Identification of an early-stage Parkinson's disease neuromarker using event-related potentials, brain network analytics and machine-learning.

OBJECTIVE: The purpose of this study is to explore the possibility of developing a biomarker that can discriminate early-stage Parkinson's disease from healthy brain function using electroencephalography (EEG) event-related potentials (ERPs) in combination with Brain Network Analytics (BNA) technology and machine learning (ML) algorithms. BACKGROUND: Currently, diagnosis of PD depends mainly on motor signs and symptoms. However, there is need for biomarkers that detect PD at an earlier stage to allow intervention and monitoring of potential disease-modifying therapies. Cognitive impairment may appear before motor symptoms, and it tends to worsen with disease progression. While ERPs obtained during cognitive tasks performance represent processing stages of cognitive brain functions, they have not yet been established as sensitive or specific markers for early-stage PD. METHODS: Nineteen PD patients (disease duration of ≤2 years) and 30 healthy controls (HC) underwent EEG recording while performing visual Go/No-Go and auditory Oddball cognitive tasks. ERPs were analyzed by the BNA technology, and a ML algorithm identified a combination of features that distinguish early PD from HC. We used a logistic regression classifier with a 10-fold cross-validation. RESULTS: The ML algorithm identified a neuromarker comprising 15 BNA features that discriminated early PD patients from HC. The area-under-the-curve of the receiver-operating characteristic curve was 0.79. Sensitivity and specificity were 0.74 and 0.73, respectively. The five most important features could be classified into three cognitive functions: early sensory processing (P50 amplitude, N100 latency), filtering of information (P200 amplitude and topographic similarity), and response-locked activity (P-200 topographic similarity preceding the motor response in the visual Go/No-Go task). CONCLUSIONS: This pilot study found that BNA can identify patients with early PD using an advanced analysis of ERPs. These results need to be validated in a larger PD patient sample and assessed for people with premotor phase of PD.

Dicer Sequencing, Whole Genome Methylation Profiling, mRNA and smallRNA Sequencing Analysis in Basal Cell Carcinoma.

BACKGROUND/AIMS: Perturbations in the expression of microRNAs (miRNAs) and their maturing machinery components such as Dicer have been previously described for basal cell carcinoma (BCC). However, the mutational status of Dicer in BCC is unclear. Further, the sclerodermiform subtype of BCC (sBCC) has not been previously investigated regarding its methylation profile or its smallRNA expression profile via RNA sequencing. We conducted this study to investigate the mutational status of Dicer in BCC. METHODS: Dicer sequencing was performed on the Illumina MiSeq System in a total of 16 BCC samples (8 nodular BCCs, 8 sBCCs) and mapped against the human reference genome (i.e., hg19). Dicer sequencing was performed in all 16 BCC samples. We performed whole genome methylation profiling with Infinium MethylationEPIC BeadChips as well as mRNA and smallRNA sequencing in 5 sBCCs with the Illumina NextSeq500 next-generation sequencing system. RESULTS: Compared to the wildtype Dicer sequence, we found 5 to 7 variants per sBCC sample including insertion, deletion, and multiple nucleotide variants. Global methylation profiles were highly similar between groups. mRNA sequencing revealed S100A9, KRT14, KRT10, S100A8, S100A7, COX1, KRT1, COX3, and smallRNA sequencing analysis miR-21, miR-99a, miR26-a-2, let-7f, let-7g, let-7i, miR-100, and miR-205 were the most strongly expressed in sBCCs. CONCLUSION: We identified a variety of Dicer mutations that could play a role in aberrant miRNA expression in BCC. The noted RNA sequences should be further evaluated in functional studies to explore their potential pathogenetic role in sBCC.

Circular RNA expression in cutaneous squamous cell carcinoma.

BACKGROUND: CircularRNAs (circRNAs) are a reinvented class of abundant, stable, and evolutionary conserved non-coding RNAs with pivotal impacts on the cellular regulatory network and epigenetics by sequestering microRNAs (miRNAs) like a sponge. OBJECTIVE: Purpose of the present study was to investigate circRNA expression in cutaneous squamous cell carcinoma (cSCC). METHODS: A total of six cSCC and six non-lesional skin (control) biopsies were harvested. Microarray based circRNA expression was determined in the cSCC (n=3) and compared with the non-lesional skin (n=3) from a group of 13,617 distinct human circRNAs found in the Arraystar circRNA Array V2.0 (Arraystar, Rockville, USA). Microarray data were validated by quantitative real-time reverse transcription polymerase chain reaction in a separate group (cSCC, n=3 and non-lesional skin, n=3). miRNA binding to miRNA response elements (MREs) sequence data were acquired bioinformatically. Further data mining was performed to identify circRNAs containing MRE sequences that interacted with previously described miRNAs playing a role in cSCC formation. RESULTS: A total of 322 circRNAs (143 up- and 179 down-regulated; fold change ≥2 and p<0.05) were identified as differentially expressed in cSCC. Furthermore, we identified a total of 1603 MREs that were part of the differentially expressed circRNAs. Among those circRNAs, a complementary MRE sequence was identified in 23 miRNAs previously known to be cSCC relevant. CONCLUSION: This study showed that circRNAs are differentially expressed in cSCC and play an important role in tumor formation by interfering with cSCC relevant miRNAs through miRNA sequence complementary MREs participating in epigenetic control.

Expression profiles of long noncoding RNAs in cutaneous squamous cell carcinoma.

BACKGROUND: Despite there being over 35,000 different long noncoding RNA (lncRNA) sequences described little is known regarding their molecular-pathological role in cutaneous squamous cell carcinoma (cSCC). MATERIALS & METHODS: In this pilot study, lncRNA and mRNA expression profiles were determined in cSCC and control (n = 6) by an Arraystar human lncRNA Microarray. Kyoto Encyclopedia of Genes and Genomes pathway enrichment and gene ontology analysis of mRNAs was performed. RESULTS: Analysis of differential expression revealed 1516 upregulated lncRNAs and 2586 downregulated lncRNAs in cSCC compared with controls. Data analysis identified known oncogenic lncRNAs, such as the HOX transcript antisense RNA HOTAIR, among the differentially expressed lncRNA sequences. Kyoto Encyclopedia of Genes and Genomes pathway analysis showed that focal adhesion, extracellular matrix and the oncogenic phosphatidylinositol 3'-kinase-Akt signaling pathway had the highest enrichment scores. CONCLUSION: This study provides the first evidence for differential expression of lncRNA in cSCC and serves as a template for further, larger functional in-depth analyses regarding cSCC molecular lncRNAs.

Circular RNA expression in basal cell carcinoma.

AIM: Circular RNAs (circRNAs), are nonprotein coding RNAs consisting of a circular loop with multiple miRNA, binding sites called miRNA response elements (MREs), functioning as miRNA sponges. This study was performed to identify differentially expressed circRNAs and their MREs in basal cell carcinoma (BCC). MATERIALS & METHODS: Microarray circRNA expression profiles were acquired from BCC and control followed by qRT-PCR validation. Bioinformatical target prediction revealed multiple MREs. Sequence analysis was performed concerning MRE interaction potential with the BCC miRNome. RESULTS: We identified 23 upregulated and 48 downregulated circRNAs with 354 miRNA response elements capable of sequestering miRNA target sequences of the BCC miRNome. CONCLUSION: The present study describes a variety of circRNAs that are potentially involved in the molecular pathogenesis of BCC.

Long-noncoding RNAs in basal cell carcinoma.

Long noncoding RNAs (lncRNAs) are fundamental regulators of pre- and post-transcriptional gene regulation. Over 35,000 different lncRNAs have been described with some of them being involved in cancer formation. The present study was initiated to describe differentially expressed lncRNAs in basal cell carcinoma (BCC). Patients with BCC (n = 6) were included in this study. Punch biopsies were harvested from the tumor center and nonlesional epidermal skin (NLES, control, n = 6). Microarray-based lncRNA and mRNA expression profiles were identified through screening for 30,586 lncRNAs and 26,109 protein-coding transcripts (mRNAs). The microarray data were validated by RT-PCR in a second set of BCC versus control samples. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses of mRNAs were performed to assess biologically relevant pathways. A total of 1851 lncRNAs were identified as being significantly up-regulated, whereas 2165 lncRNAs were identified as being significantly down-regulated compared to nonlesional skin (p < 0.05). Oncogenic and/or epidermis-specific lncRNAs, such as CASC15 or ANRIL, were among the differentially expressed sequences. GO analysis showed that the highest enriched GO targeted by up-regulated transcripts was "extracellular matrix." KEGG pathway analysis showed the highest enrichment scores in "Focal adhesion." BCC showed a significantly altered lncRNA and mRNA expression profile. Dysregulation of previously described lncRNAs may play a role in the molecular pathogenesis of BCC and should be subject of further analysis.

A pilot study of quality of life in German prehospital emergency care physicians.

BACKGROUND: Quality of life in patients represents an important area of assessment. However, attention to health professionals should be equally important. The literature on the quality of life (QOL) of emergency physicians is scarce. This pilot study investigated QOL in emergency physicians in Germany. MATERIALS AND METHODS: We conducted a cross-sectional study from January to June in 2015. We approached the German Association of Emergency Medicine Physicians and two of the largest recruitment agencies for emergency physicians in Germany and invited their members to participate. We used the WHO Q-BREF to obtain QOL scores in four domains that included physical, mental, social, and environmental health. RESULTS: The 478 German emergency physicians included in the study held board certifications in general medicine (n = 40; 8.4%), anesthesiology (n = 243; 50.8%), surgery (n = 63; 13.2%), internal medicine (n = 81; 17.0%), or others (n = 51; 10.7%). The women surveyed tended to report a better QOL but worse general health than the men. Regarding specific domains, women scored worse in physical health, particularly energy during everyday work (relative risk ratio [RRR]: 1.98 [1.21-3.24]). Both men and women scored worse in psychological health than general health, particularly young women. Women were also more likely to view their safety (RRR: 1.87 [1.07-3.28]) and living place (RRR: 2.51 [1.10-5.73]) as being poor than their male counterparts. CONCLUSION: QOL in German prehospital emergency care physicians is satisfactory for the included participants; however, there were some negative effects in the psychological health domain. This is particularly obvious in young female emergency physicians.

Mutation Scanning of D1705 and D1709 in the RNAse IIIb Domain of MicroRNA Processing Enzyme Dicer in Cutaneous Melanoma.

Since the discovery of microRNAs (miRNAs) there have been performed several studies showing perturbations in the expression of miRNAs and the miRNA expression machinery in cutaneous melanoma. Dicer, a pivotal cytosolic enzyme of miRNA maturation has shown to be affected by both somatic and germline mutations in a variety of cancers. Recent studies have shown that recurrent somatic mutations of Dicer frequently affect the metal-ion-binding sites D1709 and D1705 of its RNase IIIb domain, therefore called hot spot mutations. The present study investigates metal-ion-binding sites D1709 and D1705 of the Dicer RNase IIIb domain in cutaneous melanomas and melanoma metastasis by Sanger sequencing. All investigated samples showed wildtype sequence and no single mutation was detected. The miRNA processing enzyme Dicer of melanoma and melanoma metastasis does not appear to be affected by mutation in the metal-ion-binding sites D1709 and D1705 of its RNase IIIb domain.

Comparative microarray analysis of microRNA expression profiles in primary cutaneous malignant melanoma, cutaneous malignant melanoma metastases, and benign melanocytic nevi.

Perturbations in microRNA (miRNA) expression profiles have been reported for cutaneous malignant melanoma (CMM) predominantly when examined in cell lines. Despite the rapidly growing number of newly discovered human miRNA sequences, the availability of up-to-date miRNA expression profiles for clinical samples of primary cutaneous malignant melanoma (PCMM), cutaneous malignant melanoma metastases (CMMM), and benign melanocytic nevi (BMN) is limited. Specimens excised from the center of tumors (lesional) from patients with PCMM (n=9), CMMM (n=4), or BMN (n=8) were obtained during surgery. An exploratory microarray analysis was performed by miRNA expression profiling based on Agilent platform screening for 1205 human miRNAs. The results from the microarray analysis were validated by TaqMan quantitative real-time polymerase chain reaction. In addition to several miRNAs previously known to be associated with CMM, 19 unidentified miRNA candidates were found to be dysregulated in CMM patient samples. Among the 19 novel miRNA candidates, the genes hsa-miR-22, hsa-miR-130b, hsa-miR-146b-5p, hsa-miR-223, hsa-miR-301a, hsa-miR-484, hsa-miR-663, hsa-miR-720, hsa-miR-1260, hsa-miR-1274a, hsa-miR-1274b, hsa-miR-3663-3p, hsa-miR-4281, and hsa-miR-4286 were upregulated, and the genes hsa-miR-24-1*, hsa-miR-26a, hsa-miR-4291, hsa-miR-4317, and hsa-miR-4324 were downregulated. The results of this study partially confirm previous CMM miRNA profiling studies identifying miRNAs that are dysregulated in CMM. However, we report several novel miRNA candidates in CMM tumors; these miRNA sequences require further validation and functional analysis to evaluate whether they play a role in the pathogenesis of CMM.

MicroRNA in non-melanoma skin cancer.

MicroRNAs (miRNAs) are a fairly novel class of 17- to 23-nucleotide (nt), short, non-coding RNA molecules that have revolutionized our understanding of gene regulation and opened new possibilities in the future of gene therapy. Here, we review the potential role of miRNAs in non-melanoma skin cancer (NMSC) and summarize the current studies available in this new aspect of NMSC research.

Microarray analysis of microRNA expression in cutaneous squamous cell carcinoma.

BACKGROUND: MicroRNAs (miRNAs) are a novel class of short RNAs that are capable epigenetically regulating gene expression in eukaryotes. MicroRNAs have been shown to be dysregulated in a variety of cancers. The data on miRNA expression in cutaneous squamous cell carcinoma (cSCC) are very limited, and microarray-based miRNA expression profiles of cSCC have not yet been determined. OBJECTIVE: To describe differentially expressed miRNAs in cSCC. METHODS: Seven patients with cSCC were enrolled in the present study. Tumor biopsies (n=7) were taken from the center of each tumor. Adjacent healthy skin (n=7) was biopsied as a control (intraindividual control). miRNA expression profiles of all specimens were detected by microarray miRNA expression profiling based on miRBAse 16 scanning for 1205 potential human miRNA target sequences. The microarray results were confirmed by TaqMan quantitative real-time polymerase chain reaction (qRT-PCR). RESULTS: Non-stringent filtering with a non-adjusted p ≤ 0.05 revealed thirteen up-regulated and eighteen down-regulated miRNAs. Non-stringent filtering with a non-adjusted p ≤ 0.01 revealed three up-regulated (hsa-miR-135b, hsa-miR-424 and hsa-miR-766) and six down-regulated (hsa-miR-30a*, hsa-miR-378, hsa-miR-145, hsa-miR-140-3p, hsa-miR-30a and hsa-miR-26a) miRNAs in cSCC. CONCLUSION: This study reveals differentially expressed miRNAs that may play a role in the molecular pathogenesis of cSCC and that are excellent candidates for further validation and functional analysis.

The miRNA machinery in primary cutaneous malignant melanoma, cutaneous malignant melanoma metastases and benign melanocytic nevi.

Although several studies have shown a dysregulation of microRNA (miRNA) expression profiles in cutaneous melanoma, there has been little research on the miRNA machinery itself. In this study, we investigated the mRNA expression profiles of different miRNA machinery components in primary cutaneous malignant melanoma (PCMM), cutaneous malignant melanoma metastases (CMMM) and benign melanocytic nevi (BMN). Patients with PCMM (n = 7), CMMM (n = 6) and BMN (n = 7) were included in the study. Punch biopsies were harvested from the centers of tumors (lesional) and from BMN (control). In contrast to previous reports exploring specific clusters of miRNAs in PCMM, the present study investigates mRNA expression levels of Dicer, Drosha, Exp5, DGCR8 and the RISC components PACT, argonaute-1, argonaute-2, TARBP1, TARBP2, MTDH and SND1, which were detected by TaqMan real-time reverse transcription polymerase chain reaction (RT-PCR). Argonaute-1, TARBP2 and SND1 expression levels were significantly higher in BMN compared to PCMM (p < 0.05). TARBP2 expression levels were significantly higher in CMMM compared to PCMM (p < 0.05). SND1 expression levels were significantly higher in CMMM compared to PCMM and BMN (p < 0.05). Dicer, Drosha, DGCR8, Exp5, argonaute-2, PACT, TARBP1 and MTDH expression levels showed no significant differences within groups (p > 0.05). The results of this study show that the miRNA machinery components argonaute-1, TARBP2 and SND1 are dysregulated in PCMM and CMMM compared to BMN and may play a role in the process of malignant transformation.

Expression levels of the microRNA maturing microprocessor complex component DGCR8 and the RNA-induced silencing complex (RISC) components argonaute-1, argonaute-2, PACT, TARBP1, and TARBP2 in epithelial skin cancer.

The microprocessor complex mediates intranuclear biogenesis of precursor microRNAs from the primary microRNA transcript. Extranuclear, mature microRNAs are incorporated into the RNA-induced silencing complex (RISC) before interaction with complementary target mRNA leads to transcriptional repression or cleavage. In this study, we investigated the expression profiles of the microprocessor complex subunit DiGeorge syndrome critical region gene 8 (DGCR8) and the RISC components argonaute-1 (AGO1), argonaute-2 (AGO2), as well as double-stranded RNA-binding proteins PACT, TARBP1, and TARBP2 in epithelial skin cancer and its premalignant stage. Patients with premalignant actinic keratoses (AK, n = 6), basal cell carcinomas (BCC, n = 15), and squamous cell carcinomas (SCC, n = 7) were included in the study. Punch biopsies were harvested from the center of the tumors (lesional), from healthy skin sites (intraindividual controls), and from healthy skin sites in a healthy control group (n = 16; interindividual control). The DGCR8, AGO1, AGO2, PACT, TARBP1, and TARBP2 mRNA expression levels were detected by quantitative real-time reverse transcriptase polymerase chain reaction. The DGCR8, AGO1, AGO2, PACT, and TARBP1 expression levels were significantly higher in the AK, BCC, and SCC groups than the healthy controls (P < 0.05). There was no significant difference in the TARBP2 expression levels between groups (P > 0.05). This study indicates that major components of the miRNA pathway, such as the microprocessor complex and RISC, are dysregulated in epithelial skin cancer.

Immunohistochemical expression patterns of the microRNA-processing enzyme Dicer in cutaneous malignant melanomas, benign melanocytic nevi and dysplastic melanocytic nevi.

Dicer is an essential cytosolic enzyme necessary for processing pre-microRNAs into mature microRNAs (miRNAs). Although a variety of malignancies have been attributed to perturbations in the miRNA machinery, there has been little research conducted on the role of miRNAs in cutaneous malignant melanoma and its premalignant lesions. In this small pilot study, we therefore investigated the distribution of Dicer by immunohistochemistry in cutaneous malignant melanomas, as well as in benign and dysplastic melanocytic nevi. Dicer was assessed in ten cutaneous malignant melanomas (CMM), benign melanocytic nevi (BMN), and dysplastic melanocytic nevi (DMN), by standard immunohistochemical staining. Semiquantitative analyses determined expression indices (EIs), which associate the conventional area fraction of labeled cells with immunostaining intensity scores, based on visual qualitative examination by two independent observers. Mean EI scores were significantly higher in the CMM group compared to those in the BMN group (p < 0.05). However, EI differences between BMN and DMN as well as between CMM and DMN were not significant (p > 0.05). For CMM we observed a significant correlation of Breslow tumor thickness and Dicer EI (r â€Š=  0.84, p â€Š=  0.022). For all three groups investigated, Dicer-positive staining was primarily located in the epidermis, specifically in melanocytes. By immunohistochemistry, Dicer staining was significantly higher in melanoma cells than in benign melanocytes. This preliminary study indicates that alterations in the miRNA machinery could exist and should be subject of further investigation.

Cutaneous lesions of the nose.

Skin diseases on the nose are seen in a variety of medical disciplines. Dermatologists, otorhinolaryngologists, general practitioners and general plastic and dermatologic surgeons are regularly consulted regarding cutaneous lesions on the nose. This article is the second part of a review series dealing with cutaneous lesions on the head and face, which are frequently seen in daily practice by a dermatologic surgeon. In this review, we focus on those skin diseases on the nose where surgery or laser therapy is considered a possible treatment option or that can be surgically evaluated.

Expression levels of the microRNA processing enzymes Drosha and dicer in epithelial skin cancer.

BACKGROUND: Dysregulation of microRNA (miRNA) metabolism has been observed in a variety of human cancers. In this pilot study, we investigated expression profiles of the two most important enzymes of the miRNA machinery, Drosha and Dicer, in relation to epithelial skin cancer and its premalignant stage. METHODS: Patients with premalignant actinic keratoses (AK, n = 6), basal cell carcinomas (BCC, n = 15), and squamous cell carcinomas (SCC, n = 7) were included in the study. Punch biopsies were harvested from the center of the tumors (lesional) as well as from sites of healthy skin (intraindividual controls). Skin samples (n = 14) were also obtained from healthy subjects for additional controls. Dicer and Drosha mRNA levels were detected by quantitative real-time reverse transcriptase polymerase chain reaction. RESULTS: Drosha expression levels were significantly upregulated in both the BCC and SCC groups compared to those in the healthy controls (p < .01), while Dicer expression levels in the BCC group were significantly lower (p < .05). Dicer expression in the SCC group was significantly higher compared to intraindividual controls (p < .05), while Dicer expression levels in both the SCC and AK groups were not significantly different from healthy control samples (p > .05). In the premalignant AK group, we could not observe any significant difference in Drosha or Dicer expression levels compared to either healthy or intraindividual controls (p > .05). CONCLUSIONS: We observed dysregulation of Drosha and Dicer expression in epithelial tumors when compared to healthy control samples. Therefore, we favor the hypothesis that miRNAs are involved in the carcinogenesis of epithelial skin cancer.

Diagnostic value of hyperbilirubinemia as a predictive factor for appendiceal perforation in acute appendicitis.

BACKGROUND: Appendiceal perforation in patients with acute appendicitis may cause a variety of potentially life-threatening complications. Escherichia coli endotoxin has been shown to impact physiological bile flow in vivo. This had led to the theory that hyperbilirubinemia in patients with appendicitis may have a predictive potential for the preoperative diagnosis of appendiceal perforation. The aim of this retrospective study was to investigate the diagnostic value of hyperbilirubinemia as a preoperative laboratory marker for appendiceal perforation in patients with acute appendicitis. METHODS: We identified 538 patients (306 female; 232 male, mean age, 35.6 y) with histologically proved acute appendicitis who underwent laparoscopic or conventional appendectomy between January 2004 and December 2007 in a surgical department of an academic teaching hospital. A retrospective multiple chart review of the medical records including laboratory values and histologic results was conducted. RESULTS: The mean bilirubin level of all patients was .9 mg/dL (+/-.6 SD mg/dL; range, .1-4.3 mg/dL; median, .7 mg/dL). Patients with appendiceal perforation, however, had a mean bilirubin level of 1.5 mg/dL (+/-.9 SD mg/dL; range, .4-4.3 mg/dL; median, 1.4 mg/dL), which was significantly higher than those with a nonperforated appendicitis (P < .05). The specificity of hyperbilirubinemia for appendiceal perforation was .86 compared with .55 for white blood count and .35 for C-reactive protein. Sensitivity was .7 compared with .81 for white blood count and .96 for C-reactive protein. CONCLUSIONS: Patients with hyperbilirubinemia and clinical symptoms of appendicitis should be identified as having a higher probability of appendiceal perforation than those with normal bilirubin levels.

Orbital fibroblasts from patients with thyroid-associated ophthalmopathy overexpress CD40: CD154 hyperinduces IL-6, IL-8, and MCP-1.

PURPOSE: Fibroblast diversity represents an emerging concept critical to our understanding of tissue inflammation, repair, and remodeling. Orbital fibroblasts heterogeneously display Thy-1 and exhibit unique phenotypic attributes that may explain the susceptibility of the human orbit to thyroid-associated ophthalmopathy (TAO). In the present study the authors investigated the role of CD40 ligation on macrophage chemoattractant protein-1 (MCP-1), IL-6, and IL-8 expression in fibroblasts from patients with TAO. METHODS: Human orbital fibroblasts were cultured from tissues obtained with informed consent from patients with TAO and from patients undergoing surgery for other noninflammatory conditions. The fibroblasts were then examined by flow cytometry, microscopy, and cytokine assays. RESULTS: The authors report that orbital fibroblasts from patients with TAO expressed elevated levels of CD40. Surface CD40 could be further upregulated by IFN-gamma in TAO and control fibroblasts. This upregulation was mediated through Jak2 and could be blocked by dexamethasone and AG490, a powerful and specific inhibitor of tyrosine kinase. Treatment with CD154, the ligand for CD40, upregulated the expression of IL-6, IL-8, and MCP-1 in TAO fibroblasts but failed to do so in control cultures. Thy-1(+) fibroblasts displayed higher CD40 levels than did their Thy-1(-) counterparts and were largely responsible for this cytokine production. IL-1beta also induced MCP-1, IL-6, and IL-8 more vigorously in TAO-derived fibroblasts. CONCLUSIONS: Characterization of orbital fibroblasts and their differential expression of cytokines and receptors should prove invaluable in understanding the site-specific nature of TAO and the development of specific therapies.

Surgical and medical emergencies on board European aircraft: a retrospective study of 10189 cases.

INTRODUCTION: In-flight medical and surgical emergencies (IMEs) onboard commercial aircrafts occur quite commonly. However, little epidemiological research exists concerning these incidents. METHODS: Thirty-two European airlines were asked to provide anonymous data on medical flight reports of IMEs for the years 2002 to 2007. The total number of incidents was correlated to revenue passenger kilometers (rpk). Additionally, on-board births and deaths, flight diversions, flight routes (continental/intercontinental) and involvement of a physician or medical professional in providing therapy were analysed. RESULTS: Only four airlines, of which two participated in this study, were able to provide the necessary data. A total of 10,189 cases of IMEs were analysed. Syncope was the most common medical condition reported (5307 cases, 53.5%) followed by gastrointestinal disorders (926 cases, 8.9%) and cardiac conditions (509 cases, 4.9%). The most common surgical conditions were thrombosis (47 cases, 0.5%) and appendicitis (27 cases, 0.25%). In 2.8% of all IMEs, an aircraft diversion was performed. In 86% of cases, a physician or medical professional was involved in providing therapy. A mean (standard deviation) of 14 (+/- 2.3, 10.8 to 16.6 interquartile range) IMEs per billion rpk was calculated. CONCLUSIONS: The study demonstrates that although aviation is regulated by a variety of national and international laws, standardised documentation of IMEs is inadequate and needs further development.