Prevalence of oral HPV infection in cervical HPV positive women and their sexual partners.

PURPOSE: Human papillomavirus (HPV) infection represents the primary cause of anogenital premalignant and malignant disease. Regarding the high prevalence of cervical HPV infection and the increasing incidence of HPV associated oropharyngeal cancer in recent years, a significant viral transmission from the cervical to the oral site, possibly depending on the sexual behavior must be considered. The present study aims to determine the prevalence of oral HPV infection in cervical HPV positive and negative women and their sexual partners. METHODS: Cervical HPV positive and negative women and their sexual partners took part in the study. Cervical smears, oral smears and mouthwashes were taken from women attending gynecological outpatient clinics in two different institutions. Further, oral smears as well as mouthwashes of their sexual partners were obtained whenever possible. HPV genotyping was performed using the Cobas® polymerase chain reaction and nucleic acid hybridization assay for the detection of 14 high-risk HPV types. In addition, all participants were invited to complete a personal questionnaire. RESULTS: 144 HPV positive and 77 HPV negative women and altogether 157 sexual partners took part in the study. Age, sexual behaviour, medication, smoking and alcohol consumption were distributed equally in both groups. Cervical HPV positive women had a significantly higher number of sexual partners. One woman with a HPV positive cervical smear and one partner of a woman with a HPV positive cervical smear showed an oral HPV infection. No oral HPV infections were detected in the HPV negative control group. The overall incidence of oral HPV infection was 0.5%, the incidence of oral HPV infection in women with a positive cervical smear was 0.7%. CONCLUSION: The data demonstrate that the overall risk of an oral HPV infection is low. HPV transmission to the oropharynx by autoinoculation or oral-genital contact constitute a rare and unlikely event.

Clinical impact of malnutrition on complication rate and length of stay in elective ENT patients: a prospective cohort study.

Malnutrition is considered as an independent risk factor for morbidity, mortality and a prolonged hospital stay for in-hospital patients. While most available data on the impact of malnutrition on health-related and financial implications refer to gastroenterologic or abdominal surgery patients, little is known about the impact of malnutrition on Ear Nose Throat (ENT)/head and neck surgery patients. The objective of this study was to investigate the impact of malnutrition on morbidity and length of hospital stay in an elective ENT/head and neck surgery patient cohort. The study was performed as a single-center, prospective cohort study at a tertiary referral centre. Nutritional risk at admission was assessed using the NRS-2002 screening tool. Multivariate regression models were used to determine independent risk factors for complications and a prolonged hospitalization. Three hundred fifty one participants were included in the study. A malignant disease was found in 62 participants (17.7 %). 62 patients (17.7 %) were at a moderate to severe risk of malnutrition. A bad general health condition and complications during hospital stay could be identified as independent risk factors for a prolonged hospitalization. Patients with a malignant tumor showed a more than fourfold higher risk of developing at least one complication. Malnutrition, however, was not statistically associated with a higher complication rate or a prolonged hospital stay. Our data suggests that malnutrition does not seem to play such an important role as a risk factor for complications and a prolonged hospital stay in ENT patients as it does in other disciplines like abdominal surgery or gastroenterology.

Reduced cortical BACE1 content with one bout of exercise is accompanied by declines in AMPK, Akt, and MAPK signaling in obese, glucose-intolerant mice.

Obesity and type 2 diabetes are significant risk factors in the development of neurodegenerative diseases, such as Alzheimer's disease. A variety of cellular mechanisms, such as altered Akt and AMPK and increased inflammatory signaling, contribute to neurodegeneration. Exercise training can improve markers of neurodegeneration, but the underlying mechanisms remain unknown. The purpose of this study was to determine the effects of a single bout of exercise on markers of neurodegeneration and inflammation in brains from mice fed a high-fat diet. Male C57BL/6 mice were fed a low (LFD; 10% kcal from lard)- or a high-fat diet (HFD; 60% kcal from lard) for 7 wk. HFD mice underwent an acute bout of exercise (treadmill running: 15 m/min, 5% incline, 120 min) followed by a recovery period of 2 h. The HFD increased body mass and glucose intolerance (both P < 0.05). This was accompanied by an approximately twofold increase in the phosphorylation of Akt, ERK, and GSK in the cortex (P < 0.05). Following exercise, there was a decrease in beta-site amyloid precursor protein cleaving enzyme 1 (BACE1; P < 0.05) and activity (P < 0.001). This was accompanied by a reduction in AMPK phosphorylation, indicative of a decline in cellular stress (P < 0.05). Akt and ERK phosphorylation were decreased following exercise in HFD mice to a level similar to that of the LFD mice (P < 0.05). This study demonstrates that a single bout of exercise can reduce BACE1 content and activity independent of changes in adiposity. This effect is associated with reductions in Akt, ERK, and AMPK signaling in the cortex.

Circulating microRNAs as prognostic therapy biomarkers in head and neck cancer patients.

BACKGROUND: The prediction of therapy response in head and neck squamous cell cancer (HNSCC) requires biomarkers, which are also a prerequisite for personalised therapy concepts. The current study aimed to identify therapy-responsive microRNAs (miRNAs) in the circulation that can serve as minimally invasive prognostic markers for HNSCC patients undergoing radiotherapy. METHODS: We screened plasma miRNAs in a discovery cohort of HNSCC patients before therapy and after treatment. We further compared the plasma miRNAs of the patients to age- and sex-matched healthy controls. All miRNAs identified as biomarker candidates were then confirmed in an independent validation cohort of HNSCC patients and tested for correlation with the clinical outcome. RESULTS: We identified a signature of eight plasma miRNAs that differentiated significantly (P=0.003) between HNSCC patients and healthy donors. MiR-186-5p demonstrated the highest sensitivity and specificity to classify HNSCC patients and healthy individuals. All therapy-responsive and patient-specific miRNAs in plasma were also detectable in tumour tissues derived from the same patients. High expression of miR-142-3p, miR-186-5p, miR-195-5p, miR-374b-5p and miR-574-3p in the plasma correlated with worse prognosis. CONCLUSIONS: Circulating miR-142-3p, miR-186-5p, miR-195-5p, miR-374b-5p and miR-574-3p represent the most promising markers for prognosis and therapy monitoring in the plasma of HNSCC patients. We found strong evidence that the circulating therapy-responsive miRNAs are tumour related and were able to validate them in an independent cohort of HNSCC patients.

[The supraclavicular flap for reconstruction of the head and neck]. / Der supraclaviculäre Lappen zur Rekonstruktion im Kopf-Hals-Bereich.

The complex anatomy of the head and neck region requires the ability to raise a wide spectrum of pedicled and free flaps, to ensure optimal reconstruction of various defects by the reconstructive surgeon. The supraclavicular (island) flap, which has almost been buried in oblivion, provides excellent potential to reconstruct even bigger defects of the head and neck region, while causing minimal donor site morbidity at the same time. Its benefits lie in the reliable skin island and its wide arc of rotation, resulting in excellent cosmetic and functional outcomes.

[Pedunculated osteoma of the frontal sinus]. / Gestieltes Osteom der Stirnhöhle.

Osteoma, the most frequent tumor of the paranasal sinuses (PNS), is often asymptomatic. Men are more commonly affected than women. A 52-year-old patient complained of increasing incidence of headaches following the resolution of frontal sinusitis. Computer tomography demonstrated a pedunculated osteoma of the frontal sinus. Histomorphologically, PNS osteomas usually show cortical bone differentiation with sparse medullary space and a lamellar configuration. At 6 months following surgical resection, the patient was still symptom-free.

Essential role of the unfolded protein response regulator GRP78/BiP in protection from neuronal apoptosis.

Neurodegenerative diseases are often associated with dysfunction in protein quality control. The endoplasmic reticulum (ER), a key site for protein synthesis, senses stressful conditions by activating the unfolded protein response (UPR). In this study we report the creation of a novel mouse model in which GRP78/BiP, a major ER chaperone and master regulator of UPR, is specifically eliminated in Purkinje cells (PCs). GRP78-depleted PCs activate UPR including the induction of GRP94, PDI, CHOP and GADD34, feedback suppression of eIF2alpha phosphorylation and apoptotic cell death. In contrast to current models of protein misfolding in which an abnormal accumulation of ubiquitinated protein is prominent, cytosolic ubiquitin staining is dramatically reduced in GRP78-null PCs. Ultrastructural evaluation reveals that the ER shows prominent dilatation with focal accumulation of electron-dense material within the ER. The mice show retarded growth and severe motor coordination defect by week 5 and cerebellar atrophy by week 13. Our studies uncover a novel link between GRP78 depletion and reduction in cytosolic ubiquitination and establish a novel mouse model of accelerated cerebellar degeneration with basic and clinical applications.

Chemopreventive action of dexamethasone and alpha-tocopherol in oxidative stressed cells.

INTRODUCTION: Recent research indicates a close connection of inflammation and cancer as presumed by Virchow in 1893. The growing understanding of cellular signalling and regulatory pathways reveals multiple links between inflammation and cancer. This study was designed to evaluate the influence of the anti-inflammatory drug dexamethasone and the antioxidant alpha-tocopherol on oxidative induced DNA damage, a major factor in the development of malignancies. MATERIAL AND METHODS: Miniorgan cultures (MOC) of fresh biopsied human nasal mucosa were used to keep cells in their microenvironment and thus to mimic in vivo conditions. MOC were pretreated with dexamethasone and alpha-tocopherol in different concentrations on 1 or on 5 days before oxidative DNA damage was introduced by hydrogen peroxide. The effect of these substances on DNA damage was evaluated using the alkaline single cell microgel electrophoresis (Comet Assay). RESULTS: Dexamethasone induced slight, but considerable DNA fragmentation by itself. It effectively protected cells from hydrogen peroxide induced DNA damage, leading to a maximum decrease of about 45% when preincubated on 5 days at 20 microM. alpha-Tocopherol most effectively reduced oxidative DNA fragmentation by about 38% when MOC were pretreated 5 days at 20 microM. DISCUSSION: Our experimental data clearly shows the DNA protective action of dexamethasone and alpha-tocopherol with regard to oxidatively induced DNA damage, a major pathogenetic factor that inflammation and cancer have in common.

[DNA-protective potential of polyphenols in human mucosa cell cultures]. / DNA-protektives Potential von Polyphenolen in humanen Schleimhautzellkulturen.

BACKGROUND: The concept of field cancerization in the head and neck offers an excellent basis for chemopreventive interventions. Within the last few years, polyphenols, the most abundant phytochemicals in our diet, have been identified as interesting chemopreventive agents based on their multiple actions. This study was designed to add more experimental data regarding the chemopreventive features of epigallocatechin gallate (EGCG) and tannin (TA) in cultures of fresh biopsied tissue to epidemiologic studies and animal and cell line experiments. MATERIALS AND METHODS: Miniorgan cultures (MOC) were produced from oropharyngeal mucosa-cubes about 1 mm(3), epithelialized and with their tissue structure preserved. The MOC were incubated with EGCG (0.1 and 5 microM) and TA (1 and 5 microM) for 30 min on three consecutive days. On the 3rd day, DNA damage was introduced with metabolically activated tobacco carcinogen benzo[a]pyren-7,8-dihydrodiol-9,10-epoxid (BPDE) [9 microM] for 60 min. The resulting DNA damage was measured with alkaline single-cell microgel electrophoresis (comet assay) and quantified using the olive tail moment (OTM). RESULTS: By incubating MOC with the polyphenols, the DNA damage caused by BPDE was significantly decreased at all concentrations. CONCLUSION: To our knowledge, this is the first test using cell cultures produced from fresh biopsies that demonstrates ECGC and TA as promising chemopreventive agents and confirms nutritional studies.

[Carcinogenic and co-carcinogenic effects of metals and ethanol on human salivary gland tissue]. / Karzinogene und kokarzinogene Effekte von Metallen und Ethylalkohol in humanen Speicheldrüsenzellen.

BACKGROUND: The etiology of malignomas of human salivary glands is examined. MATERIAL AND METHODS: Macroscopic, healthy salivary gland tissue from 46 donors was harvested during surgery. Single cells were isolated by enzymatic digestion. These were then incubated for 60 min with Na(2)Cr(2)O(7), NiSO(4), CdSO(4), ZnCl(2) and ethanol. Additionally, incubation with Na(2)Cr(2)O(7) was combined with NiSO(4), CdSO(4), ZnCl(2) and ethanol. The influence of CdSO(4) was analyzed by altered combinations with Na(2)Cr(2)O(7) during incubation and by the DNA-repair period. Evaluation was performed using fluorescent staining and digital analysis. RESULTS: Of all of the substances tested, only Na(2)Cr(2)O(7) showed genotoxic effects. NiSO(4), ZnCl(2) and ethanol had neither genotoxic nor cofactorial impacts. CdSO(4), however, caused additional genotoxic effects in combination with Na(2)Cr(2)O(7), although it lacked direct genotoxic potential. A reduction of DNA-repair of Na(2)Cr(2)O(7)-induced oxidative damage by CdSO(4) could be demonstrated. CONCLUSIONS: In this investigation, sodium dichromate was identified as genotoxic in association with human salivary gland tissue. These effects could be increased by CdSO(4), reinforcing DNA damage based on oxidative stress.

Identification of TFII-I as the endoplasmic reticulum stress response element binding factor ERSF: its autoregulation by stress and interaction with ATF6.

When mammalian cells are subjected to stress targeted to the endoplasmic reticulum (ER), such as depletion of the ER Ca(2+) store, the transcription of a family of glucose-regulated protein (GRP) genes encoding ER chaperones is induced. The GRP promoters contain multiple copies of the ER stress response element (ERSE), consisting of a unique tripartite structure, CCAAT(N(9))CCACG. Within a subset of mammalian ERSEs, N(9) represents a GC-rich sequence of 9 bp that is conserved across species. A novel complex (termed ERSF) exhibits enhanced binding to the ERSE of the grp78 and ERp72 promoters using HeLa nuclear extracts prepared from ER-stressed cells. Optimal binding of ERSF to ERSE and maximal ERSE-mediated stress inducibility require the conserved GGC motif within the 9-bp region. Through chromatographic purification and subsequent microsequencing, we have identified ERSF as TFII-I. Whereas TFII-I remains predominantly nuclear in both nontreated NIH 3T3 cells and cells treated with thapsigargin (Tg), a potent inducer of the GRP stress response through depletion of the ER Ca(2+) store, the level of TFII-I transcript was elevated in Tg-stressed cells, correlating with an increase in TFII-I protein level in the nuclei of Tg-stressed cells. Purified recombinant TFII-I isoforms bind directly to the ERSEs of grp78 and ERp72 promoters. The stimulation of ERSE-mediated transcription by TFII-I requires the consensus tyrosine phosphorylation site of TFII-I and the GGC sequence motif of the ERSE. We further discovered that TFII-I is an interactive protein partner of ATF6 and that optimal stimulation of ERSE by ATF6 requires TFII-I.

Design of a wavelength-division multiplexing bandpass with quasi-chebyshev spectral shape.

By proper selection of the radiant reflectance of the reflectors that are interleaved between the half-wave thickness spacers it is possible to design an all-dielectric bandpass for wavelength-division multiplexing. Its passband spectral shape approximates a Chebyshev polynomial.

Design of a coarse WDM bandpass filter using the Thelen bandpass design method.

A starting design for a prototype bandpass is modeled as a periodic structure, following the teachings of Thelen. A sample prototype bandpass contains twenty-one cavities and, after computer optimization, manifests a quasi-Chebyshev transmissive response in its passband. When the prototype is converted to a thin film multilayer bandpass, its spectral bandwidth is 12.70 nm at the -0.5 dB transmittance level and 12.99 nm at the -25 dB level.

Heterogeneous nuclear ribonucleoproteins as regulators of gene expression through interactions with the human thymidine kinase promoter.

In search for nuclear proteins that interact with the human thymidine kinase (htk) promoter, we discovered that p37AUF, a hnRNP C-like protein, and hnRNP A1, both members of the heterogeneous ribonucleoprotein family, can bind with high affinity to an ATTT sequence motif contained within the cell cycle regulatory unit (CCRU). We report here that over-expression of p37AUF stimulates gene expression mediated by the htk promoter in a promoter-sequence specific manner, whereas hnRNP A1 suppresses it. Both recombinant p37AUF and hnRNP A1 can bind the htk CCRU, suggesting that their binding to the DNA target does not require additional cellular components. We further discovered that hnRNP K is a potent suppressor of htk mediated gene activity. However, its mechanism of action is mediated through protein-protein interaction, since hnRNP K itself cannot bind the htk CCRU but can competitively inhibit the binding of other hnRNPs. The binding site for the hnRNPs on the htk CCRU is not required for S-phase induction of the htk promoter. However, in stable but not transient transfectants, the mutation of the hnRNP binding site results in 5- to 10-fold reduction of htk mediated gene activity in synchronized and exponentially growing cells. Collectively, these findings support emerging evidence that hnRNPs, in addition to their traditional role in RNA biogenesis, could be regulators of gene expression through direct DNA binding or interaction with other proteins.

ATF6 as a transcription activator of the endoplasmic reticulum stress element: thapsigargin stress-induced changes and synergistic interactions with NF-Y and YY1.

ATF6, a member of the leucine zipper protein family, can constitutively induce the promoter of glucose-regulated protein (grp) genes through activation of the endoplasmic reticulum (ER) stress element (ERSE). To understand the mechanism of grp78 induction by ATF6 in cells subjected to ER calcium depletion stress mediated by thapsigargin (Tg) treatment, we discovered that ATF6 itself undergoes Tg stress-induced changes. In nonstressed cells, ATF6, which contains a putative short transmembrane domain, is primarily associated with the perinuclear region. Upon Tg stress, the ATF6 protein level dropped initially but quickly recovered with the additional appearance of a faster-migrating form. This new form of ATF6 was recovered as soluble nuclear protein by biochemical fractionation, correlating with enhanced nuclear localization of ATF6 as revealed by immunofluorescence. Optimal ATF6 stimulation requires at least two copies of the ERSE and the integrity of the tripartite structure of the ERSE. Of primary importance is a functional NF-Y complex and a high-affinity NF-Y binding site that confers selectivity among different ERSEs for ATF6 inducibility. In addition, we showed that YY1 interacts with ATF6 and in Tg-treated cells can enhance ATF6 activity. The ERSE stimulatory activity of ATF6 exhibits properties distinct from those of human Ire1p, an upstream regulator of the mammalian unfolded protein response. The requirement for a high-affinity NF-Y site for ATF6 but not human Ire1p activity suggests that they stimulate the ERSE through diverse pathways.

Evaluation of the Solutions for two Design Problems Presented at the 1998 Optical Interference Coatings Conference.

Two problems were proposed at the 1998 Conference on Optical Interference Coatings: dual-band antireflection coatings and bandpass filters. In excess of 40 solutions were submitted. An evaluation of those solutions is presented.

Dependence of the reflectance of a multilayer reflector on the thickness of the outer layer.

At nonnormal incidence, the radiant reflectance of a highly reflecting multilayer coating strongly depends on the thickness of the outer layer.

Bandpass filters for wavelength division multiplexing-modification of the spectral bandwidth.

Dispersion of the phase shift upon reflection of the reflectors is used to narrow the spectral bandwidth of an all-dielectric bandpass filter for wavelength division multiplexing. The bandwidth is altered by the shifting of the order numbers of the spacer layers (of multiple half-wave optical thicknesses).

Phase properties of multilayers.

The phase shift upon transmission of a nonabsorbing multilayer is shown to be a monotonically decreasing function of the wave number, with an average slope proportional to the optical thickness of the coating. Two limiting situations of the phase shift upon reflection are examined: In one the phase monotonically increases with wavelength, and in the other the phase oscillates. The phase shift upon reflection is derivable from Kramers-Kronig-type relationships, provided the radiant reflectance and the Blaschke factors are known. Characteristic features of the refractive-index profile related to these factors are discussed.