23 research outputs found

    The complement system in the retina

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    Correlation between Age, Emergency Department Length of Stay and Hospital Admission Rate in Emergency Department Patients Aged ≥70 Years

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    Background: Interdisciplinary emergency departments (EDs) are confronted with trauma and nontrauma patients of any age group. Length of stay (LOS) and admission rates reflect both disease complexity and severity. Objective: To evaluate LOS and admission rates in different age groups according to traumatic and nontraumatic etiologies. Patients and Methods: During May 2011 a total of 4,653 adult patients (defined as ≥18 years old) seen in the ED of our municipal hospital were evaluated for their primary problem, Emergency Severity Index, LOS and admission rate. 1,841 trauma patients (mean age: 51.9 years; SD 22.5 years) and 2,812 nontrauma patients (mean age: 60.0 years; SD 20.4 years) were included. Results: Median LOS in the ED was 1:41 h (trauma) and 1:52 h (nontrauma). Trauma patients aged ≥70 years spent more time in the ED than nontrauma patients of this age group (patients aged ≥70 years median: 2:08 vs. 1:56 h; p < 0.0001). However, no significant difference was found in patients aged <70 years (1:33 vs. 1:48 h; p = 0.64). Comparing older with younger patients, median LOS within the ED was about 8 min longer in nontrauma patients aged ≥70 years (p = 0.22) and about 35 min longer in trauma patients aged ≥70 years (p < 0.00001). Conclusions: The correlation between age and LOS is stronger for trauma patients, which might indicate a special need for geriatric expertise in elderly trauma ED patients. Thus an interdisciplinary approach including surgical and geriatric expertise may be advantageous

    Sodium Iodate-Induced Degeneration Results in Local Complement Changes and Inflammatory Processes in Murine Retina

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    Age-related macular degeneration (AMD), one of the leading causes of blindness worldwide, causes personal suffering and high socioeconomic costs. While there has been progress in the treatments for the neovascular form of AMD, no therapy is yet available for the more common dry form, also known as geographic atrophy. We analysed the retinal tissue in a mouse model of retinal degeneration caused by sodium iodate (NaIO3)-induced retinal pigment epithelium (RPE) atrophy to understand the underlying pathology. RNA sequencing (RNA-seq), qRT-PCR, Western blot, immunohistochemistry of the retinas and multiplex ELISA of the mouse serum were applied to find the pathways involved in the degeneration. NaIO3 caused patchy RPE loss and thinning of the photoreceptor layer. This was accompanied by the increased retinal expression of complement components c1s, c3, c4, cfb and cfh. C1s, C3, CFH and CFB were complement proteins, with enhanced deposition at day 3. C4 was upregulated in retinal degeneration at day 10. Consistently, the transcript levels of proinflammatory ccl-2, -3, -5, il-1β, il-33 and tgf-β were increased in the retinas of NaIO3 mice, but vegf-a mRNA was reduced. Macrophages, microglia and gliotic Müller cells could be a cellular source for local retinal inflammatory changes in the NaIO3 retina. Systemic complement and cytokines/chemokines remained unaltered in this model of NaIO3-dependent retinal degeneration. In conclusion, systemically administered NaIO3 promotes degenerative and inflammatory processes in the retina, which can mimic the hallmarks of geographic atrophy

    As in Real Estate, Location Matters: Cellular Expression of Complement Varies Between Macular and Peripheral Regions of the Retina and Supporting Tissues.

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    The cellular events that dictate the initiation of the complement pathway in ocular degeneration, such as age-related macular degeneration (AMD), is poorly understood. Using gene expression analysis (single cell and bulk), mass spectrometry, and immunohistochemistry, we dissected the role of multiple retinal and choroidal cell types in determining the complement homeostasis. Our scRNA-seq data show that the cellular response to early AMD is more robust in the choroid, particularly in fibroblasts, pericytes and endothelial cells. In late AMD, complement changes were more prominent in the retina especially with the expression of the classical pathway initiators. Notably, we found a spatial preference for these differences. Overall, this study provides insights into the heterogeneity of cellular responses for complement expression and the cooperation of neighboring cells to complete the pathway in healthy and AMD eyes. Further, our findings provide new cellular targets for therapies directed at complement

    Common Genetic Variants Associate with Serum Phosphorus Concentration

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    Phosphorus is an essential mineral that maintains cellular energy and mineralizes the skeleton. Because complex actions of ion transporters and regulatory hormones regulate serum phosphorus concentrations, genetic variation may determine interindividual variation in phosphorus metabolism. Here, we report a comprehensive genome-wide association study of serum phosphorus concentration. We evaluated 16,264 participants of European ancestry from the Cardiovascular Heath Study, Atherosclerosis Risk in Communities Study, Framingham Offspring Study, and the Rotterdam Study. We excluded participants with an estimated GFR &lt;45 ml/min per 1.73 m(2) to focus on phosphorus metabolism under normal conditions. We imputed genotypes to approximately 2.5 million single-nucleotide polymorphisms in the HapMap and combined study-specific findings using meta-analysis. We tested top polymorphisms from discovery cohorts in a 5444-person replication sample. Polymorphisms in seven loci with minor allele frequencies 0.08 to 0.49 associate with serum phosphorus concentration (P = 3.5 x 10(-16) to 3.6 x 10(-7)). Three loci were near genes encoding the kidney-specific type IIa sodium phosphate co-transporter (SLC34A1), the calcium-sensing receptor (CASR), and fibroblast growth factor 23 (FGF23), proteins that contribute to phosphorus metabolism. We also identified genes encoding phosphatases, kinases, and phosphodiesterases that have yet-undetermined roles in phosphorus homeostasis. In the replication sample, five of seven top polymorphisms associate with serum phosphorous concentrations (P &lt; 0.05 for each). In conclusion, common genetic variants associate with serum phosphorus in the general population. Further study of the loci identified in this study may help elucidate mechanisms of phosphorus regulation

    Bioabsorbable metal screws in traumatology: A promising innovation

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    MAGNEZIX® CS (Syntellix AG, Hanover, Germany) is a bioabsorbable compression screw made of a magnesium alloy (MgYREZr). Currently there are only two clinical studies reporting on a limited number of elective patients who received this screw in a hallux valgus operation. We applied MAGNEZIX® CS for fixation of distal fibular fracture in a trauma patient who had sustained a bimalleolar fracture type AO 44-B2.3. Clinical course was uneventful, fracture healing occurred within three months. Follow-up X-rays showed a radiolucent area around the implant for some months, yet this radiolucent area had disappeared in the 17-months follow-up X-ray. Keywords: Magnesium, Bioabsorbable, Compression screw, Osteosynthesis, Ankle fractur

    Magnesium-Based Absorbable Metal Screws for Intra-Articular Fracture Fixation

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    MAGNEZIX® (Syntellix AG, Hanover, Germany) is a biodegradable magnesium-based alloy (MgYREZr) which is currently used to manufacture bioabsorbable compression screws. To date, there are very few studies reporting on a limited number of elective foot surgeries using this innovative implant. This case report describes the application of this screw for osteochondral fracture fixation at the humeral capitulum next to a loose radial head prosthesis, which was revised at the same time. The clinical course was uneventful. Degradation of the magnesium alloy did not interfere with fracture healing. Showing an excellent clinical result and free range-of-motion, the contour of the implant was still visible in a one-year follow-up

    Cell-Type-Specific Complement Profiling in the ABCA4−/− Mouse Model of Stargardt Disease

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    Stargardt macular degeneration is an inherited retinal disease caused by mutations in the ATP-binding cassette subfamily A member 4 (ABCA4) gene. Here, we characterized the complement expression profile in ABCA4(-/-) retinae and aligned these findings with morphological markers of retinal degeneration. We found an enhanced retinal pigment epithelium (RPE) autofluorescence, cell loss in the inner retina of ABCA4(-/-) mice and demonstrated age-related differences in complement expression in various retinal cell types irrespective of the genotype. However, 24-week-old ABCA4(-/-) mice expressed more c3 in the RPE and fewer cfi transcripts in the microglia compared to controls. At the protein level, the decrease of complement inhibitors (complement factor I, CFI) in retinae, as well as an increased C3b/C3 ratio in the RPE/choroid and retinae of ABCA4(-/-), mice was confirmed. We showed a corresponding increase of the C3d/C3 ratio in the serum of ABCA4(-/-) mice, while no changes were observed for CFI. Our findings suggest an overactive complement cascade in the ABCA4(-/-) retinae that possibly contributes to pathological alterations, including microglial activation and neurodegeneration. Overall, this underpins the importance of well-balanced complement homeostasis to maintain retinal integrity

    Dorsal versus transgluteal approach for hip hemiarthroplasty: an analysis of early complications in seven hundred and four consecutive cases

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    Purpose Hemiarthroplasty (HA) is an established treatment for femoral neck fractures of the elderly. Several surgical approaches are currently used including dorsal and transgluteal. It is still unclear whether one approach may be advantageous. We compared early complication rates after dorsal and transgluteal approaches. Methods We retrospectively analysed a cohort including 704 consecutive patients who received HA for femoral neck fracture; 212 male and 492 female patients were included, and the mean age was 80.4 years (SD 9.8 years). In 487 patients a dorsal and in 217 a transgluteal approach was chosen. In all patients an Excia® stem with self-centring bipolar head manufactured by Aesculap (Tuttlingen, Germany) was used. We evaluated early postoperative complications including dislocation, infection, haematoma, seroma and perioperative fracture. Complication rates after dorsal and transgluteal approaches were calculated and compared by the chi-square test. Results After a dorsal approach 10.5 % [confidence interval (CI) 7.7–13.2 %] of the patients suffered one or more early complications. Following a transgluteal approach this proportion was 9.7 % (CI 5.7–13.6 %), which was not significantly different (p = 0.75). The predominant complication after a dorsal approach was dislocation (3.9 %; CI 2.2–5.6 %). The dislocation rate after a transgluteal approach was significantly lower (0.5 %; CI 0–1.4 %). Postoperative haematoma however was seen after a transgluteal approach in 5.5 % (CI 2.5–8.6 %), which was significantly more frequent than after a dorsal approach (1.2 %; CI 0.2–2.2 %). The frequency of the other types of complications did not significantly differ. Conclusions The rate of early surgical complications after dorsal and transgluteal approaches is not significantly different. However, the dorsal approach predisposed to dislocation, whereas the transgluteal approach predisposed to haematoma

    PDGF Receptor Alpha Signaling Is Key for Muller Cell Homeostasis Functions

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    Muller cells, the major retinal macroglia, are key to maintaining vascular integrity as well as retinal fluid and ion homeostasis. Although platelet derived growth factor (PDGF) receptor expression in Muller glia has been reported earlier, their actual role for Muller cell function and intimate interaction with cells of the retinal neurovascular unit remains unclear. To close this gap of knowledge, Muller cell-specific PDGF receptor alpha (PDGFR alpha) knockout (KO) mice were generated, characterized, and subjected to a model of choroidal neovascularization (CNV). PDGFR alpha-deficient Muller cells could not counterbalance hypoosmotic stress as efficiently as their wildtype counterparts. In wildtypes, the PDGFR alpha ligand PDGF-BB prevented Muller cell swelling induced by the administration of barium ions. This effect could be blocked by the PDGFR family inhibitor AC710. PDGF-BB could not restore the capability of an efficient volume regulation in PDGFR alpha KO Muller cells. Additionally, PDGFR alpha KO mice displayed reduced rod and cone-driven light responses. Altogether, these findings suggest that Muller glial PDGFR alpha is central for retinal functions under physiological conditions. In contrast, Muller cell-specific PDGFR alpha KO resulted in less vascular leakage and smaller lesion areas in the CNV model. Of note, the effect size was comparable to pharmacological blockade of PDGF signaling alone or in combination with anti-vascular endothelial growth factor (VEGF) therapy-a treatment regimen currently being tested in clinical trials. These data imply that targeting PDGF to treat retinal neovascular diseases may have short-term beneficial effects, but may elicit unwarranted side effects given the putative negative effects on Muller cell homeostatic functions potentially interfering with a long-term positive outcome
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