Comparison of coercive practices in worldwide mental healthcare: overcoming difficulties resulting from variations in monitoring strategies.

BACKGROUND: Coercive or restrictive practices such as compulsory admission, involuntary medication, seclusion and restraint impinge on individual autonomy. International consensus mandates reduction or elimination of restrictive practices in mental healthcare. To achieve this requires knowledge of the extent of these practices. AIMS: We determined rates of coercive practices and compared them across countries. METHOD: We identified nine country- or region-wide data-sets of rates and durations of restrictive practices in Australia, England, Germany, Ireland, Japan, New Zealand, The Netherlands, the USA and Wales. We compared the data-sets with each other and with mental healthcare indicators in World Health Organization and Organisation for Economic Cooperation and Development reports. RESULTS: The types and definitions of reported coercive practices varied considerably. Reported rates were highly variable, poorly reported and tracked using a diverse array of measures. However, we were able to combine duration measures to examine numbers of restrictive practices per year per 100 000 population for each country. The rates and durations of seclusion and restraint differed by factors of more than 100 between countries, with Japan showing a particularly high number of restraints. CONCLUSIONS: We recommend a common set of international measures, so that finer comparisons within and between countries can be made, and monitoring of trends to see whether alternatives to restraint are successful. These measurements should include information about the total numbers, durations and rates of coercive measures. We urge the World Health Organization to include these measures in their Mental Health Atlas.

Clinical Characteristics of Cryopyrin-Associated Periodic Syndrome and Long-Term Real-World Efficacy and Tolerability of Canakinumab in Japan: Results of a Nationwide Survey.

OBJECTIVE: We assess the clinical characteristics of patients with cryopyrin-associated periodic syndrome (CAPS) in Japan and evaluate the real-world efficacy and safety of interleukin-1 (IL-1) inhibitors, primarily canakinumab. METHODS: Clinical information was collected retrospectively, and serum concentrations of canakinumab and cytokines were analyzed. RESULTS: A total of 101 patients were included, with 86 and 15 carrying heterozygous germline and somatic mosaic mutations, respectively. We identified 39 mutation types, and the common CAPS-associated symptoms corresponded with those in previous reports. Six patients (5.9% of all patients) died, with four of the deaths caused by CAPS-associated symptoms. Notably, 73.7% of patients (100%, 79.6%, and 44.4% of familial cold autoinflammatory syndrome, Muckle-Wells syndrome, and chronic infantile neurological cutaneous articular syndrome/neonatal onset multisystem inflammatory disease, respectively) achieved complete remission with canakinumab, and early therapeutic intervention was associated with better auditory outcomes. In some patients, canakinumab treatment stabilized the progression of epiphysial overgrowth and improved height gain, visual acuity, and renal function. However, 23.7% of patients did not achieve inflammatory remission with crucial deterioration of organ damage, with two dying while receiving high-dose canakinumab treatment. Serological analysis of canakinumab and cytokine concentrations revealed that the poor response was not related to canakinumab shortage. Four inflammatory nonremitters developed inflammatory bowel disease (IBD)-unclassified during canakinumab treatment. Dual biologic therapy with canakinumab and anti-tumor necrosis factor-α agents was effective for IBD- and CAPS-associated symptoms not resolved by canakinumab monotherapy. CONCLUSION: This study provides one of the largest epidemiologic data sets for CAPS. Although early initiation of anti-IL-1 treatment with canakinumab is beneficial for improving disease prognosis, some patients do not achieve remission despite a high serum concentration of canakinumab. Moreover, IBD may develop in CAPS after canakinumab treatment.

Efficacy and safety of intravenous fosphenytoin for patients with acute herpes zoster-associated pain: A placebo-controlled randomized trial.

Acute zoster-associated pain develops in most patients with herpes zoster. Nonopioid analgesics are usually used to treat acute zoster-associated pain but are frequently ineffective. We administered intravenous fosphenytoin, the prodrug of phenytoin, to patients with acute zoster-associated pain to examine its analgesic efficacy and safety. At 13 medical institutions in Japan, we conducted a phase II, double-blind, placebo-controlled, randomized trial of intravenous fosphenytoin in Japanese inpatients with acute zoster-associated pain for whom nonopioid analgesics had shown an insufficient analgesic effect. The patients were randomly assigned (1:1:1) to receive a single intravenous dose of fosphenytoin at 18 mg/kg (high dose), a single intravenous dose of fosphenytoin at 12 mg/kg (low dose), or placebo. The primary endpoint was the mean change per hour (slope) in the numerical rating scale score from the baseline score until 120 min after dosing. Seventeen patients were randomly assigned to the low-dose fosphenytoin group (n = 6, median age 62.5 years, range 39-75 years), high-dose fosphenytoin group (n = 5, median age 69.0 years, range 22-75 years), and placebo group (n = 5, median age 52.0 years, range 38-72 years). One patient was excluded because of investigational drug dilution failure. This study was discontinued because of the influences of coronavirus disease 2019. The slope was significantly lower in the high- and low-dose fosphenytoin groups than in the placebo group (P < 0.001 and P = 0.016, respectively). Responsiveness to intravenous fosphenytoin (≥2-point reduction in the numerical rating scale score from baseline to 120 min after dosing) was inferred at plasma total phenytoin concentrations of 10-15 µg/mL. Treatment-emergent adverse events caused no safety concerns in the clinical setting and intravenous fosphenytoin was well tolerated. Intravenous fosphenytoin appears to be an effective and promising alternative treatment for acute zoster-associated pain. Trial Registration: ClinicalTrials.gov NCT04139330.

A Systemic Lupus Erythematosus Patient with Cutaneous Mycobacterium haemophilum Infection under Belimumab Treatment: A Case Report.

A 38-year-old female with systemic lupus erythematosus (SLE) initiated belimumab treatment. One month later, she presented with a reddish painful swelling on her right lower leg. She was treated with ceftriaxone and vancomycin. However, novel erythematous papules and indurated nodules appeared on both her lower legs. Skin biopsy revealed microabscess formation with mixed cell granuloma surrounded by inflammatory cell infiltration within the dermis with subcutaneous fat tissue. A large number of acid-fast bacilli were observed with Ziehl-Neelsen staining. DNA sequencing of both the hsp65 and the 16S rRNA sequences showed a 100% match with the corresponding region of Mycobacterium haemophilum. Mycobacterial culture revealed satellite growth enhancement on Middlebrook 7H11 agar plates around a paper strip containing hemin. She was treated with levofloxacin, rifabutin, and ethambutol. Within 13 months, her cutaneous lesions improved markedly without any side effects. The B cell-targeted biologic belimumab, a fully humanized IgG1γ monoclonal antibody that inactivates B lymphocyte stimulator, has been considered to be beneficial for active SLE. However, this therapy could increase the risk for the development of biologic therapy-associated mycobacterial infections, both tuberculosis and nontuberculous mycobacteria infections.

Analysis of cell death in Bacillus subtilis caused by sesquiterpenes from Chrysopogon zizanioides (L.) Roberty.

Recently, the antibacterial effects of essential oils have been investigated in addition to their therapeutic purposes. Owing to their hydrophobic nature, they are thought to perturb the integrity of the bacterial cell membrane, leading to cell death. Against such antibiotic challenges, bacteria develop mechanisms for cell envelope stress responses (CESR). In Bacillus subtilis, a gram-positive sporulating soil bacterium, the extracytoplasmic function (ECF) sigma factor-mediated response system plays a pivotal role in CESR. Among them, σM is strongly involved in response to cell envelope stress, including a shortage of available bactoprenol. Vetiver essential oil, a product of Chrysopogon zizanioides (L.) Roberty root, is also known to possess bactericidal activity. σM was exclusively and strongly induced when the cells were exposed to Vetiver extract, and depletion of multi-ECF sigma factors (ΔsigM, ΔsigW, ΔsigX, and ΔsigV) enhanced sensitivity to it. From this quadruple mutant strain, the suppressor strains, which restored resistance to the bactericidal activity of Vetiver extract, emerged, although attempts to obtain resistant strains from the wild type did not succeed. Whole-genome resequencing of the suppressor strains and genetic analysis revealed inactivation of xseB or pnpA, which code for exodeoxyribonuclease or polynucleotide phosphorylase, respectively. This allowed the quadruple mutant strain to escape from cell death caused by Vetiver extract. Composition analysis suggested that the sesquiterpene, khusimol, might contribute to the bactericidal activity of the Vetiver extract.

Keratinocyte-Like Cells Trans-Differentiated from Human Adipose-Derived Stem Cells, Facilitate Skin Wound Healing in Mice.

BACKGROUND: Mesenchymal stem cells (MSCs) have been reported to promote wound healing in both animal models and human studies. Among MSCs, adipose-derived stem cells (ADSCs) can be easily harvested in large quantities. OBJECTIVE: We investigated whether skin wound healing in mice can be facilitated by keratinocyte-like cells differentiated from ADSCs (KC-ADSCs). METHODS: For the wound contraction and epithelialization model, a 20 mm×20 mm fullthickness skin wound was made on the dorsum. For the wound epithelialization model, a 6 mm×6 mm full-thickness skin wound was made on the dorsum. A nitrile rubber stent with an inner diameter of 8 mm was sutured around the wounds to minimize wound contraction. Undifferentiated ADSCs (uADSCs) or KC-ADSCs was injected around the wound base in both models. To evaluate whether the injected ADSCs could enhance wound contraction in a skin wound, the contractile activity of ADSCs was assessed by an in vitro type I collagen gel contraction assay. Alpha-smooth muscle actin (αSMA) expressions in uADSCs and KC-ADSCs were also evaluated by flow cytometry and real-time polymerase chain reaction. RESULTS: In a wound contraction and epithelialization model, KC-ADSCs further facilitated wound healing compared with uADSCs. In a wound epithelialization model, KC-ADSCs also further facilitated wound epithelialization compared with uADSCs. The contractile activity of KC-ADSCs was lower than that of uADSCs. The uADSCs expressed high levels of αSMA, which decreased after the differentiation into keratinocyte-like cells. CONCLUSION: Our results suggest that the wound healing effect of KC-ADSCs depends primarily on re-epithelialization rather than wound contraction.

Melanocyte progenitor cells reside in human subcutaneous adipose tissue.

Based on the assumption that some progenitor cells in an organ might reside in neighboring adipose tissue, we investigated whether melanocyte progenitor cells reside in human subcutaneous adipose tissue. First, we examined the expression of human melanoma black 45 (HMB45) and microphthalmia-associated transcription factor (MITF) in undifferentiated adipose-derived stem cells (ADSCs) by immunostaining, RT-PCR, and western blotting. These two markers were detected in undifferentiated ADSCs, and their expression levels were increased in differentiated ADSCs in melanocyte-specific culture medium. Other melanocytic markers (Melan A, MATP, Mel2, Mel EM, tyrosinase, KIT, and PAX3) were also detected at variable levels in undifferentiated ADSCs, and the expression of some markers was increased during differentiation into the melanocyte lineage. We further showed that ADSCs differentiated in melanocyte-specific culture medium localized in the basal layer and expressed tyrosinase and HMB45 in a 3D epidermal culture system. Melanin deposits were also induced by ultraviolet-light-B (UVB) irradiation. These results demonstrate that melanocyte progenitor cells reside in human subcutaneous adipose tissue and that these cells might have the potential to differentiate into mature melanocytes. Melanocyte and keratinocyte progenitors residing in human subcutaneous tissue can be used for the treatment of skin diseases and skin rejuvenation in the future.

Skin advanced glycation end products as biomarkers of photosensitivity in schizophrenia.

OBJECTIVES: Photosensitivity to ultraviolet A (UVA) radiation from sunlight is an important side effect of treatment with antipsychotic agents. However, the pathophysiology of drug-induced photosensitivity remains unclear. Recent studies demonstrated the accumulation of advanced glycation end products (AGEs), annotated as carbonyl stress, to be associated with the pathophysiology of schizophrenia. In this study, we investigated the relationship among skin AGE levels, minimal response dose (MRD) with UVA for photosensitivity, and the daily dose of antipsychotic agents in patients with schizophrenia and healthy controls. METHODS: We enrolled 14 patients with schizophrenia and 14 healthy controls. Measurement of skin AGE levels was conducted with AGE scanner, a fluorometric method for assaying skin AGE levels. Measurement of MRD was conducted with UV irradiation device. RESULTS: Skin AGE levels and MRD at 24, 48, and 72 hr in patients with schizophrenia showed a higher tendency for photosensitivity than in the controls, but the difference was statistically insignificant. Multiple linear regression analysis using skin AGE levels failed to show any influence of independent variables. MRD did not affect skin AGE levels. CONCLUSIONS: Photosensitivity to UVA in patients with schizophrenia receiving treatment with antipsychotic agents might not be affected by skin AGE levels.

Analysis of finger vein variety in patients with various diseases using vein authentication technology.

In finger vein authentication technology, near-infrared rays penetrate the finger and are absorbed by the hemoglobin in blood. The veins appear as dark areas. The finger vein pattern images of patients with various diseases were acquired; a new evaluation method applying image processing technique ("E value") was developed, and it was examined whether the patterns have any characteristics differentiating them from those of healthy volunteers. As a result, low E values appeared in systemic sclerosis, mixed connective tissue disease, Sjögren's syndrome, and polymyositis/dermatomyositis. No statistical reduction in E value was shown in patients with rheumatoid arthritis, pernio (without rheumatic diseases), arteriosclerosis obliterans, diabetes, hypertension, hypothyroidism and alopecia areata. This technology could be used for screening and evaluation of some diseases and their conditions with impaired peripheral venous circulation. E value may be useful as an indicator of venous circulation.

An Agonistic Antibody to EPHA2 Exhibits Antitumor Effects on Human Melanoma Cells.

BACKGROUND/AIM: EPH receptor A2 (EPHA2) is highly expressed in aggressive types of human cancer, and is expected to be an excellent target molecule for antibody treatments. In this study, we investigated the therapeutic potential of antibody to EPHA2 against melanoma in vitro. MATERIALS AND METHODS: We generated three monoclonal antibodies (mAbs) to EPHA2 and examined cell-surface expression by flow cytometry. To investigate the ability to inhibit tumor cell migration therapy with mAbs to EPHA2, we performed a wound scratch assay and invasion assay. We investigated the therapeutic effects of immunotoxins consisting of toxin-conjugated EPHA2 mAbs. RESULTS: All human melanoma cell lines studied expressed EPHA2. Like natural ligand ephrin-A1, one of EPHA2 mAbs, SHM16, inhibited metastatic behavior of cells, such as migration and invasion. In addition, drastic growth inhibition and cytotoxicity were found using immunotoxin-conjugated SHM16. CONCLUSION: These observations indicate a promising role for EPHA2 as a target in antibody treatments for melanoma, and demonstrate the potential therapeutic effects of an agonistic antibody to EPHA2.

Adipose-derived stem cells express higher levels of type VII collagen under specific culture conditions.

Type VII collagen (Col7) is a major component of the anchoring fibrils at the dermoepidermal junction. Adipose-derived stem cells (ADSCs) are a cell population highly useful in regenerative medicine because of their ease of isolation and their potential for multilineage differentiation. Based on the observations that K14 was expressed in undifferentiated ADSCs and the expression was downregulated after differentiation into adipocytes, we speculated that ADSCs are keratinocyte stem/progenitor cells. ADSCs were co-cultured with fibroblasts on type IV collagen in a medium containing all-trans retinoic acid and bone morphogenetic protein 4. At day 14 of culture in keratinocyte serum-free medium, the cells were harvested and subjected to immunofluorescence, flow cytometry, real-time PCR, and western blotting. Approximately, 45% of ADSCs were immunostained positively for anti-human cytokeratin 10, and approximately 80% were stained positively for Col7. Flow cytometry, real-time PCR, and western blotting also confirmed that differentiated ADSCs expressed higher levels of Col7. These findings support the therapeutic potential of ADSCs, not only for wound healing, but also for the correction of Col7 deficiencies.

Characteristic Changes in the Aroma Profile of Patchouli Depending on Manufacturing Process.

Patchouli is used as an incense material and essential oil. The characteristic odor of patchouli leaves results from the drying process used in their production; however, there have to date been no reports on the changes in the odor of patchouli leaves during the drying process. We investigated the aroma profile of dried patchouli leaves using the hexane extracts of fresh and dried patchouli leaves. We focused on the presence or absence of the constituents of the fresh and dried extracts, and the differences in the content of the common constituents. Fourteen constituents were identified as characteristic of dried patchouli extract odor by gas chromatography-olfactometry analysis. The structures of seven of the 14 constituents were determined by gas chromatography-mass spectrometry (α-patchoulene, seychellene, humulene, α-bulnesene, isoaromadendrene epoxide, caryophyllene oxide, and patchouli alcohol). The aroma profile of the essential oil obtained from the dried patchouli leaves was clearly different from that of dried patchouli. The aroma profile of the essential oil was investigated by a similar method. We identified 12 compounds as important odor constituents. The structures of nine of the 12 constituents were determined by gas chromatography-mass spectrometry (cis-thujopsene, caryophyllene, α-guaiene, α-patchoulene, seychellene, α-bulnesene, isoaromadendrene epoxide, patchouli alcohol, and corymbolone). Comparing the odors and constituents demonstrated that the aroma profile of patchouli depends on the manufacturing process.

Aroma Profile of Galangal Composed of Cinnamic Acid Derivatives and Their Structure-Odor Relationships.

Cinnamic acid derivatives are important odorants due to their characteristic scent. Some fragrance materials, such as cinnamon bark, matsutake mushrooms, and Kaempferia galanga L. rhizome (galangal), contain several cinnamic acid derivatives as important odor constituents. The main odor constituent of glangal is (E)-ethyl 4-methoxycinnamate, but the odor of this compound is different from that of galangal. We investigated the aroma profile of galangal using our previously described method that considers the intermolecular interactions of the odorant compounds with their receptors. Odorant compounds in galangal were extracted by hexane extraction, steam distillation, and headspace sampling. The odor of the hexane extract was different from that of the steam - distillate and similar to that of galangal; therefore, we searched for the key compounds contributing to the aroma profile of galangal by separating the constituents of the hexane extract. A fraction with a galangal-like odor was obtained by bulb-to-bulb distillation of the hexane extract. The main component of this fraction was not (E)-ethyl 4-methoxycinnamate, but rather ethyl cinnamate. These results indicate that ethyl cinnamate is more important in the aroma profile of galangal than (E)-ethyl 4-methoxycinnamate. GC-MS analysis revealed that this fraction contained aromatic compounds, cyclic terpenes, and linear chain compounds in addition to ethyl cinnamate. We synthesized cinnamic acid derivatives and examined the importance of the odor expression of these cinnamic acid derivatives. Cinnamic acid derivatives lacking a p-methoxy group had a strong fruity odor. Replacement of the hydrogen atom at the para position with a methoxy group altered and weakened the odor. We found that a p-methoxy group in cinnamic acid derivatives plays an important role in the aroma profile of galangal.

Characteristic Aroma Features of Tencha and Sencha Green Tea Leaves Manufactured by Different Processes.

There are many varieties of tea (Camellia sinensis) obtained by different processing methods. In Japan, sencha tea has been used to brew beverages f6r centuries, and tencha leaves are used to make powdered green tea, matcha, which is used as an important food additive to impart the odor of green tea. We investigated the differences between the odors of sencha and tencha and their aroma profiles. We used our new technique to evaluate the odor of green tea, based on the theory that the aroma characteristics of materials arise from the interactions of groups of compounds with similar structures. Hexane extracts from sencha and tencha leaves were analyzed by gas chromatography-olfactometry. We detected several important compounds for tencha. The hexane extracts were separated by distillation, and groups of compounds with different boiling points were obtained. We investigated the group of high-boiling point constituents, which had a matcha-like odor and consisted of a group of odor constituents common to sencha and tencha. Tencha had a characteristic seaweed-like odor, and the low-boiling point constituents caused the differences in the tencha and sencha odors.

Aroma of Turmeric: Dependence on the Combination of Groups of Several Odor Constituents.

Turmeric is a popular material that plays an important role in the flavor and fragrance industries. Although many compounds have been reported as components of turmeric, its aroma profile has not been clarified. Recently we have developed a new approach for evaluating the complex odors of materials based on recent research on the mechanism of odor recognition. Here we report the characteristic aroma properties of turmeric obtained through the investigation of its aroma profile. The hexane extract of turmeric had a turmeric-like odor, whereas the steam distillate of turmeric had a pungent, non-turmeric-like odor. We carried out bulb-to-bulb distillations of the extract and the steam distillate. For the hexane extract, two fractions with completely different odors were obtained. One was a high boiling point fraction (group A) with a turmeric-like odor, which consisted of ar-turmerone and ß-turmerone as the main components, and the other was a low boiling point fraction (group B), which consisted of α-curcumene and ß-sesquiphellandrene. In contrast, the bulb-to-bulb distillation of the steam distillate gave a fraction (group C) with a very different odor from groups A and B. Group C was composed of several kinds of alcohols that were not present in groups A and B. These results indicate that the group C fraction causes the different, pungent odor of the turmeric oil obtained by steam distillation. The variation in the aroma of turmeric depended on the combination of these three groups of odor constituents.

The present status of and perspectives on home hemodialysis therapy in Japan.

Home hemodialysis (HHD) is one of the best choices for improving the quality of life and survival rate of dialysis patients because it can lead to longer and more frequent dialysis programs to aid in achieving adequate dialysis. There were 461 dialysis patients treated with HHD as of the end of 2013 in Japan, comprising only 0.1% of all dialysis patients in this country. Although this is a very small expansion rate, the number of HHD patients has been rapidly increasing in recent years. The Japanese Society for Home Hemodialysis was established in 1998 and formed the following 3 working groups to survey various problems underlying current HHD: Patient Registry, Supply and Waste, and Self-pay Burden. In order to achieve a successful HHD program in Japan, there are several issues to be resolved, including the development of standard recruitment and education programs, optimization of the composition of dialysis fluid, sufficient reimbursement for HHD, and the establishment of a business model for HHD similar to that for peritoneal dialysis.

Surgical excision of madelung disease using bilateral cervical lymphnode dissection technique-its effect and the influence of previous injection lipolysis.

Madelung disease, also known as benign symmetrical lipomatosis, is a rare condition characterized by symmetrical diffuse adipose tissue in the neck, shoulders, and arms. The present report described the case of a 51-year-old man diagnosed with Madelung disease who presented with masses primarily in the neck. He had previously shown partial improvement after injection lipolysis and shoulder surgery. However, 4 years later, following corticosteroid administration for the treatment of acute deafness, cervical lipomatosis progressed to the extent that he was unable to fasten his shirt. The initial treatment plan involved bilateral surgical excision of the lipomatous masses of the neck and liposuction for those in the submental area. However, the lipomas were adherent to the surrounding tissue and were partially fibrosed, presumably due to the previous injection lipolysis; thus, liposuction was not possible, and all the masses around the neck were carefully excised using cervical lymph node dissection technique. Thirty-two months later, the patient showed good cosmetic results, with no recurrence of cervical lipomatosis. Radical resection of the lipomas using a cervical dissection technique is useful in the treatment of Madelung disease; however, clinicians must consider the potential for adhesions and plan a meticulous dissection in those who have undergone injection lipolysis before the surgery.

Keratinocyte progenitor cells reside in human subcutaneous adipose tissue.

The differentiation of adipose-derived stem cells (ASCs) towards epithelial lineages has yet to be demonstrated using a standardized method. This study investigated whether keratinocyte progenitor cells are present in the ASC population. ASCs isolated from subcutaneous adipose tissue were cultured and examined for the expression of the keratinocyte progenitor markers p63 and desmoglein 3 (DSG3) by immunofluorescence microscopy and flow cytometry. In addition, p63 and DSG3 expression levels were assessed before and after differentiation of ASCs into adipocytes by real-time PCR and western blot analysis, as well as in subcutaneous adipose tissue by real-time reverse transcriptase polymerase chain reaction. Both markers were expressed in ASCs, but were downregulated after the differentiation of ASCs into adipocytes; p63-positive cells were also detected in subcutaneous adipose tissue. ASCs co-cultured with human fibroblasts and incubated with all-trans retinoic acid and bone morphologic protein 4 showed an upregulation in DSG3 level, which was also increased in the presence of type IV collagen. They also showed an upregulation in cytokeratin-5 level only in the presence of type IV collagen. These results provide the demonstration that keratinocyte progenitor cells reside in subcutaneous adipose tissue.