Depletion of Ppp6c in hematopoietic and vascular endothelial cells causes embryonic lethality and decreased hematopoietic potential.

Protein phosphatase 6 (PP6) is a serine/threonine (Ser/Thr) protein phosphatase, and its catalytic subunit is Ppp6c. PP6 forms the PP2A subfamily with PP2A and PP4. The diverse phenotypes observed following small interfering RNA (siRNA)-based knockdown of Ppp6c in cultured mammalian cells suggest that PP6 plays roles in cell growth and DNA repair. There is also evidence that PP6 regulates nuclear factor kappa B (NF-κB) signaling and mitogen-activated protein kinases and inactivates transforming growth factor-ß-activated kinase 1 (TAK1). Loss of Ppp6c causes several abnormalities, including those of T cell and regulatory T cell function, neurogenesis, oogenesis, and spermatogenesis. PP2A has been reported to play an important role in erythropoiesis. However, the roles of PP6 in other hematopoietic cells have not been investigated. We generated Ppp6cfl/fl;Tie2-Cre (Ppp6cTKO) mice, in which Ppp6c was specifically deleted in hematopoietic and vascular endothelial cells. Ppp6cTKO mice displayed embryonic lethality. Ppp6c deficiency increased the number of dead cells and decreased the percentages of erythroid and monocytic cells during fetal hematopoiesis. By contrast, the number of Lin-Sca-1+c-Kit+ cells, which give rise to all hematopoietic cells, was slightly increased, but their colony-forming cell activity was markedly decreased. Ppp6c deficiency also increased phosphorylation of extracellular signal-regulated kinase 1/2 and c-Jun amino (N)-terminal kinase in fetal liver hematopoietic cells.

Oncogenic K-RasG12V cannot overcome proliferation failure caused by loss of Ppp6c in mouse embryonic fibroblasts.

Protein phosphatase 6 is a Ser/Thr protein phosphatase and its catalytic subunit is Ppp6c. Ppp6c is thought to be indispensable for proper growth of normal cells. On the other hand, loss of Ppp6c accelerates growth of oncogenic Ras-expressing cells. Although it has been studied in multiple contexts, the role(s) of Ppp6c in cell proliferation remains controversial. It is unclear how oncogenic K-Ras overcomes cell proliferation failure induced by Ppp6c deficiency; therefore, in this study, we attempted to shed light on how oncogenic K-Ras modulates tumor cell growth. Contrary to our expectations, loss of Ppp6c decreased proliferation, anchorage-independent growth in soft agar, and tumor formation of oncogenic Ras-expressing mouse embryonic fibroblasts (MEFs). These findings show that oncogenic K-RasG12V cannot overcome proliferation failure caused by loss of Ppp6c in MEFs.

Sex differences in the characteristics of stimulant offenders with a history of substance use disorder treatment.

We analyzed the results of a nationwide questionnaire administered to 699 stimulant offenders and examined sex differences in the association between various psychosocial problems and treatment history for substance use disorder. Based on their attributes, we predominantly evaluated the treatment and support provided to women with substance use disorder. The rates of childhood (before the age of 18) traumatic experiences (physical, psychological, and sexual abuse and neglect) and lifetime intimate partner violence were significantly higher in women than in men. The history of treatment for substance use disorder was also significantly higher in women than in men, at 15.8% for men and 42.4% for women [χ2 (1) = 41.223, p < 0.001]. Logistic regression analysis was performed using the treatment history of substance use disorder as the dependent variable. The results showed that treatment history was significantly associated with the total drug abuse screening test-20 score and suicidal ideation in men and with survivors of child abuse and eating disorders in women. A comprehensive assessment is required for several issues, such as child abuse, domestic violence, trauma symptoms, eating disorders, and drug problems. Moreover, an integrated treatment for substance use disorder, trauma, and eating disorders is required for female stimulant offenders.

Prevalence of adverse childhood experiences and their association with suicidal ideation and non-suicidal self-injury among incarcerated methamphetamine users in Japan.

BACKGROUND: Adverse childhood experiences (ACEs) are distressing and/or traumatic events that occur during childhood that increase the risk of negative health outcomes in adulthood. OBJECTIVE: This study estimated the prevalence of ACEs in a nationwide sample of Japanese methamphetamine users in prison and examined associations among ACEs, suicidal ideation, and non-suicidal self-injury. PARTICIPANTS AND SETTING: Participants were 636 inmates (418 male and 218 female) who were newly incarcerated in Japan for Stimulants Control Act violations. METHODS: First, 699 participants completed an anonymous self-report questionnaire. Of these, 636 participants who did not have any missing responses were included in the analysis. After calculating descriptive statistics, the associations between ACEs and suicidal behaviors were assessed using binary logistic regression analyses. RESULTS: Results showed that 76.1 % of the participants reported at least one ACE before the age of 18, and female participants reported a significantly higher number of adversities than their male counterparts. The most common ACEs were parental death or divorce, followed by psychological abuse. Logistic regression analyses revealed that ACE scores significantly increased the risk of suicidal ideation (SI; adjusted odd ratio [AOR] = 1.18, p < .001) and non-suicidal self-injury (NSSI; AOR = 1.18, p < .001) after controlling for possible confounding variables. CONCLUSIONS: Findings suggest the importance of early prevention and intervention for traumatic experiences, and have implications for the recommendation of gender-responsive, trauma-focused interventions, especially for female inmates in the criminal justice system, to break the intergenerational chain of abuse. Future research directions and treatment are discussed.

Gender Differences in the Relationship between Methamphetamine Use and High-risk Sexual Behavior among Prisoners: A Nationwide, Cross-sectional Survey in Japan.

This study aimed to examine the relationship between methamphetamine (MA) use and high-risk sexual behavior among newly incarcerated prisoners in Japan. We conducted a secondary analysis using cross-sectional survey data, which constituted a nationwide prison sample surveyed between July and November 2017. In total, 699 participants (462 male and 237 female prisoners), who completed the self-administered questionnaire during imprisonment were recruited for the study. The prevalence of high-risk sexual behaviors was as follows: inconsistent condom use (78.4% male, 81.7% female), multiple sexual partners (61.3% male, 41.3% female), history of sexually transmitted diseases (14.1% male, 23.6% female), and trading sex for drugs (15.6% male, 17.7% female). A logistic regression analysis showed that MA use during sex increased the likelihood of high-risk sexual behavior in both male (adjusted odds ratio [AOR] = 5.86; 95% confidence interval [CI] = 3.41-10.07) and female prisoners (AOR = 2.58; 95% CI = 1.33-5.00). Additionally, in female prisoners, a history of sharing MA injection (AOR = 1.60; 95% CI = 1.06-2.42) increased high-risk sexual behavior. Our results indicate that harm reduction programs tailored according to the specific necessities of each gender to reduce high-risk sexual behaviors among MA users should be included in Japanese drug policies.

The relationship between severity of drug problems and perceived interdependence of drug use and sexual intercourse among adult males in drug addiction rehabilitation centers in Japan.

BACKGROUND: Consuming drugs in conjunction with sexual intercourse may shape the perceived interdependence of drug use and sexual intercourse (PIDS). Additionally, the severity of drug problems may have a significant impact on PIDS. However, this relationship remains unverified. Therefore, this study investigates whether the severity of drug problems is associated with PIDS among adult males in drug addiction rehabilitation centers (DARC) in Japan. METHODS: This study was a secondary analysis of the "DARC Follow-Up Study in Japan" conducted by the National Center of Neurology and Psychiatry in 2016, in which participants from 46 facilities completed a self-report questionnaire. A total of 440 males with drug dependence were included in the analysis. We analyzed participants' demographic characteristics, history of sexually transmitted disease diagnoses, and responses to questions related to drug use (e.g., primary drug use and PIDS). Additionally, we measured the severity of drug problems using the Japanese version of the Drug Abuse Screening Test-20 (DAST-20). RESULTS: The median age of the participants was 42 years. The median DAST-20 score was 14.0, the primary drug was methamphetamine (61.4%) and new psychoactive substances (NPS: 13.6%). Multivariate analysis indicated that participants' experiences with unprotected sexual intercourse ("mostly a non-condom user": adjusted odds ratio (AOR) = 4.410), methamphetamine use (AOR = 3.220), new psychoactive substances use (AOR = 2.744), and the DAST-20 score (AOR = 1.093) were associated with PIDS. CONCLUSIONS: This study indicated that the frequency of unprotected sexual intercourse under the influence of drugs, methamphetamine and NPS use were strongly associated with PIDS. The severity of drug problems was also significantly associated with PIDS. It is necessary to develop culturally appropriate treatment programs adapted to the needs of patients who experience strong PIDS.

Gender Differences in Triggers of Stimulant Use Based on the National Survey of Prisoners in Japan.

BACKGROUND: There are a few studies on gender differences in terms of reasons and motives for methamphetamine use. Purpose/Objectives: To examine gender differences in triggers of methamphetamine use Methods: We provided a questionnaire survey to 699 inmates who were incarcerated because of violation of the Stimulants Control Act. Results: The results of DAST-20 (the severity of drug dependence) moderately correlated with the applicable numbers of the 37 situational triggers and 34 emotional triggers for stimulant use, respectively. Regarding gender differences, items including "when having sex" [46.3% (men) vs. 25.3% (women)], "when I have some money" (39.4% vs. 25.3%), and "after getting paid from work" (22.1% vs. 11.4%) were applicable in a significantly higher proportion in males (p < 0.001 and p = 0.008, respectively), whereas items including "worried about the body shape" (3.5% vs. 31.2%) and "after quarreling with someone" (11.7% vs. 29.1%) were applicable in a significantly higher proportion in females (p < 0.001 for both comparisons). Further, most trigger (emotions) items that exhibited gender differences were significantly higher in females. Many females answered that they had used drugs to relieve discomfort symptoms associated with menstrual periods. Conclusions/Importance: Thus, the awareness of important factors including learning how to deal with negative emotions (e.g. depression), repairing self-image, and recognizing physical and emotional changes associated with the menstrual cycle is helpful in providing proper care and treatment of drug addiction in females.

[Effectiveness evaluation of the drug dependency outpatient program "STEM"].

A cognitive behavioral therapy program entitled "STEM" was implemented with 42 drug dependent outpatients at Okayama Psychiatric Medical Center. Characteristics of 1 group who completed the program were examined, with the effectiveness of the program evaluated through monitoring longitudinal changes over a period of 8.5 months. Results showed that the percentage of patients who completed the program was 52.4% (22 out of 42 people), those who completed had a longer educational history than the dropouts, a high proportion of those who completed held some form of employment and that their motivation to recover was high. Evaluation results of the program effectiveness showed significant improvement in short-term drug self-efficacy, with a tendency for later improvement in feelings and emotions also observed. While a certain level of effectiveness was proven, approximately half the group dropped out; so it is necessary to consider alternative options at an early stage for participants with a high risk of dropout, such as strengthening individual support based on their specific characteristics.

[The Characteristics of Law-evading Drug Users and Effective Approaches].

  The increasing number of law-evading drug users in Japan is becoming a serious social problem. Previous studies have shown that law-evading drug users are younger, more educated, and less antisocial than methamphetamine users. They also tend to have some type of psychiatric disorder before starting drug use; therefore one of the reasons that they start using drugs may be to alleviate certain psychiatric symptoms. Furthermore, if drug users are successful in avoiding arrest, they often lack the motivation to stop, which makes treatment difficult. Therapists are required to be non-confrontational, to keep pace with their patients, and to take their patients' other existing disorders into account. Recently, the Matrix Model has shown promise as a new treatment strategy for drug abusers in Japan. The Matrix Model, which was originally developed in response to the 1980s cocaine epidemic in the USA, is an intensive outpatient treatment approach for drug abuse and dependence. The Matrix Model integrates cognitive-behavioral therapy, contingency management, motivational interviewing, 12-step facilitation, family involvement, and so on, with a directive, non-confrontational approach, and this style of therapy seems to fit with law-evading drug users. A Matrix Model-based treatment program was first established in Japan in 2006. The aim of this report is to introduce and assess the benefits of the TAMA Mental Health and Welfare Center Relapse Prevention Program, a Matrix Model-based treatment program established at the Tama Mental Health and Welfare Center in 2007.

Effectiveness evaluation of Serigaya Methamphetamine Relapse Prevention Program in drug addiction rehabilitation center.

The Serigaya Methamphetamine Relapse Prevention Program (SMARPP) cognitive behavioral therapy was implemented among 38 substance. abusers in 12-Step Program Treatment Centers operated by:the Drug Addiction Rehabilitation Center (DARC). Tochigi DARC members (20 patients) started SMARPP after attending daily programs in the treatment centers for an extended time (mean period, 17.4 months). Chiba and Tateyama DARC members (18 patients) started SMARPP soon after initiation of treatment (mean period, 1.2 months). We provided SMARPP for approximately 70 days in the treatment centers, in addition to the regular programs, and examined changes in the participants before and after SMARPP. The results showed that the Tochigi DARC members improved significantly after 70 days based on scores from the "taking steps" subscale of the Stages of Change Readiness and Treatment Eagerness Scale (SOCRATES) (Wilcoxon rank sum test, p=0.041) and the "tension-anxiety" subscale of the Profile of Mood States (POMS) (Wilcoxon rank sum test, p=0.004). However, the Chiba and Tateyama DARC members did not improve. In the 12-Step Program Treatment Centers, cognitive behavioral therapy-such as SMARPP seems to be more effective if it is implemented later rather immediately after regular programs.

[Evaluation of the relapse prevention program for substance abusers called "TAMARPP" at mental health and welfare center].

We developed the TAMA mental health and welfare center Relapse Prevention Program (TAMARPP) and evaluated the efficacy of the program. We provided the program for 59 substance abusers at Tokyo Tama Comprehensive Mental Health and Welfare Center, and conducted brief interviews and questionnaire surveys to them four times during eight months follow-up period. The main results were as follows. 1) Most of the subjects were before "hitting bottom". 2) More than half of the subjects continued participating in the program for more than 2 months and their attendance rate was fairly high. 3) Some of the subjects began joining a self-help group as N.A. and A.A. during the follow up period. 4) The mood states of the subjects were gradually improved during the period. 5) About one-third of the subjects abused substance again after two-month' program, but all of them continued to attend the program or a private counseling. Most of their families also continued having support from the center. These findings suggested it was meaningful to have such a friendly and less confrontational program as TAMARPP at our center to provide support for many substance abusers before "hitting bottom" and their families.

[Qualitative evaluation of TAMARPP, the relapse prevention program for substance abusers at the Mental Health and Welfare Center].

The development of an effective treatment system for patients with addiction-related problems like substance abuse or pathological gambling is urgently needed. The purpose of this study was to clarify the therapeutic factors of the Tama Mental Health and Welfare Center Relapse Prevention Program (TAMARPP). The program is provided at the Tama Comprehensive Center for Mental Health and Welfare, which is operated publicly by the Tokyo Metropolitan Government. Seven personnel (3 clinical psychologists, 2 public health nurses, and 2 recovering counselors) searched the consultation records of 31 participants who had continued treatment longer than 1 year, and made a list of qualitative factors that may positively impact participant outcome. The following six factors were extracted: 1) a "no-blame" atmosphere that makes participants feel safe and free; 2) a mutual helping process that enables participants to empathize with one another; 3) an individual-centered approach that focuses on a participant's motivation to recover; 4) a psycho-educational process that establishes treatment goals; 5) a treatment goal that involves some type of social role; and 6) the referral of graduates to another long-term treatment program such as Narcotics Anonymous. Our results suggest the need of personnel to provide treatment as follows: 1) keep the circumstances safe; 2) use a method that matches the participant's motivation; 3) refer graduates to another in-depth treatment program; 4) emphasize the relationship between thinking, emotion, and behavior; and 5) improve the quality of life of the participant. The missions of our center, an official institution that runs such a program, are as follows: 1) to be the first place at which addicts seek aid during the early stage; 2) to cooperate with other facilities in order to provide social resources that support recovery; and 3) to support patients suffering from both addiction and comorbid psychiatric diseases.

Purification and characterization of cellulase from North Pacific krill (Euphausia pacifica). Analysis of cleavage specificity of the enzyme.

Krill are filter feeders that consume algae, plankton and detritus, indicating that krill possess an adequate cellulose digesting system. However, less is known about the enzymatic properties of crustacean cellulases compared to termite cellulases. In the present study, 48 kDa-cellulase was highly purified from krill (Euphausia pacifica) in an effort to determine the cleavage specificity of the enzyme. The most notable characteristic of the enzyme was its high activity against both lichenan and carboxymethyl cellulose. The enzyme hydrolyzed internal ß-1,4 glycosidic bonds within lichenan as well as carboxymethyl cellulose to release oligosaccharides and glucose. The effects of pH and temperature on the activity and stability of both enzyme activities were almost identical. Cello-oligosaccharides with a degree of polymerization of 4-6 were hydrolyzed by the enzyme, and the same endo-products, cellotriose, cellobiose and glucose, were produced from these oligosaccharides. Neither cellotriose nor cellobiose was hydrolyzed by the enzyme. The enzyme digested filter paper and sea lettuce to produce cellobiose, cellotriose and glucose as major products. Although amino acid sequence homology of the enzyme with termite cellulases and the presence of oligosaccharides in the enzyme suggested that the enzyme is produced by krill itself, further analysis is necessary.

[Relapse prevention program for drug addicts in center for mental health and welfare].

The relapse prevention program named TAMARPP is provided for drug addicts at Tama comprehensive center for mental health and welfare. The TAMARPP is a group cognitive therapy based on manual and simple textbook. We are going to present the outline of the TAMARPP, and discuss the effectiveness of this program from the findings of clinical observation on 15 variables. Both of the treatment-retain rate and abstinence rate during the term to attend this program turns is rather high. This textbook-based program appears to be relatively easy for beginner therapists to conduct group sessions and to support drug addicts. The TAMARPP has possibility to prevail to perform in the other public health institutions.

Phthalate esters reveal skin-sensitizing activity of phenethyl isothiocyanate in mice.

Phenethyl isothiocyanate (PEITC) is a constituent of edible cruciferous vegetables and has received attention due to its potential cancer chemopreventive activity. Although its protein-binding activity is known, PEITC has not been studied as a contact sensitizer. We previously demonstrated that phthalate esters, including dibutyl phthalate (DBP) and di-n-propyl phthalate (DPP), enhance skin sensitization in a fluorescein isothiocyanate (FITC)-induced contact hypersensitivity mouse model. In this study, we examined whether DBP and DPP enhance skin sensitization to haptens other than FITC. During this study, we tested PEITC as a contact sensitizer. BALB/c mice were epicutaneously sensitized with a suboptimal dose of a hapten with or without a phthalate ester. Sensitization was evaluated as the ear swelling response after a challenge with the respective hapten. DBP and DPP did not enhance the sensitization to two T-helper 1-type (2,4-dinitrofluorobenzene and oxazolone) or three T-helper 2-type (trimellitic anhydride, methylenediphenyl 4,4'-diisocyanate, and tolulene 2,4-diisocyanate) haptens. In contrast, DBP and DPP enhanced the sensitization to two FITC analogues (eosin 5-isothiocyanate and rhodamine B isothiocyanate) as well as to PEITC. Adjuvant effects of DBP and DPP were observed in contact hypersensitivity to haptens other than FITC, including a food ingredient PEITC.

The effectiveness of a mutual-help group activity for drug users and family members in Japan.

AIMS: To understand the efficacy of a mutual-help group activity for drug users and family members in terms of: (a) family members' behavioral changes (b) treatment engagement rate of the drug users, and (c) life satisfaction of family members. METHODS: A total of 186 family members answered questionnaires. RESULTS: Attending the group changed the family members' behaviors. The treatment engagement rates within 1, 6, and 12 months for untreated drug users were 23.2%, 39.2%, and 52.3%, respectively. The well-being (Subjective Well-Being Inventory [SUBI]) of long-term group members is higher than that of short-term group members.

[Current situation of and the political measures for drug abuse/dependence].

More than 10 years has passed since 1995 when the third epidemic of methamphetamine abuse started in Japan. We are now still in the third epidemic of methamphetamine abuse, thought the current situation of drug abuse/dependence has obviously changed from previously. Considering several kinds of nationwide surveys and censuses, the authors summarized the change as follows: a) obvious decrease in solvent abuse/dependence, b) stabilization of methamphetamine abuse/dependence, c) increase in abuse of such drugs as cannabis or MDMA which don't have high potential to cause drug-induced psychosis, and d) emergence of non-regulatory drugs represented by designer drugs. These imply the change a) from "hard drugs" to "soft drugs", b) from Japanese unique situation which is symbolized by solvent abuse to Western situation which is symbolized by cannabis abuse, and c) from "illicit drugs" to "non-regulatory drugs". These characteristics reveal that there is the limitation to the Japanese Government policy which has tried to control the drug issue mainly as criminal cases for many years and that it is time now to change its policy. The authors stress the necessities of development of medical treatment targeting drug dependence and of its social support system.

Development and validation of the Stimulant Relapse Risk Scale for drug abusers in Japan.

OBJECTIVE: To develop and validate a multidimensional measure of relapse risk for stimulants in Japanese drug abusers. METHODS: A Stimulant Relapse Risk Scale (SRRS) was developed based on the Marijuana Craving Questionnaire and a discussion among three psychiatrists. We created 48 items after confirming the items including a variety of relapse risk, such as craving (expectancy, compulsivity, etc.) and emotionality problems. One hundred inpatients and outpatients with a history of stimulant abuse (71 males and 29 females) were recruited with informed consent, and were administered the SRRS. The Visual Analogue Scale for drug craving (VAS), Addiction Severity Index for Japanese (ASI-J), and data on relapse within 3 and 6 months after the rating were used for the validation. RESULTS: Exploratory factor analysis highlighted five factors: anxiety and intention to use drug (AI), emotionality problems (EP), compulsivity for drug use (CD), positive expectancies and lack of control over drug (PL), and lack of negative expectancy for drug use (NE). These accounted for 48.3% of the total variance. Thirty of the 43 items were classified into the five subscales. Cronbach's alpha coefficient for each subscale ranged from .55 to .82, and was .86 for the total SRRS, indicating their adequate internal consistency. AI, CD, PL, and total SRRS were significantly correlated with the drug-use composite score of the ASI-J, supporting their concurrent validity. AI, PL, NE, and total SRRS were significantly correlated with relapse, implying their predictive validity. CONCLUSIONS: The SRRS has multidimensional psychometric properties useful for assessing the various aspects of stimulant relapse risk.

Reliability and validity of the Japanese version of the Addiction Severity Index (ASI-J).

The Addiction Severity Index (ASI) is a frequently used clinical and research instrument that collects data from substance abusers in seven problem areas: medical, employment, alcohol, drug use, legal, family-social functioning, and psychiatric status. In each area, the ASI provides a composite score and severity rating that estimate the seriousness of the problem and the client's need for treatment. In the present study, we investigated the reliability and validity of the Japanese version of the ASI (ASI-J). One hundred and eleven subjects with a history of drug abuse were interviewed with a test battery including the ASI with informed consent. This revealed that: (a) the problem areas were independent of each other, underscoring the need for multidimensional assessment, (b) the inter-rater correlation of severity ratings in each area ranged from 0.68 to 0.99, and Cronbach's alpha coefficient for the items used for the composite score in each area ranged from 0.57 to 0.86, indicating their reliability with the exception of the drug and employment areas, and (c) several composite scores were significantly correlated with the drug craving levels assessed by a visual analogue scale, the abstinence period, mental health, and/or relapse, supporting their concurrent and predictive validity. These results suggest that the ASI-J has acceptable reliability and validity.