New liposidomycin congeners produced by Streptomyces sp. TMPU-20A065, anti-Mycobacterium avium complex agents with therapeutic efficacy in a silkworm infection model.

Three new liposidomycin congeners (1, 2, and 4), together with 14 known liposidomycins (3 and 5-17), were isolated from the culture broth of Streptomyces sp. TMPU-20A065 as anti-Mycobacterium avium complex agents. The structures of liposidomycins were elucidated by spectroscopic analyses, including NMR and MS. Compounds 1, 2, and 4 belong to type-I liposidomycin-containing sulfate groups and methylglutaric acid, each with a different acyl side chain in the structure. Compounds 1-17 exhibited in vitro anti-M. avium and M. intracellulare activities with MIC values ranging between 2.0 and 64 µg ml-1. Furthermore, 1-17 exerted potent therapeutic effects in an in vivo-mimic silkworm infection model with ED50 values ranging between 0.12 and 3.7 µg larva-1 g-1.

Case Report: Kawasaki disease associated with acute generalized exanthematous pustulosis secondary to carbocysteine.

Acute generalized exanthematous pustulosis (AGEP) is an uncommon eruption characterized by sterile pustules on an erythematous background, which is usually associated with drugs. AGEP is described as a self-limiting disease with favorable prognosis. We reported a case of Kawasaki Disease (KD) following AGEP. A 3-year-old male, who was admitted with pustules and five days of fever at our hospital, was diagnosed with AGEP. Despite the skin lesions and fever improving drastically after prednisolone therapy, the fever recurred on hospitalization day 5. The following symptoms suggestive of KD also appeared: bulbar conjunctival hyperemia, cervical lymphadenopathy, erythema of the lips, eruption on his trunk, and erythema and edema of the hands and feet. He was diagnosed with KD and treated with intravenous immunoglobulin. He was discharged on the thirteenth day of hospitalization without cardiac complications. Drug-induced lymphocyte stimulation test revealed carbocysteine as the suspected cause of AGEP, which consequently triggered KD. Because a mucosal lesion is uncommon in AGEP, bulbar conjunctival hyperemia suggested that KD sequentially occurred after AGEP. Since AGEP is benign and self-limited in most cases, it is necessary to differentiate other diseases, including KD, when recurrent fever or rash occurs in the course of AGEP.

Ultrasound and computed tomography findings of hepatic portal venous gas associated with acute appendicitis in a paediatric patient: A case report.

Introduction: Hepatic portal venous gas is a rare and life-threatening condition characterised by the presence of gas in the portal vein. Hepatic portal venous gas is frequently associated with intestinal ischaemia and necrosis. We present the case of a paediatric patient with acute appendicitis with hepatic portal venous gas detected using ultrasonography. Case report: A 5-year-old boy was admitted to our hospital with a respiratory tract infection. The boy started vomiting on day 2 of hospitalisation. He did not complain of any symptoms due to developmental retardation. We performed bedside point-of-care ultrasound, which detected hepatic portal venous gas, although the appendix could not be detected due to an acoustic shadow associated with bowel gas. Contrast-enhanced computed tomography revealed perforated appendicitis and pneumatosis intestinalis associated with paralytic ileus. An emergency laparoscopic appendectomy was performed. He was discharged on day 25 of hospitalisation after antibiotic therapy. Discussion: The present case suggests that the mechanism of hepatic portal venous gas was paralytic ileus, which caused gas-forming bacterial proliferation. The gas produced by bacteria and/or the gas-forming bacteria entered the bowel wall, which caused pneumatosis intestinalis. The bubbles in the intestinal wall floated in the portal system and were detected as hepatic portal venous gas. Perforated appendicitis and paralytic ileus seemed to be caused by a delayed diagnosis of appendicitis. The point-of-care ultrasound examination was useful for detecting hepatic portal venous gas and for helping establish the diagnosis of appendicitis. Conclusion: Hepatic portal venous gas is a rare finding associated with appendicitis in children. In addition, point-of-care ultrasound is useful for detecting hepatic portal venous gas in paediatric patients.

The Gilles de la Tourette Syndrome-Quality of Life Scale (GTS-QOL): A Validation in Japanese Patients.

Background: Though Gilles de la Tourette's syndrome (GTS) has significant impact on the quality of life of its patients, measures of health-related quality of life (HR-QOL) specific to adolescents and adults with GTS were not developed until recently. The present study provides evidence on the validity of the Gilles de la Tourette Syndrome-Quality of Life Scale (GTS-QOL), the first disease-specific HR-QOL instrument for GTS patients, for the first time in an East Asian sample. Methods: One hundred and two Japanese individuals aged 13 and above with GTS were included in our study. Internal consistency was evaluated using Cronbach's alpha. The 4-factor structure of the GTS-QOL was assessed using confirmatory factor analysis, using goodness of fit indices, factor loadings of each questionnaire item, and covariances between factors. Validity was assessed using interscale correlations. Convergent and discriminate construct validity was evaluated using correlations with other scales such as the 28-item General Health Questionnaire, the Yale Global Tic Severity Scale, and the short version of the Padua Inventory. Results: Scaling assumptions were met. Internal consistency reliability was high, with a Cronbach's alpha of 0.96. Confirmatory factor analysis revealed sufficient factor loadings and goodness of fit. All measures of goodness of fit corroborated the fit of the 4-factor model. Standardized covariances between factors in the confirmatory factor analysis were >0.8. There were significant correlations with other well-validated scales, and thus convergent and discriminate construct validity was sufficient. Conclusion: The GTS-QOL is a valid and reliable instrument to measure disease-specific HR-QOL of GTS patients in Japan.

The effects of comorbid Tourette symptoms on distress caused by compulsive-like behavior in very young children: a cross-sectional study.

BACKGROUND: Many children 4 to 6 years old exhibit compulsive-like behavior, often with comorbid Tourette symptoms, making this age group critical for investigating the effects of having comorbid Tourette symptoms with compulsive-like behavior. However, these effects have not yet been elucidated: it is unclear whether having comorbid tics with compulsive-like behavior leads to lower quality of life. This cross-sectional study aims to investigate the effect of comorbid Tourette symptoms on distress caused by compulsive-like behavior in very young children. METHODS: Self-administered questionnaires were distributed to guardians of children aged 4 to 6 attending any of the 59 public preschools in a certain ward in Tokyo, Japan. The questionnaire contained questions on the presence of Tourette symptoms, the presence of specific motor and vocal tics, frequency/intensity of compulsive-like behavior, and the distress caused by compulsive-like behavior, which was rated on a scale of 1 to 5. Additionally, questions on autism spectrum disorder (ASD) traits, attention-deficit/hyperactivity disorder (ADHD) traits, internalizing behavior traits, and externalizing behavior traits were included in the questionnaire as possible confounders of distress caused by compulsive-like behavior. Wilcoxon rank-sum tests were conducted to compare the distress caused by compulsive-like behavior and frequency/intensity of compulsive-like behavior between children in the Tourette symptoms group and the non-Tourette symptoms group. Furthermore, a stepwise regression analysis was performed to assess the effects of the independent variables on distress caused by compulsive-like behavior. Another stepwise regression analysis was performed to assess the relationship between distress caused by compulsive-like behavior and the presence of five specific motor and vocal tics. RESULTS: Of the 675 eligible participants, distress due to compulsive-like behavior was significantly higher in children in the Tourette symptoms group compared to the non-Tourette symptoms group (2.00 vs 1.00, P < 0.001). Stepwise regression analysis showed that frequency/intensity of compulsive-like behavior, being in the Tourette symptoms group, ASD traits, and internalizing behavior traits were predictors of distress due to compulsive-like behavior. Two specific tics, repetitive noises and sounds and repetitive neck, shoulder, or trunk movements, were significant predictors of distress due to compulsive-like behavior. CONCLUSIONS: Comorbid Tourette symptoms may worsen distress caused by compulsive-like behavior in children 4 to 6 years old, and specific motor and vocal tics may lead to greater distress.

Assessing the Efficacy of Very Early Motor Rehabilitation in Children with Down Syndrome.

Among children with Down syndrome, the frequency of motor rehabilitation intervention and the age at the start of this intervention are independently related to the age at onset of independent walking. Early motor rehabilitation, before age 6 months, may be effective in reducing motor delay in children with Down syndrome.

Improved bacterial identification directly from urine samples with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry.

BACKGROUND: Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) contributes to rapid identification of pathogens in the clinic but has not yet performed especially well for Gram-positive cocci (GPC) causing complicated urinary tract infection (UTI). The goal of this study was to investigate the possible clinical use of MALDI-TOF MS as a rapid method for bacterial identification directly from urine in complicated UTI. METHODS: MALDI-TOF MS was applied to urine samples gathered from 142 suspected complicated UTI patients in 2015-2017. We modified the standard procedure (Method 1) for sample preparation by adding an initial 10 minutes of ultrasonication followed by centrifugation at 500 g for 1 minutes to remove debris such as epithelial cells and leukocytes from the urine (Method 2). RESULTS: In 133 urine culture-positive bacteria, the rate of corresponded with urine culture in GPC by MALDI-TOF MS in urine with standard sample preparation (Method 1) was 16.7%, but the modified sample preparation (Method 2) significantly improved that rate to 52.2% (P=.045). Method 2 also improved the identification accuracy for Gram-negative rods (GNR) from 77.1% to 94.2% (P=.022). The modified Method 2 significantly improved the average MALDI score from 1.408±0.153 to 2.166±0.045 (P=.000) for GPC and slightly improved the score from 2.107±0.061 to 2.164±0.037 for GNR. CONCLUSION: The modified sample preparation for MALDI-TOF MS can improve identification accuracy for complicated UTI causative bacteria. This simple modification offers a rapid and accurate routine diagnosis for UTI, and may possibly be a substitute for urine cultures.

A lard-rich high-fat diet increases hepatic peroxisome proliferator-activated receptors in endotoxemic rats.

BACKGROUND: Diets high in saturated fatty acids activate chronic inflammation. We previously reported that, in even acute inflammation caused by lipopolysaccharide (LPS), liver injury was exacerbated in rats fed a lard-rich diet. Peroxisome proliferator-activated receptors (PPARs) are related to inflammation and are also key regulators of lipid metabolism. In this study, we examined effects of high-fat diet on liver injury and hepatic lipid metabolism during endotoxemia, measuring hepatic PPARs and other markers. MATERIALS AND METHODS: Male Wistar rats were fed a high-fat diet (HFD, 60 kcal% fat) or control diet (CD, 10 kcal% fat) for 4 or 12 wk, injected with LPS and sacrificed at 0, 1.5, or 6 h. Analyses included plasma aspartate transaminase (AST) and alanine transaminase (ALT) levels, messenger RNA (mRNA) and protein levels of hepatic PPARα and PPARγ, and mRNA levels of enzymes related to fatty acid oxidation and synthesis. RESULTS: Endotoxemic rats on HFD for 12 wk, but not 4 wk, had higher mRNA and protein levels for hepatic PPARs, than did those on CD (P < 0.01-0.05). Similarly, these rats had increased mRNA expression of hepatic fatty acid oxidation- and synthesis-related enzymes (P < 0.01-0.05). Rats injected with LPS had more severe liver injury, indicated by plasma AST/ALT, if on the HFD for 12 wk, compared with for 4 wk. CONCLUSIONS: Consumption of a lard-rich diet for 12 wk worsened liver injury and increased hepatic PPARα and PPARγ expression in endotoxemic rats.

Changes of hepatic lipid mediators associated with intake of high-fat diet for 12 weeks in endotoxemic rats using LC-ESI-MS/MS.

BACKGROUND & AIMS: It has recently been reported that anti-inflammatory lipid mediators are increased in the late phase of acute inflammation, whereas proinflammatory lipid mediators are regulated at the initiation of inflammation. The purpose of this study was to evaluate changes of hepatic lipid mediators due to high-fat diet (HFD) feeding in endotoxemic rats. METHODS: Male Wistar rats were fed either HFD or control diet for 12 weeks, and were then killed 0, 1.5, and 6 h after lipopolysaccharide (LPS) injection. Analyses included lipidomics assessment of mediators using liquid chromatography-electrospray ionization/multi-stage mass spectrometry; measuring expression of hepatic polyunsaturated fatty acid (PUFA)-oxidizing enzyme, tumor necrosis factor (TNF)-α, interleukin (IL)-6, and inducible nitric oxide synthase mRNA levels; blood biochemical tests; and liver histology. RESULTS: HFD feeding worsened liver injury, increased expression of TNF-α and IL-6 mRNA, and increased oxidative stress after LPS injection. PUFA-oxidizing enzymes were higher in HFD-fed rats after LPS injection. The proinflammatory prostaglandin (PG)E2 and thromboxane B2 were increased 1.5 h after LPS injection, and had decreased by 6 h in HFD-fed rats. In contrast, potent pro-resolving resolvins derived from eicosapentaenoic acid and docosahexaenoic acid were not detected, but anti-inflammatory epoxyeicosatrienoic acids, lipoxin A4, and 15-deoxy-PGJ2 were increased after LPS injection in HFD-fed rats. CONCLUSIONS: HFD feeding for 12 weeks enhanced proinflammatory lipid mediators 1.5 h after LPS injection suggesting relation to liver injury.

Lard-based high-fat diet increases secretory leukocyte protease inhibitor expression and attenuates the inflammatory response of acute lung injury in endotoxemic rats.

BACKGROUND & AIMS: Acute lung injury (ALI) is less severe in obese than in nonobese patients, but the mechanism is unclear. Secretory leukocyte protease inhibitor (SLPI) is the key anti-inflammatory protein in various lung diseases. We have previously reported changes of the surgical stress in obese rats using lard-based high-fat diet (HFD). The purpose of this study was to elucidate the effect of lard-based HFD on the pathophysiology of lipopolysaccharide (LPS)-induced ALI, and the role of SLPI expression. METHODS: Male Wistar rats were fed lard-based HFD (60 kcal% fat) or control diet (CD) for either 4 or 12 weeks and were killed after intraperitoneal LPS injection. Analyses included messenger RNA expression of TNF-α, macrophage inflammatory protein (MIP)-2, inducible nitric oxide synthase (iNOS), IL-10 and SLPI in the lung tissue and bronchoalveolar lavage fluid, and histology of the lungs. RESULTS: Rats fed HFD for 12 weeks showed suppression of the lung injury and oxidative stress after LPS injection, as indicated by reduction of pulmonary TNF-α, MIP-2 and iNOS mRNA expression and 8-hydroxy-2'-deoxyguanosine immunostaining. The increased pulmonary SLPI caused by lard was associated with decreased pro-inflammatory cytokines and oxidative stress, which eventually resulted in the prevention of ALI. Those effects of lard on LPS-induced ALI were greater after 12 weeks than after 4 weeks feeding, as indicated by the reduction of TNF-α, MIP-2 and iNOS levels. CONCLUSIONS: Feeding lard-based HFD for 12 weeks attenuated LPS-induced ALI with increased pulmonary SLPI expression in rats.

Oral tributyrin prevents endotoxin-induced lipid metabolism disorder.

BACKGROUND & AIMS: Sepsis leads to dysregulation of lipid and lipoprotein metabolism. Butyrate increases peroxisome proliferator-activated receptors (PPARs), which are key nuclear hormone receptors to induce fatty acid oxidation and synthesis. Oral administration of tributyrin, a prodrug of butyrate contained in dairy products, suppresses lipopolysaccharide (LPS)-induced liver injury through attenuating nuclear factor-κB activity with an increased hepatoportal butyrate level. In this study, we elucidated the protective effect of oral administration of tributyrin against LPS-mediated lipid metabolism disorder in rats. METHODS: Male Wistar rats were randomly divided and were administered tributyrin or vehicle orally 1 h before LPS injection and then sacrificed at 0, 1.5, 6, and 24 h after LPS. Liver tissue expressions of nuclear hormone receptors, enzymes associated with fatty acid metabolism, and histone acetylation were analyzed by real-time polymerase chain reaction or western blotting. Plasma lipids levels were measured. RESULTS: Tributyrin enhanced expression of PPARs and histone H3 in the liver at basal levels. Tributyrin suppressed LPS-induced repression of PPARs fatty acid oxidation-associated enzymes: fatty acid transport protein and fatty acid binding protein, and fatty acid synthesis-associated enzyme: sterol regulatory element binding protein-1c. Tributyrin reduced the increase in plasma triglyceride, total cholesterol (TC), and low-density lipoprotein cholesterol (LDL-C) levels at 24 h after LPS injection. CONCLUSIONS: Oral tributyrin administration prevented elevation of plasma triglyceride, TC, and LDL-C levels through improved fatty acid oxidation in endotoxemic rats.

IL18 production and IL18 promoter polymorphisms correlate with mortality in ICU patients.

BACKGROUND: Single nucleotide polymorphisms in the promoter of interleukin (IL)-18 (-607C/A and -137G/C) may affect the clinical course of inflammatory diseases. This study examined the relationship between the plasma IL18 levels, IL18 promoter polymorphism, and outcomes in the intensive care unit (ICU) setting. PATIENTS AND METHODS: Plasma IL18 levels, IL18 promoter genotype, clinical variables, including APACHE II score, and mortality were examined in 70 ICU patients. RESULTS: Plasma IL18 levels were significantly higher in patients who did not survive the ICU stay than in patients who survived, and were correlated with APACHE II score. When examined by IL18 promoter genotype, only patients with the -607CA genotype exhibited differences in IL18 expression between survivors and non-survivors. CONCLUSION: Plasma IL18 levels may predict outcome in patients with sepsis. IL18 promoter polymorphism, especially at -607, may increase IL18 production in some patients and might be useful in predicting the outcome of patients with sepsis in the ICU.

Supplementation of parenteral nutrition with fish oil attenuates acute lung injury in a rat model.

Fish oil rich in n-3 polyunsaturated fatty acids has diverse immunomodulatory properties and attenuates acute lung injury when administered in enternal nutrition. However, enteral nutrition is not always feasible. Therefore, we investigated the ability of parenteral nutrition supplemented with fish oil to ameliorate acute lung injury. Rats were infused with parenteral nutrition solutions (without lipids, with soybean oil, or with soybean oil and fish oil) for three days. Lipopolysaccharide (15 mg/kg) was then administered intratracheally to induce acute lung injury, characterized by impaired lung function, polymorphonuclear leukocyte recruitment, parenchymal tissue damage, and upregulation of mRNAs for inflammatory mediators. Administration of parenteral nutrition supplemented with fish oil prior to lung insult improved gas exchange and inhibited neutrophil recruitment and upregulation of mRNAs for inflammatory mediators. Parenteral nutrition supplemented with fish oil also prolonged survival. To investigate the underlying mechanisms, leukotriene B4 and leukotriene B5 secretion was measured in neutrophils from the peritoneal cavity. The neutrophils from rats treated with fish oil-rich parenteral nutrition released significantly more leukotriene B5, an anti-inflammatory eicosanoid, than neutrophils isolated from rats given standard parenteral nutrition. Parenteral nutrition with fish oil significantly reduced lipopolysaccharide-induced lung injury in rats in part by promoting the synthesis of anti-inflammatory eicosanoids.

Mild obesity reduces survival and adiponectin sensitivity in endotoxemic rats.

BACKGROUND: Recent meta-analyses have reported that critically ill patients with morbid obesity (body mass index >40 kg/m(2)) have poor outcomes, but the effects and mechanisms of action of mild obesity are still unclear. The purpose of this study was to evaluate the effect of mild obesity using a lard-based, high-fat diet (HFD) on pathologic conditions and the mechanisms of adiponectin action in endotoxemic rats. MATERIALS AND METHODS: Male Wistar rats underwent HFD feeding for 4 wk and were killed at 0, 1.5, and 6 h after lipopolysaccharide (LPS) injection. Plasma levels of adiponectin, nitric oxide, and interleukin 6; messenger RNA expression of adiponectin receptors (AdipoR1 and AdipoR2) in the liver and the skeletal muscle; blood biochemical test results; and histology of the liver were analyzed. RESULTS: HFD-fed rats had a lower survival rate (12.8% versus 85.2%) and lower plasma adiponectin levels after LPS injection (P < 0.01). Messenger RNA expression of adiponectin receptors in the liver, but not the skeletal muscle, also decreased in HFD-fed rats (P < 0.05). Tissue injury and oxidative stress in the liver and plasma inflammatory mediator levels increased, and worsened lipid metabolism abnormalities were noted. The findings indicated that HFD decreased the sensitivity of adiponectin and was associated with an increase in oxidative stress and inflammation, which finally resulted in worsened liver injury and poor survival rate after LPS injection. CONCLUSIONS: Short-term, HFD-induced, mild obesity is harmful to the septic host, reduces adiponectin sensitivity, and could be the cause of worsening pathologic conditions.