Toll-like receptors (TLR) expressed on inflammatory cells play a key role in host defense against pathogens, benefiting the host. TLR are also expressed on tumor cells. To evaluate the role of TLR in tumor cells, we investigated TLR4 signaling effects on human head and neck squamous cell carcinoma (HNSCC). Tumor tissues were obtained from 27 patients with laryngeal and 12 with oral cavity cancers. Normal mucosa was obtained from 10 patients with nonneoplastic disorders. Smears for bacteria were taken from all patients during surgery. TLR4 expression in tumors and HNSCC cell lines (PCI-1, PCI-13, and PCI-30) was detected by reverse transcription-PCR and immunohistochemistry. Cell growth, apoptosis, nuclear factor-κB (NF-κB) translocation, and MyD88 and IRAK-4 expression, as well as Akt phosphorylation were measured following tumor cell exposure to the TLR4 ligand lipopolysaccharide (LPS). Tumor cell sensitivity to NK-92–mediated lysis was evaluated in 4-hour 51Cr-release assays. Cytokine levels in HNSCC supernatants were measured in Luminex-based assays. TLR4 was expressed in all tumors, HNSCC cell lines, and normal mucosa. The TLR4 expression intensity correlated with tumor grade. LPS binding to TLR4 on tumor cells enhanced proliferation, activated phosphatidylinositol 3-kinase/Akt pathway, up-regulated IRAK-4 expression, induced nuclear NF-κB translocation, and increased production (P < 0.05) of interleukin (IL)-6, IL-8, vascular endothelial growth factor, and granulocyte macrophage colony-stimulating factor. TLR4 triggering protected tumor cells from lysis mediated by NK-92 cells. TLR4 ligation on tumor cells supports HNSCC progression.
Multiple genes and their variants that lend susceptibility to many diseases will play a major role in clinical routine. Genetics-based cost reduction strategies in diagnostic processes are important in the setting of multiple susceptibility genes for a single disease. Head and neck paraganglioma (HNP) is caused by germline mutations of at least three succinate dehydrogenase subunit genes (SDHx). Mutation analysis for all 3 costs fUS$2,700 per patient. Genetic classification is essential for downstream management of the patient and preemptive management of family members. Utilizing HNP as a model, we wanted to determine predictors to prioritize the most heritable clinical presentations and which gene to begin testing in HNP presentations, to reduce costs of genetic screening. Patients were tested for SDHB, SDHC, and SDHD intragenic mutations and large deletions. Clinical parameters were analyzed as potential predictors for
The incidence of sensorineural hearing loss ranges from 1 to 3 per 1,000 live births in term healthy neonates, and 2-4 per 100 in high-risk infants, a 10-fold increase. Early identification and intervention with hearing augmentation within 6 mo yields optimal effect. If undetected and without treatment, significant hearing impairment may negatively impact speech development and lead to disorders in psychological and mental behaviors. Hearing screening programs in newborns enable detection of hearing impairment in the first days after birth. Programs to identify hearing deficit have significantly improved over the two decades, and their implementation continues to grow throughout the world. Initially based on risk factors, these programs identified only 50-75% of infants with hearing loss. Current recommendations are to conduct universal hearing screening in all infants. Techniques used primarily include automated auditory brainstem responses and otoacoustic emissions that provide noninvasive recordings of physiologic auditory activity and are easily performed in neonates and infants. The aim of this review is to present the objectives, benefits, and results of newborn hearing screening programs including the pros and cons of universal vs. selective screening. A brief history and the anticipated future development of these programs will also be discussed.
Background: Juvenile nasopharyngeal angiofibroma (JNA) is a rare, highly vascularized neoplasm of the nasopharynx that affects boys and young men. The underlying dysregulated molecular mechanisms remain unclear. The participation of angiogenic growth factors has been suggested, but few studies have been published. Objectives: To evaluate the expression and localization of vascular endothelial growth factor (VEGF), proliferating cells, and vessel density in JNA. Study Design: Immunohistochemical examination of 10 consecutive JNAs (8 primary tumors and 2 recurrent tumors). Methods: Paraffin-embedded and cryopreserved JNA samples were included. VEGF-, CD31-, and Ki67specific antibodies were applied and visualized using light microscopy. Vascularization was determined by counting CD31-positive vessels. Proliferating and VEGFexpressing vessels as well as stromal cells were quantified by the same method. Patients' age at the time of surgery and tumor stage were correlated with the immunohistochemical data. Results: All tumors were heavily vascularized, but major differences were noted between the samples. About half of the vessels were proliferating (Ki67 positive) and half of the Ki67-positive cells were also VEGF positive. The tumor stroma was VEGF positive in 8 of 10 samples and proliferating in 5 of these 8. The 5 samples with both VEGF-and Ki67-positive stroma showed high vessel densities. No correlation was observed between age or tumor stage and vessel density, VEGF expression, or Ki67 expression. Conclusions: In JNA, VEGF is frequently expressed by stromal cells and vessels and is associated with proliferation and increased vessel density. We suggest the promotion of vascularization by VEGF, but the involvement of androgens in JNA angiogenesis still needs to be analyzed.
Chronic rhinosinusitis (CRS) is a very common disorder that remains poorly understood from a pathogenic standpoint. Recent research on the pathogenesis of CRS has been focused on the potential role of biofilms in this chronic infection. The aim of this study was to assess the sinuses’ microflora and biofilm formation on the sino-nasal mucosa in patients with CRS. Paranasal sinus mucosa specimens were harvested at the time of functional endoscopic sinus surgery (FESS). Classical microbiology techniques for the isolation and identification of sinus mucosa microbial flora were used. Scanning electron microscopy (SEM) was used to detect biofilm on the surface of mucosa. A microtiter plate assay for in vitro biofilm formation was employed, divided into three aliquots. One part was assessed for bacterial presence, utilizing an API manual system and the Vitek® 2 Compact system. The two remaining aliquots were tested by in vitro conventional microbiological assay with the use of the Infinite M200 (Tecan) microtiter plate reader, and also by scanning electron microscopy (SEM). A microbiological examination of mucosal specimens had taken during FESS operation revealed the presence of various types of bacteria in 29 out of 30 tested samples. Out of 62 different strains isolated from patients with CRS, 23 strains of coagulase-negative Staphylococcus epidermidis and 6 strains of Escherichia coli were the most frequently isolated microorganisms, accounting for 37.1 and 9.7 %, respectively. Among the 62 isolated strains, 58 were used to assess biofilm formation. From the total of 58 isolates, 8.6 % were strong biofilm producers, 20.7 % were moderate, and 70.7 % of isolates were considered to be non- or weak biofilm producers. SEM of the 30 nasal concha mucosal samples taken from patients with CRS revealed biofilm in 23 specimens. A marked destruction of the epithelium was observed, with variation in degrees of severity, from disarrayed cilia to complete absence of cilia. The vast majority of nasal concha mucosal samples of patients affected by chronic sinusitis presented with biofilm formation. Our study showed that 76.7 % of patients having FESS for CRS had evidence of biofilms on SEM micrographs. Although certain detection methods could lead to various discrepancies in the amount of biofilm produced, the consistent demonstration of biofilms in patients with CRS suggests that this convoluted three-dimensional structures might play a significant role in either the pathogenesis or persistence of chronic rhinosinusitis.
Angiogenic factors are discussed to participate in growth and promotion of juvenile nasopharyngeal angiofibroma (JNA). However, only few data are available and mechanisms remain unclear. In the presented study we analysed the expression and subcellular distribution of several angiogenic growth factors and receptors potentially involved in JNA-growth and -vascularisation. In a retrospective, descriptive, multicenter-study, we analysed 13 formalin-fixed, paraffin-embedded or cryopreserved JNA-tumors (eleven primary tumors and two recurrent ones) after immunohistochemical staining. We used monoclonal antibodies specific for transforming growth factor beta 1 (TGF-beta(1)), basic fibroblast growth factor (bFGF), the VEGF-receptors 1 and -2 (FLT-1 and FLK-1), and the hypoxia inducible factor (Hif-1alpha). Data were compared to the vessel density. Quantitative analysis of staining intensities was performed by a computer assisted quantification technique. Endothelial and stromal compartments of the samples were analysed separately. Data were compared to vessel densities and patients data. The VEGF-Receptor-2 (FLK) was frequently unregulated in the stroma and endothelium of those samples with high vessel densities. Similarly, we observed high bFGF- and TGF-beta(1) levels in the stroma of strong vascularised samples. No correlations of expression levels to patients' data were found. The reported data support the concept of JNA-growth and -vascularisation driven by factors released from stromal fibroblasts. Therefore, inhibition of these factors might be beneficial for the therapy of inoperable JNA.
The aim of this study was to determine the effect of tinnitus (experiment I) and the combined effect of tinnitus and sensorineural hearing loss (experiment II) on the distortion product otoacoustic emission (DPOAE) for two age groups of tinnitus patients. Tinnitus patients with normal earing, along with normal-hearing control subjects, participated in experiment I. They were divided into two age groups, below 50 and above 50 years. Experiment I showed that the DPOAE levels in the tinnitus patients were lower than those in the normal-hearing (nontinnitus) subjects. The differences depended on the frequency and the age of the patients, suggesting the confounding influence of presbyacusis. The second group of tinnitus patients with increasing and notch-like hearing loss participated in experiment II. They were also divided into two age groups, below 50 and above 50 years. The data from experiment II showed that DPOAE activity well reflects the increasing and notch-like hearing loss functions up to about 40 dB HL. The effect of age on the DPOAE level was clearly noted only for the tinnitus patients with clinically normal-hearing thresholds and was ambiguous for the tinnitus patients with hearing loss.
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