Elevated Levels of Matrix Metalloproteinase 9 and Tissue Inhibitor of Metalloproteinase 1 during the Acute Phase of Kawasaki Disease

Kawasaki disease (KD) is an acute, self-limiting, multisystem vasculitis of unknown etiology affecting infants and young children. Unless treated promptly with high-dose intravenous gamma globulin and aspirin, patients frequently develop coronary aneurysms. Previously, matrix metalloproteinase 9 (MMP-9), which is secreted complexed to tissue inhibitor of metalloproteinase 1 (TIMP-1), has been implicated in abdominal aortic aneurysm formation. Since the clinical and pathological features of KD include inflammation and weakening of blood vessels, we analyzed acute- and convalescent-phase paired plasma or serum samples from 31 KD patients, 7 patients who did not completely meet the criteria for KD, and 26 non-KD controls (9 febrile and 17 afebrile patients) for pro-MMP-9 (92 kDa) enzyme activity by gelatin zymography and for active MMP-9 (83 kDa), pro-MMP-9, and TIMP-1 protein levels by enzyme-linked immunosorbent assay. Statistical analysis was performed by using Student t tests, linear regression, and the Wilcoxon rank-sum test. Markedly elevated pro-MMP-9 enzymatic activity, pro-MMP-9 protein levels, and TIMP-1 protein levels were found during the acute phase of illness in patients with clinically established KD and in patients who were suspected of having KD but did not meet all of the criteria. There was no significant difference in active MMP-9 levels. Furthermore, pro-MMP-9 and TIMP-1 protein levels were significantly elevated among KD patients, compared to those of febrile and afebrile non-KD controls. The significantly elevated pro-MMP-9 enzyme and protein levels during the acute phase of KD may reflect vascular remodeling or an inflammatory response to a microbial agent, suggesting a pathophysiological role for MMP-9 in coronary aneurysm formation.     

Sputum microbiome profiles identify severe asthma phenotypes of relative stability at 12 to 18 months

1. Download : Download high-res image (203KB)
2. Download : Download full-size image

     

Identification and distribution ofEchinostoma lindoense,E. audyi andE. revolutum (Trematoda; Echinostomatidae)

The closely relatedEchinostoma lindoense, E. audyi andE. revolutum can be differentiated by morphological characteristics of their adults and cercariae. We have foundE. lindoense andE. audyi in Southeast and Southwest Asia and Central Europe and the former species also in South America. However, using the morphological characteristics described by Beaver (1937) forE. revolutum which is assumed to be cosmopolitan, we did not find this species in these regions.     

Nitrosative stress in the bronchial mucosa of severe chronic obstructive pulmonary disease

BACKGROUND: Reactive nitrogen species, formed via the reaction of nitric oxide (NO) with superoxide anion and via (myelo)peroxidase-dependent oxidation of NO(2)(-), have potent proinflammatory and oxidizing actions. Reactive nitrogen species formation and nitrosative stress are potentially involved in chronic obstructive pulmonary disease (COPD) pathogenesis. OBJECTIVES: To investigate the expression of markers of nitrosative stress, including nitrotyrosine (NT), inducible NO synthase (iNOS), endothelial NO synthase (eNOS), myeloperoxidase (MPO), and xanthine oxidase (XO) in bronchial biopsies and bronchoalveolar lavage from patients with mild to severe stable COPD compared with control groups (smokers with normal lung function and nonsmokers). METHODS: The expression of NT, iNOS, eNOS, MPO and XO in the bronchial mucosa and bronchoalveolar lavage of patients was measured by using immunohistochemistry, Western blotting, and ELISA and correlated with the inflammatory cell profile. RESULTS: Patients with severe COPD in stable phase had higher numbers of NT(+) and MPO(+) cells in their bronchial submucosa compared with mild/moderate COPD, smokers with normal lung function, and nonsmokers (P < .01). iNOS(+) and eNOS(+) but not XO(+) cells were significantly increased in smokers with COPD or normal lung function compared with nonsmokers (P < .05 and P < .01, respectively). In patients with COPD, the number of MPO(+) cells was significantly correlated with the number of neutrophils (r = +0.61; P < .0025) in the bronchial submucosa. Furthermore, the number of NT(+) and MPO(+) cells was negatively correlated with postbronchodilator FEV(1). CONCLUSION: These data suggest that nitrosative stress, mainly mediated by MPO and neutrophilic inflammation, may contribute to the pathogenesis of severe COPD.     

In Vitro and In Vivo Characterization of MEMS Microneedles

Transdermal drug delivery TDD systems have many advantages but are conventionally limited by the low permeability of skin. The idea of using microneedles to painlessly penetrate the topmost impermeable stratum corneum has previously been put forward. In this paper, the fabrication of solid and hollow silicon microneedles with straight side-walls and with the following dimensions: 20–100 m in diameter and 100–150 m in length is described. In vitro tests demonstrate that with prior solid microneedle application, transdermal drug transport is significantly increased by 10–20 times, with the degree of enhancement being related to needle diameter. In vivo tests in diabetic animals, however, were unable to demonstrate any delivery of insulin through the hollow microneedles. It is proposed that two factors, microneedle length and tip sharpness, have to be improved for systemic drug delivery to be seen in vivo.     

Loss of Fhit expression in head and neck squamous cell carcinoma and its potential clinical implication.

PURPOSE: Abnormalities of FHIT, a candidate tumor suppressor gene, have frequently been found in multiple malignancies, including head and neck squamous cell carcinoma (HNSCC). To define its role in HNSCC treated with surgery and postoperative radiotherapy (PORT), the Fhit protein expression status was investigated in 80 patients enrolled in a prospective Phase III clinical trial addressing the dose and fractionation regimen of PORT. EXPERIMENTAL DESIGN: Immunohistochemical staining of HNSCC tissue sections for Fhit expression was performed. The Fhit expression status was correlated with the clinicopathological characteristics and clinical course. The median follow-up duration was 4.9 years. RESULTS: Loss of Fhit expression was found in 52 of the 80 study patients (65%). There was not a significant association between Fhit expression and clinical characteristics. Patients whose tumor exhibited negative Fhit expression had a significantly worse 5-year overall survival duration [hazard ratio = 0.49; 95% confidence interval, 0.23-1.03; P = 0.05 (log-rank test)] than did those whose tumor exhibited positive Fhit expression. One third of the patients with a Fhit-negative tumor had distant metastasis during the follow-up period. Paradoxically, patients classified as high risk who had a Fhit-negative tumor experienced locoregional recurrence less often (18%) than did high-risk patients who had a Fhit-positive tumor (33%). CONCLUSIONS: Loss of Fhit expression is a poor prognostic indicator in patients with HNSCC. However, tumors lacking Fhit expression may be more sensitive to PORT and therefore more susceptible to locoregional control.     

CT-based delineation of lymph node levels and related CTVs in the node-negative neck: DAHANCA, EORTC, GORTEC, NCIC,RTOG consensus guidelines.

BACKGROUND AND PURPOSE: The appropriate application of 3-D CRT and IMRT for HNSCC requires a standardization of the procedures for the delineation of the target volumes. Over the past few years, two proposals--the so-called Brussels guidelines from Grégoire et al., and the so-called Rotterdam guidelines from Nowak et al.--emerged from the literature for the delineation of the neck node levels. Detailed examination of these proposals however revealed some important discrepancies. MATERIALS AND METHODS: Within this framework, the Brussels and Rotterdam groups decided to review their guidelines and derive a common set of recommendations for delineation of neck node levels. This proposal was then discussed with representatives of major cooperative groups in Europe (DAHANCA, EORTC, GORTEC) and in North America (NCIC, RTOG), which, after some additional refinements, have endorsed them. The objective of the present article is to present the consensus guidelines for the delineation of the node levels in the node-negative neck. RESULTS AND CONCLUSIONS: First a short discussion of the discrepancies between the previous Brussels and the Rotterdam guidelines is presented. The general philosophy of the consensus guidelines and the methodology used to resolve the various discrepancies are then described. The consensus proposal is then presented and representative CTVs that are consistent with these guidelines are illustrated on CT sections. Last, the limitations of the consensus guidelines are discussed and some concerns about the direct applications of these guidelines to the node-positive neck and the post-operative neck are described.     

Concomitant boost radiation plus concurrent cisplatin for advanced head and neck carcinomas: radiation therapy oncology group phase II trial 99-14.

PURPOSE: To investigate the feasibility of combining concomitant boost accelerated radiation regimen (AFX-C) with cisplatin and to assess its toxicity and the relapse pattern and survival in patients with advanced head and neck carcinoma (HNC). PATIENTS AND METHODS: Between April and November of 2000, 84 patients with stage III to IV HNC who met the eligibility criteria were enrolled; 76 of these patients were analyzable. Radiation consisted of 72 Gy in 42 fractions over 6 weeks (daily for 3.5 weeks, then twice a day for 2.5 weeks). Cisplatin dose was 100 mg/m(2) on days 1 and 22. Tumor and clinical status were assessed, and acute late toxicities were graded. RESULTS: Sixty-five patients (86%) received both radiation and chemotherapy per protocol or with minor variations. The estimated 2-year locoregional relapse and distant metastasis rates were 34.7% and 16.1%, respectively. The estimated 2-year overall survival and disease-free survival rates were 71.6% and 53.5%, respectively. Three patients (4%) died of complications, 19 patients (25%) had acute grade 4 toxicity, and 49 patients (64%) had acute grade 3 toxicity. The 2-year cumulative incidence of late grade 3 to 5 toxicities was 51.3%. CONCLUSION: These data showed that it was feasible to combine AFX-C with cisplatin. The compliance to therapy was high, and the locoregional control and survival rates achieved compared favorably with AFX-C alone or other concurrent chemoradiation regimens tested by the Radiation Therapy Oncology Group. A phase III trial comparing AFX-C plus cisplatin against standard radiation plus cisplatin is ongoing to determine whether the use of AFX-C in the concurrent chemoradiation setting further improves outcome.     

RAGE: a new frontier in chronic airways disease

Asthma and chronic obstructive pulmonary disease (COPD) are heterogeneous inflammatory disorders of the respiratory tract characterized by airflow obstruction. It is now clear that the environmental factors that drive airway pathology in asthma and COPD, including allergens, viruses, ozone and cigarette smoke, activate innate immune receptors known as pattern-recognition receptors, either directly or indirectly by causing the release of endogenous ligands. Thus, there is now intense research activity focused around understanding the mechanisms by which pattern-recognition receptors sustain the airway inflammatory response, and how these mechanisms might be targeted therapeutically. One pattern-recognition receptor that has recently come to attention in chronic airways disease is the receptor for advanced glycation end products (RAGE). RAGE is a member of the immunoglobulin superfamily of cell surface receptors that recognizes pathogen- and host-derived endogenous ligands to initiate the immune response to tissue injury, infection and inflammation. Although the role of RAGE in lung physiology and pathophysiology is not well understood, recent genome-wide association studies have linked RAGE gene polymorphisms with airflow obstruction. In addition, accumulating data from animal and clinical investigations reveal increased expression of RAGE and its ligands, together with reduced expression of soluble RAGE, an endogenous inhibitor of RAGE signalling, in chronic airways disease. In this review, we discuss recent studies of the ligand–RAGE axis in asthma and COPD, highlight important areas for future research and discuss how this axis might potentially be harnessed for therapeutic benefit in these conditions.