Delayed Presentation and Referral Time from General Practitioners Contribute to Increased Complicated Appendicitis during the Initial COVID-19 Pandemic Period in Japan.

Objectives: This study aims to investigate the impact of the coronavirus disease 2019 (COVID-19) pandemic on the situation of acute appendicitis (AA) with respect to patients' and general practitioners' behaviors in a general community hospital in Japan. Methods: The surgical outcomes and periods from symptom onset to medical presentation besides practitioners' referral time for consecutive AA patients were compared between the control (January 2016 to March 2020) and COVID-19 periods (April 2020 to April 2021). Results: Eighty-three patients who underwent emergency surgery for AA were reviewed. Complicated appendicitis significantly increased in the COVID-19 period (63.6% vs. 31.2%, P = 0.023). In the COVID-19 period, the time from symptom onset to the medical presentation (2.2 vs. 0.9 days, P < 0.001) was significantly longer than in the control period. Among the patients who first presented to a general practitioner, the referral time from the practitioner to our hospital was significantly longer in the COVID-19 period (1.6 vs. 0.7 days, P = 0.017). Furthermore, among patients with a fever of higher than 38°C at medical presentation, the time from symptom onset to medical presentation was significantly longer in the COVID-19 period (3.0 vs. 0.7 days, P = 0.015). There was no difference in severe postoperative complications. Conclusions: Hesitation to seek surgical treatment for AA was seen in both the patients and practitioners in the COVID-19 period. The delay in surgical treatment presumably led to the increase in severe AA. In a pandemic era, timely care for emergent conditions is a crucial challenge.

Colonic gallstone ileus treated by a transanal ileus tube followed by spontaneous gallstone dislodgement: A case report.

A 71-year-old obese woman was referred to our hospital with lower left abdominal pain. Computed tomography showed a 46 mm elliptic calcification lodged in the sigmoid-descending colon junction (SDJ), which had been detected 5 years prior but was not within the gall bladder at presentation. Therefore, we diagnosed colonic gallstone ileus with obstructive colitis caused by a gallstone. Colonoscopy revealed a smooth gallstone impacted at the sigmoid-descending colon junction, which was not fixed and could be pushed proximally with the endoscope. Dislodgement of the stone was unsuccessful with both a large polypectomy snare and a retrieval basket. Considering the high risk of surgery, we chose a non-surgical treatment strategy for obstructive colitis. Accordingly, a transanal ileus tube was placed to drain the proximal portion of the gallstone. The drainage of the colon by the ileus tube was satisfactory; the proximal colon was decompressed, ameliorating the obstructive colitis. Five days after tube placement, a colonoscopy revealed spontaneous passage of the gallstone into the rectum where it was finally removed. Cholecystocolonic fistula formation was confirmed by magnetic resonance imaging. We decided to surgically close the cholecystocolonic fistula to prevent future retrograde biliary infections. The surgery used a surgical stapler and was successful, with an uneventful postoperative course. Since radical surgical treatment of colonic gallstones and cholecystoenteric fistulas has a risk of postoperative morbidity and mortality, this case illustrates the importance of thoroughly considering nonsurgical interventions and surgeries for the safe treatment of colonic gallstone ileus.

Proposal of a Novel Index of Abdominal Compliance and the Association With Postoperative Pain After Laparoscopic Inguinal Hernia Repair.

BACKGROUND: In laparoscopic surgery, low pneumoperitoneum pressure is reported to reduce pain, which suggests that easing abdominal expansion is crucial for less postoperative pain. However, although abdominal compliance (AC) is associated with the degree of abdominal expansion, the role of AC in pain by pneumoperitoneum is unknown. In this study, we devised a novel index as a surrogate of AC to evaluate the association between AC and postoperative pain in laparoscopic inguinal hernia repair. MATERIALS AND METHODS: We reviewed 83 patients who underwent elective transabdominal preperitoneal repair from 2019 to 2021 at Heisei Memorial Hospital. Insufflation pressure was set to low pressure (8 mm Hg). The abdominal compliance index [ACI; insufflated intra-abdominal volume (L)/body surface area (m2)] was utilized to evaluate the association between AC and postoperative pain. RESULTS: ACI was evaluated in 30 patients. Median ACI was 1.53 (1.00 to 2.48) L/m2. Although there was no difference in the average body constitution, the high ACI group (n=15) had significantly higher intra-abdominal volume at 8 mm Hg pressure, compared with the low ACI group (n=15) (3.1 vs. 2.1 L, P<0.0001). The high ACI group had significantly higher pain than the low ACI group on the day of surgery (2.0 vs. 1.0, P=0.006) and the day after (0.8 vs. 0.3, P=0.007). In addition, 46.7% of the patients in the high ACI group experienced pneumoperitoneum-associated pain, whereas patients in the low ACI group experienced incision pain only. Additional analgesics were administered in 53.3% of the high ACI group, compared with 33.3% in the low ACI group. CONCLUSIONS: AC was suggested to be a vital factor of postoperative pain after laparoscopic inguinal hernia repair. Patients with high AC may be susceptible to higher pain by pneumoperitoneum, even in low-pressure settings.

Significance of umbilical trocar size and intra-abdominal pressure on postoperative pain after transabdominal preperitoneal repair for inguinal hernia.

INTRODUCTION: Laparoscopic inguinal hernia repair is reported to be associated with lower postoperative pain than open repair. However, in the actual clinical setting, some patients experience relatively severe pain. This study aimed to elucidate surgical factors that affect pain after transabdominal preperitoneal (TAPP) repair. METHODS: We evaluated 199 patients who underwent elective TAPP for inguinal hernia from 2014 to 2019 in Heisei Memorial Hospital. The umbilical trocar size was changed from 12 to 5 mm from October 2017. The pneumoperitoneum intra-abdominal pressure was changed from 10 to 8 mmHg from 2019. Postoperative pain scores and analgesics were compared between patients who were grouped according to trocar size and intra-abdominal pressure, as well as 80 patients who received open repair. RESULTS: Patients with a 12 mm trocar had significantly higher pain than open repair patients (P < .0001). Patients with a 5 mm umbilical trocar and 8 mm Hg intra-abdominal pressure had significantly lower pain than a 12 mm trocar (P = .025) and did not significantly differ with pain after open repair. Analgesic use significantly decreased in patients using a 5 mm trocar than 12 mm (P = .002). CONCLUSION: Umbilical trocar size and pneumoperitoneum intra-abdominal pressure were significantly associated with post-TAPP pain. Using a 5 mm umbilical trocar and 8 mm Hg intra-abdominal pressure achieved pain levels as comparatively low as open repair.

Discovery of 4-Piperazine Isoquinoline Derivatives as Potent and Brain-Permeable Tau Prion Inhibitors with CDK8 Activity.

Tau prions feature in the brains of patients suffering from Alzheimer's disease and other tauopathies. For the development of therapeutics that target the replication of tau prions, a high-content, fluorescence-based cell assay was developed. Using this high-content phenotypic screen for nascent tau prion formation, a 4-piperazine isoquinoline compound (1) was identified as a hit with an EC50 value of 390 nM and 0.04 K p,uu. Analogs were synthesized using a hypothesis-based approach to improve potency and in vivo brain penetration resulting in compound 25 (EC50 = 15 nM; K p,uu = 0.63). We investigated the mechanism of action of this series and found that a small set of active compounds were also CDK8 inhibitors.

Studies on novel HIF activators, A-503451s.I. Producing organism, fermentation, isolation and structural elucidation.

In the course of our screening for activators of hypoxia-inducible factor (HIF), A-503451 A and virantmycin were isolated from the cultured broth of an actinomycete strain, Streptomyces sp. SANK 60101. From the same culture, the non-active homologs A-503451 B and D were also isolated. A-503451 A and virantmycin activated HIF-dependent reporter gene expression with EC50 values of 8 and 17 ng ml-1, respectively. They are highly potent activators of HIF and thus may be therapeutically useful for erythropoiesis and neural cell protection.

Studies on novel HIF activators, A-503451sII: biological activities of A-503451A.

In the course of our screening, we discovered a novel compound, A-503451A, as a potent hypoxia-inducible factor (HIF) activator. In human hepatocarcinoma HepG2 cells, A-503451A induced HIF-mediated luciferase reporter gene expression and stabilized HIF-1α protein. A-503451A increased the mRNA expression levels and the protein secretion of HIF-dependent genes, vascular endothelial growth factor and erythropoietin. Addition of excess ferric chloride to the culture medium suppressed the HIF-induction activity of A-503451A. A-503451A did not have iron-chelating activity in vitro, but decreased the intracellular labile iron pool concentration. These data indicate that A-503451A is a unique HIF activator.

Propagation of prions causing synucleinopathies in cultured cells.

Increasingly, evidence argues that many neurodegenerative diseases, including progressive supranuclear palsy (PSP), are caused by prions, which are alternatively folded proteins undergoing self-propagation. In earlier studies, PSP prions were detected by infecting human embryonic kidney (HEK) cells expressing a tau fragment [TauRD(LM)] fused to yellow fluorescent protein (YFP). Here, we report on an improved bioassay using selective precipitation of tau prions from human PSP brain homogenates before infection of the HEK cells. Tau prions were measured by counting the number of cells with TauRD(LM)-YFP aggregates using confocal fluorescence microscopy. In parallel studies, we fused α-synuclein to YFP to bioassay α-synuclein prions in the brains of patients who died of multiple system atrophy (MSA). Previously, MSA prion detection required ∼120 d for transmission into transgenic mice, whereas our cultured cell assay needed only 4 d. Variation in MSA prion levels in four different brain regions from three patients provided evidence for three different MSA prion strains. Attempts to demonstrate α-synuclein prions in brain homogenates from Parkinson's disease patients were unsuccessful, identifying an important biological difference between the two synucleinopathies. Partial purification of tau and α-synuclein prions facilitated measuring the levels of these protein pathogens in human brains. Our studies should facilitate investigations of the pathogenesis of both tau and α-synuclein prion disorders as well as help decipher the basic biology of those prions that attack the CNS.

Structural basis of digoxin that antagonizes RORgamma t receptor activity and suppresses Th17 cell differentiation and interleukin (IL)-17 production.

The retinoic acid-related orphan nuclear receptor γt (RORγt)/RORγ2 is well known as a master regulator of interleukin 17 (IL-17)-producing helper T (Th17) cell development. To develop a therapeutic agent against Th17-mediated autoimmune diseases, we screened chemical compounds and successfully found that digoxin inhibited IL-17 production. Further studies revealed that digoxin bound to the ligand binding domain of RORγt and suppressed Th17 differentiation without affecting Th1 differentiation. To better understand the structural basis for the inhibitory activity of digoxin, we determined the crystal structure of the RORγt ligand-binding domain in complex with digoxin at 2.2 Å resolution. The structure reveals that digoxin binds to the ligand-binding pocket protruding between helices H3 and H11 from the pocket. In addition, digoxin disrupts the key interaction important for the agonistic activity, resulting in preventing the positioning of helix H12 in the active conformation, thus antagonizing coactivator interaction. Functional studies demonstrated that digoxin inhibited RORγt activity and decreased IL-17 production but not RORα activity. Digoxin inhibited IL-17 production in CD4(+) T cells from experimental autoimmune encephalomyelitis mice. Our data indicates that RORγt is a promising therapeutic target for Th17-derived autoimmune diseases and our structural data will help to design novel RORγt antagonists.

Clinical outcome and management of ureteral obstruction secondary to gastric cancer.

BACKGROUND: The clinical outcome of ureteral obstruction secondary to gastric cancer remains unclear. The present study was designed to evaluate the clinical outcome and predictive factors of survival in patients with ureteral obstruction secondary to gastric cancer. METHODS: Twenty-five consecutive patients with ureteral obstruction secondary to gastric cancer between January 1998 and December 2007 were retrospectively analyzed. All patients had hydronephrosis; 13 patients had bilateral hydronephrosis, and 12 patients had unilateral hydronephrosis. RESULTS: Ten patients presented with pain, 3 patients with urinary tract infection, and 2 patients with acute renal failure. Seven (58%) of 12 patients with unilateral ureteral obstruction experienced progression to bilateral ureteral obstruction during the follow-up period. Eighteen patients (61%) were eventually managed with urinary diversion. In total, 5 patients were managed with percutaneous nephrostomy, and 15 patients with retrograde ureteral stenting. All symptomatic patients responded to urinary diversion. The overall median survival was 5.8 months, and the 6-month and 1-year survival rates were 48 and 32%, respectively. Chemotherapy was found to be the only independent predictor of survival (p=0.0498). Median survival in patients who received chemotherapy was 11.2 months, in comparison to 3.1 months in patients who did not receive chemotherapy (p=0.0002). CONCLUSIONS: The prognosis of ureteral obstruction secondary to gastric cancer was extremely poor, particularly when chemotherapy was not administered. The indications for palliative urinary diversion should be determined after considering the patient's symptoms, the expected survival time, the possibility of further chemotherapeutic options, and the current quality of life.

Formyl peptide receptor 1 and 2 dual agonist inhibits human neutrophil chemotaxis by the induction of chemoattractant receptor cross-desensitization.

Formyl peptide receptor 1 (FPR1) and FPR2/ALX are known to control neutrophil chemotaxis in response to various ligands. In this study, we investigated the inhibitory mechanism of compound 43 (Cpd43), an FPR1 and FPR2/ALX dual agonist, on human neutrophil chemotaxis. Precedent stimulation of human peripheral blood neutrophils with Cpd43 rendered the cells unresponsive in calcium mobilization induced by interleukin-8, C5a, or leukotriene B4. In addition, neutrophils pretreated with Cpd43 lost their chemotactic responses against these chemoattractants, wherein the expressions of chemoattractant receptors CXCR1, CXCR2, C5a receptor, and leukotriene B4 receptor 1 on the surface of neutrophils were all diminished significantly by treatment with Cpd43. By evaluating its pharmacological effect on 341 molecules, including receptors and enzymes, we also confirmed that Cpd43 has a highly specific affinity to FPR1 and FPR2/ALX and does not show binding affinity to the other chemoattractant receptors. These results indicate a previously unrecognized inhibitory mechanism of Cpd43 on neutrophil chemotaxis: the induction of cross-desensitization of multiple chemoattractant receptors in human neutrophils through its FPR1 and FPR2/ALX dual agonism.

Inhibition of neutrophil migration in mice by mouse formyl peptide receptors 1 and 2 dual agonist: indication of cross-desensitization in vivo.

It has been reported that the stimulation of neutrophils with N-formyl-Met-Leu-Phe (fMLF), an agonist for formyl peptide receptor (Fpr) 1, renders cells unresponsive to other chemoattractants in vitro. This is known as cross-desensitization, but its functional relevance in neutrophil migration in vivo has not been investigated. Here, we show that precedent stimulation of mouse neutrophils with compound 43, a non-peptidyl agonist for mouse Fpr1 and Fpr2, rendered the cells unresponsive to a second stimulation with C5a, leukotriene B4, or keratinocyte-derived cytokine (KC) in calcium mobilization and chemotaxis assays in vitro. The expression of chemokine (C-X-C motif) receptor 2 (CXCR2) on the surface of neutrophils was concomitantly diminished by stimulating the cells with the compound. Moreover, oral administration of the compound to mice before they were exposed to lipopolysaccharide (LPS) aerosol resulted in a dose-dependent reduction in the neutrophil count in bronchoalveolar lavage fluid. The expression of CXCR2 on blood neutrophils was also reduced in the compound-administered mice. The recipient mice that underwent adoptive transfer of fluorescence-labelled neutrophils that had been incubated with the compound showed a substantial decrease in neutrophil counts in bronchoalveolar lavage fluid after they were exposed to LPS, when compared with the control mice to which vehicle-treated neutrophils had been transferred. These results are consistent with the idea that the agonist for Fpr1 and Fpr2 induced cross-desensitization in neutrophils and attenuated neutrophil migration into the airways. Our results also revealed the unpredicted effect of an Fpr1 and Fpr2 dual agonist, which may act as a functional antagonist for multiple chemoattractant receptors in vivo.

Solitary fibrous tumor of the abdominal wall.

Solitary fibrous tumors (SFTs) are uncommon neoplasms of mesenchymal origin that usually arise from the pleura. SFTs of the abdominal wall are extremely rare, and only 12 cases have been reported in the English language literature. This report presents a new case of SFT of the abdominal wall in a 74-year-old female. Positron emission tomography demonstrated the heterogeneous 18F-fluorodeoxyglucose uptake of the tumor (the maximum standardized uptake value was 2.8). Histologically, the mitotic count was 1 to 2/10 high-power fields. The patient is alive without recurrence at 10 months after undergoing a surgical excision. We discuss the clinicopathological features and differential diagnosis and present a review of the pertinent literature.

The pyrazolone originally reported to be a formyl peptide receptor (FPR) 2/ALX-selective agonist is instead an FPR1 and FPR2/ALX dual agonist.

A pyrazolone compound acting as a formyl peptide receptor (FPR) 2/ALX-selective agonist has been reported, but its pharmacological activities on human FPRs (hFPRs) and mouse FPRs (mFprs) have not been well demonstrated. In this study, we found that this compound, designated as compound A, induced concentration-dependent calcium flux not only in Chinese hamster ovary (CHO) cells expressing hFPR2/ALX but also in cells expressing hFPR1, mFpr1, or mFpr2. It also induced the receptor internalization of hFPR1 and hFPR2/ALX and, accordingly, induced calcium influx and chemotactic responses in both human and mouse neutrophils. Our study revealed that compound A is in fact an FPR1 and FPR2/ALX dual agonist.

Clinical outcome of malignant biliary obstruction caused by metastatic gastric cancer.

BACKGROUND: The clinical outcome of malignant biliary obstruction caused by metastatic gastric cancer remains unclear. This study was designed to evaluate the clinical outcome and predictive factors of survival in patients who underwent percutaneous transhepatic biliary drainage (PTBD) for malignant biliary obstruction caused by metastatic gastric cancer. METHODS: Between April 1997 and March 2006, 38 consecutive patients with malignant biliary obstruction caused by metastatic gastric cancer were retrospectively analyzed. All patients underwent PTBD. RESULTS: After PTBD, serum bilirubin levels significantly decreased in 29 (76%) of 38 patients. Pruritus, fever, jaundice, anorexia, abdominal pain, and general fatigue improved significantly in 100%, 100%, 78%, 64%, 53%, and 48% of patients, respectively. Early complications related to the intervention occurred in ten patients. Seven patients developed symptoms of recurrent jaundice or cholangitis. Overall median survival was 79 days, and 6-month and 1-year survival rates after PTBD were 39.5% and 13.2%, respectively. Serum bilirubin level after PTBD (P < 0.0001), chemotherapy after PTBD (P < 0.0001), and performance status at presentation (P = 0.0363) were found to be independent predictors of survival. CONCLUSION: PTBD with metallic stent placement is a safe and effective palliation for patients with malignant biliary obstruction caused by metastatic gastric cancer. Our results suggest that patients in good clinical condition are candidates for aggressive treatment with a combination of PTBD with metallic stent placement and chemotherapy.

Role of angiotensin II type 1 receptor on retinal vascular leakage in a rat oxygen-induced retinopathy model.

AIM: To investigate the role of angiotensin type 1 (AT1) and type 2 (AT2) receptors in hypoxia-induced retinal vascular hyperpermeability. METHODS: Brown-Norway rat pups were exposed to hyperoxic conditions from postnatal day 7 (P7) to P12, and to subsequent normal air for 5 days [oxygen-induced retinopathy (OIR) model]. Olmesartan medoxomil (AT1 receptor antagonist; administered orally), PD123319 (AT2 receptor antagonist; administered subcutaneously) or a vehicle was administered once daily during the last 5 days. At P16, the retinal permeability was determined by measuring the leaked fluorescein-conjugated dextran concentration in the retina. The vascular endothelial growth factor (VEGF) and hypoxia-inducible factor 1 (HIF-1) alpha proteins in the retina were assessed by an ELISA and western blotting, respectively. RESULTS: Olmesartan medoxomil partially, but significantly, inhibited the retinal vascular hyperpermeability induced by hypoxia. In contrast, PD123319 did not show a significant effect. The VEGF and HIF-1alpha protein levels were significantly elevated in the OIR retina; however, there was no significant effect of olmesartan medoxomil on the expression of either protein. CONCLUSIONS: These results suggest that the AT1 receptor is, at least partly, responsible for hyperpermeability in the OIR rat retina via a mechanism independent of HIF-1 and VEGF expression.

Mast cell-expressed orphan receptor CCRL2 binds chemerin and is required for optimal induction of IgE-mediated passive cutaneous anaphylaxis.

Mast cells contribute importantly to both protective and pathological IgE-dependent immune responses. We show that the mast cell-expressed orphan serpentine receptor mCCRL2 is not required for expression of IgE-mediated mast cell-dependent passive cutaneous anaphylaxis but can enhance the tissue swelling and leukocyte infiltrates associated with such reactions in mice. We further identify chemerin as a natural nonsignaling protein ligand for both human and mouse CCRL2. In contrast to other "silent" or professional chemokine interreceptors, chemerin binding does not trigger ligand internalization. Rather, CCRL2 is able to bind the chemoattractant and increase local concentrations of bioactive chemerin, thus providing a link between CCRL2 expression and inflammation via the cell-signaling chemerin receptor CMKLR1.

[A case of multiple bone metastases from gastric cancer treated with combination chemotherapy of S-1 and CDDP].

We report a case of multiple bone metastases from gastric cancer treated with combination chemotherapy of S-1 and CDDP. A 54-year-old man underwent distal gastrectomy for gastric cancer (Stage II) in March 2003. Multiple bone metastases complicated with DIC were diagnosed in September 2005. The patient was treated with combination chemotherapy of S-1 and CDDP. S-1 (80 mg/m2/day) was administered for 21 days followed by 14 days rest as one course. CDDP (60 mg/m2) administration was begun 8 days after the start of S-1. After one course of the treatment, DIC was resolved. The abnormal uptake at the bone metastases was found to have decreased by bone scintigraphy. Bone metastases recurred in April 2006. Although combination chemotherapy of S-1 and DOC was administered, the patient died of DIC in August 2006. Combination chemotherapy of S-1 and CDDP is considered effective treatment for prolonging survival in cases of gastric cancer with bone metastases.

Staphylococcus aureus-derived staphopain B, a potent cysteine protease activator of plasma chemerin.

Chemerin is an attractant for cells that express the serpentine receptor CMKLR1, which include immature plasmacytoid dendritic cells (pDC) and macrophages. Chemerin circulates in the blood where it exhibits low biological activity, but upon proteolytic cleavage of its C terminus, it is converted to a potent chemoattractant. Enzymes that contribute to this conversion include host serine proteases of the coagulation, fibrinolytic, and inflammatory cascades, and it has been postulated that recruitment of pDC and macrophages by chemerin may serve to balance local tissue immune and inflammatory responses. In this work, we describe a potent, pathogen-derived proteolytic activity capable of chemerin activation. This activity is mediated by staphopain B (SspB), a cysteine protease secreted by Staphylococcus aureus. Chemerin activation is triggered by growth medium of clinical isolates of SspB-positive S. aureus, but not by that of a SspB(null) mutant. C-terminal processing by SspB generates a chemerin isoform identical with the active endogenous attractant isolated from human ascites fluid. Interestingly, SspB is a potent trigger of chemerin even in the presence of plasma inhibitors. SspB may help direct the recruitment of specialized host cells, including immunoregulatory pDC and/or macrophages, contributing to the ability of S. aureus to elicit and maintain a chronic inflammatory state.

Chemoattractants, extracellular proteases, and the integrated host defense response.

The host response to tissue injury and/or infection is dependent on the action of numerous extracellular proteases. Proteolytic cascades trigger blood clotting, fibrinolysis, and complement activation, while proteases released upon leukocyte degranulation are integral to the processes of inflammation and immunity. Modulation of effector protein activity by proteases provides a critical layer of posttranslational control that enables rapid enzymatic regulation of target proteins. This report reviews the emerging literature describing a novel class of proteolytic targets, leukocyte chemoattractants, and, in particular, chemerin, a dendritic cell and macrophage chemoattractant activated by serine proteases of the coagulation, fibrinolytic, and inflammatory cascades. As chemoattractants are critical for both systemic leukocyte positioning by triggering integrin activation and subsequent recruitment from circulation, and local intratissue leukocyte positioning via chemotaxis, modulation of attractant activities by proteases may have profound effects on the immune response.