T cells and mast cells as a major source of interleukin-13 in atopic dermatitis

BACKGROUND: Interleukin (IL)-13 is a T-cell-derived cytokine that shares several functions with IL-4, including the induction of immunoglobulin E synthesis. Recent studies suggest that cytokines expressed locally in the skin play several critical roles in atopic dermatitis (AD), however, little is known about the role of IL-13 in AD lesions. OBJECTIVES: The present study was designed to characterize the involvement of IL-13 in AD in the skin and peripheral blood mononuclear cells (PBMC). METHODS: Using lesional and nonlesional skin from adult AD patients and normal skin from healthy volunteers, we performed RT-PCR, in situ RT and immunostaining to determine the IL-13 expression at the mRNA and protein levels. The actual numbers of IL-13 expressing cells in biopsy specimens were counted under the microscope. IL-13 mRNA expression in PBMC from AD patients and healthy volunteers was examined by RT-PCR analysis. RESULTS: IL-13 mRNA expression was detected by RT-PCR in lesional and nonlesional skin and in PBMC from AD patients, but not in normal skin or PBMC from healthy volunteers. In AD lesional skin, numerous IL-13 mRNA-positive cells were demonstrated by in situ RT, and similar numbers of IL-13-positive cells were also detected immunohistochemically. Smaller numbers of IL-13-positive cells were observed in AD nonlesional skin and in normal skin. The differences in the numbers of IL-13-expressing cells between lesional and nonlesional skin were statistically significant. Double immunostaining revealed that IL-13 was produced in approximately 40% of T cells and 20% of mast cells in AD lesional skin, suggesting that T cells and mast cells are major sources of IL-13 in AD lesions. CONCLUSION: IL-13 may play a local as well as a systemic role in the development of AD lesions.     

Matrix metalloproteinases and their inhibitors in the foreign body reaction on biomaterials

Matrix metalloproteinases (MMPs) can degrade structural components within the extracellular matrix and at the cellular surface producing changes in cellular behavior (i.e., adhesion and migration) and subsequent pathological responses (i.e., the foreign body reaction and wound healing). We continue to study the foreign body reaction that occurs following biomaterial implantation by investigating secretory responses of biomaterial-adherent macrophages and foreign body giant cells (FBGCs) as directed by material surface chemistry and further this research by determining whether secreted MMPs play a role in macrophage adhesion and fusion. We have identified numerous MMPs and their tissue inhibitors (TIMPs) in in vitro cell-culture supernatants using antibody arrays and quantified select MMP/TIMPs with ELISAs. MMP-9 concentrations were significantly greater than both TIMP-1 and TIMP-2 on all materials. The ratios of MMP-9/TIMP-1 and MMP-9/TIMP-2 increased with time because of an increase in MMP-9 concentrations over time, while the TIMP concentrations remained constant. Total MMP-9 concentrations in the supernatants were comparable on all materials at each timepoint, while TIMP-1 and TIMP-2 concentrations tended to be greater on hydrophilic/anionic surfaces. Analysis of the MMP/TIMP quantities produced per cell revealed that the hydrophilic/neutral surfaces, which inhibited macrophage adhesion, activated the adherent macrophages/FBGCs to produce a greater quantity of MMP-9, TIMP-1, and TIMP-2 per cell. Pharmacological inhibition of MMP-1,-8,-13, and -18 reduced macrophage fusion without affecting adhesion, while inhibitors of MMP-2,-3,-9, and -12 did not affect adhesion or fusion. These findings demonstrate that material surface chemistry does modulate macrophage/FBGC-derived MMP/TIMP secretion and implicates MMP involvement in macrophage fusion.     

Endoscopic recurrence of esophageal varices is associated with the specific EUS abnormalities: severe periesophageal collateral veins and large perforating veins

BACKGROUND: Endoscopic ultrasonography (EUS) with a 20 MHz ultrasound (US) catheter probe can clearly demonstrate esophageal collateral veins. The presence of large periesophageal collateral veins has been correlated with large esophageal varices in patients with portal hypertension. The correlation between the size of esophageal collateral veins and endoscopic recurrence of esophageal varices in patients with portal hypertension who had undergone endoscopic injection sclerotherapy was investigated. Furthermore, whether EUS findings could predict the variceal recurrence was retrospectively studied. METHODS: Thirty-eight patients who had undergone endoscopic injection sclerotherapy were examined every 3 to 4 months with endoscopy and US catheter probe for a period of 2 years. Recurrence of esophageal varices was determined by endoscopic findings of either new varix formation or appearance of red color sign. Esophageal collateral veins were identified by US catheter probe as peri-esophageal collateral veins (adjacent to the esophageal wall) and para-esophageal collateral veins (separated from the esophageal wall) along with perforating veins; and they were graded as severe and mild type by US catheter probe. RESULT: Ten of the 38 patients (26.3%) had endoscopic recurrence at a mean of 10.9 months after endoscopic injection sclerotherapy. In patients with endoscopic recurrences, EUS findings included a significantly (p < 0.001) higher incidence of severe type peri-esophageal collateral veins, a significantly larger number of perforating veins (p < 0.001) and a significantly larger diameter of perforating veins (p < 0.001) compared with patients without recurrence (8 of 10, 80% vs. 2 of 28, 7.1%; 1.30 vs. 0.21; 2.00 vs. 0.32 mm, respectively). The presence of veins at the esophagogastric junction did not correlate with recurrence. CONCLUSION: Severe type peri-esophageal collateral veins and large perforating veins of the esophagus detected by EUS in patients treated by endoscopic injection sclerotherapy signify recurrence of esophageal varices and predict endoscopic recurrence of varices in subsequent months.     

An association study of asthma and related phenotypes with polymorphisms in negative regulator molecules of the TLR signaling pathway

Although associations between endotoxin exposure or respiratory infection and asthma have been recognized, the genetic effects in these conditions are unclear. Toll-like receptors (TLRs) play an essential role in innate host defense and in the control of adaptive immune responses. IL-1R-associated kinase-M (IRAK-M) and single immunoglobulin IL-1R-related molecule (SIGIRR) negatively regulate TLR-signaling pathways. To investigate whether polymorphisms in these genes were associated with asthma or asthma-related phenotypes, we screened these genes for polymorphisms by direct sequencing of 24 asthmatics and identified 19 variants in IRAK-M and 12 variants in SIGIRR. We next conducted linkage disequilibrium mapping of the genes, and examined the association of polymorphisms and haplotypes using 391 child patients with asthma, 462 adult patients with asthma, and 639 controls. None of the alleles or haplotypes of IRAK-M and SIGIRR were associated with asthma susceptibility or asthma-related phenotype. Our results indicate that polymorphisms in IRAK-M and SIGIRR are not likely to be associated with the development of asthma in the Japanese population.Electronic Supplementary Material Supplementary material is available for this article at and is accessible for authorized users.     

Chitosan hydrogel as a drug delivery carrier to control angiogenesis

An aqueous solution of photocrosslinkable chitosan containing azide groups and lactose moieties (Az-CH-LA) incorporating paclitaxel formed an insoluble hydrogel within 30 s of ultraviolet light (UV) irradiation. The chitosan hydrogel showed strong potential for use as a new tissue adhesive in surgical applications and wound dressing. The fibroblast growth factor (FGF)-2 molecules retained in the chitosan hydrogel and in an injectable chitosan/IO₄-heparin hydrogel remain biologically active, and were gradually released from the hydrogels as they biodegraded in vivo. The controlled release of biologically active FGF-2 molecules from the hydrogels caused induction of angiogenesis and collateral circulation occurred in healing-impaired diabetic (db/db) mice and in the ischemic limbs of rats. Paclitaxel, which is an antitumor reagent, was also retained in the chitosan hydrogel and remained biologically active as it was released on degradation of the hydrogel in vivo. The chitosan hydrogels incorporating paclitaxel effectively inhibited tumor growth and angiogenesis in mice. The purpose of this review is to describe the effectiveness of chitosan hydrogel as a local drug delivery carrier for agents (e.g., FGF-2 and paclitaxel) to control angiogenesis. It is thus proposed that chitosan hydrogel may be a promising new local carrier for drugs such as FGF-2 and paclitaxel to control vascularization.     

Sporadic acute hepatitis E occurred constantly during the last decade in northeast Japan

Background  Recent studies have shown that indigenous hepatitis E virus (HEV) strains cause hepatitis E in industrialized countries. We aimed to clarify the characteristics of HEV infection in sporadic hepatitis patients during the last decade in Miyagi, northeast Japan. Methods  We analyzed 94 serum samples obtained from acute or fulminant hepatitis patients of non-A, non-B, and non-C etiology between 1999 and 2008. Antibody to HEV (anti-HEV) was assayed, and patients who were positive for IgM- and/or IgA-class anti-HEV were diagnosed with hepatitis E. HEV RNA was tested in these patients, and phylogenetic analysis was performed. The occurrence of hepatitis E was compared with that of hepatitis A. Results  Eight acute hepatitis patients (8.5%) were diagnosed with hepatitis E, and HEV RNA was detectable in seven patients. Five isolates of HEV were segregated into genotype 3 and the remaining two isolates into genotype 4. The year of the occurrence of hepatitis E was distributed almost equally from 1999 to 2008, whereas the cases of acute hepatitis A (n = 16) have decreased markedly in the last several years. In 2004–2008, the occurrence of hepatitis E was greater than that of hepatitis A (five cases vs. one case). As for seasonality, hepatitis E occurred more frequently from September to December than hepatitis A (five cases vs. four cases), although less frequently from January to April (one case vs. seven cases). Conclusion  The occurrence of hepatitis E has not decreased during the last decade in northeast Japan, in contrast to hepatitis A. The nucleotide sequence data reported in this study have been assigned GenBank/EMBL/DDBJ accession numbers AB206467 and AB453332–AB453337.     

Natural resistance of 129/SvJ mice to Strongyloides venezuelensis infection

The susceptibility of 129/SvJ mice to infection with Strongyloides venezuelensis was compared with that of C57BL/6 mice. After a primary infection, daily egg output in faeces (EPG) from 129/SvJ mice was lower and terminated earlier than that from C57BL/6 mice. Adult worm recovery from the small intestine of 129/SvJ mice on day 7 was also lower than that of C57BL/6 mice. When the numbers of larvae recovered from the lungs were examined on days 2, 3 and 4 after a primary infection, they were comparable between the two strains. On the other hand, when an equal number of larvae recovered from the lungs of each strain on day 3 were implanted orally into homologous strain mice, the magnitude of EPG and the number of adult worms in the small intestine on day 5 after implantation were significantly lower in 129/SvJ than in C57BL/6 mice. The number of mucosal mast cells in the jejunum was not significantly different between 129/SvJ and C57BL/6 naive mice. Total chondroitin sulphate concentration in the gut washings obtained from naive mice was significantly higher in 129/SvJ (11.34 +/- 9.48) than in C57BL/6 mice (1.09 +/- 0.77, P < 0.05). These results indicate that the natural resistance of 129SvJ mice to S. venezuelensis infection is expressed at the intestine, probably due to higher concentration of chondroitin sulphate, which prevents establishment of S. venezuelensis.     

Regulatory mechanisms of circulating fibroblast growth factor 23 in parathyroid diseases

Fibroblast growth factor-23 (FGF-23) is a circulating factor regulating phosphate and vitamin D homeostasis. Phosphate intake and an administration of 1,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)) increase circulating FGF-23 levels, and elevated FGF-23 prevents hyperphosphatemia and vitamin D toxicity by hyperphosphaturia and suppression of circulating 1,25(OH)(2)D level, comprising a feedback loop to maintain phosphate and vitamin D homeostasis. Excess secretion of parathyroid hormone (PTH), another phosphaturic factor, elevates the serum calcium level in primary hyperparathyroidism. PTH also elevates circulating FGF-23 level, which cooperatively enhances the phosphaturia, resulting in hypophosphatemia. The circulating FGF-23 level increases as renal function declines in chronic kidney disease (CKD), and it exhibits significant and positive correlations with serum phosphate, calcium, and PTH in CKD patients on maintenance hemodialysis, suggesting that these parameters regulate circulating FGF-23 level. Tight associations between circulating FGF-23 and calcium levels were observed both in patients with primary hyperparathyroidism and in CKD patients on maintenance hemodialysis, suggesting the role of serum calcium on FGF-23 regulatory mechanisms. FGF-23 may have a physiological role in preventing tissue damage such as ectopic calcifications, partly via suppressing the serum calcium x phosphate product by accelerating urinary phosphate excretion and suppressing vitamin D activation.     

Transmission via the face is one route of methicillin-resistant Staphylococcus aureus cross-infection within a hospital

BACKGROUND: It is generally accepted that hospital personnel must not touch their faces, and indeed must not elevate their hands above the shoulder in the ward, because many bacteria including Staphylococcus aureus colonize the face. However, possible methicillin-resistant Staphylococcus aureus (MRSA) cross-infection by way of faces has not yet been properly examined. METHODS: One hundred and seventy-eight isolates from 159 inpatients from February 1999 to January 2000 were subjected to chromosomal DNA analysis by pulsed-field gel electrophoresis (PFGE). RESULTS: The 178 MRSA isolates were classified into 43 PFGE types. Cross-infection was more frequent in the Department of Neurology [average number of patients per PFGE pattern (n/PFGE) = 4.0] than in the other six nonsurgical departments (n/PFGE = 1.0-1.6), and more frequent in four surgical departments (n/PFGE = 2.0-4.5) than in the other eight (n/PFGE = 1.0-1.7). In neurology, patients' faces were more often touched for examination of the cranial nerves than in the other departments. In the above four surgical departments, organs in the face were chiefly operated upon, and the patients' faces were also touched for care before and after the operation. CONCLUSIONS: Our study reveals the possibility of MRSA being transmitted by way of patients' faces in a hospital.