Publications by authors named "J Graw"

228 Publications

Hemolysis in patients with Extracorporeal Membrane Oxygenation therapy for severe Acute Respiratory Distress Syndrome - a systematic review of the literature.

Int J Med Sci 2021 18;18(8):1730-1738. Epub 2021 Feb 18.

Department of Anesthesiology and Operative Intensive Care Medicine CCM/CVK, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health.

The Acute Respiratory Distress Syndrome (ARDS) is common in patients on the Intensive Care Unit and associated with significant mortality rates. In situations of severe respiratory insufficiency and failure of all possible conservative therapeutic approaches, veno-venous extracorporeal membrane oxygenation (VV ECMO) is used as a final option for temporary replacement of pulmonary function. ARDS as well as sepsis and VV ECMO treatment are all associated with intravascular hemolysis. The extent and relevance of intravascular hemolysis in the context of ARDS therapy is unclear. This systematic review aims to summarize the current evidence on the incidence and associated complications of intravascular hemolysis in adult patients with ARDS and treatment with VV ECMO. The databases MEDLINE, EMBASE and Web of Science were systematically searched and 19 publications fulfilled inclusion criteria. The incidence of hemolysis in patients with ARDS and treatment with VV ECMO ranged from 0 to 41% with survivors showing lower incidences and less severe hemolysis. A pump head thrombosis and high blood flows (≥3 l/min) as well as use of dual-lumen cannulas but not different pump models were associated with increased hemolysis. In conclusion, intravascular hemolysis in patients with ARDS and treatment with VV ECMO is a common and relevant complication that appears associated with increased mortality. Apart from ECMO hardware-settings, no additional possible causes for increased red cell breakdown such as disease severity, duration of ECMO therapy, or number and quality of red blood cell transfusions were investigated. Further research is needed to determine the origin and relevance of intravascular hemolysis in patients with ARDS and treatment with VV ECMO.
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http://dx.doi.org/10.7150/ijms.50217DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7976579PMC
February 2021

On the Nature of Murine Radiation-Induced Subcapsular Cataracts: Optical Coherence Tomography-Based Fine Classification, In Vivo Dynamics and Impact on Visual Acuity.

Radiat Res 2021 Feb 25. Epub 2021 Feb 25.

Institute of Developmental Genetics, Helmholtz Zentrum München GmbH - German Research Center for Environmental Health, Neuherberg, Germany.

Ionizing radiation is widely known to induce various kinds of lens cataracts, of which posterior subcapsular cataracts (PSCs) have the highest prevalence. Despite some studies regarding the epidemiology and biology of radiation-induced PSCs, the mechanism underscoring the formation of this type of lesions and their dose dependency remain uncertain. Within the current study, our team investigated the in vivo characteristics of PSCs in B6C3F1 mice (F1-hybrids of BL6 × C3H) that received 0.5-2 Gy γ-ray irradiation after postnatal day 70. For purposes of assessing lenticular damages, spectral domain optical coherence tomography was utilized, and the visual acuity of the mice was measured to analyze their levels of visual impairment, and histological sections were then prepared in to characterize in vivo phenotypes. Three varying in vivo phenotype anterior and posterior lesions were thus revealed and correlated with the applied doses to understand their marginal influence on the visual acuity of the studied mice. Histological data indicated no significantly increased odds ratios for PSCs below a dose of 1 Gy at the end of the observation time. Furthermore, our team demonstrated that when the frequencies of the posterior and anterior lesions were calculated at early time points, their responses were in accordance with a deterministic model, whereas at later time points, their responses were better described via a stochastic model. The current study will aid in honing the current understanding of radiation-induced cataract formation and contributes greatly to addressing the fundamental questions of lens dose response within the field of radiation biology.
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http://dx.doi.org/10.1667/RADE-20-00163.1DOI Listing
February 2021

Posterior subcapsular cataracts are a late effect after acute exposure to 0.5 Gy ionizing radiation in mice.

Int J Radiat Biol 2021 1;97(4):529-540. Epub 2021 Mar 1.

Institute of Developmental Genetics, Helmholtz Zentrum München GmbH, German Research Center for Environmental Health, Neuherberg, Germany.

Purpose: The long-term effect of low and moderate doses of ionizing radiation on the lens is still a matter of debate and needs to be evaluated in more detail.

Material And Methods: We conducted a detailed histological analysis of eyes from B6C3F1 mice cohorts after acute gamma irradiation (Co source; 0.063 Gy/min) at young adult age of 10 weeks with doses of 0.063, 0.125, and 0.5 Gy. Sham irradiated (0 Gy) mice were used as controls. To test for genetic susceptibility heterozygous mutant mice were used and compared to wild-type mice of the same strain background. Mice of both sexes were included in all cohorts. Eyes were collected 4 h, 12, 18 and 24 months after irradiation. For a better understanding of the underlying mechanisms, metabolomics analyses were performed in lenses and plasma samples of the same mouse cohorts at 4 and 12 h as well as 12, 18 and 24 months after irradiation. For this purpose, a targeted analysis was chosen.

Results: This analysis revealed histological changes particularly in the posterior part of the lens that rarely can be observed by using Scheimpflug imaging, as we reported previously. We detected a significant increase of posterior subcapsular cataracts (PSCs) 18 and 24 months after irradiation with 0.5 Gy (odds ratio 9.3; 95% confidence interval 2.1-41.3) independent of sex and genotype. Doses below 0.5 Gy (i.e. 0.063 and 0.125 Gy) did not significantly increase the frequency of PSCs at any time point. In lenses, we observed a clear effect of sex and aging but not of irradiation or genotype. While metabolomics analyses of plasma from the same mice showed only a sex effect.

Conclusions: This article demonstrates a significant radiation-induced increase in the incidence of PSCs, which could not be identified using Scheimpflug imaging as the only diagnostic tool.
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http://dx.doi.org/10.1080/09553002.2021.1876951DOI Listing
March 2021

Ionising radiation causes vision impairment in neonatal B6C3F1 mice.

Exp Eye Res 2021 Mar 14;204:108432. Epub 2021 Jan 14.

Helmholtz Zentrum München GmbH - German Research Center for Environmental Health, Institute of Developmental Genetics, Neuherberg, Germany. Electronic address:

Ionising radiation interacts with lenses and retinae differently. In human lenses, posterior subcapsular cataracts are the predominant observation, whereas retinae of adults are comparably resistant to even relatively high doses. In this study, we demonstrate the effects of 2 Gy of low linear energy transfer ionising radiation on eyes of B6C3F1 mice aged postnatal day 2. Optical coherence tomography and Scheimpflug imaging were utilised for the first time to monitor murine lenses and retinae in vivo. The visual acuity of the mice was determined and histological analysis was conducted. Our results demonstrated that visual acuity was reduced by as much as 50 % approximately 9 months after irradiation in irradiated mice. Vision impairment was caused by retinal atrophy and inner cortical cataracts. These results help to further our understanding of the risk of ionising radiation for human foeti (∼ 8 mo), which follow the same eye development stages as neonatal mice.
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http://dx.doi.org/10.1016/j.exer.2020.108432DOI Listing
March 2021

Imbalances in the eye lens proteome are linked to cataract formation.

Nat Struct Mol Biol 2021 02 11;28(2):143-151. Epub 2021 Jan 11.

Center for Integrated Protein Science Munich (CIPSM) at the Department of Chemistry, Technische Universität München, Garching, Germany.

The prevalent model for cataract formation in the eye lens posits that damaged crystallin proteins form light-scattering aggregates. The α-crystallins are thought to counteract this process as chaperones by sequestering misfolded crystallin proteins. In this scenario, chaperone pool depletion would result in lens opacification. Here we analyze lenses from different mouse strains that develop early-onset cataract due to point mutations in α-, β-, or γ-crystallin proteins. We find that these mutant crystallins are unstable in vitro; in the lens, their levels are substantially reduced, and they do not accumulate in the water-insoluble fraction. Instead, all the other crystallin proteins, including the α-crystallins, are found to precipitate. The changes in protein composition and spatial organization of the crystallins observed in the mutant lenses suggest that the imbalance in the lenticular proteome and altered crystallin interactions are the bases for cataract formation, rather than the aggregation propensity of the mutant crystallins.
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http://dx.doi.org/10.1038/s41594-020-00543-9DOI Listing
February 2021

Application of WES Towards Molecular Investigation of Congenital Cataracts: Identification of Novel Alleles and Genes in a Hospital-Based Cohort of South India.

Int J Mol Sci 2020 Dec 16;21(24). Epub 2020 Dec 16.

Department of Genetics, Dr. ALM Post Graduate Institute of Basic Medical Sciences, University of Madras, Tamil Nadu 600 113, India.

Congenital cataracts are the prime cause for irreversible blindness in children. The global incidence of congenital cataract is 2.2-13.6 per 10,000 births, with the highest prevalence in Asia. Nearly half of the congenital cataracts are of familial nature, with a predominant autosomal dominant pattern of inheritance. Over 38 of the 45 mapped loci for isolated congenital or infantile cataracts have been associated with a mutation in a specific gene. The clinical and genetic heterogeneity of congenital cataracts makes the molecular diagnosis a bit of a complicated task. Hence, whole exome sequencing (WES) was utilized to concurrently screen all known cataract genes and to examine novel candidate factors for a disease-causing mutation in probands from 11 pedigrees affected with familial congenital cataracts. Analysis of the WES data for known cataract genes identified causative mutations in six pedigrees (55%) in (two variants), and an additional likely causative mutation in a novel gene , which represents the first dominant mutation in this gene. This study identifies a novel cataract gene not yet linked to human disease. NCOA6 is a transcriptional coactivator that interacts with nuclear hormone receptors to enhance their transcriptional activator function.
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http://dx.doi.org/10.3390/ijms21249569DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7765966PMC
December 2020

Lower versus higher hemoglobin threshold for transfusion in ARDS patients with and without ECMO.

Crit Care 2020 12 16;24(1):697. Epub 2020 Dec 16.

Department of Anesthesiology and Operative Intensive Care Medicine CCM / CVK Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Augustenburger Platz 1, 13353, Berlin, Germany.

Background: Efficacy and safety of different hemoglobin thresholds for transfusion of red blood cells (RBCs) in adults with an acute respiratory distress syndrome (ARDS) are unknown. We therefore assessed the effect of two transfusion thresholds on short-term outcome in patients with ARDS.

Methods: Patients who received transfusions of RBCs were identified from a cohort of 1044 ARDS patients. After propensity score matching, patients transfused at a hemoglobin concentration of 8 g/dl or less (lower-threshold) were compared to patients transfused at a hemoglobin concentration of 10 g/dl or less (higher-threshold). The primary endpoint was 28-day mortality. Secondary endpoints included ECMO-free, ventilator-free, sedation-free, and organ dysfunction-free composites.

Measurements And Main Results: One hundred ninety-two patients were eligible for analysis of the matched cohort. Patients in the lower-threshold group had similar baseline characteristics and hemoglobin levels at ARDS onset but received fewer RBC units and had lower hemoglobin levels compared with the higher-threshold group during the course on the ICU (9.1 [IQR, 8.7-9.7] vs. 10.4 [10-11] g/dl, P < 0.001). There was no difference in 28-day mortality between the lower-threshold group compared with the higher-threshold group (hazard ratio, 0.94 [95%-CI, 0.59-1.48], P = 0.78). Within 28 days, 36.5% (95%-CI, 27.0-46.9) of the patients in the lower-threshold group compared with 39.5% (29.9-50.1) of the patients in the higher-threshold group had died. While there were no differences in ECMO-free, sedation-free, and organ dysfunction-free composites, the chance for successful weaning from mechanical ventilation within 28 days after ARDS onset was lower in the lower-threshold group (subdistribution hazard ratio, 0.36 [95%-CI, 0.15-0.86], P = 0.02).

Conclusions: Transfusion at a hemoglobin concentration of 8 g/dl, as compared with a hemoglobin concentration of 10 g/dl, was not associated with an increase in 28-day mortality in adults with ARDS. However, a transfusion at a hemoglobin concentration of 8 g/dl was associated with a lower chance for successful weaning from the ventilator during the first 28 days after ARDS onset.

Trial Registration: ClinicalTrials.gov NCT03871166.
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http://dx.doi.org/10.1186/s13054-020-03405-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7740070PMC
December 2020

Timing, Outcome, and Risk Factors of Intracranial Hemorrhage in Acute Respiratory Distress Syndrome Patients During Venovenous Extracorporeal Membrane Oxygenation.

Crit Care Med 2021 Feb;49(2):e120-e129

Department of Anesthesiology and Operative Intensive Care Medicine CCM/CVK, Charité - Universitätsmedizin Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.

Objectives: Intracranial hemorrhage is a serious complication in patients receiving venovenous extracorporeal membrane oxygenation during treatment of the acute respiratory distress syndrome. We analyzed timing, outcome, and risk factors of intracranial hemorrhage in patients on venovenous extracorporeal membrane oxygenation.

Design: Retrospective cohort study.

Setting: Single acute respiratory distress syndrome referral center.

Patients: Patients receiving venovenous extracorporeal membrane oxygenation were identified from a cohort of 1,044 patients with acute respiratory distress syndrome. Patients developing an intracranial hemorrhage during venovenous extracorporeal membrane oxygenation therapy were compared with patients without evidence for intracranial hemorrhage. The primary objective was to assess the association of intracranial hemorrhage with 60-day mortality. Further objectives included the identification of risk factors for intracranial hemorrhage and the evaluation of clinical cutoff values.

Interventions: None.

Measurements And Main Results: Among 444 patients treated with venovenous extracorporeal membrane oxygenation, 49 patients (11.0% [95% CI, 8.3-14.4%]) developed an intracranial hemorrhage. The median time to intracranial hemorrhage occurrence was 4 days (95% CI, 2-7 d). Patients who developed an intracranial hemorrhage had a higher 60-day mortality compared with patients without intracranial hemorrhage (69.4% [54.4-81.3%] vs 44.6% [39.6-49.6%]; odds ratio 3.05 [95% CI, 1.54-6.32%]; p = 0.001). A low platelet count, a high positive end expiratory pressure, and a major initial decrease of Paco2 were identified as independent risk factors for the occurrence of intracranial hemorrhage. A platelet count greater than 100/nL and a positive end expiratory pressure less than or equal to 14 cm H2O during the first 7 days of venovenous extracorporeal membrane oxygenation therapy as well as a decrease of Paco2 less than 24 mm Hg during venovenous extracorporeal membrane oxygenation initiation were identified as clinical cutoff values to prevent intracranial hemorrhage (sensitivity 91% [95% CI, 82-99%], 94% [85-99%], and 67% [48-81%], respectively).

Conclusions: Intracranial hemorrhage occurs early during venovenous extracorporeal membrane oxygenation and is a determinant for 60-day mortality. Appropriate adjustment of identified modifiable risk factors might lower the prevalence of intracranial hemorrhage during venovenous extracorporeal membrane oxygenation therapy.
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http://dx.doi.org/10.1097/CCM.0000000000004762DOI Listing
February 2021

Dose-dependent long-term effects of a single radiation event on behaviour and glial cells.

Int J Radiat Biol 2021 15;97(2):156-169. Epub 2020 Dec 15.

Institute of Developmental Genetics, Helmholtz Zentrum München, German Research Centre for Environmental Health, Neuherberg, Germany.

Purpose: The increasing use of low-dose ionizing radiation in medicine requires a systematic study of its long-term effects on the brain, behaviour and its possible association with neurodegenerative disease vulnerability. Therefore, we analysed the long-term effects of a single low-dose irradiation exposure at 10 weeks of age compared to medium and higher doses on locomotor, emotion-related and sensorimotor behaviour in mice as well as on hippocampal glial cell populations.

Materials And Methods: We determined the influence of radiation dose (0, 0.063, 0.125 or 0.5 Gy), time post-irradiation (4, 12 and 18 months p.i.), sex and genotype (wild type versus mice with DNA repair gene point mutation) on behaviour.

Results: The high dose (0.5 Gy) had early-onset adverse effects at 4 months p.i. on sensorimotor recruitment and late-onset negative locomotor effects at 12 and 18 months p.i. Notably, the low dose (0.063 Gy) produced no early effects but subtle late-onset (18 months) protective effects on sensorimotor recruitment and exploratory behaviour. Quantification and morphological characterization of the microglial and the astrocytic cells of the dentate gyrus 24 months p.i. indicated heightened immune activity after high dose irradiation (0.125 and 0.5 Gy) while conversely, low dose (0.063 Gy) induced more neuroprotective features.

Conclusion: This is one of the first studies demonstrating such long-term and late-onset effects on brain and behaviour after a single radiation event in adulthood.
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http://dx.doi.org/10.1080/09553002.2021.1857455DOI Listing
December 2020

Intraventricular Tension Pneumocephalus After Subarachnoid Hemorrhage and Removal of an External Ventricular Drain.

World Neurosurg 2021 Feb 3;146:78-79. Epub 2020 Nov 3.

Department of Anaesthesiology and Operative Intensive Care Medicine, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany; Berlin Institute of Health, Berlin, Germany. Electronic address:

Pneumocephalus is defined as an accumulation of air or gas in the intracranial space. It is a common complication after skull surgery or craniofacial trauma, sometimes also caused by gas-producing organisms in the context of an infection, and reported with cerebrospinal fluid draining procedures. Here we report a case of a large intraventricular tension pneumocephalus after removal of an external ventricular drain in a patient with subarachnoid hemorrhage. The acute management included therapy with normobaric oxygen. Despite the large volume of trapped air and its diffuse distribution inside the skull and spine, therapy with 100% normobaric oxygen appears to be safe and efficient for a rapid improvement of the patient's symptoms and the neuroradiological imaging.
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http://dx.doi.org/10.1016/j.wneu.2020.10.157DOI Listing
February 2021

-butylhydroquinone augments Nrf2-dependent resilience against oxidative stress and improves survival of ventilator-induced lung injury in mice.

Am J Physiol Lung Cell Mol Physiol 2021 01 7;320(1):L17-L28. Epub 2020 Oct 7.

Department of Anesthesiology and Operative Intensive Care Medicine CCM/CVK, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.

Oxidative stress caused by mechanical ventilation contributes to the pathophysiology of ventilator-induced lung injury (VILI). A key mechanism maintaining redox balance is the upregulation of nuclear factor-erythroid-2-related factor 2 (Nrf2)-dependent antioxidant gene expression. We tested whether pretreatment with an Nrf2-antioxidant response element (ARE) pathway activator -butylhydroquinone (tBHQ) protects against VILI. Male C57BL/6J mice were pretreated with an intraperitoneal injection of tBHQ ( = 10), an equivalent volume of 3% ethanol (EtOH3%, vehicle, = 13), or phosphate-buffered saline (controls, = 10) and were then subjected to high tidal volume (HV) ventilation for a maximum of 4 h. HV ventilation severely impaired arterial oxygenation ( = 49 ± 7 mmHg, means ± SD) and respiratory system compliance, resulting in a 100% mortality among controls. Compared with controls, tBHQ improved arterial oxygenation ( = 90 ± 41 mmHg) and respiratory system compliance after HV ventilation. In addition, tBHQ attenuated the HV ventilation-induced development of lung edema and proinflammatory response, evidenced by lower concentrations of protein and proinflammatory cytokines (IL-1β and TNF-α) in the bronchoalveolar lavage fluid, respectively. Moreover, tBHQ enhanced the pulmonary redox capacity, indicated by enhanced Nrf2-depentent gene expression at baseline and by the highest total glutathione concentration after HV ventilation among all groups. Overall, tBHQ pretreatment resulted in 60% survival ( < 0.001 vs. controls). Interestingly, compared with controls, EtOH3% reduced the proinflammatory response to HV ventilation in the lung, resulting in 38.5% survival ( = 0.0054 vs. controls). In this murine model of VILI, tBHQ increases the pulmonary redox capacity by activating the Nrf2-ARE pathway and protects against VILI. These findings support the efficacy of pharmacological Nrf2-ARE pathway activation to increase resilience against oxidative stress during injurious mechanical ventilation.
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http://dx.doi.org/10.1152/ajplung.00131.2020DOI Listing
January 2021

[Atraumatic instability of the anterior cruciate ligament caused by an intraligamentous cyst].

Sportverletz Sportschaden 2020 Aug 20. Epub 2020 Aug 20.

Klinik für Anästhesiologie mit Schwerpunkt operative Intensivmedizin (CCM, CVK), Charité-Universitätsmedizin Berlin, Berlin, Deutschland.

A 28-year-old man reported that he has a feeling of "giving away" in his knee while playing soccer. He has had no previous injury. At a physical examination, the results of Lachman's test and the pivot shift test were pathological. Magnetic resonance imaging revealed an intraligamentous cyst of the anterior cruciate ligament (ACL). During arthroscopy it became evident that the cyst had destroyed the ACL. After ACL reconstruction, physiological stability of the knee joint was achieved. Joint cysts are rare and frequently cause pain and a limited range of motion. An association between intraligamentous cysts and instabilities of the affected joint has not been described so far. Preventive resection of asymptomatic and incidentally found intraligamentous cysts should be discussed.
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http://dx.doi.org/10.1055/a-1222-3235DOI Listing
August 2020

A novel E128* mutation underlying an autosomal dominant nuclear cataract in a south Indian kindred.

Ophthalmic Genet 2020 12 18;41(6):556-562. Epub 2020 Aug 18.

Department of Genetics, Dr. ALM Post Graduate Institute of Basic Medical Sciences, University of Madras , Chennai, India.

Purpose: To identify the mutation causing an autosomal dominant congenital nuclear cataract in a south Indian family by whole exome sequencing and to characterize further phenotypically the same in a zebra fish model.

Methods: A six-generation family (DKEC1) with several affected members registered at the Regional Institute of Ophthalmology (RIO), Chennai was documented to have congenital nuclear cataract. Detailed clinical history and blood samples were collected from all available family members. Genomic DNA of the proband was subjected to whole exome sequencing. Sequence variations suggestive of putative mutations were further confirmed by bidirectional sequencing and restriction site analysis. Functional analysis of the mutant E128* in zebrafish embryos was done to dissect out the pathogenicity.

Results: A unique variation viz., c.382 G > T in the coding region of the gene, resulting in a premature stop codon at position 128 (E128*) was documented in the affected family members. The same was absent in unaffected family members and in 120 unrelated population controls checked. Bioinformatic tools predicted that the mutation might cause a deleterious effect on protein structure and function. Molecular function analysis of this novel mutation (p. E128*, ) in the zebrafish indicated this mutation to impair lens transparency.

Conclusion: This study identified a novel mutation, E128* to cause autosomal dominant congenital nuclear cataract in a large south Indian family. Our study provides a new insight onto how the mutation might affect the γC-crystallin structure and function besides emphasizing the need for genetic diagnosis toward vision restoration.
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http://dx.doi.org/10.1080/13816810.2020.1807027DOI Listing
December 2020

Polymorphisms in CRYBB2 encoding βB2-crystallin are associated with antisaccade performance and memory function.

Transl Psychiatry 2020 04 21;10(1):113. Epub 2020 Apr 21.

Department of Psychiatry, Psychotherapy and Psychosomatics, Martin-Luther-University Halle-Wittenberg, Halle, Germany.

βB2-crystallin (gene symbol: Crybb2/CRYBB2) was first described as a structural protein of the ocular lens before it was detected in various brain regions of the mouse, including the hippocampus and the cerebral cortex. Mutations in the mouse Crybb2 gene lead to alterations of sensorimotor gating measured as prepulse inhibition (PPI) and reduced hippocampal size, combined with an altered number of parvalbumin-positive GABAergic interneurons. Decreased PPI and alterations of parvalbumin-positive interneurons are also endophenotypes that typically occur in schizophrenia. To verify the results found in mice, we genotyped 27 single nucleotide polymorphisms (SNPs) within the CRYBB2 gene and its flanking regions and investigated different schizophrenia typical endophenotypes in a sample of 510 schizophrenia patients and 1322 healthy controls. In the case-control study, no association with schizophrenia was found. However, 3 of the 4 investigated haplotype blocks indicated a decreased CRYBB2 mRNA expression. Two of these blocks were associated with poorer antisaccade task performance and altered working memory-linked functional magnetic resonance imaging signals. For the two haplotypes associated with antisaccade performance, suggestive evidence was found with visual memory and in addition, haplotype block 4 showed a nominally significant association with reduced sensorimotor gating, measured as P50 ratio. These results were not schizophrenia-specific, but could be detected in a combined sample of patients and healthy controls. This is the first study to demonstrate the importance of βB2-crystallin for antisaccade performance and memory function in humans and therefore provides implications for βB2-crystallin function in the human brain.
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http://dx.doi.org/10.1038/s41398-020-0791-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7174396PMC
April 2020

Gender differences in blood transfusion strategy for patients with hip fractures - a retrospective analysis.

Int J Med Sci 2020 21;17(5):620-625. Epub 2020 Feb 21.

Department of Anaesthesiology and Operative Intensive Care Medicine (CCM, CVK) Charité - Universitätsmedizin Berlin, Berlin, Germany.

In the last decades, transfusion therapy with allogenic blood has progressively shifted to a more restrictive approach. The current study analyzed the transfusion practice and transfusion-associated factors in a regional trauma center over the course of five years. Retrospective analysis of all patients undergoing surgery for hip fractures in a level 1 trauma center of an academic teaching hospital from 2010 to 2014 (n=650). The number of transfused packed red blood cells (PRBCs), preoperative Hb concentrations, and intensive care unit (ICU) and hospital length of stay (LOS) were analyzed. A logistic regression analysis was performed to evaluate transfusion and ICU LOS-associated risk factors. (Ethical Review Board approval: 2015-497-f-S). From 2010 to 2014 the average number of PRBCs transfused per patient decreased continuously despite similar preoperative Hb levels. During the same period, ICU LOS increased while hospital LOS decreased. Advanced patient age, preoperative Hb concentrations, surgical complications, and ICU LOS were associated with increased transfusion requirements. Although preoperative Hb levels were lower, females received fewer PRBCs compared to males. Over the course of five years, a restrictive transfusion strategy was implemented within clinical practice in patients undergoing surgery for hip fractures. In parallel, a significant reduction in the hospital LOS and an increased ICU LOS was noted. Whether there is an association between increased ICU LOS and decreasing hospital LOS and whether there is a gender effect on transfusion requirements in patients with surgery for hip fractures should be subject to further research.
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http://dx.doi.org/10.7150/ijms.33954DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7085213PMC
December 2020

Mutation in Bmpr1b Leads to Optic Disc Coloboma and Ventral Retinal Gliosis in Mice.

Invest Ophthalmol Vis Sci 2020 02;61(2):44

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Purpose: The clinical phenotype of retinal gliosis occurs in different forms; here, we characterize one novel genetic feature, (i.e., signaling via BMP-receptor 1b).

Methods: Mouse mutants were generated within a recessive ENU mutagenesis screen; the underlying mutation was identified by linkage analysis and Sanger sequencing. The eye phenotype was characterized by fundoscopy, optical coherence tomography, optokinetic drum, electroretinography, and visual evoked potentials, by histology, immunohistology, and electron-microscopy.

Results: The mutation affects intron 10 of the Bmpr1b gene, which is causative for skipping of exon 10. The expression levels of pSMAD1/5/8 were reduced in the mutant retina. The loss of BMPR1B-mediated signaling leads to optic nerve coloboma, gliosis in the optic nerve head and ventral retina, defective optic nerve axons, and irregular retinal vessels. The ventral retinal gliosis is proliferative and hypertrophic, which is concomitant with neuronal delamination and the reduction of retinal ganglion cells (RGCs); it is dominated by activated astrocytes overexpressing PAX2 and SOX2 but not PAX6, indicating that they may retain properties of gliogenic precursor cells. The expression pattern of PAX2 in the optic nerve head and ventral retina is altered during embryonic development. These events finally result in reduced electrical transmission of the retina and optic nerve and significantly reduced visual acuity.

Conclusions: Our study demonstrates that BMPR1B is necessary for the development of the optic nerve and ventral retina. This study could also indicate a new mechanism in the formation of retinal gliosis; it opens new routes for its treatment eventually preventing scar formation in the retina.
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http://dx.doi.org/10.1167/iovs.61.2.44DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7329948PMC
February 2020

A comprehensive and comparative phenotypic analysis of the collaborative founder strains identifies new and known phenotypes.

Mamm Genome 2020 02 14;31(1-2):30-48. Epub 2020 Feb 14.

German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Ingolstädter Landstrasse 1, 85764, Neuherberg, Germany.

The collaborative cross (CC) is a large panel of mouse-inbred lines derived from eight founder strains (NOD/ShiLtJ, NZO/HILtJ, A/J, C57BL/6J, 129S1/SvImJ, CAST/EiJ, PWK/PhJ, and WSB/EiJ). Here, we performed a comprehensive and comparative phenotyping screening to identify phenotypic differences and similarities between the eight founder strains. In total, more than 300 parameters including allergy, behavior, cardiovascular, clinical blood chemistry, dysmorphology, bone and cartilage, energy metabolism, eye and vision, immunology, lung function, neurology, nociception, and pathology were analyzed; in most traits from sixteen females and sixteen males. We identified over 270 parameters that were significantly different between strains. This study highlights the value of the founder and CC strains for phenotype-genotype associations of many genetic traits that are highly relevant to human diseases. All data described here are publicly available from the mouse phenome database for analyses and downloads.
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http://dx.doi.org/10.1007/s00335-020-09827-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7060152PMC
February 2020

Point-of-Care diagnostics of coagulation in the management of bleeding and transfusion in trauma patients.

Curr Opin Anaesthesiol 2020 Apr;33(2):246-252

Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health. Klinik für Anästhesiologie mit Schwerpunkt operative Intensivmedizin CCM/CVK, Augustenburger Platz 1, 13353 Berlin, Germany.

Purpose Of Review: Trauma-associated bleeding and coagulopathy require timely identification, prevention, and effective treatment. The present review summarizes the recent literature around point-of-care (POC) coagulation tests, their usefulness in the management of trauma-induced coagulopathy (TIC), their impact on trauma patient outcomes, and the requirement of quality assurance.

Recent Findings: Best practice algorithms to manage TIC have been compiled in the 2019 European Guideline on the management of major bleeding and coagulopathy after trauma. Evidence supports the use of goal-directed approaches to manage TIC. POC coagulation tests can accelerate and tailor individualized therapies. Recent findings emphasize: the time sparing of POC tests in prehospital settings and the validity of POC measurements in extreme environments; the potential scalability of POC-guided TIC algorithms in burn injuries and the pediatric population; the need for careful considerations of strategies to monitor and reverse the effects of direct oral anticoagulants in major trauma.

Summary: In contrast to an abundance of reviews and practical approaches to POC coagulation management in trauma patients, there is a scarcity of research in the field and large-scale clinical trials are urgently needed. The paneuropean multicenter trial Implementing Treatment Algorithms for the Correction of Trauma Induced Coagulopathy (iTACTIC) will inform on the potential of viscoelastic tests to augment transfusion protocols for better patient outcomes.
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http://dx.doi.org/10.1097/ACO.0000000000000836DOI Listing
April 2020

Spectral domain - Optical coherence tomography (SD-OCT) as a monitoring tool for alterations in mouse lenses.

Exp Eye Res 2020 01 18;190:107871. Epub 2019 Nov 18.

Helmholtz Zentrum München GmbH - German Research Center for Environmental Health, Institute of Experimental Genetics, Neuherberg, Germany. Electronic address:

The eye lens displays a variety of phenotypes in the wake of genetic modifications or environmental influences. Therefore, a high-resolution in vivo imaging method for the lens is desirable. Optical coherence tomography (OCT) has become a powerful imaging tool in ophthalmology, especially for retinal imaging in small animal models such as mice. Here, we demonstrate an optimized approach specifically for anterior eye segment imaging with spectral domain OCT (SD-OCT) on several known murine lens cataract mutants. Scheimpflug and histological section images on the same eye were used in parallel to assess the observed pathologies. With SD-OCT images, we obtained detailed information about the different alterations from the anterior to the posterior pole of the lens. This capability makes OCT a valuable high-resolution imaging modality for the anterior eye segment in mouse.
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http://dx.doi.org/10.1016/j.exer.2019.107871DOI Listing
January 2020

Selective Inactivation of Reelin in Inhibitory Interneurons Leads to Subtle Changes in the Dentate Gyrus But Leaves Cortical Layering and Behavior Unaffected.

Cereb Cortex 2020 03;30(3):1688-1707

Institute for Structural Neurobiology, Center for Molecular Neurobiology, ZMNH, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany.

Reelin is an extracellular matrix protein, known for its dual role in neuronal migration during brain development and in synaptic plasticity at adult stages. During the perinatal phase, Reelin expression switches from Cajal-Retzius (CR) cells, its main source before birth, to inhibitory interneurons (IN), the main source of Reelin in the adult forebrain. IN-derived Reelin has been associated with schizophrenia and temporal lobe epilepsy; however, the functional role of Reelin from INs is presently unclear. In this study, we used conditional knockout mice, which lack Reelin expression specifically in inhibitory INs, leading to a substantial reduction in total Reelin expression in the neocortex and dentate gyrus. Our results show that IN-specific Reelin knockout mice exhibit normal neuronal layering and normal behavior, including spatial reference memory. Although INs are the major source of Reelin within the adult stem cell niche, Reelin from INs does not contribute substantially to normal adult neurogenesis. While a closer look at the dentate gyrus revealed some unexpected alterations at the cellular level, including an increase in the number of Reelin expressing CR cells, overall our data suggest that Reelin derived from INs is less critical for cortex development and function than Reelin expressed by CR cells.
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http://dx.doi.org/10.1093/cercor/bhz196DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7132935PMC
March 2020

CREB Signaling Mediates Dose-Dependent Radiation Response in the Murine Hippocampus Two Years after Total Body Exposure.

J Proteome Res 2020 01 8;19(1):337-345. Epub 2019 Nov 8.

Institute of Radiation Biology, Helmholtz Zentrum München GmbH , German Research Center for Environmental Health GmbH (HMGU) , 85764 Neuherberg , Germany.

The impact of low-dose ionizing radiation (IR) on the human brain has recently attracted attention due to the increased use of IR for diagnostic purposes. The aim of this study was to investigate low-dose radiation response in the hippocampus. Female B6C3F1 mice were exposed to total body irradiation with 0 (control), 0.063, 0.125, or 0.5 Gy. Quantitative label-free proteomic analysis of the hippocampus was performed after 24 months. CREB signaling and CREB-associated pathways were affected at all doses. The lower doses (0.063 and 0.125 Gy) induced the CREB pathway, whereas the exposure to 0.5 Gy deactivated CREB. Similarly, the lowest dose (0.063 Gy) was anti-inflammatory, reducing the number of activated microglia. In contrast, induction of activated microglia and reactive astroglia was found at 0.5 Gy, suggesting increased inflammation and astrogliosis, respectively. The apoptotic markers BAX and cleaved CASP-3 and oxidative stress markers were increased only at the highest dose. Since the activated CREB pathway plays a central role in learning and memory, these data suggest neuroprotection at the lowest dose (0.063 Gy) but neurodegeneration at 0.5 Gy. The response to 0.5 Gy resembles alterations found in healthy aging and thus may represent radiation-induced accelerated aging of the brain.
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http://dx.doi.org/10.1021/acs.jproteome.9b00552DOI Listing
January 2020

Transfusion of red blood cells does not impact progression-free and overall survival after surgery for ovarian cancer.

Transfusion 2019 12 21;59(12):3589-3600. Epub 2019 Oct 21.

Department of Anesthesiology and Operative Intensive Care Medicine CCM/CVK, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.

Background: Allogeneic red blood cells (RBCs) have the potential to impact the immunosurveillance of the recipient and may therefore increase the risk of recurrence after cancer surgery. In this article the relationship between perioperative RBC transfusion and the risk of recurrence after ovarian cancer surgery is examined.

Study Design And Methods: This is a retrospective cohort analysis of a prospective database of patients who underwent surgery due to primary ovarian cancer between 2006 and 2014 and who had no residual disease after surgery. Patients who did and did not receive perioperative RBC transfusion were compared. The primary endpoint was progression-free survival (PFS). Propensity score matching (PSM) and Cox proportional hazards regression (CPH) was used to control for between-group differences of prognostic determinants.

Results: A total of 529 patients with a median follow-up of 51.4 months (95% CI, 46.1-56.5) were eligible for analysis. Of those, 408 patients (77.1%) received allogeneic, leukoreduced RBCs with a median of 4 units (IQR, 2-6) per patient. There was a strong selection bias of prognostic determinants between patients with and without transfusion. In unadjusted analysis, transfusion of RBCs was associated with an increased risk of cancer recurrence (hazard ratio [HR] of PFS 2.71 [95% CI, 1.94-3.77], p < 0.001). After bias reduction, transfusion of RBCs was no longer associated with an increased risk of cancer recurrence, neither in PSM-adjusted (HR 1.03 [95% CI, 0.59-1.80], p = 0.91), nor in multivariable CPH-adjusted analysis (HR 1.26 [95% CI, 0.85-1.86], p = 0.23).

Conclusion: Perioperative transfusion of RBCs did not increase the risk of recurrence after ovarian cancer surgery.
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http://dx.doi.org/10.1111/trf.15552DOI Listing
December 2019

Efficiency of platelet-rich plasma therapy in knee osteoarthritis does not depend on level of cartilage damage.

J Orthop Surg Res 2019 May 24;14(1):153. Epub 2019 May 24.

Department of Anaesthesiology and Operative Intensive Care Medicine (CCM, CVK) Charité, Universitätsmedizin Berlin, Berlin, Germany.

Objectives: Osteoarthritis of the knee is common and often leads to significant physical disability. While classic conservative therapeutic approaches aim for symptoms like pain and inflammation, procedures like the intraarticular application of hyaluronic acids (HA) or platelet-rich plasma (PRP) are thought to stimulate the endogenous HA production, stop catabolism of cartilage tissue, and promote tissue regeneration. To analyse whether the positive effects of PRP injections are associated with the level of cartilage damage, patient satisfaction with the treatment was correlated with the level of knee joint osteoarthritis quantified by MRI.

Methods: PRP was performed with a low-leukocyte autologous conditioned plasma (ACP) system in 59 patients. A pre-treatment MRI was performed and a Whole-Organ MRI Score (WORMS) was used to score the level of knee osteoarthritis by 14 features: integrity of the cartilage, affection of the bone marrow, subcortical cysts, bone attrition, osteophytes, integrity of the menisci and ligaments, presence of synovitis, loose bodies, and periarticular cysts. A multivariate analysis with ordinary least squares regressions was used.

Results: Although pain symptoms and severity of clinical osteoarthritis symptoms decreased, regression analysis could not detect a correlation between the degree of cartilage damage measured by the WORMS score and a positive response to PRP therapy.

Conclusion: This study suggests that intraarticular injection of PRP might improve osteoarthritis symptoms and reduces the pain in patients suffering from osteoarthritis of the knee joint independent from the level of cartilage damages quantified by the whole-organ MRI scoring method WORMS.
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http://dx.doi.org/10.1186/s13018-019-1203-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6534904PMC
May 2019

Indicated trauma emergency department utilization - A comparison between patients' self-assessment and professional evaluation.

Int Emerg Nurs 2019 05 17;44:30-34. Epub 2019 Apr 17.

Department of Anesthesiology and Operative Intensive Care Medicine (CCM, CVK), Charité - Universitätsmedizin Berlin, Berlin, Germany; Berlin Institute of Health (BIH), Berlin, Germany. Electronic address:

Introduction: Patient visits to emergency departments (EDs) increase in many countries. As a result, these facilities are often congested and the socioeconomic burden of growing workload is a well-known problem. In this study, patients' reasons attending an ED with non-emergent needs were analyzed.

Methods: From October 2015 to March 2016 patients (n = 499), attending the ED of an academic teaching hospital without referral from a General Practitioner (GP) were surveyed regarding circumstances of their visit, a self-assessment of illness-severity, and reasons for choosing the ED instead of a GP. Results were compared to responses of ED staff (n = 40).

Results: Most patients assessed their case as urgent (patients: 65% vs. ED staff: 28%, p < 0.001) and felt that their medical problem could not to be treated by a GP (74%). However, most patients ranked their injuries as mild (45.7%) or moderate (41.7%). Reasons to prefer an ED instead of a GP were not responded in 80.1% of cases.

Conclusion: In contrast to the self-evaluation of patients, ED staff believed that a significant portion of medical problems could be treated by a GP. Understanding patient-centred reasons and the discrepancy between self-perceived emergencies and minor medical problems might help to reduce inappropriate ED-admissions.
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http://dx.doi.org/10.1016/j.ienj.2019.02.006DOI Listing
May 2019

Mutation in the mouse histone gene Hist2h3c1 leads to degeneration of the lens vesicle and severe microphthalmia.

Exp Eye Res 2019 11 13;188:107632. Epub 2019 Apr 13.

Helmholtz Center Munich, German Research Center for Environmental Health, Institute of Developmental Genetics, D-85764 Neuherberg, Germany. Electronic address:

During an ENU (N-ethyl-N-nitrosourea) mutagenesis screen, we observed a dominant small-eye mutant mouse with viable homozygotes. A corresponding mutant line was established and referred to as Aey69 (abnormality of the eye #69). Comprehensive phenotyping of the homozygous Aey69 mutants in the German Mouse Clinic revealed only a subset of statistically significant alterations between wild types and homozygous mutants. The mutation causes microphthalmia without a lens but with retinal hyperproliferation. Linkage was demonstrated to mouse chromosome 3 between the markers D3Mit188 and D3Mit11. Sequencing revealed a 358 A-> C mutation (Ile120Leu) in the Hist2h3c1 gene and a 71 T-> C (Val24Ala) mutation in the Gja8 gene. Detailed analysis of eye development in the homozygous mutant mice documented a perturbed lens development starting from the lens vesicle stage including decreasing expression of crystallins as well as of lens-specific transcription factors like PITX3 and FOXE3. In contrast, we observed an early expression of retinal progenitor cells characterized by several markers including BRN3 (retinal ganglion cells) and OTX2 (cone photoreceptors). The changes in the retina at the early embryonic stages of E11.5-E15.5 happen in parallel with apoptotic processes in the lens at the respective stages. The excessive retinal hyperproliferation is characterized by an increased level of Ki67. The hyperproliferation, however, does not disrupt the differentiation and appearance of the principal retinal cell types at postnatal stages, even if the overgrowing retina covers finally the entire bulbus of the eye. Morpholino-mediated knock-down of the hist2h3ca1 gene in zebrafish leads to a specific perturbation of lens development. When injected into zebrafish zygotes, only the mutant mouse mRNA leads to severe malformations, ranging from cyclopia to severe microphthalmia. The wild-type Hist2h3c1 mRNA can rescue the morpholino-induced defects corroborating its specific function in lens development. Based upon these data, it is concluded that the ocular function of the Hist2h3c1 gene (encoding a canonical H3.2 variant) is conserved throughout evolution. Moreover, the data highlight also the importance of Hist2h3c1 in the coordinated formation of lens and retina during eye development.
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http://dx.doi.org/10.1016/j.exer.2019.03.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6876282PMC
November 2019

Improving the Continuum of Care by Bridging the Gap between Prehospital and Hospital Discharge Data through Stepwise Deterministic Linkage.

Prehosp Emerg Care 2020 Jan-Feb;24(1):1-7. Epub 2019 May 9.

: To describe the process, benefits, and challenges of linking Arizona's prehospital registry to hospital discharge data. Data were queried from the Arizona Prehospital Information and Emergency Medical Services Registry System (AZ-PIERS) and the Arizona Hospital Discharge Database (HDD) for the calendar year 2015. To maximize the number of matched records, the databases were deterministically linked in 17 steps using different combinations/variations of patient personal identifiers. Random samples of at least 1% of matched pairs from each of 16 linkage steps (excluding Step 1) were manually reviewed to assess the rate of false positive matches. A total of 626,413 records were reported to AZ-PIERS in 2015. Of those, 503,715 qualified for linkage. These records were matched against 3,125,689 discharge records reported to the HDD in 2015. The first step, which involved exact matching on first name, last name, date of birth, gender, and date of incident/date of admission, yielded a linkage of 64.6% ( = 325,156). The 16 successive steps yielded a further linkage of 26.6% ( = 134,006) for a total linkage of 91.2% ( = 459,162). The manual review indicated an overall false positive match rate for the 16 reviewed steps of 6.96% ( = 99). The 2 steps with the highest false positive match rates were Step 16 (43.02%,  = 77) and Step 17 (31.43%,  = 11). It is feasible to link prehospital and hospital data using stepwise deterministic linkage; this method returns a high linkage rate with a low false positive error rate. Data linkage is vital to identifying and bridging gaps in the continuum of care and is a useful tool in statewide and agency-specific research and quality improvement.
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http://dx.doi.org/10.1080/10903127.2019.1604925DOI Listing
October 2020

Mouse models for microphthalmia, anophthalmia and cataracts.

Authors:
Jochen Graw

Hum Genet 2019 Sep 27;138(8-9):1007-1018. Epub 2019 Mar 27.

Institute of Developmental Genetics, Helmholtz Center Munich, German Research Center for Environmental Health, Ingolstädter Landstrasse 1, 85764, Neuherberg, Germany.

Mouse mutants are a long-lasting, valuable tool to identify genes underlying eye diseases, because the absence of eyes, very small eyes and severely affected, cataractous eyes are easily to detect without major technical equipment. In mice, actually 145 genes or loci are known for anophthalmia, 269 for microphthalmia, and 180 for cataracts. Approximately, 25% of the loci are not yet characterized; however, some of the ancient lines are extinct and not available for future research. The phenotypes of the mutants represent a continuous spectrum either in anophthalmia and microphthalmia, or in microphthalmia and cataracts. On the other side, mouse models are still missing for some genes, which have been identified in human families to be causative for anophthalmia, microphthalmia, or cataracts. Finally, the mouse offers the possibility to genetically test the roles of modifiers and the role of SNPs; these aspects open new avenues for ophthalmogenetics in the mouse.
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http://dx.doi.org/10.1007/s00439-019-01995-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6710221PMC
September 2019

A mouse model for intellectual disability caused by mutations in the X-linked 2'‑O‑methyltransferase Ftsj1 gene.

Biochim Biophys Acta Mol Basis Dis 2019 09 14;1865(9):2083-2093. Epub 2018 Dec 14.

Department of Functional Genomics, Interfaculty Institute of Genetics and Functional Genomics, University Medicine Greifswald, Felix-Hausdorff-Strasse 8, 17489 Greifswald, Germany.

Mutations in the X chromosomal tRNA 2'‑O‑methyltransferase FTSJ1 cause intellectual disability (ID). Although the gene is ubiquitously expressed affected individuals present no consistent clinical features beyond ID. In order to study the pathological mechanism involved in the aetiology of FTSJ1 deficiency-related cognitive impairment, we generated and characterized an Ftsj1 deficient mouse line based on the gene trapped stem cell line RRD143. Apart from an impaired learning capacity these mice presented with several statistically significantly altered features related to behaviour, pain sensing, bone and energy metabolism, the immune and the hormone system as well as gene expression. These findings show that Ftsj1 deficiency in mammals is not phenotypically restricted to the brain but affects various organ systems. Re-examination of ID patients with FTSJ1 mutations from two previously reported families showed that several features observed in the mouse model were recapitulated in some of the patients. Though the clinical spectrum related to Ftsj1 deficiency in mouse and man is variable, we suggest that an increased pain threshold may be more common in patients with FTSJ1 deficiency. Our findings demonstrate novel roles for Ftsj1 in maintaining proper cellular and tissue functions in a mammalian organism.
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http://dx.doi.org/10.1016/j.bbadis.2018.12.011DOI Listing
September 2019

Crybb2 Mutations Consistently Affect Schizophrenia Endophenotypes in Mice.

Mol Neurobiol 2019 Jun 6;56(6):4215-4230. Epub 2018 Oct 6.

Institute of Developmental Genetics, Helmholtz Zentrum München, German Research Centre for Environmental Health, 85764, Neuherberg, Germany.

As part of the βγ-superfamily, βB2-crystallin (CRYBB2) is an ocular structural protein in the lens, and mutation of the corresponding gene can cause cataracts. CRYBB2 also is expressed in non-lens tissue such as the adult mouse brain and is associated with neuropsychiatric disorders such as schizophrenia. Nevertheless, the robustness of this association as well as how CRYBB2 may contribute to disease-relevant phenotypes is unknown. To add further clarity to this issue, we performed a comprehensive analysis of behavioral and neurohistological alterations in mice with an allelic series of mutations in the C-terminal end of the Crybb2 gene. Behavioral phenotyping of these three βB2-mutant lines Crybb2, Crybb2, and Crybb2 included assessment of exploratory activity and anxiety-related behavior in the open field, sensorimotor gating measured by prepulse inhibition (PPI) of the acoustic startle reflex, cognitive performance measured by social discrimination, and spontaneous alternation in the Y-maze. In each mutant line, we also quantified the number of parvalbumin-positive (PV+) GABAergic interneurons in selected brain regions that express CRYBB2. While there were allele-specific differences in individual behaviors and affected brain areas, all three mutant lines exhibited consistent alterations in PPI that paralleled alterations in the PV+ cell number in the thalamic reticular nucleus (TRN). The direction of the PPI change mirrored that of the TRN PV+ cell number thereby suggesting a role for TRN PV+ cell number in modulating PPI. Moreover, as both altered PPI and PV+ cell number are schizophrenia-associated endophenotypes, our result implicates mutated Crybb2 in the development of this neuropsychiatric disorder.
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http://dx.doi.org/10.1007/s12035-018-1365-5DOI Listing
June 2019

Influence of Time to Surgery in Ankle Fractures on the Rate of Complications and Length of Stay - a Multivariate Analysis.

Z Orthop Unfall 2019 Apr 24;157(2):183-187. Epub 2018 Aug 24.

Klinik für Unfallchirurgie, Orthopädie und Sporttraumatologie, Klinikum Köln-Merheim, Kliniken der Stadt Köln gGmbH.

Background: With an incidence of 9/1000 per year, ankle fracture is one of the most common skeletal injuries. It is currently unclear whether time to surgery affects the complication rate or the hospital length of stay and whether there are confounders in patient characteristics or comorbidities.

Material And Methods: In a retrospective cohort study (n = 421), the risk of perioperative complications in patients with a primary operative fracture treatment within 6 hours of trauma was compared to a secondary surgical treatment. Furthermore, the influence of patient characteristics and comorbidities was examined in a multivariate regression analysis.

Results: In comparison to secondary therapy, there was no benefit of a surgical fracture treatment within 6 hours after trauma was detected with regard to the perioperative complication rate or the hospital length of stay. Advanced patient age and severe soft tissue damage were associated with prolonged hospital length of stay but not with an increased rate of local perioperative complications.

Conclusion: The occurrence of severe local perioperative complications after surgical treatment of an ankle fracture is not associated with the time to surgery or covariates such as patient age or comorbidities. Current German guidelines for ankle fractures recommend surgical treatment within 6 - 8 hours, but these should be re-evaluated in further prospective randomised studies.
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http://dx.doi.org/10.1055/a-0658-1753DOI Listing
April 2019