and degradation. Here, we show that another BTB-kelch protein KLHL39 is recruited to the substrate-binding domain of KLHL20 but is not a substrate of Cul3-KLHL20 complex. Interestingly, KLHL39 does not bind Cul3 because of the absence of certain conserved residues in the BTB domain. Instead, KLHL39 blocks KLHL20-mediated ubiquitination of PML and DAPK by disrupting the binding of these substrates to KLHL20 as well as the binding of KLHL20 to Cul3. Through the two mechanisms, KLHL39 increases the stability of PML and DAPK. In human colon cancers, downregulations of KLHL39, PML and DAPK are associated with metastatic progression. Furthermore, preclinical data indicate that KLHL39 promotes colon cancer migration, invasion and survival in vitro and metastasis in vivo through a PML- and DAPK-dependent mechanism. Our study identifies KLHL39 as a negative regulator of Cul3-KLHL20 ubiquitin ligase and reveals a role of KLHL39-mediated PML and DAPK stabilization in colon cancer metastasis.

Bcl-2 stabilization by paxillin confers 5-fluorouracil resistance in colorectal cancer.

5-Fluorouracil (5-FU) is chemotherapeutic agent widely used for the treatment of colorectal cancer. Unfortunately, advanced colorectal cancer is often resistance to such chemotherapy and poor outcome. An adaptor protein paxillin (PXN) is phosphorylated at Y31/Y118 (pPXN-Y31/Y118) by Src contributes to cell mobility and Ser (S)272 of PXN in LD4 domain is important to the interaction between PXN and Bcl-2. We thus hypothesized that pPXN-Y31/Y118 may be required for Bcl-2 protein stability via PXN interacting with Bcl-2 to confer 5-FU resistance in colorectal cancer. Mechanistically, pPXN-S272 is phosphorylated through pPXN-Y31/Y118-mediated p21 protein-activated kinase 1 (PAK1) activation and pPXN-S272 is required for PXN to interact with Bcl-2. The interaction between PXN and Bcl-2 is essential for Bcl-2 protein stability through phosphorylation of Bcl-2 at S87 (pBcl-2-S87) by pPXN-Y31/Y118-mediated ERK activation. An increase in Bcl-2 expression by PXN is responsible for resistance to 5-FU. The resistance to 5-FU can be abolished by inhibitor of Src and PAK1 or Bcl-2 antagonist in cell and animal models. Among patients, Bcl-2 expression is positively correlated with expression of PXN and pPXN-S272, respectively. Patients with high PXN/high Bcl-2 or high pPXN-S272/high Bcl-2 tumors are commonly to have an unfavorable response to 5-FU-based chemotherapy, compared with patients who have high PXN, high pPXN-S272 or high Bcl-2 tumors alone. Therefore, we suggest that Src, PAK1 or Bcl-2 inhibitor may potentially overcome the resistance of 5-FU-based chemotherapy and consequently to improve outcomes in patients with PXN/Bcl-2 and pPXN-S272/Bcl-2-positive tumors.

Novel loci associated with usual sleep duration: the CHARGE Consortium Genome-Wide Association Study.

Usual sleep duration is a heritable trait correlated with psychiatric morbidity, cardiometabolic disease and mortality, although little is known about the genetic variants influencing this trait. A genome-wide association study (GWAS) of usual sleep duration was conducted using 18 population-based cohorts totaling 47 180 individuals of European ancestry. Genome-wide significant association was identified at two loci. The strongest is located on chromosome 2, in an intergenic region 35- to 80-kb upstream from the thyroid-specific transcription factor PAX8 (lowest P=1.1 × 10(-9)). This finding was replicated in an African-American sample of 4771 individuals (lowest P=9.3 × 10(-4)). The strongest combined association was at rs1823125 (P=1.5 × 10(-10), minor allele frequency 0.26 in the discovery sample, 0.12 in the replication sample), with each copy of the minor allele associated with a sleep duration 3.1 min longer per night. The alleles associated with longer sleep duration were associated in previous GWAS with a more favorable metabolic profile and a lower risk of attention deficit hyperactivity disorder. Understanding the mechanisms underlying these associations may help elucidate biological mechanisms influencing sleep duration and its association with psychiatric, metabolic and cardiovascular disease.

Impaired thrombin generation in Reelin-deficient mice: a potential role of plasma Reelin in hemostasis.

BACKGROUND: Reelin is a large extracellular glycoprotein that is present in the peripheral blood. That Reelin interacts with the coagulation components and elicits a functional role in hemostasis has not yet been elucidated. OBJECTIVES: The hemostatic activity of Reelin is investigated and defined in this study. METHODS: The interplay of Reelin with coagulation components was elucidated by far-Western and liposome/platelet binding assays. In vivo and ex vivo hemostasis-related analyses of Reelin-deficient mice and plasma were also performed. RESULTS: Reelin interacted with the liposomes containing phosphatidylserine (PS) or phosphatidylcholine. Instead of interacting with known Reelin receptors (ApoE receptor 2, very low density lipoprotein receptor and integrin ß1), Reelin interacted with PS of the activated platelets. The interaction between Reelin and the coagulation factors of thrombin and FXa was also demonstrated with the Kd of 11.7 and 21.2 nm, respectively. Reelin-deficient mice displayed a prolonged bleeding time and an increase in rebleeding rate. Despite the fact that Reelin deficiency had no significant effect on the clotting time of prothrombin and activated partial thromboplastin time, the fibrin clot formation was abnormal and the fibrin clot structure was relatively loosened with reduced clot strength. Abnormal fibrinogen expression did not account for the hemostatic defects associated with Reelin deficiency. Instead, thrombin generation was impaired concomitant with an altered prothrombin cleavage pattern. CONCLUSIONS: By interacting with platelet phospholipids and the coagulation factors, thrombin and FXa, Reelin plays a selective role in coagulation activation, leading to thrombin generation and formation of a normal fibrin clot.