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.

Paradoxical effects of cigarette smoke and COPD on SARS-CoV2 infection and disease.

INTRODUCTION: How cigarette smoke (CS) and chronic obstructive pulmonary disease (COPD) affect severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and severity is controversial. We investigated the protein and mRNA expression of SARS-CoV-2 entry receptor ACE2 and proteinase TMPRSS2 in lungs from COPD patients and controls, and lung tissue from mice exposed acutely and chronically to CS. Also, we investigated the effects of CS exposure on SARS-CoV-2 infection in human bronchial epithelial cells. METHODS: In Cohort 1, ACE2-positive cells were quantified by immunostaining in FFPE sections from both central and peripheral airways. In Cohort 2, we quantified pulmonary ACE2 protein levels by immunostaining and ELISA, and both ACE2 and TMPRSS2 mRNA levels by RT-qPCR. In C57BL/6 WT mice exposed to air or CS for up to 6 months, pulmonary ACE2 protein levels were quantified by triple immunofluorescence staining and ELISA. The effects of CS exposure on SARS-CoV-2 infection were evaluated after 72hr in vitro infection of Calu-3 cells. After SARS-CoV-2 infection, the cells were fixed for IF staining with dsRNA-specific J2 monoclonal Ab, and cell lysates were harvested for WB of viral nucleocapsid (N) protein. Supernatants (SN) and cytoplasmic lysates were obtained to measure ACE2 levels by ELISA. RESULTS: In both human cohorts, ACE2 protein and mRNA levels were decreased in peripheral airways from COPD patients versus both smoker and NS controls, but similar in central airways. TMPRSS2 levels were similar across groups. Mice exposed to CS had decreased ACE2 protein levels in their bronchial and alveolar epithelia versus air-exposed mice exposed to 3 and 6 months of CS. In Calu3 cells in vitro, CS-treatment abrogated infection to levels below the limit of detection. Similar results were seen with WB for viral N protein, showing peak viral protein synthesis at 72hr. CONCLUSIONS: ACE2 levels were decreased in both bronchial and alveolar epithelial cells from uninfected COPD patients versus controls, and from CS-exposed versus air-exposed mice. CS-pre-treatment did not affect ACE2 levels but potently inhibited SARS-CoV-2 replication in this in vitro model. These findings urge to further investigate the controversial effects of CS and COPD on SARS-CoV2 infection.

The German approach to regulate indoor air contaminants.

Indoor air quality (IAQ) and exposure to indoor chemicals are widely discussed in terms of personal discomfort and health risks. In contrast to ambient air and working environments, legally binding regulations are only partially established for indoor contaminants, and other available European guidelines are limited. To correct these deficits, the German Committee on Indoor Guide Values (AIR), formerly known as the Ad hoc Working Group (Ad hoc AG), performed health assessments of indoor air contaminants. The main tasks were to develop toxicologically based indoor air guide values, health-based guideline values, and reference values largely based on the 95th percentile of the concentrations found in a reference population. Here, we provide a comprehensive overview of the indoor air values set in Germany and discuss the basis of their derivation. This overview includes a description of legally binding standards, indoor air guide values for 38 substances or groups, and guidelines for TVOC (total volatile organic compounds), particulate matter, and carbon dioxide as well as risk-related guidelines for carcinogenic substances.

In-vivo Intradermal Delivery of Co-57 labeled Vitamin B-12, and Subsequent Comparison with Standard Subcutaneous Administration.

Vitamin B-12 (cobalamin) deficiency in humans is a worldwide problem emanating from varied causes such as insufficient dietary intake or malabsorption of the micronutrient due to an underlying condition (absence or failure of intrinsic factor, atrophic gastritis, post-operative bariatric surgery, inflammatory bowel disease, cobalt deficiency etc.). As oral supplementation is limited by its bioavailability due to the absorptive property of intrinsic factor, clinicians often prescribe parenteral forms of administration to replenish diminished levels rapidly. The gold standard in parenteral delivery of cobalamin is subcutaneous and/or intramuscular injections. The relatively large molecular size of cobalamin (1355.39 Da) makes passive transdermal patch-based delivery via the stratum corneum quite challenging. Hence, the primary goal of this study is to investigate the feasibility of intradermal (ID) delivery of Vitamin B-12 via an almost painless microneedle injection and subsequent comparison with standard subcutaneous (SC) delivery. This work reports on a custom-made microneedle device built from a commercial insulin needle and it's use to perform ID delivery of Co-57 radiolabeled Vitamin B-12 in-vivo in rabbits. The pharmacokinetic profile and bioavailability were studied and compared with SC delivery. It is the first comprehensive study, to our best knowledge, that compares a micronutrient (eg. Vitamin B-12) delivery via ID and SC routes in-vivo. While the bioavailability for the SC route is found to be slightly higher compared to the ID route (99% vs. 96%), the Tmax for both are almost identical. Thus, ID delivery of Vitamin B-12 using a microneedle injection could be a viable and minimally invasive alternative to existing parenteral options.

The sphingosine analog fingolimod (FTY720) enhances tone and contractility of rat gastric fundus smooth muscle.

BACKGROUND: Sphingosine and its metabolite sphingosine phosphate (S1P) regulate a multitude of biological functions, including the contractile state of smooth. Gastrointestinal side effects have been reported in patients treated with FTY720, a sphingosine analog that is approved for the treatment of multiple sclerosis. The aim of this study was to characterize the effects of FTY720 on rat gastric fundus smooth muscle under basal conditions and during activation induced by high-K+ solution. METHODS: Isometric contractions of isolated circular strips of gastric fundus smooth muscle were recorded using the organ bath method. The effects of FTY720 or vehicle were recorded under control conditions and in the presence of indomethacin, L-NAME, HA-1100, nifedipine, JTE-013, and suramin. Tone and contractions recorded in the presence of FTY720 or vehicle are reported as % of the amplitude of an initial high-K+ contraction obtained under control conditions. KEY RESULTS: From a concentration of 10 µmol L-1 onwards, FTY720 increased the tone, reaching 8.9% ± 7.5% at 100 µmol L-1 (P < .05). With indomethacin in the solution, the effects of FTY720 were enhanced (32.1% ± 7.7%; P < .001). The FTY720-induced increase in tone was abolished in the absence of extracellular Ca2+ and reduced by nifedipine, HA-1100, JTE-013, and suramin. Furthermore, FTY720 increased high-K+ contractions in the presence of indomethacin. CONCLUSIONS & INFERENCES: FTY720 increases tone and contractile responses to depolarization in gastric fundus smooth muscle by triggering calcium entry and calcium sensitization in a S1P receptor-dependent manner. Taken together, the experimental results presented in this work suggest that FTY720 may increase gastric tone and contractility in patients.

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).

Quantification of all 209 PCB congeners in blood-Can indicators be used to calculate the total PCB blood load?

Polychlorinated biphenyls (PCBs) are a substance group of 209 theoretically possible compounds. The human body burden of PCBs is commonly calculated based on so-called indicator congeners such as PCB 138, PCB 153 and PCB 180, which are analyzed in human blood. The German "Human Biomonitoring (HBM) Commission" assumes that the sum of these indicator congeners multiplied by a factor of 2 represents the total PCB burden. This norm is based on data obtained from exposure studies after dietary intake. Data from indoor air shows a different congener pattern, which might lead to a relatively higher intake of lower chlorinated PCBs by inhalation. In two independent studies with adult participants from two regions in Germany, we measured all 209 PCB congeners in 44 whole blood and 42 plasma samples. Participants from the whole blood study group had additional exposure to PCBs via indoor air. With our analytical method, 141 individual PCB congeners, 27 coeluted pairs of PCB congeners and 2 records of 3 and 4 coeluted PCBs could be determined. Thus, 172 analysis results were reported per sample. In the whole blood samples, 50 congeners showed values below the limit of quantification (LOQ), whereas 94 congeners could not be detected in any of plasma samples. Total PCB concentrations (Σ 209 PCB congeners, incl. ½ LOQ) in the whole blood samples ranged from 99 to 2152ng PCB/g lipid (Median: 454ng/g lipid; 95th Percentile: 1404ng/g lipid). The sum of all 209 measured PCB (incl. ½ LOQ) in plasma samples showed levels between 52 and 933ng PCB/g lipid (Median: 226ng/g lipid; 95th Percentile: 642ng/g lipid). Our results show that the burden of PCBs on the human body is caused mainly by the three highly chlorinated indicator congeners PCB 138, PCB 153 and PCB 180. In median approximately 50% of the total PCB content in human whole blood or plasma samples can be attributed to these congeners. Total PCB, calculated by multiplying the sum of the three indicator congeners by 2, showed a strong and highly significant correlation to the sum of all 209 measured congeners for each sample. A slightly stronger correlation in the whole blood samples could be achieved by choosing six indicator congeners, including the lower chlorinated congeners (PCB 28, 52 and 101) into the calculation. Although this difference is very small, it must be considered that higher PCB levels in indoor air than those measured in the present study might be associated with a higher burden of indoor-air-related congeners in exposed individuals. For precautionary reasons, it could therefore be recommended that the assessment of individuals exposed to PCB via indoor air should be carried out based on the sum of the 6 indicator congeners PCB 28, PCB 52, PCB 101, PCB 138, PCB 153 and PCB 180 multiplied by a factor of 2.

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.

Non-phthalate plasticizers in German daycare centers and human biomonitoring of DINCH metabolites in children attending the centers (LUPE 3).

Plasticizers have been widely used for decades as additives in diverse applications, including consumer and building products, toys, cables, and floorings. Due to toxicological concerns and restrictions of different dialkyl ortho-phthalates, other plasticizers have been increasingly used in recent years. Therefore, di-isononyl cyclohexane-1,2-dicarboxylate (DINCH), di(2-ethylhexyl) terephthalate (DEHT), di(2-ethylhexyl) adipate (DEHA), acetyl tri-n-butyl citrate (ATBC), and trioctyl trimellitate (TOTM) plasticizer levels in indoor air and dust samples from 63 daycare centers in Germany were measured. Moreover, the urine samples of 208 children who attend 27 of these facilities were analyzed for the presence of four DINCH metabolites. DINCH, DEHT, and DEHA were present in indoor air with median values of 108 ng/m(3), 20 ng/m(3), and 34 ng/m(3), respectively. Median values of 302 mg/kg for DINCH, 49 mg/kg for DEHA, 40 mg/kg for DEHT, and 24 mg/kg ATBC were found in dust. In the urine samples, the three secondary metabolites of DINCH were observed with median values (95th percentiles) of 1.7 µg/l (10.0 µg/l) for OH-MINCH, 1.5 µg/l (8.0 µg/l) for oxo-MINCH, and 1.1 µg/l (6.1 µg/l) for cx-MINCH. Overall, these metabolite levels are orders of magnitude lower than the current HBM I values set by the German Human Biomonitoring Commission. Using general exposure assumptions, the intake resulting from dust ingestion and inhalation is low for children. The total daily DINCH intake calculated from biomonitoring data was 0.5 µg/kg b.w. using median values and 9.8 µg/kg b.w. as the maximum value. At present, non-phthalate plasticizers, especially DINCH, can be found in considerable amounts in dust samples from daycare centers and as DINCH metabolites in the urine of children. In relation to previous studies, the concentrations of DINCH in dust and urine have an increasing time trend. Compared with tolerable daily intake values, the total daily intake of DINCH reached only 1% of its maximum value to date; however, due to its increased use, higher exposure of DINCH is expected in the future.

[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.

Long-lived plasma cells are generated in mucosal immune responses and contribute to the bone marrow plasma cell pool in mice.

During systemic immune responses, plasma blasts are generated in secondary lymphoid organs and migrate to the bone marrow, where they can become long-lived, being responsible for the maintenance of long-term antibody titers. Plasma blasts generated in mucosal immune responses of the small intestine home to the lamina propria (LP), producing mainly immunoglobulin A. The migration of these antibody-secreting cells is well characterized during acute immune responses. Less is known about their lifetime and contribution to the long-lived bone marrow compartment. Here we investigate the lifetime of plasma cells (PCs) and the relationship between the PC compartments of the gut and bone marrow after oral immunization. Our findings indicate that PCs in the LP can survive for extended time periods. PCs specific for orally administered antigens can be detected in the bone marrow for at least 9 months after immunization, indicating that the mucosal PC compartment can contribute to the long-lived PC pool in this organ, independent of the participation of splenic B cells. Our findings suggest that the compartmentalization between mucosal and systemic PC pools is less strict than previously thought. This may have implications for the development of vaccines as well as for autoantibody-mediated diseases.

[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.