Loganin Exerts Sedative and Hypnotic Effects via Modulation of the Serotonergic System and GABAergic Neurons

Corni fructus, the fruit of Cornus officinalis Sieb. et Zucc., has been used as a tonic for the kidney in China for thousands of years. Loganin is one of the major constituents derived from Corni fructus. In this study, we revealed the sedative and hypnotic activity of loganin and investigated its mechanisms for the first time. Pentobarbital-induced sleep test and insomnia mice models [induced by caffeine and p-chlorophenylalanine (PCPA)] were used for the assessment of sedative and hypnotic effects of loganin. It was found that loganin (20–50 mg/kg) exerted sedative effect in normal mice. Loganin exhibited hypnotic effect by increasing sleep onset and sleep duration in pentobarbital-treated mice, recovering PCPA-induced insomnia and exerting synergistic hypnosis effect with 5-HTP. In addition, electroencephalograph (EEG) and electromyography (EMG) recordings of rats showed that loganin (35 mg/kg) prolonged the ratio of non-rapid eye movement (NREM) sleep and shortened wakefulness significantly, further immunohistochemistry showed that loganin (35 mg/kg) increased c-Fos expression in GABAergic neurons of rats in the ventrolateral preoptic nucleus (VLPO). The levels of norepinephrine (NE), dopamine (DA), serotonin (5-HT) and its metabolite were measured in the hippocampus, prefrontal cortex and striatum of mice, 1 h after loganin (35 mg/kg) treatment. 5-HT, 5-HIAA/5-HT, DA, and DOPAC were decreased significantly in the prefrontal cortex. In conclusion, these results indicated that loganin produced beneficial sedative and hypnotic activity, which might be mainly mediated by modification of the serotonergic system and GABAergic neurons

Do asian patients require only half of the clozapine dose prescribed for caucasians? A critical overview

© 2020 Indian Psychiatric Society - South Zonal Branch | Published by Wolters Kluwer - Medknow. Since 1997, studies have found that Asians need lower clozapine doses than Caucasians. Caucasians with average clozapine metabolism may need from 300 to 600 mg/day to reach the therapeutic range (350 ng/ml). Thus, serum clozapine concentration-to-dose (C/D) ratios typically range between 0.60 (male smokers) and 1.20 (female non-smokers). A 2019 systematic review of clozapine levels demonstrated weighted mean C/D ratios of 1.57 in 876 East Asians and 1.07 in 1147 Caucasians (

Liposarcoma: exploration of clinical prognostic factors for risk based stratification of therapy

<p>Abstract</p> <p>Background</p> <p>Prognosis and optimal treatment strategies of liposarcoma have not been fully defined. The purpose of this study is to define the distinctive clinical features of liposarcomas by assessing prognostic factors.</p> <p>Methods</p> <p>Between January 1995 and May 2008, 94 liposarcoma patients who underwent surgical resection with curative intent were reviewed.</p> <p>Results</p> <p>Fifty patients (53.2%) presented with well differentiated, 22 (23.4%) myxoid, 15 (16.0%) dedifferentiated, 5 (5.3%) round cell, and 2 (2.1%) pleomorphic histology. With the median 14 cm sized of tumor burden, about half of the cases were located in the retroperitoneum (46.8%). Seventy two (76.6%) patients remained alive with 78.1%, and 67.5% of the 5- and 10-year overall survival (OS) rates, respectively. Low grade liposarcoma (well differentiated and myxoid) had a significantly prolonged OS and disease free survival (DFS) with adjuvant radiotherapy when compared with those without adjuvant radiotherapy (5-year OS, 100% vs 66.3%, P = 0.03; 1-year DFS, 92.9% <it>vs </it>50.0%, respectively, P = 0.04). Independent prognostic factors for OS were histologic variant (P = 0.001; HR, 5.1; 95% CI, 2.0 – 12.9), and margin status (P = 0.005; HR, 4.1; 95% CI, 1.6–10.5). We identified three different risk groups: group 1 (n = 66), no adverse factors; group 2, one or two adverse factors (n = 28). The 5-year OS rate for group 1, and 2 were 91.9%, 45.5%, respectively.</p> <p>Conclusion</p> <p>The histologic subtype, and margin status were independently associated with OS, and adjuvant radiotherapy seems to confer survival benefit in low grade tumors. Our prognostic model for primary liposarcoma demonstrated distinct three groups of patients with good prognostic discrimination.</p

Heterodimerization of Glycosylated Insulin-Like Growth Factor-1 Receptors and Insulin Receptors in Cancer Cells Sensitive to Anti-IGF1R Antibody

Identification of predictive biomarkers is essential for the successful development of targeted therapy. Insulin-like growth factor 1 receptor (IGF1R) has been examined as a potential therapeutic target for various cancers. However, recent clinical trials showed that anti-IGF1R antibody and chemotherapy are not effective for treating lung cancer.In order to define biomarkers for predicting successful IGF1R targeted therapy, we evaluated the anti-proliferation effect of figitumumab (CP-751,871), a humanized anti-IGF1R antibody, against nine gastric and eight hepatocellular cancer cell lines. Out of 17 cancer cell lines, figitumumab effectively inhibited the growth of three cell lines (SNU719, HepG2, and SNU368), decreased p-AKT and p-STAT3 levels, and induced G 1 arrest in a dose-dependent manner. Interestingly, these cells showed co-overexpression and altered mobility of the IGF1R and insulin receptor (IR). Immunoprecipitaion (IP) assays and ELISA confirmed the presence of IGF1R/IR heterodimeric receptors in figitumumab-sensitive cells. Treatment with figitumumab led to the dissociation of IGF1-dependent heterodimeric receptors and inhibited tumor growth with decreased levels of heterodimeric receptors in a mouse xenograft model. We next found that both IGF1R and IR were N-linked glyosylated in figitumumab-sensitive cells. In particular, mass spectrometry showed that IGF1R had N-linked glycans at N913 in three figitumumab-sensitive cell lines. We observed that an absence of N-linked glycosylation at N913 led to a lack of membranous localization of IGF1R and figitumumab insensitivity.The data suggest that the level of N-linked glycosylated IGF1R/IR heterodimeric receptor is highly associated with sensitivity to anti-IGF1R antibody in cancer cells

Robust estimation of bacterial cell count from optical density

Optical density (OD) is widely used to estimate the density of cells in liquid culture, but cannot be compared between instruments without a standardized calibration protocol and is challenging to relate to actual cell count. We address this with an interlaboratory study comparing three simple, low-cost, and highly accessible OD calibration protocols across 244 laboratories, applied to eight strains of constitutive GFP-expressing E. coli. Based on our results, we recommend calibrating OD to estimated cell count using serial dilution of silica microspheres, which produces highly precise calibration (95.5% of residuals &lt;1.2-fold), is easily assessed for quality control, also assesses instrument effective linear range, and can be combined with fluorescence calibration to obtain units of Molecules of Equivalent Fluorescein (MEFL) per cell, allowing direct comparison and data fusion with flow cytometry measurements: in our study, fluorescence per cell measurements showed only a 1.07-fold mean difference between plate reader and flow cytometry data

Joint analysis of three genome-wide association studies of esophageal squamous cell carcinoma in Chinese populations

We conducted a joint (pooled) analysis of three genome-wide association studies (GWAS) 1-3 of esophageal squamous cell carcinoma (ESCC) in ethnic Chinese (5,337 ESCC cases and 5,787 controls) with 9,654 ESCC cases and 10,058 controls for follow-up. In a logistic regression model adjusted for age, sex, study, and two eigenvectors, two new loci achieved genome-wide significance, marked by rs7447927 at 5q31.2 (per-allele odds ratio (OR) = 0.85, 95% CI 0.82-0.88; P=7.72x10−20) and rs1642764 at 17p13.1 (per-allele OR= 0.88, 95% CI 0.85-0.91; P=3.10x10−13). rs7447927 is a synonymous single nucleotide polymorphism (SNP) in TMEM173 and rs1642764 is an intronic SNP in ATP1B2, near TP53. Furthermore, a locus in the HLA class II region at 6p21.32 (rs35597309) achieved genome-wide significance in the two populations at highest risk for ESSC (OR=1.33, 95% CI 1.22-1.46; P=1.99x10−10). Our joint analysis identified new ESCC susceptibility loci overall as well as a new locus unique to the ESCC high risk Taihang Mountain region

Global, regional, and national comparative risk assessment of 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks, 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015

Forouzanfar MH, Afshin A, Alexander LT, et al. Global, regional, and national comparative risk assessment of 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks, 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015. LANCET. 2016;388(10053):1659-1724.Background The Global Burden of Diseases, Injuries, and Risk Factors Study 2015 provides an up-to-date synthesis of the evidence for risk factor exposure and the attributable burden of disease. By providing national and subnational assessments spanning the past 25 years, this study can inform debates on the importance of addressing risks in context. Methods We used the comparative risk assessment framework developed for previous iterations of the Global Burden of Disease Study to estimate attributable deaths, disability-adjusted life-years (DALYs), and trends in exposure by age group, sex, year, and geography for 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks from 1990 to 2015. This study included 388 risk-outcome pairs that met World Cancer Research Fund-defined criteria for convincing or probable evidence. We extracted relative risk and exposure estimates from randomised controlled trials, cohorts, pooled cohorts, household surveys, census data, satellite data, and other sources. We used statistical models to pool data, adjust for bias, and incorporate covariates. We developed a metric that allows comparisons of exposure across risk factors-the summary exposure value. Using the counterfactual scenario of theoretical minimum risk level, we estimated the portion of deaths and DALYs that could be attributed to a given risk. We decomposed trends in attributable burden into contributions from population growth, population age structure, risk exposure, and risk-deleted cause-specific DALY rates. We characterised risk exposure in relation to a Socio-demographic Index (SDI). Findings Between 1990 and 2015, global exposure to unsafe sanitation, household air pollution, childhood underweight, childhood stunting, and smoking each decreased by more than 25%. Global exposure for several occupational risks, high body-mass index (BMI), and drug use increased by more than 25% over the same period. All risks jointly evaluated in 2015 accounted for 57.8% (95% CI 56.6-58.8) of global deaths and 41.2% (39.8-42.8) of DALYs. In 2015, the ten largest contributors to global DALYs among Level 3 risks were high systolic blood pressure (211.8 million [192.7 million to 231.1 million] global DALYs), smoking (148.6 million [134.2 million to 163.1 million]), high fasting plasma glucose (143.1 million [125.1 million to 163.5 million]), high BMI (120.1 million [83.8 million to 158.4 million]), childhood undernutrition (113.3 million [103.9 million to 123.4 million]), ambient particulate matter (103.1 million [90.8 million to 115.1 million]), high total cholesterol (88.7 million [74.6 million to 105.7 million]), household air pollution (85.6 million [66.7 million to 106.1 million]), alcohol use (85.0 million [77.2 million to 93.0 million]), and diets high in sodium (83.0 million [49.3 million to 127.5 million]). From 1990 to 2015, attributable DALYs declined for micronutrient deficiencies, childhood undernutrition, unsafe sanitation and water, and household air pollution; reductions in risk-deleted DALY rates rather than reductions in exposure drove these declines. Rising exposure contributed to notable increases in attributable DALYs from high BMI, high fasting plasma glucose, occupational carcinogens, and drug use. Environmental risks and childhood undernutrition declined steadily with SDI; low physical activity, high BMI, and high fasting plasma glucose increased with SDI. In 119 countries, metabolic risks, such as high BMI and fasting plasma glucose, contributed the most attributable DALYs in 2015. Regionally, smoking still ranked among the leading five risk factors for attributable DALYs in 109 countries; childhood underweight and unsafe sex remained primary drivers of early death and disability in much of sub-Saharan Africa. Interpretation Declines in some key environmental risks have contributed to declines in critical infectious diseases. Some risks appear to be invariant to SDI. Increasing risks, including high BMI, high fasting plasma glucose, drug use, and some occupational exposures, contribute to rising burden from some conditions, but also provide opportunities for intervention. Some highly preventable risks, such as smoking, remain major causes of attributable DALYs, even as exposure is declining. Public policy makers need to pay attention to the risks that are increasingly major contributors to global burden. Copyright (C) The Author(s). Published by Elsevier Ltd