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1.
Nat Commun ; 14(1): 2285, 2023 04 21.
Article in English | MEDLINE | ID: mdl-37085477

ABSTRACT

Normothermic machine perfusion (NMP) has emerged as an innovative organ preservation technique. Developing an understanding for the donor organ immune cell composition and its dynamic changes during NMP is essential. We aimed for a comprehensive characterization of immune cell (sub)populations, cell trafficking and cytokine release during liver NMP. Single-cell transcriptome profiling of human donor livers prior to, during NMP and after transplantation shows an abundance of CXC chemokine receptor 1+/2+ (CXCR1+/CXCR2+) neutrophils, which significantly decreased during NMP. This is paralleled by a large efflux of passenger leukocytes with neutrophil predominance in the perfusate. During NMP, neutrophils shift from a pro-inflammatory state towards an aged/chronically activated/exhausted phenotype, while anti-inflammatory/tolerogenic monocytes/macrophages are increased. We herein describe the dynamics of the immune cell repertoire, phenotypic immune cell shifts and a dominance of neutrophils during liver NMP, which potentially contribute to the inflammatory response. Our findings may serve as resource to initiate future immune-interventional studies.


Subject(s)
Liver Transplantation , Humans , Aged , Liver Transplantation/methods , Liver , Perfusion/methods , Organ Preservation/methods , Sequence Analysis, RNA
2.
Front Immunol ; 13: 982018, 2022.
Article in English | MEDLINE | ID: mdl-36311746

ABSTRACT

The liver has been proposed as an important "immune organ" of the body, as it is critically involved in a variety of specific and unique immune tasks. It contains a huge resident immune cell repertoire, which determines the balance between tolerance and inflammation in the hepatic microenvironment. Liver-resident immune cells, populating the sinusoids and the space of Disse, include professional antigen-presenting cells, myeloid cells, as well as innate and adaptive lymphoid cell populations. Machine perfusion (MP) has emerged as an innovative technology to preserve organs ex vivo while testing for organ quality and function prior to transplantation. As for the liver, hypothermic and normothermic MP techniques have successfully been implemented in clinically routine, especially for the use of marginal donor livers. Although there is evidence that ischemia reperfusion injury-associated inflammation is reduced in machine-perfused livers, little is known whether MP impacts the quantity, activation state and function of the hepatic immune-cell repertoire, and how this affects the inflammatory milieu during MP. At this point, it remains even speculative if liver-resident immune cells primarily exert a pro-inflammatory and hence destructive effect on machine-perfused organs, or in part may be essential to induce liver regeneration and counteract liver damage. This review discusses the role of hepatic immune cell subtypes during inflammatory conditions and ischemia reperfusion injury in the context of liver transplantation. We further highlight the possible impact of MP on the modification of the immune cell repertoire and its potential for future applications and immune modulation of the liver.


Subject(s)
Organ Preservation , Reperfusion Injury , Humans , Organ Preservation/methods , Perfusion/methods , Liver , Inflammation
3.
Clin Neuroradiol ; 29(1): 87-94, 2019 Mar.
Article in English | MEDLINE | ID: mdl-28913609

ABSTRACT

PURPOSE: Strabismus influences not only the individual with nonparallel eyes but also the observer. It has previously been demonstrated by fMRI that adults viewing images of strabismic adults have a negative reaction to the images as demonstrated by limbic activation, especially activation of the left amygdala. The aim of this study was to see if mothers would have a similar reaction to viewing strabismic children and whether or not that reaction would be different in mothers of strabismic children. METHODS: Healthy mothers of children with strabismus (n = 10, Group I) and without strabismus (n = 15, Group II) voluntarily underwent fMRI at 3T. Blood oxygen level dependent signal responses to viewing images of strabismic and non-strabismic children were analyzed. RESULTS: Group II, while viewing images of strabismic children, showed significantly increased activation of the limbic network (p < 0.05) and bilateral amygdala activation. Group I showed considerably less limbic activation, compared to the group II, and had no amygdala activation. Both groups revealed statically significant activation in the FEF (frontal eye field) when they were viewing images of strabismic children as compared to when they were viewing children with parallel eyes. The activated FEF area for Group II was much larger than for group I. CONCLUSION: Mothers of non-strabismic children showed similar negative emotional fMRI patterns as adults did while viewing strabismic adults. Strabismus is an interpersonal organic issue for the observer, which also impacts the youngest members of our society.


Subject(s)
Emotions/physiology , Limbic System/physiology , Magnetic Resonance Imaging/methods , Mothers/psychology , Strabismus/psychology , Adult , Amygdala/physiology , Child , Female , Humans , Middle Aged , Oxygen/blood , Photography
4.
Eye (Lond) ; 32(5): 924-930, 2018 05.
Article in English | MEDLINE | ID: mdl-29456252

ABSTRACT

Normal tension glaucoma (NTG) is an exception in the "glaucoma family" where the major risk factor, increased intraocular pressure, is missing. If not increased intraocular pressure, then what other causes can then lead to glaucomatous optic disc change and visual field loss in NTG? Several possibilities will be discussed. Among them a higher sensitivity to normal pressure, vascular dysregulation, an abnormally high translaminar pressure gradient and a neurodegenerative process due to impaired cerebrospinal fluid dynamics in the optic nerve sheath compartment. There are many excellent review papers published on normal tension glaucoma (NTG). The aim of this paper is therefore not to add another extensive review on NTG but rather to focus on and to discuss some possible mechanisms that are thought to be involved in the pathophysiology of NTG and to discuss the stronger and weaker aspects of each concept. The fact that several concepts exist suggests that NTG is still not very well understood and that no single mechanism on its own might adequately explain NTG.


Subject(s)
Low Tension Glaucoma/physiopathology , Blood Pressure/physiology , Cerebrospinal Fluid/physiology , Humans , Intraocular Pressure/physiology , Peripheral Vascular Diseases/physiopathology , Regional Blood Flow/physiology , Visual Fields/physiology
5.
Eye (Lond) ; 31(9): 1365-1372, 2017 Sep.
Article in English | MEDLINE | ID: mdl-28452990

ABSTRACT

PurposeTo investigate on the relationship between the optic nerve sheath diameter (ONSD) and the lumbar cerebrospinal fluid pressure (CSF-p) in Caucasian patients with normal tension glaucoma (NTG).Patients and methodsRetrospective analysis of medical records of patients with open-angle glaucoma in the period from 2005 to 2015 from the Ophthalmology Department, Cantonal Hospital Aarau, Switzerland was performed. A total of 38 patients (mean age 68.6±11.3 years, 21 females and 17 males) fulfilled the diagnostic criteria of NTG and underwent computed tomography (CT) of the orbit and lumbar puncture (LP). In total, 38 age- and gender-matched Caucasian subjects (mean age: 68.9±10.9 years) without known ON diseases served as controls for ONSD measurements. ONSDs were measured at a distance of 3 mm from the posterior globe and lumbar CSF-p was related to the measurements. Statistical analysis was performed by using the independent two-tailed t-test and the non-parametric Spearman's correlation test.ResultsThe mean ONSD in NTGs measured 6.4±0.9 mm and in controls 5.4±0.6 mm. The difference between NTGs and controls showed statistical significance (t-test: P<0.000). The mean CSF-p in NTG was 11.6±3.7 mm Hg. There was no statistical significant correlation between ONSD and CSF-p (Spearman's correlation coefficient ρ=0.06, P=0.72).ConclusionsThis study demonstrates enlarged ONSDs and normal lumbar CSF-p in 38 Caucasian NTG patients. As enlarged ONSDs generally are associated with increased intracranial CSF-p, these results can be explained by a disturbed communication of CSF-p between the intracranial and intraorbital subarachnoid spaces.


Subject(s)
Cerebrospinal Fluid Pressure/physiology , Low Tension Glaucoma/physiopathology , Myelin Sheath/pathology , Optic Nerve/pathology , Aged , Female , Humans , Intraocular Pressure/physiology , Male , Optic Nerve/diagnostic imaging , Retrospective Studies , Spinal Puncture , Subarachnoid Space , Tomography, X-Ray Computed , Tonometry, Ocular , Visual Field Tests , White People
6.
Prostate Cancer Prostatic Dis ; 20(3): 271-275, 2017 09.
Article in English | MEDLINE | ID: mdl-28322234

ABSTRACT

BACKGROUND: One of the major challenges in prostate cancer (PCa) treatment is distinguishing insignificant PCa from those forms that need active treatment. We evaluated the impact of PSA isoforms on risk stratification in patients with low-risk PCa as well as in active surveillance (AS) candidates who underwent radical prostatectomy. METHODS: A total of 112 patients with biopsy confirmed Gleason score (GS) 6 PCa of four different international institutions were prospectively enrolled in the study. Blood withdrawal was performed the day before radical prostatectomy. In addition, patients were classified according to the EAU and NCCN criteria for AS candidates. PSA, free PSA (fPSA) and proPSA were measured using dual monoclonal antibody sandwich immunoassays. In addition, the Prostate Health Index (PHI=proPSA/fPSA × âˆšPSA) was calculated. Final histology of the radical prostatectomy specimens was correlated to PSA, its isoforms and PHI. RESULTS: Serum proPSA levels were significantly elevated in those patients with an upgrade in final histology (GS⩾7). In addition, higher proPSA levels were predictive for extraprostatic extension (⩾pT3a) as well as for positive surgical margins. Interestingly, PHI had an even higher predictive power when compared with proPSA alone concerning GS upgrading, extraprostatic extension and surgical margins in both the total and the AS patient group. CONCLUSION: We showed in a multicenter study that proPSA is a valuable biomarker to detect patients with aggressive PCa in a cohort of GS 6 patients, who would benefit from active tumor therapy. Combining proPSA with the standard markers PSA and fPSA using PHI further increases the predictive accuracy significantly. Moreover, our data support the use of PHI for monitoring PCa patients under AS.


Subject(s)
Kallikreins/blood , Prostate-Specific Antigen/blood , Prostatic Neoplasms/blood , Protein Precursors/blood , Adult , Aged , Humans , Male , Middle Aged , Neoplasm Grading , Prospective Studies , Prostate/pathology , Prostate/surgery , Prostatectomy , Prostatic Neoplasms/pathology , Prostatic Neoplasms/surgery , Treatment Outcome
8.
Lung Cancer ; 85(3): 395-400, 2014 Sep.
Article in English | MEDLINE | ID: mdl-25043642

ABSTRACT

OBJECTIVES: Neoadjuvant therapy with a platinum based doublet is an option in NSCLC patients with upfront resectable disease. However, the role of neoadjuvant induction in stages IIIA and IIIB and in initially not resectable patients is unclear. PATIENTS AND METHODS: In this phase II trial, 78 patients with locally advanced NSCLC, of whom 56 were considered not resectable at initial diagnosis, were treated with three neoadjuvant cycles of docetaxel and cisplatin and subjected to radical surgery if resectable. Definitive radiochemotherapy (RCT) using weekly docetaxel was the prespecified alternative if patients were not resectable at restaging. The primary objective was response to neoadjuvant induction. RESULTS: After induction, 36 (46%) were radically operated and 24 (31%) were treated with RCT. Overall, 32 patients (41%) completed the entire study plan. Partial response to induction therapy was observed in 43 patients (55%); furthermore, 19 of 56 initially not resectable cases (34%) became resectable upon induction. Median progression-free (PFS) and overall survival (OS) were 8.5 and 16.4 months for the whole cohort. Encouragingly, conversion to resectability was predictive for favorable outcome. On the other hand, patients who were not resectable at restaging and received RCT were characterized by a rather unfavorable prognosis (5-year and 10-year OS, whole cohort: 20% and 12%; RCT: 8% and 0%; surgery: 37% and 24%, respectively). CONCLUSION: Neoadjuvant induction with the doublet docetaxel/cisplatin and subsequent radical resection resulted in favorable survival. Of note, conversion to resectability was mandatory for the chance of cure in patients considered initially not resectable.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/pathology , Lung Neoplasms/drug therapy , Lung Neoplasms/pathology , Aged , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Carcinoma, Non-Small-Cell Lung/mortality , Carcinoma, Non-Small-Cell Lung/radiotherapy , Carcinoma, Non-Small-Cell Lung/surgery , Chemoradiotherapy , Chemotherapy, Adjuvant , Cisplatin/administration & dosage , Combined Modality Therapy , Docetaxel , Female , Humans , Lung Neoplasms/mortality , Lung Neoplasms/radiotherapy , Lung Neoplasms/surgery , Male , Middle Aged , Neoadjuvant Therapy , Neoplasm Staging , Taxoids/administration & dosage , Treatment Outcome
9.
Lung Cancer ; 84(2): 168-74, 2014 May.
Article in English | MEDLINE | ID: mdl-24646832

ABSTRACT

BACKGROUND: It is not clear whether or not the fate of patients suffering from small-cell lung cancer (SCLC) has improved. To better understand the course of disease, we aimed at documenting disease features at initial diagnosis, sequences of therapy modalities and outcome in consecutive patients over two decades. We postulated that SCLC patients might have benefitted from refined diagnosis and treatment options during the last decade. METHODS: All SCLC cases diagnosed at the Innsbruck University Hospital and associated institutions between 1991 and 2011 have been documented in detail in accordance with a prespecified protocol. RESULTS: A total of 484 patients diagnosed with SCLC were followed. The most important symptoms at initial diagnosis were cough, dyspnea and tumor pain in 55%, 51% and 44%, respectively. Patients who were operated during early stage of disease (n = 26) had a favorable 5-year, relapse-free survival (74%). A total of 112 patients with locally advanced disease were treated by radiochemotherapy in curative intent (RCT), and achievement of CR offered a chance of long term overall survival (OS), reaching 44% after 10-years. In the palliative setting (median OS in 304 evaluable patients, 9.7 months), a therapeutic progress in the more recent decade could not be observed. Parameters independently associated with favorable OS were: response to therapy and prophylactic brain irradiation in patients with RCT; and response, age < 70 years and absence of LDH elevation in the palliative setting. CONCLUSIONS: In this comprehensive view on SCLC, the findings on symptomatology, comorbidity, and spectrum of treatments may help to better understand individual courses of the disease. Overall, modern medicine failed to translate into substantial benefit of SCLC patients, except in patients in locally advanced disease receiving multimodal therapy.


Subject(s)
Lung Neoplasms/therapy , Small Cell Lung Carcinoma/therapy , Adult , Aged , Aged, 80 and over , Chemoradiotherapy, Adjuvant , Disease-Free Survival , Female , Humans , Kaplan-Meier Estimate , Lung Neoplasms/mortality , Male , Middle Aged , Neoadjuvant Therapy , Palliative Care , Proportional Hazards Models , Quality Improvement , Retrospective Studies , Small Cell Lung Carcinoma/mortality , Treatment Outcome
10.
Lung Cancer ; 83(3): 408-10, 2014 Mar.
Article in English | MEDLINE | ID: mdl-24412619

ABSTRACT

We report the case of a female never-smoking patient with an epidermal growth factor receptor (EGFR) mutation positive advanced non-small cell lung cancer (NSCLC) who received multiple lines of treatment. When she evolved clinical resistance to first generation EGFR tyrosine kinase inhibitors (TKI), she was treated with a fifth-line combination therapy with cetuximab and vinorelbine. This combination was highly active with a treatment response lasting for 9 months supporting the hypothesis that EGFR monoclonal antibodies in combination with chemotherapy may play a role in reversing EGFR-TKI resistance in EGFR mutation-positive NSCLC.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Lung Neoplasms/drug therapy , Aged , Antibodies, Monoclonal, Humanized/administration & dosage , Antibodies, Monoclonal, Humanized/adverse effects , Carcinoma, Non-Small-Cell Lung/genetics , Cetuximab , Drug Resistance, Neoplasm , ErbB Receptors/antagonists & inhibitors , ErbB Receptors/genetics , Erlotinib Hydrochloride , Female , Gefitinib , Humans , Lung Neoplasms/genetics , Mutation/genetics , Neoplasm Staging , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/adverse effects , Quinazolines/administration & dosage , Quinazolines/adverse effects , Remission Induction , Vinblastine/administration & dosage , Vinblastine/adverse effects , Vinblastine/analogs & derivatives , Vinorelbine
11.
Free Radic Res ; 31 Suppl: S243-9, 1999 Dec.
Article in English | MEDLINE | ID: mdl-10694066

ABSTRACT

Cyanobacteria (blue-green algae) are oxygenic phototrophic bacteria carrying out plant-type photosynthesis. The only hydrogen peroxide scavenging enzymes in at least two unicellular species have been demonstrated to be bifunctional cytosolic catalase-peroxidases (CatPXs) having considerable homology at the active site with plant ascorbate peroxidases (APXs). In this paper we examined optical and kinetic properties of CatPXs from the cyanobacteria Anacystis nidulans and Synechocystis PCC 6803 and discuss similarities and differences to plant APXs. Both CatPXs and APX showed similar spectra of the ferric enzyme, the redox intermediate Compound I and the cyanide complex, whereas the spectrum of CatPX Compound II had characteristics reminiscent of the spectrum of the native enzyme. Both steady-state and multi-mixing transient-state kinetic studies were performed in order to characterize the kinetic behaviour of CatPXs. Bimolecular rate constants of both formation and reduction of a CatPX Compound I are presented. Because of its intrinsic high catalase activity (which cannot be found in APXs), the rate constants for Compound I formation were measured with peroxoacetic acid and are shown to be 5.9 x 10(4) M(-1) s(-1) for CatPX from A. nidulans and 8.7 x 10(3) M(-1) s(-1) for the Synechocystis enzyme. Compared with o-dianisidine (2.7-6.7 x 10(6) M(-1) s(-1)) and pyrogallol (8.6 x 10(4)-1.6 x 10(5) M(-1) s(-1)), the rate constant for Compound I reduction by ascorbate was extremely low (5.4 x 10(3) M(-1) s(-1) at pH 7.0 and 15 degrees C), in marked contrast to the behaviour of APXs.


Subject(s)
Bacterial Proteins , Catalase/chemistry , Catalase/metabolism , Cyanobacteria/enzymology , Peroxidases/chemistry , Peroxidases/metabolism , Ascorbate Peroxidases , Hydrogen-Ion Concentration , Kinetics , Spectrophotometry
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