Isolation of OXA-48-like carbapenemase-producing Escherichia coli susceptible to piperacillin/tazobactam in a Japanese patient without a history of travel abroad.

Oxacillinase (OXA)-48-like ß-lactamases are the most common carbapenemases in Enterobacterales in certain regions of the world and are being introduced on a regular basis into regions of non-endemicity. Japan has been characterized by low rates of carbapenemase-producing Enterobacterales, and among them, OXA-48-like carbapenemase-producing isolates are extremely rare. Here we describe a Japanese medical worker, without a history of travel abroad, who was diagnosed as having a community-acquired urinary tract infection, and whose urine sample was found to be positive for OXA-48-like carbapenemase-producing Escherichia coli. None of her close contacts had a history of foreign travel, and the same drug-resistant organism was not observed in other patients who had been hospitalized and undergone environmental culture tests in the same medical institution. This isolate was resistant to penicillins, narrow-spectrum cephalosporins, fluoroquinolones, and cefmetazole, but was susceptible to broad-spectrum cephalosporins, piperacillin/tazobactam, and meropenem and displayed reduced susceptibility to imipenem. The modified carbapenem inactivation test supported carbapenemase production, but inhibitor-based synergistic tests yielded negative results of carbapenemase production. Multiplex polymerase chain reaction revealed the presence of the carbapenemase gene (blaOXA-48) blaTEM and AmpC ß-lactamase gene (blaDHA). Singleplex polymerase chain reaction targeting the blaOXA-48 region amplified a product sequencing to nearly the full length (722 bp) and matching 100% with OXA-48. The present case highlights a new concern regarding OXA-48-like carbapenemase-producing Enterobacterales, which remain challenging to detect for clinical laboratories in regions of non-endemicity, and may already be latent in Japan.

[Three Cases of Remnant Pancreatic Cancer after Surgery for Invasive Ductal Carcinoma of Pancreas].

We report here 3 cases of remnant pancreatic cancer after surgery for invasive ductal carcinoma. Case 1 was a 73-year-old male who underwent distal pancreatectomy(pap, pT3, pN0, M0): fStage II A(JPS 7th). He developed a remnant pancreatic cancer 39 months later, and total remnant pancreatectomy was performed. He died from sepsis 9 months after surgery. Case 2 was a 72-year-old female who underwent subtotal stomach-preserving pancreatoduodenectomy(SSPPD)(tub2, pT1c, pN1a, M0): fStage II B. She developed a remnant pancreatic cancer 82 months later. This lesion seemed to be resectable. But she hoped to take a best supportive care, and died 13 months after diagnosis. Case 3 was a 68-year-old female who underwent SSPPD(tub1, pT3, pN1a, M0): fStage II B. She developed a remnant pancreatic cancer 20 months later and was successfully treated by chemotherapy and carbon-ion radiotherapy.

[A Case of Remnant Pancreatic Cancer after Pancreatoduodenectomy Successfully Treated Using Chemotherapy and Carbon-Ion Radiotherapy].

We report a case of remnant pancreatic cancer after pancreatoduodenectomy that was successfully treated using chemotherapy and carbon-ion radiotherapy. A 68-year-old woman received SSPPD for pancreatic head cancer. Gemcitabine(GEM) was administered for a year as postoperative chemotherapy. One year 8 months after surgery, abdominal CT showed a 20 mm solid mass in the stump of the remnant pancreas and dilation of the distal pancreatic duct. FDG-PET revealed a solitary tumor without any recurrence. We diagnosed the patient with a solitary recurrence of pancreatic cancer. Chemotherapy (GEM)and carbon-ion radiotherapy were performed. After treatment, the lesion was not detected on CT or FDG-PET. Chemotherapy(GEM)and carbon-ion radiotherapy for locally advanced pancreatic cancer seems to be effective and there might result in a survival benefit.

[A Case of Male Hereditary Breast Cancer Involving a Sentinel Lymph Node Biopsy].

We report a rare case of male hereditary breast cancer in which a sentinel lymph node biopsy was performed. A 62-yearold man was admitted to our hospital because of a palpable tumor in his right breast. Both his younger sister and daughter had had breast cancer. Genetic testing revealed a morbid mutation in the BRCA2 gene. The tumor was palpated to an elastic hard mass and had a clear border in the right DCE area. We performed a core needle biopsy and diagnosed invasive ductal carcinoma, specifically, cT1cN0cM0, cStage I hereditary breast cancer. The patient underwent mastectomy and a sentinel lymph node biopsy. Nine days later, tamoxifen therapy was initiated. There has been no sign of recurrence during the 9 months after the operation.

Laparoscopic remnant cholecystectomy for calculi in the remnant gallbladder following subtotal-cholecystectomy: a report of two cases.

Two cases of laparoscopic remnant cholecystectomy using near-infrared fluorescence cholangiography (NIFC) for remnant gallbladder calculi following subtotal-cholecystectomy are reported. Case 1: a 36-year-old woman was referred to our hospital with acute abdomen. Computed tomography showed remnant gallbladder calculi, with detected no other findings as the cause of the abdominal pain. For intraoperative exploration of the biliary anatomy, 0.25 mg/kg of indocyanine green (ICG) was administered intravenously the day before the operation. NIFC clearly showed the common bile duct and enabled safe laparoscopic remnant cholecystectomy. She was free from symptoms after the operation. Case 2: a 40-year-old woman was referred to our hospital with epigastralgia due to remnant gallbladder calculi after open cholecystectomy. ICG was administered intravenously the day before the operation. Severe adhesions were observed in the upper abdominal cavity and there was tight adherence of the duodenum to the remnant gallbladder. NIFC showed a clear margin that appeared to be the margin between the duodenum and remnant gallbladder. However, dissection of the margin observed by NIFC caused perforation of the duodenum. The clear margin seen with NIFC was likely due to visualization of the gallbladder through the duodenum. Although NIFC is a useful modality for confirming the intraoperative biliary anatomy, it is important not to rely too heavily on NIFC alone, which may lead to misinterpretation of the anatomy.

A pyridone derivative activates SERCA2a by attenuating the inhibitory effect of phospholamban.

The cardiac sarco/endoplasmic reticulum Ca2+-dependent ATPase 2a (SERCA2a) plays a central role in Ca2+ handling within cardiomyocytes and is negatively regulated by phospholamban (PLN), a sarcoplasmic reticulum (SR) membrane protein. The activation of SERCA2a, which has been reported to improve cardiac dysfunction in heart failure, is a potential therapeutic approach for heart failure. Therefore, we developed a novel small molecule, compound A and characterized it both in vitro and in vivo. Compound A activated the Ca2+-dependent ATPase activity of cardiac SR vesicles but not that of skeletal muscle SR vesicles that lack PLN. The surface plasmon resonance assay revealed a direct interaction between compound A and PLN, suggesting that the binding of compound A to PLN attenuates its inhibition of SERCA2a, resulting in SERCA2a activation. This was substantiated by inhibition of the compound A-mediated increase in Ca2+ levels within the SR of HL-1 cells by thapsigargin, a SERCA inhibitor. Compound A also increased the Ca2+ transients and contraction and relaxation of isolated adult rat cardiomyocytes. In isolated perfused rat hearts, the compound A enhanced systolic and diastolic functions. Further, an infusion of compound A (30mg/kg, i.v. bolus followed by 2mg/kg/min, i.v. infusion) significantly enhanced the diastolic function in anesthetized normal rats. These results indicate that compound A is a novel SERCA2a activator, which attenuates PLN inhibition and enhances the systolic and diastolic functions of the heart in vitro and in vivo. Therefore, compound A might be a novel therapeutic lead for heart failure.

PDZRN3 negatively regulates BMP-2-induced osteoblast differentiation through inhibition of Wnt signaling.

PDZRN3 is a member of the PDZ domain-containing RING finger family of proteins. We previously showed that PDZRN3 is essential for the differentiation of C2C12 mouse mesenchymal progenitor cells into myotubes. Mesenchymal progenitor cells differentiate into osteoblasts, chondrocytes, and adipocytes in addition to myotubes, and we have now examined the potential role of PDZRN3 in the differentiation of C2C12 cells into osteoblasts. The abundance of PDZRN3 in C2C12 cells was increased after the induction of osteoblast differentiation by exposure to bone morphogenetic protein (BMP)-2 in low-serum medium. Depletion of PDZRN3 in C2C12 cells by RNA interference resulted in marked enhancement of the BMP-2-induced up-regulation of alkaline phosphatase (ALP) activity. Dkk1, an inhibitor of Wnt signaling, markedly attenuated the enhancement of the BMP-2-induced increase in ALP activity by PDZRN3 depletion. The up-regulation of ALP activity by Wnta3a was also promoted by depletion of PDZRN3. Furthermore, the expression and Wnt3a-induced phosphorylation of LRP6 as well as the increase in the cytosolic abundance of ß-catenin induced by Wnt3a were potentiated in PDZRN3-depleted cells. These results indicate that PDZRN3 plays an important role in negative feedback control of BMP-2-induced osteoblast differentiation in C2C12 cells through inhibition of Wnt-ß-catenin signaling.

PDZRN3 (LNX3, SEMCAP3) is required for the differentiation of C2C12 myoblasts into myotubes.

PDZRN3 contains a RING-finger motif in its N-terminal region, two PDZ domains in its central region and a consensus-binding motif for PDZ domains at its C-terminus. It was identified in silico as a homolog of the protein known as LNX1 or SEMCAP1, which possesses ubiquitin ligase activity and binds the membrane protein Semaphorin 4C. However, PDZRN3 itself has not previously been characterized. We have now evaluated the properties and functions of PDZRN3. The PDZRN3 gene was shown to be expressed in various human tissues including the heart, skeletal muscle and liver and its expression in mouse skeletal muscle was developmentally regulated. Both the differentiation of C2C12 mouse skeletal myoblasts into myotubes and injury-induced muscle regeneration in vivo were found to be accompanied by up-regulation of PDZRN3. The differentiation-associated increase in the expression of PDZRN3 in C2C12 cells follows that of myogenin and precedes that of myosin heavy chain. Depletion of PDZRN3 by RNA interference inhibited the formation of myotubes as well as the associated up-regulation of myosin heavy chain in C2C12 cells. Our data suggest that PDZRN3 plays an essential role in the differentiation of myoblasts into myotubes by acting either downstream or independently of myogenin.