Threonine phosphorylation of STAT1 restricts interferon signaling and promotes innate inflammatory responses.

Since its discovery over three decades ago, signal transducer and activator of transcription 1 (STAT1) has been extensively studied as a central mediator for interferons (IFNs) signaling and antiviral defense. Here, using genetic and biochemical assays, we unveil Thr748 as a conserved IFN-independent phosphorylation switch in Stat1, which restricts IFN signaling and promotes innate inflammatory responses following the recognition of the bacterial-derived toxin lipopolysaccharide (LPS). Genetically engineered mice expressing phospho-deficient threonine748-to-alanine (T748A) mutant Stat1 are resistant to LPS-induced lethality. Of note, T748A mice exhibited undisturbed IFN signaling, as well as total expression of Stat1. Further, the T748A point mutation of Stat1 recapitulates the safeguard effect of the genetic ablation of Stat1 following LPS-induced lethality, indicating that the Thr748 phosphorylation contributes inflammatory functionalities of Stat1. Mechanistically, LPS-induced Toll-like receptor 4 endocytosis activates a cell-intrinsic IκB kinase-mediated Thr748 phosphorylation of Stat1, which promotes macrophage inflammatory response while restricting the IFN and anti-inflammatory responses. Depletion of macrophages restores the sensitivity of the T748A mice to LPS-induced lethality. Together, our study indicates a phosphorylation-dependent modular functionality of Stat1 in innate immune responses: IFN phospho-tyrosine dependent and inflammatory phospho-threonine dependent. Better understanding of the Thr748 phosphorylation of Stat1 may uncover advanced pharmacologically targetable molecules and offer better treatment modalities for sepsis, a disease that claims millions of lives annually.

Dynamic change of fecal microbiota and metabolomics in a polymicrobial murine sepsis model.

Aim: Sepsis causes a systemic inflammatory reaction by destroying intestinal flora, which leads to a poor prognosis. In this study, we sought to clarify the characteristics of fecal flora and metabolites in a mouse model of sepsis by comprehensive metagenomic and metabolomic analysis. Methods: We performed a cecal ligation and puncture model procedure to create a mild sepsis model. We collected fecal samples on day 0 (healthy condition) and days 1 and 7 after the cecal ligation and puncture to determine the microbiome and metabolites. We analyzed fecal flora using 16S rRNA gene sequencing and metabolites using capillary electrophoresis mass spectrometry with time-of-flight analysis. Results: The abundance of bacteria belonging to the family Enterobacteriaceae significantly increased, but that of order Clostridiales such as the families Lachnospiraceae and Ruminococcaceae decreased on day 1 after the cecal ligation and puncture compared with those before the cecal ligation and puncture. The family Enterobacteriaceae significantly decreased, but that of order Clostridiales such as the families Lachnospiraceae and Ruminococcaceae increased on day 7 compared with those on day 1 after the cecal ligation and puncture. In the fecal metabolome, 313 metabolites were identified. Particularly, essential amino acids such as valine and non-essential amino acids such as glycine increased remarkably following injury. Betaine and trimethylamine also increased. In contrast, short-chain fatty acids such as isovaleric acid, butyric acid, and propionic acid decreased. Conclusion: The fecal microbiota following injury showed that Enterobacteriaceae increased in acute phase, and Lachnospiraceae and Ruminococcaceae increased in subacute phase. The metabolites revealed an increase in essential amino acids and choline metabolites and a decrease in short-chain fatty acids.

Evaluation of urinary extravasation after non-operative management of traumatic renal injury: a multi-center retrospective study.

PURPOSE: Urinary extravasation is one of the major complications after non-operative management of traumatic renal injury and may lead to urinary tract infection and sepsis. The purpose of this study was to evaluate these factors in patients with traumatic renal injury. METHODS: This was a multi-center, retrospective, observational study performed at three tertiary referral hospitals in Osaka prefecture. We included patients with traumatic renal injury transported to the centers between January 2008 and December 2018. We excluded patients who either died or underwent nephrectomy within 24 h after admission. We investigated the occurrence of urinary extravasation and the related factors after traumatic renal injury using multivariable logistic regression analysis. RESULTS: In total, 146 patients were eligible for analysis. Their median age was 44 years and 68.5% were male. Their median Injury Severity Score was 17. Renal injuries were graded as American Association for Surgery of Trauma (AAST) grade I in 33 (22.6%), II in 27 (18.5%), III in 38 (26.0%), IV in 28 (19.2%), and V in 20 (13.7%) patients. Urinary extravasation was diagnosed in 26 patients (17.8%) and was statistically significantly associated with AAST grades IV-V (adjusted odds ratio, 33.8 [95% confidence interval 7.12-160], p < 0.001). CONCLUSION: We observed urinary extravasation in 17.8% of patients with non-operative management of traumatic renal injury and the diagnosed was made in mostly within 7 days after admission. In this study, the patients with AAST grade IV-V injury were associated with having urinary extravasation.

Dynamic changes of the hemoglobin index during resuscitation in patients with out-of-hospital cardiopulmonary arrest due to freshwater drowning: A retrospective observational study.

BACKGROUND: The hemoglobin index (HbI) represents the amount of hemoglobin, which reflects the regional tissue blood volume. The HbI is calculated by a regional oxygen saturation monitor. In freshwater drowning, inhaled water is immediately absorbed into the blood causing hemodilution. We hypothesized that this blood dilution could be observed in real time using HbI values in patients with out-of-hospital cardiac arrest (OHCA) due to freshwater drowning. METHODS: In this single-center retrospective, observational study, we examined the HbI in patients with OHCA due to freshwater drowning from April 2015 to May 2020. Patients with OHCA due to hanging were selected as a control group. RESULTS: Thirty-two patients in the freshwater drowning group and 21 in the control group were eligible for inclusion. In the freshwater drowning group, the HbI values in the return of spontaneous circulation (ROSC) group were significantly decreased in comparison to the non-ROSC group (-0.28 [IQR -0.55, -0.12] vs. -0.04 [IQR -0.16, 0.025]; p = 0.024). In the control group, the change of HbI during resuscitation in the ROSC and non-ROSC groups was not significantly different (0.11 [IQR -0.3525, 0.4225] vs. -0.02 [IQR -0.14, 0.605]; p = 0.8228). In each patient with ROSC in the freshwater drowning group, the HbI value after ROSC was significantly decreased in comparison to before ROSC (1.2±0.5 vs. 0.9±0.5]; p = 0.0156). In contrast, this difference was not observed in patients with an ROSC in the control group (3.7±1.3 vs. 3.8±1.4]; p = 0.7940). CONCLUSION: Blood dilution induced by freshwater drowning might be detected in real time using the HbI. To prove the validity of this research's result, further prospective large study is needed.

Effectiveness of near-infrared spectroscopy-guided continuous chest compression resuscitation without rhythm check in patients with out-of-hospital cardiac arrest: The prospective multicenter TripleCPR 16 study.

BACKGROUND: The proportion of adult patients with return of spontaneous circulation (ROSC) following out-of-hospital cardiac arrest (OHCA) remains unchanged since 2012. A better resuscitation strategy is needed. This study evaluated the effectiveness of a regional cerebral oxygen saturation (rSO2)-guided resuscitation protocol without rhythm check based on our previous study. METHODS: Because defibrillation is the definitive therapy that should be performed without delay for shockable rhythm, the study subjects were OHCA patients with non-shockable rhythm on hospital arrival at three emergency departments. They were divided into three groups based on their baseline rSO2 value (%): ≥50, ≥40 to <50, or <40. Continuous chest compression without rhythm checks was performed for 16 minutes or until a maximum increase in rSO2 of 10%, 20%, or 35% was achieved in each group, respectively. This intervention cohort was compared with a historical control cohort regarding the probability of ROSC using inverse probability of treatment weighting (IPTW) with propensity score. RESULTS: The control and intervention cohorts respectively included 86 and 225 patients. The rate of ROSC was not significantly different between the groups (adjusted OR 0.91 [95% CI, 0.64-1.29], P = 0.60), but no serious adverse events occurred. Sensitivity analyses 1 and 2 showed a significant difference or positive tendency for higher probability of ROSC (adjusted OR 1.63 [95% CI, 1.22-2.17], P < 0.001) (adjusted OR 1.25 [95% CI, 0.95-1.63], P = 0.11). CONCLUSIONS: This trial suggested that a new cardiopulmonary resuscitation protocol with different rhythm check timing could be created using the rSO2 value. Clinical trial number: UMIN000025684.

Usefulness of simultaneous measurement of brain and muscle regional oxygen saturation in shock patients: A report of three cases.

The regional oxygen saturation (rSO2) values of brain and muscle tissues can be measured simultaneously even if blood pressure cannot be measured due to circulatory failure associated with shock and may continuously reflect the oxygen supply-demand balance.

Combination of Procalcitonin Value on Hospital Admission and Its Subsequent Change in Value Is Associated With the Prognosis of Sepsis.

To evaluate the relationship between the procalcitonin value in blood on hospital admission and its subsequent change and prognosis among sepsis patients. DESIGN: A single-center, retrospective, observational study. SETTING: Critical care center in Japan. PATIENTS: Sepsis patients 18 years old or older admitted from January 1, 2015, to March 31, 2018. INTERVENTIONS: None. MEASUREMENT AND MAIN RESULTS: Among 173 sepsis patients enrolled, the median age was 74 years old (interquartile range, 64-79 yr old), and there were 102 men. The median value of procalcitonin in blood on hospital admission was 14.8 ng/mL (interquartile range, 3.5-78.4 ng/mL), and the median change in serum procalcitonin value between hospital admission and the next day was 0 ng/mL (interquartile range, -4.5 to 5.2 ng/mL). Mortality at 28 days after hospital admission was 5.8% (10/173). In univariate logistic regression analysis, elderly (crude odds ratio, 5.314; 95% CI, 1.094-25.806; p = 0.044), procalcitonin value of less than 33.2 ng/mL on hospital admission (p = 0.007), and change in serum procalcitonin of less than 0.0 ng/mL (crude odds ratio, 5.056; 95% CI, 1.041-24.545; p = 0.046) were associated with mortality at 28 days after hospital admission. The mortality of patients with a procalcitonin value of less than 33.2 ng/mL on hospital admission and change in serum procalcitonin of less than 0.0 ng/mL was 18.6% (8/43) and was significantly higher than that of other patients (p < 0.001). CONCLUSIONS: Our study showed the sepsis patients with a procalcitonin value in blood of less than 33.2 ng/mL on hospital admission and change in serum procalcitonin of less than 0.0 ng/mL had high mortality at 28 days after hospital admission.

Factors associated with bowel necrosis in patients with hepatic portal venous gas and pneumatosis intestinalis.

AIM: Historically, the presence of hepatic portal venous gas (HPVG) and pneumatosis intestinalis (PI) have been reported to be associated with bowel necrosis and fatal outcome. However, there are no criteria to judge whether bowel necrosis has occurred. We aimed to examine the factors associated with bowel necrosis in patients with HPVG and PI. METHODS: The study comprised 25 patients who were diagnosed as having HPVG and/or PI based on computed tomography (CT) findings in the Department of Emergency and Critical Care Medicine, Kansai Medical University Hospital (Osaka, Japan) between April 2013 and August 2017. We compared various factors, including clinical history, severity of present illness, laboratory data, and CT findings, and examined whether they were related to bowel necrosis. RESULTS: Both Sequential Organ Failure Assessment scores and total bilirubin levels were significantly higher in the necrosis group than those in the non-necrosis group (P = 0.03 and P = 0.02, respectively). The quantity of portal venous gas observed on computed tomography was associated with bowel necrosis in patients with HPVG. In contrast, the presence of air-type PI, defined as PI with emphysema covering the total circumference of the intestine in the absence of wall edema, and the presence of free air were significantly higher in the non-necrosis group (both P < 0.01). CONCLUSIONS: This study showed that the quantity of HPVG was associated with bowel necrosis, whereas the presence of free air or air-type PI was associated with non-necrosis of the bowel.

A strategy for improving the prognosis of non-occlusive mesenteric ischemia (NOMI): a single-center observational study.

AIM: The purpose of this study was to determine the prognostic factors of non-occlusive mesenteric ischemia (NOMI) and to examine treatment strategies that could improve its prognosis. METHODS: We retrospectively identified 30 patients who underwent emergency laparotomy for NOMI in Kansai Medical University Hospital (Hirakata, Japan) from April 2013 to December 2017. We examined prognostic factors related to discharge outcome and also examined the prognostic impact of open abdominal management and second look operation strategy (OSS) by dividing the patients into the non-OSS group and the OSS group. RESULTS: The primary end-point was a prognostic factor for outcome at discharge of the 30 patients. The outcome at discharge was compared between the survival group and the death group. Multivariate analysis was undertaken on two items from the univariate analysis that showed a significant difference (computed tomography findings of intestinal pneumatosis and acute disseminated intravascular coagulation [DIC] score). As a result, there was a significant difference in the factors of intestinal pneumatosis (odds ratio = 0.054; 95% confidence interval, 0.005-0.607; P = 0.018) and DIC score (odds ratio = 1.892; 95% confidence interval, 1.077-3.323; P = 0.027). The secondary end-point was the treatment outcome before and after the application of OSS. Operation time was significantly shorter and the amount of bleeding was also significantly less in the OSS group. CONCLUSION: Computed tomography findings of intestinal pneumatosis and the acute disseminated intravascular coagulation score were found to be prognostic factors for survival in patients with NOMI. Aggressive laparotomy to determine the definitive diagnosis is needed and OSS could be useful to improve patient prognosis for survival from NOMI.

Gastric emphysema with portal emphysema due to superior mesenteric artery syndrome developing septic shock: a case report.

BACKGROUND: Superior mesenteric artery syndrome (SMAS) is often associated with gastric dilatation but, very rarely, it can be associated with gastric emphysema. In addition, there are few reported cases accompanied by septic shock. CASE PRESENTATION: A 64-year-old man was transferred to our hospital with vomiting and abdominal distention. He went into shock and showed impaired consciousness. Blood biochemistry tests showed elevated levels of C-reactive protein. An abdominal computed tomography scan revealed a dilated stomach and proximal duodenum, and constriction of the third portion of the duodenum with gastric and portal emphysema. We thus diagnosed him with gastric and portal emphysema associated with SMAS that progressed to septic shock. We treated him conservatively by giving antibiotics and undertaking gastric drainage and feeding by way of the jejunum through a double elementary diet tube. CONCLUSION: This is the first report to describe a case of SMAS with gastric and portal emphysema that progressed to septic shock.

Study of the prognostic factor of the colon perforation case with the pan-peritonitis that needed emergency surgery: a single-center observational study.

AIM: We divided patients treated with emergency surgery for pan-peritonitis caused by colon perforation into the survival group and the death group based on outcome at postoperative day 30 and examined the prognostic factors for colon perforation. METHODS: The prognostic factors for colon perforation in 76 consecutive patients who underwent emergency surgery at Kansai Medical University Hospital (Hirakata, Japan) from April 2011 to March 2017 were investigated based on outcome at postoperative day 30. RESULTS: The average age of the 76 patients (41 men/35 women) was 73 years, and the causative disease of colon perforation was malignant/benign in 18/58 cases, with ileocecal perforation site in 8 cases, ascending colon in 6, transverse colon in 2, descending colon in 4, sigmoid colon in 49, and rectum in 7. All patients received laparotomy with irrigation drainage, and 9 patients (11.8%) were dead at 30 days. Upon comparing the 67 survivors with the 9 dead patients, we recognized a significant difference on preoperative spread of ascites on computed tomography (CT) (P = 0.002) in univariate analysis and on acute disseminated intravascular coagulation (DIC) score (odds ratio 2.289; 95% confidence interval, 1.188-4.410; P = 0.013) in multivariate analysis. CONCLUSION: In our hospital, the preoperative acute DIC score was found to be a prognostic factor for colon perforation accompanied by pan-peritonitis. Appropriate evaluation of the spread of ascites on the preoperative CT might also help predict patient prognosis.

Takotsubo cardiomyopathy in the intensive care unit.

AIMS: An angiographic examination is necessary for the diagnosis of takotsubo cardiomyopathy (TTC). However, in the intensive care unit (ICU), intensivists often see patients in whom TTC cannot be diagnosed because they cannot undertake angiography due to the patient's poor general condition. We defined such cases as clinical TTC (cTTC) and investigated the incidence and background of cTTC in the ICU at Kansai Medical University Hospital (Osaka, Japan). METHODS: The study involved 5,084 patients who were admitted to the ICU of Kansai Medical University Hospital between January 2013 and December 2017. We retrospectively investigated the frequency and background of TTC and cTTC. RESULTS: Of the 5,084 patients, 5 (0.09%) patients admitted to the ICU were diagnosed as having TTC and 19 patients (0.37%) were diagnosed as having cTTC. The most common primary disease among the evaluated patients was sepsis (n = 10) followed by subarachnoid hemorrhage (SAH) (n = 5). Ten of the 335 patients with sepsis (3.0%) were admitted to the ICU with complications due to cTTC. Their blood pressure and heart rate on admission tended to be high, and their Sequential Organ Failure Assessment scores tended to be low. Five of the 172 patients with SAH (2.9%) were admitted to the ICU with complications due to cTTC. These patients were often classified as grade 5 on the Hunt and Hess scale. CONCLUSION: Our study suggests that patients with sepsis or SAH are complicated with cTTC in the ICU. In addition, there might be no correlation between the severity of sepsis and the development of TTC.

[Two Cases of Hepatic Encephalopathy after Chemotherapy for Metastatic Colorectal Cancer].

We reported 2 cases of hepatic encephalopathy after chemotherapy for advanced colorectal cancer. Case 1: A 49-year-old male was diagnosed advanced sigmoid colon cancer with peritoneal dissemination, multiple liver metastasis and multiple osseous metastasis. After resection of primary lesion, we administered mFOLFOX6 plus bevacizumab combination therapy. He was in comatose(Japan coma scale 200)3 days after 2 courses of administration of this regimen. Case 2: A 57-year-old female was diagnosed advanced rectal cancer with multiple huge liver metastasis and multiple osseous metastasis. We administered mFOLFOX6 plus panitumumab combination therapy. She was in comatose(Japan coma scale 100)3 days after 10 courses of administration of this regimen. In both cases, radiographic imaging showed no abnormal sign and blood examination revealed a high level of serum ammonia. We diagnosed their disturbance of consciousness as a symptom of hepatic encephalopathy. Branched-chain amino acid infusion rapidly improved disturbance of consciousness. We must consider the symptom, hepatic encephalopathy in patients receiving chemotherapy for advanced colorectal cancer.

[A Colorectal Cancer with Invasive Micropapillary Carcinoma].

A 76-year-old woman with bloody stool visited a nearby hospital. Colonoscopy showed a type 1 tumor in the rectum, and the biopsy indicated moderately differentiated adenocarcinoma. She was referred to our hospital. Abdominal contrast-enhanced CT did not show swollen lymph nodes in the regional nodes or distant metastases. Laparoscopic lower anterior resection was performed. Histopathological examination indicated pT1b, pN3, ly3, and v1, fStage III b, which had a partial invasive micropapillary carcinoma(IMPC)component of papillary adenocarcinoma. Although she received postoperative adjuvant chemotherapy, she died of a thromboembolism with paraneoplastic syndrome 20 months after the operation. IMPC has a high incidence of lymphatic invasion and lymph node metastases. IMPC is rare in cases of colorectal cancer and it is important to accumulate and investigate colorectal cancer patients with IMPC.

[Anorectal Malignant Melanoma Is a Very Rare Disease and Has a Poor Prognosis].

We performed abdomino-perineal-resection(APR)on 2 cases of anorectal malignant melanoma. The first case was a 70- year-old woman suffering from bloody stool. Colonoscopy showed a black tumor in the rectum. Biopsy revealed a malignant melanoma. A CT scan showed multiple lung metastases and liver metastasis. She underwent surgery for the purpose of bleeding control, but died shortly thereafter because her liver and lung metastases had worsened. The second case was a 43- years-old man suffering from bloody stool. He had a black type 3 tumor in the rectum. A biopsy revealed malignant melanoma. A CT scan showed lateral lymph node swelling. He underwent APR with right side-lateral dissection. An established treatment for anorectal malignant melanoma has not been agreed upon and it is controversial. We experienced 2 cases that underwent surgery and we report them along with relevant information from the literature.

[Pathological Complete Response in a Case of Multiple Liver Metastases from Rectal Cancer Treated with XELOX plus Bevacizumab(Bev)Therapy].

The patient was a 56-year-old woman who had synchronous multiple liver metastases and underwent laparoscopic-assisted high anterior resection for rectal cancer. According to the Japanese classification of colorectal carcinoma(8th edition), the tumor was considered to be pStage IV (pT4bN2M1a[H3]). Following resection of the primary tumor, she received XELOX plus bevacizumab(Bev)therapy. After 5 courses, the tumors were markedly reduced in size. According to the RECIST criteria, the tumor response was determined to be a partial response(-44%). Therefore, on the basis of the morphologic response criteria, the patient had Group 1 disease. Because the chemotherapy seemed to be effective, we performed partial hepatectomies. Histologically, no cancer cells were detected in any of the resected tumors. After the partial hepatectomies, she received no additional chemotherapy. Her CEA levels decreased to a normal range and no tumor recurrence was detected over 2 and a half years. XELOX plus Bev therapy may be effective for unresectable multiple liver metastasis from rectal cancer.

[Clinical Experience with Nutrition and Anticoagulation Therapy for a Patient with a 30 cm Residual Jejunum].

Patients with short bowel syndrome experience malabsorption and digestive disorders. They are unable to maintain adequate nutrition by the oral or enteral route alone, and their requirements for liquids, electrolytes, nutrients, microelements, vitamins, etc., are not completely met. Managing the nutritional needs of these patients is important. Another concern is these patients' inability to absorb medication, because the small intestine that is shortened in short bowel syndrome is the principal site of drug absorption. Here, we report a case of a 74-year-old woman with a 30 cm residual jejunum after surgery for acute occlusion of the superior mesenteric artery and the clinical management of nutrition and anticoagulant medication in this patient.

Ventricular septal perforation after blunt chest trauma due to blows from a fist.

Case: A 40-year-old man received fist blows to his chest and abdomen. He presented with external jugular vein distention and facial congestion. Chest X-ray showed bilateral pulmonary congestion. A Levine V/VI holosystolic murmur was audible. Echocardiography showed left-to-right shunt flow across the perimembranous region of the ventricular septum. The diameter of the hole was approximately 13 mm. We diagnosed ventricular septal perforation, started an infusion, and administered vasopressors. However, circulatory dynamics could not be maintained. The ventricular septal perforation was repaired directly with mattress sutures through the right ventricle. A small residual ventricular septal perforation was detected, which was repaired with a patch sutured through the left ventricle. Outcome: The patient was discharged without cardiovascular complications 43 days after admission. Conclusion: Ventricular septal perforation following blunt chest trauma is a rare form of cardiac trauma. It is important to consider the timing of the operation and the best method to ensure cardiac repair.