The D-mannose/L-galactose pathway plays a predominant role in ascorbate biosynthesis in the liverwort Marchantia polymorpha but is not regulated by light and oxidative stress.

Ascorbate plays an indispensable role in plants, functioning as both an antioxidant and a cellular redox buffer. It is widely acknowledged that the ascorbate biosynthesis in the photosynthetic tissues of land plants is governed by light-mediated regulation of the D-mannose/L-galactose (D-Man/L-Gal) pathway. At the core of this light-dependent regulation lies the VTC2 gene, encoding the rate-limiting enzyme GDP-L-Gal phosphorylase. The VTC2 expression is regulated by signals via the photosynthetic electron transport system. In this study, we directed our attention to the liverwort Marchantia polymorpha, representing one of the basal land plants, enabling us to conduct an in-depth analysis of its ascorbate biosynthesis. The M. polymorpha genome harbors a solitary gene for each enzyme involved in the D-Man/L-Gal pathway, including VTC2, along with three lactonase orthologs, which may be involved in the alternative ascorbate biosynthesis pathway. Through supplementation experiments with potential precursors, we observed that only L-Gal exhibited effectiveness in ascorbate biosynthesis. Furthermore, the generation of VTC2-deficient mutants through genome editing unveiled the inability of thallus regeneration in the absence of L-Gal supplementation, thereby revealing the importance of the D-Man/L-Gal pathway in ascorbate biosynthesis within M.  polymorpha. Interestingly, gene expression analyses unveiled a distinct characteristic of M. polymorpha, where none of the genes associated with the D-Man/L-Gal pathway, including VTC2, showed upregulation in response to light, unlike other known land plants. This study sheds light on the exceptional nature of M. polymorpha as a land plant that has evolved distinctive mechanisms concerning ascorbate biosynthesis and its regulation.

Evolutionary insights into strategy shifts for the safe and effective accumulation of ascorbate in plants.

Plants accumulate high concentrations of ascorbate, commonly in their leaves, as a redox buffer. While ascorbate levels have increased during plant evolution, the mechanisms behind this phenomenon are unclear. Moreover, has the increase in ascorbate concentration been achieved without imposing any detrimental effects on the plants? In this review, we focus on potential transitions in two regulatory mechanisms related to ascorbate biosynthesis and the availability of cellular dehydroascorbate (DHA) during plant evolution. The first transition might be that the trigger for the transcriptional induction of VTC2, which encodes the rate-limiting enzyme in ascorbate biosynthesis, has shifted from oxidative stress (in green algae) to light/photosynthesis (in land plants), probably enabling the continuous accumulation of ascorbate under illumination. This could serve as a preventive system against the unpredictable occurrence of oxidative stress. The second transition might be that DHA-degrading enzymes, which protect cells from the highly reactive DHA in green algae and mosses, have been lost in ferns or flowering plants. Instead, flowering plants may have increased glutathione concentrations to reinforce the DHA reduction capacity, possibly allowing ascorbate accumulation and avoiding the toxicity of DHA. These potential transitions may have contributed to strategies for plants' safe and effective accumulation of ascorbate.

Discovery of nitrate-CPK-NLP signalling in central nutrient-growth networks.

Nutrient signalling integrates and coordinates gene expression, metabolism and growth. However, its primary molecular mechanisms remain incompletely understood in plants and animals. Here we report unique Ca2+ signalling triggered by nitrate with live imaging of an ultrasensitive biosensor in Arabidopsis leaves and roots. A nitrate-sensitized and targeted functional genomic screen identifies subgroup III Ca2+-sensor protein kinases (CPKs) as master regulators that orchestrate primary nitrate responses. A chemical switch with the engineered mutant CPK10(M141G) circumvents embryo lethality and enables conditional analyses of cpk10 cpk30 cpk32 triple mutants to define comprehensive nitrate-associated regulatory and developmental programs. Nitrate-coupled CPK signalling phosphorylates conserved NIN-LIKE PROTEIN (NLP) transcription factors to specify the reprogramming of gene sets for downstream transcription factors, transporters, nitrogen assimilation, carbon/nitrogen metabolism, redox, signalling, hormones and proliferation. Conditional cpk10 cpk30 cpk32 and nlp7 mutants similarly impair nitrate-stimulated system-wide shoot growth and root establishment. The nutrient-coupled Ca2+ signalling network integrates transcriptome and cellular metabolism with shoot-root coordination and developmental plasticity in shaping organ biomass and architecture.

Reduced Expression of APUM24, Encoding a Novel rRNA Processing Factor, Induces Sugar-Dependent Nucleolar Stress and Altered Sugar Responses in Arabidopsis thaliana.

Ribosome biogenesis is one of the most energy-consuming events in the cell and must therefore be coordinated with changes in cellular energy status. Here, we show that the sugar-inducible gene ARABIDOPSIS PUMILIO PROTEIN24 (APUM24) encodes a Pumilio homology domain-containing protein involved in pre-rRNA processing in Arabidopsis thaliana Null mutation of APUM24 resulted in aborted embryos due to abnormal gametogenesis and embryogenesis, whereas reduced expression of APUM24 caused several phenotypes characteristic of ribosome biogenesis or function-related mutants. APUM24 interacted with other pre-rRNA processing factors and a putative endonuclease for the removal of the internal transcribed spacer 2 (ITS2) of pre-rRNA in the nucleolus. The APUM24-containing complex also interacted with ITS2, and reduced APUM24 expression caused the overaccumulation of processing intermediates containing ITS2. Thus, APUM24 likely functions as an ITS2 removal-associated factor. Most importantly, the apum24 knockdown mutant was hypersensitive to highly concentrated sugar, and the mutant showed sugar-dependent overaccumulation of processing intermediates and nucleolar stress (changes in nucleolar size). Furthermore, reduced APUM24 expression diminished sugar-induced promotion of leaf and root growth. Hence, a breakdown in the coordinated expression of ribosome biogenesis-related genes with energy status may induce nucleolar stress and disturb proper sugar responses in Arabidopsis.

The Transcriptional Cascade in the Heat Stress Response of Arabidopsis Is Strictly Regulated at the Level of Transcription Factor Expression.

Group A1 heat shock transcription factors (HsfA1s) are the master regulators of the heat stress response (HSR) in plants. Upon heat shock, HsfA1s trigger a transcriptional cascade that is composed of many transcription factors. Despite the importance of HsfA1s and their downstream transcriptional cascade in the acquisition of thermotolerance in plants, the molecular basis of their activation remains poorly understood. Here, domain analysis of HsfA1d, one of several HsfA1s in Arabidopsis thaliana, demonstrated that the central region of HsfA1d is a key regulatory domain that represses HsfA1d transactivation activity through interaction with HEAT SHOCK PROTEIN70 (HSP70) and HSP90. We designated this region as the temperature-dependent repression (TDR) domain. We found that HSP70 dissociates from HsfA1d in response to heat shock and that the dissociation is likely regulated by an as yet unknown activation mechanism, such as HsfA1d phosphorylation. Overexpression of constitutively active HsfA1d that lacked the TDR domain induced expression of heat shock proteins in the absence of heat stress, thereby conferring potent thermotolerance on the overexpressors. However, transcriptome analysis of the overexpressors demonstrated that the constitutively active HsfA1d could not trigger the complete transcriptional cascade under normal conditions, thereby indicating that other factors are necessary to fully induce the HSR. These complex regulatory mechanisms related to the transcriptional cascade may enable plants to respond resiliently to various heat stress conditions.

Effect of a concomitant elemental diet with maintenance anti-tumor necrosis factor-α antibody therapy in patients with Crohn's disease: A multicenter, prospective cohort study.

BACKGROUND AND AIM: The aim of this study was to clarify the additional effect of a concomitant elemental diet (ED) for patients with Crohn's disease on maintenance anti-tumor necrosis factor-α antibody (anti-TNF). METHODS: Crohn's disease patients who received anti-TNF induction therapy were enrolled. Patients who achieved clinical response (defined as delta Crohn's disease activity index [CDAI] > 70 and CDAI < 200) at 10-14 weeks after the start of infliximab or adalimumab were included. Eligible patients took a tolerability test of ED (900 kcal/day) for 3 days. Then, patients who preferred concomitant ED and whose ED tolerance was confirmed were allocated to the ED group and given Elental 900 kcal/day or more. Other patients were allocated to the non-ED group. The primary endpoint was the cumulative remission rate at 2 years after baseline. Clinical relapse was defined as CDAI > 200 and/or need for additional treatment. Adherence to the ED was confirmed at each visit. RESULTS: Seventy-two patients were included. Thirty-seven were allocated to the ED group, and 35 were allocated to the non-ED group. The cumulative remission rate at 2 years was not significantly different between the two groups (60.9% vs 56.7%, P = 0.98). Adherence to the ED in the ED group was relatively low, and only 11 patients were maintained on an ED of 900 kcal/day. CONCLUSIONS: The addition of ED for Crohn's disease patients who responded to initial anti-TNF induction therapy was not found to improve outcomes. The efficacy of concomitant ED in other clinical settings, such as loss of response, needs to be clarified in the future (UMIN000009789).

Clinical and Pharmacokinetic Factors Associated With Adalimumab-Induced Mucosal Healing in Patients With Crohn's Disease.

BACKGROUND & AIMS: We previously reported results from a prospective randomized controlled trial comparing the efficacy of adalimumab monotherapy versus combination with azathioprine for patients with Crohn's disease (CD) who were naive to biologics and thiopurines. We performed a subanalysis of data from this study to evaluate factors associated with endoscopic response and mucosal healing in study participants. METHODS: We compared simple endoscopic scores for CD between patients with moderate to severe active CD randomly assigned groups that received adalimumab monotherapy (n = 85) or adalimumab in combination with azathioprine (n = 91), from June 2011 to June 2014 in Japan. We evaluated associations of simple endoscopic scores for CD with clinical factors and trough levels of adalimumab. Ultimately, 135 patients at Week 26 and 139 patients at Week 52 from 44 referral sites were analyzed for the present investigation. RESULTS: The odds for endoscopic response were significantly higher in the combination group than in the monotherapy group at Week 26 (odds ratio [OR], 2.12; 95% confidence interval [CI], 1.04-4.32) but not at Week 52 (OR, 1.50; 95% CI, 0.77-2.94). The odds of mucosal healing did not differ significantly between groups at Weeks 26 or 52. Simple endoscopic scores for CD at Week 0 was significantly associated with mucosal healing at Week 26 (OR, 0.80; 95% CI, 0.72-0.90) and at Week 52 (OR, 0.91; 95% CI, 0.84-0.99). Higher adalimumab trough level at Week 26 associated with mucosal healing at Week 52 (OR, 1.34; 95% CI, 1.14-1.58; P for trend = .001) and was significantly higher in patients with endoscopic response than in patients without endoscopic response at Weeks 26 and 52 (P < .001). CONCLUSIONS: In a post hoc analysis of data from a randomized controlled trial of patients with moderate to severe CD, we found that adalimumab in combination with azathioprine increased trough levels of adalimumab. Higher trough levels of adalimumab associated with endoscopic response and mucosal healing at Weeks 26 and 52. UMIN registration No: 000005146.

Direct transcriptional activation of BT genes by NLP transcription factors is a key component of the nitrate response in Arabidopsis.

Nitrate modulates growth and development, functioning as a nutrient signal in plants. Although many changes in physiological processes in response to nitrate have been well characterized as nitrate responses, the molecular mechanisms underlying the nitrate response are not yet fully understood. Here, we show that NLP transcription factors, which are key regulators of the nitrate response, directly activate the nitrate-inducible expression of BT1 and BT2 encoding putative scaffold proteins with a plant-specific domain structure in Arabidopsis. Interestingly, the 35S promoter-driven expression of BT2 partially rescued growth inhibition caused by reductions in NLP activity in Arabidopsis. Furthermore, simultaneous disruption of BT1 and BT2 affected nitrate-dependent lateral root development. These results suggest that direct activation of BT1 and BT2 by NLP transcriptional activators is a key component of the molecular mechanism underlying the nitrate response in Arabidopsis.

Induction of plant disease resistance upon treatment with yeast cell wall extract.

It has been reported that treatment with yeast cell wall extract (YCWE) induces PDF1 and PR-1 gene expression; these transcripts are important markers of plant disease resistance, though the detailed signaling mechanisms that induce these defense responses are still unknown. In this report, we found that YCWE treatment triggered rice cell suspension cultures to accumulate phenylalanine (Phe), cis-12-oxo-phytodienoic acid (OPDA), 12-hydroxyjasmonoyle isoleucine (12OHJA-Ile), and azelaic acid (AzA). YCWE treatment also reduced endogenous triacylglycerol (TG) content. The addition of 13C-uniform-labeled oleic, linoleic and linolenic acids to the rice cell suspension cultures gave rise to 13C-uniform-labeled AzA. It was also found that YCWE treatment for Arabidopsis thaliana resulted in accumulations of OPDA, AzA, Phe, and camalexin together with enhanced resistance against Botrytis cinerea infection. This suggested that YCWE treatment upon plants may activate JA and AzA signaling systems to induce plant disease resistance.

A case of an intractable duodenal ulcer associated with a pancreatic arteriovenous malformation.

A 62-year-old man with epigastralgia was referred to our hospital for the evaluation of an intractable duodenal ulcer, which did not improve following proton pump inhibitor treatment. An upper gastrointestinal endoscopy revealed that the base of the ulcer was gray-white in color with conspicuous fibrosis tissue, unlike the appearance of common ulcers. A contrast-enhanced abdominal CT scan and angiography revealed tortuous and dilated vascular structures in the pancreatic head. This was diagnosed as a pancreatic arteriovenous malformation. We suggest that the intractable duodenal ulcer was caused by the pancreatic arteriovenous malformation. Therefore, we performed a pancreaticoduodenectomy. Pancreatic arteriovenous malformations should be considered as one of the causes of treatment-resistant duodenal ulcers.

Two distinct families of protein kinases are required for plant growth under high external Mg2+ concentrations in Arabidopsis.

Protein phosphorylation events play key roles in maintaining cellular ion homeostasis in higher plants, and the regulatory roles of these events in Na(+) and K(+) transport have been studied extensively. However, the regulatory mechanisms governing Mg(2+) transport and homeostasis in higher plants remain poorly understood, despite the vital roles of Mg(2+) in cellular function. A member of subclass III sucrose nonfermenting-1-related protein kinase2 (SnRK2), SRK2D/SnRK2.2, functions as a key positive regulator of abscisic acid (ABA)-mediated signaling in response to water deficit stresses in Arabidopsis (Arabidopsis thaliana). Here, we used immunoprecipitation coupled with liquid chromatography-tandem mass spectrometry analyses to identify Calcineurin B-like-interacting protein kinase26 (CIPK26) as a novel protein that physically interacts with SRK2D. In addition to CIPK26, three additional CIPKs (CIPK3, CIPK9, and CIPK23) can physically interact with SRK2D in planta. The srk2d/e/i triple mutant lacking all three members of subclass III SnRK2 and the cipk26/3/9/23 quadruple mutant lacking CIPK26, CIPK3, CIPK9, and CIPK23 showed reduced shoot growth under high external Mg(2+) concentrations. Similarly, several ABA biosynthesis-deficient mutants, including aba2-1, were susceptible to high external Mg(2+) concentrations. Taken together, our findings provided genetic evidence that SRK2D/E/I and CIPK26/3/9/23 are required for plant growth under high external Mg(2+) concentrations in Arabidopsis. Furthermore, we showed that ABA, a key molecule in water deficit stress signaling, also serves as a signaling molecule in plant growth under high external Mg(2+) concentrations. These results suggested that SRK2D/E/I- and CIPK26/3/9/23-mediated phosphorylation signaling pathways maintain cellular Mg(2+) homeostasis.

[A case of serous cystic neoplasm with atypical imaging results suggestive of a prismatic internal structure].

The patient was a 67-year-old man with a 39-mm unilocular pancreatic tumor detected by computed tomography (CT). Further examinations with contrast-enhanced CT, magnetic resonance imaging, endoscopic ultrasonography, and endoscopic retrograde cholangiopancreatography revealed an internal heterogeneous structure attributed to bleeding or necrosis. Consequently, we expected either a pancreatic neuroendocrine tumor or a solid pseudopapillary neoplasm and performed pancreaticoduodenectomy. Pathological examination showed that the tumor had a denatured structure with evidence of internal bleeding and cubic epithelial cysts of various sizes. The final diagnosis was a macrocystic-type serous cystic neoplasm.

Visual Assessment of Therapeutic Relationships in Psychiatric Patients: A Pilot Study Using the Pictorial Representation of Illness and Self Measure.

BACKGROUND: Although the therapeutic relationship (or 'alliance') is well known to be a key component of psychiatric treatment, there has been no simple way to objectively measure the patient-therapist relationship. Here, we measured the psychological distance between patients and their therapists by using the Pictorial Representation of Illness and Self Measure (PRISM). PATIENTS AND METHODS: We analyzed the patient-therapist relationship of 112 patients from two hospitals in Japan (54 males, 57 females, 1 unknown; age 46.20 ± 15.03 years [mean ± SD]) who completed the PRISM and self report questionnaires (LSNS-6, K6, and BASIS-32) about their social network, psychological distress, and outcomes of mental health treatment. RESULTS: PRISM measurements were available for all patients who consented to participate. In the comparison by disease category, schizophrenia recorded the closest distance to the psychiatrist in charge, followed by bipolar disorder, depression, and neurotic disorder. Regarding the distance to the psychiatrist in charge, PRISM showed a weak negative correlation (r = -0.23, p < 0.05) with age, indicating that with increasing age, the therapeutic rela tionship was more important to the patients. CONCLUSION: Our findings indicate the possibility of implementing PRISM to assess the impact of the therapeutic relationship in patients with a wide range of psychiatric disorders, and they suggest that PRISM holds great potential for clinical application.

White opaque substance represents an intracytoplasmic accumulation of lipid droplets: immunohistochemical and immunoelectron microscopic investigation of 26 cases.

BACKGROUND AND AIM: White opaque substance (WOS) in gastric neoplasias is a unique finding visualized in magnifying endoscopy (ME) with narrow band imaging (NBI) and it represents intramucosal accumulation of lipid droplets using oil red O staining. METHODS: Subjects were 26 WOS-positive (13 adenomas and 13 well-differentiated adenocarcinomas) and 27 WOS-negative gastric epithelial neoplasias. We carried out immunohistochemical staining using a monoclonal antibody specific for adipophilin as a marker of lipids. Immunoelectron microscopy was used to evaluate morphology of the lipid droplets. RESULTS: Adipophilin was detected in 24 of 25 (96.0%) WOS-positive neoplasias, but it was detected in only two of 27 (7.4%) WOS-negative neoplasias. Lipid droplets were only seen in the surface epithelium in 10 of 11 (91.1%) adenomas, whereas the lipid droplets also existed in the cryptal epithelium in seven of 13 (53.8%) adenocarcinomas. Immunoelectron microscopy revealed numerous lipid droplets mainly existing in the subnuclear cytoplasm of the epithelium. The shape of the lipid droplets in adenomas was round and uniform, whereas that in adenocarcinomas was irregular. CONCLUSIONS: The present study confirmed that the presence of WOS in gastric neoplasias was dependent upon intramucosal accumulation of lipid droplets using anti-adipophilin staining. Intraepithelial distribution and morphology of the lipid droplets differed between adenoma and adenocarcinoma.

A genetic regulatory network in the development of trichomes and root hairs.

Trichomes and root hairs differentiate from epidermal cells in the aerial tissues and roots, respectively. Because trichomes and root hairs are easily accessible, particularly in the model plant Arabidopsis, their development has become a well-studied model of cell differentiation and growth. Molecular genetic analyses using Arabidopsis mutants have demonstrated that the differentiation of trichomes and root hair/hairless cells is regulated by similar molecular mechanisms. Transcriptional complexes regulate differentiation into trichome cells and root hairless cells, and formation of the transcriptional complexes is inhibited in neighboring cells. Control of cell growth after fate determination has also been analyzed using Arabidopsis mutants. The progression of endoreduplication cycles, reorientation of microtubules, and organization of the actin cytoskeleton play important roles in trichome growth. Various cellular components such as ion channels, the actin cytoskeleton, microtubules and cell wall materials, and intracellular signal transduction act to establish and maintain root hair tip growth.

Pilot-scale tests of an innovative 'serial self-turning reactor' composting technology in Thailand.

Composting facilities in Thailand have faced various operational problems, resulting in the emission of odours, incomplete digestion of waste organics, and higher than desired costs. Composting technologies imported from developed countries tend to be sized for larger communities and are otherwise not suited for the rural communities that comprise more than 80% of all communities in Thailand. This article addresses the research and development of a novel composting technology aimed at filling this observed need. The study was divided into two parts: (1) the development of a new composting technology and fabrication of a prototype configuration of equipment; and (2) scale-up and study on a pilot-scale using real rubbish. The proposed technology, called 'serial self-turning reactor (STR)', entailed a vertical flow composting system that consisted of a set of aerobic reactors stacked on a set of gravity fed turning units. In-vessel bioreactor technology enables the operator to control composting conditions. The researchers found that a tower-like STR results in flexibility in size scale and waste processing residence time. The pilot-scale experiments showed that the proposed system can produce good quality compost while consuming comparatively little energy and occupying a compact space, compared to traditional land-intensive windrow composting facilities.

Proteomic characterization of the greening process in rice seedlings using the MS spectral intensity-based label free method.

Illumination-induced greening in dark-grown plants is one of the most dramatic developmental processes known in plants. In our current study, we characterized the greening process of rice seedlings using comparative proteome analysis. We identified 886 different proteins in both whole cell lysates of illuminated and nonilluminated rice shoots and performed comparative proteome analysis based on the MS spectral intensities obtained for unique peptides from respective proteins. Furthermore, the changes in the levels of individual proteins were then compared with those of the corresponding mRNAs. The results revealed well-coordinated increases in the enzymes involved in the Calvin cycle at both the protein and mRNA levels during greening, and that the changes at the mRNA level precede those at the protein level. Although a much lower effect of illumination was found on the enzymes associated with glycolysis and the TCA cycle, coordinated increases during greening were evident for the enzymes involved in photorespiration and nitrogen assimilation as well as the components of the chloroplastic translational machinery. These results thus define the differential regulation of distinct biological systems during greening in rice and demonstrate the usefulness of comprehensive and comparative proteome analysis for the characterization of biological processes in plant cells.

Interactions of CUP-SHAPED COTYLEDON and SPATULA genes control carpel margin development in Arabidopsis thaliana.

A characteristic feature of flowering plants is the fusion of carpels, which results in the formation of an enclosed gynoecium. In Arabidopsis thaliana, the gynoecium is formed by the fusion of two carpels along their margins, which also act as a meristematic site for the formation of internal structures such as ovules, the septum and transmitting tract. How gene interactions coordinate the fusion and differentiation of the marginal structures during gynoecium development is largely unknown. It was previously shown that the SPATULA (SPT) gene is required for carpel fusion, whereas overexpression of the CUP-SHAPED COTYLEDON genes CUC1 and CUC2 prevents it. Here we provide evidence that SPT promotes carpel fusion in the apical gynoecium partly through the negative regulation of CUC1 and CUC2 expression. In spt, transcripts of both CUC genes accumulated ectopically, and addition of cuc1 and cuc2 mutations to spt suppressed the split phenotype of carpels specifically along their lateral margins. In the basal gynoecium, on the other hand, all three genes promoted the formation of margin-derived structures, as revealed by the synergistic interactions of spt with each of the cuc mutations. Our results suggest that differential interactions among SPT, CUC1 and CUC2 direct the formation of domain-specific structures of the Arabidopsis gynoecium.

Involvement of PpDof1 transcriptional repressor in the nutrient condition-dependent growth control of protonemal filaments in Physcomitrella patens.

In higher plants, the Dof transcription factors that harbour a conserved plant-specific DNA-binding domain function in the regulation of diverse biological processes that are unique to plants. Although these factors are present in both higher and lower plants, they have not yet been characterized in lower plants. Here six genes encoding Dof transcription factors in the moss Physcomitrella patens are characterized and two of these genes, PpDof1 and PpDof2, are functionally analysed. The targeted disruption of PpDof1 caused delayed or reduced gametophore formation, accompanied by an effect on development of the caulonema from the chloronema. Furthermore, the ppdof1 disruptants were found to form smaller colonies with a reduced frequency of branching of protonemal filaments, depending on the nutrients in the media. Most of these phenotypes were not apparent in the ppdof2 disruptant, although the ppdof2 disruptants also formed smaller colonies on a particular medium. Transcriptional repressor activity of PpDof1 and PpDof2 and modified expression of a number of genes in the ppdof disruptant lines were also shown. These results thus suggest that the PpDof1 transcriptional repressor has a role in controlling nutrient-dependent filament growth.

Does the 'hikikomori' syndrome of social withdrawal exist outside Japan? A preliminary international investigation.

PURPOSE: To explore whether the 'hikikomori' syndrome (social withdrawal) described in Japan exists in other countries, and if so, how patients with the syndrome are diagnosed and treated. METHODS: Two hikikomori case vignettes were sent to psychiatrists in Australia, Bangladesh, India, Iran, Japan, Korea, Taiwan, Thailand and the USA. Participants rated the syndrome's prevalence in their country, etiology, diagnosis, suicide risk, and treatment. RESULTS: Out of 247 responses to the questionnaire (123 from Japan and 124 from other countries), 239 were enrolled in the analysis. Respondents' felt the hikikomori syndrome is seen in all countries examined and especially in urban areas. Biopsychosocial, cultural, and environmental factors were all listed as probable causes of hikikomori, and differences among countries were not significant. Japanese psychiatrists suggested treatment in outpatient wards and some did not think that psychiatric treatment is necessary. Psychiatrists in other countries opted for more active treatment such as hospitalization. CONCLUSIONS: Patients with the hikikomori syndrome are perceived as occurring across a variety of cultures by psychiatrists in multiple countries. Our results provide a rational basis for study of the existence and epidemiology of hikikomori in clinical or community populations in international settings.