Proteomic, miRNA and bacterial biomarker patterns in atopic dermatitis patients and their course upon anti-IL-4Rα therapy.

BACKGROUND: Identification of biomarkers is required for a systems medicine approach and personalized treatment in atopic dermatitis (AD). These biomarkers may not only aid in diagnosing but also might be suitable to predict the effectiveness of targeted treatment. OBJECTIVE: We aimed to identify proteomic, microbial and miRNA biomarkers in AD patients and investigated their course in relation to the clinical response upon anti-IL-4Rα therapy. METHODS: Proteomic and miRNA screening was performed in AD patients in comparison to healthy controls. Differentially regulated serum proteins, miRNA and selected skin microbiota were measured consecutively in 50 AD patients before and upon systemic dupilumab treatment. A random forest classifier was used to predict the outcome of dupilumab therapy based on the initial biomarker patterns. RESULTS: We identified 27 proteomic candidates, miRNA and three microbial strains to be dysregulated in AD. CCL17, CCL13, CCL22, E-selectin and BDNF were differently regulated and significantly associated with treatment response. In contrast, neither the microbial composition nor the miRNA pattern was associated with treatment response upon dupilumab treatment. CONCLUSION: AD patients display defined dysregulations regarding their systemic proteomic serum profile, miRNA patterns and their skin microbiome. The proteomic profile and selected skin bacteria changed profoundly upon anti-IL-4Rα therapy which was associated with an overall clinical response. This was not seen in miRNA-related biomarkers. Our findings support the hypothesis that biomarker profiles reflect treatment responses and may in the future be used to develop a personalized medicine approach for the treatment of AD patients.

Paradoxical effects of cigarette smoke and COPD on SARS-CoV-2 infection and disease.

BACKGROUND: How cigarette smoke (CS) and chronic obstructive pulmonary disease (COPD) affect severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) infection and severity is controversial. We investigated the effects of COPD and CS on the expression of SARS-CoV-2 entry receptor ACE2 in vivo in COPD patients and controls and in CS-exposed mice, and the effects of CS on SARS-CoV-2 infection in human bronchial epithelial cells in vitro. METHODS: We quantified: (1) pulmonary ACE2 protein levels by immunostaining and ELISA, and both ACE2 and/or TMPRSS2 mRNA levels by RT-qPCR in two independent human cohorts; and (2) pulmonary ACE2 protein levels by immunostaining and ELISA in C57BL/6 WT mice exposed to air or CS for up to 6 months. The effects of CS exposure on SARS-CoV-2 infection were evaluated after in vitro infection of Calu-3 cells and differentiated human bronchial epithelial cells (HBECs), respectively. RESULTS: ACE2 protein and mRNA levels were decreased in peripheral airways from COPD patients versus controls but similar in central airways. Mice exposed to CS had decreased ACE2 protein levels in their bronchial and alveolar epithelia versus air-exposed mice. CS treatment decreased viral replication in Calu-3 cells, as determined by immunofluorescence staining for replicative double-stranded RNA (dsRNA) and western blot for viral N protein. Acute CS exposure decreased in vitro SARS-CoV-2 replication in HBECs, as determined by plaque assay and RT-qPCR. CONCLUSIONS: ACE2 levels were decreased in both bronchial and alveolar epithelial cells from COPD patients versus controls, and from CS-exposed versus air-exposed mice. CS-pre-exposure potently inhibited SARS-CoV-2 replication in vitro. These findings urge to investigate further the controversial effects of CS and COPD on SARS-CoV-2 infection.

Mono-, di-, and trichlorinated biphenyls (PCB 1-PCB 39) in the indoor air of office rooms and their relevance on human blood burden.

Exposure to polychlorinated biphenyls (PCBs) from indoor air can lead to a significant increase in lower chlorinated congeners in human blood. Lower chlorinated congeners with short biological half-lives can exhibit an indirect genotoxic potential via their highly reactive metabolites. However, little is known about their occurrence in indoor air and, therefore, about the effects of possible exposure to these congeners. We analyzed all mono-, di-, and trichlorinated biphenyls in the indoor air of 35 contaminated offices, as well as in the blood of the 35 individuals worked in these offices for a minimum of 2 years. The median concentration of total PCB in the indoor air was 479 ng/m3 . The most prevalent PCBs in the indoor air samples were the trichlorinated congeners PCB 31, PCB 18, and PCB 28, with median levels of 39, 31, and 26 ng/m3 , respectively. PCB 8 was the most prevalent dichlorinated congener (median: 9.1 ng/m3 ). Monochlorinated biphenyls were not detected in relevant concentrations. In the blood samples, the most abundant congener was PCB 28; nearly 90% of all mono-, di-, and trichlorinated congeners were attributed to this congener (median: 12 ng/g blood lipid).

Narrow band imaging for early diagnosis of epithelial dysplasia and microinvasive tumors in the upper aerodigestive tract.

The various stages of tumor growth are characterized by typical epithelial, vascular, and secondary connective tissue changes. Narrow Band Imaging (NBI) endoscopy is a minimally invasive imaging technique that presents vascular structures in particular at a higher contrast than white light endoscopy alone. In combination with high-resolution image recording and reproduction (high-definition television, HDTV; ultra-high definition, 4K), progress has been made in otolaryngological differential diagnostics, both pre- and intraoperatively. This progress represents an important step toward a so-called optical biopsy. Flexible endoscopy in combination with NBI allows for a detailed assessment of areas of the upper aerodigestive tract that are difficult to assess by rigid endoscopy. Papillomas along with precancerous and cancerous lesions are characterized by epithelial and connective tissue changes as well as by typical perpendicular vascular changes. Systematic use of NBI is recommended in the differential diagnosis of malignant lesions of the upper aerodigestive tract. NBI also offers a significant improvement in the pre- and intraoperative assessment of superficial resection margins. In particular, the combination of NBI and contact endoscopy (compact endoscopy) facilitates excellent therapeutic decisions during tumor surgery. Intraoperative determination of resection margins at an unprecedented precision is possible. In addition, assessment of the form and extent of the perpendicular vessel loops stimulated by epithelial signaling enables differential diagnostic decisions to be made, approximating our goal of an optical biopsy.

Tollip SNP rs5743899 modulates human airway epithelial responses to rhinovirus infection.

BACKGROUND: Rhinovirus (RV) infection in asthma induces varying degrees of airway inflammation (e.g. neutrophils), but the underlying mechanisms remain unclear. OBJECTIVE: The major goal was to determine the role of genetic variation [e.g. single nucleotide polymorphisms (SNPs)] of Toll-interacting protein (Tollip) in airway epithelial responses to RV in a type 2 cytokine milieu. METHODS: DNA from blood of asthmatic and normal subjects was genotyped for Tollip SNP rs5743899 AA, AG and GG genotypes. Human tracheobronchial epithelial (HTBE) cells from donors without lung disease were cultured to determine pro-inflammatory and antiviral responses to IL-13 and RV16. Tollip knockout and wild-type mice were challenged with house dust mite (HDM) and infected with RV1B to determine lung inflammation and antiviral response. RESULTS: Asthmatic subjects carrying the AG or GG genotype (AG/GG) compared with the AA genotype demonstrated greater airflow limitation. HTBE cells with AG/GG expressed less Tollip. Upon IL-13 and RV16 treatment, cells with AG/GG (vs. AA) produced more IL-8 and expressed less antiviral genes, which was coupled with increased NF-κB activity and decreased expression of LC3, a hallmark of the autophagic pathway. Tollip co-localized and interacted with LC3. Inhibition of autophagy decreased antiviral genes in IL-13- and RV16-treated cells. Upon HDM and RV1B, Tollip knockout (vs. wild-type) mice demonstrated higher levels of lung neutrophilic inflammation and viral load, but lower levels of antiviral gene expression. CONCLUSIONS AND CLINICAL RELEVANCE: Our data suggest that Tollip SNP rs5743899 may predict varying airway response to RV infection in asthma.

[Fluorescence imaging in laryngology: Physical principles, clinical applications and study results]. / Fluoreszenzbildgebung in der Laryngologie: Physikalische Grundlagen, klinische Anwendung und Studienergebnisse.

BACKGROUND: Early detection and adequate preoperative assessment of neoplastic lesions of the larynx allow for voice-preserving therapy concepts. OBJECTIVE: The physical principles, clinical applications and most important study results of fluorescence imaging are presented. MATERIALS AND METHODS: The entire literature on autofluorescence endoscopy of the larynx was analysed and compared to induced fluorescence endoscopy. RESULTS: In detecting malignant and premalignant lesions of the larynx, autofluorescence endoscopy shows a significantly higher sensitivity, specificity and accuracy than white light endoscopy alone. Induced fluorescence endoscopy achieved an even higher sensitivity, albeit at the expense of specificity. CONCLUSION: Autofluorescence endoscopy represents a simple screening procedure for early detection of laryngeal cancer and its precursor lesions, whereas induced fluorescence endoscopy is more suited for the identification of recurrent disease.

[Narrow band imaging for early diagnosis of epithelial dysplasias and microinvasive tumors in the upper aerodigestive tract]. / "Narrow band imaging" zur Früherkennung epithelialer Dysplasien und mikroinvasiver Karzinome im oberen Luft-Speise-Weg.

The various stages of tumor growth are characterized by typical epithelial, vascular, and secondary connective tissue changes. Narrow band imaging (NBI) endoscopy is a minimally invasive imaging technique that presents vascular structures in particular at a higher contrast than white light endoscopy alone. In combination with high-resolution image recording and reproduction (high-definition television, HDTV; ultra-high definition, 4K), progress has been made in otolaryngological differential diagnostics, both pre- and intraoperatively. This progress represents an important step towards a so-called optical biopsy. Flexible endoscopy in combination with NBI allows detailed assessment of areas of the upper aerodigestive tract which are difficult to assess by rigid endoscopy. Papillomas, precancerous, and cancerous lesions are characterized by epithelial and connective tissue changes, as well as by typical perpendicular vascular changes. Systematic use of NBI is recommended in the differential diagnosis of malignant lesions of the upper aerodigestive tract. NBI also convinces by a significant improvement in pre- and intraoperative assessment of superficial resection margins. In particular, the combination of NBI and contact endoscopy (compact endoscopy) permits excellent therapeutic decisions during tumor surgery. Intraoperative determination of resection margins at unprecedented precision is possible. In addition, assessment of the form and extent of the perpendicular vessel loops stimulated by epithelial signaling enables differential diagnostic decisions to be made, approximating our goal of an optical biopsy.

[Noninvasive imaging using autofluorescence endoscopy: Value for the early detection of laryngeal cancer]. / Nichtinvasive Bildgebung mittels Autofluoreszenzendoskopie: Stellenwert bei der Früherfassung des Kehlkopfkarzinoms.

BACKGROUND: Autofluorescence endoscopy is able to delineate malignancy from normal tissue by color change. The objective of the present study was to assess the value of this noninvasive imaging method for the early detection of laryngeal cancer and its precursor lesions. PATIENTS AND METHODS: In a prospective study, 152 patients with a laryngeal lesion who were undergoing microlaryngoscopy were investigated. Autofluorescence endoscopy was performed after conventional white light endoscopy, just before excisional biopsy was carried out for histologic verification. RESULTS: In the early detection of laryngeal cancer and its precursor lesions, autofluorescence endoscopy showed a significantly higher sensitivity (98 vs. 88%) and accuracy (97 vs. 90%) than white light endoscopy alone, whereas the specificity (97 vs. 93%) was essentially equal in both methods. CONCLUSION: Autofluorescence endoscopy qualifies as a simple screening procedure for rapid detection of suspicious lesions and assessment of their horizontal extension. This allows for guided biopsy or tumor resection, and can also be used in oncological follow-up.

[Optical coherence tomography for early diagnosis of epithelial dysplasia and microinvasive carcinoma of the upper aerodigestive tract]. / Optische Kohärenztomographie zur Früherkennung epithelialer Dysplasien und mikroinvasiver Karzinome im oberen Luft-Speise-Weg.

BACKGROUND: Gold standard in the evaluation of upper aerodigestive tract (UADT) lesions is white light endoscopy followed by invasive tissue biopsy. This procedure is time consuming and expensive. Optical coherence tomography (OCT) is a noninvasive method, which provides high resolution, cross-sectional images of superficial tissue layers in real time. OBJECTIVE: This article aims to present a contemporary and comprehensive review on the role of OCT in differentiating between epithelial dysplasias and early invasive carcinomas of the UADT. MATERIALS AND METHODS: PubMed was searched using "optical coherence tomography/larynx" and other appropriate search strings in August 2015. RESULTS: OCT enables differentiation between benign, premalignant, and early malignant lesions of the UADT with high sensitivity and specificity. In addition, OCT holds promise as a clinical tool for guidance of surgical biopsies, follow-up of recurrent lesions, and for demarcation of tumor margins. Inadequate evidence and technical limitations hamper implementation of OCT into clinical routine. CONCLUSION: If the aforementioned problems are successfully solved, OCT seems to have the potential to substantially improve both diagnosis and management of precancerous and early cancerous lesions of the UADT.

[Optical diagnostic methods for early tumour diagnosis in the upper aerodigestive tract: Quo vadis?]. / Optische Diagnoseverfahren zur Tumorfrühdiagnostik im oberen Luft-Speise-Weg: Quo vadis?

BACKGROUND: Optical diagnostic methods may simplify and improve the early diagnosis of tumours of the upper aerodigestive tract; however, these have not yet found their way into clinical routine. OBJECTIVE: This article aims to define the problems that have prevented routine use of optical diagnostic methods so far, as well as listing and also explaining potential trendsetting approaches to overcome these difficulties. MATERIALS AND METHODS: The study is based on a combined analysis of publically accessible databases (PubMed MEDLINE, Thompson Reuters Web of Science, SPIE. Digital Library; full time period available; search strings: "oral cavity", "pharynx", "larnyx", "optical diagnosis", "optical biopsy", "optical coherence tomography", "confocal endomicroscopy", "fluorescence endoscopy", "narrow band imaging", "non-linear imaging", "fluorescence lifetime imaging"), as well as personal experiences. RESULTS: Both conceptual and methodical problems were determined, and possible solutions based on current developments are discussed. CONCLUSION: Optical diagnostic methods have the potential to revolutionise early diagnosis of upper aerodigestive tract malignancies, providing the different hurdles listed in this review can be overcome.

Detecting organic materials with a CCD camera.

Absorption bands in the near-infrared are used to detect materials composed of organic molecules, in scenes imaged with a conventional CCD camera. A simple model of reflectance spectra (between 850 and 980 nm) is proposed and tested on a wide range of materials. An existing vision system that was designed to detect materials with high water content is tested on organic materials. The system cannot detect materials (such as cellulose and starch) that consist of chains of sugars. It is able to robustly detect materials such as fats and aliphatic plastics (in their pure form), whose molecules are essentially long chains of CH(2) and CH(3) groups. The ability of the system to detect plastic objects is limited by inorganic additives in the plastics.

[Safe reprocessing of medical devices with a view of the entire process chain. Recommendations of the VDI 5700 guidelines]. / Aufbereitung von Medizinprodukten unter Einbeziehung von Risikomanagementprozessen. Empfehlungen der Richtlinie VDI 5700.

The reprocessing of medical devices for low pathogen or sterile use is in itself potentially risky even though the aim of reprocessing is the avoidance of hygienic or technically functional risks. The methodological principles of risk management for medical devices are described in the standard DIN EN ISO 14971. The recommendations of the Commission for Hospital Hygiene and Infectious Disease Prevention (Kommission für Krankenhaushygiene und Infektionsprävention KRINKO) of the Robert Koch Institute (RKI) and the Federal Institute for Drugs and Medical Devices (Bundesinstituts für Arzneimittel und Medizinprodukte BfArM) "hygiene requirements for the reprocessing of medical devices" clarify numerous reprocessing-specific risks and are structured with reference to the different steps of reprocessing. The aim was a practical combination of the normative risk management methodology with the process-oriented KRINKO/BfArM recommendations, which has provided an interdisciplinary group of experts moderated by the Association of German Engineers (VDI). The main contents of the VDI 5700 guidelines on "hazards associated with the reprocessing--risk management in the reprocessing of medical devices--measures for risk control" and the process of the development of these guidelines is described.

[Economic aspects of inpatient treatment for decompensated liver cirrhosis: a prospective study employing an evidence-based clinical pathway]. / Gesundheitsökonomische Aspekte der stationären Behandlung von Patienten mit dekompensierter Leberzirrhose: eine prospektive Studie unter Nutzung eines evidenzbasierten Behandlungspfads.

The introduction of the G-DRG reimbursement system has greatly increased the pressure to provide cost effective treatment in German hospitals. Reimbursement based on diagnosis-related groups, which requires stratification of costs incurred is still not sufficiently discriminating the disease severity and severity in relation to the intensive costs in gastroenterology. In a combined retrospective and prospective study at a tertial referral centre we investigated whether this also applies for decompensated liver cirrhosis. In 2006, 64 retrospective cases (age 57 ± 12.9; ♂ 69.2 %, ♀ 29.8 %) with decompensated liver cirrhosis (ICD code K76.4) were evaluated for their length of hospitalisation, reimbursement as well as Child and MELD scores. In 2008, 74 cases with decompensated liver cirrhosis were treated in a prospective study according to a standardised and evidence-based clinical pathway (age 57 ± 12.2; 73 % ♂, ♀ 27 %). Besides a trend in the reduction of length of hospital stay (retrospective: 13.6 ± 8.6, prospective 13.0 ± 7.2, p = 0.85) overall revenues from patients treated according to a evidence-based clinical pathway were lower than the calculated costs from the InEK matrix. Costs of medication as a percentage of reimbursement amount increased with increasing severity. In both years we could demonstrate an inverse correlation between daily reimbursement and disease severity which precluded cost coverage. For the cost-covering hospital treatment of patients with decompensated liver cirrhosis an adjustment of the DRG based on clinical severity scores such as Child-Pugh or MELD is warranted, if evidence-based treatment standards are to be kept.

[The occurrence of plasticisers (phthalates) in communal facilities under special consideration of results from LUPE 3]. / Vorkommen von Weichmachern (Phthalaten) in Gemeinschaftseinrichtungen unter besonderer Bedeutung der Ergebnisse von LUPE 3.

Children are a very susceptible subgroup of the general population and therefore health authorities have a special interest to prevent them from health hazards. In a study of 3 German Bundesländer the indoor air and dust samples of altogether 63 German daycare centres were analysed for the presence of phthalate diesters in 2011/12 (LUPE 3 study). Inhalable dust and gas phases were collected with a glass fibre filter and polyurethane foam over approximately 6 h while children were attending these facilities. Settled dust was collected by vacuuming the floor of the room using an ALK dust sampler. Indoor air and dust were analysed using a GC/MS system. Median values in the dust samples were 888 mg/kg for di-2-ethylhexyl phthalate (DEHP), 302 mg/kg for diisononyl phthalate (DiNP), 34 mg/kg for diisodecyl phthalate (DiDP), 21 mg/kg for di-n-butyl phthalate (DnBP), and 20 mg/kg for diisobutyl phthalate (DiBP). For DEHP and DiNP maximum values of 10,086 mg/kg and 7,091 mg/kg were observed, respectively. DEHP and DiNP were responsible for 70% and 24% of the total phthalate concentration in the dust. In indoor air phthalates are found mainly in the particulate phase of the filters. Only the more volatile phthalates dimethyl phthalate and diethyl phthalate were found also in the gas phase. The median values in the indoor air were 470 ng/m³ for DiBP, 230 ng/m³ for DnBP, 190 ng/m³ for DEHP, and 100 ng/m³ for DiNP. DnBP and DiBP were together responsible for 55% of the total phthalate concentration in the indoor air. Overall, our study showed that the concentrations of phthalates in indoor air of daycare centers are slightly higher and in dust samples lower compared with schools.

Do small airway abnormalities characterize asthma phenotypes? In search of proof.

The role of small airway abnormalities in asthma pathogenesis has been extensively studied and debated for several decades. However, whether or not small airway abnormalities play a relevant role in specific phenotypes of asthmatic patients and contribute to clinical presentation is largely unknown. In the present review, we evaluated available data on the role of small airways in severe asthma, with a further focus on asthma in smokers and asthma in the elderly. These phenotypes are characterized by a poor response to treatment and they can represent a model of greater small airway impairment. In severe asthmatics, small airway involvement has been shown through evidence of both distal inflammation and of increased air trapping. The few available data on asthmatics who smoke, and elderly asthmatics, similarly suggests that small airway abnormalities contribute to the pathogenesis of the disease. In this perspective, there could be a rationale for specifically assessing small airway impairment in these patients and for clinical studies evaluating whether pharmacological approaches targeting the more peripheral airways result in clinical benefits beyond conventional therapy.

[Advances in endoscopic diagnosis of dysplasia and carcinoma of the larynx]. / Fortschritte der endoskopischen Diagnostik von Dysplasien und Karzinomen des Larynx.

To improve the preoperative and intraoperative diagnosis of laryngeal cancer and its precursors, various endoscopic imaging techniques have been developed in recent years. These techniques differ markedly in their specific applications and goals. Precisely distinguishing among normal mucosa, dysplasia and invasive carcinoma with these procedures is necessary. Furthermore, the exact identification of tumor margins should be possible. The long-term goal is the development of optical biopsy. Since so far there have only been small studies regarding the evaluation of the presented methods, it is necessary to establish multi-center trials with large sample sizes to accurately estimate the value of these endoscopic imaging techniques.

[Ultrasound of the larynx, hypopharynx and upper esophagus]. / Ultraschall des Larynx, Hypopharynx sowie des oberen Ösophagus.

Sonography is an integral part of the routine diagnosis of diseases of the head and neck area. Ultrasound plays an important role in particular in the diagnosis, treatment and follow-up of head and neck cancer. Sonographic imaging of the larynx, hypopharynx and upper esophagus is often difficult due to the anatomical conditions. Therefore, CT and MRI are performed as the imaging techniques of first choice for diseases of these organs. In addition to the well-established transcutaneous ultrasound, endoscopic endoluminal ultrasound has developed as a promising new technique in recent years. Hollow organs can be displayed in high resolution transcutaneously and endoluminally. Thus, the attending otolaryngologist can use endoscopy and ultrasonography for accurate surgical planning. The aim of the present paper is to present the possibilities and limitations of ultrasonography of the larynx, hypopharynx and upper esophagus.

[Ultrasound microscopy in the upper aerodigestive tract. Initial clinical experiences]. / Ultraschallmikroskopie im oberen Aerodigestivtrakt. Erste klinische Erfahrungen.

PURPOSE: Initial clinical experiences with ultrasound microscopy in the upper aerodigestive tract are described. MATERIALS AND METHODS: In the present pilot study, 20 healthy probands and 10 patients with lesions of the oral cavity, pharynx and larynx undergoing surgery were examined using a new prototype of an ultrasound microscope. RESULTS: A total of 24 normal and six pathological findings of the upper aerodigestive tract were assessed. These included normal mucosa of the floor of the mouth, the inner cheek, the palate and the vocal fold. In addition, invasive carcinoma of the floor of the mouth, the aryepiglottic fold and the vocal fold was found. Furthermore, a papilloma of the palatal arch and two epiglottic cysts were examined. CONCLUSION: Our results demonstrate that ultrasound microscopy is also viable in hollow organs. Pathological lesions differed clearly from normal mucosa. However, to recognize the regular pattern of different lesions of the upper aerodigestive tract, further investigations need to be carried out with a larger number of patients.

Induction of Fas ligand expression by HIV involves the interaction of Nef with the T cell receptor zeta chain.

During HIV/SIV infection, there is widespread programmed cell death in infected and, perhaps more importantly, uninfected cells. Much of this apoptosis is mediated by Fas-Fas ligand (FasL) interactions. Previously we demonstrated in macaques that induction of FasL expression and apoptotic cell death of both CD4(+) and CD8(+) T cells by SIV is dependent on a functional nef gene. However, the molecular mechanism whereby HIV-1 induces the expression of FasL remained poorly understood. Here we report a direct association of HIV-1 Nef with the zeta chain of the T cell receptor (TCR) complex and the requirement of both proteins for HIV-mediated upregulation of FasL. Expression of FasL through Nef depended upon the integrity of the immunoreceptor tyrosine-based activation motifs (ITAMs) of the TCR zeta chain. Conformation for the importance of zeta for Nef-mediated signaling in T cells came from an independent finding. A single ITAM motif of zeta but not CD3epsilon was both required and sufficient to promote activation and binding of the Nef-associated kinase (NAK/p62). Our data imply that Nef can form a signaling complex with the TCR, which bypasses the requirement of antigen to initiate T cell activation and subsequently upregulation of FasL expression. Thus, our study may provide critical insights into the molecular mechanism whereby the HIV-1 accessory protein Nef contributes to the pathogenesis of HIV.