Transcriptomic Changes in the Myocardium and Coronary Artery of Donation after Circulatory Death Hearts following Ex Vivo Machine Perfusion.

Donation after circulatory death (DCD) hearts are predominantly maintained by normothermic blood perfusion (NBP). Nevertheless, it was shown that hypothermic crystalloid perfusion (HCP) is superior to blood perfusion to recondition left ventricular (LV) contractility. However, transcriptomic changes in the myocardium and coronary artery in DCD hearts after HCP and NBP have not been investigated yet. In a pig model, DCD hearts were harvested and maintained for 4 h by NBP (DCD-BP group, N = 8) or HCP with oxygenated histidine-tryptophane-ketoglutarate (HTK) solution (DCD-HTK, N = 8) followed by reperfusion with fresh blood for 2 h. In the DCD group (N = 8), hearts underwent reperfusion immediately after procurement. In the control group (N = 7), no circulatory death was induced. We performed transcriptomics from LV myocardial and left anterior descending (LAD) samples using microarrays (25,470 genes). We applied the Boruta algorithm for variable selection to identify relevant genes. In the DCD-BP group, compared to DCD, six genes were regulated in the myocardium and 1915 genes were regulated in the LAD. In the DCD-HTK group, 259 genes were downregulated in the myocardium and 27 in the LAD; and 52 genes were upregulated in the myocardium and 765 in the LAD, compared to the DCD group. We identified seven genes of relevance for group identification: ITPRIP, G3BP1, ARRDC3, XPO6, NOP2, SPTSSA, and IL-6. NBP resulted in the upregulation of genes involved in mitochondrial calcium accumulation and ROS production, the reduction in microvascular endothelial sprouting, and inflammation. HCP resulted in the downregulation of genes involved in NF-κB-, STAT3-, and SASP-activation and inflammation.

HTK vs. HTK-N for Coronary Endothelial Protection during Hypothermic, Oxygenated Perfusion of Hearts Donated after Circulatory Death.

Protection of the coronary arteries during donor heart maintenance is pivotal to improve results and prevent the development of coronary allograft vasculopathy. The effect of hypothermic, oxygenated perfusion (HOP) with the traditional HTK and the novel HTK-N solution on the coronary microvasculature of donation-after-circulatory-death (DCD) hearts is known. However, the effect on the coronary macrovasculature is unknown. Thus, we maintained porcine DCD hearts by HOP with HTK or HTK-N for 4 h, followed by transplantation-equivalent reperfusion with blood for 2 h. Then, we removed the left anterior descending coronary artery (LAD) and compared the endothelial-dependent and -independent vasomotor function of both groups using bradykinin and sodium-nitroprusside (SNP). We also determined the transcriptome of LAD samples using microarrays. The endothelial-dependent relaxation was significantly better after HOP with HTK-N. The endothelial-independent relaxation was comparable between both groups. In total, 257 genes were expressed higher, and 668 genes were expressed lower in the HTK-N group. Upregulated genes/pathways were involved in endothelial and vascular smooth muscle cell preservation and heart development. Downregulated genes were related to ischemia/reperfusion injury, oxidative stress, mitochondrion organization, and immune reaction. The novel HTK-N solution preserves the endothelial function of DCD heart coronary arteries more effectively than traditional HTK.

Sex-Specific Protection of Endothelial Function after Vascular Ischemia/Reperfusion Injury by the Senomorphic Agent Ruxolitinib.

Ischemia/reperfusion (I/R)-induced endothelial dysfunction occurs in various cardiovascular disorders. I/R injury is partially driven by the release of cytokines. Known for its use in senotherapy, the JAK inhibitor ruxolitinib is able to block the release of cytokines. We investigated the effect of ruxolitinib on the cytokine release and endothelial-dependent vasorelaxation in an in vitro model of I/R. Aortic segments of C57BL/6J mice (N = 12/group) were divided into three groups: control, in vitro I/R (I/R group), and in vitro I/R with ruxolitinib during ischemic incubation (I/R+Ruxo group). We determined cytokine expression. In organ bath chambers, we investigated the maximal endothelial-dependent relaxation to acetylcholine (RmaxACh) and maximal endothelial-independent relaxation to sodium-nitroprusside (RmaxSNP). RmaxACh was decreased in I/R compared to the control (83.6 ± 2.4 vs. 48.6 ± 3.4%; p < 0.05) and I/R+Ruxo (74.4 ± 2.6 vs. 48.6 ± 3.4%; p < 0.05). RmaxSNP was comparable between all groups. IL-10 was detectable only in I/R+Ruxo. CXCL5, CCL2, CCL3, CCL8, CCL11, ICAM-1, IL-1α, IL-7, TNF-α, and G-CSF were decreased or not detectable in I/R+Ruxo. In I/R+Ruxo, ICAM-1 was reduced in rings only from male mice. Treatment of the aorta from mice during in vitro ischemia with the senomorphic agent ruxolitinib reduces cytokine release and protects the endothelium from I/R-mediated dysfunction.

A novel approach to brachycephalic syndrome. 3. Isolated laser-assisted turbinectomy of caudal aberrant turbinates (CAT LATE).

OBJECTIVE: To describe isolated laser-assisted turbinectomy of caudal aberrant turbinates (CAT LATE) as a new minimally invasive surgical procedure for the treatment of brachycephalic dogs with obstructing caudal aberrant turbinates (CAT). STUDY DESIGN: Prospective clinical study. ANIMALS: Brachycephalic dogs (24 Pugs, 1 English Bulldog) with CAT but adequate air spaces between the lamellae of the nonobstructing ventral nasal concha. METHODS: A rhinoscopically guided diode laser fiber introduced from anterior was used to dissect CAT within the nasopharyngeal meatus, while leaving the intranasal turbinates intact. Small grasping forceps were used to extract the dissected CAT from anterior or to push it through the nasopharyngeal meatus for extraction from posterior. RESULTS: Isolated CAT LATE was successfully performed on 32 CAT in 25 dogs. Intranasally applied xylometazoline helped shrink the ventral concha, making the approach and extraction easier. Minor bleeding was the only complication observed. CONCLUSION: It is possible to remove CAT with endoscopically applied diode-laser energy while leaving the nonobstructing ventral nasal concha intact.

The role of supervisor emotional support on individual job satisfaction: A multilevel analysis.

INTRODUCTION: Supervisor emotional support is a strong determinant of job satisfaction. There is no study examining the effect of supervisor emotional support at the group level on job satisfaction. Multilevel statistical techniques can help disentangle the effects of subjective assessments from those of group factors. AIM: The study's aim was to examine the moderating role of supervisor emotional support (group-level variable) on the relationship between work engagement and job satisfaction (individual-level variables). METHOD: A cross-sectional study was performed in 39units from three Belgian hospitals. A total of 323 nurses completed a self-reported questionnaire. We carried out a multilevel analysis by using Hierarchical Linear Modeling. RESULTS: The results showed that the cross-level interaction was significant. Hence, at individual-level, the nurses with high levels of work engagement showed high levels of job satisfaction and this relationship was stronger when supervisor emotional support at group-level was high. CONCLUSIONS: Contextual differences among groups had an impact on the form of the work engagement-job satisfaction relationship. This relationship between work engagement and job satisfaction is an individual and group level phenomenon. Ways to enhance emotional supervisor support include training supervisors in providing support and enhancing communication between nurses and supervisors.

A Novel Approach to Brachycephalic Syndrome. 2. Laser-Assisted Turbinectomy (LATE).

OBJECTIVE: To introduce a new surgical procedure based on interventional, laser-assisted removal of obstructing turbinate tissue to improve endonasal airway patency in brachycephalic dogs and to confirm the short and long term results using computed tomography (CT) and rhinoscopy. STUDY DESIGN: Prospective clinical study. ANIMALS: Brachycephalic dogs (n = 158; 70 Pugs, 77 French Bulldogs, 11 English Bulldogs) referred for treatment of severe respiratory distress because of brachycephalic syndrome. METHODS: Computed tomography and anterior and posterior rhinoscopy were performed to evaluate endonasal obstruction. Laser-assisted turbinectomy (LATE) using a diode laser was performed as part of a multilevel surgery. Nasal conchae that were causing airway obstruction were removed. RESULTS: The obstructing parts of the conchae were safely and efficiently removed by LATE, shaping a patent nasal airway in all dogs. The newly developed surgical procedure involved 3 steps: turbinectomy of the (1) concha nasalis ventralis; (2) rostral aberrantly growing turbinates (RAT); and (3) caudal aberrantly growing turbinates (CAT). Complications of the procedure included transient intraoperative hemorrhage in 51 of 158 dogs (32.3%); however, a temporary tamponade was necessary in only 2/158 dogs (1.3%). After 6 months, regrowth of turbinates required resection of possibly re-obstructing tissue in 25/158 dogs (15.8%; 1 Pug and 24 French Bulldogs). CONCLUSION: LATE is an effective method for creating a patent nasal airway in brachycephalic dogs with intranasal obstruction.

A Novel Approach to Brachycephalic Syndrome. 1. Evaluation of Anatomical Intranasal Airway Obstruction.

OBJECTIVE: To evaluate airway obstruction due to abnormal intranasal anatomy in 3 brachycephalic dog breeds using computed tomography and rhinoscopy. STUDY DESIGN: Prospective clinical study. ANIMALS: A total of 132 brachycephalic dogs (66 Pugs, 55 French Bulldogs, and 11 English Bulldogs) with severe respiratory distress due to brachycephalic syndrome. METHODS: Computed tomography and anterior and posterior rhinoscopy were performed to evaluate endonasal obstruction. RESULTS: All dogs had abnormal conchal growth that obstructed the intranasal airways. Rostral aberrant turbinates (RAT) were common in Pugs (90.9%) but less frequent in French (56.4%) and English (36.4%) Bulldogs. Caudal aberrant turbinates (CAT) obstructing the nasopharyngeal meatus were commonly found in all breeds (66.7%). Deviation of the nasal septum was an almost consistent finding in Pugs (98.5%) but was less common in bulldogs. Obstructing turbinates had multiple points of mucosal contact responsible for obstruction of the intranasal airway. Interconchal and intraconchal mucosal contacts were evident in 91.7% of dogs. CONCLUSION: Selective breeding for short head conformation reduces the size of the nasal cavities to such an extent that intranasal structures grow aberrantly and malformed, leading to obstructed air conducting spaces. Intranasal airway obstruction of brachycephalic dogs may contribute to their exercise and heat intolerance because of impaired pulmonary ventilation and compromised thermoregulatory functions of the canine nose. Failure to address intranasal obstruction might be an explanation for lack of therapeutic success after conventional surgery for brachycephalic syndrome. Future consideration should be given to the diagnosis, management, and treatment of this newly described aspect of airway obstruction.

Nasal angioleiomyoma in 2 dogs.

This case report describes 2 dogs, an Appenzeller Mountain dog and an Irish Wolfhound, with angioleiomyoma within the nasal cavity. Endoscopic surgical resection resulted in cure in both dogs. Macroscopically and on diagnostic imaging, tumor masses may appear malignant because of local turbinate destruction. This highlights the importance of histological examination before any recommendations are made to owners because tumors of the nasal cavity may be benign and surgery curative.

Work engagement, emotional exhaustion, and OCB-civic virtue among nurses: a multilevel analysis of emotional supervisor support.

Introduction: This study investigates the moderating role of supervisor emotional support at the group level on the relationship between emotional exhaustion and work engagement with organizational citizenship behavior-civic virtue (OCB-civic virtue) at the individual level among nurses. Method: A cross-sectional study was carried out on 558 nurses nested in 36 working units from two hospitals in Algiers. A multilevel analysis using Hierarchical Linear Modeling was performed. Results: Results show that the positive effect of work engagement on OCB-civic virtue was moderated by supervisor emotional support at group level. The nurses emotional exhaustion and OCB-civic virtue negative relationship at the individual level is buffered by supervisor emotional support at group level. Discussion: In consequence, supervisor emotional support experienced by the team has an influence on the emotional exhaustion and work engagement OCB-civic virtue relationship.

Impact of Age on Endothelial Function of Saphenous Vein Grafts in Coronary Artery Bypass Grafting.

BACKGROUND: An intact and functionally preserved endothelial layer in the graft is crucial for myocardial perfusion and graft patency after coronary artery bypass grafting (CABG). We hypothesized that old age is a risk factor for decreased endothelial function of bypass grafts. Thus, we investigated the impact of age in patients treated with CABG on endothelial function in saphenous vein grafts. METHODS: We mounted the saphenous vein graft segments of CABG patients < 70 (n = 33) and ≥70 (n = 40) years of age in organ bath chambers and exposed them to potassium chloride (KCl) and phenylephrine (PE) to test the receptor-independent and -dependent contractility, followed by exposure to acetylcholine (ACh) and sodium nitroprusside (SNP) to test the endothelial-dependent and -independent relaxation. RESULTS: The maximal contraction induced by KCl (2.3 ± 1.8 vs. 1.8 ± 2 g) was stronger in patients ≥ 70 years of age. The relative contraction induced by PE in % of KCl (167 ± 64 vs. 163 ± 59%) was similar between groups. Patients aged < 70 years showed a higher endothelial-dependent relaxation induced by acetylcholine than patients ≥ 70 years (51 ± 27 vs. 42 ± 18%). The relaxation induced by SNP was similar between both groups. CONCLUSIONS: The endothelial function of saphenous vein bypass grafts decreases during aging. Thus, age should be considered when improving graft maintenance.

Cytokine Adsorber Use during DCD Heart Perfusion Counteracts Coronary Microvascular Dysfunction.

Microvascular dysfunction (MVD) in cardiac allografts is associated with an impaired endothelial function in the coronary microvasculature. Ischemia/reperfusion injury (IRI) deteriorates endothelial function. Hearts donated after circulatory death (DCD) are exposed to warm ischemia before initiating ex vivo blood perfusion (BP). The impact of cytokine adsorption during BP to prevent MVD in DCD hearts is unknown. In a porcine DCD model, we assessed the microvascular function of hearts after BP with (DCD-BPCytoS, n = 5) or without (DCD-BP, n = 5) cytokine adsorption (CytoSorb®). Microvascular autoregulation was assessed by increasing the coronary perfusion pressure, while myocardial microcirculation was measured by Laser-Doppler-Perfusion (LDP). We analyzed the immunoreactivity of arteriolar oxidative stress markers nitrotyrosine and 4-hydroxy-2-nonenal (HNE), endothelial injury indicating cell adhesion molecules CD54, CD106 and CD31, and eNOS. We profiled the concentration of 13 cytokines in the perfusate. The expression of 84 genes was determined and analyzed using machine learning and decision trees. Non-DCD hearts served as a control for the gene expression analysis. Compared to DCD-BP, relative LDP was improved in the DCD-BPCytoS group (1.51 ± 0.17 vs. 1.08 ± 0.17). Several pro- and anti-inflammatory cytokines were reduced in the DCD-BPCytoS group. The expression of eNOS significantly increased, and the expression of nitrotyrosine, HNE, CD54, CD106, and CD31, markers of endothelial injury, majorly decreased in the DCD-BPCytoS group. Three genes allowed exact differentiation between groups; regulation of HIF1A enabled differentiation between perfusion (DCD-BP, DCD-BPCytoS) and non-perfusion groups. CAV1 allowed differentiation between BP and BPCytoS. The use of a cytokine adsorption device during BP counteracts preload-dependent MVD and preserves the microvascular endothelium by preventing oxidative stress and IRI of coronary arterioles of DCD hearts.

How Digital Technologies Modify The Work Characteristics: A Preliminary Study.

New technologies with unprecedented agentic capabilities (i.e., action selection, protocol development) are now introduced in organizations such as Big Data, 3D printing or artificial intelligence. Because they are endowed with novel capabilities that might compete with human agency, they might disrupt the way employees work. Based on the work design model, this study aims to examine their introduction in the daily work activities and the consequent perceptions of the work characteristics. Building on Murray's et al. (2020) proposal, we offer a classification of the digital technologies to conceptualize their relationship with the work characteristics. To explore the changes induced by two digital technologies (i.e., drones, robotic automation process), we interviewed 3 types of employees (i.e., experts, managers, users) from an organization which has started a digitalization process and we conducted a thematic analysis. Our analysis revealed three main themes that are discussed: A technological theme (arresting, assisting), a work characteristic theme and a theme about the human-technology relationship (agentic, non-agentic). Results showed that employee autonomy has not been reduced when digital technologies executed repetitive and unmotivated tasks and that jobs in the digital work context may be marked by a high level of knowledge characteristics. Moreover, technologies with agentic capabilities may be perceived as a non-human agent. Theoretical contributions for the work design model are then examined.

Inhibition of Glyoxalase-I Leads to Reduced Proliferation, Migration and Colony Formation, and Enhanced Susceptibility to Sorafenib in Hepatocellular Carcinoma.

Background: Glyoxalase-I (Glo-I) is essential for detoxification of methylglyoxal (MGO), a byproduct of glycolysis. Overexpression of Glo-I has been linked to multi-drug resistance in cancer therapy. The aim of this study was to analyze Glo-I in hepatocellular carcinoma (HCC) and the effect of the multi-tyrosine kinase inhibitor sorafenib on Glo-I. Methods: Expression and specific activity of Glo-I was measured in human HCC samples, HCC-cell lines (HepG2, Huh7) and a hepatocyte cell line (AML 12). Cells were either treated with Glo-I inhibitors, ethyl pyruvate (EP, 1-20 mM) and BrBzGSHCp2 (1-10 µM), or sorafenib (2.5-10 µM) and protein expression (Western Blot), proliferation (WST-assay), migration (scratch assay), and colony formation (clonogenic assay) were assessed. Results: High expression of Glo-I was detected in human HCC tissue samples. Huh7 showed highest expression and activity of Glo-I and revealed highest proliferation compared to AML 12 and HepG2. Targeting Glo-I by EP or BrBzGSHCp2 led to significantly reduced proliferation (20 mM EP 24 h: 57 ± 12%), migration and colony formation. Glo-I inhibition by 20 mM EP resulted in reduced expression of PDGFR-ß (18 ± 10%), VEGFR2 (46 ± 11%), VEGF (61 ± 10%), pERK/ERK (62 ± 6%), NF-κB (44 ± 12%) as well as stimulation of Nrf2 (243 ± 36%). Similar results were seen with BrBzGSHCp2. Sorafenib treatment revealed elevation of Glo-I (10 µM: 209 ± 25%) and MGO. Co-treatment of EP and sorafenib led to an additional reduction of proliferation compared to sorafenib alone. Conclusion: Glo-I is positively correlated with HCC proliferation. Inhibition of Glo-I reduced proliferation, migration, and colony formation. In turn, sorafenib increases Glo-I. Co-treatment using Glo-I inhibitors could enhance susceptibility of HCC to sorafenib.

Moral Attitudes Toward Pharmacological Cognitive Enhancement (PCE): Differences and Similarities Among Germans With and Without PCE Experience.

Pharmacological cognitive enhancement (PCE), the use of illicit and/or prescription drugs to increase cognitive performance, has spurred controversial discussion in bioethics. In a semi-structured interview study with 60 German university students and employees, differences and similarities in moral attitudes toward PCE among 30 experienced participants (EPs) vs. 30 inexperienced participants (IPs) were investigated. Substances EPs used most often are methylphenidate, amphetamines, tetrahydrocannabinol and modafinil. Both EPs and IPs addressed topics such as autonomous decision making or issues related to fairness such as equality in test evaluation and distortion of competition. While most EPs and IPs were convinced that the decision of whether or not to use PCE is part of their individual freedom, their views varied considerably with regard to fairness. IPs considered issues related to fairness as much more critical than EPs. Thus, a person's moral attitudes toward PCE may not only depend on moral common sense, but also on whether they have used illegal and/or prescription drugs for PCE before. This points to the importance of including the various relevant stakeholder perspectives in debates on the ethical and social implications of PCE.

The selective mineralocorticoid receptor antagonist eplerenone prevents decompensation of the liver in cirrhosis.

BACKGROUND AND PURPOSE: The mineralocorticoid receptor (MR) contributes to fibrosis in various tissues, and MR antagonists, like eplerenone, are used to prevent fibrosis. The role of MR antagonists in hepatic fibrosis and cirrhosis is unknown. Here, we investigated the role of MRs and eplerenone in cirrhosis development. EXPERIMENTAL APPROACH: Liver fibrosis (5 weeks) and cirrhosis, without (8 weeks) and with ascites (12 weeks), were induced by CCl4 in rats and comprehensively analysed. The effect of eplerenone on the development of cirrhosis with ascites was assessed. MR expression, cellular and subcellular distribution and impact of hypoxia were investigated in vivo and ex vivo. Primary rat hepatocytes and cell lines were used to investigate MR trafficking and transcriptional activity mechanistically. KEY RESULTS: In cirrhosis with ascites, MR mRNA and protein expressions were reduced in hepatocytes of hypoxic areas. While in normoxic areas MRs were mainly cytosolic, the remaining MRs in hypoxic areas were mainly localized in the nuclei, indicating activation followed by translocation and degradation. Accordingly, eplerenone treatment prevented nuclear MR translocation and the worsening of cirrhosis. Exposing hepatocytes ex vivo to hypoxia induced nuclear MR translocation and enhanced transcriptional MR activity at response elements of the NF-κB pathway. CONCLUSIONS AND IMPLICATIONS: We showed for the first time that hypoxia leads to a pathogenetic ligand-independent activation of hepatic MRs during cirrhosis resulting in their nuclear translocation and transcriptional activation of the NF-κB pathway. Treatment with eplerenone prevented the worsening of cirrhosis by blocking this ligand-independent activation of the MR.

Clinical and microbiological effects of a combined mechanic-antibiotic therapy in subjects with Actinobacillus actinomycetemcomitans-associated periodontitis.

PURPOSE: To evaluate the clinical and microbiological effects of a combined mechanic-antibiotic periodontal therapy in subjects that were tested positive for subgingival Actinobacillus actinomycetemcomitans (A.a.). METHODS: The postoperative follow-up ranged from 12-115 months (average 39.2 months). This follow-up study analyzed the data of 53 subjects (37 females) aged from 16-59 years, who underwent systemic periodontal therapy with adjunctive systemic antibiotics between 1992-2001 and had their last re-examination including microbiological analysis done in 2003. The antibiotic regime was either amoxicillin/metronidazole or ciprofloxacine/metronidazole. During this study, A.a. was detected with two gene probe tests (IAI PadoTest 4.5 and DMDx/PathoTek) and cultivation on TSBV agar plates. The clinical situation was characterized with the help of pocket probing depths and subsequent categorization into three different groups (< or = 4 mm, 5-6 mm and > or = 7 mm). RESULTS: After therapy, A.a. was detected with IAI PadoTest 4.5 in a magnitude between 3.0 x 10(3) up to 2.06 x 10(5) counts per specimen in 9 out of 53 subjects. Only two subjects tested positive for A.a. with the DMDx/PathoTek-assays and the agar cultivation. The clinical situation improved significantly in all subjects after systemic periodontal therapy. The treatment results remained stable during the course of the postoperative follow-up. Concerning the clinical data, no differences were found between the subjects that were tested positive and negative for A.a in the postoperative period.

The influence of intergroup comparisons on Africans' intelligence test performance in a job selection context.

Sub-Saharan Africans living in Belgium (N = 69) completed a culture-free intelligence test in a simulated job selection environment. Prior to testing, the authors instructed participants that Africans' average performance on this test was generally better (positive comparison), worse (negative comparison), or equal to Belgians' performance. In a control condition, no such information was given. Results indicated that, compared with the equal and control conditions, performance was lower when intergroup comparisons were negative. In the former condition, participants were also more likely to endorse external factors that may account for lower performance. The authors interpreted the findings in line with stereotype threat theory (C. M. Steele & J. Aronson, 1995). In the context of job selection, the validity of intelligence tests conducted with members of stigmatized groups may be affected by the salience of social stereotypes and intergroup social comparisons.

Expression of glyoxalase-I is reduced in cirrhotic livers: A possible mechanism in the development of cirrhosis.

BACKGROUND: High concentrations of methylglyoxal (MGO) cause cytotoxiticy via formation of advanced glycation endproducts (AGEs) and inflammation. MGO is detoxificated enzymatically by glyoxalase-I (Glo-I). The aim of this study was to analyze the role of Glo-I during the development of cirrhosis. METHODS: In primary hepatocytes, hepatic stellate cells (pHSC) and sinusoidal endothelial cells (pLSEC) from rats with early (CCl4 8wk) and advanced cirrhosis (CCl4 12wk) expression and activity of Glo-I were determined and compared to control. LPS stimulation (24h; 100ng/ml) of HSC was conducted in absence or presence of the partial Glo-I inhibitor ethyl pyruvate (EP) and the specific Glo-I inhibitor BrBzGSHCp2. MGO, inflammatory and fibrotic markers were measured by ELISA and Western blot. Additional rats were treated with CCl4 ± EP 40mg/kg b.w. i.p. from wk 8-12 and analyzed with sirius red staining and Western blot. RESULTS: Expression of Glo-I was significantly reduced in cirrhosis in whole liver and primary liver cells accompanied by elevated levels of MGO. Activity of Glo-I was reduced in cirrhotic pHSC and pLSEC. LPS induced increases of TNF-α, Nrf2, collagen-I, α-SMA, NF-kB and pERK of HSC were blunted by EP and BrBzGSHCp2. Treatment with EP during development of cirrhosis significantly decreased the amount of fibrosis (12wk CCl4: 33.3±7.3%; EP wk 8-12: 20.7±6.2%; p<0.001) as well as levels of α-SMA, TGF-ß and NF-κB in vivo. CONCLUSIONS: Our results show the importance of Glo-I as major detoxifying enzyme for MGO in cirrhosis. The reduced expression of Glo-I in cirrhosis demonstrates a possible explanation for increased inflammatory injury and suggests a "vicious circle" in liver disease. Blunting of the Glo-I activity decrease the amount of fibrosis in established cirrhosis and constitutes a novel target for antifibrotic therapy.

How does multilevel upper airway surgery influence the lives of dogs with severe brachycephaly? Results of a structured pre- and postoperative owner questionnaire.

Brachycephalic airway syndrome in dogs is typified by a variety of anatomical abnormalities causing a diverse spectrum of clinical signs of varying intensity. This variability makes the assessment of the surgical outcome after upper airway surgery difficult. Using a structured questionnaire, the present study investigated the dog owner-perceived severity and frequency of a broad spectrum of welfare-relevant impairments 2 weeks before and 6 months after brachycephalic dogs underwent a recently developed multi-level upper airway surgery. All dogs underwent surgical treatment of stenotic nares (ala-vestibuloplasty), the nasal cavity (laser-assisted turbinectomy, LATE), the pharynx (palatoplasty and tonsillotomy), and if indicated, laryngeal surgery (laser-assisted ablation of everted ventricles and partial cuneiformectomy). Owners of brachycephalic dogs (n = 102) referred for upper airway surgery were eligible to participate. Questionnaire data from owners of 37 Pugs and 25 French bulldogs were evaluated. In all dogs, the clinical signs associated with brachycephaly improved markedly after surgery. Most encouraging was the striking reduction in life-threatening events by 90% (choking fits decreased from 60% to 5% and collapse from 27% to 3%). The incidence of sleeping problems decreased from 55% to 3%, and the occurrence of breathing sounds declined by approximately 50%. There was a marked improvement in exercise tolerance and a modest improvement in heat tolerance. Dogs with severe brachycephaly benefitted substantially from multi-level surgery, and there were particular improvements in the incidences of severe impairment and life-threatening events. However, despite the marked improvement perceived by dog owners, these dogs remained clinically affected and continued to show welfare-relevant impairments caused by these hereditary disorders.

Orthodontic treatment in a patient with Papillon-Lefèvre syndrome.

BACKGROUND: Report of a combined periodontal and orthodontic treatment in a patient with Papillon-Lefevre Syndrome (PLS). METHODS: A patient with PLS was treated orthodontically 26 months after the start of a combined mechanical and antibiotic therapy. Clinical periodontal parameters were obtained 26 (t1), 60 (t2), and 79 (t3) months after anti-infective therapy. The deepest site of each tooth was sampled for microbiological analysis at 26 and 60 months. Periodontal maintenance therapy was provided every 6 weeks. After a stable periodontal situation was achieved, orthodontic treatment, consisting of space opening for the upper canines with a multibracket appliance and coil springs, was carried out. In the lower jaw, crowding was resolved by an orthodontic mesialization of the canines. RESULTS: Twenty-six months (t1) after the beginning of the combined mechanical and antibiotic therapy, 6% of the sites exhibited 4 mm probing depth (PD) with bleeding on probing (BOP) or PD > or =5 mm. Sixty months (t2) after therapy the number of sites with 4 mm PD with BOP or PD > or =5 mm had increased to 17%, and 79 months after therapy (t3) 13% of all sites were similarly affected. From 26 to 60 months, a slight mean clinical attachment level (CAL) gain was observed, whereas the mean PD increased. From 60 to 79 months, there was a mean PD reduction. However, a significant mean attachment loss was also noted. After 26 months (t1), RNA probes failed to detect A. actinomycetemcomitans, P. gingivalis, or T. forsythensis from any site. Thirty-four months later (t2), subgingival recolonization was observed. A. actinomycetemcomitans was detected by RNA probes at three sites. At 26 and 60 months (t1, t2), trypticase-soy with serum, bacitracin, and vancomycin (TSBV) culture failed to detect A. actinomycetemcomitans at any of the sampled sites. Eighty-two months after the beginning of therapy (t4), none of the applied methods could detect A. actinomycetemcomitans from the pooled samples from the deepest pockets of each quadrant or the oral mucosa. In the present case, concomitant orthodontic treatment with a fixed appliance could be performed without further pronounced periodontal deterioration. Space for eruption of the canines and premolars was created, in addition to an alignment of the teeth. CONCLUSION: After a successful combined mechanical and antibiotic periodontal therapy of the PLS periodontitis, moderate orthodontic tooth movements may be possible within a complex interdisciplinary treatment regimen.