Morphological characteristics of coronoid process and revisiting definition of coronoid hyperplasia.

The aim of this study was to assess the morphological characteristics of the coronoid process (CP) and define coronoid hyperplasia (CH) using cadaveric mandibles of a Caucasian population. A sample of 151 adult dry cadaveric mandibles (302 CPs) was acquired. Three distances were measured, which included the width, height, and length of CP. The surface area measurements involved area A: above the width distance line; area B: between incisura mandibulae-Alveolar ridge line and width distance line; area C: between distance lines of width and height. Finally, angulations of the CP and gonial angles were identified. Both length and surface area A + B acted as hyperplastic indicators. Based on the selection criteria, a sample of 197 CPs was included. The hooked shape (59%) was most commonly observed. No significant difference existed between left and right sides (p > 0.05). The mean values of length and surface area A + B were 2.2 ± 0.3 cm and 3.3 ± 0.8 cm2, and any values above 2.7 cm (n = 5 CPs- 2.5%) and 5.0 cm2 (n = 9 CPs- 4.6%) were described as hyperplastic, respectively. The presented data could act as quantitative reference for differentiating between normal and hyperplastic conditions.

Mechanistic incorporation of FcRn binding in plasma and endosomes in a whole body PBPK model for large molecules.

Monoclonal antibodies, endogenous IgG, and serum albumin bind to FcRn in the endosome for salvaging and recycling after pinocytotic uptake, which prolongs their half-life. This mechanism has been broadly recognized and is incorporated in currently available PBPK models. Newer types of large molecules have been designed and developed, which also bind to FcRn in the plasma space for various mechanistic reasons. To incorporate FcRn binding affinity in PBPK models, binding in the plasma space and subsequent internalisation into the endosome needs to be explicitly represented. This study investigates the large molecules model in PK-Sim® and its applicability to molecules with FcRn binding affinity in plasma. With this purpose, simulations of biologicals with and without plasma binding to FcRn were performed with the large molecule model in PK-Sim®. Subsequently, this model was extended to ensure a more mechanistic description of the internalisation of FcRn and the FcRn-drug complexes. Finally, the newly developed model was used in simulations to explore the sensitivity for FcRn binding in the plasma space, and it was fitted to an in vivo dataset of wild-type IgG and FcRn inhibitor plasma concentrations in Tg32 mice. The extended model demonstrated a strongly increased sensitivity of the terminal half-life towards the plasma FcRn binding affinity and could successfully fit the in vivo dataset in Tg32 mice with meaningful parameter estimates.

Lemierre Syndrome of the Femoral Vein, Related to Fusobacterium necrophorum Abscess of Vastus Lateralis.

BACKGROUND: Lemierre syndrome is an uncommon, potentially lethal disorder combining acute oropharyngeal infection caused by Fusobacterium necrophorum, with jugular vein suppurative thrombosis, complicated by anaerobic sepsis with secondary multiple metastatic abscesses. Optimal treatment outcome with reduced or absence of sequelae can be achieved with early diagnosis. CASE REPORT: We present a clinical case of Fusobacterium necrophorum abscess complicated with femoral vein thrombosis, called atypical localization of Lemierre syndrome. This uncommon disease was diagnosed on the basis of clinical, biological, and imaging tests, with a favorable outcome, after a well-orientated antibiotic and surgical course of therapy. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Since its first description in 1936, Lemierre syndrome has been reported in locations other than its initial oropharyngeal site. Because optimal treatment outcome is dependent on early diagnosis, it is imperative for emergency physicians to be aware of this uncommon disease, because in many instances they are the patient's initial point of contact with medical care.

Opinion of Belgian Egg Farmers on Hen Welfare and Its Relationship with Housing Type.

As of 2012, the EU has banned the use of conventional cages (CC) for laying hens, causing a shift in housing systems. This study's aim was to gain insight into farmers' opinions on hen health and welfare in their current housing systems. A survey was sent to 218 Belgian egg farmers, of which 127 (58.3%) responded, with 84 still active as egg farmer. Hen welfare tended to be less important in choosing the housing system for farmers with cage than with non-cage systems. Respondents currently using cage systems were more satisfied with hen health than respondents with non-cage systems. Reported mortality increased with farm size and was higher in furnished cages than in floor housing. Feather pecking, cannibalism, smothering and mortality were perceived to be higher in current housing systems than in CC, but only by respondents who shifted to non-cage systems from previously having had CC. Health- and production-related parameters were scored to be more important for hen welfare as compared to behavior-related parameters. Those without CC in the past rated factors relating to natural behavior to be more important for welfare than those with CC. This difference in opinion based on farmer backgrounds should be taken into account in future research.

Glucocorticoid receptor dimerization induces MKP1 to protect against TNF-induced inflammation.

Glucocorticoids acting through the glucocorticoid receptor (GR) inhibit TNF-induced lethal inflammation. Here, we demonstrate that GR dimerization plays a role in reducing TNF sensitivity. In mutant mice unable to dimerize GR, we found that TNF failed to induce MAPK phosphatase 1 (MKP1). We assessed TNF sensitivity in Mkp1(-/-) mice and found increased inflammatory gene induction in livers, increased circulating cytokines, cell death in intestinal epithelium, severe intestinal inflammation, hypothermia, and death. Mkp1(-/-) mice had increased levels of phosphorylated JNK, which promotes apoptosis, in liver tissue. We further examined JNK-deficient mice for their response to TNF. Although Jnk1(-/-) mice showed no change in sensitivity to TNF, Jnk2(-/-) mice were significantly protected against TNF, identifying JNK2 as an essential player in inflammation induced by TNF. Furthermore, we found that loss of Jnk2 partially rescued the increased sensitivity of Mkp1(-/-) and mutant GR mice to TNF. Our data show that GR dimerization inhibits JNK2 through MKP1 and protects from TNF-induced apoptosis and lethal inflammation.

Tumor necrosis factor inhibits glucocorticoid receptor function in mice: a strong signal toward lethal shock.

As glucocorticoid resistance (GCR) and the concomitant burden pose a worldwide problem, there is an urgent need for a more effective glucocorticoid therapy, for which insights into the molecular mechanisms of GCR are essential. In this study, we addressed the hypothesis that TNFα, a strong pro-inflammatory mediator in numerous inflammatory diseases, compromises the protective function of the glucocorticoid receptor (GR) against TNFα-induced lethal inflammation. Indeed, protection of mice by dexamethasone against TNFα lethality was completely abolished when it was administered after TNFα stimulation, indicating compromised GR function upon TNFα challenge. TNFα-induced GCR was further demonstrated by impaired GR-dependent gene expression in the liver. Furthermore, TNFα down-regulates the levels of both GR mRNA and protein. However, this down-regulation seems to occur independently of GC production, as TNFα also resulted in down-regulation of GR levels in adrenalectomized mice. These findings suggest that the decreased amount of GR determines the GR response and outcome of TNFα-induced shock, as supported by our studies with GR heterozygous mice. We propose that by inducing GCR, TNFα inhibits a major brake on inflammation and thereby amplifies the pro-inflammatory response. Our findings might prove helpful in understanding GCR in inflammatory diseases in which TNFα is intimately involved.

Crosstalk between TNF and glucocorticoid receptor signaling pathways.

TNF is a Janus-faced protein. It possesses impressive anti-tumor activities, but it is also one of the strongest known pro-inflammatory cytokines, which hampers its use as a systemic anti-cancer agent. TNF has been shown to play a detrimental role in inflammatory diseases such as rheumatoid arthritis and inflammatory bowel disease. Glucocorticoids are strongly anti-inflammatory and exert their therapeutic effects through binding to their receptor, the glucocorticoid receptor. Therefore, glucocorticoids have been used for over half a century for the treatment of inflammatory diseases. However, many patients are or become resistant to the therapeutic effects of glucocorticoids. Inflammatory cytokines have been suggested to play an important role in this steroid insensitivity or glucocorticoid resistance. This review aims to highlight the mechanisms of mutual inhibition between TNF and GR signaling pathways.

Protection of zinc against tumor necrosis factor induced lethal inflammation depends on heat shock protein 70 and allows safe antitumor therapy.

Tumor necrosis factor (TNF)-induced inflammation prevents its broad application as an antitumor agent. We here report that addition of ZnSO(4) to the drinking water of mice induces expression of heat shock protein 70 (HSP70) in several organs, notably the gastrointestinal track. Zinc conferred dose-responsive protection against TNF-induced hypothermia, systemic induction of interleukin-6 and NO(x), as well as against TNF-induced bowel cell death and death of the organism. The protective effect of zinc was completely absent in mice deficient in the major HSP70-inducible gene, hsp70.1, whereas transgenic mice constitutively expressing the human HSP70.A gene, under control of a beta-actin promoter, was also protected against TNF, indicating that an increase in HSP70 is necessary and sufficient to confer protection. The therapeutic potential of the protection induced by ZnSO(4) was clearly shown in a TNF/IFNgamma-based antitumor therapy using three different tumor models. In hsp70.1 wild-type mice, but not in hsp70.1-deficient mice, zinc very significantly protected against lethality but left the antitumor effect intact. We conclude that zinc protects against TNF in a HSP70-dependent way and that protection by zinc could be helpful in developing a safer anticancer therapy with TNF/IFNgamma.

Benchmarking the CATMA microarray. A novel tool for Arabidopsis transcriptome analysis.

Transcript profiling is crucial to study biological systems, and various platforms have been implemented to survey mRNAs at the genome scale. We have assessed the performance of the CATMA microarray designed for Arabidopsis (Arabidopsis thaliana) transcriptome analysis and compared it with the Agilent and Affymetrix commercial platforms. The CATMA array consists of gene-specific sequence tags of 150 to 500 bp, the Agilent (Arabidopsis 2) array of 60mer oligonucleotides, and the Affymetrix gene chip (ATH1) of 25mer oligonucleotide sets. We have matched each probe repertoire with the Arabidopsis genome annotation (The Institute for Genomic Research release 5.0) and determined the correspondence between them. Array performance was analyzed by hybridization with labeled targets derived from eight RNA samples made of shoot total RNA spiked with a calibrated series of 14 control transcripts. CATMA arrays showed the largest dynamic range extending over three to four logs. Agilent and Affymetrix arrays displayed a narrower range, presumably because signal saturation occurred for transcripts at concentrations beyond 1,000 copies per cell. Sensitivity was comparable for all three platforms. For Affymetrix GeneChip data, the RMA software package outperformed Microarray Suite 5.0 for all investigated criteria, confirming that the information provided by the mismatch oligonucleotides has no added value. In addition, taking advantage of replicates in our dataset, we conducted a robust statistical analysis of the platform propensity to yield false positive and false negative differentially expressed genes, and all gave satisfactory results. The results establish the CATMA array as a mature alternative to the Affymetrix and Agilent platforms.