Biennial Changes in the Characteristics of Patients with Methamphetamine Use Disorder in Japan from 2000 to 2020.

Methamphetamine is an illegal drug with the greatest burdens in Japan. Social and medical measures to combat methamphetamine dependence have been implemented, but no reports on changes in the characteristics of methamphetamine use disorder patients have been conducted. We aimed to describe these changes, and provide information on the results of social and medical measures. We concatenated cross-sectional surveys from 2000 to 2020 and analyzed biennial changes. Twenty-year data from 2000 to 2018 were age-weighted according to the age structure in 2020. We performed Cochran-Armitage trend tests for crude and age-weighted changes in patient variables. There was an increase in the number of patients with methamphetamine use disorder undergoing treatment and those with a history of drug-related arrests. Patients who achieved 1-year abstinence increased, and those diagnosed with psychotic disorders decreased. Patients with a history of non-drug-related arrests and without revealing their source of methamphetamine decreased. The ages of the patient population increased, and patients with a history of benzodiazepine misuse increased. Social measures linking methamphetamine users to psychiatric care may increase the number of patients who undergo treatment.

Potent bystander effect and tumor tropism in suicide gene therapy using stem cells from human exfoliated deciduous teeth.

Herpes simplex virus thymidine kinase (HSVTK)/ganciclovir (GCV) suicide gene therapy has a long history of treating malignant gliomas. Recently, stem cells from human exfoliated deciduous teeth (SHED), which are collected from deciduous teeth and have excellent harvestability, ethical aspects, and self-renewal, have been attracting attention mainly in the field of gene therapy. In the present study, we assessed SHED as a novel cellular vehicle for suicide gene therapy in malignant gliomas, as we have previously demonstrated with various cell types. SHED was transduced with the HSVTK gene (SHEDTK). In vitro experiments showed a significant bystander effect between SHEDTK and glioma cell lines in coculture. Furthermore, apoptotic changes caused by caspase 3/7 activation were simultaneously observed in SHEDTK and glioma cells. Mice implanted with a mixture of U87 and SHEDTK and treated with intraperitoneal GCV survived for longer than 100 days. Additionally, tumors in treatment model mice were significantly reduced in size during the treatment period. SHEDTK implanted at the contralateral hemisphere migrated toward the tumor crossing the corpus callosum. These results suggested that SHEDTK-based suicide gene therapy has potent tumor tropism and a bystander-killing effect, potentially offering a new promising therapeutic modality for malignant gliomas.

Efficacy of HSV-TK/GCV system suicide gene therapy using SHED expressing modified HSV-TK against lung cancer brain metastases.

Lung cancer is one of the most common cancers, and the number of patients with intracranial metastases is increasing. Previously, we developed an enzyme prodrug suicide gene therapy based on the herpes simplex virus thymidine kinase (HSV-TK)/ganciclovir (GCV) system using various mesenchymal stem cells to induce apoptosis in malignant gliomas through bystander killing effects. Here, we describe stem cells from human exfoliated deciduous teeth (SHED) as gene vehicles of the TK/GCV system against a brain metastasis model of non-small cell lung cancer (NSCLC). We introduced the A168H mutant TK (TKA168H) into SHED to establish the therapeutic cells because of the latent toxicity of wild type. SHED expressing TKA168H (SHED-TK) exhibited chemotaxis to the conditioned medium of NSCLC and migrated toward implanted NSCLC in vivo. SHED-TK demonstrated a strong bystander effect in vitro and in vivo and completely eradicated H1299 NSCLC in the brain. SHED-TK cells implanted intratumorally followed by GCV administration significantly suppressed the growth of H1299 and improved survival time. These results indicate that the TKA168H variant is suitable for establishing therapeutic cells and that intratumoral injection of SHED-TK followed by GCV administration may be a useful strategy for therapeutic approaches.

Variables associated with methamphetamine use within the past year and sex differences among patients with methamphetamine use disorder: A cross-sectional study in Japan.

BACKGROUND AND OBJECTIVES: Methamphetamine use disorder is the most common reason for psychiatrist visits among illicit drug users in Japan. Although variables associated with methamphetamine use and sex differences have been reported in the United States, Australia, and Asian countries, such studies are rare in Japan. We examined methamphetamine use within the past year among patients receiving treatment by sex and proposed important treatment targets. METHODS: This cross-sectional study analyzed the Nationwide Mental Hospital Survey on Drug-related Psychiatric Disorders. We divided 1086 men and 376 women into two groups according to methamphetamine use within the past year and conducted log-binomial regression analyses by sex to examine the variables associated with methamphetamine use. For methamphetamine users, the source was identified. RESULTS: Women were more likely to obtain methamphetamine from their friends, acquaintances, family members, or partners than men. Multivariable regression analysis showed that younger age in both sexes and higher educational attainment (prevalence ratio [PR] = 1.29; 95% confidence interval [CI] = 1.06-1.57) and employment (PR = 1.26; 95% CI = 1.05-1.51) were associated with methamphetamine use in men. Age-adjusted regression analysis showed that the variables associated with methamphetamine use were comorbid alcohol abuse and cannabis abuse in women and benzodiazepine abuse in both sexes. CONCLUSION AND SCIENTIFIC SIGNIFICANCE: In women, in particular, the surrounding relationships related to methamphetamine might be considered treatment targets. Young and working patients might need more accessible outpatient clinics and treatment programs. Comorbid substance abuse should be assessed and treated.

Risk and resilience in trajectories of post-traumatic stress symptoms among first responders after the 2011 Great East Japan Earthquake: 7-year prospective cohort study.

BACKGROUND: First responders to disasters are at risk of developing post-traumatic stress disorder (PTSD). The trajectories of post-traumatic stress symptom severity differ among individuals, even if they are exposed to similar events. These trajectories have not yet been reported in non-Western first responders. AIMS: We aimed to explore post-traumatic stress symptom severity trajectories and their risk factors in first responders to the 2011 Great East Japan Earthquake (GEJE) - a historically large earthquake that resulted in a tsunami and a nuclear disaster. METHOD: A total of 55 632 Japan Ground Self-Defense Force (JGSDF) personnel dispatched to the GEJE were enrolled in this 7-year longitudinal cohort study. PTSD symptom severity was measured using the Impact of Event Scale-Revised. Trajectories were identified using latent growth mixture models (LGMM). Nine potential risk factors for the symptom severity trajectories were analysed using multinomial logistic regression. RESULTS: Five symptom severity trajectories were identified: 'resilient' (54.8%), 'recovery' (24.6%), 'incomplete recovery' (10.7%), 'late-onset' (5.7%), and 'chronic' (4.3%). The main risk factors for the four non-resilient trajectories were older age, personal disaster experiences and working conditions. These working conditions included duties involving body recovery or radiation exposure risk, longer deployment length, later or no post-deployment leave and longer post-deployment overtime. CONCLUSIONS: The majority of first responders to GEJE were resilient and developed few or no PTSD symptoms. A substantial minority experienced late-onset and chronic symptom severity trajectories. The identified risk factors can inform policies for prevention, early detection and intervention in individuals at risk of developing symptomatic trajectories.

Migration Capacity of Stem Cells from Human Exfoliated Deciduous Teeth Towards Glioma.

BACKGROUND: Stem cells from human exfoliated deciduous teeth (SHED) are a mesenchymal stem cell type and have recently attracted attention for their high proliferative rate, multipotency, and immunosuppressive properties. However, SHED have not yet been investigated for anticancer properties. We therefore investigated whether SHED can be used as a treatment modality, particularly for anti-glioma therapy. METHODS: In vitro, we examined the mobility of SHED and their ability to migrate towards glioma-conditioned medium and specific growth factors secreted by malignant gliomas. In vivo, we transplanted SHED into the left hemisphere of nude mice that had been previously implanted with human malignant glioma U87 cells into the right hemisphere. We assessed whether SHED had tumorigenic potential. RESULTS: SHED exhibited strong migration ability towards malignant glioma in both in vitro and in vivo assays. In vitro, SHED migrated towards glioma-conditioned medium and specific growth factors such as stem cell factor, platelet-derived growth factor BB, C-X-C motif chemokine ligand 12, and vascular endothelial growth factor. SHED were accumulated around tumor cells in the contralateral hemisphere 1 week after transplantation. Moreover, SHED remained in the brains of nude mice 150 days after transplantation. Finally, we verified that SHED had no malignant transformation or engraftment of SHED in the mouse brain. CONCLUSIONS: Our findings indicate that SHED can potentially be applied to track malignant glioma.

Axonal damage and behavioral deficits in rats with repetitive exposure of the brain to laser-induced shock waves: Effects of inter-exposure time.

Much attention has been given to effects of repeated exposure to a shock wave as a possible factor causing severe higher brain dysfunction and post-traumatic stress disorder (PTSD)-like symptoms in patients with mild to moderate blast-induced traumatic brain injury (bTBI). However, it is unclear how the repeated exposure and the inter-exposure time affect the brain. In this study, we topically applied low-impulse (∼54 Pa·s) laser-induced shock waves (LISWs; peak pressure, ∼75.7 MPa) to the rat brain once or twice with the different inter-exposure times (15 min, 1 h, 3 h, 24 h and 7 days) and examined anxiety-related behavior and motor dysfunction in the rats as well as expression of ß-amyloid precursor protein (APP) as an axonal damage marker in the brains of the rats. The averaged APP expression scores for the rat brains doubly-exposed to LISWs with inter-exposure times from 15 min to 24 h were significantly higher than those for rats with a single exposure (P < 0.0001). The rats with double exposure to LISWs showed significantly more frequent anxiety-related behavior (P < 0.05) and poorer motor function (P < 0.01) than those of rats with a single exposure. When the inter-exposure time was extended to 7 days, however, the rats showed no significant differences either in axonal damage score or level of motor dysfunction. The results suggest that the cumulative effects of shock wave-related brain injury can be avoided with an appropriate inter-exposure time. However, clinical bTBI occurs in much more complex environments than those in our model. Further study considering other factors, such as the effects of acceleration, is needed to know the clinically-relevant, necessary inter-exposure time.

Does cognitive behavioral therapy for anxiety disorders assist the discontinuation of benzodiazepines among patients with anxiety disorders? A systematic review and meta-analysis.

Long-term use of benzodiazepines (BZD) is not recommended for the treatment of anxiety disorders. Cognitive behavioral therapy (CBT) is an effective treatment option for discontinuation of BZD in patients with anxiety disorders. This systematic review and meta-analysis sought to clarify whether CBT is effective for discontinuing BZD anxiolytics in patients with anxiety disorders. This study was preregistered with PROSPERO (registration number: CRD42019125263). A literature search of major electronic databases was conducted in December 2018. Three randomized controlled trials were included in this review, and meta-analyses were performed. The proportion of discontinuing BZD anxiolytics was significantly higher in the CBT plus gradual tapering group than in the gradual tapering alone group, both in the short term (3 months after allocation; number needed to treat: 3.2, 95% confidence interval [CI]: 2.1 to 7.1; risk ratio: 1.96, 95%CI: 1.29 to 2.98, P = 0.002, three studies) and long term (6 to 12 months after allocation; number needed to treat: 2.8, 95%CI: 1.9 to 5.3; risk ratio: 2.16, 95%CI: 1.41 to 3.32, P = 0.0004, three studies). CBT may be effective for discontinuing BZD anxiolytics, both in the short term and in the long term after the allocation. Further studies with larger sample sizes are necessary to draw definitive conclusions regarding the efficacy and safety of CBT for discontinuing BZD anxiolytics in patients with anxiety disorders.

A reciprocal inhibition model of alternations between under-/overemotional modulatory states in patients with PTSD.

Patients with posttraumatic stress disorder (PTSD) appear to manifest two opposing tendencies in their attentional biases and symptoms. However, whether common neural mechanisms account for their opposing attentional biases and symptoms remains unknown. We here propose a model in which reciprocal inhibition between the amygdala and ventromedial prefrontal cortex (vmPFC) predicts synchronized alternations between emotional under- and overmodulatory states at the neural, behavioral, and symptom levels within the same patients. This reciprocal inhibition model predicts that when the amygdala is dominant, patients enter an emotional undermodulatory state where they show attentional bias toward threat and manifest re-experiencing symptoms. In contrast, when the vmPFC is dominant, patients are predicted to enter an emotional overmodulatory state where they show attentional bias away from threat and avoidance symptoms. To test the model, we performed a behavioral meta-analysis (total N = 491), analyses of own behavioral study (N = 20), and a neuroimaging meta-analysis (total N = 316). Supporting the model, we found the distributions of behavioral attentional measurements to be bimodal, suggesting alternations between the states within patients. Moreover, attentional bias toward threat was related to re-experiencing symptoms, whereas attentional bias away from threat was related with avoidance symptoms. We also found that the increase and decrease of activity in the left amygdala activity was related with re-experiencing and avoidance symptoms, respectively. Our model may help elucidate the neural mechanisms differentiating nondissociative and dissociative subtypes of PTSD, which usually show differential emotional modulatory levels. It may thus provide a new venue for therapies targeting each subtype.

Assessment of Factors Associated With Long-term Posttraumatic Stress Symptoms Among 56 388 First Responders After the 2011 Great East Japan Earthquake.

Importance: First responders are at risk for developing symptoms of posttraumatic stress disorder (PTSD). Little is known about the risk factors for developing PTSD during a years-long period after complex mass disasters. Objective: To explore the long-term course of PTSD symptoms and to identify risk factors and their relative association with PTSD among first responders dispatched to the 2011 Japanese earthquake, tsunami, and nuclear disaster. Design, Setting, and Participants: This 6-year, large, prospective cohort study was part of a continuous longitudinal study of Japan Ground Self-Defense Force first responders. The data were collected at 1, 6, 12, 24, 36, 48, 60, and 72 months after mission completion from 2011 to 2017. Of approximately 70 000 eligible participants, 56 388 were enrolled in this study. Data were analyzed from 2017 to 2020. Exposures: Stress exposures owing to personal or professional disaster experience (eg, duties with body recovery or radiation exposure risk) and working conditions (eg, deployment length, postdeployment overtime work). Main Outcomes and Measures: The Impact of Event Scale-Revised score assessed PTSD symptoms; scores of at least 25 were defined as probable PTSD. Cox proportional hazards regression models assessed the risk factors for incidence of probable PTSD. Results: Among the 56 388 participants, 97.1% were men, and the median age at enrollment was 34 (range, 18-63) years. A probable PTSD rate was 2.7% at 1 month and showed a downward trend in the first year and a subsequent plateau. The cumulative incidence of probable PTSD was 6.75%. The severity of PTSD symptoms demonstrated a high degree of rank-order stability over time. Rather than professional disaster experience, sociodemographic factors and working conditions were independently associated with the incidence of probable PTSD: personal experience of the disaster (hazard ratio [HR], 1.96; 95% CI, 1.72-2.24), deployment length of at least 3 months (HR vs <1 month, 1.75; 95% CI, 1.52-2.02), increased age (HR for ≥46 vs ≤25 years, 2.28; 95% CI, 1.79-2.92), and postdeployment overtime work of at least 3 months (HR vs little to none, 1.61; 95% CI, 1.39-1.87). Conclusions and Relevance: Given these findings, in the future, first responders' PTSD symptoms might be mitigated by shortening deployment length, avoiding postdeployment overtime work, and paying special attention to the needs of personnel with personal experience of the disaster or older age. Efforts to alleviate responders' initial symptoms will be required.

General psychological distress among Japan Self-Defense Forces personnel dispatched on United Nations peacekeeping operations and their spouses.

AIM: The importance of family care during international deployment is emphasized within military organizations, but mental health interactions between deployed personnel and their spouses have not yet been assessed. This study addressed this gap by examining couples' mental health throughout a deployment period. METHODS: The mental health of 324 spousal dyads of Japan Self-Defense Forces personnel dispatched for a half-year United Nations Disengagement Observer Force mission was examined, using longitudinal data derived from a survey at four time points: one-month pre-deployment, initial deployment, middle deployment, and immediately after homecoming. The 30-item General Health Questionnaire was used to evaluate general psychological distress, with high scores (≥7) indicating adverse mental health. RESULTS: The spouses' general psychological distress was significantly higher compared with the deployed personnel (P < 0.001). The high general psychological distress of personnel was significantly related to that of their spouses (odds ratio = 2.24; 95% confidence interval, 1.32-3.80), and vice versa (odds ratio = 2.38; 95% confidence interval 1.39-4.08). CONCLUSION: Mental health care will be beneficial for not only deployed personnel but also their spouses.

The Psychological Impact of the Great East Japan Earthquake on Japan Ground Self-Defense Force Personnel: A Three-Wave, One-Year Longitudinal Study.

OBJECTIVE: Approximately 70,000 Japan Ground Self-Defense Force (JGSDF) personnel were dispatched in the wake of the 2011 Great East Japan Earthquake and the tsunami and nuclear disaster that followed. This study was conducted to evaluate the mental health of the JGSDF personnel and the correlates. METHODS: Data collected from 56,753 participants at three time points (one, six, and 12 months after mission completion) were analyzed. Those who scored 25 or more points on the Impact of Events Scale-Revised (IES-R) and the Kessler Psychological Distress Scale (K10) were allocated into the high posttraumatic stress response (high-PTSR) group, and the high general psychological distress (high-GPD) group, respectively. RESULTS: The multiple logistic regression analysis identified the following factors as the significant risk factor related to high-PTSR or high-GPD status, with odds ratios of 2.0 or higher: deployment length of three or more months, being personally affected by the disaster, and being overworked continuously for three or more months after mission completion. No significant association was observed for duties with radiation exposure risk. CONCLUSIONS: Our findings suggest that disaster workers may be able to conduct disaster relief activities more safely with mission-related considerations of shorter deployment length and recognizing the effects on personnel personally affected by the disaster, in addition to avoiding overworking personnel after mission completion.

Therapeutic effect of paroxetine on stress-induced gastric lesions in mice.

Compared to the well-known anti-ulcerogenic properties of tricyclic antidepressants, the impact of selective serotonin reuptake inhibitors (SSRIs) on gastric mucosa is less clear. Human clinical trials have shown that SSRIs and non-steroidal anti-inflammatory drugs (NSAIDs) act synergistically and promote stomach ulcer formation and upper gastrointestinal tract bleeding. Acute SSRI treatment confers an additional risk for the formation of NSAID-induced gastric ulcers through increase in gastric acid secretion. Stress, which is often experienced by depressed patients, also deteriorates the gastric environment. Thus the potential for exacerbating stress-induced gastric lesions must be considered before prescribing SSRIs. Therefore, we evaluated the effects of paroxetine by using a water-immersion stress-induced stomach ulcer model of mice, by examining single vs. repeated paroxetine treatments for 8 and 22 days before stress induction. Repeated administration of paroxetine significantly decreased the area of stress-induced stomach lesions. Although stress significantly increased the serum corticosterone concentrations, the levels were not affected by the 8-day paroxetine treatment. We confirmed the anxiolytic and antidepressive effects of 8-day paroxetine treatment at 1 and 5 days after stress induction by using the elevated plus-maze and tail-suspension tests. We concluded that repeated paroxetine treatment significantly attenuates the stress-induced ulcerogenic process in the stomach.

Evaluation of a game controller using human stiffness estimated from electromyogram.

A motion controller which has an acceleration sensor increases reality and intuitiveness in sports games. But we adjust not only visible posture but also invisible force like stiffness and viscosity when we play sports. We propose a game controller using player's movement and force by using acceleration and electromyogram(EMG). In this research, we compared conventional motion controller and proposed method by using a golf game. The score was the distance between cup position and carried ball position. For beginner of video games, proposed method is superior than conventional. For well-trained video game players conventional button type controller wins on accurate input. Because it was difficult to keep arm stiffness constant than button. Using coarsely-quantized EMG might resolve this problem, then achieve intuitive and easy-to-use game controller.

Mental health in Japanese members of the United Nations peacekeeping contingent in the Golan Heights: effects of deployment and the Middle East situation.

This study evaluates the mental health of Japan Self-Defense Force (JSDF) members of the peacekeeping contingent in the Golan Heights before and since the Second Gulf War between 1998 and 2003. Before the war, the General Health Questionnaire 30 (GHQ30) scores during and after duty tended to be lower than those before duty; all scores were lower than those of adult Japanese men in general. After the war, GHQ30 scores did not significantly change between before, during, and after duty. Manifest Anxiety Scale (MAS) scores were not significantly different between groups. Stressors identified included problems with foreign language and familial matters at home. Post war stressors included work content and relationships with collaborating foreign army units. These findings suggest that the mental health of contingent members remained stable, with some variation in mental health conditions influenced by the situation in the Middle East. This study suggests that the stable mental condition of JSDF personnel during their deployment in the absence of combat, and that this could be enhanced by education about mental health issues and by providing counseling support to their families.

Incidence of cancer among female flight attendants: a meta-analysis.

BACKGROUND: Airline flight personnel work in a unique environment with exposure to known or suspected carcinogens and mutagens including ionizing cosmic radiation. A meta-analysis was conducted to study whether the occupational exposure of female flight attendants (FA) increased their relative risk of cancer incidence. METHODS: A bibliographical computer search from 1966 to 2005 of cancer incidence cohort studies of female FA was performed. Combined relative risks (RRc) in cancer incidence were calculated by means of meta-analysis. RESULTS: RRc and 95% confidence interval (CI) for malignant melanoma and breast cancer in female FA were 2.13 (95% CI: 1.58-2.88) and 1.41 (1.22-1.62) (p < 0.0001). Excess risk was not significant for all-site cancer with RRc of 1.10 (0.99-1.21). CONCLUSIONS: The meta-analysis confirmed the significantly increased risks for malignant melanoma and breast cancer in female FA. Increased exposure to cosmic radiation during flight has been suggested as a potential occupational risk factor. Ultraviolet radiation exposure on board seems an unlikely occupational risk, but nonoccupational leisure time sun exposure is a possible risk factor. The etiology of the observed increase in incidence of some cancers remains controversial because assessment of possible confounders, especially nonoccupational exposure factors, has thus far been limited.

Effect of counterion species on colloidal crystal.

The effect of counterion species on the colloidal crystal structure in a dispersion was carefully investigated as a function of the degree of neutralization (alpha) by the ultra-small-angle X-ray scattering technique. The nearest neighbor interparticle distance (2D(exp)) first increased with decreasing alpha, and then decreased after passing through the maximum. This behavior was confirmed for K(+), Li(+), Ca(2+), TMA(+) (tetramethylammonium) as a counterion, and Na(+) in our previous report (Harada, T.; Matsuoka, H.; Ikeda, T.; Yamaoka, H. Langmuir 2000, 16, 1612). However, the alpha value of the maximum position (alpha(max)) largely depended on the counterion species, and it was in the order K(+) < Na(+) < TMA(+) approximately Li(+). This behavior was well characterized by the specific features of each ion: the alpha(max) map could be well superimposed in the Stokes radius-crystal ion radius relationship of counterions. The alpha(max) dependence on Stokes radius was very similar to that of the B coefficient by Jones and Dole except in the case of Ca(2+). In principle, the smaller the value for B, the smaller alpha(max), indicating that a water structure breaker such as K(+) can more easily destroy the colloidal crystal structure. In other words, the effect of the counterion species on colloidal crystal stability follows the Hofmeister series. Including Ca(2+), the relationship was linear for the alpha(max) values plotted as a function of the limiting equivalent conductivity of small ions. A counterion with larger conductivity would be a stronger breaker for the colloidal crystal structure.