Herbert Riechelmann

A Controlled Challenge Study on Di(2-ethylhexyl) Phthalate (DEHP) in House Dust and the Immune Response in Human Nasal Mucosa of Allergic Subjects

Background Few studies have yet addressed the effects of di(2-ethylhexyl) phthalate (DEHP) in house dust on human nasal mucosa. Objectives We investigated the effects of house dust containing DEHP on nasal mucosa of healthy and house dust mite (HDM)–allergic subjects in a short-term exposure setting. Methods We challenged 16 healthy and 16 HDM-allergic subjects for 3 hr with house dust at a concentration of 300 μg/m3 containing either low (0.41 mg/g) or high (2.09 mg/g) levels of DEHP. Exposure to filtered air served as control. After exposure, we measured proteins and performed a DNA microarray analysis. Results Nasal exposure to house dust with low or high DEHP had no effect on symptom scores. Healthy subjects had almost no response to inhaled dust, but HDM-allergic subjects showed varied responses: DEHPlow house dust increased eosinophil cationic protein, granulocyte-colony–stimulating factor (G-CSF), interleukin (IL)-5, and IL-6, whereas DEHPhigh house dust decreased G-CSF and IL-6. Furthermore, in healthy subjects, DEHP concentration resulted in 10 differentially expressed genes, whereas 16 genes were differentially expressed in HDM-allergic subjects, among them anti-Müllerian hormone, which was significantly up-regulated after exposure to DEHPhigh house dust compared with exposure to DEHPlow house dust, and fibroblast growth factor 9, IL-6, and transforming growth factor-β1, which were down-regulated. Conclusions Short-term exposure to house dust with high concentrations of DEHP has attenuating effects on human nasal immune response in HDM-allergic subjects, concerning both gene expression and cytokines.

An update on the diagnosis and treatment of sinusitis and nasal polyposis

IntroductionTerminologySinusitis (more properly known as rhinosinusitis due tothe regular involvement of the nasal cavity) is a conditionwith a high and clearly increasing prevalence. According1to figures from IMS Health,acute sinusitis was diagnosed6.3 million times and chronic sinusitis 2.6 million times ina country like Germany over the course of one year (July2000–June 2001),resulting in 8.5 million and 3.4 millionprescriptions,respectively. The number of diagnoses of‘‘nasal polyposis’’ was approximately 221 000 (accordingto IMS Health 2001). Even though no reliable epidemi-ological studies of the incidence of sinusitis exist,thesefigures do indicate that sinusitis represents a considerablesocioeconomic problem. Alongside allergic and viralconditions of the upper airways,sinusitis thereforeconstitutes one of the most common respiratory tractconditions in humans.Similar data are reported from the USA: in 1997,sinusitis was prevalent in approximately 15% of thepopulation. In the last decade,the frequency of diagnosisin the USA rose by around 18%. The economicsignificance of sinusitis is huge: for 1992,the total cost,including costs resulting from loss of work,was estima-ted at over 6 billion dollars for the USA. In the periodfrom 1985 to 1992,the number of antibiotic prescrip-tions for sinusitis rose from 7.2 million to 13 million(1,2).Sinusitis is an inflammatory process involving themucous membranes of one or more sinuses. Generallyspeaking,the mucous lining of the nose is also involved.Even in the presence of a viral cold,a CT scan will revealthe involvement of the paranasal sinuses in 87% of cases,which is why we speak of rhinosinusitis (3). Bacterialrhinosinusitis (acute sinusitis) is generally preceded by avirus-induced inflammation of the sinuses; approximately5–10% of childhood upper airway infections develop intoacute sinusitis (4). The swelling and ‘‘immunologicalweakness’’ of the mucous membrane and the blockageof the ostia by the viral infection are today believed tocause bacterial infection of the intrinsically sterile para-nasal sinuses by local microorganisms. This gives rise toacute sinusitis,with severe inflammatory infiltration ofC.Bachert

Distinct features of chronic rhinosinusitis with and without nasal polyps.

Background:  Based on the presence of nasal polyps on endoscopy, chronic rhinosinusitis (CRS) may be clinically divided in CRS with nasal polyps and CRS without nasal polyps. It is unclear, whether CRS with nasal polyps and CRS without nasal polyps represent different disease entities or just different stages of one single disease. In case of one disease, only minor histopathological differences between CRS with small early‐stage polyps (CRSNP(+)) and CRS without nasal polyps (CRSNP−) were expected.

Temperature profile in the nasal cavity.

Objectives/Hypothesis Inspired air is heated and moistened as it passes the nasal cavity. The temperature increase should be similar to a heated tube model, depending on the airflow.

Long-term treatment with aspirin desensitization: a prospective clinical trial comparing 100 and 300 mg aspirin daily

Background:  The daily dose of aspirin in desensitization in aspirin‐sensitive asthmatics with nasal polyps is still a matter of debate.

Phase I trial with the CD44v6-targeting immunoconjugate bivatuzumab mertansine in head and neck squamous cell carcinoma

CD44v6 is a tumor associated antigen abundantly expressed in head and neck squamous cell carcinomas (HNSCC) and in normal squamous epithelium. The immunoconjugate bivatuzumab mertansine (BIWI 1) consists of a highly potent antimicrotubule agent coupled to a monoclonal antibody against CD44v6. The maximum tolerated dose (MTD), safety and efficacy of BIWI 1 administered IV in patients with HNSCC has not been determined. In a clinical phase I trial, adult patients with recurrent or metastatic HNSCC were treated intravenously with BIWI 1. Starting with 25mg/m(2), the dose was escalated in steps of 25mg/m(2) until dose limiting toxicity was observed. Six women and 25 men were included. The MTD was 300 mg/m(2). Twelve patients were treated with at least the MTD. The principal toxic effects were maculopapular rashes, focal blister formation and skin exfoliation. Three patients had partial responses at doses of 200, 275 and 325 mg/m(2). The concept that bivatuzumab can direct mertansine activity to CD44v6 expressing tumors was confirmed. Although CD44v6 was abundantly expressed in all tumors, the response to BIWI 1 was variable. Binding to CD44v6 on skin keratinocytes mediated serious skin toxicity with a fatal outcome in a parallel trial, which led to the termination of the development program of bivatuzumab mertansine and the present study.

International Consensus Statement on Allergy and Rhinology: Rhinosinusitis

Isam Alobid, MD, PhD1, Nithin D. Adappa, MD2, Henry P. Barham, MD3, Thiago Bezerra, MD4, Nadieska Caballero, MD5, Eugene G. Chang, MD6, Gaurav Chawdhary, MD7, Philip Chen, MD8, John P. Dahl, MD, PhD9, Anthony Del Signore, MD10, Carrie Flanagan, MD11, Daniel N. Frank, PhD12, Kai Fruth, MD, PhD13, Anne Getz, MD14, Samuel Greig, MD15, Elisa A. Illing, MD16, David W. Jang, MD17, Yong Gi Jung, MD18, Sammy Khalili, MD, MSc19, Cristobal Langdon, MD20, Kent Lam, MD21, Stella Lee, MD22, Seth Lieberman, MD23, Patricia Loftus, MD24, Luis Macias‐Valle, MD25, R. Peter Manes, MD26, Jill Mazza, MD27, Leandra Mfuna, MD28, David Morrissey, MD29, Sue Jean Mun, MD30, Jonathan B. Overdevest, MD, PhD31, Jayant M. Pinto, MD32, Jain Ravi, MD33, Douglas Reh, MD34, Peta L. Sacks, MD35, Michael H. Saste, MD36, John Schneider, MD, MA37, Ahmad R. Sedaghat, MD, PhD38, Zachary M. Soler, MD39, Neville Teo, MD40, Kota Wada, MD41, Kevin Welch, MD42, Troy D. Woodard, MD43, Alan Workman44, Yi Chen Zhao, MD45, David Zopf, MD46

The bacteriology of chronic rhinosinusitis with and without nasal polyps.

OBJECTIVE To compare the bacteriologic findings in ethmoidal biopsy specimens and nasal lavage samples from healthy control patients and from patients with chronic rhinosinusitis (CRS) with nasal polyps (CRSNP+) and without nasal polyps (CRSNP-). DESIGN Comparative microbiologic investigation. SETTING University hospital. PATIENTS The study included 31 CRSNP+ patients, 13 CRSNP- patients, and 21 control patients. INTERVENTION Aerobe and anaerobe bacterial culture of nasal lavage samples and biopsy specimens of anterior ethmoidal mucosa. MAIN OUTCOME MEASURE Analysis of biopsy specimens from 65 patients and nasal lavage samples from 63 patients. RESULTS Mixed cultures of aerobe and anaerobe bacteria were mainly detected in the biopsy specimens. The most common aerobe bacteria found in the biopsy specimens were coagulase-negative staphylococci, Corynebacterium species, Staphylococcus aureus, and alpha-hemolytic streptococci. Propionibacterium and Peptostreptococcus species were the most common anaerobes. Pathogenic bacteria such as S. aureus, Enterobacteriaceae, and Haemophilus influenzae were detected in biopsy specimens from 16 of 31 CRSNP+ patients (52%), 4 of 13 CRSNP- patients (31%), and 10 of 21 control patients (48%). There were no significant differences in the bacterial cultures of the biopsy specimens between the 3 patient groups (P >.30). The majority of bacteria detected in the biopsy specimens were also detected in the corresponding lavage samples; however, in 35% of patients, pathogenic bacteria were found only in nasal lavage samples and not in corresponding biopsy specimens. CONCLUSIONS There are no significant differences in the bacteriologic features of ethmoidal biopsy specimens between CRSNP+, CRSNP-, and control patients. Therefore, a bacteriologic pathogenesis of the polyps in CRSNP+ patients seems unlikely. The general use of antibiotics in patients with CRS appears questionable. Investigation of nasal lavage samples is not suitable for predicting the bacteriologic features of inflamed sinuses of patients with CRS.

Diagnostic Accuracy of Peak Nasal Inspiratory Flow and Rhinomanometry in Functional Rhinosurgery

Objectives: Sensitivity and specificity of active anterior rhinomanometry (RMM) and peak nasal inspiratory flow (PNIF) in the diagnosis of functionally relevant structural nasal deformities should be assessed. The reference standard was clinical judgment based on all clinical data available.

Tumor cell and carcinoma-associated fibroblast interaction regulates matrix metalloproteinases and their inhibitors in oral squamous cell carcinoma

Co-culture of periodontal ligament (PDL) fibroblasts and SCC-25 oral squamous carcinoma cells (OSCC), results in conversion of PDLs into carcinoma-associated fibroblasts (CAFs). Paracrin circuits between CAFs and OSCC cells were hypothesized to regulate the gene expression of matrix remodeling enzymes in their co-culture, which was performed for 7 days, followed by analysis of the mRNA/protein expression and activity of metalloproteinases (MMPs), their tissue inhibitors (TIMPs) and other relevant genes. Interleukin1-β, transforming growth factor-β1, fibronectin and αvβ6 integrin have shown to be involved in the regulation of the MMP and TIMP gene expression in co-culture of CAFs and tumor cells. In addition, these cells also cooperated in activation of MMP pro-enzymes. It is particularly interesting that the fibroblast-produced inactive MMP-2 has been activated by the tumor-cell-produced membrane-type 1 matrix metalloproteinase (MT1-MMP). The crosstalk between cancer- and the surrounding fibroblast stromal-cells is essential for the fine tuning of cancer cells invasivity.