Emerging treatments in the management of bipolar disorder – focus on risperidone long acting injection

Bipolar disorder is a life-long psychiatric illness characterized by a high frequency of relapses and substantial societal costs. Almost half of the patients are prescribed second generation antipsychotics for treatment of manic states, or as the maintenance therapy. Risperidone long acting injection (RLAI) as a monotherapy or as adjunctive therapy to lithium or valproate for the maintenance treatment of bipolar I disorder was approved by Food and Drug Administration (FDA) in United States in May 2009. In this review we will consider the aspects of pharmacology, pharmacokinetics, metabolism, safety and tolerability, and clinical trials focusing on the efficacy of RLAI in bipolar disorder. The patients’ perspective and attitudes to long-acting injections will also be discussed

Measurement and conceptualization of maternal PTSD following childbirth: Psychometric properties of the City Birth Trauma Scale-French Version (City BiTS-F).

The City Birth Trauma Scale (City BiTS) assesses posttraumatic stress disorder symptoms following childbirth (PTSD-FC). Recent studies investigating the latent factor structure of PTSD-FC in women reported mixed results. No validated French questionnaire exists to measure PTSD-FC symptoms. Therefore, this study first aimed to validate the French version of the City BiTS (City BiTS-F). Second, it aimed to establish the latent factor structure of PTSD-FC. French-speaking women with infants aged 1 to 12 months old (n = 541) completed an online cross-sectional survey. Questionnaires included the City BiTS-F, the PTSD Checklist, the Edinburgh Postnatal Depression Scale, and the anxiety subscale of the Hospital Anxiety and Depression Scale. Additionally, sociodemographic and medical data were collected. The two-factor model with birth-related symptoms (BRS) and general symptoms (GS) fit the data well, whereas the four-factor model was not confirmed. The bifactor model with a general factor and the BRS and GS gave the best fit to the data, suggesting that use of the total score in addition to the BRS and GS subscales scores is justified. High reliability (α = .88 to .90) and good convergent and divergent validity were obtained. Discriminant validity was calculated with weeks of gestation, gravidity, history of traumatic childbirth and event, and mode of delivery. The City BiTS-F is a reliable and valid measure of PTSD-FC symptoms in French-speaking women. Both total score and BRS or GS subscale scores can be calculated. This psychometric tool is of importance for clinical and research purposes. (PsycInfo Database Record (c) 2021 APA, all rights reserved)

Validation of the French ADNM-20 in the assessment of emotional difficulties resulting from COVID-19 quarantine and outbreak

Background: Multiple psychological consequences of the COVID-19 outbreak and quarantine have been described. However, there is a lack of global conceptualization. We argue that the stressful aspects of the situation, the multiple environmental consequences of the outbreak, and the diversity of symptoms observed in such a situation, suggest that Adjustment disorder (AD) is a promising way to conceptualize the psychological consequences of the outbreak and quarantine. The first aim of the study was to validate the French version of the ADNM. The second aim was to set out adjustment difficulties resulting from COVID-19 outbreak and quarantine. Method: We recruited 1010 (840 women, 170 men) who consented online to participate. They filled out the French ADNM, visual analogic scales, HADS, IES, and the COPE, to evaluate coping strategies. Results: We confirmed the factor structure of the ADNM and we found good psychometric properties. We found that 61.3% of participants presented an adjustment disorder related to COVID-19 outbreak. We found multiple risk factors and protective factors to AD due to quarantine and outbreak. We also identified the coping strategies negatively and positively associated with AD. Conclusion: Adjustment disorder is a relevant concept to understand psychological manifestations caused by quarantine and outbreak. The French ANDM has good psychometric properties to evaluate such manifestations. The association between coping strategies and AD symptoms suggest that CBT may be the best intervention to help people suffering from AD

Parasite Manipulation of the Invariant Chain and the Peptide Editor H2-DM Affects Major Histocompatibility Complex Class II Antigen Presentation during Toxoplasma gondii Infection

Toxoplasma gondii is an obligate intracellular protozoan parasite. This apicomplexan is the causative agent of toxoplasmosis, a leading cause of central nervous system disease in AIDS. It has long been known that T. gondii interferes with major histocompatibility complex class II (MHC-II) antigen presentation to attenuate CD4(+) T cell responses and establish persisting infections. Transcriptional downregulation of MHC-II genes by T. gondii was previously established, but the precise mechanisms inhibiting MHC-II function are currently unknown. Here, we show that, in addition to transcriptional regulation of MHC-II, the parasite modulates the expression of key components of the MHC-II antigen presentation pathway, namely, the MHC-II-associated invariant chain (Ii or CD74) and the peptide editor H2-DM, in professional antigen-presenting cells (pAPCs). Genetic deletion of CD74 restored the ability of infected dendritic cells to present a parasite antigen in the context of MHC-II in vitro. CD74 mRNA and protein levels were, surprisingly, elevated in infected cells, whereas MHC-II and H2-DM expression was inhibited. CD74 accumulated mainly in the endoplasmic reticulum (ER), and this phenotype required live parasites, but not active replication. Finally, we compared the impacts of genetic deletion of CD74 and H2-DM genes on parasite dissemination toward lymphoid organs in mice, as well as activation of CD4(+) T cells and interferon gamma (IFN-γ) levels during acute infection. Cyst burdens and survival during the chronic phase of infection were also evaluated in wild-type and knockout mice. These results highlight the fact that the infection is influenced by multiple levels of parasite manipulation of the MHC-II antigen presentation pathway

Exploration of bivalent ligands targeting putative mu opioid receptor and chemokine receptor CCR5 dimerization

Modern antiretroviral therapies have provided HIV-1 infected patients longer lifespans and better quality of life. However, several neurological complications are now being seen in these patients due to HIV-1 associated injury of neurons by infected microglia and astrocytes. In addition, these effects can be further exacerbated with opiate use and abuse. One possible mechanism for such potentiation effects of opiates is the interaction of the mu opioid receptor (MOR) with the chemokine receptor CCR5 (CCR5), a known HIV-1 co-receptor, to form MOR-CCR5 heterodimer. In an attempt to understand this putative interaction and its relevance to neuroAIDS, we designed and synthesized a series of bivalent ligands targeting the putative CCR5-MOR heterodimer. To understand how these bivalent ligands may interact with the heterodimer, biological studies including calcium mobilization inhibition, binding affinity, HIV-1 invasion, and cell fusion assays were applied. In particular, HIV-1 infection assays using human peripheral blood mononuclear cells, macrophages, and astrocytes revealed a notable synergy in activity for one particular bivalent ligand. Further, a molecular model of the putative CCR5-MOR heterodimer was constructed, docked with the bivalent ligand, and molecular dynamics simulations of the complex was performed in a membrane-water system to help understand the biological observation

Functional morphological imaging of autism spectrum disorders: Current position and theories proposed

AbstractAutism is a pervasive disorder of childhood development. Polymorphous clinical profiles combining various degrees of communication and social interaction with restricted and stereotyped behaviour are grouped under the heading of ‘autism spectrum disorders’ (ASD). Many teams are trying to pick out the underlying cerebral abnormalities in order to understand the neuronal networks involved in relationships with others. Here we review the morphological, spectroscopic and functional abnormalities in the amygdala-hippocampal circuit, the caudate nuclei, the cerebellum, and the frontotemporal regions, which have been described in subjects with ASD. White matter abnormalities have also been described in diffusion tensor imaging, leading to suspected damage to the subjacent neural networks, such as mirror neurones or the social brain

The effect of completeness of revascularization during CABG with single versus multiple arterial grafts

IntroductionIncomplete coronary revascularization is associated with suboptimal outcomes. We investigated the longâ term effects of Incomplete, Complete, and Supraâ complete revascularization and whether these effects differed in the setting of singleâ arterial and multiâ arterial coronary artery bypass graft (CABG).MethodsWe analyzed 15â year mortality in 7157 CABG patients (64.1â ±â 10.5 years; 30% women). All patients received a left internal thoracic artery to left anterior descending coronary artery graft with additional venous grafts only (singleâ arterial) or with at least one additional arterial graft (multiâ arterial) and were grouped based on a completeness of revascularization index (CRIâ =â number of grafts minus the number of diseased principal coronary arteries): Incomplete (CRIâ â ¤â â 1 [Nâ =â 320;4.5%]); Complete (CRIâ =â 0 [Nâ =â 2882;40.3%]; reference group); and two Supraâ complete categories (CRIâ =â +1[Nâ =â 3050; 42.6%]; CRIâ â ¥â +â 2 [Nâ =â 905; 12.6%]). Riskâ adjusted mortality hazard ratios (AHR) were calculated using comprehensive propensity score adjustment by Cox regression.ResultsIncomplete revascularization was rare (4.5%) but associated with increased mortality in all patients (AHR [95% confidence interval]â =â 1.53 [1.29â 1.80]), those undergoing singleâ arterial CABG (AHRâ =â 1.27 [1.04â 1.54]) and multiâ arterial CABG (AHRâ =â 2.18 [1.60â 2.99]), as well as in patients with 3â Vessel (AHRâ =â 1.37 [1.16â 1.62]) and, to a lesser degree, with 2â Vessel (AHRâ =â 1.67 [0.53â 5.23]) coronary disease. Supraâ complete revascularization was generally associated with incrementally decreased mortality in all patients (AHR [CRIâ =â +1]â =â 0.94 [0.87â 1.03]); AHR [CRIâ â ¥â +2]â =â 0.74 [0.64â 0.85]), and was driven by a significantly decreased mortality risk in singleâ arterial CABG (AHR [CRIâ =â +1]â =â 0.90 [0.81â 0.99]; AHR [CRIâ â ¥â +2]â =â 0.64 [0.53â 0.78]); and 3â Vessel disease patients (AHR [CRIâ =â +1]â =â 0.94 [0.86â 1.04]; and AHR [CRIâ â ¥â +2]â =â 0.75 [0.63â 0.88]) with no impact in multiâ arterial CABG (AHR [CRIâ =â +1]â =â 1.07 [0.91â 1.26]; AHR [CRIâ â ¥â +2]â =â 0.93 [0.73â 1.17]).ConclusionsIncomplete revascularization is associated with decreased late survival, irrespective of grafting strategy. Alternatively, supraâ complete revascularization is associated with improved survival in patients with 3â Vessel CAD, and in singleâ arterial but not multiâ arterial CABG.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/146364/1/jocs13810.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/146364/2/jocs13810_am.pd

Extending Halogen-based Medicinal Chemistry to Proteins: IODO-INSULIN AS A CASE STUDY

Insulin, a protein critical for metabolic homeostasis, provides a classical model for protein design with application to human health. Recent efforts to improve its pharmaceutical formulation demonstrated that iodination of a conserved tyrosine (Tyr(B26)) enhances key properties of a rapid-acting clinical analog. Moreover, the broad utility of halogens in medicinal chemistry has motivated the use of hybrid quantum- and molecular-mechanical methods to study proteins. Here, we (i) undertook quantitative atomistic simulations of 3-[iodo-Tyr(B26)]insulin to predict its structural features, and (ii) tested these predictions by X-ray crystallography. Using an electrostatic model of the modified aromatic ring based on quantum chemistry, the calculations suggested that the analog, as a dimer and hexamer, exhibits subtle differences in aromatic-aromatic interactions at the dimer interface. Aromatic rings (Tyr(B16), Phe(B24), Phe(B25), 3-I-Tyr(B26), and their symmetry-related mates) at this interface adjust to enable packing of the hydrophobic iodine atoms within the core of each monomer. Strikingly, these features were observed in the crystal structure of a 3-[iodo-Tyr(B26)]insulin analog (determined as an R6 zinc hexamer). Given that residues B24-B30 detach from the core on receptor binding, the environment of 3-I-Tyr(B26) in a receptor complex must differ from that in the free hormone. Based on the recent structure of a "micro-receptor" complex, we predict that 3-I-Tyr(B26) engages the receptor via directional halogen bonding and halogen-directed hydrogen bonding as follows: favorable electrostatic interactions exploiting, respectively, the halogen's electron-deficient σ-hole and electronegative equatorial band. Inspired by quantum chemistry and molecular dynamics, such "halogen engineering" promises to extend principles of medicinal chemistry to proteins

Coupling of transient near infrared photonic with magnetic nanoparticle for potential dissipation-free biomedical application in brain

Combined treatment strategies based on magnetic nanoparticles (MNPs) with near infrared ray (NIR) biophotonic possess tremendous potential for non-invasive therapeutic approach. Nonetheless, investigations in this direction have been limited to peripheral body region and little is known about the potential biomedical application of this approach for brain. Here we report that transient NIR exposure is dissipation-free and has no adverse effect on the viability and plasticity of major brain cells in the presence or absence superparamagnetic nanoparticles. The 808?nm NIR laser module with thermocouple was employed for functional studies upon NIR exposure to brain cells. Magnetic nanoparticles were characterized using transmission electron microscopy (TEM), X-ray diffraction (XRD), dynamic laser scattering (DLS), and vibrating sample magnetometer (VSM). Brain cells viability and plasticity were analyzed using electric cell-substrate impedance sensing system, cytotoxicity evaluation, and confocal microscopy. When efficacious non-invasive photobiomodulation and neuro-therapeutical targeting and monitoring to brain remain a formidable task, the discovery of this dissipation-free, transient NIR photonic approach for brain cells possesses remarkable potential to add new dimension