The effect of 1-hydroxy-vitamin D treatment in hospitalized patients with COVID-19: A retrospective study.

BACKGROUND & AIMS: The efficacy of vitamin D supplementation in coronavirus disease 2019 (COVID-19) remains unclear. This study aimed to evaluate the effect of 1-hydroxy-vitamin D on the prevention of severe disease and mortality in patients hospitalized for COVID-19. METHODS: This retrospective study included 312 patients with COVID-19 who were admitted to our hospital between April 2021 and October 2021 (primarily the Delta variant) and between July 2022 and September 2022 (primarily Omicron variant). Serum 25-hydroxyvitamin D (25(OH)D) levels were measured at the time of admission and 1-hydroxy-vitamin D was prescribed by the treating physicians. The patients were divided into two groups: those administered 1-hydroxy-vitamin D (Vit D group) and those who were not (control group). The composite primary endpoint was the need for additional respiratory support, including high-flow oxygen therapy or invasive mechanical ventilation, and in-hospital mortality rate. RESULTS: Of 312 patients, 122 (39%) received 1-hydroxy-vitamin D treatment. Although the median age was not significantly higher in the Vit D group than in the control group (66 vs. 58 years old, P = 0.06) and there was no significant difference in the proportion of vitamin D deficiency (defined as serum 25(OH)D level less than 20 ng/mL, 77% vs. 65%, P = 0.07), patients in the control group had a more severe baseline profile compared to the Vit D group according to the Japanese disease severity definition for COVID-19 (P = 0.01). The proportion of those requiring more respiratory support and in-hospital mortality was significantly lower in the Vit D group than in the control group (6% vs. 14%, P = 0.01 log-rank test). After propensity score matching, a statistically significant difference in the primary endpoint was observed (P = 0.03 log-rank test). CONCLUSIONS: 1-hydroxy-vitamin treatment may improve outcomes in hospitalized patients with COVID-19, reducing composite outcomes including the need for additional respiratory support and in-hospital mortality.

Defining the treatment strategy for uncomplicated appendicitis based on patient satisfaction feedback: A cross-sectional study.

BACKGROUND: Two surgical strategies are available for appendicitis: emergency laparoscopic appendectomy and interval laparoscopic appendectomy. However, timing of surgical intervention remains debatable. This study aimed to compare the surgical outcomes of emergency laparoscopic appendectomy and interval laparoscopic appendectomy and conduct a questionnaire survey to investigate the use of emergency laparoscopic appendectomy and patient satisfaction with regard to treatment. METHODS: We included 162 patients who underwent laparoscopic appendectomy at our hospital. Outcomes were assessed by operation time, blood loss, postoperative fasting time, length of hospital stay, and complication rate. Patient satisfaction was measured by questionnaire addressing degree of satisfaction, presurgery anxiety, and length of hospital stay. RESULTS: Of 162 patients, 74 (46%) and 88 (54%) received emergency and interval laparoscopic appendectomy, respectively. No significant difference was observed in the operation time, blood loss, length of hospital stay, or complication rate. Among 66 patients who responded to the questionnaire (28 emergency, 38 interval), a significant difference was observed only in the degree of satisfaction regarding the timing of the surgical intervention (p = 0.04). CONCLUSION: Surgical outcomes of emergency and interval appendectomy were equivalent; however, patient satisfaction favored emergency appendectomy, suggesting it is a preferable approach for the treatment of uncomplicated appendicitis.

Cumulative incidence of venous thromboembolism in patients with advanced cancer in prospective observational study.

Venous thromboembolism (VTE) is frequently observed in patients with advanced cancer. The objective of this prospective observational study was to estimate, based on intensive screening, using computed tomography, lower-extremity ultrasonography, and D-dimer testing, the prevalence of VTE in patients with advanced cancer. Patients with metastatic or locally advanced cancer without anticoagulant therapy, who were planning to receive chemotherapy during 4 weeks, were eligible. Evaluations of VTE were performed at pretreatment, 12 weeks, and 24 weeks after the start of chemotherapy. Primary endpoint was cumulative incidence of VTE for 24 weeks. Secondary endpoints included incidence of VTE (pretreatment, 12 weeks, and 24 weeks after the start of chemotherapy), VTE according to primary cancer site, symptomatic VTE, pulmonary thromboembolism (PE), and treatment of VTE. We enrolled 860 patients with a median age of 68 years, including 34% female and 71% lung cancer. Cumulative incidence of VTE for 24 weeks was 22.6% (95% confidence interval: 19.8%-25.5%) (194 of 860 patients). Incidence of VTE was 11.3% pretreatment, 16.8% 12 weeks, and 14.1% 24 weeks. Symptomatic VTE was observed in 4.0% and PE in 1.0% of patients. By multivariate analysis, sex, D-dimer level, and platelet count were independent risk factors of VTE for 24 weeks. This large prospective observational study showed that cumulative incidence of VTE was high in advanced cancer patients, mainly lung cancer. Although most patients showed asymptomatic VTE, intensive screening of VTE may be considered in advanced cancer patients, especially in women with high level of D-dimer and decreased platelet count (UMIN000015243).

Malignant solitary fibrous tumor of the pancreas: a case report.

BACKGROUND: Solitary fibrous tumors (SFTs) are rare tumors, mostly derived from connective tissue mesenchymal cells that arise from the pleura. There are very few reports of primary pancreatic SFT. Preoperative diagnosis is difficult owing to the lack of distinctive radiological findings. We report a case of pancreatic SFT with particularly rare malignant findings. CASE PRESENTATION: A 60-year-old man was referred to the hospital because of a right upper quadrant mass and abnormal liver function test results. Contrast-enhanced computed tomography (CT) showed a well-defined enhanced tumor measuring approximately 8 cm in the pancreatic head. Magnetic resonance imaging (MRI) showed T1WI hypointensity, T2WI hyperintensity, and DWI hyperintensity. The main pancreatic duct and common bile duct were dilated owing to obstruction by the tumor. The following tumor markers were mildly elevated: carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA19-9), SPan-1, and DUPAN-2. The histological diagnosis obtained by endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) was negative for pancreatic ductal carcinoma, malignant lymphoma and neuroendocrine tumor, suggesting the possibility of mesenchymal tumor, but the diagnosis was not confirmed. The patient was judged suitable for surgery and underwent subtotal stomach-preserving pancreatoduodenectomy with D2 lymph node dissection. On histopathological examination of the resected specimen, infiltrating spindle-shaped cells had proliferated, containing numerous mitotic figures, with necrotic findings inside the tumor. Immunostaining was positive for cluster of differentiation-34 (CD34), B cell CLL/lymphoma-2 (Bcl-2), and signal transducer and activator of transcription (STAT6). On the basis of these findings, a diagnosis of malignant pancreatic SFT was made. The patient remains free of recurrent disease after 12 months of follow-up without adjuvant therapy and he is being carefully followed up as an outpatient. CONCLUSIONS: We experienced a case of malignant pancreatic head SFT. Immunohistochemical staining of the extracted specimens was useful for diagnosis.

[Postoperative Adjuvant Chemotherapy for Descending Colon Cancer Treated with Imatinib for Chronic Myeloid Leukemia].

A66 -year-old man was diagnosed with chronic myeloid leukemia(CML). Imatinib treatment had been initiated, and a major molecular response(MMR)was achieved. The patient had anemia and was diagnosed with descending colon cancer. The patient was surgically treated, and then received postoperative adjuvant chemotherapy with UFT/LV. However, imatinib was not administered during that period. The patient could undergo postoperative adjuvant chemotherapy for 6 months without acute exacerbation of the CML.

Effect of eicosapentaenoic acid on prevention of lean body mass depletion in patients with exacerbation of chronic obstructive pulmonary disease: A prospective randomized controlled trial.

BACKGROUND & AIMS: Systemic inflammation plays an important role in the pathogenesis of chronic obstructive pulmonary disease (COPD), resulting in depletion of lean body mass (LBM) and muscle mass. Both frequent exacerbation of COPD and low LBM are associated with poor prognosis. This study aimed to evaluate whether supplementation of eicosapentaenoic acid (EPA) prevents depletion of LBM and muscle mass in hospitalized patients with exacerbation of COPD. METHODS: This was a prospective randomized controlled trial, conducted between November 2014 and October 2017. Fifty patients were randomly assigned to receive 1 g/day of EPA-enriched oral nutrition supplementation (ONS) (EPA group) or EPA-free ONS of similar energy (control group) during hospitalization. The LBM index (LBMI) and the skeletal muscle mass index (SMI) were measured using a bioelectrical impedance analyzer at the time of admission and at the time of discharge. Patients underwent pulmonary rehabilitation and wore a pedometer to measure step counts and physical activity. RESULTS: Forty-five patients that completed the experiment were analyzed. Baseline characteristics were similar between the EPA (n = 24) and control groups (n = 21). There were no significant differences in energy intake, step counts, physical activity, or length of hospitalization between the two groups. Although the plasma levels of EPA significantly increased only in the EPA group, we found an insignificant increase in LBMI and SMI in the EPA group compared with the control group (LBMI: +0.35 vs. +0.19 kg/m2, P = 0.60, and SMI: +0.2 vs. -0.3 kg/m2, P = 0.17, respectively). The change in the SMI was significantly correlated with the length of hospitalization in the EPA group, but not in the control group (r = 0.53, P = 0.008, and r = -0.09, P = 0.70, respectively). CONCLUSIONS: EPA-enriched ONS in patients with exacerbation of COPD during short-time hospitalization had no significant advantage in preservation of LBM and muscle mass compared with EPA-free ONS. EPA supplementation for a longer duration might play an important role in the recovery of skeletal muscle mass after exacerbation of COPD.

Hepatic resection for hepatocellular carcinoma in a patient with situs ambiguous with polysplenia: report of a case.

We report a case of successful resection of hepatocellular carcinoma (HCC) in a patient with situs ambiguous with polysplenia (PS), a rare congenital anomaly. A 62-year-old Japanese man was admitted to our hospital for investigation and treatment of a hepatic tumor. Imaging studies revealed two HCCs, 2.5 and 0.7 cm in diameter, in the anterior section and segment 3 of the reversed liver, respectively. He also had multiple spleens in the right side of the abdomen, right side of the stomach, and duodenum, as well as azygous continuation of the inferior vena cava (IVC) with absence of the retro-hepatic IVC, a truncated pancreas, rare variation of the hepatic artery, and dextrocardia. We performed anterior sectionectomy of the liver and partial resection of segment 3. We found only two previous reports of HCC in patients with situs ambiguous with PS, but our patient is the first to have undergone anatomical hepatic resection of the reversed liver. Accurate anatomical assessment is essential during surgery on such patients.

Interleukin-17A plays a pivotal role in polymicrobial sepsis according to studies using IL-17A knockout mice.

BACKGROUND: Interleukin (IL)-17A is a proinflammatory cytokine and plays an important role in neutrophil recruitment. We investigate the role of IL-17A in a mouse polymicrobial sepsis model. MATERIALS AND METHODS: IL-17A knockout mice (KO) and wild-type (WT) mice were subjected the cecal ligation and puncture (CLP). Survival was assessed for the following 7 d after the CLP operation, and histopathologic findings were evaluated 12 h after CLP. Bacterial outgrowth in blood was assessed by blood culture 12 h after CLP. After CLP, expression of inflammatory mediators in serum was assessed by enzyme-linked immunosorbent assay (ELISA). Furthermore, expression of FOXP3 and IL-17A in the spleen was assessed by immunohistochemical staining and flow cytometry. RESULTS: Mortality was increased in KO mice compared with WT mice after CLP. Furthermore, bacterial outgrowth in blood and serum high mobility group box 1 (HMGB1) levels were also significantly greater in KO mice than WT mice. The expression of FOXP3 in the spleen was significantly greater in KO mice than WT mice. CONCLUSION: IL-17A play pivotal role in host defense during septic peritonitis.

The Kupffer cell inhibition exacerbates but splenectomy prevents mortality in a rat septic peritonitis model.

OBJECTIVE: The purpose of this study was to investigate whether inhibition of Kupffer cells (KCs) affects the expression of high mobility group box 1 (HMGB1) and mortality in septic peritonitis. The role of the spleen in septic peritonitis was also investigated. METHODS: Rats were given liposome-entrapped dichloromethylene diphosphonate (lipo-MDP) to eliminate KCs or non-entrapped liposome (lipo) before cecal ligation and puncture (CLP), and serum HMGB1 levels and mortality were assessed after CLP. Furthermore, KCs and tissue macrophages were isolated, and production of HMGB1 was investigated. Effects of splenectomy on serum HMGB1 levels and mortality were also investigated after CLP. RESULTS: Elimination of the Kupffer cells by lipo-MDP increased serum HMGB1 concentrations and mortality significantly. Furthermore, HMGB1 expression in both the periportal area of the liver and the spleen was greater in the lipo-MDP group than the lipo group. On the other hand, splenectomy blunted serum HMGB1 levels and improved mortality after CLP. The HMGB1 expression was greater in the spleen compared with the liver after CLP. Furthermore, production of HMGB1 was greatest in splenic macrophages in vitro. The number of ED3-positive cells increased significantly in non-splenectomized animals but not in splenectomized animals after CLP. In the lipo-MDP treated groups, the number of ED3-positive macrophages also increased in the liver from non-splenectomized animals but not in the splenectomized animals after CLP. CONCLUSIONS: The liver and the spleen play key roles in host defense during septic peritonitis. Migrating macrophages into the liver are, in part, derived from the spleen after CLP.

Role of IL-17A in neutrophil recruitment and hepatic injury after warm ischemia-reperfusion mice.

Recent evidence suggests that IL-17A regulates neutrophil-dependent organ injury. Accordingly, the purpose of this study was to determine the role of IL-17A in neutrophil recruitment after ischemia-reperfusion (I/R) and in subsequent liver injury. Two mouse models including wild-type and IL-17A knockout mice were evaluated for I/R injury. The medial largest lobe of the liver was clamped for 90 min. In another set of experiments, recombinant mouse (rm)IL-17A homodimer or rmIL-17A/F heterodimer were administered to knockout mice before I/R, and liver injury was investigated. Isolated Kupffer cells were incubated with rmIL-17A or rmIL-17F, and production of TNF-α was measured. Studies evaluating the extent of liver injury as measured by serum transaminase levels demonstrated similar levels in the acute phase (6 h) in these two models. In contrast, in the subacute phase (20 h) after I/R, both serum transaminase levels and percent of hepatic necrosis were significantly reduced in the knockout mice compared with the wild-type mice. This reduction in liver injury seen in the knockout mice was associated with suppression of chemokine and adhesion molecule expression and reduction in infiltration of neutrophils into the liver. Administration of rmIL-17A homodimer, but not IL-17A/F heterodimer, increased liver injury in the subacute phase of I/R in KO mice. TNF-α production by isolated Kupffer cells increased significantly in the cells incubated with rmIL-17A compared with rmIL-17F. These results indicate that IL-17A is a key regulator in initiating neutrophil-induced inflammatory responses and hepatic injury in the subacute phase after reperfusion.

Glycyrrhizin prevents liver injury by inhibition of high-mobility group box 1 production by Kupffer cells after ischemia-reperfusion in rats.

High-mobility group box 1 (HMGB1) acts as an early mediator of inflammation and organ damage in hepatic ischemia-reperfusion (I/R) injury. Glycyrrhizin is a natural anti-inflammatory and antiviral triterpene in clinical use. The purpose of this study was to investigate the effect of glycyrrhizin on liver injury caused by I/R and production of HMGB1 by Kupffer cells in rats. In the first test period, rats were given saline or glycyrrhizin 20 min before segmental hepatic warm I/R. Serum alanine aminotransferase and HMGB1 levels and hepatic histopathological findings were evaluated after I/R. Furthermore, expression of HMGB1 in the liver was assessed by immunohistochemical staining after I/R. Kupffer cells were isolated by collagenase digestion and differential centrifugation, and production of HMGB1 was assessed. In another set of experiments, the effect of inhibition of Kupffer cells by injection of liposome-entrapped dichloromethylene diphosphonate (lipo-MDP) on liver injury and expression of HMGB1 were investigated after I/R. Liver injury was prevented in the glycyrrhizin group compared with the control group. Furthermore, serum HMGB1 levels were also significantly blunted in the glycyrrhizin group compared with the control group. Cells expressing HMGB1 were detected in the hepatic sinusoid by immunohistochemistry and recognized morphologically as Kupffer cells. Furthermore, the expression of HMGB1 was reduced in the glycyrrhizin group compared with the control group. Production of HMGB1 was reduced in Kupffer cells isolated from the glycyrrhizin group compared with the control group. It is noteworthy that treatment with lipo-MDP significantly blunted serum HMGB1 levels and prevented liver injury after I/R. These results suggest that glycyrrhizin has the therapeutic potential to prevent warm I/R-induced injury during hepato-biliary surgery.

HCV-related proteins activate Kupffer cells isolated from human liver tissues.

PURPOSE: It was reported from this laboratory that Kupffer cells (KCs) were activated in patients infected with HCV. Since dendritic cells, monocytes, and macrophages were activated by stimulation with HCV-related proteins, the specific aim of this study was to investigate the role of HCV-related proteins in activation of KCs, the signal pathway of activation of KCs mediated by Toll-like receptor (TLR) 4, and the influence of HCV infection on function of KCs. METHODS: Kupffer cells isolated from non-cancerous surgical specimen were co-cultured with HCV-related proteins (Core, NS3, NS4, and NS5), and production of cytokines (TNF-α, IL-1ß, and IL-10) and hydrogen peroxide were assessed. Furthermore, effects of neutralization antibodies against the TLR2, TLR3, or TLR4, and cytochalasin B on the production TNF-α by KCs were investigated. RESULTS: Kupffer cells produced markedly a proinflammatory cytokine TNF-α by stimulation with all HCV-related proteins studied, and values were as same as production by KCs stimulated with LPS. Importantly, this production in the case of NS3 was significantly blunted by about 60% by neutralization antibodies against the TLR4, but not cytochalasin B. Production of TNF-α by isolated KCs stimulated with LPS was significantly greater in the HCV-infected livers than the HCV/HBV-negative livers. CONCLUSIONS: These results indicated that HCV-related proteins may cause prolonged activation of KCs in the HCV-infected liver, leading to accumulation of inflammatory cytokines that contribute to DNA damage and carcinogenesis. Furthermore, function of KCs was difference between patients infected with and without HCV infection.

Role of macrophage colony-stimulating factor in polymicrobial sepsis according to studies using osteopetrotic (op/op) mice.

BACKGROUND: The specific purpose of this study was to investigate the role of macrophage colony-stimulating factor (M-CSF)-induced macrophages in mouse polymicrobial sepsis model. MATERIALS AND METHODS: M-CSF deficient (op/op) mice and their littermate mice w ere subjected the cecal ligation and puncture (CLP). Survival was assessed for the following 7 d after the CLP operation, and histopathologic findings were evaluated 12h after CLP. After CLP, expression of inflammatory mediators in serum was assessed by enzyme immunosorbent assay (ELISA). Furthermore, isolated peritoneal macrophages were stimulated with lipopolysaccharide (LPS) (10µg/mL) for 4h, and cytokine concentration in the supernatant was then measured by ELISA. Moreover, phagocytosis of isolated macrophages was assessed using fluorescent rates beads. In another set of experiments, effects of neutralization antibodies against high mobility group box 1 (HMGB1) were investigated in CLP model. RESULTS: Mortality was increased in op/op mice compared with op/? mice after CLP. Furthermore, serum HMGB1 levels were also significantly greater in op/op mice than op/? mice. Production of HMGB1 by isolated peritoneal macrophages was significantly greater in op/op mice than op/? mice. Furthermore, the phagocytosis index was significantly blunted in op/op mice compared with op/? mice. Importantly, treatment with neutralization antibodies against HMGB1 markedly prevented acute lung injury and mortality in op/op mice. CONCLUSION: Matured macrophages by M-CSF play pivotal role by scavenging endotoxin in inflammation. Furthermore, HMGB1 is involved in pathophysiology in polymicrobial sepsis, consistent with previous reports.

Enteral diets enriched with medium-chain triglycerides and N-3 fatty acids prevent chemically induced experimental colitis in rats.

The specific purpose of this study was to evaluate the significant effects of medium-chain triglycerides (MCTs) and N-3 fatty acids on chemically induced experimental colitis induced by 2,4,6-trinitrobenzene sulphonic acid (TNBS) in rats. Male Wistar rats were fed liquid diets enriched with N-6 fatty acid (control diets), N-3 fatty acid (MCT- diets), and N-3 fatty acid and MCT (MCT+ diets) for 2 weeks and then were given an intracolonic injection of TNBS. Serum and tissue samples were collected 5 days after ethanol or TNBS enema. The severity of colitis was evaluated pathologically, and tissue myeloperoxidase activity was measured in colonic tissues. Furthermore, protein levels for inflammatory cytokines and a chemokine were assessed by an enzyme-linked immunosorbent assay in colonic tissues. Induction of proinflammatory cytokines tumor necrosis factor-α and interleukin-1ß in the colon by TNBS enema was markedly attenuated by the MCT+ diet among the 3 diets studied. Furthermore, the induction of chemokines macrophage inflammatory protein-2 and monocyte chemotactic protein-1 also was blunted significantly in animals fed the MCT+ diets. As a result, MPO activities in the colonic tissue also were blunted significantly in animals fed the MCT+ diets compared with those fed the control diets or the MCT- diets. Furthermore, the MCT+ diet improved chemically induced colitis significantly among the 3 diets studied. Diets enriched with both MCTs and N-3 fatty acids may be effective for the therapy of inflammatory bowel disease as antiinflammatory immunomodulating nutrients.

Dietary medium-chain triglycerides prevent chemically induced experimental colitis in rats.

The effects of dietary medium-chain triglycerides (MCTs) on experimental colitis induced by 2,4,6-trinitrobenzene sulphonic acid (TNBS) were investigated in rats. Male Wistar rats were given an intracolonic injection of TNBS and were then fed liquid diets containing MCTs or corn oil (AIN93) as controls. Serum and tissue samples were collected 1 week after TNBS enema. The severity of colitis was evaluated pathologically, and tissue myeloperoxidase (MPO) activity was measured. Furthermore, messenger RNA (mRNA) and protein levels for inflammatory cytokines and a chemokine were assessed by reverse-transcription polymerase chain reaction and enzyme-linked immunosorbent assay, respectively. In another set of experiments, the protein expression of Toll-like receptor (TLR)-4 in the colon was measured 1 week after feeding of liquid diets. To investigate the effects of MCTs on macrophages, RAW246.7 macrophages were incubated with media containing albumin conjugated with MCT or linoleic acid, which is the major component of corn oil. Then, the production of tumor necrosis factor-alpha (TNF-alpha) was measured. Dietary MCTs blunted significantly the protein levels of TLR-4 in the colon. Furthermore, the expression of TLR-4 was significantly blunted in RAW264.7 cells incubated with MCTs compared with cells incubated with linoleic acid. Induction of interleukin 1beta (IL-1beta), TNF-alpha, and macrophage inflammatory protein-2 (MIP-2) in the colon was attenuated by dietary MCT. Furthermore, MPO activities in the colonic tissue were significantly blunted in animals fed the MCT diets compared with those fed the control diets. As a result, dietary MCTs improved chemically induced colitis significantly. MCTs most likely are useful for the therapy of inflammatory bowel disease as an anti-inflammatory immunomodulating nutrient.