Discovery of new genetic loci for male sexual orientation in Han population.

Epidemiological studies have demonstrated that the genetic factors partly influence the development of same-sex sexual behavior, but most genetic studies have focused on people of primarily European ancestry, potentially missing important biological insights. Here, we performed a two-stage genome-wide association study (GWAS) with a total sample of 1478 homosexual males and 3313 heterosexual males in Han Chinese populations and identified two genetic loci (rs17320865, Xq27.3, FMR1NB, Pmeta = 8.36 × 10-8, OR = 1.29; rs7259428, 19q12, ZNF536, Pmeta = 7.58 × 10-8, OR = 0.75) showing consistent association with male sexual orientation. A fixed-effect meta-analysis including individuals of Han Chinese (n = 4791) and European ancestries (n = 408,995) revealed 3 genome-wide significant loci of same-sex sexual behavior (rs9677294, 2p22.1, SLC8A1, Pmeta = 1.95 × 10-8; rs2414487, 15q21.3, LOC145783, Pmeta = 4.53 × 10-9; rs2106525, 7q31.1, MDFIC, Pmeta = 6.24 × 10-9). These findings may provide new insights into the genetic basis of male sexual orientation from a wider population scope. Furthermore, we defined the average ZNF536-immunoreactivity (ZNF536-ir) concentration in the suprachiasmatic nucleus (SCN) as lower in homosexual individuals than in heterosexual individuals (0.011 ± 0.001 vs 0.021 ± 0.004, P = 0.013) in a postmortem study. In addition, compared with heterosexuals, the percentage of ZNF536 stained area in the SCN was also smaller in the homosexuals (0.075 ± 0.040 vs 0.137 ± 0.103, P = 0.043). More homosexual preference was observed in FMR1NB-knockout mice and we also found significant differences in the expression of serotonin, dopamine, and inflammation pathways that were reported to be related to sexual orientation when comparing CRISPR-mediated FMR1NB knockout mice to matched wild-type target C57 male mice.

Changes of Hypocretin (Orexin) System in Schizophrenia: From Plasma to Brain.

Hypocretin (also called orexin) regulates various functions, such as sleep-wake rhythms, attention, cognition, and energy balance, which show significant changes in schizophrenia (SCZ). We aimed to identify alterations in the hypocretin system in SCZ patients. We measured plasma hypocretin-1 levels in SCZ patients and healthy controls and found significantly decreased plasma hypocretin-1 levels in SCZ patients, which was mainly due to a significant decrease in female SCZ patients compared with female controls. In addition, we measured postmortem hypothalamic hypocretin-1-immunoreactivity (ir), ventricular cerebrospinal fluid (CSF) hypocretin-1 levels, and hypocretin receptor (Hcrt-R) mRNA expression in the superior frontal gyrus (SFG) in SCZ patients and controls We observed a significant decrease in the amount of hypothalamic hypocretin-1 ir in SCZ patients, which was due to decreased amounts in female but not male patients. Moreover, Hcrt-R2 mRNA in the SFG was decreased in female SCZ patients compared with female controls, while male SCZ patients showed a trend of increased Hcrt-R1 mRNA and Hcrt-R2 mRNA expression compared with male controls. We conclude that central hypocretin neurotransmission is decreased in SCZ patients, especially female patients, and this is reflected in the plasma.

Tuning chain extender structure to prepare high-performance thermoplastic polyurethane elastomers.

In this work, a novel strategy is developed to solve the issue of mutually exclusive high mechanical robustness and thermo-stability for thermoplastic polyurethane (PU). A leaf-like and reticulate interfingering superstructure can be seen. The superstructure of polyurethanes can also be tuned by the polarity of chain extender molecular via changing the number for ferrocene redox centres, thus to further enhance the thermal stability and elasticity of PUs. As a result, by incorporating bisferrocene units into the main chain of PU, a high-performance PU elastomer can be synthesized with a highest initial degradation temperature of T 5% of 345 °C, a highest tensile strength of 42.3 MPa with an elongation over 1000%, as well as a toughness of 19.6 GJ m-3. These results conclusively suggest that high-performance thermoplastic polyurethane elastomers had great promise for potential application in a wide range of practical fields.

Relationships between dorsolateral prefrontal cortex metabolic change and cognitive impairment in first-episode neuroleptic-naive schizophrenia patients.

The present study aimed to explore the possible associations between the dorsolateral prefrontal cortex (DLPFC) metabolites and the cognitive function in first-episode schizophrenia (FES).This study included 58 patients with FES (29 males and 29 females; mean age, 22.66 ±â€Š7.64 years) recruited from the First Affiliated Hospital, College of Medicine, Zhejiang University, and 43 locally recruited healthy controls (16 males and 27 females; mean age, 23.07 ±â€Š7.49 years). The single-voxel proton magnetic resonance spectroscopy was used to measure the levels of N-acetylaspartate (NAA); complex of glutamate, glutamine, and γ-aminobutyric acid (Glx); choline-containing compounds; and myo-inositol in the DLPFC. The ratios of metabolites to creatine (Cr) were calculated. The cognitive function was assessed by Measurement and Treatment Research to Improve Cognition in Schizophrenia Consensus Cognitive Battery (MCCB). Correlation analysis was used to assess the relationships between the DLPFC metabolites and the cognitive function.Compared with the healthy controls, the patients with FES showed significantly reduced scores in each part of the MCCB, significantly reduced NAA/Cr, and significantly increased Glx/Cr in the left DLPFC. Poor performance in verbal learning and visual learning was correlated to the reduced NAA/Cr ratio in the left DLPFC.These findings suggest that a lower NAA/Cr ratio in the left DLPFC is associated with the cognitive deficits in patients with FES, and may be an early biochemical marker for the cognitive impairment in schizophrenia.

Circulating T lymphocyte subsets, cytokines, and immune checkpoint inhibitors in patients with bipolar II or major depression: a preliminary study.

This study aimed to investigate the less known activation pattern of T lymphocyte populations and immune checkpoint inhibitors on immunocytes in patients with bipolar II disorder depression (BD) or major depression (MD). A total of 23 patients with BD, 22 patients with MD, and 20 healthy controls (HCs) were recruited. The blood cell count of T lymphocyte subsets and the plasma level of cytokines (IL-2, IL-4, IL-6, IL-10, TNF-α, and IFN-γ) were selectively investigated. The expression of T-cell immunoglobulin and mucin-domain containing-3 (TIM-3), programmed cell death protein 1 (PD-1) and its ligands, PD-L1 and PD-L2, on T lymphocytes and monocytes, was detected. In results, blood proportion of cytotoxic T cells significantly decreased in BD patients than in either MD patients or HCs. The plasma level of IL-6 increased in patients with BD and MD. The expression of TIM-3 on cytotoxic T cells significantly increased, whereas the expression of PD-L2 on monocytes significantly decreased in patients with BD than in HCs. These findings extended our knowledge of the immune dysfunction in patients with affective disorders.

Efficacy of repetitive transcranial magnetic stimulation with quetiapine in treating bipolar II depression: a randomized, double-blinded, control study.

The clinical and cognitive responses to repetitive transcranial magnetic stimulation (rTMS) in bipolar II depressed patients remain unclear. In this study, thirty-eight bipolar II depressed patients were randomly assigned into three groups: (i) left high-frequency (n = 12), (ii) right low-frequency (n = 13), (iii) sham stimulation (n = 13), and underwent four-week rTMS with quetiapine concomitantly. Clinical efficacy was evaluated at baseline and weekly intervals using the 17-item Hamilton Depression Rating Scale (HDRS-17) and Montgomery-Asberg Depression Rating Scale (MADRS). Cognitive functioning was assessed before and after the study with the Wisconsin Card Sorting Test (WCST), Stroop Word-Color Interference Test (Stroop), and Trail Making Test (TMT). Thirty-five patients were included in the final analysis. Overall, the mean scores of both the HDRS-17 and the MADRS significantly decreased over the 4-week trial, which did not differ among the three groups. Exploratory analyses revealed no differences in factor scores of HDRS-17s, or in response or remission rates. Scores of WCST, Stroop, or TMT did not differ across the three groups. These findings indicated active rTMS combined with quetiapine was not superior to quetiapine monotherapy in improving depressive symptoms or cognitive performance in patients with bipolar II depression.

Does amantadine induce acute psychosis? A case report and literature review.

BACKGROUND: Over-the-counter cold medicines, which contain amantadine, are widely used in the People's Republic of China. Clinicians are familiar with the psychosis caused by long-term treatment with amantadine, especially in elderly patients; however, early-onset psychotic complications among healthy young individuals have rarely been reported. CASE PRESENTATION: This article reports the case of a 28-year-old patient who presented with hallucination-delusion syndrome soon after treatment with cold medicine containing amantadine hydrochloride and acetaminophen. The symptoms resolved completely after a 2-week course of paliperidone treatment. CONCLUSION: Clinicians should be sensitive to the acute psychotic complications induced by an interaction between amantadine and acetaminophen.

Enhanced dissolution and oral bioavailability of valsartan solid dispersions prepared by a freeze-drying technique using hydrophilic polymers.

This study aimed to improve the dissolution rate and oral bioavailability of valsartan (VAL), a poorly soluble drug using solid dispersions (SDs). The SDs were prepared by a freeze-drying technique with polyethylene glycol 6000 (PEG6000) and hydroxypropylmethylcellulose (HPMC 100KV) as hydrophilic polymers, sodium hydroxide (NaOH) as an alkalizer, and poloxamer 188 as a surfactant without using any organic solvents. In vitro dissolution rate and physicochemical properties of the SDs were characterized using the USP paddle method, differential scanning calorimetry (DSC), X-ray diffractometry (XRD) and Fourier transform-infrared (FT-IR) spectroscopy, respectively. In addition, the oral bioavailability of SDs in rats was evaluated by using VAL (pure drug) as a reference. The dissolution rates of the SDs were significantly improved at pH 1.2 and pH 6.8 compared to those of the pure drug. The results from DSC, XRD showed that VAL was molecularly dispersed in the SDs as an amorphous form. The FT-IR results suggested that intermolecular hydrogen bonding had formed between VAL and its carriers. The SDs exhibited significantly higher values of AUC 0-24 h and Cmax in comparison with the pure drug. In conclusion, hydrophilic polymer-based SDs prepared by a freeze-drying technique can be a promising method to enhance dissolution rate and oral bioavailability of VAL.

Crystal structure of 1,1'-bis-(2-meth-oxy-carbonyl-2-methyl-prop-yl)ferrocene.

The Fe atom in the title ferrocene derivative, [Fe(C11H15O2)2], is situated on an inversion centre. As a result of the point-group symmetry -1 of the mol-ecule, the ferrocene moiety adopts a staggered conformation. The average Fe-C(Cp) bond length (Cp is cyclo-penta-dien-yl) is 2.045 (4) Å, in agreement with that of other disubstituted ferrocenes. The Fe-C bond length involving the substituted C atom is slightly longer [2.0521 (17) Å] than the remaining Fe-C bond lengths caused by the inductive effect of the methyl-ene group on the Cp ring. Apart from van der Waals forces, no significant inter-molecular inter-actions are observed in the crystal packing.

In vitro dissolution and physicochemical characterizations of novel PVP-based solid dispersions containing valsartan prepared by a freeze-drying method.

Valsartan (VAL) shows poor oral bioavailability mainly as a result of its low water solubility at low pH. This study is designed to investigate the dissolution properties and physicochemical characteristics of novel PVP-based solid dispersions (SDs) containing VAL. The SDs were prepared with polyvinylpyrrolidone (PVP-K30) as a hydrophilic polymer, sodium hydroxide (NaOH) as an alkalizer, and poloxamer 188 (F68) as a surfactant, without using any organic solvents by a freeze-drying method. The dissolution study was carried out and the physicochemical properties of SDs were also characterized by using differential scanning calorimetry (DSC), fourier transform-infrared (FT-IR) spectroscopy, X-ray diffractometry (XRD) and scanning electron microscopy (SEM). The dissolution rates of SDs were significantly improved at pH1.2 and pH6.8 compared to that of pure drug. The results of physicochemical properties suggested that some interactions between VAL and carriers had occurred in the molecular level and the drug presented in the SDs was amorphous. It was concluded that the novel PVP-based SDs has been successfully prepared by a freeze-drying method, resulting in significant dissolution improvement of VAL.

Formulation and in vitro characterization of novel sildenafil citrate-loaded polyvinyl alcohol-polyethylene glycol graft copolymer-based orally dissolving films.

This work was aimed to develop novel sildenafil citrate (SC)-loaded polyvinyl alcohol (PVA)-polyethylene glycol (PEG) graft copolymer (Kollicoat(®) IR)-based orally dissolving films (ODFs) using a solvent casting method. Formulation factors such as plasticizers and disintegrants were optimized on the basis of characteristics of blank ODFs. The SC-loaded ODF with a loading capacity up to 6.25mg in an area of 6 cm(2) was prepared and evaluated in terms of mechanical properties, disintegration time and dissolution rate. The physicochemical properties of drug-loaded ODF were also investigated using the scanning electron microscope (SEM), X-ray diffraction (XRD), differential scanning calorimetry (DSC) and Fourier transform infrared spectroscopy (FT-IR). The blank ODF composed of Kollicoat(®) IR, sodium alginate (ALG-Na) and glycerol (10:2:1.5, w/w) had a remarkably short disintegration time of about 20s. The SC-loaded ODF showed a delayed disintegration time (about 25s), but exhibited improved mechanical properties when compared to the blank ODF. SC was homogeneously dispersed throughout the ODF and the crystalline form of drug had been partly changed, existing strong hydrogen bonding between the drug and carriers. The Kollicoat(®) IR/ALG-Na based ODFs containing SC might be an alternative to conventional tablet for the treatment of male erectile dysfunction.

Preparation, characterization and in vitro evaluation of a polyvinyl alcohol/sodium alginate based orodispersible film containing sildenafil citrate.

In this work, we developed a sildenafil citrate (SC)-loaded polyvinyl alcohol (PVA)/sodium alginate (ALG-Na) based orodispersible film (ODF) using a solvent casting method. Formulation factors such as the type and amount of plasticizers and disintegrants were optimized on the basis of characteristics of blank ODF, including the disintegration time, elastic modulus (EM) and percentage of elongation (E%). SC-loaded ODF with a loading capacity up to 25 mg in an area of 6 cm2 was prepared and evaluated in terms of mechanical properties, disintegration time and dissolution rate. The surface morphology of ODF was visualized under a scanning electron microscope (SEM). The physicochemical properties of ODF were investigated using X-ray diffraction (XRD), differential scanning calorimetry (DSC) and Fourier transform infrared spectroscopy (FT-IR). The blank ODF composed of PVA, polyethylene glycol 400 (PEG 400) and ALG-Na (20:5:2, w/w) had a remarkably short disintegration time of about 20 s. However, the loading of drug extended the disintegration time (100 s) of ODF, while it still maintained satisfactory mechanical properties. SC was homogenously dispersed throughout the films and the crystalline form of drug changed, with strong hydrogen bonding between the drug and carriers. The PVA/ALG-Na based ODF containing SC prepared by the simple solvent casting method might be an alternative to conventional SC tablets for the treatment of male erectile dysfunction.

Role of Beclin 1-dependent autophagy in cardioprotection of ischemic preconditioning.

Emerging evidence indicates that ischemic preconditioning (IPC) induces autophagy which attenuates myocardial ischemia/reperfusion (I/R) injury. However, the precise mechanisms remain complex and unclear. The present study was to investigate which autophagy pathway was involved in the cardioprotection induced by IPC, so that we can acquire an attractive treatment way for ischemic heart disease. Adult male Sprague-Dawley (SD) rats were randomly divided into sham group, I/R group and IPC group. IPC was induced with three cycles of 5 min regional ischemia alternating with 5 min reperfusion in a heart I/R model. Samples were taken from the center of the infracted heart and examined by using the electron microscopy, the terminal deoxynucleotidyl transferase-mediated nick end-labeling (TUNEL) method, Western blotting and co-immunoprecipitation (Co-IP). A large number of autophagic vacuoles were observed in the cardiomyocytes of IPC group as compared with I/R group. LC3-II formation, an autophagy marker, was up-regulated in IPC group as compared with I/R group (P<0.05). Moreover, the interaction between Beclin 1 and Bcl-2 was significantly increased in IPC group as compared with I/R group (P<0.01). It was also found that IPC decreased I/R-induced apoptosis (P<0.01). These results suggest that IPC inhibits Beclin 1-dependent excessive autophagy in reperfusion phase and cooperates with anti-apoptosis pathway to diminish the cell death induced by the myocardial I/R injury.

A formulation approach for development of HPMC-based sustained release tablets for tolterodine tartrate with a low release variation.

OBJECTIVE: The purpose of this study was to develop hydroxypropylmethylcellulose (HPMC)-based sustained release (SR) tablets for tolterodine tartrate with a low drug release variation. METHODS: The SR tablets were prepared by formulating a combination of different grades of HPMC as the gelling agents. The comparative dissolution study for the HPMC-based SR tablet as a test and Detrusitol SR capsule as a reference was carried out, and the bioequivalence study of the two products was also conducted in human volunteers. RESULTS: The amount of HPMC, the grade of HPMC and the combination ratio of different grades of HPMC had remarkable effects on drug release from the SR tablets. Both the test and reference products had no significant difference in terms of comparative dissolution patterns in four different media (f2 > 50). Furthermore, the dissolution method and rotation speed showed no effects on the drug release from the two products. The 90% confidence intervals of the AUC(0-36) and C(max) ratios for the test and reference products were within the acceptable bioequivalence intervals of log0.8-log1.25. CONCLUSIONS: A HPMC-based SR tablet for tolterodine tartrate with a low release variation was successfully developed, which was bioequivalent to Detrusitol® SR capsule.

Enhanced oral bioavailability of novel mucoadhesive pellets containing valsartan prepared by a dry powder-coating technique.

The aim of this study was to develop novel mucoadhesive pellets containing valsartan (VAL) with enhanced oral bioavailability. Two types of VAL loaded core pellets were prepared by an extrusion/spheronization method, and further dry-coated with a mixture of hydroxypropylmethylcellulose (HPMC) and carbomer (CB) at different ratios. The effects of the pellet core composition, HPMC:CB ratio and coating level on the drug release from the coated pellets were investigated. The physicochemical properties of the core and coated pellets were characterized by scanning electron microscopy (SEM), X-ray diffraction (XRD), differential scanning calorimetry (DSC) and Fourier transform infrared spectroscopy (FT-IR). In addition, the in vitro and in vivo mucoadhesion properties as well as the bioavailability of the coated pellets in rats were evaluated by using VAL suspension and core pellets as control preparations. The results of the release study demonstrated that the two types of core pellets, especially the pellets formulated with a solubilizer and a pH modulator gave considerably faster drug release than the VAL powder. However, the core and coated pellets exhibited similar release profiles indicating that the dry powder-coating did not retard the drug release. Strong molecular interactions were observed between the drug and the carriers in FT-IR analysis. The coated pellets displayed distinct mucoadhesive property in vitro and delayed gastrointestinal (GI) transit in vivo. Furthermore, the coated pellets exhibit significantly higher AUC(0-12h) and C(max), as compared to the core pellets and drug suspension. It was concluded that the mucoadhesive pellets could render poorly water soluble drugs like VAL with a rapid drug release, delayed GI transit and enhanced oral bioavailability.