Use of noninvasive brain stimulation and neurorehabilitation devices to enhance poststroke recovery: review of the current evidence and pitfalls.

Neurorehabilitation devices and technologies are crucial for enhancing stroke recovery. These include noninvasive brain stimulation devices that provide repetitive transcranial magnetic stimulation or transcranial direct current stimulation, which can remodulate an injured brain. Technologies such as robotics, virtual reality, and telerehabilitation are suitable add-ons or complements to physical therapy. However, the appropriate application of these devices and technologies, which target specific deficits and stages, for stroke therapy must be clarified. Accordingly, a literature review was conducted to evaluate the theoretical and practical evidence on the use of neurorehabilitation devices and technologies for stroke therapy. This narrative review provides a practical guide for the use of neurorehabilitation devices and describes the implications of use and potential integration of these devices into healthcare.

[Clinical Applications of Aromatherapy].

Aromatherapy is a natural therapy that utilizes essential oils that enter the body through the skin, inhalation, or ingestion to promote health. Clinical aromatherapy refers to the incorporation of essential oils as a complementary therapy within the medical field and is conducted in accordance with medical safety, ethical, and regulatory requirements. Healthcare professionals must have a comprehensive understanding of clinical aromatherapy management and enhance their knowledge of aromatherapy. Based on a meta-analysis of the related literature, clinical aromatherapy management procedures and the various applications of aromatherapy for anxiety, depression, sleep disorders, and pain are introduced. The goal is to help appropriately integrate aromatherapy into the healthcare system to enhance quality of care and improve well-being in patients and healthcare providers.

Concurrent Imaging and Clinical Study of the Efficacy of Hyaluronic Acid Injection for Knee Osteoarthritis: A Synovial Membrane Investigation with Ultrasound Imaging.

We investigated whether hyaluronic acid (HA) injections can ameliorate ultrasound-detected synovitis in knee osteoarthritis (OA). We recruited 103 patients with symptomatic knee OA and ultrasound-detected synovitis and performed two ultrasound-guided fluid drainage procedures, followed by the administration of a low-molecular-weight HA injection (2.5 mL) in the subpatellar bursa, at a 2-week interval. Knee ultrasound imaging evaluations were performed before injection (baseline) and at 1 and 6 months after the second injection and included the measurements of synovial vascularity by using color Doppler ultrasound, synovial fluid depth over the suprapatellar bursa (SF), and synovial hypertrophy (SH). Initial clinical assessments included a visual analog scale (VAS) and the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). VAS scores decreased significantly at both 1-month and 6-month evaluations (p < 0.001). WOMAC scores also significantly decreased at 1 month (p < 0.001), but not at 6 months (p = 0.23). The ultrasound parameters did not significantly change, except color Doppler grading, which tended to decrease at the 6-month evaluation (p = 0.059). Our findings revealed that two ultrasound-guided HA injections following fluid drainage improved pain and knee function but did not considerably influence imaging-detected synovitis in patients with knee OA.

Functional, antioxidant, and sensory properties of mixed-fruit (pitaya, watermelon, and mint) and pitaya wines.

Fermentation of fruits offers a diverse range of flavors, smells, and colors. Colored fruits are rich in naturally occurring pigments, such as betacyanin. Hence, they are considered to possess powerful antioxidant activities. However, in wine production, such pigments often diversify the flavor and color of the wine. The objective of this study was to compare the quality of two types of wines: a single-fruit (pitaya) wine and a mixed-fruit wine that contains watermelon (Citrullus lanatus), mint (Mintha spicata), and pitaya (Hylocereus costaricensis). In this study, fresh pitaya, watermelon, and mint leaves were fermented using Saccharomyces cerevisiae. Juice extracts underwent fermentation at room temperature for 7 days under dark conditions. Physicochemical changes, such as pH, sugar content, specific gravity, and alcohol content, were observed daily. The antioxidant activities were measured by the 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay, the ferric reducing antioxidant power (FRAP) assay, and total phenolic contents (TPCs). After 14 days of fermentation, the alcohol contents of mixed and pitaya wine were 11.22% (v/v) and 11.25%, respectively. The total sugar content of the mixed wine was 8.0 °Brix, while that of pitaya wine was 7.0 °Brix. Moreover, pitaya wine exhibited a higher TPC (22.7 mg GAE/100 g D.W.), and better FRAP (3578 µmole/L) and DPPH scavenging ability (80.2%) compared to the mixed wine with a TPC of 21.4 mg GAE/100 g D.W., FRAP of 2528 µmole/L, and DPPH of 75.6%., while the addition of watermelon and mint did not change the alcohol percentage contents of wine.

Social cognition and apathy between two cognitive subtypes of schizophrenia: Are there the same or different profiles?

Objective: Cognitive impairment is an essential feature of schizophrenia, and it involves a broad array of nonsocial and social cognitive domains. This study aimed to examine whether there are the same or different social cognition profiles between two cognitive subtypes of schizophrenia. Method: There were one hundred and two chronic and institutionalized patients with schizophrenia from two referral tracks. One group is "Cognitively Normal Range" (CNR) (N = 52), and another group is "Below Normal Range" (BNR) (N = 50). We assessed or collected their apathy, emotional perception judgment, facial expression judgment, and empathy by the Apathy Evaluation Scale, the International Affective Picture System, the Japanese and Caucasian Facial Expression of Emotion, and the Interpersonal Reactivity Index, respectively. Results: We found different impairment profiles depending on the cognitive subtypes of the patient with schizophrenia. Surprisingly, the CNR presented impairments in apathy, emotional perception judgment, facial expression judgment, and empathy and feature impairment in empathy and affective apathy. In contrast, even though the BNR had significant neurocognition impairments, they had almost intact empathy with significantly impaired cognitive apathy. Both groups' global deficit scores (GDSs) were comparable, and all reached at least a mild impairment level. Conclusions: The CNR and the BNR had similar abilities in emotional perception judgment and facial emotion recognition. They also had differentiable deficits in apathy and empathy. Our findings provide important clinical implications for neuropsychological pathology and treatment in schizophrenia.

Identification of rare missense mutations in the glutamate ionotropic receptor AMPA type subunit genes in schizophrenia.

OBJECTIVE: The alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptors significantly regulate the synaptic transmission and functions of various synaptic receptors. This study aimed to identify single nucleotide mutations in the glutamate receptor, ionotropic, AMPA type (GRIA) gene family, which is associated with schizophrenia. METHODS: The exon regions of four genes (GRIA1, GRIA2, GRIA3, and GRIA4) encoding glutamate ionotropic receptor AMPA type proteins were resequenced in 516 patients with schizophrenia. We analyzed the protein function of the identified rare mutants via immunoblotting. RESULTS: A total of 24 coding variants were detected in the GRIA gene family, including six missense mutations, 17 synonymous mutations, and one frameshift insertion. Notably, three ultra-rare missense mutations (GRIA1p.V182A, GRIA2p.P123Q, and GRIA4p.Y491H) were not documented in the single nucleotide polymorphism database, gnomAD genomes, and 1517 healthy controls available from Taiwan BioBank. Immunoblotting revealed GRIA4p.Y491H mutant with altered protein expressions in cultured cells compared with the wild type. CONCLUSION: Our findings suggest that, in some patients affected by schizophrenia, the GRIA gene family harbors rare functional mutations, which support rare coding variants that could contribute to the genetic architecture of this illness. The in-vitro impacts of these rare pathological mutations on the pathophysiology of schizophrenia are worthy of future investigation.

The effect of computerized working memory training on working memory and emotion perception for patients with chronic schizophrenia and normal cognition.

BACKGROUND: Cognitive impairment and affective symptoms are hallmark features of patients with schizophrenia. This study determines whether a computerized working memory training program improves the patient's working memory and affective perception. METHODS: Thirty-nine male patients with schizophrenia, aged 25-65, participated in this study. The study uses a single-blind randomized controlled design. Twenty subjects were assigned to the experimental group and received an eight-week working memory computerized training course comprising four modules of the CogniPlus system. Nineteen subjects were assigned to the control group and received treatment as usual. All subjects received the same assessments twice, including the Mini-Mental Status Examination (MMSE), Working Memory Index (WMI) of Wechsler Adult Intelligence Scale-Third Edition, and the subjective rating of pictures of the International affective picture system by Self-Assessment Manikin (SAM). RESULTS: This study shows that computerized working memory training improves WMI and the score for MMSE and produces a significant increase in the pleasure score for S.A.M. for negative pictures, between the pretest and post-test for the experimental group. CONCLUSIONS: Working memory training improves working memory and emotion perception for patients with chronic schizophrenia and normal cognition. The limitations of this study and suggestions for future study are also discussed.

Ultrarare Loss-of-Function Mutations in the Genes Encoding the Ionotropic Glutamate Receptors of Kainate Subtypes Associated with Schizophrenia Disrupt the Interaction with PSD95.

Schizophrenia is a complex mental disorder with a genetic component. The GRIK gene family encodes ionotropic glutamate receptors of the kainate subtype, which are considered candidate genes for schizophrenia. We screened for rare and pathogenic mutations in the protein-coding sequences of the GRIK gene family in 516 unrelated patients with schizophrenia using the ion semiconductor sequencing method. We identified 44 protein-altered variants, and in silico analysis indicated that 36 of these mutations were rare and damaging or pathological based on putative protein function. Notably, we identified four truncating mutations, including two frameshift deletion mutations (GRIK1p.Phe24fs and GRIK1p.Thr882fs) and two nonsense mutations (GRIK2p.Arg300Ter and GRIK4p.Gln342Ter) in four unrelated patients with schizophrenia. They exhibited minor allele frequencies of less than 0.01% and were absent in 1517 healthy controls from Taiwan Biobank. Functional analysis identified these four truncating mutants as loss-of-function (LoF) mutants in HEK-293 cells. We also showed that three mutations (GRIK1p.Phe24fs, GRIK1p.Thr882fs, and GRIK2p.Arg300Ter) weakened the interaction with the PSD95 protein. The results suggest that the GRIK gene family harbors ultrarare LoF mutations in some patients with schizophrenia. The identification of proteins that interact with the kainate receptors will be essential to determine kainate receptor-mediated signaling in the brain.

Identification of rare mutations of the vasoactive intestinal peptide receptor 2 gene in schizophrenia.

OBJECTIVE: Studies showed that rare copy number variations (CNVs) encompassing the vasoactive intestinal peptide receptor 2 gene (VIPR2) were associated with schizophrenia, indicating VIPR2 is a risk gene for schizophrenia. We hypothesized that besides CNV, rare pathogenic single-nucleotide variant (SNV) or small insertion/deletion (Indel) of VIPR2 might be present in some patients and contribute to the pathogenesis of schizophrenia. METHODS: We performed genome-wide CNV analysis to screen CNV at the VIPR2 locus and targeted sequencing of all the exons of VIPR2 to search for SNV and indel in a sample of patients with chronic schizophrenia from Taiwan. RESULTS: We detected a 230-kb microduplication encompassing the VIPR2 in 1 out of 200 patients. Furthermore, we identified six ultrarare SNVs, including one splicing SNV and five missense SNVs, in 516 patients. In-silico analyses showed these SNVs had a damaging effect on the function of VIPR2. CONCLUSION: Our findings support the idea that besides CNV, rare pathogenic SNVs of VIPR2 might contribute to the pathogenesis of schizophrenia in some patients.

Effectiveness of aromatherapy for intrapartum and postpartum emotional problems among parturient women: A meta-analysis of randomized controlled trials.

AIM: Perinatal negative emotions are common in parturient women, but the problems are often ignored. We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) that investigated the effectiveness of aromatherapy for intrapartum anxiety (IPA) and postpartum emotional symptoms (PES). METHODS: We searched PubMed, Embase, Cochrane library, and ClinicalTrials.gov to identify suitable RCTs for analysis, and the study was reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. RESULTS: Nine RCTs were included. The meta-analysis showed aromatherapy reduced IPA during the early to active phase (standardized mean difference [SMD]: -1.56 [-2.55, -0.61]) and during the transition phase (SMD: -3.30 [-4.97, -1.63]) when compared with controls. For the postpartum period, the meta-analyses showed a reduction of postpartum depression (PPD) at week 2 (SMD: -0.43 [-0.82, -0.03]), and a non-significant trend toward the reduction of PPD at weeks 4-6 (SMD: -0.70 [-1.40, 0.01]). CONCLUSION: Our study found some evidence supporting the effectiveness of aromatherapy in reducing intrapartum anxiety and PES. We recommend the optional use of aromatherapy for intrapartum and postpartum care.

Chromosomal Microarray Analysis as First-Tier Genetic Test for Schizophrenia.

Schizophrenia is a chronic, devastating mental disorder with complex genetic components. Given the advancements in the molecular genetic research of schizophrenia in recent years, there is still a lack of genetic tests that can be used in clinical settings. Chromosomal microarray analysis (CMA) has been used as first-tier genetic testing for congenital abnormalities, developmental delay, and autism spectrum disorders. This study attempted to gain some experience in applying chromosomal microarray analysis as a first-tier genetic test for patients with schizophrenia. We consecutively enrolled patients with schizophrenia spectrum disorder from a clinical setting and conducted genome-wide copy number variation (CNV) analysis using a chromosomal microarray platform. We followed the 2020 "Technical Standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen)" to interpret the clinical significance of CNVs detected from patients. We recruited a total of 60 patients (36 females and 24 males) into this study. We detected three pathogenic CNVs and one likely pathogenic CNV in four patients, respectively. The detection rate was 6.7% (4/60, 95% CI: 0.004-0.13), comparable with previous studies in the literature. Also, we detected thirteen CNVs classified as uncertain clinical significance in nine patients. Detecting these CNVs can help establish the molecular genetic diagnosis of schizophrenia patients and provide helpful information for genetic counseling and clinical management. Also, it can increase our understanding of the pathogenesis of schizophrenia. Hence, we suggest CMA is a valuable genetic tool and considered first-tier genetic testing for schizophrenia spectrum disorders in clinical settings.

Multiple Rare Risk Coding Variants in Postsynaptic Density-Related Genes Associated With Schizophrenia Susceptibility.

OBJECTIVE: Schizophrenia is a chronic debilitating neurobiological disorder of aberrant synaptic connectivity and synaptogenesis. Postsynaptic density (PSD)-related proteins in N-methyl-D-aspartate receptor-postsynaptic signaling complexes are crucial to regulating the synaptic transmission and functions of various synaptic receptors. This study examined the role of PSD-related genes in susceptibility to schizophrenia. METHODS: We resequenced 18 genes encoding the disks large-associated protein (DLGAP), HOMER, neuroligin (NLGN), neurexin, and SH3 and multiple ankyrin repeat domains (SHANK) protein families in 98 schizophrenic patients with family psychiatric history using semiconductor sequencing. We analyzed the protein function of the identified rare schizophrenia-associated mutants via immunoblotting and immunocytochemistry. RESULTS: We identified 50 missense heterozygous mutations in 98 schizophrenic patients with family psychiatric history, and in silico analysis revealed some as damaging or pathological to the protein function. Ten missense mutations were absent from the dbSNP database, the gnomAD (non-neuro) dataset, and 1,517 healthy controls from Taiwan BioBank. Immunoblotting revealed eight missense mutants with altered protein expressions in cultured cells compared with the wild type. CONCLUSION: Our findings suggest that PSD-related genes, especially the NLGN, SHANK, and DLGAP families, harbor rare functional mutations that might alter protein expression in some patients with schizophrenia, supporting contributing rare coding variants into the genetic architecture of schizophrenia.

Differential Expression of Multiple Disease-Related Protein Groups Induced by Valproic Acid in Human SH-SY5Y Neuroblastoma Cells.

Valproic acid (VPA) is a multifunctional medication used for the treatment of epilepsy, mania associated with bipolar disorder, and migraine. The pharmacological effects of VPA involve a variety of neurotransmitter and cell signaling systems, but the molecular mechanisms underlying its clinical efficacy is to date largely unknown. In this study, we used the isobaric tags for relative and absolute quantitation shotgun proteomic analysis to screen differentially expressed proteins in VPA-treated SH-SY5Y cells. We identified changes in the expression levels of multiple proteins involved in Alzheimer's disease, Parkinson's disease, chromatin remodeling, controlling gene expression via the vitamin D receptor, ribosome biogenesis, ubiquitin-mediated proteolysis, and the mitochondrial oxidative phosphorylation and electron transport chain. Our data indicate that VPA may modulate the differential expression of proteins involved in mitochondrial function and vitamin D receptor-mediated chromatin transcriptional regulation and proteins implicated in the pathogenesis of neurodegenerative diseases.

Detection of Rare Methyl-CpG Binding Protein 2 Gene Missense Mutations in Patients With Schizophrenia.

Deleterious mutations of MECP2 are responsible for Rett syndrome, a severe X-linked childhood neurodevelopmental disorder predominates in females, male patients are considered fatal. However, increasing reports indicate that some MECP2 mutations may also present various neuropsychiatric phenotypes, including intellectual disability, autism spectrum disorder, depression, cocaine addiction, and schizophrenia in both males and females, suggesting varied clinical expressivity in some MECP2 mutations. Most of the MECP2 mutations are private de novo mutations. To understand whether MECP2 mutations are associated with schizophrenia, we systematically screen for mutations at the protein-coding regions of the MECP2 gene in a sample of 404 schizophrenic patients (171 females, 233 males) and 390 non-psychotic controls (171 females, 218 males). We identified six rare missense mutations in this sample, including T197M in one male patient and two female controls, L201V in nine patients (three males and six females) and 4 controls (three females and one male), L213V in one female patient, A358T in one male patient and one female control, P376S in one female patient, and P419S in one male patient. These mutations had been reported to be present in patients with various neuropsychiatric disorders other than Rett syndrome in the literature. Furthermore, we detected a novel double-missense mutation P376S-P419R in a male patient. The family study revealed that his affected sister also had this mutation. The mutation was transmitted from their mother who had a mild cognitive deficit. Our findings suggest that rare MECP2 mutations exist in some schizophrenia patients and the MECP2 gene could be considered a risk gene of schizophrenia.

Functional analyses and effect of DNA methylation on the EGR1 gene in patients with schizophrenia.

EGR1, involved in the regulation of synaptic plasticity, learning, and memory, is considered a candidate gene for schizophrenia. We resequenced the exonic regions of EGR1 in 516 patients with schizophrenia and conducted a reporter gene assay. We found two mutations including a rare mutation (c.-8C>T, rs561524195) and one common SNP (c.308-42C>T, rs11743810). The reporter gene assay showed c.-8C>T mutant did not affect promoter activity. Gene expression analyses showed that the average EGR1 mRNA and protein levels in lymphoblastoid cell lines of schizophrenia in male, but not female, were significantly higher than those in controls. We conducted in vitro DNA methylation reaction, luciferase activity assay, and pyrosequencing to assess DNA methylation of EGR1 expression underlying the pathophysiology of schizophrenia. DNA methylation of the EGR1 promoter region attenuated reporter activity, suggesting that DNA methylation regulates EGR1 expression. There were no statistically significant differences in DNA methylation levels of 17 CpG sites at the EGR1 promoter region between 64 patients with schizophrenia compared with 64 controls. These results suggest that the exonic mutations in EGR1 and DNA methylation regulating EGR1 expression might not be associated with schizophrenia. However, the gender-specific association of elevated EGR1 expression might be involved in the pathophysiology of schizophrenia.

Labour pain control by aromatherapy: A meta-analysis of randomised controlled trials.

BACKGROUND: Aromatherapy is a treatment method that applies fragrant extracts from herbal plants, existed long ago in medical history as a major treatment approach and now used as an auxiliary treatment and sometimes a major treatment for pain and stress management, including those that occur in labour. AIM: We aimed to conduct a meta-analysis of randomised controlled trials of the effectiveness of aromatherapy on labour pain and duration reduction. METHODS: We searched the Pubmed, EMBASE, Cochrane Central Register of Controlled Trials, Google Scholar and Clinicaltrials.gov for randomised controlled trials investigating the effectiveness of aromatherapy on labour pain and duration. RESULTS: A total of 17 trials with low-risk labouring women were included for meta-analysis using the Review Manager 5.3. Meta-analyses showed that aromatherapy reduced labour pain in the transition phase and the duration of active phase and third stage labour; a trend toward shortened duration was observed in the second stage. Also, aromatherapy had no influences on emergency caesarean section, membrane rupture, and spontaneous labour onset. CONCLUSION: Our findings suggest that aromatherapy is effective in reducing labour pain and duration, and generally safe to the mothers. However, due to the heterogeneity across trials in some of the outcomes, further trials with device-based pain measurements, larger sample size, and more stringent design, should be conducted before strong recommendation.

Mutation analysis of the WNT7A gene in patients with schizophrenia.

Aberrant WNT signaling has been implicated in the pathophysiology of schizophrenia. WNT7A, a member of the WNT gene family, is considered a potential candidate of schizophrenia. All exons of WNT7A in 570 schizophrenic patients and 563 controls were sequenced, and protein functional analysis was conducted. Five common variants were identified, but none were noted to be associated with schizophrenia. Nevertheless, nine rare mutations, including one schizophrenia-specific missense mutation (c.305G > A), were discovered. However, immunoblot analysis findings revealed that the c.305G > A mutation did not affect protein expression. These results suggest that WNT7A is unlikely to be associated with susceptibility to schizophrenia.

DNA methylation analysis of the EGR3 gene in patients of schizophrenia.

DNA methylation has been implicated in the pathogenesis of schizophrenia. EGR3 is considered as a potential candidate gene for schizophrenia. We conducted in vitro DNA methylation reaction, Lucia luciferase activity assay, and pyrosequencing assay to assess the DNA methylation of the EGR3 expression underlying the pathophysiology of schizophrenia. We found that DNA methylation of the putative EGR3 regulatory regions attenuated Lucia luciferase activity. There was no difference in the DNA methylation pattern of EGR3 between in 50 schizophrenic patients and 47 controls. Our data suggest that DNA methylation regulated the expression of EGR3 might not be associated with schizophrenia.

Rare mutations and hypermethylation of the ARC gene associated with schizophrenia.

Activity-regulated cytoskeleton-associated protein (ARC), which interacts with the N-methyl-d-aspartate receptor (NMDAR) complex, is a critical effector molecule downstream of multiple neuronal signaling pathways. Dysregulation of the ARC/NMDAR complex can disrupt learning, memory, and normal brain functions. This study examined the role of ARC in susceptibility to schizophrenia. We used a resequencing strategy to identify the variants of ARC in 1078 subjects, including patients with schizophrenia and normal controls. We identified 16 known SNPs and 27 rare mutations. SNP-based analysis showed no association of ARC with schizophrenia. In addition, the rare mutations did not increase the burden in patients compared with controls. However, one patient-specific allele in the putative ARC promoter region and seven patient-specific mutants in ARC exon regions significantly reduced the reporter gene activity compared with ARC wild-type. Methylation of a putative ARC promoter attenuated reporter activity in vitro, suggesting that ARC expression is regulated by DNA methylation. Pyrosequencing revealed eight hypermethylated CpG sites in the putative ARC promoter region in 64 schizophrenic patients compared with 63 controls. Taken together, our results suggest that both rare variants and epigenetic regulation of ARC contribute to the pathogenesis of schizophrenia in some patients.