Distribution of MHC II (+) cells in skin of the Atlantic bottlenose dolphin (Tursiops truncatus): an initial investigation of dolphin dendritic cells

The skin is an important tissue of the immune system; however, little is known about immune cells in dolphin skin, and very few cetacean-specific immunoreagents are available for investigative purposes. Therefore, in this study immunohistochemistry techniques were used with species-specific and non-species-specific antibodies to characterize immune cells, primarily focusing on Langerhans cells, in skin from the Atlantic bottlenose dolphin (Tursiops truncatus). An antibody to human major histocompatibility complex (MHC) class II molecules labeled cells with a dendritic-like morphology. The immunophenotype, morphology, and distribution of some of these cells are consistent with those of Langerhans cells. The cells were predominantly found in dermal papillae, primarily along the epidermal-dermal junction. Thus, the location of these cells was somewhat different from that in terrestrial mammals. Other MHC II (+) cells of varying morphology were observed deeper in the dermis, with a perivascular concentration, and had characteristics of macrophages and dermal dendritic cells. There was no immunostaining with cetacean-specific CD2 or CD21. In diseased skin, a subjective increase of MHC II (+) cells, most notably in the superficial skin layers, was associated with an ulcerative dermatitis. A few CD2 (+) cells were also present. Differences between dolphins and terrestrial mammals in terms of morphology, mechanisms of response to insult and repair, and environmental challenges may explain the modified distribution of MHC II (+) cells in dolphin skin. An elucidation of the immune cells in cetacean skin will contribute to our understanding of the evolution of functional adaptations to various environments, facilitate diagnosis of skin diseases, and define the potential for intradermal administration of vaccines and other immunotherapeutics.     

Persistent organochlorines, sedentary occupation, obesity and human male subfertility

BACKGROUND: Studies have suggested that the quality of human semen has been declining over recent decades, presumably because of lifestyle or environmental factors. METHODS: Polychlorinated biphenyls and organochlorine pesticides were analysed in the plasma of 25 men with poor semen quality, 20 men with normal semen quality and idiopathic subfertility and 27 men with normal semen quality and female factor subfertility. Samples of seminal fluid were also analysed to assess the relationship between the levels in blood and semen. RESULTS: The results indicate no difference in the levels of organochlorines between the groups. The levels of organochlorines in seminal fluid were proportional to the levels in plasma, but approximately 40 times lower. Men with poor semen quality were three times more likely to be obese than men with normal semen quality. There was also a significant negative correlation between semen quality parameters and body mass index among men with normal semen quality. The prevalence of sedentary work was lowest among men with the best semen quality. CONCLUSIONS: Poor semen quality was found to be associated with sedentary work and obesity but not with plasma levels of persistent organochlorines. More research is needed to assess whether sedentary lifestyle and obesity are causal factors in the decline of semen quality.     

Influence of scaffold thickness and scaffold composition on bioartificial graft survival

Biological scaffolds exhibit advantageous properties for tissue engineering of small diameter vessels. The influence of their extracellular matrix (ECM) components during in vivo repopulation is unknown. We implanted different xenogenic vascular matrices in a rat model to determine the influence of scaffold-thickness and ECM composition on in vivo repopulation. Decellularized ovine jugular vein (JV, n=42), carotid artery (CA, n=42) and aorta (AO, n=42) were implanted subcutaneously in the neck of adult male rats. Animals were sacrificed 2, 4 and 8 weeks after implantation. Cell and matrix morphology of explanted scaffolds were characterized by hematoxylin-eosin and pentachrome staining. Monoclonal anti-rat-CD31 was used to identify revascularization. Quantification of cell density was done by DNA-isolation.THICKNESS OF IMPLANTED XENOGENIC SCAFFOLDS VARIED ACCORDING TO THE MATERIAL USED (AO: 3.0-3.8mm; CA: 0.7-0.88mm; JV: 0.35-0.61mm). Immunohistology revealed complete repopulation of AO, CA, and JV scaffolds with endothelial cells and myofibroblasts within 2 weeks. After 8 weeks of implantation, AO scaffolds were completely covered by an endothelial monolayer and showed signs of a central matrix degeneration. JV scaffolds were completely degenerated at this stage. In contrast, CA scaffolds showed preserved ECM with a normal myofibroblast population and endothelial cell coverage.     

Vegan Diet and Bone Health—Results from the Cross-Sectional RBVD Study

Scientific evidence suggests that a vegan diet might be associated with impaired bone health. Therefore, a cross-sectional study (n = 36 vegans, n = 36 omnivores) was used to investigate the associations of veganism with calcaneal quantitative ultrasound (QUS) measurements, along with the investigation of differences in the concentrations of nutrition- and bone-related biomarkers between vegans and omnivores. This study revealed lower levels in the QUS parameters in vegans compared to omnivores, e.g., broadband ultrasound attenuation (vegans: 111.8 ± 10.7 dB/MHz, omnivores: 118.0 ± 10.8 dB/MHz, p = 0.02). Vegans had lower levels of vitamin A, B2, lysine, zinc, selenoprotein P, n-3 fatty acids, urinary iodine, and calcium levels, while the concentrations of vitamin K1, folate, and glutamine were higher in vegans compared to omnivores. Applying a reduced rank regression, 12 out of the 28 biomarkers were identified to contribute most to bone health, i.e., lysine, urinary iodine, thyroid-stimulating hormone, selenoprotein P, vitamin A, leucine, α-klotho, n-3 fatty acids, urinary calcium/magnesium, vitamin B6, and FGF23. All QUS parameters increased across the tertiles of the pattern score. The study provides evidence of lower bone health in vegans compared to omnivores, additionally revealing a combination of nutrition-related biomarkers, which may contribute to bone health. Further studies are needed to confirm these findings.     

Challenges and Opportunities for Real-World Evidence in Metastatic Luminal Breast Cancer

BackgroundThe therapeutic armamentarium for patients with metastatic breast cancer is becoming more and more specific. Recommendations from clinical trials are not available for all treatment situations and patient subgroups, and it is therefore important to collect real-world data.SummaryTo develop recommendations for up-to-date treatments and participation in clinical trials for patients with metastatic breast cancer, the Prospective Academic Translational Research PRAEGNANT Network was established to optimize the quality of oncological care in the advanced therapeutic setting. The main aim of PRAEGNANT is to systematically record medical care for patients with metastatic breast cancer in the real-life setting, including the outcome and side effects of different treatment strategies, to monitor quality-of-life changes during therapy, to identify patients eligible for participation in clinical studies, and to allow targeted therapies based on the molecular structures of breast carcinomas.Key MessagesThis article describes the PRAEGNANT network and sheds light on the question of whether the various end points from clinical trials can be transferred to the real-world treatment situation.     

Asthma und asthmatypische Beschwerden bei Schulkindern: Vergleich von Gebieten in Deutschland und Osterreich

Conclusion

Geographical differences in morbidity of asthma and asthmalike complaints were ascertained and remained stable after adjustment for potential confounders. However, the choice of the way of presentation (relative risk versus deviation from the weighted mean of the prevalences) can provoke different suggestive effects.     

Beihilfe zum Suizid bei psychisch Kranken

In the region of Basel in Switzerland 43 assisted suicides were registered between 1992 and 1997, eight percent of all suicides in the region. Assisted suicide was administered by the help-to-die society Exit. There was a psychiatric history in six of the suicides. Four of them suffered of serious physical illness as well. The analyses of these six suicides focuses on the conditions of assisted suicide in people with mental illness and the ethical problems arising.     

Imiquimod treatment induces expression of opioid growth factor receptor: a novel tumor antigen induced by interferon-alpha?

PURPOSE: Imiquimod represents a synthetic local immune response modifier that has demonstrated efficacy in clearing basal cell carcinoma. Via interaction with Toll-like receptor 7 on immune cells, imiquimod induces local production of cytokines, such as interferon (IFN)-alpha. EXPERIMENTAL DESIGN: To more closely define and elucidate mechanisms leading to basal cell carcinoma clearance in vivo, we examined gene expression profiles of skin basal cell carcinoma before and after treatment with 5% imiquimod cream (Aldara) by using high-density oligonucleotide arrays. RESULTS: We show that imiquimod predominantly induces genes involved in different aspects of immune response. In addition to effects on immunity, imiquimod treatment modulates the expression of genes involved in the control of apoptosis and oncogenesis. Array data indicated that imiquimod treatment induces expression of opioid growth factor receptor, a molecule recently reported to be a target for antitumor antibody responses. Immunohistochemistry revealed in vivo up-regulation of opioid growth factor receptor protein on tumor and on infiltrating cells after treatment. By using basal cell carcinoma cell lines treated with IFN-alpha or imiquimod, we show that opioid growth factor receptor up-regulation is IFN-alpha-mediated, rather then directly imiquimod-mediated. By using tissue microarray containing 52 basal cell carcinomas, we demonstrate opioid growth factor receptor expression in almost half of the cases. Expression of opioid growth factor receptor correlated with a longer recurrence-free period in basal cell carcinoma that recurred after radiotherapy (Kaplan-Meier analysis, P = 0.041). CONCLUSIONS: In addition to its immunomodulatory and antiproliferative activity, opioid growth factor receptor seems to have a prognostic significance in basal cell carcinoma patients. Our data add to the growing list of basal cell carcinoma-associated tumor antigens.     

Phase I study of the humanized antiepidermal growth factor receptor monoclonal antibody EMD72000 in patients with advanced solid tumors that express the epidermal growth factor receptor.

PURPOSE: To investigate the safety and tolerability and to explore the pharmacokinetic and pharmacodynamic profile of the humanized antiepidermal growth factor receptor monoclonal antibody EMD72000 in patients with solid tumors that express epidermal growth factor receptor (EGFR). PATIENTS AND METHODS: This was a phase I dose-escalation trial of EMD72000 in patients with advanced, EGFR-positive, solid malignancies that were not amenable to any established chemotherapy or radiotherapy treatment. EMD72000 was administered weekly without routine premedication until disease progression or unacceptable toxicity. RESULTS: Twenty-two patients were treated with EMD72000 at five different dose levels (400 to 2,000 mg/wk). National Cancer Institute common toxicity criteria grade 3 headache and fever occurring after the first infusion were dose limiting at 2,000 mg/wk; thus, the maximum-tolerated dose was 1,600 mg/wk. No other severe side effects, especially no allergic reactions or diarrhea, were observed. Acneiform skin reaction was the most common toxicity, but it was mild, with grade 1 in 11 patients (50%) and grade 2 in three patients (14%). Pharmacokinetic analyses demonstrated a predictable pharmacokinetic profile for EMD72000. Pharmacodynamic studies on serial skin biopsies revealed that EMD72000 effectively abrogated EGFR-mediated cell signaling (eg, reduced phosphorylation of EGFR and mitogen-activated protein kinase), with no alteration in total EGFR protein. Objective responses (23%; 95% CI, 8% to 45%) and disease stabilization (27%; 95% CI, 11% to 50%) were achieved at all dose levels, and responding patients received treatment for up to 18 months without cumulative toxicity. CONCLUSION: Treatment with EMD72000 was well tolerated and showed evidence of activity in heavily pretreated patients with EGFR-expressing tumors. EMD72000 at the investigated doses significantly inhibited downstream EGFR-dependent processes.