Search

We have developed a simple and straightforward way to realize controlled postdoping toward 2D transition metal dichalcogenides (TMDs). The key idea is to use low-kinetic-energy dopant beams and a high-flux chalcogen beam simultaneously, leading to substitutional doping with controlled dopant densities. Atomic-resolution transmission electron microscopy has revealed that dopant atoms injected toward TMDs are incorporated substitutionally into the hexagonal framework of TMDs. The electronic properties of doped TMDs (Nb-doped WSe2) have shown drastic change and p-type action with more than 2 orders of magnitude increase in current. Position-selective doping has also been demonstrated by the postdoping toward TMDs with a patterned mask on the surface. The postdoping method developed in this work can be a versatile tool for 2D-based next-generation electronics in the future.

An 85-year-old Japanese woman with acute primary angle closure in her right eye underwent cataract extraction. Because of the weakness of the Zinn’s zonules, all of the lens tissue including the lens capsule was removed by phacoemulsification. Because of the absence of vitreous prolapse into the anterior chamber, vitrectomy was not performed. Nine days postoperatively, acute angle closure due to pupillary block by an anterior vitreous membrane developed. To resolve the pupillary block, anterior vitrectomy was performed on the same day. Postoperatively, her symptoms resolved, the anterior chamber deepened, and the intraocular pressure normalized. Although rare, acute angle closure due to pupillary block by an anterior vitreous membrane can occur after total lens extraction with phacoemulsification. If no vitreous prolapse occurs with total lens extraction, an intentional hyaloidotomy using an anterior vitreous cutter or iridectomy should be considered to avoid secondary angle closure.

Background and Aims: Synthetic cyclin-dependent kinase (CDK) 4/6 inhibitors exert antitumor effects by forcing RB1 in unphosphorylated status, causing not only cell cycle arrest but also cellular senescence, apoptosis, and increased immunogenicity. These agents currently have an indication in advanced breast cancers and are in clinical trials for many other solid tumors. HCC is one of promising targets of CDK4/6 inhibitors. RB family dysfunction is often associated with the initiation of HCC; however, this is revivable, as RB family members are not frequently mutated or deleted in this malignancy. Approach and Results: Loss of all Rb family members in transformation related protein 53 (Trp53)−/− mouse liver resulted in liver tumor reminiscent of human HCC, and re-expression of RB1 sensitized these tumors to a CDK4/6 inhibitor, palbociclib. Introduction of an unphosphorylatable form of RB1 (RB7LP) into multiple liver tumor cell lines induced effects similar to palbociclib. By screening for compounds that enhance the efficacy of RB7LP, we identified an I kappa B kinase (IKK)β inhibitor Bay 11-7082. Consistently, RB7LP expression and treatment with palbociclib enhanced IKKα/β phosphorylation and NF-κB activation. Combination therapy using palbociclib with Bay 11-7082 was significantly more effective in hepatoblastoma and HCC treatment than single administration. Moreover, blockade of IKK–NF-κB or AKT pathway enhanced effects of palbociclib on RB1-intact KRAS Kirsten rat sarcoma viral oncogene homolog mutated lung and colon cancers. Conclusions: In conclusion, CDK4/6 inhibitors have a potential to treat a wide variety of RB1-intact cancers including HCC when combined with an appropriate kinase inhibitor. Refereed/Peer-reviewed

Bullous pemphigoid (BP) varies in severity and stratified treatments are needed. However, there are no definitive standards for choosing appropriate treatments. To elucidate the factors involved in choosing treatments and the clinical outcomes of BP, we retrospectively reviewed the clinical records of 78 BP patients at a single center. Of the 78 patients, 49 (62.8%) were treated with oral prednisolone (PSL) and 29 (37.2%) were treated without PSL. The patients with older age, lower Bullous Pemphigoid Disease Area Index (BPDAI), and/or lower anti-BP180NC16a antibody titer at onset tended to be treated without oral PSL. Notably, only 9.1% patients without PSL experienced relapse, whereas 36.7% patients with oral PSL experienced relapse when the PSL was around 0.1 mg/kg. It suggests that the patients with mild disease severity could be well controlled without oral PSL. Receiver-operator curve analysis demonstrated that the cut-off value for the use of oral PSL was 31 for total BPDAI and was 7 for BPDAI skin urticaria/erythema, with a high (>0.9) area under the curve. Notably, none of the patients who were negative for the anti-BP180NC16a antibody at onset experienced relapse even though they were treated without PSL. In conclusion, in BP patients who were negative for anti-BP180NC16a antibody at onset, with a total BPDAI score of less than 31 or with an urticaria/erythema score of less than 7 can be treated without PSL. When the PSL is tapered to around 0.1 mg/kg, we should carefully monitor the patients to detect relapse.

Background Regulatory T (Treg) cells play an essential role in peripheral immune tolerance. Bullous pemphigoid (BP) is the most common blistering disease and is caused by autoantibodies to two BP antigens: type XVII collagen and BP230. Recently, we reported that Treg cell dysfunction may cause the production of autoantibodies to BP antigens. Several studies have suggested an association between Treg cells and BP pathogenesis. However, Treg cells are heterogeneous in humans, leading to inconsistent results in previous studies. Objective To assess functional Treg subsets in BP. Methods We examined three distinct Treg subsets in conventional BP (cBP) patients before versus after systemic corticosteroid treatment, dipeptidyl peptidase-4 inhibitor-associated BP (DPP-4i-BP) patients, younger controls and older controls. Results We found that total Treg cells and all Treg cell subsets were increased in cBP patients before treatment and decreased by systemic corticosteroid treatment. In contrast, neither total Treg cells nor all Treg subsets were increased in DPP-4i-BP. Notably, CD45RA− Foxp3hi effector Treg cells positively correlated with disease severity in cBP, whereas CD45RA+Foxp3lo naive Treg cells positively correlated with the disease severity in DPP-4i-BP. Conclusion These findings suggest that Treg cells are differently involved in the pathogeneses of cBP and DPP-4i-BP.

Introduction An ongoing outbreak of a novel coronavirus disease (coronavirus disease 2019, COVID-19) has become a global threat. While clinical reports from China to date demonstrate that the majority of cases remain relatively mild and recover with supportive care, it is also crucial to be well prepared for severe cases warranting intensive care. Initiating appropriate infection control measures may not always be achievable in primary care or in acute-care settings. Case A 45-year-old man was admitted to the intensive care unit due to severe pneumonia, later confirmed as COVID-19. His initial evaluation in the resuscitation room and treatments in the intensive care unit was performed under droplet and contact precaution with additional airborne protection using the N95 respirator mask. He was successfully treated in the intensive care unit with mechanical ventilation and extracorporeal membrane oxygenation for respiratory support; and antiretroviral treatment with lopinavir/ritonavir. His total intensive care unit stay was 15 days and was discharged on hospital day 24. Conclusions Strict infection control precautions are not always an easy task, especially under urgent care in an intensive care unit. However, severe cases of COVID-19 pneumonia, or another novel infectious disease, could present at any moment and would be a continuing challenge to pursue appropriate measures. We need to be well prepared to secure healthcare workers from exposure to infectious diseases and nosocomial spread, as well as to provide necessary intensive care.

A long-term immunosuppressive treatment can provoke latent infections. Autoimmune blistering diseases (AIBD) are mostly treated with systemic immunosuppressive agents. To prevent the reactivation or exacerbation of existing latent infections, patients must be screened for infectious diseases before immunosuppressive treatments are initiated. However, the prevalence of infectious diseases in AIBD remains to be elucidated. To evaluate the necessity of screening infectious diseases in AIBD, we retrospectively reviewed the clinical records of 215 patients at a single center with AIBD for hepatitis B virus (HBV), hepatitis C virus (HCV), Mycobacterium tuberculosis, Treponema pallidum, human T-cell leukemia virus type 1 (HTLV-1) and HIV infections. Approximately 40% of patients were infected with HBV. During systemic corticosteroid treatment, HBV DNA became positive in 3.4% of cases. Antibodies to HCV, interferon-γ release assays for M. tuberculosis and the T. pallidum latex agglutination test were positive in 0.6%, 6.6% and 1.2% cases, respectively. Neither HTLV-1 nor HIV infections were detected. In conclusion, checks for HBV and M. tuberculosis infections should be made before immunosuppressive treatments are started, because of the high prevalence of these potentially life-threatening infections. Other infections should be tested for depending on the patient's risk factors.

Do apprenticeships enhance product quality? Whether guilds and apprenticeships have promoted technological change has been debated, but the issue remains unsettled because of the lack of data which...

In amyotrophic lateral sclerosis (ALS), it remains elusive how the initial lesions develop and further extend in the upper and lower motor neuron (UMN and LMN) systems. Several studies of ALS using cell or animal models have demonstrated that the disease-related protein, transactive response DNA-binding protein 43 kDa (TDP-43), propagates in the nervous system by sequential cell-to-cell transmission and/or anterograde/retrograde axonal transport.1 However, it is often difficult to trace the trajectory of disease progression in living patients, or propagation of TDP-43 in human autopsied tissues. This is partly due to the diverse clinical phenotypes of ALS and the resulting inter-individual variations in both the rate and manner of disease progression.2 Among the variants of ALS, hemiplegic-type ALS is characterised by prominent asymmetry of the clinical symptoms throughout the illness.3 Here we report the clinicopathological features of two autopsy cases of hemiplegic-type ALS with special reference to the clinicopathological link between chronological evolution of lateralised clinical symptoms and asymmetric lesion extension and a degenerative link between the UMN and LMN systems. We further discuss the possible pathomechanism that may facilitate the above-mentioned links, or more strictly the propagation routes of TDP-43 that may be inherent to this rare variant of ALS. The patients, two unrelated men in their 70s and 80s, initially presented with unilateral (patient 1, left; patient 2, right) leg weakness that spread to involve the ipsilateral arm and bulbar muscles within the following 3 and 2 years, respectively. In both patients, UMN signs including spasticity and hyper-reflexia were also lateralised to the predominant side of muscle weakness. They died of respiratory failure 3 and 4 years after onset, when limb weakness asymmetry was still evident online supplemental method. Autopsy revealed that the degree of degeneration in the motor systems apparently reflected the clinical asymmetry and chronological …

Bullous pemphigoid (BP) is a cutaneous autoimmune blistering disorder. Recently, it has been reported that dipeptidyl peptidase-4 inhibitors (DPP4i) is associated with the development of BP (DPP4i-BP). Patients with DPP4i-BP have autoantibodies (autoAbs) preferentially targeting full-length BP180, but not the BP180NC16a domain. In this report, we described a case of anti-BP230 antibody (Ab)-positive BP receiving DPP4i. A 78-year-old male with a medical history of type 2 diabetes receiving vildagliptin at 100 mg daily for 38 months was referred to our hospital with itching blisters on his body and extremities. Skin biopsy showed subepidermal bulla with eosinophil infiltration. Direct immunofluorescence staining revealed a linear staining pattern with complement C3 and IgG at the subepidermal basement membrane zone. By laboratory testing, autoAbs against BP180NC16a and full-length BP180 were negative by enzyme-linked immunosorbent assay (ELISA); however, anti-BP230 Abs were positive by ELISA (index: 123.91). His HLA genotype was DQB1*04:01 and 05:01. Based on these results, we diagnosed the patient with anti-BP230 Abs-positive BP associated with DPP4i. To the best of our knowledge, this is the first case of DPP4i-BP with only anti-BP230 Abs. Further accumulation of DPP4i-BP cases is needed to clarify the relationship between overall features of DPP4i-BP and anti-BP230 Abs.

Background A new platelet (PLT) additive solution, bicarbonated Ringer's solution supplemented with acid-citrate-dextrose Formula A, termed BRS-A, as well as a new automated closed system cell processor for washing PLTs have recently been developed. This study evaluated the in vitro properties of PLTs with the automated system versus the manual method, using the BRS-A additive solution for washing and storage. Methods ABO-identical apheresis PLTs in 100% plasma were pooled and split equally for control (in 100% plasma or a manual method) and test (ACP215 automated system) units. In vitro characteristics of PLTs washed with the automated system were compared to those of PLTs in 100% plasma (Study 1) or washed with a manual method (Study 2) during the 7-day storage. Results In Study 1, hypotonic shock response, aggregation response, mitochondrial membrane potential, adenosine triphosphate, and CD42b mean fluorescence intensity were comparable in the control and test groups during the 7-day storage. CD62P expression was lower in the test group than controls on Days 3 and 7. The level of platelet-derived microparticles (PDMPs) in the test group on Days 1 and 2 were higher than those in controls. In contrast, the levels of soluble CD40 ligand (sCD40L) and regulated upon activation of normal T-cell expressed and secreted (RANTES) in the test units were lower than controls. In Study 2, no significant differences were found in all in vitro properties except for PLT count and the levels of PDMPs in the test units were higher than controls during storage. Conclusion Apheresis PLTs washed with the automated system using BRS-A additive solution maintained in vitro properties during storage. Washing methods influenced PDMP levels but not sCD40L and RANTES.

The pemphigoid group is a category of autoimmune subepidermal blistering diseases in which autoantibodies deposit linearly at the epidermal basement membrane zone (BMZ). The main subtypes of pemphigoid mediated by immunoglobulin G autoantibodies are bullous pemphigoid (BP), mucous membrane pemphigoid (MMP) and epidermolysis bullosa acquisita (EBA). To establish the first guidelines approved by the Japanese Dermatological Association for the management of pemphigoid diseases, the Committee for Guidelines for the Management of Pemphigoid Diseases (Including EBA) was founded as part of the Study Group for Rare Intractable Skin Diseases under the Ministry of Health, Labor and Welfare Research Project on Overcoming Intractable Diseases. These guidelines aim to provide current information for the management of BP, MMP and EBA in Japan. Based on evidence, the guidelines summarize the clinical and immunological manifestations, pathophysiologies, diagnostic criteria, disease severity determination criteria, treatment algorithms and treatment recommendations. Because of the rarity of these diseases, there are few clinical studies with a high degree of evidence, so several parts of these guidelines were established based on the opinions of the Committee. To further optimize these guidelines, periodic revision in line with the new evidence is necessary.

A 73-year-old man was transferred to our hospital with dyspnea and left hemiplegia. The diagnosis of pulmonary embolism, entrapped thrombus in patent foramen ovale (PFO), and internal carotid artery occlusion was made by imaging studies. We decided to perform endovascular treatment without the administration of tissue plasminogen activator (tPA) for cerebral embolism because of concern about further embolism caused by fragmented thrombi. After endovascular treatment, he successfully underwent surgical embolectomy for entrapped thrombus in PFO. Endovascular treatment without tPA administration and subsequent surgical embolectomy seems to be a viable treatment strategy for patients with occlusion of the large cerebral artery accompanied by entrapped thrombus in PFO.

Cutaneous lupus erythematosus (CLE) is a rare, potentially disfiguring, chronic autoimmune disease with extremely variable skin and mucosal membrane manifestations. Hydroxychloroquine (HCQ) is an antimalarial drug that has been used in various countries to treat autoimmune diseases including CLE. HCQ was banned for a long time in Japan because of severe chloroquine retinopathy and was reapproved as a first-line treatment for CLE in 2015. There are no case reports describing the effectiveness of HCQ for CLE with oral mucosal lesions in the dental field. We present a case of CLE whose oral lesions were successfully treated with HCQ.

Aims/Introduction Bullous pemphigoid (BP) might be drug‐induced. The present study evaluated the relationship between BP and dipeptidyl peptidase‐4 inhibitors (DPP4Is). Materials and Methods We recruited patients diagnosed with BP at Ogaki Municipal Hospital from 1 December 2009 through 31 December 2017. We retrospectively collected data from medical records and divided patients into two groups based on whether they received DPP4Is. Additionally, we determined the incidence of BP in patients who were first prescribed DPP4Is at our hospital during the study period. Results Of 168 patients diagnosed with BP, 133 (79.1%) were positive for anti‐BP180NC16a antibody. A total of 32 (19.0%) patients had been prescribed a DPP4I, 21 of whom (65.6%) were positive for anti‐BP180NC16a antibody; this rate was lower than that in patients not receiving a DPP4I (82.3%; P = 0.0360). A total of 16 patients with type 2 diabetes mellitus had not been prescribed a DPP4I; only one (6.3%) was positive for anti‐BP180NC16a antibody (P = 0.0339). During the study period, 9,304 patients were prescribed DPP4Is, eight of whom developed BP; six (75.0%) had non‐inflammatory BP, and five of the six (83.3%) were negative for anti‐BP180NC16a antibody. Conclusions The positive rate of anti‐BP180NC16a antibody was lower in BP patients with DPP4I than without DPP4I, regardless of type 2 diabetes mellitus. The antibody titer was low in both the overall and type 2 diabetes mellitus populations. The prevalence of BP in 9,304 patients receiving DPP4Is was 0.0859%, which is higher than that in the general population. As DPP4Is are common diabetes treatments, we must be aware of the risk of BP.

Epidermolysis bullosa (EB) is a group of genodermatoses characterized by generalized blisters from mutations in the genes encoding the basement membrane zone (BMZ) proteins.1 The infusion of allogeneic cells such as mesenchymal stem/stromal cells (MSCs), which have intact BMZ genes, is a promising treatment.

研究グループは、グランザイムBが類天疱瘡疾患の治療標的となることを明らかにしました。難病に指定されている類天疱瘡は全身にかゆみを伴う水膨れができる疾患で、高齢者に多く発症し、無治療では最悪の場合死に至ることがあります。現在の一般的な治療ではステロイドをはじめとした免疫抑制剤を使用しますが、細菌やウイルスに感染しやすくなるなど、場合によっては命に関わる副作用を伴います。また、高齢化社会において患者がより増えていくことが予想され、高齢者ほど免疫抑制剤の副作用リスクが高いため、副作用のほとんどない治療薬の開発が急務となっています。そこで本研究では、類天疱瘡の水膨れの近くに沢山存在することが知られており、その役割が研究されてこなかったグランザイムBに着目しました。3種類の独立した動物モデルを用いた実験により、グランザイムBが類天疱瘡の症状をより重篤にしていることを発見しました。また、グランザイムBの働きを阻害する外用薬が、類天疱瘡の動物モデルの水膨れを治療することがわかりました。さらに、ヒト患者の水膨れの周囲や水膨れの内容液ではグランザイムBが増加していることが本研究でわかりました。今回グランザイムB阻害薬(VTI-1002)の外用が類天疱瘡動物モデルの水膨れを治療することが明らかとなり、それをヒト患者にも用いることができる可能性が期待できます。, Pemphigoid diseases refer to a group of severe autoimmune skin blistering diseases characterized by subepidermal blistering and loss of dermal-epidermal adhesion induced by autoantibody and immune cell infiltrate at the dermal-epidermal junction and upper dermis. Here, we explore the role of the immune cell-secreted serine protease, granzyme B, in pemphigoid disease pathogenesis using three independent murine models. In all models, granzyme B knockout or topical pharmacological inhibition significantly reduces total blistering area compared to controls. In vivo and in vitro studies show that granzyme B contributes to blistering by degrading key anchoring proteins in the dermal-epidermal junction that are necessary for dermal-epidermal adhesion. Further, granzyme B mediates IL-8/macrophage inflammatory protein-2 secretion, lesional neutrophil infiltration, and lesional neutrophil elastase activity. Clinically, granzyme B is elevated and abundant in human pemphigoid disease blister fluids and lesional skin. Collectively, granzyme B is a potential therapeutic target in pemphigoid diseases.

Chronic enteroviral meningoencephalitis is a well-known complication in patients with X-linked agammaglobulinemia (XLA). However, progressive neurodegenerative disorders or chronic neuroinflammatory diseases with no causative microorganisms have been recognized as rare central nervous system (CNS) complications in XLA. We herein report a family in which two of three members with XLA had developed progressive meningoencephalitis with an unknown etiology. A 15-month-old male infant presented with left-sided ptosis. Initially, the family denied any family history of inherited diseases, but later disclosed a family history of agammaglobulinemia previously diagnosed in two family members. In the early 1980s, one of the elder brothers of the index patient's mother who had been treated with intramuscular immunoglobulin [or later intravenous immunoglobulin (IVIG)] for agammaglobulinemia deceased at 10 years of age after showing progressive neurological deterioration during the last several years of his life. The index patient was diagnosed with XLA caused by Bruton tyrosine kinase deficiency (654delG; Val219Leufs*9), and chronic meningoencephalitis with an unknown infectious etiology. Magnetic resonance imaging of the brain demonstrated inflammatory changes in the basal ganglia, hypothalamus, midbrain, and pons, with multiple nodular lesions with ring enhancement, which showed impressive amelioration after the initiation of IVIG replacement therapy. Pleocytosis, which was characterized by an increase in CD4-positive and CD8-positive T cells expressing an activation marker and an elevation in inflammatory cytokines in the cerebrospinal fluid, was identified. No microorganism was identified as a cause of CNS complications. He thereafter developed brain infarction at 19 months of age and fatal status epilepticus at 5 years of age, despite regular IVIG with high trough levels and regular intraventricular immunoglobulin administration. The etiology of this rare CNS complication in XLA is currently unknown. Previous studies have suggested a possible association of IVIG, which was clearly denied in our index case because of the demonstration of his neurological disorder at presentation. In the future, extensive and unbiased molecular methods to detect causative microorganisms, as well as to investigate the possible role of autoimmunity are needed to clarify the etiology of CNS complications.

Progressive supranuclear palsy (PSP) presents with a wide variety of signs/symptoms, making early initial diagnosis difficult. We investigated the clinical and neuropathological features of five patients with autopsy-proven PSP of short duration, ranging from 11 to 41 months (average, 26.2 months) due to unexpected death, focusing particularly on the distribution and severity of neuronal loss as well as neuronal and glial tau pathology in the affected brain. Clinical features were studied retrospectively through careful review of the medical records, and neuropathological examinations were carried out, along with tau immunohistochemistry using a monoclonal antibody AT8. These patients were diagnosed as having probable PSP (n = 4) and suggestive PSP (n = 1), respectively. In all cases, neuronal loss was evident in the substantia nigra, subthalamic nucleus, globus pallidus, and locus ceruleus. AT8-identified tau lesions, that is, pretangles/neurofibrillary tangles (PTs/NFTs), tufted astrocytes (TAs), and coiled bodies/neuropil threads (CBs/NTs), were distributed widely in the brain regions, especially in patients with longer disease duration. All cases showed variation in the regional tau burden among PTs/NFTs, TAs, and CBs/NTs. There was also a tendency for tau deposition to be more predominant in neuronal cells in the brainstem and cerebellum and in glial cells in the cerebral cortex and subcortical gray matter. These findings suggest that in PSP, the initial signs/symptoms are associated with degeneration and subsequent death of neurons with pathological tau deposition, and that the tau deposition in neuronal cells is independent of that in glial cells.

There is an urgent need for new, potent antituberculosis (anti-TB) drugs with novel mechanisms of action that can be included in new regimens to shorten the treatment period for TB. After screening a library of carbostyrils, we optimized 3,4-dihydrocarbostyril derivatives and identified OPC-167832 as having potent antituberculosis activity. The MICs of the compound for Mycobacterium tuberculosis ranged from 0.00024 to 0.002 μg/ml. It had bactericidal activity against both growing and intracellular bacilli, and the frequency of spontaneous resistance for M. tuberculosis H37Rv was less than 1., There is an urgent need for new, potent antituberculosis (anti-TB) drugs with novel mechanisms of action that can be included in new regimens to shorten the treatment period for TB. After screening a library of carbostyrils, we optimized 3,4-dihydrocarbostyril derivatives and identified OPC-167832 as having potent antituberculosis activity. The MICs of the compound for Mycobacterium tuberculosis ranged from 0.00024 to 0.002 μg/ml. It had bactericidal activity against both growing and intracellular bacilli, and the frequency of spontaneous resistance for M. tuberculosis H37Rv was less than 1.91 × 10−7. It did not show antagonistic effects with other anti-TB agents in an in vitro checkerboard assay. Whole-genome and targeted sequencing of isolates resistant to OPC-167832 identified decaprenylphosphoryl-β-d-ribose 2′-oxidase (DprE1), an essential enzyme for cell wall biosynthesis, as the target of the compound, and further studies demonstrated inhibition of DprE1 enzymatic activity by OPC-167832. In a mouse model of chronic TB, OPC-167832 showed potent bactericidal activities starting at a dose of 0.625 mg/kg of body weight. Further, it exhibited significant combination effects in 2-drug combinations with delamanid, bedaquiline, or levofloxacin. Finally, 3- or 4-drug regimens comprised of delamanid and OPC-167832 as the core along with bedaquiline, moxifloxacin, or linezolid showed efficacy in reducing the bacterial burden and preventing relapse superior to that of the standard treatment regimen. In summary, these results suggest that OPC-167832 is a novel and potent anti-TB agent, and regimens containing OPC-167832 and new or repurposed anti-TB drugs may have the potential to shorten the duration of treatment for TB.

Background Hematologic malignancies occasionally cause serous retinal detachment (SRD); however, its pathogenesis remains unclear. Here we present the imaging characteristics of metastatic choroidal lymphoma masquerading as Vogt-Koyanagi-Harada (VKH) disease. Case presentation A 45-year-old Japanese woman was referred to our clinic because of bilateral SRD with blurred vision. Fluorescein angiography revealed multiple pinpoint leakage followed by pooling OU. Enhanced depth imaging optical coherence tomography showed marked choroidal thickening OU. Laser speckle flowgraphy detected choroidal circulation impairment OU. Although these results totally agreed with the inflammatory manifestations of acute VKH disease, indocyanine green angiography demonstrated various sizes of sharply marginated hypofluorescent lesions that seemed atypical for the finding of VKH disease, i.e., vaguely marginated hypofluorescent small dots. Cerebrospinal fluid pleocytosis was not detected. Blood tests revealed leukocytosis together with elevation of lactate dehydrogenase and soluble interleukin-2 receptor levels. Corticosteroid pulse therapy did not improve any ocular findings. Bone marrow biopsy was then performed, leading to a definite diagnosis of diffuse large B-cell lymphoma. After starting systemic chemotherapy, both SRD and choroidal thickening resolved rapidly with visual recovery. However, choroidal hypoperfusion persisted, which contrasted distinctly with the inflammatory pattern of VKH disease, i.e., the restoration of choroidal blood flow in parallel with normalization of choroidal thickness. Conclusions Our detailed multimodal observations highlighted the differential imaging features of choroidal lymphoma despite close resemblance to VKH disease especially at the initial stage. Impaired circulation in the thickened choroid marked the pseudo-inflammatory pathogenesis of SRD due to choroidal involvement with neoplastic, but not inflammatory cells.

International audience; Background-Several European countries recently developed international diagnostic and management guidelines for pemphigus, which have been instrumental in the standardization of pemphigus management. Objective-We now present results from a subsequent Delphi consensus to broaden the generalizability of the recommendations. Methods-A preliminary survey, based on the European Dermatology Forum and the European Academy of Dermatology and Venereology guidelines, was sent to a panel of international experts to determine the level of consensus. The results were discussed at the International Bullous Diseases Consensus Group in March 2016 during the annual American Academy of Dermatology conference. Following the meeting, a second survey was sent to more experts to achieve greater international consensus. Results-The 39 experts participated in the first round of the Delphi survey, and 54 experts from 21 countries completed the second round. The number of statements in the survey was reduced from 175 topics in Delphi I to 24 topics in Delphi II on the basis of Delphi results and meeting discussion. Limitations-Each recommendation represents the majority opinion and therefore may not reflect all possible treatment options available. Conclusions-We present here the recommendations resulting from this Delphi process. This international consensus includes intravenous CD20 inhibitors as a first-line therapy option for moderate-to-severe pemphigus. Keywords CD20 inhibitor; consensus; guidelines; pemphigus foliaceus; pemphigus vulgaris; treatment Pemphigus encompasses a spectrum of rare mucocutaneous bullous diseases that are autoimmune in origin. Because of the rarity of these diseases, it can take patients months before their pemphigus is diagnosed, during which time many are treated for other blistering diseases. 1,2 Even once the diagnosis has been made, treatment regimens can vary greatly, as

This was a multicenter study of rituximab, a chimeric monoclonal immunoglobulin G antibody directed against CD20, for the treatment of refractory autoimmune bullous diseases (pemphigus and pemphigoid). Ten patients (three with pemphigus vulgaris, six with pemphigus foliaceus and one with bullous pemphigoid) were treated with a single cycle of rituximab (four weekly infusions at a dose of 375 mg/m2 of body surface area). The primary end-points were the number of serious adverse events and rate of complete remission at 40 weeks. Five patients (50%) achieved complete remission with minimal therapy (defined as no active lesions with lower doses of systemic corticosteroids compared to that with prednisolone 10 mg/day). Improvements in clinical scores (Pemphigus Disease Area Index) and decreases in autoantibody titers in the sera were observed in the four pemphigus patients who failed to achieve complete remission. This suggests that rituximab was effective in nine of 10 cases. Two serious adverse events (Pneumocystis carinii pneumonia and septic shock due to infectious arthritis) were observed and adequately treated with hospitalization. CD19-positive B lymphocytes in the peripheral blood decreased on day 29 following rituximab treatment, and remained at low levels throughout the observation period (280 days). Our results confirmed the efficacy of rituximab therapy for refractory autoimmune bullous diseases in Japan.

Background and aim: Exposure to phthalates and phosphorus flame retardants (PFRs) is considered to be a risk factor for asthma and allergies. However, little is known about the contribution of loss-of-function mutations in the gene encoding filaggrin (FLG) gene, which are considered to be predisposing factors for eczema and asthma, to these associations. We investigated the associations between exposure to phthalates and PFRs in dust and eczema/wheeze among Japanese children, taking into consideration loss-of-function mutations in FLG. Methods: This study was part of the Hokkaido study on Environment and Children's Health. Seven phthalates and 11 PFRs in household dust were measured by gas chromatography–mass spectrometry. Eczema and wheeze were assessed in children aged 7 years using the International Study of Asthma and Allergies in Childhood questionnaire. Eight FLG mutations previously identified in the Japanese population were extracted from cord blood samples. Children with one or more FLG mutations were considered to be positive for FLG mutations. The study included 296 children who had complete data (birth records, FLG mutations, first trimester and 7 years questionnaires, and phthalate/PFR levels). Odds ratios (ORs) and 95% confidential intervals (CIs) of eczema and wheeze were calculated for log-transformed phthalate/PFR levels by logistic regression. We also performed stratified analyses based on FLG mutations. Results: The prevalence rates of eczema and wheeze were 20.6% and 13.9%, respectively. Among children without any FLG mutations, tris (1, 3-dichloro-2-propyl) phosphate (TDCIPP) increased the OR of wheeze, (OR: 1.22, CI: 1.00–1.48). Significant p values for trends were found between tris (2-butoxyethyl) phosphate (TBOEP) and eczema and di-iso-nonyl phthalate (DiNP) and eczema among children without any FLG mutations, respectively. Conclusions: Despite our limited sample size and cross-sectional study design, the effects of indoor environmental factors on childhood eczema and wheeze were clearer in children without loss-of-function mutations in FLG than in children with mutations. Children with FLG mutations might already be cared for differently in terms of medication or parental lifestyle. Further studies in larger populations are warranted so that severity of symptoms and combinations of FLG mutations can be investigated. Keywords: Filaggrin, Eczema, Wheeze, Child, Phthalate, Flame retardants

Background Mycosis fungoides (MF) is the most common cutaneous T-cell lymphoma. Early-stage MF patches or plaques often resemble inflammatory skin disorders (ISDs), including psoriasis and atopic dermatitis. Cell adhesion molecule 1 gene (CADM1), which was initially identified as a tumor suppressor gene in human non–small cell lung cancer, has been reported as a diagnostic marker for adult T-cell leukemia/lymphoma. Objective We investigated CADM1 expression in MF neoplastic cells, especially during early stages, and evaluated its usefulness as a diagnostic marker for MF. Methods We conducted a retrospective study by using immunohistochemical staining and confirmed the expression of CADM1 in MF. In addition, we compared CADM1 messenger RNA expression in microdissected MF samples and ISD samples. Results In the overall study period, 55 of 58 MF samples (94.8 %) stained positive for CADM1. None of the 50 ISD samples showed positive reactivity (P Limitations We did not conduct a validation study for MF cases in other institutions. Conclusions CADM1-positive cells can be identified in early stages with fewer infiltrating cells and may be useful as a diagnostic marker for early-stage MF.

TGM1 is the most common gene responsible for lamellar ichthyosis. Previous studies have suggested that patients with lamellar ichthyosis carrying two missense mutations in TGM1 show significantly less severe phenotypes than those with at least one truncating mutation in TGM1. Here, we report a patient with severe lamellar ichthyosis who was compound heterozygous for TGM1 missense mutations, including a novel one. A 22-year-old Japanese man presented with large, dark brown, plate-like scales on the extremities and small adherent scales on the face and trunk. His other clinical findings included ectropion, hair loss, hypohidrosis, hyperthermia in summer, palmoplantar keratoderma and constriction of the fingers. Dermoscopy revealed accentuated sulci cutis with numerous large keratotic plugs in the cristae cutis. Histologically, orthohyperkeratosis and mild acanthosis were noted. Electron microscopy showed reduced cornified envelope thickness and numerous lipid droplets in the stratum corneum. Mutation analysis revealed the patient to be compound heterozygous for missense mutations, c.620T>C (p.Leu207Pro) and c.1631A>G (p.Tyr544Cys), in TGM1. Furthermore, we showed that TGM1 enzymatic activity was largely absent in his epidermis. These findings led us to diagnose him as having lamellar ichthyosis. This study has two important notions. First, even two missense mutations in TGM1 can cause severe lamellar ichthyosis. Second, this is the first report of dermoscopic findings of lamellar ichthyosis, implicating the obstruction of sweat glands by keratotic plugs in the pathogenesis of hypohidrosis in the disease. In conclusion, this study provides further insights into genotype-phenotype correlations and pathogenesis in lamellar ichthyosis.

Background Epidermolysis bullosa (EB) is a group of hereditary disorders caused by mutations in the genes encoding structural molecules of the dermal-epidermal junction (DEJ). Cell-based therapies such as allogeneic mesenchymal stem/stromal cell (MSC) transplantation have recently been explored for severe EB types, such as recessive dystrophic EB (RDEB). However, hurdles exist in current MSC-based therapies, such as limited proliferation from a single cell source and limited cell survival due to potential allogenic rejection. Objectives We aimed to develop MSCs from keratinocyte-derived induced pluripotent stem cells (iPSCs). Methods Keratinocyte-derived iPSCs (KC-iPSCs) of a healthy human and an RDEB patient were cultured with activin A, 6-bromoindirubin-3′-oxime and bone morphogenetic protein 4 to induce mesodermal lineage formation. These induced cells were subjected to immunohistochemical analysis, flow cytometric analysis and RNA microarray analysis in vitro, and were injected subcutaneously and intravenously to wounded immunodeficient mice to assess their wound-healing efficacy. Results After their induction, KC-iPSC-induced cells were found to be compatible with MSCs. Furthermore, with the subcutaneous and intravenous injection of the KC-iPSC-induced cells into wounded immunodeficient mice, human type VII collagen was detected at the DEJ of epithelized areas. Conclusions We successfully established iPSC-derived MSCs from keratinocytes (KC-iPSC-MSCs) of a normal human and an RDEB patient. KC-iPSC-MSCs may have potential in therapies for RDEB.

This study examines a new finite element/discrete element method (FE-DEM) with interchangeable modeling between FEM and DEM for tire traction analysis. In the method, named iFE-DEM, the soil in a soil bin is modeled initially by FEM except for the region under or near the tire, which is modeled using DEM. When the FEM tire model starts to travel over DEM soil elements, the updated tire location will activate new conversion of modeling from FEM to DEM so that the zone of influence around the contact interface between tire and soil can be analyzed continuously using DEM. Those mobilized DEM elements rearward of the tire might be converted again to FEM elements by assuming that the effect of the stress state in DEM generated by tire travel might be negligible. The computational time for two-dimensional iFE-DEM analysis of a slip of 40% using the smallest region of initial DEM under the tire could be reduced to 23% of that obtained using DEM only soil modeling.

A 74-year-old woman who exhibited drowsiness was referred to our hospital. Enhanced head magnetic resonance imaging (MRI) revealed multiple ring-enhancing lesions and lesions showing partial mild hemorrhaging. The patient gradually progressed to a comatose condition with notable brain deterioration of unknown cause on follow-up MRI. On day nine, the patient inexplicably died, although brain herniation was suspected. Autopsy and histopathology revealed numerous amoebic trophozoites in the perivascular spaces and within the necrotic tissue. Brain immunostaining tested positive for Balamuthia mandrillaris. Infection due to free-living amoeba is rare in Japan; however, it may increase in the near future due to unknown reasons.