Tracheobronchomalacia due to amyloidosis in a patient with rheumatoid arthritis

In this case report, we describe a patient with longstanding rheumatoid arthritis who developed tracheobronchomalacia with fatal outcome. Despite negative antemortem biopsies of abdominal fat and tongue, amyloid was found postmortem in the trachea and appeared to be associated with tracheobronchomalacia

Sphingosine 1-phosphate receptor 5 mediates the immune quiescence of the human brain endothelial barrier

BACKGROUND: The sphingosine 1-phosphate (S1P) receptor modulator FTY720P (Gilenya®) potently reduces relapse rate and lesion activity in the neuroinflammatory disorder multiple sclerosis. Although most of its efficacy has been shown to be related to immunosuppression through the induction of lymphopenia, it has been suggested that a number of its beneficial effects are related to altered endothelial and blood–brain barrier (BBB) functionality. However, to date it remains unknown whether brain endothelial S1P receptors are involved in the maintenance of the function of the BBB thereby mediating immune quiescence of the brain. Here we demonstrate that the brain endothelial receptor S1P(5) largely contributes to the maintenance of brain endothelial barrier function. METHODS: We analyzed the expression of S1P(5) in human post-mortem tissues using immunohistochemistry. The function of S1P(5) at the BBB was assessed in cultured human brain endothelial cells (ECs) using agonists and lentivirus-mediated knockdown of S1P(5). Subsequent analyses of different aspects of the brain EC barrier included the formation of a tight barrier, the expression of BBB proteins and markers of inflammation and monocyte transmigration. RESULTS: We show that activation of S1P(5) on cultured human brain ECs by a selective agonist elicits enhanced barrier integrity and reduced transendothelial migration of monocytes in vitro. These results were corroborated by genetically silencing S1P(5) in brain ECs. Interestingly, functional studies with these cells revealed that S1P(5) strongly contributes to brain EC barrier function and underlies the expression of specific BBB endothelial characteristics such as tight junctions and permeability. In addition, S1P(5) maintains the immunoquiescent state of brain ECs with low expression levels of leukocyte adhesion molecules and inflammatory chemokines and cytokines through lowering the activation of the transcription factor NFκB. CONCLUSION: Our findings demonstrate that S1P(5) in brain ECs contributes to optimal barrier formation and maintenance of immune quiescence of the barrier endothelium

Telemonitoring of Daily Activity and Symptom Behavior in Patients with COPD

Objectives. This study investigated the activity behavior of patients with COPD in detail compared to asymptomatic controls, and the relationship between subjective and objective activities (awareness), and readiness to change activity behavior. Methods. Thirtynine patients with COPD (66.0 years; FEV 1 % predicted: 44.9%) and 21 healthy controls (57.0 years) participated. Objective daily activity was assessed by accelerometry and expressed as amount of activity in counts per minute (cpm). Patients' baseline subjective activity and stage of change were assessed prior to measurements. Results. Mean daily activity in COPD patients was significantly lower compared to the healthy controls (864 ± 277 cpm versus 1162 ± 282 cpm, P < 0.001). COPD patients showed a temporary decrease in objective activities in the early afternoon. Objective and subjective activities were significantly moderately related and most patients (55.3%) were in the maintenance phase of the stages of change. Conclusions. COPD patients show a distinctive activity decrease in the early afternoon. COPD patients are moderately aware of their daily activity but regard themselves as physically active. Therefore, future telemedicine interventions might consider creating awareness of an active lifestyle and provide feedback that aims to increase and balance activity levels

Instructions for Authors

Nonadherence to medical therapy is frequently encountered in patients with inflammatory bowel disease (IBD). We aimed to identify predictors for future (non)adherence in IBD

Development and Internal Validation of a Multivariable Prediction Model for Adrenocortical-Carcinoma-Specific Mortality

Adrenocortical carcinoma (ACC) has an incidence of about 1.0 per million per year. In general, survival of patients with ACC is limited. Predicting survival outcome at time of diagnosis is a clinical challenge. The aim of this study was to develop and internally validate a clinical prediction model for ACC-specific mortality. Data for this retrospective cohort study were obtained from the nine centers of the Dutch Adrenal Network (DAN). Patients who presented with ACC between 1 January 2004 and 31 October 2013 were included. We used multivariable Cox proportional hazards regression to compute the coefficients for the prediction model. Backward stepwise elimination was performed to derive a more parsimonious model. The performance of the initial prediction model was quantified by measures of model fit, discriminative ability, and calibration. We undertook an internal validation step to counteract the possible overfitting of our model. A total of 160 patients were included in the cohort. The median survival time was 35 months, and interquartile range (IQR) 50.7 months. The multivariable modeling yielded a prediction model that included age, modified European Network for the Study of Adrenal Tumors (mENSAT) stage, and radical resection. The c-statistic was 0.77 (95% Confidence Interval: 0.72, 0.81), indicating good predictive performance. We developed a clinical prediction model for ACC-specific mortality. ACC mortality can be estimated using a relatively simple clinical prediction model with good discriminative ability and calibration

Subcutaneous tumor seeding after biopsy in gliomatosis cerebri

We observed a patient with subcutaneous seeding from gliomatosis cerebri with a low-grade histopathology. A 33-year-old woman with neurofibromatosis type 1 presented with progressive headache, diplopia, dysphagia, and a rightward instability. On neurological examination dysarthria, gait ataxia, and left-sided central facial and hypoglossal palsies were determined. MRI of the brain demonstrated diffuse, infiltrative non-enhancing lesions in the pons, both cerebellar hemispheres, the parahippocampal gyrus, and the thalamus. A stereotactic biopsy demonstrated an astrocytoma WHO grade 2. These characteristics confirmed gliomatosis cerebri. Three months later, the patient presented with hydrocephalus and a subcutaneous swelling directly underneath the surgical scar. The subcutaneous swelling was removed and the hydrocephalus was treated by ventriculoperitoneal shunting. Histopathological examination confirmed a subcutaneous manifestation of low-grade oligoastrocytoma. Gliomatosis cerebri with low-grade histology can seed subcutaneously

High-throughput Proteomics Identifies THEMIS2 as Independent Biomarker of Treatment-free Survival in Untreated CLL

It remains challenging in chronic lymphocytic leukemia (CLL) to distinguish between patients with favorable and unfavorable time-to-first treatment (TTFT). Additionally, the downstream protein correlates of well-known molecular features of CLL are not always clear. To address this, we selected 40 CLL patients with TTFT ≤24 months and compared their B cell intracellular protein expression with 40 age- and sex-matched CLL patients with TTFT &gt;24 months using mass spectrometry. In total, 3268 proteins were quantified in the cohort. Immunoglobulin heavy-chain variable (IGHV) mutational status and trisomy 12 were most impactful on the CLL proteome. Comparing cases to controls, 5 proteins were significantly upregulated, whereas 3 proteins were significantly downregulated. Of these, only THEMIS2, a signaling protein acting downstream of the B cell receptor, was significantly associated with TTFT, independently of IGHV and TP53 mutational status (hazard ratio, 2.49 [95% confidence interval, 1.62-3.84]; P &lt; 0.001). This association was validated on the mRNA and protein level by quantitative polymerase chain reaction and ELISA, respectively. Analysis of 2 independently generated RNA sequencing and mass spectrometry datasets confirmed the association between THEMIS2 expression and clinical outcome. In conclusion, we present a comprehensive characterization of the proteome of untreated CLL and identify THEMIS2 expression as a putative biomarker of TTFT.</p

Host‐derived population genomics data provides insights into bacterial and diatom composition of the killer whale skin

Recent exploration into the interactions and relationship between hosts and their microbiota has revealed a connection between many aspects of the host's biology, health and associated micro-organisms. Whereas amplicon sequencing has traditionally been used to characterize the microbiome, the increasing number of published population genomics data sets offers an underexploited opportunity to study microbial profiles from the host shotgun sequencing data. Here, we use sequence data originally generated from killer whale Orcinus orca skin biopsies for population genomics, to characterize the skin microbiome and investigate how host social and geographical factors influence the microbial community composition. Having identified 845 microbial taxa from 2.4 million reads that did not map to the killer whale reference genome, we found that both ecotypic and geographical factors influence community composition of killer whale skin microbiomes. Furthermore, we uncovered key taxa that drive the microbiome community composition and showed that they are embedded in unique networks, one of which is tentatively linked to diatom presence and poor skin condition. Community composition differed between Antarctic killer whales with and without diatom coverage, suggesting that the previously reported episodic migrations of Antarctic killer whales to warmer waters associated with skin turnover may control the effects of potentially pathogenic bacteria such as Tenacibaculum dicentrarchi. Our work demonstrates the feasibility of microbiome studies from host shotgun sequencing data and highlights the importance of metagenomics in understanding the relationship between host and microbial ecology

Detection of terahertz frequency radiation via the photothermoelastic response of zincblende crystals

We present experimental evidence for a photothermoelastic response in zincblende crystals illuminated by quantum cascade laser sources in the frequency range 2.2&#x2013;2.9&#xA0;THz. Results obtained using an optically balanced sampling arrangement indicate a mechanism whereby the stress distribution established through localized heating of the crystal induces a change in optical birefringence via the photoelastic response of the crystal. A full mathematic model of this photothermoelastic mechanism in (110)-orientated crystals is presented, and shown to agree well with experimental measurements of the magnitude, and the orientational and spatial dependencies of the sampled signal in ZnTe and GaP crystals