Japanese Society of Anxiety and Related Disorders/Japanese Society of Neuropsychopharmacology: Clinical practice guideline for social anxiety disorder (2021).

The development of clinical practice guidelines for social anxiety disorder began in March 2018 when the Joint Clinical Practice Guideline Development Committee for Anxiety and Obsessive-Compulsive Disorders was formed by the Japanese Society of Anxiety and Related Disorders and Japanese Society of Neuropsychopharmacology to jointly develop guidelines for anxiety and obsessive-compulsive disorders. Based on the universal concept of evidence-based medicine, three clinical questions (CQs) about pharmacotherapy and psychotherapy were developed for clinical guidelines for social anxiety disorder, panic disorders, and obsessive-compulsive disorder in accordance with the Minds "Manual for Guidelines Development 2017 by the Japan Council for Quality Health Care: CQ1-"What is the recommended pharmacotherapy for social anxiety disorder in adults?"; CQ2-"What is the recommended psychotherapy (psychological intervention) for social anxiety disorder in adults?"; and CQ3-"What are the recommendations regarding monotherapy and combination therapy for social anxiety disorder in adults in terms of pharmacotherapy and psychotherapy (psychological interventions)?" Summarized recommendations for social anxiety disorder in adults are selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitor for CQ1, cognitive behavioral therapy for CQ2, and there are no recommendations regarding monotherapy and combination therapy for CQ3. These were answered by considering the balance between benefits and harms based on systematic reviews of each. The aim of this brief guideline for the standard-of-care (i.e., medical treatment) for social anxiety disorder in adults (18 years and older) was to help "shared decision making," in which medical professionals, including physicians, and patients share scientific evidence to decide on a course of treatment.

Preliminary Evaluation of Translated and Culturally Adapted Internet-Delivered Cognitive Therapy for Social Anxiety Disorder: Multicenter, Single-Arm Trial in Japan.

BACKGROUND: Internet-delivered cognitive therapy for social anxiety disorder (iCT-SAD), which is a therapist-guided modular web-based treatment, has shown strong efficacy and acceptability in English-language randomized controlled trials in the United Kingdom and Hong Kong. However, it is not yet known whether iCT-SAD can retain its efficacy following linguistic translation and cultural adaptation of treatment contents and implementation in other countries such as Japan. OBJECTIVE: This study aimed to examine the preliminary efficacy and acceptability of the translated and culturally adapted iCT-SAD in Japanese clinical settings. METHODS: This multicenter, single-arm trial recruited 15 participants with social anxiety disorder. At the time of recruitment, participants were receiving usual psychiatric care but had not shown improvement in their social anxiety and required additional treatment. iCT-SAD was provided in combination with usual psychiatric care for 14 weeks (treatment phase) and for a subsequent 3-month follow-up phase that included up to 3 booster sessions. The primary outcome measure was the self-report version of the Liebowitz Social Anxiety Scale. The secondary outcome measures examined social anxiety-related psychological processes, taijin kyofusho (the fear of offending others), depression, generalized anxiety, and general functioning. The assessment points for the outcome measures were baseline (week 0), midtreatment (week 8), posttreatment (week 15; primary assessment point), and follow-up (week 26). Acceptability was measured using the dropout rate from the treatment, the level of engagement with the program (the rate of module completion), and participants' feedback about their experience with the iCT-SAD. RESULTS: Evaluation of the outcome measures data showed that iCT-SAD led to significant improvements in social anxiety symptoms during the treatment phase (P<.001; Cohen d=3.66), and these improvements were maintained during the follow-up phase. Similar results were observed for the secondary outcome measures. At the end of the treatment phase, 80% (12/15) of participants demonstrated reliable improvement, and 60% (9/15) of participants demonstrated remission from social anxiety. Moreover, 7% (1/15) of participants dropped out during treatment, and 7% (1/15) of participants declined to undergo the follow-up phase after completing the treatment. No serious adverse events occurred. On average, participants completed 94% of the modules released to them. Participant feedback was positive and highlighted areas of strength in treatment, and it included further suggestions to improve suitability for Japanese settings. CONCLUSIONS: Translated and culturally adapted iCT-SAD demonstrated promising initial efficacy and acceptability for Japanese clients with social anxiety disorder. A randomized controlled trial is required to examine this more robustly.

Antidepressants for social anxiety disorder: A systematic review and meta-analysis.

AIM: This systematic review is aimed to update and reintegrate the pharmacotherapy of social anxiety disorder (SAD), including the Japanese medical database. METHODS: We conducted a systematic review and meta-analysis of pharmacotherapy of SAD according to the Medical Information Distribution Service. We used data from a most recent systematic review, and updated search were conducted using MEDLINE, PubMed, CENTRAL, ICTRP, and ICHUSHI from August 1st, 2017 to January 31st, 2022. The outcome were response rates assessed by Clinical Global Impressions Improvement, efficacy assessed by the Liebowitz Social Anxiety Scale (LSAS), and dropout rates. We performed a random effect of meta-analysis to obtain the differences in each outcome between active medication and placebo. We used RevMan version 5.3 for analyses. RESULTS: We identified 5 studies through update search and performed meta-analysis for 33 studies on selective serotonin reuptake inhibitor (SSRI) and 6 studies on serotonin noradrenalin reuptake inhibitor (SNRI). The response rate (RR = 1.62) and the LSAS score reduction (mean difference = -9.65) of SSRI, and the response rate (RR = 1.57) and the LSAS score reduction (mean difference = -11.72) of SNRI were significantly different from placebo. The dropout rates of SSRI or SNRI were not significant. The response rates of SSRIs in both Japanese studies (RR = 1.44) and countries other than Japan (RR = 1.67) were significant. Most findings were based on low quality of evidence. CONCLUSION: SSRIs are valid option for pharmacotherapy of SAD including Japanese patients. SNRIs are another effective option. However, the results should be interpreted cautiously due to several risk of bias.

Distribution and metabolism of 14C-sulfoquinovosylacylpropanediol (14C-SQAP) after a single intravenous administration in tumor-bearing mice.

Sulfoquinovosylacylpropanediol (SQAP) is a novel potent radiosensitizer that inhibits angiogenesis in vivo and results in increased oxigenation and reduced tumor volume. We investigated the distribution, metabolism, and excretion of SQAP in male KSN-nude mice transplanted with a human pulmonary carcinoma, Lu65. For the metabolism analysis, a 2 mg (2.98 MBq)/kg of [glucose-U-14C]-SQAP (CP-3839) was intravenously injected. The injected SQAP was decomposed into a stearic acid and a sulfoquinovosylpropanediol (SQP) in the body. The degradation was relatively slow in the carcinoma tissue.1,3-propanediol[1-14C]-SQAP (CP-3635) was administered through intravenous injection of a 1 mg (3.48 MBq)/kg dose followed by whole body autoradiography of the mice. The autoradiography analysis demonstrated that SQAP rapidly distributed throughout the whole body and then quickly decreased within 4 hours except the tumor and excretion organs such as liver, kidney. Retention of SQAP was longer in tumor parts than in other tissues, as indicated by higher levels of radioactivity at 4 hours. The radioactivity around the tumor had also completely disappeared within 72 hours.

Selective Inactivation of Bacteriophage in the Presence of Bacteria by Use of Ground Rh-Doped SrTiO3 Photocatalyst and Visible Light.

Bacteriophage (denoted as phage) infection in the bacterial fermentation industry is a major problem, leading to the loss of fermented products such as alcohol and lactic acid. Currently, the prevention of phage infection is limited to biological approaches, which are difficult to apply in an industrial setting. Herein, we report an alternative chemical approach using ground Rh-doped SrTiO3 (denoted as g-STO:Rh) as a visible-light-driven photocatalyst. The g-STO:Rh showed selective inactivation of phage without bactericidal activity when irradiated with visible light (λ > 440 nm). After inactivation, the color of g-STO:Rh changed from gray to purple, suggesting that the Rh valence state partially changed from 3+ to 4+ induced by photocatalysis, as confirmed by diffuse reflectance spectroscopy. To study the effect of the Rh4+ ion on phage inactivation under visible-light irradiation, the survival rate of phage for g-STO:Rh was compared to that for ground Rh,Sb-codoped SrTiO3 (denoted as g-STO:Rh,Sb), where the change of Rh valence state from 3+ to 4+ is almost suppressed under visible-light irradiation due to charge compensation by the Sb5+ ion. Only g-STO:Rh effectively inactivated phage, which indicated that Rh4+ ion induced by photocatalysis particularly contributed to phage inactivation under visible-light irradiation. These results suggested that g-STO:Rh has potential as an antiphage material in bacterial fermentation.

Sporicidal performance induced by photocatalytic production of organic peroxide under visible light irradiation.

Bacteria that cause serious food poisoning are known to sporulate under conditions of nutrient and water shortage. The resulting spores have much greater resistance to common sterilization methods, such as heating at 100 °C and exposure to various chemical agents. Because such bacteria cannot be inactivated with typical alcohol disinfectants, peroxyacetic acid (PAA) often is used, but PAA is a harmful agent that can seriously damage human health. Furthermore, concentrated hydrogen peroxide, which is also dangerous, must be used to prepare PAA. Thus, the development of a facile and safe sporicidal disinfectant is strongly required. In this study, we have developed an innovative sporicidal disinfection method that employs the combination of an aqueous ethanol solution, visible light irradiation, and a photocatalyst. We successfully produced a sporicidal disinfectant one hundred times as effective as commercially available PAA, while also resolving the hazards and odor problems associated with PAA. The method presented here can potentially be used as a replacement for the general disinfectants employed in the food and health industries.

[The psychological effects of taking in "Shikohin": A cross-sectional exploratory study].

This study explores the psychological effects that Japanese people experience when consuming their "Shikohin", such as alcohol, tea, coffee, and tobacco. We'conducted a cross-sectional study among 542 people, from 20-to 69-year-old; who regularly consumed any one of "Shikohin" in Tokyo, Kanagawa, Saitama, and Chiba. The participants responded to an anonymous questionnaire concerning the consumption patterns of their "Shikohin" and the psychological effects that they experienced in taking in their "Shikohin". Results obtained using the K-J methods showed three common psychological effects in each "Shikohin". These effects included an increase in relaxation response, the promotion of social relationships, and an increase in positive mood. Our findings suggest that Japanese people may get some common effects through consumption of different "Shikohin".

Novel anticancer agent, SQAP, binds to focal adhesion kinase and modulates its activity.

SQAP is a novel and promising anticancer agent that was obtained by structural modifications from a natural compound. SQAP inhibits angiogenesis in vivo resulting in increased hypoxia and reduced tumor volume. In this study, the mechanism by which SQAP modifies the tumor microenvironment was revealed through the application of a T7 phage display screening. This approach identified five SQAP-binding proteins including sterol carrier protein 2, multifunctional enzyme type 2, proteasomal ubiquitin receptor, UV excision repair protein and focal adhesion kinase (FAK). All the interactions were confirmed by surface plasmon resonance analysis. Since FAK plays an important role in cell turnover and angiogenesis, the influence of SQAP on FAK was the principal goal of this study. SQAP decreased FAK phosphorylation and cell migration in human umbilical vein endothelial cells and A549 cancer cells. These findings suggest that inhibition of FAK phosphorylation works as the mechanism for the anti-angiogenesis activity of SQAP.

Enhancement of Cellulose Degradation by Cattle Saliva.

Saccharification of cellulose is a promising technique for producing alternative source of energy. However, the efficiency of conversion of cellulose into soluble sugar using any currently available methodology is too low for industrial application. Many additives, such as surfactants, have been shown to enhance the efficiency of cellulose-to-sugar conversion. In this study, we have examined first whether cattle saliva, as an additive, would enhance the cellulase-catalyzed hydrolysis of cellulose, and subsequently elucidated the mechanism by which cattle saliva enhanced this conversion. Although cattle saliva, by itself, did not degrade cellulose, it enhanced the cellulase-catalyzed degradation of cellulose. Thus, the amount of reducing sugar produced increased approximately 2.9-fold by the addition of cattle saliva. We also found that non-enzymatic proteins, which were present in cattle saliva, were responsible for causing the enhancement effect. Third, the mechanism of cattle saliva mediated enhancement of cellulase activity was probably similar to that of the canonical surfactants. Cattle saliva is available in large amounts easily and cheaply, and it can be used without further purification. Thus, cattle saliva could be a promising additive for efficient saccharification of cellulose on an industrial scale.

fMRI Study of Social Anxiety during Social Ostracism with and without Emotional Support.

Social anxiety is characterized by an excessive fear of being embarrassed in social interactions or social performance situations. Emotional support can help to decrease or diminish social distress. Such support may play an important role at different points of social interaction. However, it is unclear how the beneficial effects of social support are represented in the brains of socially anxious individuals. To explore this, we used the same paradigm previously used to examine the effects of emotional support on social pain caused by exclusion. Undergraduates (n = 46) showing a wide range of social anxiety scores underwent functional magnetic resonance imaging (fMRI) while participating in a Cyberball game. Participants were initially included and later excluded from the game. In the latter half of the session in which participants were excluded, they were provided with supportive messages. In line with our previous work, we found that social exclusion led to increased anterior cingulate cortex (ACC) activity, whereas emotional support led to increased left dorsolateral prefrontal cortex (DLPFC) activity. Despite validation of the paradigm, social anxiety was not associated with increased ACC activity during social exclusion, or during perceived emotional support. Instead, fear of negative evaluation as assessed by the Brief Fear of Negative Evaluation (BFNE) scale showed positive associations with left DLPFC activation while receiving emotional support, compared to while being socially excluded. The more socially anxious an individual was, the greater was the left DLPFC activity increased during receipt of messages. This suggests that highly socially anxious people still have the ability to perceive social support, but that they are nevertheless susceptible to negative evaluation by others.

Promotion of crystalline cellulose degradation by expansins from Oryza sativa.

MAIN CONCLUSION: Enzymatic activities of Oryza sativa expansins, which were heterologously overexpressed in Escherichia coli , were analyzed. Results suggested that expansins promote degradation of cellulose by cellulase in a synergistic manner. Sustainable production of future biofuels is dependent on efficient saccharification of lignocelluloses. Expansins have received a lot of attention as proteins promoting biological degradation of cellulose using cellulase. The expansins are a class of plant cell wall proteins that induce cell wall loosening without hydrolysis. In this study, the expansins from Oryza sativa were classified using phylogenetic analysis and five proteins were selected for functional evaluation. At low cellulose loading, the cellulase in expansin mixtures was up to 2.4 times more active than in mixtures containing only cellulase, but at high cellulose loading the activity of cellulase in expansin mixtures and cellulase only mixtures did not differ. Furthermore, expansin activity was greater in cellulase mixtures compared with cellulase-deficient mixtures. Therefore, the expansins showed significant synergistic activity with cellulase. Expansin may play an important role in efficient saccharification of cellulose.

Preliminary assessment of the behavioral activation model in Japanese undergraduate students.

Many studies have reported that behavioral activation is an effective intervention for depression. The behavioral activation model is based on several formulations. For example, depressive mood leads to avoidant behaviors, avoidance negatively affects social contacts, decreased socialization lessens opportunities for positive reinforcement, and a decrease in positive reinforcement results in more depressive mood. The purpose of this study was to examine relationships among avoidant behavior, social contact, frequency of positive reinforcement, and depressive mood by using structural equation modeling to assess support for aspects of this behavioral activation model. Participants were 630 Japanese undergraduate students and vocational school students. Results provided preliminary support for the model. Treating both avoidance and activating behavior might contribute to decreased impairment.

Mapping a disordered portion of the Brz2001-binding site on a plant monooxygenase, DWARF4, using a quartz-crystal microbalance biosensor-based T7 phage display.

In small-molecule/protein interaction studies, technical difficulties such as low solubility of small molecules or low abundance of protein samples often restrict the progress of research. Here, we describe a quartz-crystal microbalance (QCM) biosensor-based T7 phage display in combination use with a receptor-ligand contacts (RELIC) bioinformatics server for application in a plant Brz2001/DWARF4 system. Brz2001 is a brassinosteroid biosynthesis inhibitor in the less-soluble triazole series of compounds that targets DWARF4, a cytochrome P450 (Cyp450) monooxygenase containing heme and iron. Using a Brz2001 derivative that has higher solubility in 70% EtOH and forms a self-assembled monolayer on gold electrode, we selected 34 Brz2001-recognizing peptides from a 15-mer T7 phage-displayed random peptide library using a total of four sets of one-cycle biopanning. The RELIC/MOTIF program revealed continuous and discontinuous short motifs conserved within the 34 Brz2001-selected 15-mer peptide sequences, indicating the increase of information content for Brz2001 recognition. Furthermore, an analysis of similarity between the 34 peptides and the amino-acid sequence of DWARF4 using the RELIC/MATCH program generated a similarity plot and a cluster diagram of the amino-acid sequence. Both of these data highlighted an internally located disordered portion of a catalytic site on DWARF4, indicating that this portion is essential for Brz2001 recognition. A similar trend was also noted by an analysis using another 26 Brz2001-selected peptides, and not observed using the 27 gold electrode-recognizing control peptides, demonstrating the reproducibility and specificity of this method. Thus, this affinity-based strategy enables high-throughput detection of the small-molecule-recognizing portion on the target protein, which overcomes technical difficulties such as sample solubility or preparation that occur when conventional methods are used.

[Study of the voxel-based specific regional analysis system for Alzheimer's disease imaging sequence after magnetic resonance apparatus replacement].

In our institute, an MR apparatus, MAGNETOM VISION (Siemens) was replaced by ECHELON Vega (HITACHI). Z-score data acquired by MPRAGE (VISION) was compared with those by radio frequency-spoiled steady-state acquisition with rewinded gradient echo (RSSG) and gradient echo inversion recovery (GEIR) (ECHELON). For this study, ten normal volunteers were recruited and their data ware obtained within two months using both apparatuses. In addition, the difference of the contrasts of the images of these apparatuses was compared. There was a significant difference between Z-scores of MPRAGE and RSSG while there was no difference between MPRAGE and GEIR. As for the contrast, data of MPRAGE were similar to those of GEIR. To compare Z-scores acquired with MAGNTOM VISION (Siemens), it seems appropriate to use GEIR in ECHELON Vega.

Early somatosensory event-related potentials reveal attentional bias for internal stimuli in social anxiety.

The present study used event-related brain potentials (ERPs) to investigate allocation of attentional resources to internal and external stimuli in individuals with social anxiety. High and low socially anxious individuals were presented with depictions of various facial expressions or household objects, followed by an internal (vibration presented to the finger) or external probe (the letter "E"). Participants were told that the vibration signals physiological changes and were asked to detect both probes. High socially anxious individuals showed larger front-central N140 amplitudes in response to vibratory internal probes as compared to non-anxious controls. ERPs elicited by picture stimuli and external probes and reaction times in response to both probe types did not differ between high and low social anxiety individuals. Early somatosensory ERPs reveal an attentional bias for internal stimuli that does not appear in overt behavior.

Camptothecin (CPT) directly binds to human heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) and inhibits the hnRNP A1/topoisomerase I interaction.

Camptothecin (CPT) is an anti-tumor natural product that forms a ternary complex with topoisomerase I (top I) and DNA (CPT-top I-DNA). In this study, we identified the direct interaction between CPT and human heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) using the T7 phage display technology. On an avidin-agarose bead pull down assay, hnRNP A1 protein was selectively pulled down in the presence of C20-biotinylated CPT derivative (CPT-20-B) both in vitro and in vivo. The interaction was also confirmed by an analysis on a quartz-crystal microbalance (QCM) device, yielding a K(D) value of 82.7 nM. A surface plasmon resonance (SPR) analysis revealed that CPT inhibits the binding of hnRNP A1 to top I (K(D): 260 nM) in a non-competitive manner. Moreover, an in vivo drug evaluation assay using Drosophila melanogaster showed that the knockout of the hnRNP A1 homolog Hrb87F gene showed high susceptibility against 5-50 µM of CPT as compared to a wild-type strain. Such susceptibility was specific for CPT and not observed after treatment with other cytotoxic drugs. Collectively, our data suggests that CPT directly binds to hnRNP A1 and non-competitively inhibits the hnRNP A1/top I interaction in vivo. The knockout strain loses the hnRNP A1 homolog as a both CPT-binding partner and naïve brakes of top I, which enhances the formation of the CPT-top I-DNA ternary complexes and subsequently sensitizes the growth inhibitory effect of CPT in D. melanogaster.

The effects of video and nonnegative social feedback on distorted appraisals of bodily sensations and social anxiety.

The effects of video feedback and nonnegative feedback from other people were examined as possibly ameliorating distorted appraisals of bodily sensations, as well as subjective and physiological anxiety in socially anxious individuals. Nonnegative feedback from a confederate emphasized the absence of negative outcomes (e.g., did not seem to tremble) rather than the presence of positive outcomes (e.g., looked calm). Socially anxious students were randomly assigned to either the experimental group, which received video and social feedback (n=12), or the control group (n 13). Participants were asked to give a videotaped speech twice. After the first speech, the experimental group watched the videotape of their speech and received feedback from a confederate, whereas the control group watched the video of another person's speech. The intervention improved distorted appraisal of bodily sensations and anticipatory anxiety for the experimental group. However, there were no differential effects on anxiety between the groups during speeches.

Implicit and explicit associations in the fear structure of social anxiety.

Summary.-Implicit associations in the fear structure of social anxiety were investigated and their relations with explicit associations were examined in the present study. The Implicit Association Test was used to assess implicit associations. Individuals scoring High (n = 26) and Low (n = 18) on Social Anxiety completed two forms of the Implicit Association Test and rated the probability and cost of negative social outcomes. Analyses showed an implicit association between anxiety responses and negative evaluations was more strongly formed in the High Social Anxiety group than in the Low Social Anxiety group. Furthermore, relations between implicit associations and explicit measures were minimal. These findings suggested that the Implicit Association Test is suitable for the assessment of implicit associations in the fear structure of social anxiety, and that implicit associations of social anxiety are relatively independent of explicit associations.

[Distorted cognition of bodily sensations in subtypes of social anxiety].

The purpose of this study was to investigate the relationship between subtypes of social anxiety and distorted cognition of bodily sensations. The package of questionnaires including the Social Phobia Scale (SPS) and the Social Interaction Anxiety Scale (SIAS) was administered to 582 undergraduate students. To identify subtypes of social anxiety, cluster analysis was conducted using scores of the SPS and SIAS. Five clusters were identified and labeled as follows: Generalized type characterized by intense anxiety in most social situations, Non-anxious type characterized by low anxiety levels in social situations, Averaged type whose anxiety levels are averaged, Interaction anxiety type who feels anxiety mainly in social interaction situations, and Performance anxiety type who feels anxiety mainly in performance situations. Results of an ANOVA indicated that individuals with interaction type fear the negative evaluation from others regarding their bodily sensations whereas individuals with performance type overestimate the visibility of their bodily sensations to others. Differences in salient aspects of cognitive distortion among social anxiety subtypes may show necessity to select intervention techniques in consideration of subtypes.

Effects of safety behaviour on the maintenance of anxiety and negative belief social anxiety disorder.

BACKGROUND: Safety behaviour plays an important role in the maintenance of social anxiety disorder (SAD). SAD patients engage in various safety behaviours in social situations in order to decrease the risk of negative evaluations from others. AIMS: The present study examined the effect of safety behaviour on the maintenance of anxiety and negative belief in SAD by using Structural Equation Modelling (SEM). METHODS: Participants were a healthy group (442) and a SAD group (46) who met the SAD criteria for DSM-IV and who had high scores of SAD symptoms. In the assumed maintenance model, independence variables were safety and avoidance behaviour and dependence variables were anxiety and negative belief. RESULTS: This result showed that the SAD group significantly has more high scores than the healthy group in all scales of anxiety, negative belief and avoidance behaviour, expect for safety behaviour. The result of the multiple-group procedure indicated that safety behaviour contributes more strongly to anxiety and negative belief in the SAD group than in the healthy group. CONCLUSIONS: It is speculated that the SAD group have a stronger link between safety behaviour and negative belief than the healthy group, whereas frequency of the use of safety behaviour is equivalent between two groups. These results support the findings of previous studies.