Activation of Hippo Pathway Damages Slit Diaphragm by Deprivation of Ajuba Proteins.

SIGNIFICANCE STATEMENT: Nuclear exclusion of the cotranscription factor YAP, which is a consequence of activation of the Hippo signaling pathway, leads to FSGS and podocyte apoptosis. Ajuba proteins play an important role in the glomerular filtration barrier by keeping the Hippo pathway inactive. In nephrocytes from Drosophila melanogaster , a well-established model system for podocyte research, Ajuba proteins ensure slit diaphragm (SD) formation and function. Hippo pathway activation leads to mislocalization of Ajuba proteins, decreased SD formation, rearrangement of the actin cytoskeleton, and increased SD permeability. Targeting the kinases of the Hippo pathway with specific inhibitors in the glomerulus could, therefore, be a promising strategy for therapy of FSGS. BACKGROUND: The highly conserved Hippo pathway, which regulates organ growth and cell proliferation by inhibiting transcriptional cofactors YAP/TAZ, plays a special role in podocytes, where activation of the pathway leads to apoptosis. The Ajuba family proteins (Ajuba, LIM domain-containing protein 1 (LIMD1) and Wilms tumor protein 1-interacting protein [WTIP]) can bind and inactivate large tumor suppressor kinases 1 and 2, (LATS1/2) two of the Hippo pathway key kinases. WTIP, furthermore, connects the slit diaphragm (SD), the specialized cell-cell junction between podocytes, with the actin cytoskeleton. METHODS: We used garland cell nephrocytes of Drosophila melanogaster to monitor the role of Ajuba proteins in Hippo pathway regulation and structural integrity of the SD. Microscopy and functional assays analyzed the interplay between Ajuba proteins and LATS2 regarding expression, localization, interaction, and effects on the functionality of the SD. RESULTS: In nephrocytes, the Ajuba homolog Djub recruited Warts (LATS2 homolog) to the SD. Knockdown of Djub activated the Hippo pathway. Reciprocally, Hippo activation reduced the Djub level. Both Djub knockdown and Hippo activation led to morphological changes in the SD, rearrangement of the cortical actin cytoskeleton, and increased SD permeability. Knockdown of Warts or overexpression of constitutively active Yki prevented these effects. In podocytes, Hippo pathway activation or knockdown of YAP also decreased the level of Ajuba proteins. CONCLUSIONS: Ajuba proteins regulate the structure and function of the SD in nephrocytes, connecting the SD protein complex to the actin cytoskeleton and maintaining the Hippo pathway in an inactive state. Hippo pathway activation directly influencing Djub expression suggests a self-amplifying feedback mechanism.

Structured Delirium Management in the Hospital.

BACKGROUND: Delirium is a common and serious complication of inpatient hospital care in older patients. The current approaches to prevention and treatment followed in German hospitals are inconsistent. The aim of this study was to test the effectiveness of a standardized multiprofessional approach to the management of delirium in inpatients. METHODS: The patients included in the study were all >65 years old, were treated for at least 3 days on an internal medicine, trauma surgery, or orthopedic ward at Münster University Hospital between January 2016 and December 2017, and showed cognitive deficits on standardized screening at the time of admission (a score of ≤=25 on the Montreal Cognitive Assessment [MoCA] test). Patients in the intervention group received standardized delirium prevention and treatment measures; those in the control group did not. The primary outcomes measured were the incidence and duration of delirium during the hospital stay; the secondary outcomes measured were cognitive deficits relevant to daily living at 12 months after discharge (MoCA and Instrumental Activities of Daily Living [I-ADL]). RESULTS: The data of 772 patients were analyzed. Both the rate and the duration of delirium were lower in the intervention group than in the control group (6.8% versus 20.5%, odds ratio 0.28, 95% confidence interval [0.18; 0.45]; 3 days [interquartile range, IQR 2-4] versus 6 days [IQR 4-8]). A year after discharge, the patients with delirium in the intervention group showed fewer cognitive deficits relevant to daily living than those in the control group (I-ADL score 2.5 [IQR 2-4] versus 1 [IQR 1-2], P = 0.02). CONCLUSION: Structured multiprofessional management reduces the incidence and duration of delirium and lowers the number of lasting cognitive deficits relevant to daily living after hospital discharge.

Prognostic implication of myocardial perfusion and contractile reserve in end-stage renal disease: A direct comparison of myocardial perfusion scintigraphy and dobutamine stress echocardiography.

BACKGROUND: We aimed to compare the prognostic value of myocardial perfusion scintigraphy (MPS) and dobutamine stress echocardiography (DSE) in patients with end-stage renal disease (ESRD) without known coronary artery disease. METHODS: Two-hundred twenty-nine ESRD patients who applied for kidney transplantation at our centre were prospectively evaluated by MPS and DSE. The primary endpoint was a composite of myocardial infarction (MI) or all-cause mortality. The secondary endpoint included MI or coronary revascularization (CR) not triggered by MPS or DSE at baseline. RESULTS: MPS detected reversible ischemia in 31 patients (13.5%) and fixed perfusion defects in 13 (5.7%) patients. DSE discovered stress-induced wall motion abnormalities (WMAs) in 28 (12.2%) and at rest in 18 (7.9%) patients. MPS and DSE results agreed in 85.6% regarding reversible defects (κ = 0.358; P < .001) and in 90.8% regarding fixed defects (κ = 0.275; P < .001). Coronary angiography detected relevant stenosis > 50% in only 15 of 38 patients (39.5%) with pathological findings in MPS and/or DSE. At a median follow-up of 8 years and 10 months, the primary endpoint occurred in 70 patients (30.6%) and the secondary endpoint in 24 patients (10.5%). The adjusted Cox hazard ratios (HRs) for the primary endpoint were 1.77 (95% CI 1.02-3.08; P = .043) for perfusion defects in MPS and 1.36 (95% CI 0.78-2.37; P = ns) for WMA in DSE. The secondary endpoint was significantly correlated with the findings of both modalities, MPS (HR 3.21; 95% CI 1.35-7.61; P = .008) and DSE (HR 2.67; 95% CI 1.15-6.20; P = .022). CONCLUSION: Perfusion defects in MPS are a stronger determinant of all-cause mortality, MI and the need for future CR compared with WMAs in DSE. Given the complementary functional information provided by MPS vs DSE, results are sometimes contradictory, which may indicate differences in the underlying pathophysiology.

Coronary artery calcium burden, carotid atherosclerotic plaque burden, and myocardial blood flow in patients with end-stage renal disease: A non-invasive imaging study combining PET/CT and 3D ultrasound.

BACKGROUND: Imaging-based measures of atherosclerosis such as coronary artery calcium score (CACS) and coronary flow reserve (CFR) as well as carotid atherosclerotic plaque burden (cPB) are predictors of cardiovascular events in the general population. The objective of this study was to correlate CACS, cPB, myocardial blood flow (MBF), and CFR in patients with end-stage renal disease (ESRD). METHODS AND RESULTS: 39 patients (mean age 53 ± 12 years) with ESRD prior to kidney transplantation were enrolled. MBF and CFR were quantified at baseline and under hyperemia by 13N-NH3-PET/CT. CACS was calculated from low-dose CT scans acquired for PET attenuation correction. cPB was assessed by 3D ultrasound. Uni- and multivariate regression analyses between these and clinical parameters were performed. Median follow-up time for clinical events was 4.4 years. Kaplan-Meier survival estimates with log-rank test were performed with regards to cardiovascular (CV) events and death of any cause. CACS and cPB were associated in ESRD patients (r = 0.48; p ≤ 0.01). While cPB correlated with age (r = 0.43; p < 0.01), CACS did not. MBFstress was negatively associated with age (r = 0.44; p < 0.01) and time on dialysis (r = 0.42; p < 0.01). There were negative correlations between MBFstress and CACS (r = - 0.62; p < 0.001) and between MBFstress and cPB (r = - 0.43; p < 0.01). Age and CACS were the strongest predictors for MBFstress. CFR was impaired (< 2.0) in eight patients who also presented with higher cPB and higher CACS compared to those with a CFR > 2.0 (p = 0.06 and p = 0.4). In contrast to MBFstress, there was neither a significant correlation between CFR and CACS (r = - 0.2; p = 0.91) nor between CFR and cPB (r = - 0.1; p = 0.55). CV event-free survival was associated with reduced CFR and MBFstress (p = 0.001 and p < 0.001) but not with cPB or CACS. CONCLUSIONS: CACS, cPB, and MBFstress are associated in patients with ESRD. Atherosclerosis is earlier detected by MBFstress than by CFR. CV event-free survival is associated with impaired CFR and MBFstress.

Case Report: Management of a Multidrug-Resistant CMV-Strain in a Renal Transplant Recipient by High-Dose CMV-Specific Immunoglobulins, Modulation in Immunosuppression, and Induction of CMV-Specific Cellular Immunity.

The management of multidrug-resistant strains of cytomegalovirus after solid organ transplantation is challenging. This case report demonstrates the successful treatment of a multidrug-resistant strain of cytomegalovirus that may represent a valuable option for problematic cases. This report illustrates the emergence of a multidrug-resistant cytomegalovirus (CMV) UL54 mutant strain in a renal transplant recipient with severe lymphopenia and thrombocytopenia. We show that the combined treatment with high-dose intravenous cytomegalovirus-specific immunoglobulins (CMV-IVIG) after the switch to a mammalian target of rapamycin (mTOR)-inhibitor and cyclosporine A was a successful treatment alternative to direct antiviral treatment with high-dose ganciclovir and foscarnet. This treatment was associated with a quantitative induction of CMV-specific CD4 and CD8 T cells that showed maturation in phenotype and functionality with decreasing viral load. Our case report illustrates that high-dose CMV-IVIG and conversion of immunosuppressive drugs to mTOR inhibitors and cyclosporine A can be a successful treatment in a situation where the use of direct antiviral drugs was considered insufficient.

Acute Kidney Injury: A Frequently Underestimated Problem in Perioperative Medicine.

BACKGROUND: Surgical patients are getting older with increasing comorbidity. Acute kidney injury (AKI) is a commonly underesti- mated perioperative complication. 2-18% of hospitalized patients and 22-57% of patients in the intensive care unit develop AKI. Even though it has a major impact on patients' outcomes, it goes unrecognized in 57-75.6% of cases. METHODS: This review is based on pertinent papers retrieved by a selective search in PubMed and the Cochrane Library employ- ing the searching terms "acute kidney injury," "biomarker," "perioperative," "renal function," and "KDIGO." RESULTS: The pathophysiology of AKI is complex. Conventional biomarkers are either not specific enough (urine output) or not sensitive enough (serum creatinine) for timely diagnosis. In view of the pathophysiology of the condition and the limited treat- ment options for it, the early detection of subclinical AKI (kidney damage without functional impairment) would seem to be a reasonable first step toward the prevention of worsening or permanent renal injury. New biomarkers of damage enable the early initiation of nephroprotective interventions. According to the "Kidney Disease: Improving Global Outcomes" (KDIGO) statement, a multimodal treatment approach is needed, including, among other things, optimization of hemodynamics and the discontinu- ation of nephrotoxic drugs. CONCLUSION: It is essential to identify patients at risk and sensitize the treating personnel to the implementation of the guidelines. The incorporation of new biomarkers into routine clinical practice is also reasonable and necessary. Future clinical trials must show in what form these biomarkers should be used (singly or collectively).

Examination of viraemia and clinical signs after challenge with a heterologous PRRSV strain in PRRS Type 2 MLV vaccinated pigs: A challenge-dose study.

Vaccination with porcine reproductive and respiratory syndrome (PRRS) Type 2 modified-live vaccines (MLVs) has been shown to improve clinical signs and survival rates in PRRS virus (PRRSV)-challenged pigs. This study evaluated the dose of PRRSV challenge needed to cause and maintain viraemia in PRRS Type 2 MLV-vaccinated pigs and assessed clinical responses to various doses of virulent challenge. This controlled, randomised, blinded vaccination-challenge study involved 95 pigs who were either vaccinated with 2 mL of a PRRS Type 2 MLV on Day 0 or left unvaccinated. On Day 28, pigs were challenged intranasally with virulent PRRSV isolate (dose range <1.5 to 4 log10 50% tissue culture infectious dose/mL). Five pigs were left unchallenged and served as environmental controls. Viraemia levels, pyrexia, average daily weight gain and clinical signs were assessed. At all challenge doses, vaccinated groups had reduced viraemia levels and clinical signs, and higher average daily weight gain compared with non-vaccinated groups. Vaccinated groups challenged with ≤2 log had similar viraemia levels and clinical performance (days pyrexic and average daily weight gain) as the non-challenged group. Vaccinated groups had significantly reduced pyrexic days compared with non-vaccinated groups across all challenge doses (P <.05). Vaccinated pigs challenged with <3 log had significantly improved average daily weight gain (P <.05). In vaccinated groups, challenge dose correlated positively with viraemia levels and number of days pyrexic, and negatively with average daily weight gain. This is the first study to use a challenge-dose model to evaluate the efficacy of vaccination against PRRSV. PRRS Type 2 MLV was shown to mitigate the consequences of PRRSV infection at all evaluated PRRSV challenge doses. Lower levels of challenge had minimal impact on health and performance of vaccinated pigs, supporting the benefit of vaccinating swine with PRRS Type 2 MLV.

Evaluation of the pathogenicity of mammalian orthoreovirus type 3 (MRV3) in germ-free gnotobiotic pigs and of the efficacy of an inactivated vaccine against MRV3 infection in neonatal conventional piglets.

A novel U.S. strain of mammalian orthoreovirus type 3 (MRV3) isolated from diarrheic pigs in 2015 was reportedly highly pathogenic in pigs. In this study, we first developed an inactivated MRV3 vaccine and determined its protective efficacy against MRV3 infection in conventional neonatal piglets. A pathogenicity study was also conducted in gnotobiotic pigs to further assess the pathogenicity of MRV3. To evaluate if piglets could be protected against MRV3 infection after immunization of pregnant sows with an inactivated MRV3 vaccine, pregnant sows were vaccinated with 2 or 3 doses of the vaccine or with PBS buffer. Four-day-old piglets born to vaccinated and unvaccinated sows were subsequently challenged with MRV3. The results showed that piglets born from vaccinated sows had lower levels of fecal viral RNA shedding at 1, 3, and 4 days post-challenge, suggesting that the inactivated MRV3 vaccine can reduce MRV3 replication. Surprisingly, although the conventional piglets were infected, they did not develop severe enteric disease as reported previously. Therefore, in an effort to further definitively assess the pathogenicity of MRV3, we experimentally infected gnotobiotic pigs, a more sensitive model for pathogenicity study, with the wild-type MRV3 virus. The infected gnotobiotic piglets all survived and exhibited only very mild diarrhea in some pigs. Taken together, the results indicate that the novel strain of MRV3 recently isolated in the United States infected but caused only very mild diarrhea in pigs, and that maternal immunity acquired from sows vaccinated with an inactivated vaccine can reduce MRV3 replication in neonatal pigs.

Inhibition of Endothelial Notch Signaling Impairs Fatty Acid Transport and Leads to Metabolic and Vascular Remodeling of the Adult Heart.

BACKGROUND: Nutrients are transported through endothelial cells before being metabolized in muscle cells. However, little is known about the regulation of endothelial transport processes. Notch signaling is a critical regulator of metabolism and angiogenesis during development. Here, we studied how genetic and pharmacological manipulation of endothelial Notch signaling in adult mice affects endothelial fatty acid transport, cardiac angiogenesis, and heart function. METHODS: Endothelial-specific Notch inhibition was achieved by conditional genetic inactivation of Rbp-jκ in adult mice to analyze fatty acid metabolism and heart function. Wild-type mice were treated with neutralizing antibodies against the Notch ligand Delta-like 4. Fatty acid transport was studied in cultured endothelial cells and transgenic mice. RESULTS: Treatment of wild-type mice with Delta-like 4 neutralizing antibodies for 8 weeks impaired fractional shortening and ejection fraction in the majority of mice. Inhibition of Notch signaling specifically in the endothelium of adult mice by genetic ablation of Rbp-jκ caused heart hypertrophy and failure. Impaired heart function was preceded by alterations in fatty acid metabolism and an increase in cardiac blood vessel density. Endothelial Notch signaling controlled the expression of endothelial lipase, Angptl4, CD36, and Fabp4, which are all needed for fatty acid transport across the vessel wall. In endothelial-specific Rbp-jκ-mutant mice, lipase activity and transendothelial transport of long-chain fatty acids to muscle cells were impaired. In turn, lipids accumulated in the plasma and liver. The attenuated supply of cardiomyocytes with long-chain fatty acids was accompanied by higher glucose uptake, increased concentration of glycolysis intermediates, and mTOR-S6K signaling. Treatment with the mTOR inhibitor rapamycin or displacing glucose as cardiac substrate by feeding a ketogenic diet prolonged the survival of endothelial-specific Rbp-jκ-deficient mice. CONCLUSIONS: This study identifies Notch signaling as a novel regulator of fatty acid transport across the endothelium and as an essential repressor of angiogenesis in the adult heart. The data imply that the endothelium controls cardiomyocyte metabolism and function.

Serum Interleukin-6 and CCL11/Eotaxin May Be Suitable Biomarkers for the Diagnosis of Chronic Nonbacterial Osteomyelitis.

OBJECTIVES: Chronic recurrent multifocal osteomyelitis (CRMO), the most severe form of chronic nonbacterial osteomyelitis (CNO), is an autoinflammatory bone disorder. In the absence of diagnostic criteria or biomarkers, CNO/CRMO remains a diagnosis of exclusion. The aim of this study was to identify biomarkers for diagnosing multifocal disease (CRMO). STUDY DESIGN: Sera from 71 pediatric CRMO patients, 11 patients with osteoarticular infections, 62 patients with juvenile idiopathic arthritis (JIA), 7 patients with para-infectious or reactive arthritis, and 43 patients with acute leukemia or lymphoma, as well as 59 healthy individuals were collected. Multiplex analysis of 18 inflammation- and/or bone remodeling-associated serum proteins was performed. Statistical analysis included univariate ANOVA, discriminant analysis, univariate receiver operating characteristic (ROC) analysis, and logistic regression analyses. RESULTS: For 14 of 18 blood serum proteins, significant differences were determined between CRMO patients, at least one alternative diagnosis, or healthy controls. Multi-component discriminant analysis delivered five biomarkers (IL-6, CCL11/eotaxin, CCL5/RANTES, collagen Iα, sIL-2R) for the diagnosis of CRMO. ROC analysis allowed further reduction to a core set of 2 biomarkers (CCL11/eotaxin, IL-6) that are sufficient to discern between CRMO, healthy controls, and alternative diagnoses. CONCLUSION: Serum biomarkers CCL11/eotaxin and IL-6 differentiate between patients with CRMO, healthy controls, and alternative diagnoses (leukemia and lymphoma, osteoarticular infections, para-infectious arthritis, and JIA). Easily accessible biomarkers may aid in diagnosing CRMO. Further studies testing biomarkers in larger unrelated cohorts are warranted.

Age susceptibility of caesarian derived colostrum deprived pigs to Mycoplasma hyorhinis challenge.

Mycoplasma hyorhinis (MHR) is a major cause of lameness, arthritis, and polyserositis among growing pigs. Reduced performance and culling due to MHR infection result in economic losses in swine production. We have previously developed an MHR challenge model in seven week-old CDCD pigs using cell-associated challenge material which results in both severe pericarditis and lameness. In this study we sequentially challenged CDCD pigs at seven, ten, thirteen, and sixteen weeks of age. Lameness was observed in >60% of the animals in the first three age groups but only 33% in the oldest age group. The number of animals with arthritis declined from 100% at seven weeks, to 56% at ten weeks and approximately 25% at both thirteen and sixteen weeks of age. Pericarditis was observed in 87% of the seven week challenge group, 28% in the ten week challenge group, 8% in the thirteen week challenge group and 4% in the sixteen week challenge group. All challenged groups showed a reduced average daily gain (ADG) compared to their age-matched non-challenged control groups. The largest disparity in ADG (1.2 lbs/day difference) was noted at thirteen weeks of age. Results of this study demonstrate that these animals were susceptible to MHR-associated lameness through sixteen weeks of age while susceptibility to MHR-associated polyserositis appeared to peak at seven weeks of age.

Cantú Syndrome Associated with Ovarian Agenesis.

Cantú syndrome is a very rare autosomal dominant disorder characterized by generalized congenital hypertrichosis, neonatal macrosomia, coarse face, cardiomegaly, and occasionally, skeletal abnormalities. The syndrome has been attributed to mutated ABCC9 or KCNJ8 genes. We present a 4-year-old girl with developmental delay, distinctive coarse facial features, and generalized hypertrichosis apparent since birth. The investigation revealed absent ovaries and a hypoplastic uterus which have not been previously described. Conventional karyotyping was normal. DNA sequencing analysis of the ABCC9 gene was performed, and a heterozygous point mutation c.3460C>T (p.Arg1154Trp) was revealed. This missense gain-of-function mutation was located in exon 27 of the ABCC9 gene and has been reported in patients with the full phenotype of Cantú syndrome. However, the absence of the ovaries could be an expansion of the phenotype and not attributed to mutations in other genes important for ovarian development. Unfortunately, it has not been proven so far if the ABCC9 gene is expressed in the ovarian tissue.

Circulating fibronectin contributes to mesangial expansion in a murine model of type 1 diabetes.

Fibronectin is ubiquitously expressed in the extracellular matrix, and its accumulation in the glomerular mesangium in diabetic nephropathy is associated with deterioration of renal function in these patients. However, the exact role of fibronectin in the pathogenesis of diabetic nephropathy remains unknown. To clarify this, we administered fluorescent-labeled plasma fibronectin to wild-type mice and found it to accumulate in the mesangium. Using liver-specific conditional-knockout mice to decrease circulating fibronectin, we reduced circulating fibronectin by more than 90%. In streptozotocin-induced diabetes of these knockout mice, the pronounced fall in circulating fibronectin resulted in a decrease in mesangial expansion by 25% and a decline in albuminuria by 30% compared to diabetic control mice. Indeed, the amount of fibronectin in the kidney was reduced, as was the total amount of collagen. In vitro experiments confirmed that matrix accumulation of fibronectin was enhanced by increasing fibronectin only, glucose only, or the combination of both. Thus, circulating fibronectin contributes to mesangial expansion and exacerbation of albuminuria in a murine model of type 1 diabetes.

How rapid is rapid? Exemplary results of real-life rapid rule-out troponin timing in troponin-positive acute coronary syndromes without persistent ST-segment elevation in two contrasting German chest pain unit facilities.

AIM: To analyse the timing of cardiac troponin (cTn) measurements in high-risk and cTn-positive acute coronary syndromes without persistent ST-segment elevation (NSTE-ACS) in two structurally different German chest pain units (CPUs), contrasting an urban university maximum care and a rural regional primary care facility. METHODS: All patients encoded as NSTEMI during the year 2013 were retrospectively enrolled in two centres: site (I)--centre of maximum care in an urban university setting and site (II)--centre of primary care in a rural regional care setting. Data acquisition included time intervals from admission to baseline cTn and first and second cTn control as well as type and timing of invasive management. RESULTS: The median times (site I vs. site II) from admission to cTn result announcement were 26.5 vs. 33.0 min (p = 0.02) for baseline, 4 vs. 4 h (p = 0.43) for the first and 11.0 vs. 16.5 h (p = 0.03) for the second control. Timely announcement, as recommended by guidelines, was available in 86.9% at baseline, 59.4% for the first or 41.1% for the second cTn control. Rates and timing of invasive management were independent from the time point of positive cTn announcement (p = 0.51 and p = 0.68, respectively). CONCLUSIONS: German CPUs provide timely identification of cTn-positive patients in a narrow and guideline-adherent time frame using a rapid rule-out protocol. Especially, baseline and early cTn timing was comparable between the urban university maximum care and the rural regional primary care facility without relevant impact on guideline-conforming invasive management, underlining the high standard of care in those highly professional institutions.

Serum biomarkers for the diagnosis and monitoring of chronic recurrent multifocal osteomyelitis (CRMO).

Chronic recurrent multifocal osteomyelitis (CRMO), the most severe form of chronic nonbacterial osteomyelitis, is an autoinflammatory bone disorder. A timely diagnosis and treatment initiation is complicated by the absence of widely accepted diagnostic criteria and an incomplete pathophysiological understanding. The aim of this study was to determine biomarkers for the diagnosis and follow-up of CRMO. Serum of 56 CRMO patients was collected at the time of diagnosis. As controls, sera from treatment-naïve age-matched patients with Crohn's disease (N = 62) or JIA (N = 28) as well as healthy individuals (N = 62) were collected. Multiplex analysis of 25 inflammation markers was performed. Statistical analysis was performed using Kruskal-Wallis and Mann-Whitney U tests, canonical discriminant analysis, and mixed model variance analysis. Mostly monocyte-derived serum proteins were detectable and differed significantly between groups: IL-1RA, IL-2R, IL-6, IL-12, eotaxin, MCP-1, MIP-1b, RANTES. Multicomponent discriminant analysis allowed for the definition of algorithms differentiating between CRMO, Crohn's disease, and healthy controls. Persistently high levels of MCP-1, IL-12, sIL-2R correlated with incomplete remission in follow-up samples from CRMO patients. Discrimination algorithms allow differentiation between patients with CRMO or Crohn's disease, and healthy individuals. IL-12, MCP-1, and sIL-2R can act as markers for treatment response. Though confirmation of our findings in larger multiethnical cohorts is warranted, they may prove valuable to differentiate between otherwise healthy individuals or Crohn's disease patients with "bone pain" and CRMO patients. The elevation of mainly monocyte-derived pro-inflammatory serum proteins supports the hypothesis of pro-inflammatory monocyte/macrophages driving inflammation in CRMO.

Comparison of the pathogenicity of the USDA challenge virus strain to a field strain of infectious laryngotracheitis virus.

Infectious laryngotracheitis virus (ILTV) causes respiratory disease in chickens. This alphaherpesvirus infects laryngeal tracheal epithelial cells and causes outbreaks culminating in decreases in egg production, respiratory distress in chickens and mortality. There are several different vaccines to combat symptoms of the virus, including chicken embryo origin, tissue culture origin and recombinant vaccines. All vaccines licensed for use in the U.S. are tested for efficacy and potency according to U.S. federal regulation using a vaccine challenge assay involving the use of an ILT challenge virus. This challenge virus is provided to biologics companies by the Center for Veterinary Biologics (CVB), United States Department of Agriculture (USDA). The current USDA challenge virus originated from a vaccine strain and has been subjected to multiple passages in eggs, and may not represent what is currently circulating in the field. The objective of this study was to evaluate and compare the pathogenicity of USDA's challenge virus strain to the pathogenicity of a recent ILT field isolate. Using the challenge virus and various dilutions of the field isolate, clinical signs, mortality and pathology were evaluated in chickens. Results indicate that the field isolate at a 1:20 dilution is comparable in pathogenicity to the USDA challenge virus at a 1:4 dilution, and that the ILTV field isolate is a viable candidate that could be used as a challenge virus when evaluating vaccine efficacy.

The Speed of Visual Attention and Motor-Response Decisions in Adult Attention-Deficit/Hyperactivity Disorder.

BACKGROUND: Adults with attention-deficit/hyperactivity disorder (ADHD) exhibit slowed reaction times (RTs) in various attention tasks. The exact origins of this slowing, however, have not been established. Potential candidates are early sensory processes mediating the deployment of focal attention, stimulus response translation processes deciding upon the appropriate motor response, and motor processes generating the response. METHODS: We combined mental chronometry (RT) measures of adult ADHD (n = 15) and healthy control (n = 15) participants with their lateralized event-related potentials during the performance of a visual search task to differentiate potential sources of slowing at separable levels of processing: the posterior contralateral negativity (PCN) was used to index focal-attentional selection times, while the lateralized readiness potentials synchronized to stimulus and response events were used to index the times taken for response selection and production, respectively. To assess the clinical relevance of event-related potentials, a correlation analysis between neural measures and subjective current and retrospective ADHD symptom ratings was performed. RESULTS: ADHD patients exhibited slower RTs than control participants, which were accompanied by prolonged PCN and lateralized readiness potentials synchronized to stimulus, but not lateralized readiness potentials synchronized to response events, latencies. Moreover, the PCN timing was positively correlated with ADHD symptom ratings. CONCLUSIONS: The behavioral RT slowing of adult ADHD patients was based on a summation of internal processing delays arising at perceptual and response selection stages; motor response production, by contrast, was not impaired. The correlation between PCN times and ADHD symptom ratings suggests that this brain signal may serve as a potential candidate for a neurocognitive endophenotype of ADHD.

Facing the challenges of chronic pruritus: a report from a multi-disciplinary medical itch centre in Germany.

The complex nature and difficult-to-establish aetiology of chronic pruritus (CP) makes it challenging to provide medical care for patients with CP. This challenge can only be met with a multidisciplinary approach. The first multidisciplinary Itch Centre in Germany was established at the University of Münster in 2002 to meet the needs of this patient population. More than 2,500 outpatients and 400 inpatients are diagnosed and receive treatment each year. To ensure evidence-based medical care, an electronic system for medical documentation and patient-reported outcomes was established. Automated data transfer to a research database enables comprehensive data analysis. Our translational research has characterized peripheral and central itch mechanisms, provided novel clustering of CP patients, and identified novel target-specific therapies (e.g. neurokinin 1 receptor-antagonist). The multidisciplinary approach, combined with basic, clinical and translational research, enables comprehensive medical care of patients as well as implementation of high-quality experimental and clinical studies.

Impact of copeptin on diagnosis, risk stratification, and intermediate-term prognosis of acute coronary syndromes.

BACKGROUND: The aim of the current study was to evaluate the diagnostic and intermediate-term prognostic impact of C-terminal portion of provasopressin (copeptin) in combination with troponin I. METHODS: In this prospective single-center study we recruited a total of 230 unselected patients with suspected recent acute coronary syndrome (ACS) presenting consecutively at our chest pain unit. Troponin I and copeptin levels were determined at presentation and after 3-6 h. Follow-up was performed after 180 days. RESULTS: Acute myocardial infarction (AMI) was the final diagnosis in 107 patients (STEMI: 24, NSTEMI: 83). The median copeptin level was significantly higher in patients having AMI than in those without (20.83 vs. 12.2 pmol/L, p < 0.0001). A troponin I level <0.04 ng/mL in combination with copeptin <14 pmol/L at admission ruled out AMI with an negative predictive value (NPV) of 97.3 %. p = 0.0045 for the added value of copeptin to troponin I. Kaplan-Meier analysis showed that copeptin levels above the diagnostic cut-off were associated with an elevated intermediate-term (180 days) mortality (p = 0.019), while no patient with copeptin values below the cut-off died. Univariate Cox regression analysis identified copeptin as strong predictor of intermediate-term mortality (HR 4.28, 95 % CI 1.58-11.6, p = 0.004). The predictive performance for prediction of 180-day mortality was significantly better if copeptin was included (C-index of 0.80) compared with that of troponin alone (C-index 0.78, p = 0.01 for the added value of copeptin to troponin I). CONCLUSIONS: Additional assessment of copeptin allows a rapid and reliable exclusion of AMI and improves diagnostic accuracy in myocardial ischemia. This study showed for the first time that copeptin provides valuable predictive information for risk stratification and intermediate-term outcome in ACS patients.