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Generalized pustular psoriasis (GPP) is a rare inflammatory skin disease that can be life-threatening. Recently, it has been reported that familial GPP is caused by homozygous or compound heterozygous mutations of IL36RN. However, the majority of GPP cases are sporadic and it is controversial whether IL36RN mutations are a causative/predisposing factor for sporadic GPP. We searched for IL36RN mutations in two groups of GPP patients in the Japanese population in this study: GPP without psoriasis vulgaris (PV), and GPP with PV. Eleven cases of GPP without PV (GPP alone) and 20 cases of GPP accompanied by PV (GPP with PV) were analyzed. Surprisingly, 9 out of 11 cases of GPP alone had homozygous or compound heterozygous mutations in IL36RN. In contrast, only 2 of 20 cases of GPP with PV had compound heterozygous mutations in IL36RN. The two cases of GPP with PV who had compound heterozygous mutations in IL36RN are siblings, and both cases had PV-susceptible HLA-A*0206. We determined that GPP alone is a distinct subtype of GPP and is etiologically distinguished from GPP with PV, and that the majority of GPP alone is caused by deficiency of the interleukin-36 receptor antagonist due to IL36RN mutations.

Background Hepatopancreatoduodenectomy (HPD) is one of the most challenging surgeries for perihilar cholangiocarcinoma. Postoperative pancreatic fistula (POPF) is a critical and fatal complication. The safety and efficacy of pancreaticogastrostomy (PG) for HPD compared to pancreaticojejunostomy (PJ) remain unclear. In this study, we aimed to investigate and compare the short-term outcomes of PG and PJ for HPD in terms of the POPF rate. Methods Two groups of patients (PG group vs. PJ group) were retrospectively compared between January 2013 and January 2024. The reconstruction method was changed from PJ to PG in March 2021. Results A total of 50 patients were enrolled in this study. The PG and PJ groups comprised 15 (30.0%) and 35 (70.0%) patients, respectively. In the PJ group, three (8.6%) patients died after surgery because of clinically relevant POPF (CR-POPF), intraabdominal bleeding, and post-hepatectomy liver failure. The operative time was longer in the PG group (909 min vs. 706 min, P  = 0.020); however, the CR-POPF rate was lower in the PG group than in the PJ group (0 [0%] vs. 19 [54.3%], P  < 0.001). Moreover, the number of patients who developed massive postoperative ascites (≥ 1,500 mL/day) was lower in the PG group than in the PJ group (3 [20.0%] vs. 16 [45.7%] patients, P  = 0.028). Conclusions Changing the method of pancreatic reconstruction for HPD from PJ to PG improved the short-term outcomes of patients at our institution. PG reconstruction is safe and effective for HPD as it reduces the incidence of CR-POPF.

Proteasomes are multisubunit proteases that play a critical role in maintaining cellular function through the selective degradation of ubiquitinated proteins. When 3 additional β subunits, expression of which is induced by IFN-γ, are substituted for their constitutively expressed counterparts, the structure is converted to an immunoproteasome. However, the underlying roles of immunoproteasomes in human diseases are poorly understood. Using exome analysis, we found a homozygous missense mutation (G197V) in immunoproteasome subunit, β type 8 (PSMB8), which encodes one of the β subunits induced by IFN-γ in patients from 2 consanguineous families. Patients bearing this mutation suffered from autoinflammatory responses that included recurrent fever and nodular erythema together with lipodystrophy. This mutation increased assembly intermediates of immunoproteasomes, resulting in decreased proteasome function and ubiquitin-coupled protein accumulation in the patient's tissues. In the patient's skin and B cells, IL-6 was highly expressed, and there was reduced expression of PSMB8. Downregulation of PSMB8 inhibited the differentiation of murine and human adipocytes in vitro, and injection of siRNA against Psmb8 in mouse skin reduced adipocyte tissue volume. These findings identify PSMB8 as an essential component and regulator not only of inflammation, but also of adipocyte differentiation, and indicate that immunoproteasomes have pleiotropic functions in maintaining the homeostasis of a variety of cell types.

Allosamidin, a typical secondary metabolite of Streptomyces , has been known as a chitinase inhibitor. We found that allosamidin can dramatically promote chitinase production and growth of its producer, Streptomyces sp. AJ9463, in a chitin medium at a few hundred nM. Allosamidin promoted production of the main chitinase detected in the culture filtrate and the chitin-hydrolytic activity of the chitinase was not inhibited by allosamidin at the concentration. The gene encoding the chitinase showed that it is a family 18 chitinase and it was revealed that two genes encoding proteins constructing two-component regulatory system were present at 5′-upstream region of the chitinase gene. Allosamidin is located in the microbial mycelia cultured in a medium without chitin, but it was released from the mycelia by responding to chitin. These results show that allosamidin acts as a key signal molecule for chitinase production in its producing strain, which may be useful for its growth in chitin-rich environment.

Endoscopic mucosectomy, comprising both endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD), is a minimally invasive treatment for patients with early esophageal carcinoma. The use of ESD is appropriate for mucosal lesions of any size. However, ESD techniques are relatively difficult and can lead to serious complications such as perforation and massive bleeding, which have been reported more frequently after ESD than after EMR. This study describes a novel technique for ESD using a newly designed multipurpose treatment hood (TxHood) as well as basic experiments to ensure its safety. The TxHood includes various therapeutic tools such as an electric needleknife, a snare wire, and an injection needle, and the lines can be selected freely before insertion of an enodoscope covered by a TxHood. The main techniques for ESD are endoscopic submucosal saline injections on demand through a working channel of the endoscope or TxHood and a cut or swing cut with a needleknife attached to the TxHood. Moreover, the target area can be grasped with a grasping forceps through a working channel of the endoscope to obtain effective countertraction. In these experiments, an electric needleknife set parallel to the shaft of the endoscope offered safety and ease of handling for the dissecting procedures. Altogether, 16 resections of mucosa with an average size of 3.5 × 2.5 cm (range, 2 × 2 to 7 × 4 cm) were performed. The average time required for each targeted endoscopic resection area was about 15 min. No perforations or instances of uncontrollable bleeding occurred. In conclusion, this basic study demonstrates that the new ESD technique with the TxHood provides a useful treatment for early esophageal carcinoma and may be applicable for all mucosal or submucosal tumors in the gastrointestinal tract.

Allosamidin, a typical secondary metabolite of Streptomyces, has been known as a chitinase inhibitor. We found that allosamidin can dramatically promote chitinase production and growth of its producer, Streptomyces sp. AJ9463, in a chitin medium at a few hundred nM. Allosamidin promoted production of the main chitinase detected in the culture filtrate and the chitin-hydrolytic activity of the chitinase was not inhibited by allosamidin at the concentration. The gene encoding the chitinase showed that it is a family 18 chitinase and it was revealed that two genes encoding proteins constructing two-component regulatory system were present at 5[variant prime]-upstream region of the chitinase gene. Allosamidin is located in the microbial mycelia cultured in a medium without chitin, but it was released from the mycelia by responding to chitin. These results show that allosamidin acts as a key signal molecule for chitinase production in its producing strain, which may be useful for its growth in chitin-rich environment.

In Streptomyces sp. AJ9463, a producer of chitinase inhibitor allosamidin, allosamidin strongly enhances production of the chitinase mainly secreted to the culture broth in a chitin medium. To clarify the mechanism for regulation of the chitinase production by allosamidin, a disruption experiment of genes encoding proteins constructing a two-component regulatory system present at 5′-upstream region of the chitinase gene was performed. In the disruptant obtained, allosamidin could not promote the chitinase production, but N , N ′-diacetylchitobiose, which also enhances production of the same chitinase more weakly than allosamidin, promoted the chitinase production similarly to the case observed in the wild-type strain. Furthermore, by the experiment in an inorganic salt solution, it was shown that allosamidin could not induce the chitinase production without addition of N , N ′-diacetylchitobiose. These results show that allosamidin can activate transcription of the chitinase gene through the two-component regulatory system in the presence of N , N ′-diacetylchitobiose.

Background It is difficult to undergo a second endoscopic mucosal resection (EMR) for local cancer recurrence because ulcer scars caused by the previous EMR are frequently located near the tumor. The main objective of this study was to evaluate whether argon plasma coagulation (APC) is an effective and safe modality for treating early esophageal cancer recurrence untreatable by EMR. Methods We reviewed the experience of this clinic in the administration of EMR for the treatment of mucosal esophageal cancer in 249 patients with 276 lesions (142, m1; 98, m2; 36, m3) between December 1989 and March 2005. A local recurrence of the disease after the EMR was detected in 24 cases (9.6%). Seventeen patients were treated with APC. An argon gas flow of 2 l/min was used at a power setting of 60 W. The follow-up period of the 17 patients ranged from 13 to 87 months (median, 68 months). Results The depth of tumor invasion, estimated by endoscopy, was mucosal in all patients. Seventy-three sessions (mean, 4.3 sessions/person; range, 1–12 sessions) were performed. All lesions were easily irradiated. No serious complications such as bleeding, perforation, or stenosis occurred. Complete local control was achieved in 16 of the 17 patients, but the remaining patient required further surgery. Death occurred in 3 cases. Two patients died as a result of other disease, and 1 patient died of other carcinomas, but no patient died of esophageal carcinoma. Conclusion APC is a safe and effective method for the treatment of local recurrence of squamous cell carcinoma of the esophagus after an EMR.

In Streptomyces sp. AJ9463, a producer of chitinase inhibitor allosamidin, allosamidin strongly enhances production of the chitinase mainly secreted to the culture broth in a chitin medium. To clarify the mechanism for regulation of the chitinase production by allosamidin, a disruption experiment of genes encoding proteins constructing a two-component regulatory system present at 5[variant prime]-upstream region of the chitinase gene was performed. In the disruptant obtained, allosamidin could not promote the chitinase production, but N,N[variant prime]-diacetylchitobiose, which also enhances production of the same chitinase more weakly than allosamidin, promoted the chitinase production similarly to the case observed in the wild-type strain. Furthermore, by the experiment in an inorganic salt solution, it was shown that allosamidin could not induce the chitinase production without addition of N,N[variant prime]-diacetylchitobiose. These results show that allosamidin can activate transcription of the chitinase gene through the two-component regulatory system in the presence of N,N[variant prime]-diacetylchitobiose.