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The pathogenesis of autoimmune complications triggered by SARS‐CoV2 has not been completely elucidated. Here, we performed an analysis of the cellular immune status, cell ratios, and monocyte populations of patients with COVID‐19 treated in the intensive care unit (ICU) (cohort 1, N = 23) and normal care unit (NCU) (cohort 2, n = 10) compared with control groups: patients treated in ICU for noninfectious reasons (cohort 3, n = 30) and patients treated in NCU for infections other than COVID‐19 (cohort 4, n = 21). Patients in cohort 1 presented significant differences in comparison with the other cohorts, including reduced frequencies of lymphocytes, reduced CD8+T‐cell count, reduced percentage of activated and intermediate monocytes and an increased B/T8 cell ratio. Over time, patients in cohort 1 who died presented with lower counts of B, T, CD4+T, CD8+T‐lymphocytes, NK cells, and activated monocytes. The B/T8 ratio was significantly lower in the group of survivors. In cohort 1, significantly higher levels of IgG1 and IgG3 were found, whereas cohort 3 presented higher levels of IgG3 compared to controls. Among many immune changes, an elevated B/T8‐cell ratio and a reduced rate of activated monocytes were mainly observed in patients with severe COVID‐19. Both parameters were associated with death in cohort 1., Patients with severe COVID‐19 present a particular set of immune changes in comparison to patients with mild disease and controls. These include consumption of certain monocyte and lymphocyte populations and an elevated B/T8 Ratio. COVID‐19 patients in general share a proinflammatory immunoglobulin profile with elevated proportions of IgG1 and/or IgG3.

Objective To compare the effects of two different intraoperative CO2 pressures (8 and 15 mmHg) during laparoscopic hysterectomy for benign uterine pathologies in terms of postoperative abdominal and shoulder pain, laparoscopy-mediated vegetative alterations, pain medication requirement, arterial CO2 pressure (pCO2 ), surgical parameters, and safety. Design Prospective randomised controlled study. Setting German university hospital. Population Female patients undergoing laparoscopic hysterectomy for benign uterine pathologies. Methods Patients were randomised to a standard pressure (SP; 15 mmHg, control) or low-pressure (LP; 8 mmHg, experimental) group. Main outcome measures Primary outcomes were postoperative abdominal and shoulder pain intensities, measured via numeric rating scale (NRS) and vegetative parameters (fatigue, nausea, vomiting, bloating) at 3, 24, and 48 hours postoperatively. Secondary outcomes were pain medication requirement (mg) and arterial pCO2 (mmHg). Surgical parameters and intra- and postoperative complications were also recorded. Results In total, 178 patients were included. Patients in the LP group (n = 91) showed significantly lower postoperative abdominal and shoulder pain scores, fewer vegetative alterations, lower pain medication requirements, a shorter postoperative hospitalization, and lower intra- and postoperative arterial pCO2 values compared with the SP group (n = 87; P ≤ 0.01). No differences in intra- and postoperative complications were observed between groups. Conclusions Low-pressure laparoscopy seems to be an effective and safe technique for the reduction of postoperative pain and laparoscopy-induced metabolic and vegetative alterations following laparoscopic hysterectomy for benign indications. Tweetable abstract Low-pressure laparoscopy seems to be an effective and safe technique for reduction of pain following laparoscopic hysterectomy.

Background Most comparisons of robot-assisted (RARC) versus open radical cystectomy (ORC) for urothelial carcinoma do not factor the inherent stage selection bias or surgical experience. Methods We compared the perioperative outcomes of 229 RARC and 335 ORC at a single tertiary referral center with propensity score matching and multiple regression models, when controlling for tumor and patient characteristics, surgeon's experience and type of urinary diversion. Results RARC had less major complications (19.8% vs. 34.1%) and ICU admissions (6.6% vs. 19.8%), with lower blood loss (400 vs. 500ml) and transfusion rates. The operating time was longer (336 vs. 286min), but decreased with surgeon's experience. RARC had less PSMs (3% vs. 8.4%) and a higher lymph node count (14 vs. 11). Conclusions In this large single center series comparing RARC with ORC controlling for stage selection bias and surgical experience, RARC proved significantly better outcomes, especially with intracorporeal urinary diversion. This article is protected by copyright. All rights reserved.

Use of protective angiotensin-converting enzyme inhibitors (ACE-I) in patients with cardiovascular disease (CVD) is sometimes limited by incident coughing. In clinical trials, cough occurred also on placebo. We performed a meta-analysis including randomized, placebo-controlled trials reporting cough on ACE-I in patients with CVD. We evaluated the attributable fraction of cough on ACE-I accounting rate on placebo: placebo-adjusted ACE-I (%) = (ACE-I (%) - Placebo (%)) / ACE-I (%). In total, 65,054 patients from 22 included studies were analyzed. Placebo-adjusted ACE-I cough was 37% of 13.5% reported cases on ACE-I, while 8.5% reported cases on placebo were equivalent to 63% of cases on ACE-I, indicating potential other factors for cough than ACE-I in a substantial number of cough cases on ACE-I. Placebo-adjusted ACE-I cough had the highest rates of arterial hypertension (85%) and the lowest of heart failure (29%). Therefore, other causes of cough, particularly in heart failure, should be excluded before ACE-I withdrawal.

Background Two recent, randomized, placebo-controlled phase II/III trials (clinicaltrials.gov: NCT01110720, NCT01049399) of davunetide and tideglusib in progressive supranuclear palsy (PSP) generated prospective, 1-year longitudinal datasets of high-resolution T1-weighted three-dimensional MRI. Objective The objective of this study was to develop a quantitative MRI disease progression measurement for clinical trials. Methods The authors performed a fully automated quantitative MRI analysis employing atlas-based volumetry and provide sample size calculations based on data collected in 99 PSP patients assigned to placebo in these trials. Based on individual volumes of 44 brain compartments and structures at baseline and 52 weeks of follow-up, means and standard deviations of annualized percentage volume changes were used to estimate standardized effect sizes and the required sample sizes per group for future 2-armed, placebo-controlled therapeutic trials. Results The highest standardized effect sizes were found for midbrain, frontal lobes, and the third ventricle. Using the annualized percentage volume change of these structures to detect a 50% change in the 1-year progression (80% power, significance level 5%) required lower numbers of patients per group (third ventricle, n = 32; midbrain, n = 37; frontal lobe, n = 43) than the best clinical scale (PSP rating scale total score, n = 58). A combination of volume changes in these 3 structures reduced the number of required patients to only 20 and correlated best with the progression in the clinical scales. Conclusions We propose the 1-year change in the volumes of third ventricle, midbrain, and frontal lobe as combined imaging read-out for clinical trials in PSP that require the least number of patients for detecting efficacy to reduce brain atrophy. © 2017 International Parkinson and Movement Disorder Society

Background and Aim Magnetic endoscope imaging (MEI) provides continuous viewing of the position of the endoscope on a monitor without using X-ray and has already been established for colonoscopy. The aim of the present study was to evaluate a new MEI probe for enteroscopy. Methods In this prospective feasibility study, consecutive patients received single-balloon enteroscopy guided by the new MEI probe. Fluoroscopy was also used in all examinations. MEI images were compared to fluoroscopy images with respect to concordance of loop configuration by two independent observers after the examinations. Main outcome measurement was the rate of concordant MEI and fluoroscopy images with respect to loop configuration. Results In all 10 patients, single-balloon enteroscopy with MEI was carried out without any adverse events or technical difficulties. Concordance of MEI and fluoroscopy images was seen in 36/38 images (95%; 95% CI, 82–99%) by both observers. Overall agreement between the two observers was 95% (κ = 0.47, 95% CI, −0.04–1). Conclusion The use of MEI in single-balloon enteroscopy is safe and feasible. Detection and control of loops can be accurately achieved.

The phenotypic variability of progressive supranuclear palsy (PSP) may account for its frequent misdiagnosis, in particular in early stages of the disease. However, large multicenter studies to define the frequency and natural history of PSP phenotypes are missing. In a cohort of 100 autopsy-confirmed patients we studied the phenotypic spectrum of PSP by retrospective chart review. Patients were derived from five brain banks with expertise in neurodegenerative disorders with referrals from multiple academic hospitals. The clinical characteristics of the 100 cases showed remarkable heterogeneity. Most strikingly, only 24% of cases presented as Richardson's Syndrome (RS), and more than half of the cases either showed overlapping features of several predescribed phenotypes, or features not fitting proposed classification criteria for PSP phenotypes. Classification of patients according to predominant clinical features in the first 2 years of the disease course allowed a more comprehensive description of the phenotypic spectrum. These predominance types differed significantly with regard to survival time and frequency of cognitive deficits. In summary, the phenotypic spectrum of PSP may be broader and more variable than previously described in single-center studies. Thus, too strict clinical criteria defining distinct phenotypes may not reflect this variability. A more pragmatic clinical approach using predominance types could potentially be more helpful in the early recognition of and for making prognostic predictions for these patients. Given the limitations arising from the retrospective nature of this analysis, a systematic validation in a prospective cohort study is imperative.

It is believed that glycogen synthase kinase-3 hyperphosphorylates tau protein in progressive supranuclear palsy (PSP). The Tau Restoration on PSP (TAUROS) trial assessed the glycogen synthase kinase-3 inhibitor tideglusib as potential treatment. For the magnetic resonance imaging (MRI) substudy reported here, we assessed the progression of brain atrophy. TAUROS was a multinational, phase 2, double-blind, placebo-controlled trial in patients with mild-to-moderate PSP who were treated with oral tideglusib (600 mg or 800 mg daily) or with placebo for 1 year. A subset of patients underwent baseline and 52-week MRI. Automated, observer-independent, atlas-based, and mask-based volumetry was done on high-resolution, T1-weighted, three-dimensional data. For primary outcomes, progression of atrophy was compared both globally (brain, cerebrum) and regionally (third ventricle, midbrain, pons) between the active and placebo groups (Bonferroni correction). For secondary outcomes, 15 additional brain structures were explored (Benjamini & Yekutieli correction). In total, MRIs from 37 patient were studied (placebo group, N = 9; tideglusib 600 mg group, N = 19; tideglusib 800 mg group, N = 9). The groups compared well in their demographic characteristics. Clinical results showed no effect of tideglusib over placebo. Progression of atrophy was significantly lower in the active group than in the placebo group for the brain (mean ± standard error of the mean: -1.3% ± 1.4% vs. -3.1% ± 2.3%, respectively), cerebrum (-1.3% ± 1.5% vs. -3.2% ± 2.1%, respectively), parietal lobe (-1.6% ± 1.9% vs. -4.1% ± 3.0%, respectively), and occipital lobe (-0.3% ± 1.8% vs. -2.7% ± 3.2%, respectively). A trend toward reduced atrophy also was observed in the frontal lobe, hippocampus, caudate nucleus, midbrain, and brainstem. In patients with PSP, tideglusib reduced the progression of atrophy in the whole brain, particularly in the parietal and occipital lobes.

The aim of this study was to evaluate perioperative flap perfusion using noninvasive monitoring with a laser-Doppler flowmetry and spectrophotometry unit (O2C) and identify whether perioperative blood flow, velocity, hemoglobin level (Hb), and oxygen saturation (SO2) measured could be used as indicators of free flap success. Measurements of blood flow, velocity, Hb, and SO2 were performed in 196 microvascular flaps, which had been transferred into the oral cavity to reconstruct ablative defects after surgery for oral cancer. The values were calculated superficially on the skin surface and at a depth of 8 mm. The results showed that perioperative absolute values measured were not associated with an increased rate of microvascular revisions or free flap failure. Independent predictors of microvascular revisions at the first postoperative day were the development of a falling trend in superficial and deep blood flow, and velocity in comparison with baseline values of variables measured. On day 2, all superficial and deep values of Hb, flow, and velocity were independent prognostic factors (P

The question of how long a flap depends on its pedicle cannot be answered clearly from the available literature. To address this, we investigated the time to flap autonomization in the wound bed and the length of time to the point when flap necrosis is reduced to a clinically negligible level. The superficial epigastric flap was raised in 24 rats. After 3, 5, 7, or 10 days of wound healing, the pedicle was again exposed, ligated, and divided. Values of blood flow (flow), velocity (velocity), hemoglobin level (Hb), and oxygen saturation (SO2) were noninvasively measured using Laser spectrophotometry. The area of necrosis of the flap was 62.77 ± 1.71% after 3 days, 16.26 ± 0.86% after 5 days, 2.88 ± 0.14% after 7 days, and 1.64 ± 0.16% after 10 days (P < 0.001). Hb, flow, and velocity were found to be significant factors on developing flap necrosis at the preoperative and postoperative time point (P < 0.0001), whereas SO2 and flow were significant predictors of necrosis at the time of pedicle ligation (P < 0.0001). The percentage changes of SO2 (P < 0.0001), flow (P < 0.0001), and velocity (P = 0.001) between the different time points were significant predictors of flap necrosis. The time needed for the complete autonomization of vascularized free flaps in their wound beds has been found as completed between the 5th and 7th day postoperatively in this rat model. The area of flap necrosis depends on the present value of SO2, Hb, flow, and velocity at different time points, but, more importantly, also on the perioperative change of these parameters. © 2011 Wiley-Liss, Inc. Microsurgery, 2011.

OBJECTIVES: To compare perioperative problems and outcomes of reconstructive surgery with microvascular flaps of a group of older (?70) and younger adults (20�69). DESIGN: Prospective clinical cohort study. SETTING: Maxillofacial surgical unit of a university teaching hospital in Munich, Germany. PARTICIPANTS: Two hundred fifteen people with head and neck carcinoma (older: n=54, mean age 75.8, range 70�96; younger: n=161, mean age 55.5, range 20�69) who underwent surgery between 2007 and 2009. MEASUREMENTS: Participant characteristics: age, sex, American Society of Anesthesiologists (ASA) status, tumor type, preoperative radiation or chemotherapy, medical comorbidities. Surgical variables: flap type, type of reconstruction (primary/secondary), length of operation (minutes). Postoperative variables: length of stay (minutes) on intensive care unit (ICU), reasons for ICU stay longer than 1,500 minutes (surgical or medical), length of hospitalization (days), and reasons for hospitalization longer than 20 days (surgical or /medical). Short-term outcome within 30 days: revisions, flap success, overall complication rate, mortality. RESULTS: Older adults had a higher ASA class (P

Background: The aim of this study was to investigate whether or not wound healing after the use of microvascular anastomosed fat flaps prelaminated with human amniotic membrane, for intraoral defect coverage, is improved when compared wth wound healing of pure fat flaps. Methods: Microsurgical transplantation of the superficial epigastric fat flap prelaminated with HAM was evaluated using 47 Sprague-Dawley rats. Standardized oral mucosa defects were created and covered by HAM or polyglactin910/polydioxanon patches only, prelaminated and bare flaps, uncovered or by HAM after flap insertion. After 7, 15, and 35 days, postoperatively, the flaps were reassessed. Results: The mean value of the defect size after 7 days was 47.73 ± 2.63 mm(2) in the control, 48.63 ± 2.23 mm(2) in the bare flaps covered by HAM after insertion, and 36.85 ± 2.79 mm(2) in the prelaminated HAM group. The mean value of the wound closure time in all rats was 13.74 ± 2.05 days (range 11-18). Intraoral defects were covered with mucosa after 15.67 ± 1.66 days in the pure flap group and 11.89 ± 0.78 days in the HAM group (p< 0.0001). Conclusions: Prelaminated flaps with HAM used in the repair of large mucosa defects complete epithelialization from the surrounding margins faster than bare flaps. Wound healing can be enhanced by using HAM as a prelaminated epithelial structure within microvascular anastomosed flaps. © 2010 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 2010.

To cite this article: Mahachie John JM, Baurecht H, Rodriguez E, Naumann A, Wagenpfeil S, Klopp N, Mempel M, Novak N, Bieber T, Wichmann H-E, Ring J, Illig T, Cattaert T, Van Steen K, Weidinger S. Analysis of the high affinity IgE receptor genes reveals epistatic effects of FCER1A variants eczema risk. Allergy 2010; 65: 875–882. Abstract Background: High levels of total and allergen-specific IgE levels are a key feature in allergic diseases. The high-affinity receptor for IgE, which is composed of one alpha (FCER1A), one beta (FCER1B), and two gamma (FCER1G) subunits, represents the central receptor of IgE-induced reactions. In a genome-wide association scan, we recently identified associations between functional FCER1A variants and total serum IgE levels. Previous studies had reported linkage and association of FCER1B variants with IgE and atopic traits. The FCER1G gene has not yet been investigated with regard to atopy. Filaggrin (FLG) is the strongest known risk gene for eczema, in particular the allergic subtype of eczema. Methods: We investigated the association of FCER1A, FCER1B, and FCER1G variants with IgE in a large population-based cohort (n = 4261) and tested for epistatic effects using the model-based multifactor dimensionality reduction (MB-MDR) method. In addition, we investigated a potential interaction between FLG and FCER1A variants in a large collection of eczema cases (n = 1018) and population controls. Results: Three strongly correlated FCER1A polymorphisms were significantly associated with total and specific IgE levels as well as allergic sensitization. No associations were seen for FCER1B and FCER1G. After adjustment for FLG effects, a significant epistatic effect of the FCER1A variants rs10489854 and rs2511211 on eczema risk was detected. Conclusions: These results suggest that FCER1A variants by themselves and in combination influence IgE levels and act synergistically to influence eczema risk.

OBJECTIVE: We aimed to investigate (1) to which extent headache diary variables correlate among each other; (2) to which extent they correlate with generic measures of quality of life and disability; (3) and whether correlations vary over time. METHODS: We performed a secondary analysis of data from 301 patients suffering from migraine and 270 patients suffering from tension-type headache collected in 2 randomized trials of acupuncture. We calculated product-moment correlation coefficients. RESULTS: Correlations between diary parameters varied to a great extent. Attack frequency, a measure recommended by the International Headache Society as a primary outcome measure for migraine prophylaxis trials, correlated only moderately with other diary outcomes. At baseline the parameters measured in the headache diary correlated only weakly with the generic outcome measures. After 12 weeks these correlations had increased considerably. CONCLUSION: Our findings suggest that participants in headache trials "learn" to fill in diaries and generic instruments in a more consistent manner during the course of the study.

Background: Toll-like receptors (TLR) play a pivotal role in the induction of first-line defense mechanisms of the innate immune system and trigger adaptive immune responses to microbial pathogens. Genetic variations in innate immunity genes have been reported to be associated with a range of inflammatory disorders. Deficiencies on the level of immunity receptors such as pathogen-recognition receptors are suspected to affect the maturation of our immune system and to avail thereby the high prevalence of atopic diseases and susceptibility of atopic patients to microbial infections. Aims of the study: We evaluated TLR9 as susceptibility gene for atopic eczema (AE). Methods: Analyses of four tag single-nucleotide polymorphisms in two panels of families containing a total of 483 parent-affected offspring trios as well as a cohort of 274 unrelated adult AE cases and 252 hypernormal population-based controls have been performed. Results: In both family cohorts, polymorphism C-1237T, which is located within the promoter region of the TLR9 gene, was significantly associated with AE, in particular the intrinsic subtype of AE. No associations were seen in the case–control cohort. Luciferase reporter gene assays revealed significantly higher promoter activity of the TT allelic variant at this single nucleotide polymorphism site. Conclusion: These observations suggest that the TLR9 promoter polymorphism C-1237T might affect AE susceptibility in particular in patients with the intrinsic variant of AE.

BACKGROUND The platelet-derived growth factor receptor (PDFG-r), a tyrosine kinase, is expressed in 88% of primary prostate cancer and in 80% of the metastases. The tyrosine kinase inhibitor imatinib blocks the PDGF signaling pathway by inhibiting PDGF-r autophosphorylation. We examined the cytotoxic effects of imatinib in combination with other anticancer agents in the human prostate cancer cell lines LNCaP, PC-3, and DU 145. METHODS The cells were exposed to imatinib and to the other drugs simultaneously for 5 days. Cell growth inhibition was determined by XTT assay. The cytotoxic effects in combinations were evaluated at the inhibitory concentration of 50% level by the isobologram. RESULTS Imatinib produced additive effects with estramustine phosphate (EMP) and 4-hydroperoxy-cyclophosphamide in all three cell lines. In combination with etoposide imatinib produced additive effects in two of three cell lines. Imatinib with docetaxel produced antagonistic effects in PC-3 and additive to antagonistic effects in LNCaP and DU 145 cells. CONCLUSIONS The simultaneous exposure of imatinib and EMP would be effective against hormone sensitive and hormone insensitive cell lines and this combination should be evaluated in clinical trials. In contrast, the simultaneous exposure of imatinib and docetaxel would have little therapeutic efficacy. Although there are gaps between in vitro studies and clinical trials, the present findings provide useful information for the establishment of clinical protocols involving imatinib in hormone-refractory prostate cancer. © 2004 Wiley-Liss, Inc.

Matthias Riemenschneider, Patricia Friedrich , Simon M. Laws , Caroline Graff, Alexander Kurz , Sebastian Wurst , Stefan Wagenpfeil, Hans Forstl , Neurochemistry and Neurogenetics Laboratory, Munich, Germany; Karolinska Institut, Stockholm, Sweden; Dept. of Psychiatry & Psychotherapy, Munich, Germany; Institute for Medical Statistics and Epidemiology, Munich, Germany. Contact e-mail: m.riemenschneider@lrz.tu-muenchen.de