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Emraclidine, a novel positive allosteric modulator of cholinergic M4 receptors, for the treatment of schizophrenia: a two-part, randomised, double-blind, placebo-controlled, phase 1b trial.

Emraclidine is a novel, brain-penetrant, highly selective M4 receptor positive allosteric modulator in development for the treatment of schizophrenia. We aimed to evaluate the safety and tolerability of multiple ascending doses of emraclidine in patients with schizophrenia.

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Immediate release fentanyl in general practices: Mostly off-label prescribing.

The immediacy of the onset of opioids may be associated with the risk of dependency and accidental overdose. Nasal and oromucosal fentanyl dosage forms are so called immediate release fentanyl (IRF). These IRFs have been approved to treat breakthrough pain in patients with cancer who are on chronic opioid treatment only. There are signals of increased off-label prescribing of IRFs in general practices.

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Efficacy and safety of glycosides as an add-on treatment in adults with chronic urticaria: a systematic review and meta-analysis.

glycosides (TG), a traditional Chinese medicine, has been used to treat chronic urticaria (CU) in China, and the evidence of TG for CU needs to be updated thoroughly.

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Prognostic factors associated with changes in knee pain outcomes, identified from initial primary care consultation data. A systematic literature review.

Data collected during initial primary care consultations could be a source of baseline prognostic factors associated with changes in outcome measures for patients with knee pain.

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Prevalence and predictors for postpartum sleep disorders: a nationwide analysis.

To describe the prevalence and predictors of postpartum sleep disorders.

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Advances for pharmacological activities of – A review.

Sieb. et Zucc (Polygonaceae), the root of which is included in the Chinese Pharmcopoeia under the name 'Huzhang', has a long history as a medicinal plant and vegetable. has been used in traditional Chinese medicine for the treatment of inflammation, hyperlipemia, etc.

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Finding a path in a methodological jungle: a qualitative research of resilience.

Qualitative research provides an in-depth understanding of lived experiences. However, these experiences can be hard to apprehend by using just one method of data analysis. A good example is the experience of resilience. In this paper, the authors describe the chain of the decision-making process in the research of the construct of "resilience". s The authors justify the implications of a multi-method, pluralistic approach, and show how the triangulation of two or more qualitative methods and integration of several qualitative data analysis methods can improve a deeper understanding of the resilience among people with chronic pain. By combining the thematic analysis, narrative analysis, and critical incident technique, lived experiences can be seen from different perspectives.Therefore, the thematic analysis describes the content and answers to "what" regarding resilience, the narrative analysis describes the dynamics of resilience, and answers to "how", while the critical incident technique clarifies the most significant experience and the answers to "why" changes happen. This integrative approach could be used in the analysis of other psychological constructs and can serve as an example of how the rigour of qualitative research could be provided.

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Argon preconditioning protects neuronal cells with a Toll-like receptor-mediated effect.

The noble gas argon has the potential to protect neuronal cells from cell death. So far, this effect has been studied in treatment after acute damage. Preconditioning using argon has not yet been investigated. In this study, human neuroblastoma SH-SY5Y cells were treated with different concentrations of argon (25%, 50%, and 74%; 21% O, 5% CO, balance nitrogen) at different time intervals before inflicting damage with rotenone (20 µM, 4 hours). Apoptosis was determined by flow cytometry after annexin V and propidium iodide staining. Surface expressions of Toll-like receptors 2 and 4 were also examined. Cells were also processed for analysis by western blot and qPCR to determine the expression of apoptotic and inflammatory proteins, such as extracellular-signal regulated kinase (ERK1/2), nuclear transcription factor-κB (NF-κB), protein kinase B (Akt), caspase-3, Bax, Bcl-2, interleukin-8, and heat shock proteins. Immunohistochemical staining was performed for TLR2 and 4 and interleukin-8. Cells were also pretreated with OxPAPC, an antagonist of TLR2 and 4 to elucidate the molecular mechanism. Results showed that argon preconditioning before rotenone application caused a dose-dependent but not a time-dependent reduction in the number of apoptotic cells. Preconditioning with 74% argon for 2 hours was used for further experiments showing the most promising results. Argon decreased the surface expression of TLR2 and 4, whereas OxPAPC treatment partially abolished the protective effect of argon. Argon increased phosphorylation of ERK1/2 but decreased NF-κB and Akt. Preconditioning inhibited mitochondrial apoptosis and the heat shock response. Argon also suppressed the expression of the pro-inflammatory cytokine interleukin-8. Immunohistochemistry confirmed the alteration of TLRs and interleukin-8. OxPAPC reversed the argon effect on ERK1/2, Bax, Bcl-2, caspase-3, and interleukin-8 expression, but not on NF-κB and the heat shock proteins. Taken together, argon preconditioning protects against apoptosis of neuronal cells and mediates its action via Toll-like receptors. Argon may represent a promising therapeutic alternative in various clinical settings, such as the treatment of stroke.

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Glial cell line-derived neurotrophic factor and brain-derived neurotrophic factor regulate the interaction between astrocytes and Schwann cells at the trigeminal root entry zone.

The trigeminal root entry zone is the zone at which the myelination switches from peripheral Schwann cells to central oligodendrocytes. Its special anatomical and physiological structure renders it susceptible to nerve injury. The etiology of most primary trigeminal neuralgia is closely related to microvascular compression of the trigeminal root entry zone. This study aimed to develop an efficient in vitro model mimicking the glial environment of trigeminal root entry zone as a tool to investigate the effects of glial cell line-derived neurotrophic factor and brain-derived neurotrophic factor on the structural and functional integrity of trigeminal root entry zone and modulation of cellular interactions. Primary astrocytes and Schwann cells isolated from trigeminal root entry zone of postnatal rats were inoculated into a two-well silicon culture insert to mimic the trigeminal root entry zone microenvironment and treated with glial cell line-derived neurotrophic factor and brain-derived neurotrophic factor. In monoculture, glial cell line-derived neurotrophic factor promoted the migration of Schwann cells, but it did not have effects on the migration of astrocytes. In the co-culture system, glial cell line-derived neurotrophic factor promoted the bidirectional migration of astrocytes and Schwann cells. Brain-derived neurotrophic factor markedly promoted the activation and migration of astrocytes. However, in the co-culture system, brain-derived neurotrophic factor inhibited the migration of astrocytes and Schwann cells to a certain degree. These findings suggest that glial cell line-derived neurotrophic factor and brain-derived neurotrophic factor are involved in the regulation of the astrocyte-Schwann cell interaction in the co-culture system derived from the trigeminal root entry zone. This system can be used as a cell model to study the mechanism of glial dysregulation associated with trigeminal nerve injury and possible therapeutic interventions.

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Neuro faces of beneficial T cells: essential in brain, impaired in aging and neurological diseases, and activated functionally by neurotransmitters and neuropeptides.

T cells are essential for a healthy life, performing continuously: immune surveillance, recognition, protection, activation, suppression, assistance, eradication, secretion, adhesion, migration, homing, communications, and additional tasks. This paper describes five aspects of normal beneficial T cells in the healthy or diseased brain. First, normal beneficial T cells are essential for normal healthy brain functions: cognition, spatial learning, memory, adult neurogenesis, and neuroprotection. T cells decrease secondary neuronal degeneration, increase neuronal survival after central nervous system (CNS) injury, and limit CNS inflammation and damage upon injury and infection. Second, while pathogenic T cells contribute to CNS disorders, recent studies, mostly in animal models, show that specific subpopulations of normal beneficial T cells have protective and regenerative effects in several neuroinflammatory and neurodegenerative diseases. These include Multiple Sclerosis (MS), Alzheimer's disease, Parkinson's disease, Amyotrophic Lateral Sclerosis (ALS), stroke, CNS trauma, chronic pain, and others. Both T cell-secreted molecules and direct cell-cell contacts deliver T cell neuroprotective, neuroregenerative and immunomodulatory effects. Third, normal beneficial T cells are abnormal, impaired, and dysfunctional in aging and multiple neurological diseases. Different T cell impairments are evident in aging, brain tumors (mainly Glioblastoma), severe viral infections (including COVID-19), chronic stress, major depression, schizophrenia, Parkinson's disease, Alzheimer's disease, ALS, MS, stroke, and other neuro-pathologies. The main detrimental mechanisms that impair T cell function are activation-induced cell death, exhaustion, senescence, and impaired T cell stemness. Fourth, several physiological neurotransmitters and neuropeptides induce by themselves multiple direct, potent, beneficial, and therapeutically-relevant effects on normal human T cells, via their receptors in T cells. This scientific field is called "Nerve-Driven Immunity". The main neurotransmitters and neuropeptides that induce directly activating and beneficial effects on naïve normal human T cells are: dopamine, glutamate, GnRH-II, neuropeptide Y, calcitonin gene-related peptide, and somatostatin. Fifth, "Personalized Adoptive Neuro-Immunotherapy". This is a novel unique cellular immunotherapy, based on the "Nerve-Driven Immunity" findings, which was recently designed and patented for safe and repeated rejuvenation, activation, and improvement of impaired and dysfunctional T cells of any person in need, by ex vivo exposure of the person's T cells to neurotransmitters and neuropeptides. Personalized adoptive neuro-immunotherapy includes an early ex vivo personalized diagnosis, and subsequent ex vivo → in vivo personalized adoptive therapy, tailored according to the diagnosis. The Personalized Adoptive Neuro-Immunotherapy has not yet been tested in humans, pending validation of safety and efficacy in clinical trials, especially in brain tumors, chronic infectious diseases, and aging, in which T cells are exhausted and/or senescent and dysfunctional.

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