Sleep disorders among Yusho patients highly intoxicated with dioxin-related compounds: A 140-case series.

PURPOSE: Patients with Yusho, a condition caused by exposure to dioxins and dioxin-like compounds, have diverse mental and physical complaints. However, the relationship between dioxins and sleep disorders has not yet been examined. This cross-sectional study was designed to investigate problems associated with sleep among patients with Yusho. METHODS: A total of 140 participants (52.9% men, average age: 67.1 ±â€¯12.2 years) were examined using questionnaires and medical interviews by an expert on sleep medicine. Demographic and clinical characteristics, including blood concentrations of 2,3,4,7,8-pentachlorodibenzofuran (PeCDF), which is the major cause of Yusho, were obtained from the results of recent surveys conducted by the Yusho Study Group. RESULTS: Moderate to severe symptoms of insomnia were present in 51.8% of the patients. The median Pittsburgh Sleep Quality Index global score (PSQI GS) was 8 (interquartile range: 5-11). The prevalence of restless legs syndrome/Willis-Ekbom disease (RLS/WED) was 30.7%; 24.3% of patients had severe RLS/WED (distressing symptoms with a frequency ≥ 1day per week). A higher blood concentration of 2,3,4,7,8-PeCDF (≥72.27 pg/g lipid) and severe RLS/WED were associated with higher odds of a PSQI GS ≥8, after adjusting for covariates (odds ratio [95% confidence interval]: 4.84 [1.10-21.25] and 4.15 [1.53-11.28], respectively). CONCLUSIONS: Symptoms of insomnia were frequent, and the prevalence of RLS/WED was high in patients with Yusho. In addition to the presence of RLS/WED, a higher blood concentration of 2,3,4,7,8-PeCDF was associated with lower subjective sleep quality.

Highlighting Interleukin-36 Signalling in Plaque Psoriasis and Pustular Psoriasis.

Plaque psoriasis and pustular psoriasis are overlapping, but distinct, disorders. The therapeutic response to biologics supports the pivotal role of the tumour necrosis alpha (TNF-?)/ interleukin (IL)-23/IL-17/IL-22 axis in the pathogenesis of these disorders. Recently, functional activation of the IL-36 receptor (IL-36R) was discovered to be another driving force in the pathogenesis of psoriasis. This was first highlighted by the discovery that a loss-of-function mutation of the IL-36R antagonist (IL-36Ra) causes pustular psoriasis. Although the TNF-?/IL-23/IL-17/IL-22 axis and the functional activation of IL-36R are fundamentally involved in plaque psoriasis and pustular psoriasis, respectively, the 2 pathways are closely related and mutually reinforced, resulting in full-blown clinical manifestations. This review summarizes current topics on how IL-36 agonists (IL-36?, IL-36?, IL-36?) signal IL-36R, the pathological expression of IL-36 agonists and IL-36Ra in plaque and pustular psoriatic lesions, and the cross-talk between the TNF-?/IL-23/IL-17/IL-22 axis and the functional activation of IL-36R in the epidermal milieu.

Long-Term Health Effects of PCBs and Related Compounds: A Comparative Analysis of Patients Suffering from Yusho and the General Population.

Yusho, which refers to a mass poisoning caused by the ingestion of rice bran oil contaminated with polychlorinated biphenyls, polychlorinated dibenzo-p-dioxins, and polychlorinated dibenzofurans, was first reported in October 1968 in Japan. Yusho patients suffer from various symptoms; however, after 40 years, some emerging symptoms have been attributed to aging. The prevalence of symptoms and diseases among Yusho patients and the general population was compared in this study. The data obtained from the survey among Yusho patients (1131 patients) by the Ministry of Health, Labour, and Welfare of Japan in 2008 were compared with the data from a survey conducted among the general population. When selecting the comparison group, the age and residential area (prefecture) were taken into account to match the baseline characteristics of Yusho patients. A logistic regression analysis was performed to identify the association between Yusho and the prevalence of symptoms and was adjusted for various potential confounding factors (age, sex, body mass index, cigarette smoking, frequency of drinking, and walking time). Skin pigmentation and acneiform eruption were found to be characteristic symptoms of Yusho and were more prevalent in these patients. Other symptoms and diseases associated with Yusho included orthostatic hypotension, hypohidrosis, dysgeusia, Basedow's disease, hoarseness, cardiac insufficiency, tachycardia, eczema, and hair loss. Symptoms related to aging, such as general fatigue, arthralgia, and numbness in the extremities, were significantly higher in Yusho patients after adjusting for age and lifestyle. This study demonstrated that, 40 years after the outbreak of Yusho, the prevalence of various symptoms and diseases in Yusho patients, including age-related diseases, was higher than that in the general population.

Effect of colestimide on the concentrations of polychlorinated dibenzo-p-dioxins, polychlorinated dizenzofurans, and polychlorinated biphenyls in blood of Yusho patients.

BACKGROUND: Oral colestimide was reported to lower the concentration of PCDDs, PCDFs, and PCB in the blood of humans. A pilot study showed that the arithmetic mean total TEQ concentrations of PCDDs, PCDFs, and PCBs in the blood of subjects after the trial decreased approximately 20 % compared to pre-trial levels, suggesting that colestimide could decrease human dioxin levels. We designed the current clinical trial study based on this information. In this study, we examined whether colestimide could reduce the individual congener concentrations of PCDDs, PCDFs, and PCBs in the blood of Yusho patients. METHODS: Out of the 36 Yusho patients who participated in the clinical trial, 26 patients self-administered colestimide 3 g/day orally for 6 months. The concentrations of PCDDs, PCDFs and PCBs in the blood of 26 Yusho patients before the trial were compared with those after the trial. RESULTS: The arithmetic mean total TEQ concentrations of PCDDs, PCDFs, non-ortho PCBs, and mono-ortho PCBs in the blood of the 26 Yusho patients before and after the clinical trial were 42-303 (mean: 130, median: 120) and 43-283 (mean: 132, median: 118) pg TEQ/g lipid, respectively. The sums of the concentrations of 58 PCB congeners measured in the blood of Yusho patients before and after the trial were 321-2643 (mean: 957, median: 872) and 286-2007 (mean: 975, median: 806) ng/g lipid, respectively, indicating that the concentrations of PCDDs, PCDFs, and PCBs after the trial were almost the same as those before the trial. Among congeners of PCDDs, PCDFs, dioxin-like PCBs, and non-dioxin-like PCBs, most congeners of these compounds did not show a statistically significant decrease after the trial. CONCLUSION: Colestimide may not be beneficial in reducing the high blood levels of dioxin-like compounds in Yusho patients.

Change in decay rates of dioxin-like compounds in Yusho patients.

BACKGROUND: Once ingested, dioxins and dioxin-like compounds are excreted extremely slowly. Excretion can be evaluated by its half-life. Half-lives estimated from observed concentrations are affected by excretion and ongoing exposure. We investigated the change in apparent half-life using a theoretical model based on exposure to dioxin and dioxin-like compounds. METHODS: We carried out longitudinal measurements of the blood concentration of dioxins and dioxin-like compounds in a Yusho cohort during 2002 to 2010. We estimated the change in decay rates of 2,3,4,7,8-PeCDF and octachlorodibenzodioxin (OCDD) using a second-order equation. RESULTS: We found that the decay rate of OCDD increased, whereas the decay rate of 2,3,4,7,8-PeCDF of patients with a relatively high concentration of 2,3,4,7,8-PeCDF decreased. OCDD results were in accordance with decreasing levels of dioxin and dioxin-like compounds in the environment. The decay rate of OCDD in the body was affected by the decay rate of OCDD in the environment by ingestion because it was near the steady-state. In contrast, the decay rate of 2,3,4,7,8-PeCDF in the body was affected less by ingestion from the environment because it was far higher than in the steady-state. CONCLUSION: We demonstrated that the level of 2,3,4,7,8-PeCDF in the environment is decreasing. The excretion half-life is longer than the environmental half-life, thus the excretion half-life in a Yusho patient is increased.

A case of Basaloid Follicular Hamartoma.

We here describe a case of solitary basaloid follicular hamartoma (BFH) : the case developing in company with senile lentigo on the nose. BFH is a relatively rare benign follicular neoplasm of undetermined etiology. Histologically, the specimen consisted of small-sized squamoid or basaloid cells and follicular germ-like cells in the periphery of the tumor nests. There were no infundibular cysts. BFH should be differentiated from infundibulocystic basal cell carcinoma (BCC), which consists of squamoid or basaloid cells in company with infundibular cysts, tumor of follicular infundibulum or trichoepithelioma. We analyzed the immunohistochemical findings of the case in comparison with those of BCC and trichoepithelioma. An immunohistochemical examination revealed 1) that Bcl-2 and CD10 was preferentially expressed in the outermost cells in the tumor nests consisting of follicular germ-like cells, 2) that most of the tumor cells, especially germ-like cells, were strongly positive for Ber-EP4, and 3) that peritumoral stroma was positive for CD34. The immunohistochemical findings of our cases supported that BFH should be differentiated from BCC, a common malignant neoplasm.

Unexpectedly long half-lives of blood 2,3,4,7,8-pentachlorodibenzofuran (PeCDF) levels in Yusho patients.

BACKGROUND: Dioxins and dioxin-like compounds have half-lives typically between 7.2 years and 15 years. Our previous study of patients poisoned by extremely high concentrations of 2,3,4,7,8-pentachlorodibenzofuran (PeCDF) in the 'Yusho incident' in 1968 found that in some the half-life of blood 2,3,4,7,8-PeCDF tended towards infinity. This suggests that there are two groups of Yusho patients, those with 2,3,4,7,8-PeCDF half-lives around 10 years, and those with half-lives near infinity. We sought to establish the proportions of each in a cohort of 395 Yusho patients, and whether the proportions were changing over time. METHODS: We undertook longitudinal measurement of the blood concentration of 2,3,4,7,8-PeCDF in our cohort between 2002 and 2010. We estimated the change in concentration for each patient using linear regression for measured 2,3,4,7,8-PeCDF concentration, then compared the distribution of changes in concentrations with our previous study. RESULTS: In patients in whom the blood concentration of 2,3,4,7,8-PeCDF exceeded 50 pg/g lipid, the proportion 8.0% of patients exhibiting half-lives less than 13.3 years fell compared with our previous study (28.2%), while the proportion with near infinity half-lives increased. CONCLUSION: The prolongation of the half-lives was likely a consequence of age-related factors.

[Latest Findings of Yusho and Its Therapeutic Development].

Yusho incident is an unprecedented mass food poisoning that occurred in the western area of Japan in 1968. It was caused by the ingestion of rice bran oil contaminated with polychlorinated biphenyls (PCBs) and various dioxins and dioxin-like compounds, such as polychlorinated dibenzo-p-dioxins (PCDDs) and polychlorinated dibenzofurans (PCDFs). The victims of Yusho have suffered from characteristic skin manifestations in company with systemic, ophthalmological, and mucosal symptoms for a long period. Since the outbreak of Yusho, the Study Group of Yusho has been conducting annual medical check-ups on Yusho victims. We describe here the latest research findings of chronic dioxin-induced toxicity to Yusho patients and the mechanisms of toxicities of dioxins through the aryl hydrocarbon receptor (AhR) pathway. High amounts of PCBs and PCDFs are still present in a number of patients with Yusho. The patients have persistent various symptoms, some of which were significantly associated with blood levels of PCBs, dioxins, or dioxin-like compounds. The adverse effects on the next generation are also found. According to the findings of recent basic studies, the biological and toxicological effects mediated by the AhR system have been becoming clear; therefore, the therapeutic interventions may be found in the near future.

[Comparison of the prevalence of symptoms and medical histories between Yusho patients and healthy controls].

Yusho disease was first reported in October 1968 in western Japan. Although a previous survey revealed that Yusho patients have suffered from various symptoms for 40 years after the outbreak of Yusho, some symptoms could be caused by aging. Therefore, we compared the prevalence of symptoms and medical histories (symptoms or patient-reported diseases) between Yusho patients and healthy controls to demonstrate the effects of Yusho on health conditions. We conducted a survey of healthy controls who had already registered to a survey company and created a dataset of symptoms and medical histories. We then merged the healthy control data with the Yusho survey data obtained from The Ministry of Health, Labour, and Welfare of Japan. Statistical analyses were performed using a chi-square analysis for the incidence of symptoms. Symptoms included in the major diagnostic criteria for Yusho, such as pigmentation and acneform eruption, were expectedly higher in the Yusho patients than in the healthy individuals. Symptoms that could be caused by aging, such as general fatigue, arthralgia, and numbness in the extremities, were also significantly higher in the Yusho patients after adjustment for age, indicating the possibility that Yusho may cause various systemic symptoms and diseases.

[Effect of Cynaropicrin on 2,3,4,7,8-Pentachlorodibenzofuran-induced Wasting Syndrome and Oxidative Stress].

The effect of cynaropicrin that is the major component of an edible plant, artichoke (Cynara scolymus) on 2,3,4,7,8-pentachlorodibenzofuran (PenCDF)-induced toxicity in mice was studied. We evaluated the effect of cynaropicrin on the wasting syndrome and oxidative stress elicited by PenCDF. However, the PenCDF dose-response relationship on the wasting syndrome has been superficial. Therefore, we determined the dose which causes wasting syndrome in C57BL/6J mice, a responsive strain to dioxins. Since 2,3,7,8-tetrachlorodibenzo-p-dioxin (0.1 mg/kg, p.o.) induces hepatic ethoxyresorfin O-deethylase (EROD) activity in mice, we set the doses of PenCDF at 0.3, 1.0, 3.0, 5.0 and 10 mg/kg (once, p.o.) on the basis of its toxic-eqivalency factor (0.3). The wasting syndrome was evaluated by measuring the daily changes of body weight. Thiobarbituric acid-reactive substances were used as an index of oxidative stress. Of PenCDF doses examined, wasting syndrome and oxidative stress took place most markedly in 5 mg/kg. In disagreement with this, EROD activity which is the marker of the aryl hydrocarbon receptor-dependent induction of cytochrome P450 1a1 was elevated most abundantly at 0.3 mg/kg. Then, we examined the effect of cynaropicrin on the wasting syndrome and oxidative stress provoked by PenCDF at 5 mg/kg. However, this compound up to 20 mg/kg (p.o.) did not attenuate PenCDF-induced wasting syndrome. On the contray, PenCDF-induced oxidateive stress was suppressed by cynaropicrin at the highest dose (20 mg/kg), although EROD activity was increased rather than reduced by cynaropicrin at lower doses. Thus, it is suggested that cynaropicrin has an ability to reduce oxidative stress caused by PenCDF.

[Relationships between Half-Lives of Dioxins and SNPs in AhR among Yusho Patients].

Half-lives of blood levels of 2,3,4,7,8-Pentachlorodibenzofuran (PeCDF) are varied in Yusho patients. The objective was to evaluate a relationship between half-lives of PeCDF levels and types of SNP rs10249788 of aryl hydrocarbon receptor (AHR) gene in 93 Yusho patients. Based on physical symptoms, age, sex, body mass index and other factors, we set up suitable calculation formulas to fit the actual PeCDF levels thorough rates of change in PeCDF. We found that patients with C/T SNP had longer half lives than patients with C/C and T/T SNPs. Patients with T/T SNP are known to express higher amount of AHR mRNAs. However, detailed analysis could not be carried out in T/T group due to a limited number of patients (n = 11). Further research is warranted to determine the cause of the longer half-lives in C/T patients.

Antioxidant Houttuynia cordata extract upregulates filaggrin expression in an aryl hydrocarbon-dependent manner.

The plant Houttuynia cordata, which is called "dokudami" in Japanese, is known as a potent antioxidant herb that has been traditionally consumed as a folk medicine for various ailments, such as diabetes, obesity, cough, fever and skin diseases, in Asia. However, its antioxidant mechanism remains largely unknown. In the present study, we investigated the effects of Houttuynia cordata extract (HCE) on human keratinocytes. HCE activated aryl hydrocarbon receptor (AHR) and nuclear factor E2-related factor 2, with subsequent induction of the antioxidative enzyme NAD (P)H: quinone oxidoreductase 1 gene. HCE inhibited the generation of reactive oxygen species (ROS) in keratinocytes stimulated with tumor necrosis factor α or benzo(α)pyrene. Moreover, HCE upregulated the gene expression of filaggrin, an essential skin barrier protein, in an AHR-dependent manner. HCE may be beneficial for treating ROS-related photoaging and barrier-disrupted skin conditions.

Localization of S100A2, S100A4, S100A6, S100A7, and S100P in the human hair follicle.

The hair follicle is a highly differentiated structure. In this study, we examined immunohistological localization of S100A2, S100A4, S100A6, S100A7, and S100P using specific monoclonal antibodies. S100A2 was strongly expressed in the entire outer-root sheath (ORS), but more weakly in cuticle and medulla in the bulb. S100A6, S100A7, and S100P were expressed in the innermost cells of ORS. The cuticular area was weakly positive for S100A2, S100A6, S100A7, and S100P. S100A4 was expressed in dendritic Langerhans cells and melanocytes. Sebaceous cells were variably immunopositive for S100A2, S100A6, and S100A7. A subset of dermal papilla cells expressed S100A4 and S100A6. None of the antibodies labeled the inner-root sheath. The distinct spatiostructural distributions of the S100 family proteins suggest that each protein is differentially involved in the physiological function of normal hair follicles.

Preferential expression of OVOL1 in inner root sheath of hair, sebaceous gland, eccrine duct and their neoplasms in human skin.

OVOL1 is an important transcription factor for epidermal keratinization, which suppresses proliferation and switches on the differentiation of keratinocytes. A recent genome-wide association study has revealed that OVOL1 is one of the genes associated with susceptibility to atopic dermatitis. Although it is known to be expressed in murine skin and hair follicles, no investigations have focused on its localization in human skin. In the present study, we thus immunolocalized the expression of OVOL1 in normal and diseased human skin. In normal human skin, OVOL1 was preferentially expressed in the suprabasal layer of the epidermis, inner root sheath of hair, mature sebocytes and the ductal portion of the eccrine glands. Compared to this, no remarkable change in the expression of OVOL1 was observed among inflammatory skin diseases. The expression of OVOL1 was evident in eccrine poroma and hidradenoma. Moreover, it was overexpressed in Bowen's disease and sebaceous adenoma, in sharp contrast to its downregulation in their more malignant counterparts, squamous cell carcinoma and sebaceous carcinoma. OVOL1 may play an important role in human skin morphogenesis and tumorigenesis.

Localization of S100A2, S100A4, S100A6, S100A7, and S100P in the human hair follicle.

The hair follicle is a highly differentiated structure. In this study, we examined immunohistological localization of S100A2, S100A4, S100A6, S100A7, and S100P using specific monoclonal antibodies. S100A2 was strongly expressed in the entire outer-root sheath (ORS), but more weakly in cuticle and medulla in the bulb. S100A6, S100A7, and S100P were expressed in the innermost cells of ORS. The cuticular area was weakly positive for S100A2, S100A6, S100A7, and S100P. S100A4 was expressed in dendritic Langerhans cells and melanocytes. Sebaceous cells were variably immunopositive for S100A2, S100A6, and S100A7. A subset of dermal papilla cells expressed S100A4 and S100A6. None of the antibodies labeled the inner-root sheath. The distinct spatiostructural distributions of the S100 family proteins suggest that each protein is differentially involved in the physiological function of normal hair follicles.

A clinical trial of kampo formulae for the treatment of symptoms of yusho, a poisoning caused by dioxins and related organochlorine compounds.

The objective of this study was to evaluate the effectiveness of traditional herbal medicines (Kampo) on the symptoms of Yusho. Yusho is a mass food poisoning that was caused by ingestion of rice oil contaminated with dioxins and related organochlorines in 1968. Patients with Yusho suffer from skin symptoms (acneform eruptions, liability to suppuration and pigmentation), respiratory symptoms (cough and expectoration of sputum), neurological symptoms (numbness and paresthesia of extremities), arthralgia and general fatigue, and no effective treatment has yet been developed. In this clinical trial, four Kampo formulae (Bakumondo-to, Keigai-rengyo-to, Gosha-jinki-gan and Hochu-ekki-to) were administered to four representative Yusho symptoms (respiratory, skin, neurological symptoms and general fatigue), respectively. Twenty-seven Yusho patients were enrolled and two formulae were administered to each patient for half-a-year each. The effectiveness of Kampo formulae was estimated by changes in the intensity of symptoms measured by a visual analogue scale (VAS) of 100 mm recorded at baseline and after administration of each formula. The influence of Kampo formulae on patients' quality of life (QOL) was also assessed by the SF-36 (NBS). Twenty-five patients completed the treatment. Bakumondo-to significantly improved respiratory symptoms as well as patients' QOL in the context of vitality, compared with other formulae. In contrast, Hochu-ekki-to impaired patients' QOL in the context of physical functioning and vitality, compared with other formulae. This study demonstrated for the first time that a Kampo formula Bakumondo-to is useful for treating respiratory symptoms caused by dioxins.

Clinical practice guide for the treatment of perforating dermatosis.

Perforating dermatoses are a heterogeneous skin disease group defined by transepidermal elimination of various skin materials. Four classical forms of primary perforating dermatosis have been described, where the transepidermal elimination mechanism represents the hallmark of the disease: acquired reactive perforating collagenosis, elastosis perforans serpiginosa, Kyrle's disease and perforating folliculitis. Acquired reactive perforating collagenosis presents with transepidermal elimination of collagen fibers. Elastosis perforans serpiginosum presents with the elimination of elastic fibers. Kyrle's disease presents with transepidermal elimination of abnormal keratin. In perforating folliculitis, it is the content of the follicle. We established diagnostic criteria and severity classification. In addition, the Japanese guideline for treatment of perforating dermatoses was updated using the Medical Information Network Distribution Service (MINDS) methodology. The guideline is based on a systematic published work review completed from 1989 to 2019, and on a formal consensus and approval process. Most medical published work on the treatment is limited to individual case reports and small series of patients. The guideline covers treatment options considered relevant by the expert panel and approved in Japan at the time of the consensus conference.

Mycobacterium tuberculosis infection in psoriatic patients treated with biologics: Real-world data from 18 Japanese facilities.

Although rare, tuberculosis has been reported with biologic treatment against psoriasis in Japan, a tuberculosis medium-burden country. Mycobacterial infection often develops after a long incubation period and might not have been adequately identified in clinical trials or post-marketing surveillance. To determine the real-world incidence of tuberculosis in psoriatic patients treated with biologics, we conducted a retrospective, multicenter, observational study in 18 facilities in Western Japan. Psoriatic patients who visited a participating facility between 2010 and March 2017 and received biologic reagents were enrolled. Information on sex, age at first biologic treatment, results of interferon-γ release assay (IGRA) for Mycobacterium tuberculosis, treatment history with isoniazid, and onset of active and/or latent tuberculosis was collected. A total of 1117 patients (830 men and 287 women) were enrolled. The mean duration of biologic treatment was 3.54 years. Sixty-five patients (5.8%) showed positive IGRA results at screening. Active tuberculosis developed in two patients after the administration of tumor necrosis factor inhibitors (both involved miliary tuberculosis). Latent tuberculosis was observed in two patients treated with anti-interleukin-12/23p40 antibody. The incidence rate of tuberculosis, including latent tuberculosis, in this survey was 0.36%. Although the incidence rate of tuberculosis was low considering the observation period of biologic treatment, active tuberculosis was found in both the screening-negative group and a screening-positive subject after isoniazid prophylaxis (both miliary tuberculosis), concluding that negative screening or isoniazid treatment does not always assure that an individual has no tuberculosis. Hence, dermatologists still need to pay careful attention to tuberculosis at every patient visit.

[Evaluation of dermatological symptom of Yusho patients in the annual examination in 2005-2007].

Yusho is recognized as a poisoning by a mixture of polychlorinated biphenyls (PCBs), dioxins and related compounds. We have continued a follow-up of skin symptoms in patients not only for supporting patients' health but also for understanding the possible prolonged effects of exposure to PCBs and dioxins in humans. We evaluated the severity grades and the skin severity scores of the symptoms who visited the annual examinations of Fukuoka prefecture from 2005 to 2007. Forty years have passed since the Yusho incident, and about 70% of the patients currently present no skin symptoms. In contrast, in about 30% of the patients, characteristic skin symptoms of Yusho, such as pigmentation of skin, black comedones and acneform eruptions, could still be observed. We analyzed statistical correlations between blood levels of PCBs or dioxin and skin severity grades.