古橋 功一

BACKGROUND: The novel coronavirus disease (COVID-19) pandemic has no end in sight. Currently, the emphasis is on policies aimed at easing movement restrictions and maintaining socio-economic activities. However, infection control in psychiatric hospitals has been challenging. There have been reports on the impact on mental health and outpatient/inpatient treatment environments in the field of child psychiatry. An outbreak of COVID-19 was experienced in a child and adolescent psychiatric ward, and considering that there have been few similar reports, it was deemed meaningful to accumulate such experiences. CASE PRESENTATION: Three COVID-19-positive cases, all 14-year-old girls, were confirmed in a cluster among seven hospitalized patients in a child and adolescent psychiatric ward. Two patients presented symptoms of upper respiratory inflammation and one was asymptomatic. The main psychiatric diagnoses were post-traumatic stress disorder in one patient and autism spectrum disorder in the other two patients. The entire hospital ward was designated as a red zone (contaminated area), and infection control measures were adopted, such as halting group activities, wearing masks, and maintaining distance between patients. Additionally, it was necessary to use the infection control ward as it was difficult to ensure patient compliance. CONCLUSION: Infection control in COVID-19 clusters at child and adolescent psychiatric wards is difficult due to patient characteristics and symptoms. Restricted activities and care also result in psychobehavioral consequences, regardless of infection status. To achieve both infection control and a better treatment environment, it is necessary to make careful preparations while learning from these experiences.

＜Key Point＞・主訴の背景には、発達障害特性がある可能性を念頭におく必要がある・発達障害患者のうつ状態は、二次障害として整理すると理解しやすい・心理社会的要因への介入は、発達障害特性の考慮が欠かせない(著者抄録)

Schizophrenia is chronically progressed disease with a functional decline and adequate treatment is needed for respective clinical stages. Duration of psychosis before treatment is called DUP (duration of untreated psychosis) and may be an important predictor of outcome. Furthermore, the early phase of schizophrenia including DUP is considered a critical period, in which long-term outcome is predictable. Therefore, that shows the importance of early detection and intervention for schizophrenia and relapse prevention during a critical period. The atypical antipsychotics now play the leading role in pharmacotherapy of schizophrenia. They clearly decrease adverse effects, and may prevent the relapse and improve long-term outcome. However, better pharmacotherapy needs the viewpoint of adherence and we do not have to remember the importance of psychosocial therapy.

統合失調症やうつ病などの精神疾患も、多くの身体疾患と同様に、複数の遺伝的要因と環境要因が関与する多因子疾患であり、その背景として遺伝子環境相互作用の存在が示唆されている。統合失調症に関しては、遺伝要因の有無と、環境要因としての母体の妊娠合併症やストレス、父親の年齢、乳幼児期の養育環境や精神的外傷、児童思春期の都市居住や移民であること、大麻使用やストレスフルライフイベントなどとの関係が研究されてきた。また、カテコールOメチルトランスフェラーゼ(COMT)遺伝子多型と大麻使用との関係についても、統合失調症の発症に関して遺伝子環境相互作用が存在することが報告された。うつ病に関しても、双生児を対象とした前向きコホート研究から、遺伝要因とストレスフルライフイベントとの遺伝子環境相互作用が認められた。今後の研究の発展のためには、疫学的および実験的な研究手法の統合を進める必要がある。(著者抄録)

Organotins are widely used as stabilizers of polyvinyl chloride and as catalysts or biocides. It is well known that dimethyltin (DMT) is less neurotoxic than trimethyltin (TMT). A Korean worker who was exposed to DMT compounds showed neurological symptoms similar to those of TMT encephalopathy, in association with high levels of both DMT and TMT in the urine and blood. The case suggested the possibility of the methylation of DMT in humans. Here, we investigated whether TMT is detected in the urine of mice and rats exposed only to DMT dichloride (DMTC). Three Slc:ICR mice and three Slc:Wistar rats were placed in individual metabolic cages, and one day later, they were injected intraperitoneally with DMTC (10 mg/kg body weight (wt); 5.4 mgSn/kg body wt; 45.5 micromol/kg body wt) over 4 consecutive days. Twenty-four hour urine samples were collected every evening for 11 consecutive days starting at baseline (before treatment). Speciation analyses of methyltin compounds in urine were performed using a combination of high performance liquid chromatograph-inductively coupled plasma mass spectrometry. High concentrations of DMT and time-dependent increase in TMT concentrations were found in both mice and rats during the 4-day treatment, and their concentrations decreased gradually after the cessation of treatment. The chemical compound of the detected peak was confirmed to be TMT by liquid chromatography-tandem mass spectrometry. Neither DMT nor TMT was detected in the samples collected at baseline. Our results indicate urinary excretion of TMT in mice and rats injected with DMTC, confirming the production of TMT in vivo, probably through methylation of DMT.

Previous experiments indicated that 1-bromopropane (1-BP), an alternative to chloroflurocarbons, is neurotoxic and inhibits spermiation in the testis. Here we investigated the reversibility of the toxic effects of 1-BP in rats. Male Wistar rats were divided into three equal groups of 24 each and exposed by inhalation to 0, 400 or 1000 ppm of 1-BP for 6 weeks (8 hrs/day, 7 days/week). Eight rats from each group were sacrificed at the end of 6 weeks exposure, and at 4 and 14 weeks after the end of exposure, to assess the recovery processes. We studied sperm count, motility, morphology and testicular histopathology, as well as blood pressure, skin temperature and hindlimb muscle strength. At the end of 6 weeks of exposure to 1000 ppm (0 week recovery), testicular weight, epididymal weight, sperm count and motility were low, morphologically abnormal sperm were increased and spermatogenic cells showed diffuse degeneration. These changes did not show full recovery at 14 weeks recovery, with the exception of the prostate and seminal vesicular weights, which recovered back to control values. At 400 ppm, increased retained spermatids at 0 week recovery returned to normal at 4 weeks recovery. Exposure to 1000 ppm produced sustained reduction of hindlimb muscle strength at 14 weeks recovery, whereas normalization of the skin temperature and blood pressure was noted after transient changes. Our study showed that the effect of 1-BP on spermatogenesis is dose-dependent; low exposure inhibited spermiation and hormone-dependent organ weight reduction and these changes were transient, while a higher dose of 1000 ppm 1-BP caused persistent depletion of spermatogenic cells.

Cardiotoxicity is a treatment-limiting side effect of the anticancer drug doxorubicin (DOX). We have now investigated the roles of oxidative stress and signaling by the protein kinase Akt in DOX-induced cardiotoxicity as well as the effects on such toxicity both of fenofibrate, an agonist of peroxisome proliferator-activated receptor-alpha, and of polyethylene glycol-conjugated superoxide dismutase (PEG-SOD), an antioxidant. Mice injected intraperitoneally with DOX were treated for 4 days with fenofibrate or PEG-SOD. Fenofibrate and PEG-SOD each prevented the induction of cardiac dysfunction by DOX. Both drugs also inhibited the activation of the transcription factor NF-kappaB and increase in lipid peroxidation in the left ventricle induced by DOX, whereas only PEG-SOD inhibited the DOX-induced activation of Akt and Akt-regulated gene expression. These results suggest that fenofibrate and PEG-SOD prevented cardiac dysfunction induced by DOX through normalization of oxidative stress and redox-regulated NF-kappaB signaling.

Di(2-ethylhexyl)phthalate (DEHP), a commonly used industrial plasticizer, causes liver tumorigenesis presumably via activation of peroxisome proliferator-activated receptor alpha (PPARalpha). The mechanism of DEHP tumorigenesis has not been fully elucidated, and to clarify whether DEHP tumorigenesis is induced via PPARalpha, we compared DEHP-induced tumorigenesis in wild-type and Pparalpha-null mice. Mice of each genotype were divided into three groups, and treated for 22 months with diets containing 0, 0.01 or 0.05% DEHP. Surprisingly, the incidence of liver tumors was higher in Pparalpha-null mice exposed to 0.05% DEHP (25.8%) than in similarly exposed wild-type mice (10.0%). These results suggest the existence of pathways for DEHP-induced hepatic tumorigenesis that are independent of PPARalpha. The levels of 8-OHdG increased dose-dependently in mice of both genotypes, but the degree of increase was higher in Pparalpha-null than in wild-type mice. NFkappaB levels also significantly increased in a dose-dependent manner in Pparalpha-null mice. The protooncogene c-jun-mRNA was induced, and c-fos-mRNA tended to be induced only in Pparalpha-null mice fed a 0.05% DEHP-containing diet. These results suggest that increases in oxidative stress induced by DEHP exposure may lead to the induction of inflammation and/or the expression of protooncogenes, resulting in a high incidence of tumorigenesis in Pparalpha-null mice.

1-Bromopropane (1-BP) exhibits neuroreproductive toxicities in adult rats and humans. Here, we determined the effects of exposure of rat dams to 1-BP during pregnancy and lactation on the growth and sexual maturation of their offspring. In Experiment 1, 40 rats were exposed to 0, 100, 400 and 800ppm 1-BP during pregnancy and lactation for 8h/day. Ten rats that were not placed in chambers throughout the experiment served to observe the effect of separation of dams from offspring. In Experiment 2, three groups of 10 pregnant rats each were exposed to fresh air in three chambers and 10 other rats were exposed to 800ppm 1-BP during pregnancy and lactation for 8h/day. After delivery, offspring of the exposed and non-exposed dams were swapped so that they were nursed by the opposite dams. In Experiment 1, the survival rate and body weight of offspring were lower than the non-exposed in 1-BP dose-dependent manner. In Experiment 2, the survival rate and body weight of offspring (Group A) nursed by exposed dams and those (Group B) of exposed dams were significantly lower than non-exposed groups. The body weight of Group A was lower than that of Group B, although the two groups showed a significant equal decrease in the survival rate. The number of dead offspring from Group A was significantly higher. Our results indicate that exposure to 1-BP during pregnancy and lactation has comparable effects on survival rate, but exposure during lactation has a more adverse effect on growth of offspring than that during pregnancy. Moreover, exposure during lactation is associated with reduced early survival of third generation (F2) rats.