Immune Metabolism in TH2 Responses: New Opportunities to Improve Allergy Treatment - Cell Type-Specific Findings (Part 2).

PURPOSE OF REVIEW: Over the last years, we have learned that the metabolic phenotype of immune cells is closely connected to the cell's effector function. Understanding these changes will allow us to better understand allergic disease pathology and improve allergy treatment by modulating immune metabolic pathways. As part two of a two-article series, this review reports on the recent studies investigating the metabolism of the cell types involved in allergies and discusses the initial application of these discoveries in allergy treatment. RECENT FINDINGS: The cell types involved in allergic reactions display pronounced and highly specific metabolic changes (here discussed for epithelial cells, APCs, ILC2s, mast cells, eosinophils, and Th2 cells). Currently, the first drugs targeting metabolic pathways are tested for their potential to improve allergy treatment. Immune-metabolic changes observed in allergy so far are complex and depend on the investigated disease and cell type. However, our increased understanding of the underlying principles has pointed to several promising target molecules that are now being investigated to improve allergy treatment.

Immune Metabolism in TH2 Responses: New Opportunities to Improve Allergy Treatment - Disease-Specific Findings (Part 1).

PURPOSE OF REVIEW: Recent high-level publications have shown an intricate connection between immune effector function and the metabolic state of the respective cells. In the last years, studies have begun analyzing the metabolic changes associated with allergies. As the first part of a two-article series, this review will briefly summarize the basics of immune metabolism and then focus on the recently published studies on metabolic changes observed in allergic patients. RECENT FINDINGS: In the last 3 years, immune-metabolic research in allergology had a clear focus on asthma with some studies also reporting findings in food allergy and atopic dermatitis. Current results suggest asthma to be associated with a shift in cellular metabolism towards increased aerobic glycolysis (Warburg metabolism), while also displaying substantial changes in fatty acid- and amino acid metabolism (depending on investigated patient collective, asthma phenotype, and disease severity). Understanding immune-metabolic changes in allergies will allow us to (I) better understand allergic disease pathology and (II) modulate immune-metabolic pathways to improve allergy treatment.

Murine colonization model by Campylobacter coli DSPV458.

AIMS: To generate a murine experimental model of colonization by Campylobacter coli DSPV458. METHODS AND RESULTS: Twelve adult Balb/cCmedc female mice were housed in a treated group (T-G) and a control group (C-G) for 4 weeks. Both experimental groups received antibiotics for 5 days during the first week. The T-G was administered with 6.68log10 CFU of C. coli DSPV458 by oesophageal gavage. Necropsies were performed weekly to evaluate translocation and intestinal colonization in the spleen and liver and in the ileum and cecum respectively. Samples were cultured to quantify intestinal microbiota members. Faeces were cultured weekly for a C. coli DSPV458 count. Campylobacter coli DSPV458 was isolated from all the inoculated mice. The recovered level of C. coli DSPV458 was, on average, 6.9 log10 CFUg-1 , 8.0 log10 CFUg-1 and 1.6 log10 CFUg-1 in faeces, cecum and ileum respectively. Colonization by C. coli DSPV458 does not alter the normal clinical and physiological status. CONCLUSIONS: Campylobacter coli DSPV458 does not have an invasive capacity, and the model is suitable for evaluating strategies to reduce intestinal loads. SIGNIFICANCE AND IMPACT OF STUDY: Farm animals have an important impact on thermotolerant Campylobacter transmission to humans. Extremely few colonization models by C. coli have been reported to date. In food-producing animals, infection is mild or absent and thermotolerant Campylobacter colonize the intestines of animals. Colonization models are specific models that do not cause infection as they do not generally result in diarrhoea or other signs of disease. Therefore, this model will allow to evaluate the evolution of colonization by thermotolerant Campylobacter and the alternative tools development to antibiotics that limit their colonization in food-producing animals.

In vitro screening and in vivo colonization pilot model of Lactobacillus plantarum LP5 and Campylobacter coli DSPV 458 in mice.

The objective of this work was to determine the antibacterial effect of Lactobacillus plantarum strains of pork origin against Campylobacter coli strains, and to conduct experimental colonization pilot models in mice for both microorganisms. Inhibition assays allowed evaluation and selection of L. plantarum LP5 as the strain with the highest antagonistic activity against C. coli and with the best potential to be used in in vivo study. Adult 6-week-old female Balb/cCmedc mice were lodged in two groups. The treated group was administered with 9.4 log10CFU/2 times/wk of L. plantarum LP5. L. plantarum LP5 was recovered from the feces and cecum of the inoculated mice. However, when bacteria stopped being administered, probiotic counts decreased. Experimental colonization with C. coli was carried out in five groups of mice. All animals were treated with antibiotics in their drinking water to weaken the indigenous microbiota and to allow colonization of C. coli. Four groups were administered once with different C. coli strains (DSPV458: 8.49 log10CFU; DSPV567: 8.09 log10CFU; DSPV570: 8.46 log10CFU; DSPV541: 8.86 log10CFU, respectively). After 8 h, mice inoculated with different C. coli strains were colonized because the pathogen was detected in their feces. L. plantarum LP5 tolerated the gastrointestinal conditions of murine model without generating adverse effects on the animals. C. coli DSPV458 colonized the mice without causing infection by lodging in their digestive tract, thus generating a reproducible colonization model. Both models combined could be used as protection murine models against pathogens to test alternative control tools to antibiotics.

Survey of current practices and opinions of German Society of Gynecologic Endoscopy members regarding the treatment of ovarian neoplasia by robotic surgery.

PURPOSE: As data on this topic are sparse and contradictory, we aimed to ascertain the opinions of the members of the German Society of Gynecologic Endoscopy (AGE) regarding the use of robotic surgery in the treatment of ovarian malignancies. METHODS: In 2015, an anonymous questionnaire was sent to AGE members to assess their views on the treatment of ovarian malignancies by robotic surgery according to T stage and the current treatment practices in their facilities. RESULTS: Of the 228 respondents, 132 (58%) were fellows or attending physicians and 156 (68%) worked at university hospitals or tertiary referral centers. Most [n = 218 (96%)] respondents reported treating < 10% of their patients using robotic surgery. Respondents felt that T1 and borderline ovarian tumors, but not T2 (51%) or T3/4 (76%) tumors, should and could be treated by robot surgery. 162 (71%) respondents considered the currently available data on this subject to be insufficient, and 42% indicated their willingness to participate in clinical studies on the applicability of robotic surgery to the treatment of T1/2 ovarian tumors. CONCLUSION: The majority of AGE members surveyed considered robotic surgery to be an option for the treatment of T1 ovarian malignancies and borderline ovarian tumors. However, prospective randomized studies are needed to determine the relevance of robotic surgery in this context.

Intraoperative and postoperative complications of gynecological laparoscopic interventions: incidence and risk factors.

PURPOSE: The aims of this study were to determine the incidence of intraoperative and postoperative complications of laparoscopic gynecological interventions and to identify risk factors for such complications. METHODS: All patients who underwent laparoscopic interventions from September 2013 to September 2017 at the Department of Gynecology, Obstetrics and Reproductive Medicine, Saarland University Hospital were identified retrospectively using a prospectively compiled clinical database. Binary logistic regression analysis was used to identify independent risk factors for intra- and postoperative complications. RESULTS: Data from 3351 patients were included in the final analysis. Overall, 188 (5.6%) intraoperative and 219 (6.5%) postoperative complications were detected. On multivariate analysis, age [odds ratio (OR), 1.03; 95% confidence interval (CI) 1.01-1.04], surgery duration (OR, 1.02; 95% CI 1.02-1.03), carbon dioxide use (OR, 0.99; 95% CI 0.99-1.00), and surgical indication (all p ≤ 0.01) were independent risk factors for intraoperative and duration of surgery (OR, 1.01; 95% CI 1.01-1.02; p ≤ 0.01), carbon dioxide use (OR, 0.99; 95% CI 0.99-1.00; p ≤ 0.01), hemoglobin drop (OR, 1.41; 95% CI 1.21-1.65; p ≤ 0.01), and ASA status (p = 0.04) for postoperative complications. CONCLUSION: In this large retrospective analysis with a generally low incidence of complications (5.6% intraoperative and 6.5% postoperative complications), a representative risk collective was identified: Patients aged > 38 years, surgery duration > 99 min, benign or malignant adnex findings were at higher risk for intraoperative and patients with surgery duration > 94 min, hemoglobin drop > 2 g/dl and ASA status III at higher risk for postoperative complications.

Gut Dysbiosis With Bacilli Dominance and Accumulation of Fermentation Products Precedes Late-onset Sepsis in Preterm Infants.

BACKGROUND: Gut dysbiosis has been suggested as a major risk factor for the development of late-onset sepsis (LOS), a main cause of mortality and morbidity in preterm infants. We aimed to assess specific signatures of the gut microbiome, including metabolic profiles, in preterm infants <34 weeks of gestation preceding LOS. METHODS: In a single-center cohort, fecal samples from preterm infants were prospectively collected during the period of highest vulnerability for LOS (days 7, 14, and 21 of life). Following 16S rRNA gene profiling, we assessed microbial community function using microbial metabolic network modeling. Data were adjusted for gestational age and use of probiotics. RESULTS: We studied stool samples from 71 preterm infants with LOS and 164 unaffected controls (no LOS/necrotizing enterocolitis). In most cases, the bacteria isolated in diagnostic blood culture corresponded to the genera in the gut microbiome. LOS cases had a decelerated development of microbial diversity. Before onset of disease, LOS cases had specific gut microbiome signatures with higher abundance of Bacilli (specifically coagulase-negative Staphylococci) and a lack of anaerobic bacteria. In silico modeling of bacterial community metabolism suggested accumulation of the fermentation products ethanol and formic acid in LOS cases before the onset of disease. CONCLUSIONS: Intestinal dysbiosis preceding LOS is characterized by an accumulation of Bacilli and their fermentation products and a paucity of anaerobic bacteria. Early microbiome and metabolic patterns may become a valuable biomarker to guide individualized prevention strategies of LOS in highly vulnerable populations.

[Medical confidentiality]. / Ärztliche Schweigepflicht.

Medical confidentiality is a fundamental prerequisite in the patient-physician relationship based on trust and goes back to the Hippocratic oath. It is clearly defined in the German Constitution as well as the medical professional code of conduct. A breach of confidentiality can result in criminal sanctions and professional consequences as well as civil claims for damages and compensation by the affected patients. In routine clinical practice situations repeatedly occur which lead to uncertainty regarding the limits of confidentiality, the right to silence and the obligation to disclosure. The purpose of this article is to explain the legal foundations of medical confidentiality, the right to silence and the obligation to disclosure and to provide practical support for critical questions in routine clinical practice.

Homer1 (VesL-1) in the rat esophagus: focus on myenteric plexus and neuromuscular junction.

Homer1, a scaffolding protein of the postsynaptic density (PSD), enriched at excitatory synapses is known to anchor and modulate group I metabotropic glutamate receptors (mGluRs) and different channel- and receptor-proteins. Homer proteins are expressed in neurons of different brain regions, but also in non-neuronal tissues like skeletal muscle. Occurrence and location of Homer1 and mGluR5 in myenteric plexus and neuromuscular junctions (NMJ) of rat esophagus have yet not been characterized. We located Homer1 and mGluR5 immunoreactivity (-iry) in rat esophagus and focused on myenteric neurons, intraganglionic laminar endings (IGLEs) and NMJs, using double- and triple-label immunohistochemistry and confocal laser scanning microscopy. Homer1-iry was found in a subpopulation of vesicular glutamate transporter 2 (VGLUT2) positive IGLEs and cholinergic varicosities within myenteric ganglia, but neither in nitrergic nor cholinergic myenteric neuronal cell bodies. Homer1-iry was detected in 63% of esophageal and, for comparison, in 35% of sternomastoid NMJs. Besides the location in the PSD, Homer1-iry colocalized with cholinergic markers, indicating a presynaptic location in coarse VAChT/CGRP/NF200- immunoreactive (-ir) terminals of nucleus ambiguus neurons supplying striated esophageal muscle. mGluR5-iry was found in subpopulations of myenteric neuronal cell bodies, VGLUT2-ir IGLEs and cholinergic varicosities within the myenteric neuropil and NMJs of esophagus and sternomastoid muscles. Thus, Homer1 may anchor mGluR5 at presynaptic sites of cholinergic boutons at esophageal motor endplates, in a small subpopulation of VGLUT2-ir IGLEs and cholinergic varicosities within myenteric ganglia possibly modulating Ca2+-currents and neurotransmitter release.

Enhanced viral clearance and reduced leukocyte infiltration in experimental herpes encephalitis after intranasal infection of CXCR3-deficient mice.

Herpes simplex virus type 1 (HSV-1) encephalitis (HSE) is the most common fatal sporadic encephalitis in developed countries. There is evidence from HSE animal models that not only direct virus-mediated damage caused but also the host's immune response contributes to the high mortality of the disease. Chemokines modulate and orchestrate this immune response. Previous experimental studies in HSE models identified the chemokine receptor CXCR3 and its ligands as molecules with a high impact on the course of HSE in mouse models. In this study, the role of the chemokine receptor CXCR3 was evaluated after intranasal infection with the encephalitogenic HSV-1 strain 17 syn+ using CXCR3-deficient mice (CXCR3-/-) and wild-type controls. We demonstrated a neurotropic viral spread into the CNS of after intranasal infection. Although viral load and histological distribution of infected neurons were independent from CXCR3 signaling early after infection, CXCR3-deficient mice cleared HSV-1 more efficiently 14 days after infection. Furthermore, CXCR3 deficiency led to a decreased weight loss in mice after HSV-1 infection. T cell infiltration and microglial activation was prominently reduced by inhibition of CXCR3 signaling. Quantitative PCR of proinflammatory cytokines and chemokines confirmed the reduced neuroinflammatory response in CXCR3-deficient mice during HSE. Our results demonstrate that the recruitment of peripheral immune cells into the CNS, induction of neuroinflammation, and consecutive weight loss during herpes encephalitis is modulated by CXCR3 signaling. Interruption of the CXCR3 pathway ameliorates the detrimental host immune response and in turn, leads paradoxically to an enhanced viral clearance after intranasal infection. Our data gives further insight into the role of CXCR3 during HSE after intranasal infection.

[Endocrinology and interdisciplinary consultation in internal medicine : Illustrated using the example of polyglandular autoimmune syndrome]. / Endokrinologie als Schnittstelle in der interdisziplinären Inneren Medizin : Veranschaulichung anhand des polyglandulären Autoimmunsyndroms.

Polyglandular autoimmune syndromes encompass several endocrine and nonendocrine autoimmune disorders with variable onset and phenotype. Rheumatoid and gastroenterological symptoms in patients with autoimmune polyglandular syndromes are suggestive of additional rheumatoid gastrointestinal and hepatological autoimmune diseases. Autoimmune gastritis, celiac disease, autoimmune hepatitis, rheumatoid arthritis, Sjögren syndrome, and systemic Lupus erythematodus are of particular clinical relevance. In addition, unspecific rheumatoid and gastrointestinal attendant symptoms of the existing autoimmune endocrinopathy must be considered. Furthermore, certain disorders of polyglandular autoimmune syndromes, e. g., type 1 diabetes are frequently associated with particular gastrointestinal diseases such as small bowel bacterial overgrowth. An optimal patient-centered care of subjects with autoimmune diseases requires a comprehensive differential diagnostic work up and emphasizes the importance of an interdisciplinary cooperation.

DAT1 and DRD4 genes involved in key dimensions of adult ADHD.

Attention-deficit hyperactivity disorder (ADHD) is a highly heritable neurodevelopmental disorder often persisting in adulthood. Genetic studies of ADHD mainly focused on the Dopamine Transporter (DAT1) and the Dopamine Receptor 4 (DRD4) genes. Nevertheless, polymorphisms of these genes explain only a small fraction of the assigned risk, suggesting that intermediate dimensions and environmental factors should also be considered. We investigated in 77 adult ADHD subjects compared to 474 controls, how polymorphisms within the genes coding for DAT1 (40-bp VNTR in 3'UTR), the Dopamine Receptor 2 (DRD2) (rs1799732) and DRD4 (48-bp VNTR in exon 3), may modulate the expression of the disorder. By genotyping DAT1, we detected a new 9.5R allele showing a deletion of 40 bp and also an insertion of 19 bp compared to the 10R allele. This novel allele was found to be significantly protective for ADHD (p < 0.0001). Another significant difference was found in the distribution of DRD4 48-bp VNTR 6R allele when comparing patients and controls (p = 0.0007). In addition significant results were also found for DAT1 9.5R allele, which was associated with impulsiveness (p = 1.98 × 10(-4)) and trait anger scores (p = 7.66 × 10(-4)). Moreover, impulsiveness scores were partly modulated by an interaction between the DRD4 48-bp VNTR 6R allele and childhood maltreatment (p = 0.01), however, this result did not resist correction for multiple comparisons. Altogether, our results show the putative involvement of DAT1 and DRD4 genes in the aetiology of ADHD with a main role in modulation of key dimensions of the disorder.

Foster children's attachment security and behavior problems in the first six months of placement: associations with foster parents' stress and sensitivity.

Both traumatic experiences in their birth families and multiple placement histories lead to increased mental health problems in foster children. The formation of secure attachments to new caregivers could be a protective factor for foster children. The current study focused on the associations between foster parents' sensitivity, parenting stress and foster children's attachment behavior as well as behavior problems. The sample consists of 48 children (aged from 1 to 6 years) and their foster caregivers. Attachment behavior and sensitivity were observed during home visits. Furthermore, caregiver reports were used to assess parenting stress and children's behavior problems. Compared to normative data, foster children showed lower levels of attachment security and more behavior problems. Foster children's attachment security and behavior problems were predicted significantly or marginally by foster parents' stress and supportive presence.

The interference of distal humeral plating with the medial and lateral collateral ligaments of the elbow.

INTRODUCTION: The aim of the present study was to determine the anatomical relationship and evaluate the potential interference of today's common distal humerus plates with the medial and lateral collateral ligaments of the elbow. MATERIALS AND METHODS: The elbow joints of 23 embalmed upper extremities were dissected. Three different brands of distal humerus double-plating systems were applied in a standardized fashion. We used a caliper to measure the amount of absolute overlap of the plates on the corresponding collateral ligaments. RESULTS: The data show contact and overlap with the medial and lateral collateral ligaments in all tested medial and lateral plates. The posterolateral and posteromedial plates showed no contact with the ligaments, yet they did contact the posterior joint capsules. The medial plates showed less contact/overlap when compared with the lateral and extended medial plates. CONCLUSION: Based on the present data, we conclude that distal humerus plating using the perpendicular technique with standard-sized medial plates shows the least amount of overlap over the medial and lateral collateral ligaments. The extent of the overlap of the ligaments by the humeral plates is clearly shown in the present study.

Organ donation following the circulatory determination of death (DCD): an audit of donation and outcomes following renal transplantation.

Organ Donation following the Circulatory determination of Death was introduced in Beaumont Hospital during 2011. The Intensive Care Society of Ireland formally endorsed a national DCD clinical practice guideline in 2012. This retrospective audit covers a 2-year period during which eleven patients were considered suitable for DCD and where consent was obtained. Nine patients died within the ninety-minute period following the withdrawal of life sustaining therapies and subsequently donated organs (82%). Eighteen kidneys were recovered and seventeen patients received renal transplants--one patient received a nephron-dosing dual renal transplant. Lungs were recovered on two occasions and one patient received a lung transplant. Heart valves were recovered on one occasion. To date sixteen of seventeen recipient patients have functioning renal transplants (94%). In conclusion, this model of deceased donation has proven acceptable to families, nursing and medical staff and the outcomes reported are consistent with international best practice.

Automatic inference of ICD-10 codes from German ophthalmologic physicians' letters using natural language processing.

Physicians' letters are the optimal source of diagnoses for registries. However, most registries demand for diagnosis codes such as ICD-10. We herein describe an algorithm that infers ICD-10 codes from German ophthalmologic physicians' letters. We assess the method in three German eye hospitals. Our algorithm is based on the nearest-neighbor method as well as on a large thesaurus for ICD-10 codes. This thesaurus was embedded into a Word2Vec space created from anonymized physicians' reports of the first hospital. For evaluation, each of the three hospitals sent all diagnoses taken from 100 letters. The inferred ICD-10 codes were evaluated for correctness by the senders. A total of 3332 natural language terms had been sent in (812 hospital one, 1473 hospital two, 1047 hospital three). A total of 526 non-diagnoses were excluded upfront. 2806 ICD-10 codes were inferred (771 hospital one, 1226 hospital two, 809 hospital three). In the first hospital, 98% were fully correct and 99% correct at the level of the superordinate disease concept. The percentages in hospital two were 69% and 86%. The respective numbers for hospital three were 69% and 91%. Our simple method is capable of inferring ICD-10 codes for German natural language diagnoses, especially when the embedding space has been built with physicians' letters from the same hospital. The method may yield sufficient accuracy for many tasks in the multi-centric setting and can easily be adapted to other languages/specialities.

Development of the 174 GHz collective Thomson scattering diagnostics at Wendelstein 7-X.

In this paper, we present the design and commissioning results of the upgraded collective Thomson scattering diagnostic at the Wendelstein 7-X stellarator. The diagnostic has a new radiometer designed to operate between the second and third harmonics of the electron cyclotron emission from the plasma at 171-177 GHz, where the emission background has a minimum and is of order 10-100 eV. It allows us to receive the scattered electromagnetic field with a significantly improved signal-to-noise ratio and extends the set of possible scattering geometries compared to the case of the original instrument operated at 140 GHz. The elements of the diagnostic are a narrowband notch filter and a frequency stabilized probing gyrotron that will allow measuring scattered radiation spectra very close to the probing frequency. Here, we characterize the microwave components applied to the radiometer and demonstrate the performance of the complete system that was achieved during the latest experimental campaign, OP2.1.

Investigation of the mutagenic potential of cold atmospheric plasma at bactericidal dosages.

In the past few years, cold atmospheric plasma (CAP) has evolved into a new tool in the fight against nosocomial infections and antibiotic-resistant microorganisms. The products generated by the plasma-electrons, ions, reactive species and UV light-represent a 'lethal cocktail' for different kinds of pathogen, which opens up possible applications in hygiene and medicine. Nevertheless, to ensure the safe usage of CAP on skin (e.g., to treat wounds or skin diseases) several pre-clinical in vitro studies have to be performed before implementing clinical trials on humans. In the study presented here, inactivation experiments with Escherichia coli were carried out to identify the necessary plasma dosage for a 5 log reduction: with a small hand-held battery-operated CAP device, these disinfection properties were achieved after application during 30s. This and higher plasma dosages were then used to analyze the mutagenicity induced in V79 Chinese hamster cells-to furthermore define a 'safe application window'-with the HPRT (hypoxanthine-guanine phosphoribosyl transferase) mutation assay. The results show that a CAP treatment of up to 240 s and repeated treatments of 30s every 12h did not induce mutagenicity at the Hprt locus beyond naturally occurring spontaneous mutations.