Post-infarction ventricular septal rupture complicated with cardiogenic shock and multiple organ hemorrhage: An autopsy case report.

Ventricular septal rupture (VSR) is a catastrophic mechanical complication of acute myocardial infarction (AMI) that can result in acute heart failure. Delaying operative intervention frequently leads to cardiogenic shock and multi-organ failure. Here we report a case of massive anterior MI complicated with VSR that was discovered through cardiac Doppler ultrasound and suspected multiple organ hemorrhage. The patient showed signs of rapid cardiogenic shock and eventually died. The morphological changes of VSR and MI were identified during necropsy, and microscopic examinations of the heart, brain, and kidney revealed multiple organ hemorrhage. This autopsy case suggested that the complication of VSR caused by AMI results in a reduction of oxygen and nutrient content of the circulating blood throughout the body and, eventually, functional failure of multiple organs. We provide clinical and pathological evidence elucidating changes in multiple organs under the severe condition of post-infarction VSR and demonstrate the consequences of a lack of immediate surgery and sufficient medical intervention for a patient suffering from AMI with VSR.

Clinical and genetic features of a case with juvenile onset sandhoff disease.

BACKGROUND: Sandhoff disease (SD) is a rare neurological disease with high clinical heterogeneity. SD in juvenile form is much rarer and it is often misdiagnosed in clinics. Therein, it is necessary to provide more cases and review the literature on juvenile onset SD. CASE PRESENTATION: A 14 years-old boy with eight years of walking difficulties, and was ever misdiagnosed as spinocerebellar ataxia. We found this patient after genetic testing carried rs201580118 and a novel gross deletion in HEXB (g.74012742_74052694del). Through review the literature, we found that was the first gross deletion identified at the 3'end of HEXB, associated with juvenile onset SD from China. CONCLUSION: This case expanded our knowledge about the genotype and phenotype correlations in SD. Comprehensive genetic testing is important for the diagnosis of unexplained ataxia.

CATRO: Channel Pruning via Class-Aware Trace Ratio Optimization.

Deep convolutional neural networks are shown to be overkill with high parametric and computational redundancy in many application scenarios, and an increasing number of works have explored model pruning to obtain lightweight and efficient networks. However, most existing pruning approaches are driven by empirical heuristics and rarely consider the joint impact of channels, leading to unguaranteed and suboptimal performance. In this article, we propose a novel channel pruning method via class-aware trace ratio optimization (CATRO) to reduce the computational burden and accelerate the model inference. Utilizing class information from a few samples, CATRO measures the joint impact of multiple channels by feature space discriminations and consolidates the layerwise impact of preserved channels. By formulating channel pruning as a submodular set function maximization problem, CATRO solves it efficiently via a two-stage greedy iterative optimization procedure. More importantly, we present theoretical justifications on convergence of CATRO and performance of pruned networks. Experimental results demonstrate that CATRO achieves higher accuracy with similar computation cost or lower computation cost with similar accuracy than other state-of-the-art channel pruning algorithms. In addition, because of its class-aware property, CATRO is suitable to prune efficient networks adaptively for various classification subtasks, enhancing handy deployment and usage of deep networks in real-world applications.

The characteristic of nonmotor symptoms with different phenotypes and onsets in multiple system atrophy patients.

OBJECTIVES: The characteristic of nonmotor symptoms in patients with multiple system atrophy (MSA) has varied among previous studies. The objective was to investigatethe nonmotor characteristics in MSA patients with different phenotypes, sex and different onset patterns. METHODS: We performed a retrospective review of 1492 MSA patients. All cases were evaluatedby neurologists and assessed with motormanifestations, nonmotor symptoms, auxiliary examinationand brain MRI scans. RESULTS: Multiple system atrophy-cerebellar ataxia (MSA-C) was the predominant phenotype in 998 patients. Average age of onset (56.8 ± 9.2 years) was earlier, the disease duration (2.4 ± 2.2 year) was shorter and brain MRI abnormalities (49.2 %) were more frequently in MSA-C (P < 0.001). Multiple system atrophy-parkinsonism (MSA-P) patients were more likely to have nonmotor symptoms. After adjusted significant parameters, urinary dysfunction (OR 1.441, 95 %CI = 1.067-1.946, P = 0.017), constipation (OR 1.482, 95 %CI = 1.113-1.973, P = 0.007), cognitive impairment (OR 1.509, 95 %CI = 1.074-2.121, P = 0.018) and drooling (OR 2.095, 95 %CI = 1.248-3.518, P = 0.005) were associated with the MSA-P phenotype. Males were more likely to have orthostatic hypotension, urinary dysfunction, sexual dysfunction, drooling and females in constipation and probable RBD. In different onset patterns, constipation (59.2 %) and probable RBD (28.4 %) were more frequently in autonomiconset pattern. CONCLUSIONS: MSA-C is the predominant phenotype in Chinese patients, while many nonmotor symptoms are more common in MSA-P phenotype. Patients with different sex and onset patterns have different nonmotor characteristics. The different clinical features identified could help the physician counseling of MSA patients more easily and more accurately.

Constructing a Surface Multi-cationic Heterojunction for CsPbI1.5Br1.5 Perovskite Solar Cells with Efficiency beyond 14.

All-inorganic CsPbI1.5Br1.5 perovskite solar cells are considered as top cell candidates for tandem cells as a result of their excellent thermal stability and photoelectric performance. However, their power conversion efficiencies (PCEs) are still low and far below the theoretical limit mainly as a result of the severe non-radiative recombination and optical loss. Herein, we introduce an versatile method to construct a surface multi-cationic heterojunction to achieve an efficient and stable CsPbI1.5Br1.5 perovskite solar cell. By precisely controlling the content of FA+ and MA+ on PbBr2-rich perovskite films, a high-quality heterojunction layer is formed to help effectively passivate the surface defects and reduce the optical loss of the CsPbI1.5Br1.5 perovskite. In addition, the incorporation of a heterojunction layer can also improve energy-level alignment and reduce interfacial charge recombination loss. As a result, the champion device with the incorporation of SMH exhibits a PCE of 14.11%, which presents the highest reported efficiency for inorganic CsPbI1.5Br1.5 solar cells thus far while retaining 85% of the initial efficiency after 1000 h of storage without encapsulation.

Neuropathological report of propionic acidemia.

Propionic acidemia (PA) is an autosomal recessive inheritable metabolic disease caused by mutations in the propionyl CoA carboxylase gene (PCC) that affects multiple systems of the human body. Here, we report neuropathological findings of a PA patient. The patient was a male infant who presented with increasing lethargy and poor feeding from four days postpartum. He gradually became comatose and died from complications after liver transplantation at three months old. The results of laboratory examination were consistent with PA, and genetic analysis revealed compound heterozygous mutations in the gene for PCC subunit beta: c.838dupC (rs769968548) and c.1127G>T (rs142982097). Brain-restricted autopsy was performed 23 h after his death, and the neuropathological examination revealed distinct astrocytosis, oligodendrocytic loss, neuronal loss, and demyelination across the brainstem, motor cortex, basal ganglia, and thalamus. Spongiosis, vacuolization, and the appearance of Alzheimer type II astrocytes and activated microglia were observed as well. This is the first brain autopsy report of PA with a clear genetic cause.

Frequency, Severity, and Duration of Autonomic Symptoms in Patients of Prodromal Dementia with Lewy Bodies.

BACKGROUND: Autonomic dysfunction is supportive clinical feature for diagnosis of prodromal dementia with Lewy bodies (DLB). OBJECTIVE: To compare the features of autonomic symptoms in patients with mild cognitive impairment (MCI) due to Lewy bodies (MCI-LB) and Alzheimer's disease (MCI-AD). METHODS: Autonomic symptoms were evaluated in the MCI-LB and MCI-AD patients using the Scales for Outcomes in Parkinson's disease for autonomic symptoms (SCOPA-AUT). RESULTS: Thirty patients with MCI-LB and 90 patients with MCI-AD were recruited. The frequency of autonomic dysfunction was higher in patients with MCI-LB compared to the MCI-AD patients (80% versus 54.4%, p = 0.013) and the gastrointestinal symptoms were predominant (73.3% versus 35.6%, p < 0.001). Salivation, constipation, incontinence, incomplete emptying, lightheadedness when standing up or standing for some times, diurnal or nocturnal hyperhidrosis, and sexual dysfunction were more severe and protracted in the MCI-LB group compared to the MCI-AD group. CONCLUSION: The MCI-LB patients showed higher frequency and severity, as well as longer duration of autonomic symptoms compared to the MCI-AD group. These symptoms can facilitate early diagnosis of patients with DLB.

Epidemiology of Constipation in Elderly People in Parts of China: A Multicenter Study.

Purpose: To investigate the epidemiological characteristics of constipation in people aged 65 years and older in several regions of China. Patients and Methods: A cross-sectional study based on a cluster sampling design was conducted in four cities of China: Tianjin, Xiamen, Cangzhou and Harbin. A total of 5,222 cases (age ≥ 65 years) were recruited, and the survey was conducted via centralized and household questionnaires that included the following: basic demographic characteristics such as sex, age, education, marital status, living status and occupation; social activities; duration of sleep at night; duration of menstruation and delivery times (in females); and if the participant had constipation symptoms, the severity of constipation. Constipation was diagnosed according to the Rome IV criteria. Results: Of the 5,222 participants, 919 were diagnosed with constipation. The prevalence of constipation was 17.60% in elderly people ≥65 years old. Prevalence increased with age and was significantly higher in females than males (P < 0.05). Prevalence was lower in the manual compared to the non-manual worker group, and significantly increased with decreasing duration of night sleep (P < 0.05). Older age, female sex and shorter sleep duration at night were risk factors for constipation in elderly people. Conclusion: The prevalence of constipation in the elderly people in four cities of China was 17.60%, and was significantly affected by age, sex and sleep duration at night.

Simulation of heavy metals behaviour during Co-processing of fly ash from municipal solid waste incineration with cement raw meal in a rotary kiln.

Fly ash produced from incineration of municipal solid wastes (MSW) contains heavy metals, such as Cd and Pb, that make this material difficult to manage and dispose of safely. Because the composition of fly ash is similar to cement raw meal, partial replacement of raw meal with fly ash may be a feasible way to reduce the health and environmental hazards of the ash, provided that the heavy metals can be effectively stabilized in the solid phase. This research employs proprietary thermochemical software to simulate the thermodynamic behavior and single-step fixation of Cd and Pb in industrial cement kilns. The effect of Cd, Pb and Cl loadings on the fixation and/or evaporation of Cd and Pb during the sintering process is analyzed using data from industrial cement kilns. A simplified model is created based on elemental mass balance to evaluate multi-step fixation of Cd and Pb with cement kiln dust recycle.The results indicate that Cd forms Cd(OH)2(g) in a highly alkaline environment, while nearly 90% Pb is volatilized as PbCl2(g). In the clinker, increased Cl-1 decreased the proportion of Pb and Cd, moreover, Pb and Cd increased in kiln dust with Cl-1 increased; Calculations using a kiln dust recycle model showed that, the concentrations of Pb and Cd in both kiln dust and clinker increased sharply after recycling of kiln dust in steady state. Under unstable conditions, the concentrations of Pb and Cd in kiln dust increased, as well as the heavy metals re-entering the cement kiln.

Genetic and Molecular Evaluation of SQSTM1/p62 on the Neuropathologies of Alzheimer's Disease.

Sequestosome 1 (SQSTM1)/p62 is a multifunctional scaffolding protein and plays a major role in the cellular processes of autophagy, upregulation of which has been shown in several neurodegenerative disorders, including Alzheimer's disease (AD). To investigate its genetic effects and relationship with AD pathologies, we analyzed the genetic associations of SQSTM1 rs4935 with the risk of AD and the levels of AD biomarkers using the AD Neuroimaging Initiative (ADNI) Database. We further analyzed the distribution pattern of p62 immunoreactivity in relation to AD pathologies in the postmortem human brain tissues from AD and non-AD controls. We found that SQSTM1 rs4935 was not associated with the risk of AD, but its T allele was significantly associated with decreased ß-amyloid (1-42) (Aß42) levels in the cerebral spinal fluid (CSF) of patients with AD (ß = -9.336, p = 0.022). In addition, p62 immunoreactivity in AD is increased, but it shows an inverse relationship to Aß deposition. A small proportion of senile plaques show p62 positive neurites. Our results suggest that SQSTM1/p62 may play an important role in the progression of AD via associations with Aß42 levels in CSF and Aß deposition in the brain of patients with AD.

Prevalence and risk factors of stroke in a rural area of northern China: a 10-year comparative study.

BACKGROUND AND AIMS: Stroke is currently the leading cause of death in China; however, the past decade has produced no new epidemiological studies of stroke. Therefore, the current study aimed to compare the prevalence and risk factors of stroke between 2010 and 2019. METHODS: A comparative study was used to analyze the prevalence of risk factors for stroke in a population aged 65 years or older between 2010 and 2019. Demographic characteristics, risk factors, medical history, and other clinical characteristics were collected for all participants via door-to-door interviews and inpatient hospital records. RESULTS: The standardized prevalence of stroke was 7.9% in 2010 and 14.2% in 2019 (p < 0.001). The prevalence of stroke was significantly higher in men than in women (p < 0.05) for all age groups. The risk factors of stroke were being male, hypertension, and diabetes mellitus in both 2010 and 2019. When comparing the risk factors between 2010 and 2019, these risk factors were statistically significantly more strongly associated with stroke in 2019 than in 2010. CONCLUSION: The current study suggests that the prevalence of stroke increased nearly by twofold in a population aged 65 years or older within the past 10 years. Hypertension, diabetes mellitus, and being male were the primary risk factors. In addition, these factors were more significantly associated with stroke in 2019 compared to 2010.

Autonomic symptoms are predictive of dementia with Lewy bodies.

INTRODUCTION: Autonomic symptoms are common in patients with dementia with Lewy bodies (DLB). Although autonomic dysfunction is considered as one of the primary early markers in patients with DLB, there are few studies that examine the timing of the onset of autonomic symptoms in these patients. The purpose of the current study was to evaluate the time of onset of autonomic symptoms in patients with DLB using a questionnaire. METHODS: Autonomic symptoms were evaluated in patients with DLB using the Scales for Outcomes in Parkinson's disease - autonomic (SCOPA-Aut) questionnaire. Time of the onset of autonomic symptoms of patients with DLB was also assessed relative to that of memory loss. RESULTS: A total of 106 patients with DLB were included. The most frequent symptom of dysautonomia in patients with DLB was constipation (60.4%), followed by orthostatic dizziness (33%), urinary frequency (30.2%), and daytime hyperhidrosis (22.6%). The gastrointestinal system was the most prominent system of autonomic dysfunction in patients with DLB. Orthostatic dizziness, daytime hyperhidrosis, and constipation all preceded the onset of memory loss by 0.2 ± 4.9, 3.3 ± 8.6, and 3.7 ± 9.2 years, respectively, while urinary incontinence occurred 1.7 ± 1.5 years following the onset of memory loss. CONCLUSION: Many autonomic symptoms precede the onset of memory loss in patients with DLB, especially constipation and daytime hyperhidrosis. These symptoms can facilitate an early diagnosis of patients with DLB.

Non-motor symptoms in multiple system atrophy: A comparative study with Parkinson's disease and progressive supranuclear palsy.

Background: Non-motor symptoms (NMS) are compulsory clinical features for the clinical diagnosis of multiple system atrophy (MSA), some of which precede motor symptoms onset. To date, few studies have systematically investigated NMS in MSA and the timing of presenting NMS as the disease progresses. Clinically, MSA is difficult to be differentiated from Parkinson's disease (PD) and progressive supranuclear palsy (PSP), and the differences in NMS between MSA and PD/PSP remain unclear. The aim of this study was to compare the burden of NMS between MSA and PD/PSP and to delineate the timing of NMS presentation relative to the onset of motor symptoms in MSA. Methods: A total of 61, 87, and 30 patients with MSA, PD, and PSP, respectively, were enrolled in this study. NMS was systematically assessed in all patients using the NMS scale (NMSS), and the onset of NMS relative to the onset of motor symptoms in MSA was investigated. Results: MSA group had higher total NMSS scores (82.15 ± 46.10) than the PD (36.14 ± 30.78) and PSP (50.30 ± 55.05) groups (p < 0.001 overall). The number distribution pattern of the NMS was significantly different among the three parkinsonian disorders (p < 0.001 overall). In total, 85.2% of patients with MSA had more than 10 NMS, which was significantly higher than PD (28.7%) and PSP (33.3%). The frequency and scores of many NMSS subdomains and symptoms were higher in MSA than in PD and PSP (all p < 0.05). Multivariate logistic regression analysis revealed that patients with fainting, lack of motivation, swallowing, and loss of sexual interest could be attributed to MSA rather than PD or PSP, while patients with loss of concentration and forgetfulness were characteristic features of PD or PSP rather than MSA. REM-sleep behavior disorder (RBD), constipation, problems having sex, and loss of sexual interest preceded the motor symptoms onset of MSA by 2.81 ± 4.51, 1.54 ± 6.32, 1.35 ± 4.70, and 0.45 ± 3.61 years, respectively. Conclusion: The NMS spectrum in MSA differs from that of PD and PSP. Patients with MSA have a higher NMS burden than patients with PD or PSP. RBD, constipation, problems having sex, and loss of sexual interest may become early diagnostic clinical markers of MSA.

Association of Elevated Plasma Total Homocysteine With Dementia With Lewy Bodies: A Case-Control Study.

Background: Elevated plasma total homocysteine (tHcy) level, a known risk factor for vascular disease, is reported to be an independent risk factor for cognitive impairment and Alzheimer's disease (AD) in most studies. tHcy may also be associated with dementia with Lewy bodies (DLB). Objective: To investigate the association between plasma tHcy levels and DLB or AD. Methods: This is a case-control study including 132 DLB patients, 264 AD patients, and 295 age-matched healthy controls. We used multivariate logistic regression model to analyze the data with adjustments for confounding variables. Results: The highest tHcy tertile (>13.9 µmol/L) was significantly independently associated with DLB [adjusted odds ratio (OR): 4.65, 95% confidence interval (CI): 1.95-11.10, P = 0.001] and AD (adjusted OR: 1.82, 95% CI: 1.02-3.23, P = 0.041) compared to the lowest tertile (<10.7 µmol/L). The cumulative frequency plots showed a shift in the distribution of the tHcy concentrations to higher values in patients with DLB compared to AD. The mean tHcy levels were stable and not altered by the duration of cognitive impairment prior to the collection of blood samples from DLB patients. Conclusion: Elevated plasma tHcy levels were independently associated with DLB, and the association was stronger for DLB than for AD. The lack of a relationship between tHcy levels and symptom duration may refute these observed associations being a consequence of DLB, and future longitudinal studies will be required to confirm whether tHcy plays a causative role in DLB.

The Association Between Hyperhidrosis and Dementia: A Community-Based Research.

BACKGROUND: Dementia and hyperhidrosis (HH) are common in the elderly while there is little research to investigate the association between them. OBJECTIVE: To clarify a possible association between HH and dementia in population of adults ≥65 years old in China. METHODS: A cross-sectional survey for elderly adults ≥65 years old was conducted from April to December 2019. A total of 5,958 participants were analyzed after two phases investigation. Goodness-of-fit tests (Pearson and deviance) were used to estimate the dispersion parameter and examine the adequacy of the models. Logistic and linear regression analyses were used to evaluate the association between HH and dementia. RESULTS: The overall prevalence of all-cause dementia was 10.17%, that of dementia with Lewy bodies (DLB) was 1.41%, and HH was 14.97%. Prevalence rates of HH were higher in participants with dementia and DLB. There was a significant positive relationship between HH duration and MMSE score (r = 0.207, p < 0.001, Durbin-Watson test = 1.806). Participants with HH were 1.275 (95% CI: 1.015-1.601, p = 0.037) times to have dementia, and 3.616 (95% CI: 2.267-5.767, p < 0.001) times to suffer from DLB than those without HH. Pearson and deviance chi square tests did not indicate overdispersion (p > 0.05 in the logistic regression models). CONCLUSION: HH was common in the Chinese population ≥65 years old. It can increase the risk of dementia, particularly in DLB, in the elderly. It is important to improve the awareness of HH among dermatologists and neurologists.

A field study of dioxins during co-processing of hazardous waste in multicomponent slurry gasifier.

A field test was conducted to study the emission and distribution characteristics of dioxins during co-processing of hazardous waste in a multicomponent slurry gasifier (MCSG). The toxicity equivalent concentrations of polychlorinated dibenzo-p-dioxins (PCDDs) and polychlorinated dibenzofurans (PCDFs) in all exhaust gas, waste water, and solid waste under both blank condition (i.e., feedstock was normal coal-water slurry) and test condition (i.e., feedstock mixed with hazardous waste and labeling reagents) were analyzed. Results showed that organic matter was fully degraded in the MCSG. The dioxin amount in the black water flash steam increased with the addition of hazardous waste and chlorine in the feedstock, and octachlorodibenzo-p-dioxins (OCDD) with the largest increase is the most easily formed monomer in dioxins. The dioxin amount in all samples was far below the standard limit in China and other countries. This indicates the low environmental risk from dioxins during the co-processing process. The dioxin distribution trend in solid, liquid, and gas phase during co-processing did not change: 86.63%-94.18%, 0.02%-0.13%, and 5.8%-13.23% of PCDDs were distributed in the exhaust gas, waste water, and solid waste, respectively, while 6.10%-22.95%, 0.59%-0.80%, and 76.45%-93.10% of PCDFs were distributed in the exhaust gas, waste water, and solid waste, respectively.

Prevalence of Constipation in Elderly and Its Association With Dementia and Mild Cognitive Impairment: A Cross-Sectional Study.

BACKGROUND: Constipation and dementia have similar epidemiological characteristics. Changes in intestinal flora and characteristics of the brain-gut axis play roles in the pathogeneses of the two diseases, suggesting that there may be a close connection between the two. Most of the studies on constipation in dementia patients have focused on the population with α-synucleinopathies [Parkinson's disease dementia (PDD), dementia with Lewy bodies (DLB)]. Few studies have reported the prevalence of constipation in all-cause dementia and mild cognitive impairment (MCI) populations. OBJECTIVE: To assess the prevalence of constipation in patients with all-cause dementia and MCI subtypes and to explore the association between constipation with dementia and MCI subtypes. METHODS: From May 2019 to December 2019, we conducted a population-based cross-sectional survey. A total of 11,743 participants aged 65 or older from nine cities in China were surveyed. Participants underwent a series of clinical examinations and neuropsychological measurements. Constipation, dementia, MCI and MCI subtype were diagnosed according to established criteria through standard diagnostic procedures. RESULTS: The overall age- and sex-adjusted prevalence of constipation in individuals aged 65 years and older was 14.8% (95% CI, 14.6-15.0). The prevalence rates of constipation were19.2% (95% CI, 17.3-21.0), 19.1% (95% CI, 16.8-21.5), 14.4% (95% CI, 12.8-15.9), and 13.8% (95% CI, 13.0-14.6) in the dementia, non-amnestic (na)-MCI, amnestic (a)-MCI and normal cognition populations, respectively. Multivariate logistic regression analysis showed that higher prevalence of constipation was associated with dementia (p = 0.0.032, OR = 1.18, 95% CI: 1.02-1.38) and na-MCI (p = 0.003, OR = 1.30, 95% CI: 1.09-1.54). CONCLUSION: The present study found a high prevalence of constipation in elderly individuals in China, and higher in patients with dementia and na-MCI.

The Impact of Rotating Night Shift Work and Daytime Recharge on Cognitive Performance Among Retired Nurses.

INTRODUCTION: The exact relationship between long-term shift work (SW) and cognitive impairment (CI) has been poorly understood. The effects of the long-term rotating night SW (RNSW) combining daytime recharge (DTR) on cognitive function were investigated. METHODS: A total 920 retired nurses and 656 retired female teachers aged ≥50 years were analyzed. Participants who worked at least once per week for 8 hat night for more than 1 year were defined as the SW group, and those without a regular nighttime shift were defined as the control group. The associations among duration, frequency, and DTR of RNSW, and neuropsychological assessments were ascertained by regression models. RESULTS: Participants with RNSW had a significantly higher proportion of mild CI (MCI), both amnestic MCI (aMCI) (14.4% in 11-20 years, p < 0.05, and 17.8% in > 20 years, p < 0.001) and non-amnestic MCI (naMCI) (8.1% in 11-20 years, p < 0.05), as well as dementia (1.5% in 1-10 years, and 11.7% in > 20 years, p < 0.05) compared to controls (8.4% with aMCI, 4.4% with naMCI, and 7.0% with dementia, respectively). There were significant negative relationships between general times of night SW and scores of Mini-Mental State Examination (MMSE) (R squared = 0.01, p = 0.0014) and Montreal Cognitive Assessment (MoCA) (R squared = 0.01, p = 0.0054). Participants with ≥1 h of DTR and ≥ 11 years of RNSW were about 2-fold more likely to experience MCI compared with the subjects in the control group, especially with 3-5 h (odds ratio [OR]: 2.35; 95% confidence interval: 1.49-3.68, p < 0.001). CONCLUSION: The long-term RNSW was associated with a higher risk of CI, especially aMCI and dementia, and the problem cannot be improved by DTR.

A Second Generation Prostanoid Receptor Antagonist Acting at Multiple Receptor Subtypes.

It has previously been reported that a prototypical compound (AGN 211377), which blocks pro-inflammatory prostanoid receptors (DP1, DP2, EP1, EP4, FP, TP) and leaves open IP and EP2 receptors so that their anti-inflammatory properties could be exerted, produced superior inhibitory effects on cytokine release from human macrophages compared to cyclooxygenase (COX) inhibitors. This favorable activity profile translated into animal studies, with AGN 211377 exceeding the level of inhibition afforded by COX inhibition. AGN 211377 was not, however, a practical drug candidate, having poor bioavailability and cost of goods concerns. Compound 1 (designated AGN 225660) represents a second-generation compound with an entirely different "druggable" core structure. Such a dramatic change in chemical scaffold created uncertainty with respect to matching the effects of AGN 211377. AGN 225660 inhibited RANTES, IL-8, and MCP-1 secretion by at least 50%, from TNFα activated human macrophages. Although AGN 225660 reduced TNFα-evoked MCP-1 release from human monocyte-derived macrophages, it increased LPS-induced MCP-1 secretion (up to 2-fold) from human monocyte-derived dendritic cells. However, AGN 225660 inhibited the release of IL12p 70 and IL-23 from human monocyte-derived dendritic cells stimulated by LPS by more than 70%. This effect of AGN 225660 was reproduced in part by the prototype compound AGN 211377 and a combination of selective DP1, EP1, EP4, FP, and TP antagonists. These findings suggest important effects on T cell skewing and disease modification by this class of therapeutic agents. AGN 225660 exhibited good ocular bioavailability and was active in reducing ocular inflammation associated with phacoemulsification surgery, LPS, and arachidonic acid induced uveitis.