International multicentre observational study to assess the efficacy and safety of a 0·5 mg kg−1 per day starting dose of oral corticosteroids to treat bullous pemphigoid

BackgroundEuropean guidelines propose a 0 center dot 5 mg kg(-1) per day dose of oral prednisone as initial treatment for bullous pemphigoid (BP). We assessed the safety and efficacy of this regimen depending on BP extent and general condition of the patients.MethodsIn a prospective international study, we consecutively included all patients diagnosed with BP. Patients received a 0 center dot 5 mg kg(-1) per day dose of prednisone, which was then gradually tapered 15 days after disease control, with the aim of stopping prednisone or maintaining minimal treatment (0 center dot 1 mg kg(-1) per day) within 6 months after the start of treatment. The two coprimary endpoints were control of disease activity at day 21 and 1-year overall survival. Disease severity was assessed according to the Bullous Pemphigoid Disease Area Index (BPDAI) score.ResultsIn total, 198 patients were included between 2015 and 2017. The final analysis comprised 190 patients with a mean age of 80 center dot 9 (SD 9 center dot 1) years. Control of disease activity was achieved at day 21 in 119 patients [62 center dot 6%, 95% confidence interval (CI) 55 center dot 3-69.5]; 18 of 24 patients (75%, 95% CI 53 center dot 3-90 center dot 2), 75 of 110 patients (68 center dot 8%, 95% CI 59 center dot 2-77 center dot 3) and 26 of 56 patients (46.4%, 95% CI 33 center dot 0-60 center dot 3) had mild, moderate and severe BP, respectively (P = 0 center dot 0218). A total of 30 patients died during the study. The overall Kaplan-Meier 1-year survival was 82 center dot 6% (95% CI 76 center dot 3-87 center dot 4) corresponding to 90 center dot 9%, 83 center dot 0% and 80 center dot 0% rates in patients with mild, moderate and severe BP, respectively (P = 0 center dot 5). Thresholds of 49 points for BPDAI score and 70 points for Karnofsky score yielded maximal Youden index values with respect to disease control at day 21 and 1-year survival, respectively.ConclusionsA 0 center dot 5 mg kg(-1) per day dose of prednisone is a valuable therapeutic option in patients with mild or moderate BP whose general condition allows them to be autonomous.</p

Lipopolysaccharide stress induces cell-type specific production of murine leukemia virus type-endogenous retroviral virions in primary lymphoid cells

Some murine-endogenous retroviruses, making up ∼10 % of the mouse genome, are induced during the course of experimental sepsis in which lipopolysaccharide (LPS), a pathogenic component of Gram-negative bacteria, often plays a critical role. In this study, we investigated whether LPS stress induces the production of murine leukemia virus type-endogenous retrovirus (MuLV-ERV) virions in primary lymphoid cells. LPS treatment of cells (single-cell suspensions and sorted B- and T-cells) isolated from seven lymphoid organs of C57BL/6J mice resulted in a differential increase in the production of MuLV-ERV virions in most cells examined. Interestingly, among the 34 unique MuLV-ERV U3 sequences cloned from the viral genomic RNAs, the nuclear respiratory factor 1 (transcription factor) element was present only in the 20 U3 sequences that were derived from the LPS-induced MuLV-ERV U3 bands. Using the U3 sequences as a probe, 55 putative MuLV-ERV loci were mapped onto the C57BL/6J mouse genome and 15 of them retained full coding potential. Furthermore, one full-length recombinant MuLV-ERV originating from a locus on chromosome 13 was determined to be responsive to LPS stress. The findings from this study suggest that LPS stress differentially activates MuLV-ERV virion production in lymphoid organs in a cell type- and MuLV-ERV-specific manner. Further investigation is needed to define the role of MuLV-ERVs in the LPS signalling pathway(s) in general, as well as in the pathogenesis of sepsis

Multiway modeling and analysis in stem cell systems biology

<p>Abstract</p> <p>Background</p> <p>Systems biology refers to multidisciplinary approaches designed to uncover emergent properties of biological systems. Stem cells are an attractive target for this analysis, due to their broad therapeutic potential. A central theme of systems biology is the use of computational modeling to reconstruct complex systems from a wealth of reductionist, molecular data (e.g., gene/protein expression, signal transduction activity, metabolic activity, etc.). A number of deterministic, probabilistic, and statistical learning models are used to understand sophisticated cellular behaviors such as protein expression during cellular differentiation and the activity of signaling networks. However, many of these models are bimodal i.e., they only consider row-column relationships. In contrast, multiway modeling techniques (also known as tensor models) can analyze multimodal data, which capture much more information about complex behaviors such as cell differentiation. In particular, tensors can be very powerful tools for modeling the dynamic activity of biological networks over time. Here, we review the application of systems biology to stem cells and illustrate application of tensor analysis to model collagen-induced osteogenic differentiation of human mesenchymal stem cells.</p> <p>Results</p> <p>We applied Tucker1, Tucker3, and Parallel Factor Analysis (PARAFAC) models to identify protein/gene expression patterns during extracellular matrix-induced osteogenic differentiation of human mesenchymal stem cells. In one case, we organized our data into a tensor of type protein/gene locus link × gene ontology category × osteogenic stimulant, and found that our cells expressed two distinct, stimulus-dependent sets of functionally related genes as they underwent osteogenic differentiation. In a second case, we organized DNA microarray data in a three-way tensor of gene IDs × osteogenic stimulus × replicates, and found that application of tensile strain to a collagen I substrate accelerated the osteogenic differentiation induced by a static collagen I substrate.</p> <p>Conclusion</p> <p>Our results suggest gene- and protein-level models whereby stem cells undergo transdifferentiation to osteoblasts, and lay the foundation for mechanistic, hypothesis-driven studies. Our analysis methods are applicable to a wide range of stem cell differentiation models.</p

The Canadian Bandaging Trial: Evidence-informed leg ulcer care and the effectiveness of two compression technologies

Background: Objective: To determine the relative effectiveness of evidence-informed practice using two high compression systems: four-layer (4LB) and short-stretch bandaging (SSB) in community care of venous leg ulcers. Design and Setting: Pragmatic, multi-centre, parallel-group, open-label, randomized controlled trial conducted in 10 centres. Cognitively intact adults (≥18 years) referred for community care (home or clinic) with a venous ulceration measuring ≥0.7cm and present for ≥1 week, with an ankle brachial pressure index (ABPI) ≥0.8, without medication-controlled Diabetes Mellitus or a previous failure to improve with either system, were eligible to participate.Methods: Consenting individuals were randomly allocated (computer-generated blocked randomization schedule) to receive either 4LB or SSB following an evidence-informed protocol. Primary endpoint: time-to- healing of the reference ulcer. Secondary outcomes: recurrence rates, health-related quality of life (HRQL), pain, and expenditures.Results: 424 individuals were randomized (4LB n = 215; SSB n = 209) and followed until their reference ulcer was healed (or maximum 30 months). An intent-to-treat analysis was conducted on all participants. Median time to ulcer healing in the 4LB group was 62 days [95% confidence interval (CI) 51 to 73], compared with 77 days (95% CI 63 to 91) in the SSB group. The unadjusted Kaplan-Meier curves revealed the difference in the distribution of cumulative healing times was not significantly different between group (log rank χ2 = 0.001, P = 0.98) nor ulcers recurrence (4LB, 10.1%; SSB, 13.3%; p = 0.345). Multivariable Cox Proportional Hazard Modeling also showed no significant between-bandage differences in healing time after controlling for significant covariates (p = 0.77). At 3-months post-baseline there were no differences in pain (no pain: 4LB, 22.7%; SSB, 26.7%; p = 0.335), or HRQL (SF-12 Mental Component Score: 4LB, 55.1; SSB, 55.8; p = 0.615; SF-12 Physical Component Score: 4LB, 39.0; SSB, 39.6; p = 0.675). The most common adverse events experienced by both groups included infection, skin breakdown and ulcer deterioration.Conclusions: The Canadian Bandaging Trial revealed that in the practice context of trained RNs using an evidence-informed protocol, the choice of bandage system (4LB and SSB) does not materially affect healing times, recurrence rates, HRQL, or pain. From a community practice perspective, this is positive news for patient-centred care allowing individual/family and practitioner choice in selecting compression technologies based on circumstances and context.Trial registration: clinicaltrials.gov Identifier: NCT00202267

Lung epithelium as a sentinel and effector system in pneumonia – molecular mechanisms of pathogen recognition and signal transduction

Pneumonia, a common disease caused by a great diversity of infectious agents is responsible for enormous morbidity and mortality worldwide. The bronchial and lung epithelium comprises a large surface between host and environment and is attacked as a primary target during lung infection. Besides acting as a mechanical barrier, recent evidence suggests that the lung epithelium functions as an important sentinel system against pathogens. Equipped with transmembranous and cytosolic pathogen-sensing pattern recognition receptors the epithelium detects invading pathogens. A complex signalling results in epithelial cell activation, which essentially participates in initiation and orchestration of the subsequent innate and adaptive immune response. In this review we summarize recent progress in research focussing on molecular mechanisms of pathogen detection, host cell signal transduction, and subsequent activation of lung epithelial cells by pathogens and their virulence factors and point to open questions. The analysis of lung epithelial function in the host response in pneumonia may pave the way to the development of innovative highly needed therapeutics in pneumonia in addition to antibiotics

Developmental history and stress responsiveness are related to response inhibition, but not judgement bias, in a cohort of European starlings (Sturnus vulgaris)

Judgement bias tasks are designed to provide markers of affective states. A recent study of European starlings (Sturnus vulgaris) demonstrated modest familial effects on judgement bias performance, and found that adverse early experience and developmental telomere attrition (an integrative marker of biological age) both affected judgement bias. Other research has shown that corticosterone levels affect judgement bias. Here, we investigated judgement bias using a modified Go/No Go task in a new cohort of starlings (n = 31) hand-reared under different early-life conditions. We also measured baseline corticosterone and the corticosterone response to acute stress in the same individuals. We found evidence for familial effects on judgement bias, of a similar magnitude to the previous study. We found no evidence that developmental treatments or developmental telomere attrition were related to judgement bias per se. We did, however, find that birds that experienced the most benign developmental conditions, and birds with the greatest developmental telomere attrition, were significantly faster to probe the learned unrewarded stimulus. We also found that the birds whose corticosterone levels were faster to return towards baseline after an acute stressor were slower to probe the learned unrewarded stimulus. Our results illustrate the potential complexities of relationships between early-life experience, stress and affectively mediated decision making. For judgement bias tasks, they demonstrate the importance of clearly distinguishing factors that affect patterns of responding to the learned stimuli (i.e. response inhibition in the case of the Go/No Go design) from factors that influence judgements under ambiguity

Mitogenic response of c3h/hej mouse lymphocytes to polyanionic polysaccharides obtained from bordetella pertussis endotoxin and from other bacterial species.

Lipopolysaccharide extracted from Bordetella pertussis was mitogenic for spleen cells of endotoxin-resistant C3H/HeJ mice. Although endotoxic lipid A was inactive, mitogenic activity of lipopolysaccharide was exhibited by purified preparations of polysaccharides I and II, which constitute the carbohydrate moiety of the macromolecule. These low-molecular-weight (2,800 and 3,600) polysaccharides, containing carboxyl groups, were not mitogenic for thymocytes and splenic T-cells of C3H/HeJ mice, but did show mitogenic activity for splenic B-cells of C3H/HeJ mice and for spleen cells of C57BL/6 athymic nude mice. The mitogenic activities of polysaccharides I and II were also compared with those of other polyanionic polysaccharides, and the results indicate that high molecular weight is not necessary, and negative charges are not sufficient, for mitogenicity

Value of dermoscopy for the diagnosis of monilethrix

Monilethrix is a rare genodermatosis characterized by a hair shaft dysplasia responsible for hypotrichosis. We report the case of a child with monilethrix with no associated cases in the family. Trichoscopy facilitated the diagnosis. A 2-year-old boy presented with diffuse alopecia and persistent fragile hair for several months. Clinical examination revealed alopecia with hairs broken several millimeters from the scalp. Trichoscopy revealed zones of dystrophic constriction of the hair shaft, separated at regular intervals by elliptical nodes of normal thickness, giving a “necklace” appearance. The diagnosis of monilethrix was made on the basis of these specific features. The diagnosis of monilethrix was more difficult to establish in our patient owing to the absence of any familial cases