Case of epidermolysis bullosa acquisita with concomitant anti‐laminin‐332 antibodies

Subepidermal autoimmune blistering disease including bullous pemphigoid, pemphigoid gestationis, mucous membrane pemphigoid, anti‐laminin‐γ1 pemphigoid, linear immunoglobulin A bullous disease and epidermolysis bullosa acquisita (EBA), are all characterized by direct immunofluorescence microscopy or immunoglobulin deposition on the basement membrane zone. Among them, EBA is a rare acquired subepidermal autoimmune blistering disease of the skin and mucous membranes reactive with type VII collagen, a major component of the epidermal basement membrane zone. Anti‐laminin‐332‐type mucous membrane pemphigoid has pathogenic autoantibodies against laminin‐332, which is a basement membrane heterotrimeric protein composed of α3, β3 and γ2 laminin chains. We describe a 73‐year‐old Japanese man presenting with multiple, annular, tense blisters on the lower legs and oral lesions. Despite the severe clinical manifestations, the disease was successfully controlled by combination therapy of oral prednisolone and mizoribine. This case was confirmed to have autoantibodies to both type VII collagen and laminin‐332 α3 chain by indirect immunofluorescence of 1 mol NaCl‐split normal human skin, various immunoblot analyses and enzyme‐linked immunosorbent assays. This case was a rare case of EBA with concomitant anti‐laminin‐332 antibodies.     

Efficacy of PCR-based open reading frame typing assay for outbreak investigation of metallo-β-lactamase-producing Pseudomonas aeruginosa in hematology unit

We investigated the efficacy of the PCR-based open reading frame typing (POT) assay for outbreak investigation of metallo-β-lactamase (MBL)-producing Pseudomonas aeruginosa (MBL-PA). A total of 53 P. aeruginosa isolates were detected between January 2010 and December 2012 on a hematology ward, of which 6 were identified as MBL-PA with the bla_IMP-1 gene. The POT assay revealed the same genotype (207-41) in 3 of 6 MBL-PA, suggesting an outbreak caused by a single strain. Environmental investigation of bathroom samples revealed the same POT genotype (207-41) as those of the clinical isolates and no other MBL-PA strains. Genetic relatedness of the MBL-PA isolates was confirmed by the DiversiLab repetitive-sequence-based PCR typing system, suggesting the POT type 207-41 as a genetically identical clone. The POT assay can be successfully applied to MBL-PA genotyping.     

Therapeutic depletion of myeloid lineage leukocytes by adsorptive apheresis for psoriatic arthritis: Efficacy of a non‐drug intervention for patients refractory to pharmacologics

Psoriatic arthritis (PsA), a chronic inflammatory arthropathy associated with psoriasis, is an intractable immune disorder and refractory to pharmacological intervention. We assessed efficacy of selective depletion of myeloid lineage leukocytes in patients with PsA in a multicenter setting. A total of 20 patients with moderate to severe PsA refractory to conventional and biological disease‐modifying antirheumatic drugs were included. Eligible patients had 3 points or more in the classification criteria for PsA. Each patient received five sessions, once a week, of adsorptive granulocyte and monocyte apheresis (GMA) with the Adacolumn^®. The primary efficacy outcome was 20% or more decrease in the American College of Rheumatology score 20 (ACR20). Partial responders could receive an additional five GMA sessions. Of 20 patients, two did not complete the study, nine responded to five GMA sessions and nine received 10 sessions. At the first evaluation 2 weeks after the last GMA session, 13 of the 20 (65.0%) patients achieved ACR20. ACR20 was maintained in seven of 10 (70%) and five of 10 (50%) patients at the follow‐up evaluation points 8 and 20 weeks after the last GMA session, respectively. GMA was well tolerated without any safety concern. This study demonstrates that GMA with the Adacolumn was effective with good safety profile in patients with PsA refractory to pharmacologicals. The results indicate a major role for myeloid leukocytes in the immunopathogenesis of PsA. A large controlled study is warranted to fully evaluate the efficacy of Adacolumn GMA in patients with PsA.     

Novel CD3‐specific antibody induces immunosuppression via impaired phosphorylation of LAT and PLCγ1 following T‐cell stimulation

The activation of T cells is known to be accompanied by the temporary downmodulation of the TCR/CD3 complex on the cell surface. Here, we established a novel monoclonal antibody, Dow2, that temporarily induces downmodulation of the TCR/CD3 complex in mouse CD4⁺ T cells without activating T cells. Dow2 recognized the determinant on CD3ε; however, differences were observed in the binding mode between Dow2 and the agonistic anti‐CD3ε Ab, 145–2C11. An injection of Dow2 in vivo resulted in T‐cell anergy, and prolonged the survival of cardiac allografts without a marked increase in cytokine release. The phosphorylated forms of the signaling proteins PLC‐γ1 and LAT in Dow2‐induced anergic T cells were markedly decreased upon stimulation. However, the levels of phosphorylated LAT and PLCγ1 in Dow2‐induced anergic T cells could be rescued in the presence of the proteasome inhibitor MG‐132. These results suggest that proteasome‐mediated degradation is involved in hypophosphorylated LAT and PLCγ1 in Dow2‐induced anergic T cells. The novel CD3‐specific Ab, Dow2, may provide us with a unique tool for inducing immunosuppression.     

Highly enantioselective synthesis of γ-, δ-, and ε-chiral 1-alkanols via Zr-catalyzed asymmetric carboalumination of alkenes (ZACA)–Cu- or Pd-catalyzed cross-coupling

Despite recent advances of asymmetric synthesis, the preparation of enantiomerically pure (≥99% ee) compounds remains a challenge in modern organic chemistry. We report here a strategy for a highly enantioselective (≥99% ee) and catalytic synthesis of various γ- and more-remotely chiral alcohols from terminal alkenes via Zr-catalyzed asymmetric carboalumination of alkenes (ZACA reaction)–Cu- or Pd-catalyzed cross-coupling. ZACA–in situ oxidation of tert-butyldimethylsilyl (TBS)-protected ω-alkene-1-ols produced both (R)- and (S)-α,ω-dioxyfunctional intermediates (3) in 80–88% ee, which were readily purified to the ≥99% ee level by lipase-catalyzed acetylation through exploitation of their high selectivity factors. These α,ω-dioxyfunctional intermediates serve as versatile synthons for the construction of various chiral compounds. Their subsequent Cu-catalyzed cross-coupling with various alkyl (primary, secondary, tertiary, cyclic) Grignard reagents and Pd-catalyzed cross-coupling with aryl and alkenyl halides proceeded smoothly with essentially complete retention of stereochemical configuration to produce a wide variety of γ-, δ-, and ε-chiral 1-alkanols of ≥99% ee. The MαNP ester analysis has been applied to the determination of the enantiomeric purities of δ- and ε-chiral primary alkanols, which sheds light on the relatively undeveloped area of determination of enantiomeric purity and/or absolute configuration of remotely chiral primary alcohols.Asymmetric synthesis remains as a significant challenge to synthetic organic chemists as the demand for enantiomerically pure compounds continues to increase. Chirality plays a vital role in chemical, biological, pharmaceutical, and material sciences. The US Food and Drug Administration requires that all chiral bioactive molecules have to be as pure as possible, containing a single pure enantiomer, because chirality significantly influences drugs’ biological and pharmacological properties. As a consequence, development of new methods for asymmetric synthesis of enantiomerically pure compounds (≥99% ee) continues to be increasingly important (1–5). We recently reported a highly selective and efficient method (6) for the preparation of 2-chirally substituted 1-alkanols via a sequence consisting of (i) Zr-catalyzed asymmetric carboalumination of alkenes (ZACA reaction hereafter) (7–10)–in situ iodinolysis of allyl alcohol, (ii) enantiomeric purification by lipase-catalyzed acetylation (11, 12) of both (S)- and (R)-ICH₂CH(R)CH₂OH (1), the latter obtained as acetate, i.e., (R)-2, and (iii) Cu- or Pd-catalyzed cross-coupling (13, 14) (Scheme 1).Open in a separate windowScheme 1.Strategy for the synthesis of enantiomerically pure 2-alkyl-1-alkanols.As satisfactory as the procedure shown in Scheme 1 is, however, its synthetic scope is limited to the preparation of 2-chirally substituted 1-alkanols. In search for an alternative and more generally applicable procedure, we came up with a strategy shown in Scheme 2, which, in principle, should be applicable to the synthesis of γ- and more-remotely chiral alcohols of high enantiomeric purity. In contrast to Scheme 1, the alkylalane intermediates prepared by the ZACA reaction of tert-butyldimethylsilyl (TBS)-protected ω-alkene-1-ols are to be subjected to in situ oxidation with O₂ to introduce OH group of α,ω-dioxyfunctional chiral intermediates (3) (Scheme 2). The strategies shown in Schemes 1 and ​and22 illustrate the versatility of ZACA represented by the organoaluminum functionality of the initially formed ZACA products. Introduction of the OH group by oxidation of initially formed alkylalane intermediates in Scheme 2 is based on two considerations: (i) the proximity of the OH group to a stereogenic carbon center is highly desirable for lipase-catalyzed acetylation to provide ultrapure (≥99% ee) difunctional intermediates, and (ii) the versatile OH group can be further transformed to a wide range of carbon groups by tosylation or iodination followed by Cu- or Pd-catalyzed cross-coupling. The TBS-protected OH group (OTBS) serves not only as a source of OH group in the final desired alkanols, but also as a proximal heterofunctional group leading to higher enantioselectivity in lipase-catalyzed acetylation (11, 12). As long as the α,ω-dioxyfunctional chiral intermediates (R)-3 and (S)-4 can be readily prepared as enantiomerically pure (≥99% ee) substances, their subsequent Cu- or Pd-catalyzed cross-coupling would proceed with retention of all carbon skeletal features to produce a wide range of γ- and more-remotely chiral alcohols in high enantiomeric purity (≥99% ee).Open in a separate windowScheme 2.Strategy for the synthesis of γ- and more-remotely chiral 1-alkanols.     

Age-Stratified Seroprevalence of SARS-CoV-2 Antibodies before and during the Vaccination Era,Japan, February 2020–March 2022

Japan has reported a relatively small number of COVID-19 cases. Because not all infected persons receive diagnostic tests for COVID-19, the reported number must be lower than the actual number of infections. We assessed SARS-CoV-2 seroprevalence by analyzing >60,000 samples collected in Japan (Tokyo Metropolitan Area and Hokkaido Prefecture) during February 2020–March 2022. The results showed that ≈3.8% of the population had become seropositive by January 2021. The seroprevalence increased with the administration of vaccinations; however, among the elderly, seroprevalence was not as high as the vaccination rate. Among children, who were not eligible for vaccination, infection was spread during the epidemic waves caused by the SARS-CoV-2 Delta and Omicron variants. Nevertheless, seroprevalence for unvaccinated children <5 years of age was as low as 10% as of March 2022. Our study underscores the low incidence of SARS-CoV-2 infection in Japan and the effects of vaccination on immunity at the population level.     

Diagnosis of the Depth of Advanced Gastric Cancer Invasion by Endoscopic Ultrasonography

Preoperative endoscopic ultrasonography (EUS) was performed in 272 patients with advanced gastric cancer who underwent gastrectomy between December 1986 and December 1993. We divided the subjects into two groups: group A consisted of patients whose stomachs were filled with water for the EUS examination (water-filling method: 1986.12–1992. 10) and group B of patients in whom EUS was performed with the water-filled balloon compression method (balloon-compression method) in addition to the water-filling method (1992.11–1993. 12). A comparative study of EUS diagnostic efficacy, as regards the depth of invasion, was made between group A and group B. The following results were obtained: 1) In group A, the depth of invasion of mass-forming type carcinoma was accurately diagnosed by EUS in 59.3% of patients with mp cancer, in 28.8% of those with ss cancer, in 78.8% of those with se cancer, and in 83.3% of those with si cancer. The accuracy rate in diagnosing the depth of invasion of wall-thickening type carcinoma was 46.2% in patients with mp cancer, 68.0% in those with ss cancer, 59.1% in those with se cancer, and 66.7% in those with si cancer. 2) In group B, the depth of invasion of mass-forming type carcinoma was accurately diagnosed by EUS in 70.6% of patients with mp cancer, in 68.4% of those with ss cancer, in 92.3% of those with se cancer, and in 100% of those with si cancer. The accuracy rate in diagnosing the depth of invasion of wall-thickening type carcinoma was 75.0% in patients with mp cancer, 72.7% in those with ss cancer, 76.5% in those with se cancer, and 100% in those with si cancer. 3) These results suggest that the diagnostic efficacy of EUS utilizing both the balloon-compression method and the water-filling method is greater, as regards the depth of advanced gastric cancer invasion, than EUS utilizing only the water-filling method.     

Fixed Drug Eruption Caused by Iopamidol,A Contrast Medium

We report a patient who developed a fixed drug eruption caused by the contrast medium, Iopamidol. We diagnosed it by her episode pattern and the results of patch tests. This substance has not been previously implicated as a cause of fixed drug eruption. Immunohistochemical studies showed Fas expression in keratinocytes of the lesion, but not in the uninvolved skin. This finding may explain the preferential localization of fixed drug eruption.