Generation of sub-MHz and spectrally-bright biphotons from hot atomic vapors with a phase mismatch-free scheme.

We utilized the all-copropagating scheme, which maintains the phase-match condition, in the spontaneous four-wave mixing (SFWM) process to generate biphotons from a hot atomic vapor. The linewidth and spectral brightness of our biphotons surpass those of the biphotons produced with the hot-atom SFWM in the previous works. Moreover, the generation rate of the sub-MHz biphoton source in this work can also compete with those of the sub-MHz biphoton sources of the cold-atom SFWM or cavity-assisted spontaneous parametric down conversion. Here, the biphoton linewidth is tunable for an order of magnitude. As we tuned the linewidth to 610 kHz, the generation rate per linewidth is 1,500 pairs/(s·MHz) and the maximum two-photon correlation function, gs,as(2), of the biphotons is 42. This gs,as(2) violates the Cauchy-Schwarz inequality for classical light by 440 folds, and demonstrates that the biphotons have a high purity. By increasing the pump power by 16 folds, we further enhanced the generation rate per linewidth to 2.3×104 pairs/(s·MHz), while the maximum gs,as(2) became 6.7. In addition, we are able to tune the linewidth down to 290±20 kHz. This is the narrowest linewidth to date among all single-mode biphoton sources of room-temperature and hot media.

Global Investigation of Immune Repertoire Suggests Kawasaki Disease Has Infectious Cause.

BACKGROUND: Kawasaki disease (KD) severely threatens young children's health worldwide. The pathogenic mechanism of KD has not yet been solved, so there is still debate over whether KD is an infectious disease or an autoimmune disease.Methods and Results:To solve this problem, an immune repertoire analysis of KD was conducted. We collected blood cell RNA samples and prepared them into amplicons with iRepertoire kits. The amplicons were sequenced and analyzed with the iRepertoire pipeline. We first identified KD-specific VJ and VDJ forms that had the potential to serve as biomarkers of KD. In addition, the KD-specific VDJ forms were contributed mostly by immunoglobulin G. The D50 value analysis showed that B-cell diversity in KD is decreased, suggesting unique immunoglobulins are produced in KD. Moreover, V, D and J segment usage in IgA, IgG and IgM was consistent with previous KD studies. Further comparison showed no difference in CDR3 peptide length between KD and fever controls (subjects with fever but not diagnosed as KD), indicting KD had B-cell selection phenomenon that has a non-autoimmune pattern. The comparison of amino acid usage of the CDR3 region demonstrated a preference for hydrophilic amino acids in KD. CONCLUSIONS: The results of D50 value, VDJ usage and CDR3 peptide length analyses suggested the characteristics of infectious disease for KD.

Differential Effects of Statins on Inflammatory Interleukin-8 and Antimicrobial Peptide Human Β-Defensin 2 Responses in Salmonella-Infected Intestinal Epithelial Cells.

Alternative therapies are needed to reduce the use of antibiotics and incidence of drug-resistant Salmonellosis. Previous studies have revealed important roles of statins in regulating innate immunity. Therefore, we investigated the effects of statins on innate immunity in Salmonella-infected intestinal epithelial cells (IECs), which are involved in mucosal innate immunity. SW480 cells and Akt siRNA- or vitamin D receptor (VDR) siRNA-transfected SW480 cells were infected by wild-type S. Typhimurium strain SL1344 in the presence or absence of statins. The mRNA or protein expression was analyzed by real-time quantitative PCR or western blot analysis, respectively. Simvastatin or fluvastatin caused IL-8 (interleukin-8) suppression, but increased hBD-2 mRNA expression in Salmonella-infected SW480 cells. Both statins enhanced phosphorylated Akt and VDR expressions. Akt or VDR knockdown by siRNA counteracted the suppressive effect of simvastatin on IL-8 expression, whereas VDR knockdown diminished the enhanced hBD-2 expression in Salmonella-infected SW480 cells. Therefore, we observed differential regulation of statins on inflammatory IL-8 and anti-microbial hBD-2 expressions in Salmonella-infected IECs via PI3K/Akt signaling and VDR protein expression, respectively. The enhanced activity of antimicrobial peptides by statins in Salmonella-infected IECs could protect the host against infection, and modulation of pro-inflammatory responses could prevent the detrimental effects of overwhelming inflammation in the host.

The Role of Sphingolipids on Innate Immunity to Intestinal Salmonella Infection.

Salmonella spp. remains a major public health problem for the whole world. To reduce the use of antimicrobial agents and drug-resistant Salmonella, a better strategy is to explore alternative therapy rather than to discover another antibiotic. Sphingolipid- and cholesterol-enriched lipid microdomains attract signaling proteins and orchestrate them toward cell signaling and membrane trafficking pathways. Recent studies have highlighted the crucial role of sphingolipids in the innate immunity against infecting pathogens. It is therefore mandatory to exploit the role of the membrane sphingolipids in the innate immunity of intestinal epithelia infected by this pathogen. In the present review, we focus on the role of sphingolipids in the innate immunity of intestinal epithelia against Salmonella infection, including adhesion, autophagy, bactericidal effect, barrier function, membrane trafficking, cytokine and antimicrobial peptide expression. The intervention of sphingolipid-enhanced foods to make our life healthy or pharmacological agents regulating sphingolipids is provided at the end.

Hepcidin-Induced Iron Deficiency Is Related to Transient Anemia and Hypoferremia in Kawasaki Disease Patients.

Kawasaki disease (KD) is a type of systemic vasculitis that primarily affects children under the age of five years old. For sufferers of KD, intravenous immunoglobulin (IVIG) has been found to successfully diminish the occurrence of coronary artery lesions. Anemia is commonly found in KD patients, and we have shown that in appropriately elevated hepcidin levels are related to decreased hemoglobin levels in these patients. In this study, we investigated the time period of anemia and iron metabolism during different stages of KD. A total of 100 patients with KD and 20 control subjects were enrolled in this study for red blood cell and hemoglobin analysis. Furthermore, plasma, urine hepcidin, and plasma IL-6 levels were evaluated using enzyme-linked immunosorbent assay in 20 KD patients and controls. Changes in hemoglobin, plasma iron levels, and total iron binding capacity (TIBC) were also measured in patients with KD. Hemoglobin, iron levels, and TIBC were lower (p < 0.001, p = 0.009, and p < 0.001, respectively) while plasma IL-6 and hepcidin levels (both p < 0.001) were higher in patients with KD than in the controls prior to IVIG administration. Moreover, plasma hepcidin levels were positively and significantly correlated with urine hepcidin levels (p < 0.001) prior to IVIG administration. After IVIG treatment, plasma hepcidin and hemoglobin levels significantly decreased (both p < 0.001). Of particular note was a subsequent gradual increase in hemoglobin levels during the three weeks after IVIG treatment; nevertheless, the hemoglobin levels stayed lower in KD patients than in the controls (p = 0.045). These findings provide a longitudinal study of hemoglobin changes and among the first evidence that hepcidin induces transient anemia and hypoferremia during KD's acute inflammatory phase.

Avoidance of antibiotic administration to Campylobacter enterocolitis mimicking severe salmonellosis by clinical and laboratory features.

BACKGROUND: To compare the clinical and laboratory features of non-typhoid Salmonella (NTS) and Campylobacter jejuni enterocolitis in children and formulate a risk scoring system (with receiver-operating characteristic curve) to facilitate early decision making and avoid antibiotic overuse in C. jejuni enterocolitis. METHODS: Between January 2008 and December 2011, children (age <18 years) diagnosed as having C. jejuni enterocolitis and NTS enterocolitis in Kaohsiung Chang Gung Memorial Hospital were retrospectively enrolled. Clinical features and laboratory data were collected for analysis and a risk calculation score is created for the identification of Campylobacter infections. RESULTS: A total of 309 cases of C. jejuni enterocolitis and 496 cases of NTS enterocolitis were enrolled. Compared with Salmonella group clinically, the Campylobacter group had older age (81.06 ± 50.65 vs. 32.70 ± 34.88 months, p <; 0.001), more abdominal pain (69.26% vs. 37.5%, p <; 0.001) and more watery diarrhea (79.94% vs. 20.77%, p <; 0.001). In laboratory data, the Campylobacter group had higher level of white blood cell count (11 208 ± 4380 vs. 9095 ± 3598 cell/mm3, p <; 0.001). CONCLUSION: Four criteria including age (≥5 years), leukocytosis (≥10 000 cell/mm3), abdominal pain and watery diarrhea were identified as good predictors of Campylobacter enterocolitis. When three criteria were fulfilled, Campylobacter enterocolitis was highly suspected and antibiotic could be withheld even when C-reactive protein is high and before stool culture results are known. When four criteria were fulfilled, antibiotic usage was absolutely unnecessary.

Differential regulation of interleukin-8 and human beta-defensin 2 in Pseudomonas aeruginosa-infected intestinal epithelial cells.

BACKGROUND: The human opportunistic pathogen, Pseudomonas aeruginosa (P. aeruginosa) carries the highest case fatality rate of all gram-negative infections. Unfortunately, antimicrobial therapy has not been demonstrated to improve clinical outcome and the emergence of multidrug resistant P. aeruginosa has become a major concern in the hospital setting. Fever and diarrhea are the two most common initial symptoms in P. aeruginosa sepsis in previously healthy infants and children. This implies that intestinal epithelial cells in first contact with the pathogen may play an important role in innate immunity to P. aeruginosa infection. Human beta-defensins-2 (hBD-2) and interleukin-8 (IL-8) are crucial for host defense at mucosa but IL-8 may give rise to characteristic pathology of colitis. RESULTS: Pseudomonas aeruginosa strain PAO1 was used to infect SW480, an intestinal epithelial cell. IL-8 and hBD-2 mRNA expression and protein secretion were then assessed in SW480 cells using RT-PCR and enzyme-linked immunosorbent assay (ELISA), respectively. Intracellular signaling pathways and nucleotide-binding oligomerization domain (NOD) 1 protein expression were analyzed by Western blot in SW480 cells in the presence or absence of inhibitors or transfected with siRNA. We demonstrate that prolonged infection by P. aeruginosa results in suppression of IL-8 but enhancement of hBD-2, either protein secretion and mRNA expression, in SW480 cells. Inhibitors of ERK suppressed but inhibitor of PI3K enhanced P. aeruginosa-induced IL-8 mRNA expression in SW480 cells while both signaling had no effect on P. aeruginosa-induced hBD-2 expression in SW480 cells. On the other hand, NOD 1 was illustrated to get involved in P. aeruginosa-induced hBD-2 mRNA expression and protein production in SW480 cells. CONCLUSIONS: The P. aeruginosa-induced antimicrobial peptide in IECs continuously protect the host against prolonged infection, while modulation of proinflammatory responses prevents the host from the detrimental effects of overwhelming inflammation. Thus, P. aeruginosa-induced innate immunity in IECs represents a host protective mechanism, which may provide new insight into the pathogenesis of inflammatory bowel diseases.

The critical role of membrane cholesterol in salmonella-induced autophagy in intestinal epithelial cells.

It was previously observed that plasma membrane cholesterol plays a critical role in the Salmonella-induced phosphatidylinositol 3-kinase-dependent (PI3K)-dependent anti-inflammatory response in intestinal epithelial cells (IECs). The PI3K/Akt pathway is associated with autophagy which has emerged as a critical mechanism of host defense against several intracellular bacterial pathogens. Plasma membrane contributes directly to the formation of early Atg16L1-positive autophagosome precursors. Therefore, this study aimed to investigate the role of plasma membrane cholesterol on the Salmonella-induced autophagy in IECs. By using methyl-beta-cyclodextrin (MBCD), it was demonstrated that disruption of membrane cholesterol by MBCD enhanced NOD2 and Atg16L1 proteins expression in membrane, and autophagic LC3II proteins expression and LC3 punctae in Salmonella-infected Caco-2 cells, which was counteracted by Atg16L1 siRNA. Nucleotide-binding oligomerization domain-containing protein 2 (NOD2) siRNA enhanced the Salmonella-induced activation of Akt in Caco-2 cells. However, inhibitors of Akt or extracellular signal-regulated kinases (ERK) had no significant effect on Salmonella-induced autophagy Beclin 1 or LC3 proteins expression. In conclusion, our study suggests that cholesterol accumulation in the plasma membrane at the entry site of Salmonella results in the formation of Salmonella-containing vacuole (SCV) and decreased autophagy. Our results offer mechanistic insights on the critical role of membrane cholesterol in the pathogenesis of Salmonella infection in intestinal epithelial cells and the therapeutic potential of its antagonists.

The Hazards of Probiotics on Gut-Derived Pseudomonas aeruginosa Sepsis in Mice Undergoing Chemotherapy.

Pseudomonas aeruginosa (P. aeruginosa) is a leading cause of nosocomial infections associated with a high mortality rate and represents a serious threat to human health and the increasing frequency of antimicrobial resistance. Cancer patients are more vulnerable to invasive infection due to ulcerative lesions in mucosal surfaces and immune suppression secondary to chemotherapy. In our in vitro study, we observed that probiotics have the potential to yield beneficial effects on intestinal epithelial cells infected with P. aeruginosa. Additionally, probiotics were found to confer advantageous effects on the innate immunity of mice suffering from Salmonella-induced colitis. As a result, we sought to investigate the impact of probiotics on gut-derived P. aeruginosa sepsis induced by chemotherapy. Following chemotherapy, gut-derived P. aeruginosa sepsis was induced in female C57BL/6 mice aged 6-8 weeks, which were raised under specific-pathogen-free (SPF) conditions in an animal center. Prior to the induction of the sepsis model, the mice were administered 1 × 108 colony-forming units (CFU) of the probiotics, namely Lactobacillus rhamnosus GG (LGG) and Bifidobacterium longum (BL) via oral gavage. We observed that LGG or BL amplified the inflammatory mRNA expression in mice undergoing chemotherapy and suffering from gut-derived P. aeruginosa sepsis. This led to a heightened severity of colitis, as indicated by histological examination. Meanwhile, there was a notable decrease in the expression of antimicrobial peptide mRNA along with reduced levels of zonulin and claudin-2 protein staining within mucosal tissue. These alterations facilitated the translocation of bacteria to the liver, spleen, and bloodstream. To our astonishment, the introduction of probiotics exacerbated gut-derived P. aeruginosa sepsis in mice undergoing chemotherapy. Conclusively, we must be prudent when using probiotics in mice receiving chemotherapy complicated with gut-derived P. aeruginosa sepsis.

Unveiling the Novel Benefits of Co-Administering Butyrate and Active Vitamin D3 in Mice Subjected to Chemotherapy-Induced Gut-Derived Pseudomonas aeruginosa Sepsis.

Cancer patients face increased susceptibility to invasive infections, primarily due to ulcerative lesions on mucosal surfaces and immune suppression resulting from chemotherapy. Pseudomonas aeruginosa (P. aeruginosa) bacteremia is notorious for its rapid progression into fatal sepsis, posing a significant threat to cancer patients, particularly those experiencing chemotherapy-induced neutropenia. This bacterial infection contributes significantly to morbidity and mortality rates among such individuals. Our latest report showed the mutually beneficial effects of postbiotic butyrate on 1,25-dihydroxyvitamin D3 (1,25D3)-controlled innate immunity during Salmonella colitis. Hence, we investigated the impact of butyrate and 1,25D3 on chemotherapy-induced gut-derived P. aeruginosa sepsis in mice. The chemotherapy-induced gut-derived P. aeruginosa sepsis model was established through oral administration of 1 × 107 CFU of the P. aeruginosa wild-type strain PAO1 in C57BL/6 mice undergoing chemotherapy. Throughout the infection process, mice were orally administered butyrate and/or 1,25D3. Our observations revealed that the combined action of butyrate and 1,25D3 led to a reduction in the severity of colitis and the invasion of P. aeruginosa into the liver and spleen of the mice. This reduction was attributed to an enhancement in the expression of defensive cytokines and antimicrobial peptides within the cecum, coupled with decreased levels of zonulin and claudin-2 proteins in the mucosal lining. These effects were notably more pronounced when compared to treatments administered individually. This study unveils a promising alternative therapy that involves combining postbiotics and 1,25D3 for treating chemotherapy-induced gut-derived P. aeruginosa sepsis.

Effects of maternal screening and universal immunization to prevent mother-to-infant transmission of HBV.

BACKGROUND & AIMS: Mother-to-infant transmission is the major cause of hepatitis B virus (HBV) infection among immunized children. There has been much debate about screening pregnant women and administering hepatitis B immunoglobulin (HBIG) to newborns. We analyzed the rate of HBV infection among children born to hepatitis B surface antigen (HBsAg)-positive mothers and whether HBIG administration reduces transmission. METHODS: We analyzed data from 2356 children born to HBsAg-positive mothers, identified through prenatal maternal screens. In addition to HBV vaccines, HBIG was given to all 583 children with hepatitis B e antigen (HBeAg)-positive mothers and to 723 of 1773 children with HBeAg-negative mothers. Serology tests for HBV were performed from 2007 to 2009, when children were 0.5-10 years old. RESULTS: A significantly greater percentage of children with HBeAg-positive mothers tested positive for antibodies against the hepatitis B core protein (16.76%) and HBsAg (9.26%) than children with HBeAg-negative mothers (1.58% and 0.29%, respectively; P < .0001 and <.001). Among the HBV-infected children, the rate of chronicity also was higher among children with HBeAg-positive mothers than children with HBeAg-negative mothers (54% vs 17%; P = .002). Similar rates of antibodies against the hepatitis B core protein (0.99% and 1.88%; P = .19) and HBsAg (0.14% and 0.29%; P = .65) were noted in children born to HBeAg-negative mothers who were or were not given HBIG. Infantile fulminant hepatitis developed in 1 of 1050 children who did not receive HBIG (.095%). CONCLUSIONS: Children born to HBeAg-positive mothers are at greatest risk for chronic HBV infection (9.26%), despite immunization. Administration of HBIG to infants born to HBeAg-negative mothers did not appear to reduce the rate of chronic HBV infection, but might prevent infantile fulminant hepatitis. Screening pregnant women for HBsAg and HBeAg might control mother-to-infant transmission of HBV.

Plasma clusterin concentrations may predict resistance to intravenous immunoglobulin in patients with Kawasaki disease.

Kawasaki disease (KD) is an acute febrile vasculitic syndrome of early childhood often complicated by coronary artery lesion that drastically reduces the quality of life. The study aimed to identify a reliable marker for predicting nonresponsiveness to the first course of intravenous immunoglobulin (IVIG) in KD patients. A total of 63 patients with KD were enrolled in the study (IVIG response, 58; IVIG resistance, 5). Plasma samples were collected before and after IVIG infusion for measurement of biomarkers. Patients' clinical characteristics and laboratory data were also analyzed. A receiver operating characteristic curve was generated to identify a cut-off value for predicting IVIG resistance. Among the biomarkers, the difference in plasma clusterin concentrations before and after IVIG infusion (CLUSTER 12) was significantly related to IVIG resistance (P = 0.040; 95% confidence interval (CI): -25.8% to -6.0%). Using a CLUSTER 12 cut-off value of <8.52 mg/L, the odds ratio for IVIG resistance was 11.467 (95% CI: 1.186 to 110.853). Patients with plasma CLUSTER 12 concentrations >8.52 mg/L had a much higher risk of IVIG resistance than those with CLUSTER 12 concentrations <8.52 mg/L. Plasma clusterin concentration shows promise as a candidate biomarker for predicting IVIG resistance in patients with KD.

The Pivotal Role of Aryl Hydrocarbon Receptor-Regulated Tight Junction Proteins and Innate Immunity on the Synergistic Effects of Postbiotic Butyrate and Active Vitamin D3 to Defense against Microbial Invasion in Salmonella Colitis.

Our recent report illustrated the unitedly advantageous effects of postbiotic butyrate on active vitamin D3 (VD3)-orchestrated innate immunity in Salmonella colitis. There is growing awareness that aryl hydrocarbon receptor (AhR) can regulate intestinal immunity and barrier function, through modulating cecal inflammation and junction proteins expression. Hence, we researched the participation of AhR-regulated tight junction functions on the united effects of butyrate and VD3 on intestinal defense to Salmonella infection. Salmonella colitis model were elicited by oral gavage with 1 × 108 CFU of a S. typhimurium wild-type strain SL1344 in C57BL/6 mice. Before and after the colitis generation, mice were fed with butyrate and/or VD3 by oral gavage in the absence or presence of intraperitoneal injection of AhR inhibitor for 4 and 7 days, respectively. We observed that butyrate and VD3 could concert together to reduce the invasion of Salmonella in colitis mice by enhancing cecal cytokines and antimicrobial peptides expression and reducing zonulin and claudin-2 protein expressions in mucosal stain, compared to single treatment, which were counteracted by AhR inhibitor. It implies that AhR is involved in the united effects of butyrate and VD3 on the intestinal defense to Salmonella infection in colitis mice. This study discloses the promising alternative therapy of combining postbiotic and VD3 for invasive Salmonellosis and the pivotal role of AhR pathway.

The Critical Role of Acyl Hydrocarbon Receptor on the Combined Benefits of Postbiotic Propionate on Active Vitamin D3-Orchestrated Innate Immunity in Salmonella Colitis.

Our recent study observed the combined beneficial effects of postbiotic butyrate on active vitamin D3-orchestrated innate immunity to Salmonella Colitis. There is increasing interest in the role of acyl hydrocarbon receptor (AhR) on colitis and innate immunity. Therefore, we investigated the involvement of AhR in the effects. Salmonella colitis model is conducted with 6-8 w/o male C57BL/6 mice: Streptomycin (20 mg/mouse p.o.)-pretreated C57BL/6 mice were mock infected with sterile PBS or infected orally with 1 × 108 CFU of an S. typhimurium wild-type strain SL1344 for 48 h. Before and after the colitis induction, mice were oral gavage with active vitamin D3 0.2 µg/25 g mice (VD3) and/or postbiotics propionate (PP), in the absence of the presence of intraperitoneal injection of AhR inhibitor for 4 and 7 days, respectively. We observed AhR inhibitor counteracted the synergistic effects of PP and VD3 on reducing the severity of Salmonella colitis and body weight loss in C57BL/6 mice, reducing the cecal inflammatory but enhancing antimicrobial peptide mRNAs expression, and reducing the bacterial translocation in liver/spleen, compared to single treatment. It suggests the involvement of AhR on the synergistic effects of postbiotics PP and VD3 on the antibacterial and anti-inflammatory responses in Salmonella colitis and the potential biological treatment of Salmonella colitis.

Regulation of Salmonella flagellin-induced interleukin-8 in intestinal epithelial cells by muramyl dipeptide.

Toll-like receptor 5 (TLR5) and nucleotide-binding oligomerization domain 2 (Nod2) are two important pattern recognition receptors involved in innate immunity to invading pathogens. Flagellin, recognized by TLR5, is Salmonella's dominant pro-inflammatory determinant in intestinal epithelial cells (IECs). Nod2 has played a pivotal role in protecting against intestinal bacterial infection. Therefore the aim of the study is to investigate regulation of Salmonella flagellin-induced interleukin (IL)-8 (IL-8) in IECs by Nod2 agonist, muramyl dipeptide (MDP). We found that MDP by itself induced only a weak IL-8 secretion in Caco-2 cells. However, it did show synergistic enhancement on flagellin-induced IL-8 production in Caco-2 cells, possibly caused by flagellin-mediated enhanced Nod2 recruitment into cell membrane. By Western blot and siRNA, we showed ERK and NF-κB, Nod2 and Rip2 were involved in the synergistic effect of MDP. These findings suggested that the cooperation of TLR5 and Nod2 in IECs regulates inflammatory response to Salmonella infection.

Sonographic gallbladder abnormality is associated with intravenous immunoglobulin resistance in Kawasaki disease.

OBJECTIVE: Kawasaki disease (KD) is an acute systematic vasculitis in children which causes coronary arterial lesions and hydrops of gallbladder. Our objective is to correlate the clinical significance and influence on disease outcome of patients with gallbladder abnormalities in Kawasaki dissease. METHODS: Children who met KD diagnosis criteria and were admitted for IVIG treatment were retrospectively enrolled for analysis. Patients with abdominal sonography were divided into 2 groups based on the absence (Group A, N = 61) or presence (Group B, N = 16) of gallbladder abnormalities (GBA), defined as hydrops or acalculous cholecystitis. Between the two groups, clinical features, demographic data (including admission days, coronary artery lesions, IVIG resistance), and laboratory data before/after IVIG treatment were collected for analysis. RESULTS: The presence of sonographic gallbladder abnormalities is correlated with higher levels of serum CRP, GPT, and neutrophils. It also points to an increased number of IVIG resistance rates in group B. There was no significant statistical difference among clinical features, age, gender, admission days, or coronary artery lesions between the two groups. CONCLUSION: Sonographic gallbladder abnormalities are associated with higher CRP, GPT, neutrophil and IVIG resistance in KD. It can be used as a predictor of IVIG resistance in patients with KD.

Evaluation of dynamic contrast-enhanced magnetic resonance imaging and diffusion-weighted imaging for predicting muscular hyperplasia/hypertrophy in Crohn's disease.

OBJECTIVES: The existence of smooth muscle alteration in Crohn's disease (CD) is often neglected. It has been found that muscular hyperplasia/hypertrophy rather than fibrosis was the primary component of bowel wall thickening. This study aimed to assess the value of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and diffusion weighted imaging for the characterization of histopathologic tissue composition of CD, particularly smooth muscle hypertrophy, as well as inflammation and fibrosis. METHODS: The study included patients diagnosed with CD who received MRI examination 30 days before resection from August 2016 to December 2020. A semiquantitative histological grading scheme was employed to evaluate the pathological tissues. Resected sections were matched with MRI according to pathological marks. Parameters evaluated included: mural thickness, T2 ratio, apparent diffusion coefficient value; and maximum enhancement, initial slope of increase, perfusion parameters of DCE-MRI and enhancement pattern. These parameters were compared with location-matched histopathological grade. RESULTS: Ninety-one sections were enrolled in this retrospective study. When active inflammation is moderate or severe, volume transfer coefficient (Ktrans), maximum enhancement (ME) and initial slope of increase (ISI) are lower, mural thickness is higher when a certain degree of smooth muscle alteration is present. When active inflammation is absent or mild, ME, mural thickness and ISI can differentiate the presence of predominant muscular alteration. By combining ME and thickness comparisons against their cutoff values to create a combined ordinal parameter, the area under the curve value for whether significant muscular alteration coexists with moderate or severe active inflammation was found to be 0.953. CONCLUSIONS: MRI predicts the degree of inflammation, and can distinguish the degree of muscular alteration coexists with moderate or severe active inflammation with reasonable accuracy.

Plasma membrane cholesterol plays a critical role in the Salmonella-induced anti-inflammatory response in intestinal epithelial cells.

Our recent study demonstrated that a phosphatidylinositol-3 kinase (PI3K)/Akt-dependent anti-inflammatory pathway was activated by Salmonella in intestinal epithelial cells. Salmonella virulence is dependent on the ability of the bacterium to invade nonphagocytic host cells and then survive and replicate within modified Salmonella-containing vacuoles where cholesterol accumulates. In addition, cholesterol in membrane lipid rafts is frequently a platform for the activation of downstream signaling pathways, including the PI3K/Akt pathway. However, the role of plasma membrane cholesterol in the Salmonella-induced anti-inflammatory response in intestinal epithelial cells has not been elucidated. Here, we show that the effect of plasma membrane cholesterol depletion on the inhibition of Akt activation allows sustained ERK activation and the subsequent upregulation of IL-8 expression. These results demonstrate that plasma membrane cholesterol plays a critical role in the PI3K-dependent anti-inflammatory pathway activated by Salmonella in intestinal epithelial cells.

The Interleukins Orchestrate Mucosal Immune Responses to Salmonella Infection in the Intestine.

Salmonella infection remains one of the major public health problems in the world, with increasing resistance to antibiotics. The resolution is to explore the pathogenesis of the infection and search for alternative therapy other than antibiotics. Immune responses to Salmonella infection include innate and adaptive immunity. Flagellin or muramyl dipeptide from Salmonella, recognized by extracellular Toll-like receptors and intracellular nucleotide-binding oligomerization domain2, respectively, induce innate immunity involving intestinal epithelial cells, neutrophils, macrophages, dendric cells and lymphocytes, including natural killer (NK) and natural killer T (NKT) cells. The cytokines, mostly interleukins, produced by the cells involved in innate immunity, stimulate adaptive immunity involving T and B cells. The mucosal epithelium responds to intestinal pathogens through its secretion of inflammatory cytokines, chemokines, and antimicrobial peptides. Chemokines, such as IL-8 and IL-17, recruit neutrophils into the cecal mucosa to defend against the invasion of Salmonella, but induce excessive inflammation contributing to colitis. Some of the interleukins have anti-inflammatory effects, such as IL-10, while others have pro-inflammatory effects, such as IL-1ß, IL-12/IL-23, IL-15, IL-18, and IL-22. Furthermore, some interleukins, such as IL-6 and IL-27, exhibit both pro- and anti-inflammatory functions and anti-microbial defenses. The majority of interleukins secreted by macrophages and lymphocytes contributes antimicrobial defense or protective effects, but IL-8 and IL-10 may promote systemic Salmonella infection. In this article, we review the interleukins involved in Salmonella infection in the literature.

The Combined Beneficial Effects of Postbiotic Butyrate on Active Vitamin D3-Orchestrated Innate Immunity to Salmonella Colitis.

Salmonella spp. Remains a major public health problem globally. Biomedicine is the cornerstone of modern health care and could be a solution for antibiotic-resistant Salmonellosis. Although postbiotics seem to be an effective treatment in various clinical conditions, their clinical effects on Salmonella colitis have not been reported. Our previous report revealed that active vitamin D attenuates the severity of Salmonella colitis and invasiveness by reducing inflammation and enhancing the production of antimicrobial peptides. Therefore, we investigated the synergistic effects of butyrate, the most studied postbiotic, and active vitamin D on the severity of Salmonella colitis, invasiveness of Salmonella, and host immune responses, as well as its novel mechanisms, using in vitro and in vivo studies. We demonstrated that a combination of butyrate and active vitamin D (1 alpha, 25-dihydroxyvitamin D3) synergically reduced the severity of Salmonella colitis in C57BL/6 mice and reduced cecal inflammatory mIL-6, mIL-8, mTNF-α, and mIL-1ß mRNA expression, but enhanced the antimicrobial peptide mhBD-3 mRNA, compared to a single treatment. Additionally, upregulated vitamin D receptor (VDR) plays a critical role in the synergistic effects. This suggests combined benefits of butyrate and active vitamin D on Salmonella colitis through VDR-mediated antibacterial and anti-inflammatory responses. The combined use of both supplements could be a potential biomedicine for infectious and autoimmune colitis.