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Beim ischämischen Schlaganfall finden weitreichende systemische immunmodulatorische Anpassungsvorgänge statt. Da Sphingosin-1-Phosphat (S1P)-Signalwege für die Immunzellrekrutierung von hoher Relevanz sind, war angesichts der bekannten immunologischen Veränderungen nach zerebraler Ischämie das Ziel dieser Dissertation die genauen Veränderungen dieses Signalweges zu charakterisieren.
Für diese Charakterisierung wurde ein transientes Fadenokklusionsmodell der A. cerebri media an der Maus verwendet. Die Sphingolipidkonzentrationen wurden drei oder 24 Stunden nach Okklusion in der Milz, im Plasma sowie im Hirngewebe gemessen. Parallel hierzu wurde die Immunzellrekrutierung in die von der Ischämie betroffenen Hemisphäre analysiert.
Zunächst konnte diese Dissertation zeigen, dass in der Akutphase des Schlaganfalls ein S1P-Konzentrationsgradient vorherrscht. Die Milz zeigt hier die niedrigsten Konzentrationen, gefolgt von Plasma und Gehirn. Darüber hinaus besteht auch in der betroffenen Hemisphäre ein S1P-Gradient mit hohen Konzentrationen im Infarktkern, jedoch verminderten Konzentrationen im Periinfarktkortex (PIC).
Zweitens führt eine fokale zerebrale Ischämie zu einer Infiltration von T- und B-Lymphozyten in die ischämische Hemisphäre. Im Gegensatz hierzu kommt es zu einer Schlaganfall-induzierten Lymphopenie im Blut. Hierzu passend konnte ich eine signifikante Abnahme des Gewichts und der B- und T-Lymphozyten der Milz 24 Stunden nach Ischämie nachweisen. Weitere von Immunzellen produzierte Zytokine (IL-6) sowie deren Transkriptionsfaktoren (SPI1, STAT3, FoxP3) zeigten in der Akutphase nach Ischämie ebenfalls eine deutliche Reduktion und wiesen auf die Rekrutierung peripherer Immunzellen (pIZ) aus dem sekundären lymphatischen Organ hin. Folgerichtig waren Leukozyten im Plasma sowohl drei als auch 24 Stunden nach Ischämie signifikant vermehrt, welche insbesondere neutrophilen Granulozyten entsprachen.
Basierend auf der nachgewiesenen Reduktion von T-Helferzellen sowie regulatorischer T-Zellen sowohl in der Milz als auch in der Zirkulation, wurde drittens die Hypothese einer zerebralen Rekrutierung dieser T-Zellpopulationen gemäß dem vorliegenden S1P-Gradienten untersucht. Dabei gelang die Darstellung einer signifikanten Infiltration von CD45+-Zellen in beide Hemisphären, welche insbesondere von T-Helferzellen geprägt war.
Viertens nimmt die S1P-Rezeptor (S1PR)-Expression auf Leukozyten eine bedeutende Stellung in der pIZ-Rekrutierung ein. In diesem Sinne konnte ich zeigen, dass nach zerebraler Ischämie S1P1 signifikant in der Milz vermindert exprimiert wurde. Dieses Ergebnis deutete auf einen Austritt S1P1+ Immunzellen aus der Milz dem etablierten S1P-Gradienten folgend hin. In der ischämischen Hemisphäre hingegen ließ sich ebenfalls eine Herunterregulation der exprimierten mRNA für S1P1 nachweisen, wohingegen S1P2 und S1P3 vermehrt transkribiert wurden. Dieses Ergebnis könnte Folge der mikroglialen Aktivierung sein, die bekanntermaßen mit einer Hochregulation von S1P2 und S1P3 einhergeht.
Abschließend habe ich die Rolle von weiteren Sphingolipiden, u.a. von Ceramiden, untersucht, die einen signifikanten Anstieg in der Milz 24 Stunden nach Ischämie zeigten. Im Gegensatz dazu konnte ich im Gehirn keine Unterschiede der untersuchten Ceramidspezies abgrenzen, sodass in dem hier verwendeten Modell eine Beteiligung an lokalen pathophysiologischen Vorgängen eher unwahrscheinlich erscheint.
Zusammenfassend beschreiben die in dieser Dissertation dargestellten Ergebnisse lokale und systemische Veränderungen des S1P-Signalwegs nach zerebraler Ischämie. Konkordante Veränderungen des Immunsystems deuten auf eine relevante Rolle veränderter S1P-Konzentrationen hin. Weitergehende, funktionelle Untersuchungen der hier beobachteten Ergebnisse müssen die potentielle therapeutische Relevanz für Patienten mit zerebraler Ischämie aufklären.
Eckes, Timon Sebastian ; Patyna, Ralf Sammy ; Koch, Alexander ; Oftring, Anke ; Gauer, Stefan ; Obermüller, Nicholas ; Schwalm, Stephanie ; Schäfer, Liliana ; Chun, Jerold ; Gröne, Hermann-Josef ; Pfeilschifter, Josef
S1P and its receptors have been reported to play important roles in the development of renal fibrosis. Although S1P5 has barely been investigated so far, there are indications that it can influence inflammatory and fibrotic processes. Here, we report the role of S1P5 in renal inflammation and fibrosis. Male S1P5 knockout mice and wild-type mice on a C57BL/6J background were fed with an adenine-rich diet for 7 days or 14 days to induce tubulointerstitial fibrosis. The kidneys of untreated mice served as respective controls. Kidney damage, fibrosis, and inflammation in kidney tissues were analyzed by real-time PCR, Western blot, and histological staining. Renal function was assessed by plasma creatinine ELISA. The S1P5 knockout mice had better renal function and showed less kidney damage, less proinflammatory cytokine release, and less fibrosis after 7 days and 14 days of an adenine-rich diet compared to wild-type mice. S1P5 knockout ameliorates tubular damage and tubulointerstitial fibrosis in a model of adenine-induced nephropathy in mice. Thus, targeting S1P5 might be a promising goal for the pharmacological treatment of kidney diseases.
Recent studies suggested an important contribution of sphingosine-1-phospate (S1P) signaling via its specific receptors (S1PRs) in the production of pro-inflammatory mediators such as Interleukin (IL)-1β in cancer and inflammation. In an inflammation-driven cancer setting, we previously reported that myeloid S1PR1 signaling induces IL-1β production by enhancing NLRP3 (NOD-, LRR- and Pyrin Domain-Containing Protein 3) inflammasome activity. However, the autocrine role of S1P and enzymes acting on the S1P rheostat in myeloid cells are unknown. Using human and mouse macrophages with pharmacological or genetic intervention we explored the relative contribution of sphingosine kinases (SPHKs) in NLRP3 inflammasome activity regulation. We noticed redundancy in SPHK1 and SPHK2 activities towards macrophage NLRP3 inflammasome transcriptional induction and IL-1β secretion. However, pharmacological blockade of both kinases in unison completely abrogated NLRP3 inflammasome induction and IL-1β secretion. Interestingly, human and mouse macrophages demonstrate varied responses towards SPHKs inhibition and IL-1β secretion. Clinical datasets of renal cell carcinoma and psoriasis patients showed a positive correlation between enzymes affecting the S1P rheostat with NLRP3 inflammasome components expression, which corroborates our finding. Our data provide a better understanding on the role of SPHKs and de novo synthesized S1P in macrophage NLRP3 inflammasome activation
Sphingosylphosphorylcholine (SPC) is a bioactive lipid that binds to G protein-coupled-receptors and activates various signaling cascades. Here, we show that in renal mesangial cells, SPC not only activates various protein kinase cascades but also activates Smad proteins, which are classical members of the transforming growth factor-β (TGFβ) signaling pathway. Consequently, SPC is able to mimic TGFβ-mediated cell responses, such as an anti-inflammatory and a profibrotic response. Interleukin-1β-stimulated prostaglandin E2 formation is dose-dependently suppressed by SPC, which is paralleled by reduced secretory phospholipase A2 (sPLA2) protein expression and activity. This effect is due to a reduction of sPLA2 mRNA expression caused by inhibited sPLA2 promoter activity. Furthermore, SPC upregulates the profibrotic connective tissue growth factor (CTGF) protein and mRNA expression. Blocking TGFβ signaling by a TGFβ receptor kinase inhibitor causes an inhibition of SPC-stimulated Smad activation and reverses both the negative effect of SPC on sPLA2 expression and the positive effect on CTGF expression. In summary, our data show that SPC, by mimicking TGFβ, leads to a suppression of proinflammatory mediator production and stimulates a profibrotic cell response that is often the end point of an anti-inflammatory reaction. Thus, targeting SPC receptors may represent a novel therapeutic strategy to cope with inflammatory diseases.
Hafizi, Redona ; Imeri, Faik ; Stepanovska Tanturovska, Bisera ; Manaila, Roxana ; Schwalm, Stephanie ; Trautmann, Sandra ; Wenger, Roland H. ; Pfeilschifter, Josef ; Huwiler, Andrea
Erythropoietin (Epo) is a crucial hormone regulating red blood cell number and consequently the hematocrit. Epo is mainly produced in the kidney by interstitial fibroblast-like cells. Previously, we have shown that in cultures of the immortalized mouse renal fibroblast-like cell line FAIK F3-5, sphingosine 1-phosphate (S1P), by activating S1P1 and S1P3 receptors, can stabilize hypoxia-inducible factor (HIF)-2α and upregulate Epo mRNA and protein synthesis. In this study, we have addressed the role of intracellular iS1P derived from sphingosine kinases (Sphk) 1 and 2 on Epo synthesis in F3-5 cells and in mouse primary cultures of renal fibroblasts. We show that stable knockdown of Sphk2 in F3-5 cells increases HIF-2α protein and Epo mRNA and protein levels, while Sphk1 knockdown leads to a reduction of hypoxia-stimulated HIF-2α and Epo protein. A similar effect was obtained using primary cultures of renal fibroblasts isolated from wildtype mice, Sphk1−/−, or Sphk2−/− mice. Furthermore, selective Sphk2 inhibitors mimicked the effect of genetic Sphk2 depletion and also upregulated HIF-2α and Epo protein levels. The combined blockade of Sphk1 and Sphk2, using Sphk2−/− renal fibroblasts treated with the Sphk1 inhibitor PF543, resulted in reduced HIF-2α and Epo compared to the untreated Sphk2−/− cells. Exogenous sphingosine (Sph) enhanced HIF-2α and Epo, and this was abolished by the combined treatment with the selective S1P1 and S1P3 antagonists NIBR-0213 and TY52156, suggesting that Sph was taken up by cells and converted to iS1P and exported to then act in an autocrine manner through S1P1 and S1P3. The upregulation of HIF-2α and Epo synthesis by Sphk2 knockdown was confirmed in the human hepatoma cell line Hep3B, which is well-established to upregulate Epo production under hypoxia. In summary, these data show that sphingolipids have diverse effects on Epo synthesis. While accumulation of intracellular Sph reduces Epo synthesis, iS1P will be exported to act through S1P1+3 to enhance Epo synthesis. Furthermore, these data suggest that selective inhibition of Sphk2 is an attractive new option to enhance Epo synthesis and thereby to reduce anemia development in chronic kidney disease.
Friedauer, Lucie ; Rezny-Kasprzak, Beata ; Steinmetz, Helmuth ; Du Mesnil de Rochemont, Richard Klaus Frieder ; Förch, Christian
Background and purpose: Superficial siderosis of the central nervous system is a sporadic finding in magnetic resonance imaging, resulting from recurrent bleedings into the subarachnoid space. This study aimed to determine the frequency of spinal dural cerebrospinal fluid (CSF) leaks amongst patients with a symmetric infratentorial siderosis pattern. Methods: In all, 97,733 magnetic resonance images performed between 2007 and 2018 in our neurocenter were screened by a keyword search for “hemosiderosis” and “superficial siderosis.” Siderosis patterns on brain imaging were classified according to a previously published algorithm. Potential causative intracranial bleeding events were also assessed. Patients with a symmetric infratentorial siderosis pattern but without causative intracranial bleeding events in history were prospectively evaluated for spinal pathologies. Results: Forty-two patients with isolated supratentorial siderosis, 30 with symmetric infratentorial siderosis and 21 with limited (non-symmetric) infratentorial siderosis were identified. Amyloid angiopathy and subarachnoid hemorrhage were causes for isolated supratentorial siderosis. In all four patients with a symmetric infratentorial siderosis pattern but without a causative intracranial bleeding event in history, spinal dural abnormalities were detected. Dural leaks were searched for in patients with symmetric infratentorial siderosis and a history of intracranial bleeding event without known bleeding etiology, considering that spinal dural CSF leaks themselves may also cause intracranial hemorrhage, for example by inducing venous thrombosis due to low CSF pressure. Thereby, one additional spinal dural leak was detected. Conclusions: Persisting spinal dural CSF leaks can frequently be identified in patients with a symmetric infratentorial siderosis pattern. Diagnostic workup in these cases should include magnetic resonance imaging of the whole spine.
Friedauer, Lucie ; Rezny-Kasprzak, Beata ; Steinmetz, Helmuth ; Du Mesnil de Rochemont, Richard Klaus Frieder ; Förch, Christian
Background and purpose: Superficial siderosis of the central nervous system is a sporadic finding in magnetic resonance imaging, resulting from recurrent bleedings into the subarachnoid space. This study aimed to determine the frequency of spinal dural cerebrospinal fluid (CSF) leaks amongst patients with a symmetric infratentorial siderosis pattern. Methods: In all, 97,733 magnetic resonance images performed between 2007 and 2018 in our neurocenter were screened by a keyword search for “hemosiderosis” and “superficial siderosis.” Siderosis patterns on brain imaging were classified according to a previously published algorithm. Potential causative intracranial bleeding events were also assessed. Patients with a symmetric infratentorial siderosis pattern but without causative intracranial bleeding events in history were prospectively evaluated for spinal pathologies. Results: Forty-two patients with isolated supratentorial siderosis, 30 with symmetric infratentorial siderosis and 21 with limited (non-symmetric) infratentorial siderosis were identified. Amyloid angiopathy and subarachnoid hemorrhage were causes for isolated supratentorial siderosis. In all four patients with a symmetric infratentorial siderosis pattern but without a causative intracranial bleeding event in history, spinal dural abnormalities were detected. Dural leaks were searched for in patients with symmetric infratentorial siderosis and a history of intracranial bleeding event without known bleeding etiology, considering that spinal dural CSF leaks themselves may also cause intracranial hemorrhage, for example by inducing venous thrombosis due to low CSF pressure. Thereby, one additional spinal dural leak was detected. Conclusions: Persisting spinal dural CSF leaks can frequently be identified in patients with a symmetric infratentorial siderosis pattern. Diagnostic workup in these cases should include magnetic resonance imaging of the whole spine.
Chhabra, Harvinder Singh ; Tamai, Koji ; Alsebayel, Hana ; AlEissa, Sami ; Alqahtani, Yahya ; Arand, Markus ; Basu, Saumyajit ; Blattert, Thomas ; Bussières, André ; Campello, Marco ; Costanzo, Giuseppe ; Côté, Pierre ; Darwano, Bambang ; Franke, Jörg ; Garg, Bhavuk ; Hasan, Rumaisah ; Ito, Manabu ; Kamra, Komal ; Kandziora, Frank ; Kassim, Nishad ; Kato, So ; Lahey, Donna ; Mehta, Ketna ; Menezes, Cristiano M. ; Muehlbauer, Eric J. ; Mullerpatan, Rajani ; Pereira, Paulo ; Roberts, Lisa ; Ruosi, Carlo ; Sullivan, William ; Shetty, Ajoy Prasad ; Tucci, Carlos ; Wadhwa, Sanjay ; Alturkistany, Ahmed ; Busari, Jamiu O. ; Wang, Jeffrey C. ; Teli, Marco G. A. ; Rajasekaran, Shanmuganathan ; Mulukutla, Raghava D. ; Piccirillo, Michael ; Hsieh, Patrick C. ; Dohring, Edward J. ; Srivastava, Sudhir K. ; Larouche, Jeremie ; Vlok, Adriaan ; Nordin, Margareta
Alix/AIP1 is an adaptor protein involved in regulating the function of receptor and cytoskeleton-associated tyrosine kinases. Here, we investigated its interaction with and regulation by Src. Tyr319 of Alix bound the isolated Src homology-2 (SH2) domain and was necessary for interaction with intact Src. A proline-rich region in the C terminus of Alix bound the Src SH3 domain, but this interaction was dependent on the release of the Src SH2 domain from its Src internal ligand either by interaction with Alix Tyr319 or by mutation of Src Tyr527. Src phosphorylated Alix at a C-terminal region rich in tyrosines, an activity that was stimulated by the presence of the Alix binding partner SETA/CIN85. Phosphorylation of Alix by Src caused it to translocate from the membrane and cytoskeleton to the cytoplasm and reduced its interaction with binding partners SETA/CIN85, epidermal growth factor receptor, and Pyk2. As a consequence of this, Src antagonized the negative regulation of receptor tyrosine kinase internalization and cell adhesion by Alix. We propose a model whereby Src antagonizes the effects of Alix by phosphorylation of its C terminus, leading to the disruption of interactions with target proteins.
Mihatovic, Ilja ; Schwarz, Frank ; Obreja, Karinna Anne-Marie ; Becker, Jürgen ; Sader, Robert Alexander ; Dard, Michel Marcel ; John, Gordon
Objective: To assess the influence of biphasic calcium phosphate materials with different surface topographies on bone formation and osseointegration of titanium implants in standardized alveolar ridge defects.
Materials and methods: Standardized alveolar ridge defects (6 × 6 mm) were created in the mandible of 8 minipigs and filled with three biphasic calcium phosphate materials (BCP1–3, 90% tricalcium phosphate/10% hydroxyapatite) with different surface properties (micro- and macroporosities) as well as a bovine-derived natural bone mineral (NBM) as a control. At 12 weeks, implants were placed into the augmented defects. After further 8 weeks of healing, dissected blocks were processed for histological analysis (e.g., mineralized (MT), residual bone graft material (BS), bone-to-implant contact (BIC)).
Results: All four biomaterials showed well-integrated graft particles and new bone formation within the defect area. MT values were comparable in all groups. BS values were highest in the NBM group (21.25 ± 13.52%) and markedly reduced in the different BCP groups, reaching statistical significance at BCP1-treated sites (9.2 ± 3.28%). All test and control groups investigated revealed comparable and statistically not significant different BIC values, ranging from 73.38 ± 20.5% (BCP2) to 84.11 ± 7.84% (BCP1), respectively.
Conclusion* All bone graft materials facilitated new bone formation and osseointegration after 12 + 8 weeks of healing.
Ohlendorf, Daniela Maren ; Pflaum, Julia ; Loewe, Christina ; Schamberger, Sebastian ; Erbe, Christina ; Wanke, Eileen M. ; Holzgreve, Fabian Christian ; Groneberg, Jan David Alexander
Background: To detect deviations from a normal postural control, standard values can be helpful for comparison purposes. Since the postural control is influenced by gender and age, the aim of the present study was the collection of standard values for women between 31 and 40 years of age.
Methods: For the study, 106 female, subjectively healthy, German subjects aged between 31 and 40 years (35 ± 2.98 years) were measured using a pressure measuring platform.
Results: Their average BMI was 21.60 ± 4.65 kg/m2. The load distribution between left and right foot was almost evenly balanced with a median 51.46% load on the left [tolerance interval (TR) 37.02%/65.90%; confidence interval (CI) 50.06/52.85%] and 48.54% [TR 43.10/62.97%; CI 47.14/49.93%] on the right foot. The median forefoot load was 33.84% [TR 20.68/54.73%; CI 31.67/37.33%] and the rearfoot load was measured at 66.16% [TR 45.27/79.33%; CI 62.67/68.33%]. The median/mean body sway in the sagittal plane was measured 12 mm [TR 5.45/23.44 mm; CI 11.00/14.00 mm] and 8.17 mm in the frontal plane [TR 3.33/19.08 mm; CI 7.67/9.33 mm]. The median of the ellipse area is 0.72 cm2 [TR 0.15/3.69 cm2; CI 0.54/0.89°]. The ellipse width has a median of 0.66 cm [TR 0.30/1.77 cm; CI 0.61/0.78 cm] and the height of 0.33 cm [TR 0.13/0.71 cm; CI 0.30/0.37 cm]. The ellipse angle (sway, left forefoot to right rearfoot) has a mean of − 19.34° [TR − 59.21/− 0.44°; CI − 22.52/− 16.16°] and the ellipse angle sway from right forefoot to left rearfoot has a mean of 12.75° [TR 0.09/59.09°; CI 9.00/16.33°].
Conclusion: The right-to-left ratio is balanced. The forefoot-to-rearfoot ratio is approximately 1:2. Also, the body sway can be classified with 12 and 8 mm as normal. The direction of fluctuation is either approx. 19° from the left forefoot to the right rearfoot or approx. 13° the opposite. Body weight, height, and BMI were comparable to the German average of women in a similar age group, so that the measured standard values are representative and might serve as baseline for the normal function of the balance system in order to support the diagnosis of possible dysfunctions in postural control.
Ohlendorf, Daniela Maren ; Kaya, Ugur ; Goecke, Julian ; Oremek, Gerhard ; Ackermann, Hanns ; Groneberg, Jan David Alexander
Background: In order to classify and analyze the parameters of upper body posture, a baseline in the form of standard values is demanded. To this date, standard values have only been published for healthy men aged 18–35 and 41–50 years. Data for male adults aged between 31 and 40 years are lacking.
Methods: The postural parameters of 101 symptom-free male volunteers aged 31–40 (35.58 ± 2.88) years were studied. The mean height of the men was 179.89 ± 7.38 cm, with a mean body weight of 86.36 ± 11.58 kg and an average BMI of 26.70 ± 3.35 kg/m2. By means of video rasterstereography, a 3-dimensional scan of the upper back surface was measured in a habitual standing position. The means or medians, confidence interval, tolerance range, and group comparisons and correlations of BMI and physical activity were calculated for all parameters.
Results: The habitual standing position was found to be almost symmetrical and the axis aligned in the spine, pelvis, and shoulder region, while the spine position was marginally inclined ventrally. The kyphosis angle of the thoracic spine was greater than the lordosis angle of the lumbar spine. All deviations fell under the measurement error margin of 1 mm/1°. The greater the BMI, the greater was the pelvic and scapular distance. The lower the BMI, the further caudally positioned was the right shoulder. The pelvic and scapular distances were also lower with the increasing athleticism of the participants.
Conclusion: The upper body posture of men between the ages of 31 and 40 years was found to be almost symmetrical and axis-conforming, with the kyphosis angle, pelvic distance, and shoulder distance enlarging with increasing BMI. Consequently, postural parameters presented in this survey allow for comparisons with other studies, as well as the evaluation of clinical diagnostics and applications.
Ohlendorf, Daniela Maren ; Krüger, Kai-Dominik ; Christian, Wolfgang ; Ackermann, Hanns ; Keil, Fee ; Oremek, Gerhard ; Maurer-Grubinger, Christian ; Groneberg, Jan David Alexander
Comparative values are essential for the classification of orthopedic abnormalities and the assessment of a necessary therapy. At present, reference values for the upper body posture for healthy, male adults exist for the age groups of 18–35, 31–40 and 41–50 years. However, corresponding data on the decade of 51 to 60 year-old healthy men are still lacking. 23 parameters of the upper body posture were analyzed in 102 healthy male participants aged 51–60 (55.36 ± 2.78) years. The average height was 180.76 ± 7.81 cm with a weight of 88.22 ± 14.57 kg. The calculated BMI was 26.96 ± 3.92 kg/m2. In the habitual, upright position, the bare upper body was scanned three-dimensionally using video raster stereography. Mean or median values, confidence intervals, tolerance ranges and group comparisons, as well as correlations of BMI and physical activity, were calculated for all parameters. The spinal column parameters exhibited a good exploration of the frontal plane in the habitual standing position. In the sagittal plane, a slight, ventral inclination of the trunk with an increased kyphosis angle of the thoracic spine and increased thoracic bending angle was observed. The parameters of the pelvis showed a pronounced symmetry with deviations from the 0° axis within the measurement error margin of 1 mm/1°. The scapula height together with the scapula angles of the right and left side described a slightly elevated position of the left shoulder compared to the right side. The upper body posture is influenced by parameters of age, height, weight and BMI. Primarily there are significant correlations to measurements of trunk lengths D (age: p ≤ 0.02, rho = -0.23; height: p ≤ 0.001, rho = 0.58; weight: p ≤ 0.001, rho = 0.33), trunk lengths S (age: p ≤ 0.01, rho = -0.27; height: p ≤ 0.001, rho = 0.58; weight: p ≤ 0.001, rho = 0.32), pelvic distance (height: p ≤ 0.01, rho = 0.26; weight: p ≤ 0.001, rho = 0.32; BMI: p ≤ 0.03, rho = 0.22) and scapula distance (weight: p ≤ 0.001, rho = .32; BMI: p ≤ 0.01, rho = 0.27), but also to sagittal parameters of trunk decline (weight: p ≤ 0.001, rho = -0.29; BMI: p ≤ 0.01, rho = -0.24), thoracic bending angle (height: p ≤ 0.01, rho = 0.27) and kyphosis angle (BMI: p ≤ 0.03, rho = 0.21). The upper body posture of healthy men between the ages of 51 and 60 years was axially almost aligned and balanced. With the findings of this investigation and the reference values obtained, suitable comparative values for use in clinical practice and for further scientific studies with the same experimental set-up have been established.
Standard reference values of the upper body posture in healthy middle-aged female adults in Germany
(2021)
Ohlendorf, Daniela Maren ; Sosnov, Polyna ; Keller, Julia ; Wanke, Eileen M. ; Oremek, Gerhard ; Ackermann, Hanns ; Groneberg, Jan David Alexander
In order to classify and analyze the parameters of upper body posture, a baseline in form of standard values is demanded. To this date, standard values have only been published for healthy young women. Data for female adults between 51 and 60 years are lacking. 101 symptom-free female volunteers aged 51–60 (55.16 ± 2.89) years. The mean height of the volunteers was 1.66 ± 0.62 m, with a mean body weight of 69.3 ± 11.88 kg and an average BMI of 25.02 ± 4.55 kg/m2. By means of video raster stereography, a 3D-scan of the upper back surface was measured in a habitual standing position. The confidence interval, tolerance range and ICCs were calculated for all parameters. The habitual standing position is almost symmetrical in the frontal plane the most prominent deviation being a slightly more ventral position of the left shoulder blade in comparison to the right. The upper body (spine position) is inclined ventrally with a minor tilt to the left. In the sagittal plane, the kyphosis angle of the thoracic spine is greater than the lordosis angle of the lumbar spine. The pelvis is virtually evenly balanced with deviations from an ideal position falling under the measurement error margin of 1 mm/1°. There were also BMI influenced postural variations in the sagittal plane and shoulder distance. The ICCs are calculated from three repeated measurements and all parameters can be classified as "almost perfect". Deflections from an ideally symmetric spinal alignment in women aged 51–60 years are small-scaled, with a minimal frontal-left inclination and accentuated sigmoidal shape of the spine. Postural parameters presented in this survey allow for comparisons with other studies as well as the evaluation of clinical diagnostics and applications.
Ohlendorf, Daniela Maren ; Kerth, Kerstin Jeanette ; Osiander, W. ; Holzgreve, Fabian Christian ; Fräulin, Laura ; Ackermann, Hanns ; Groneberg, Jan David Alexander
Background: The aim of this study was to collect standard reference values of the weight and the maximum pressure distribution in healthy adults aged 18–65 years and to investigate the influence of constitutional parameters on it.
Methods: A total of 416 healthy subjects (208 male / 208 female) aged between 18 and 65 years (Ø 38.3 ± 14.1 years) participated in this study, conducted 2015–2019 in Heidelberg. The age-specific evaluation is based on 4 age groups (G1, 18–30 years; G2, 31–40 years; G3, 41–50 years; G4, 51–65 years). A pressure measuring plate FDM-S (Zebris/Isny/Germany) was used to collect body weight distribution and maximum pressure distribution of the right and left foot and left and right forefoot/rearfoot, respectively.
Results: Body weight distribution of the left (50.07%) and right (50.12%) foot was balanced. There was higher load on the rearfoot (left 54.14%; right 55.09%) than on the forefoot (left 45.49%; right 44.26%). The pressure in the rearfoot was higher than in the forefoot (rearfoot left 9.60 N/cm2, rearfoot right 9.51 N/cm2/forefoot left 8.23 N/cm2, forefoot right 8.59 N/cm2). With increasing age, the load in the left foot shifted from the rearfoot to the forefoot as well as the maximum pressure (p ≤ 0.02 and 0.03; poor effect size). With increasing BMI, the body weight shifted to the left and right rearfoot (p ≤ 0.001, poor effect size). As BMI increased, so did the maximum pressure in all areas (p ≤ 0.001 and 0.03, weak to moderate effect size). There were significant differences in weight and maximum pressure distribution in the forefoot and rearfoot in the different age groups, especially between younger (18–40 years) and older (41–65 years) subjects.
Discussion: Healthy individuals aged from 18 to 65 years were found to have a balanced weight distribution in an aspect ratio, with a 20% greater load of the rearfoot. Age and BMI were found to be influencing factors of the weight and maximum pressure distribution, especially between younger and elder subjects. The collected standard reference values allow comparisons with other studies and can serve as a guideline in clinical practice and scientific studies.
Standard values of the upper body posture in healthy adults with special regard to age, sex and BMI
(2023)
Ohlendorf, Daniela Maren ; Avaniadi, Ioanna ; Adjami, Frederic ; Christian, Wolfgang ; Doerry, Charlotte ; Fay, Viola Nathalie ; Fisch, Vanessa ; Gerez, Ali ; Goecke, Julian ; Kaya, Ugur ; Keller, Julia ; Krüger, Kai-Dominik ; Pflaum, Julia ; Porsch, Laurin ; Loewe, Christina ; Scharnweber, Benjamin ; Sosnov, Polyna ; Wanke, Eileen M. ; Oremek, Gerhard ; Ackermann, H. ; Holzgreve, Fabian Christian ; Keil, Fee ; Groneberg, Jan David Alexander ; Maurer-Grubinger, Christian
In order to classify and analyze the parameters of upper body posture in clinical or physiotherapeutic settings, a baseline in the form of standard values with special regard to age, sex and BMI is required. Thus, subjectively healthy men and women aged 21–60 years were measured in this project. The postural parameters of 800 symptom-free male (n = 397) and female (n = 407) volunteers aged 21–60 years (Ø♀: 39.7 ± 11.6, Ø ♂: 40.7 ± 11.5 y) were studied. The mean height of the men was 1.8 ± 0.07 m, with a mean body weight of 84.8 ± 13.1 kg and an average BMI of 26.0 ± 3.534 kg/m2. In contrast, the mean height of the women was 1.67 ± 0.06 m, with a mean body weight of 66.5 ± 12.7 kg and an average BMI of 23.9 ± 4.6 kg/m2. By means of video rasterstereography, a 3-dimensional scan of the upper back surface was measured when in a habitual standing position. The means or medians, confidence intervals, tolerance ranges, the minimum, 2.5, 25, 50, 75, 97.5 percentiles and the maximum, plus the kurtosis and skewness of the distribution, were calculated for all parameters. Additionally, ANOVA and a factor analyses (sex, BMI, age) were conducted. In both sexes across all age groups, balanced, symmetrical upper body statics were evident. Most strikingly, the females showed greater thoracic kyphosis and lumbar lordosis angles (kyphosis: Ø ♀ 56°, Ø♂ 51°; lordosis: Ø ♀ 49°, Ø♂ 32°) and lumbar bending angles (Ø ♀ 14°, Ø♂ 11°) than the males. The distance between the scapulae was more pronounced in men. These parameters also show an increase with age and BMI, respectively. Pelvic parameters were independent of age and sex. The upper body postures of women and men between the ages of 21 and 60 years were found to be almost symmetrical and axis-conforming with a positive correlation for BMI or age. Consequently, the present body posture parameters allow for comparisons with other studies, as well as for the evaluation of clinical (interim) diagnostics and applications.
Remy, Janina ; Linder, Benedikt ; Weirauch, Ulrike ; Day, Bryan W. ; Stringer, Brett W. ; Herold-Mende, Christel ; Aigner, Achim ; Krohn, Knut ; Kögel, Donat
Glioblastoma (GBM) is a devastating disease and the most common primary brain malignancy of adults with a median survival barely exceeding one year. Recent findings suggest that the antipsychotic drug pimozide triggers an autophagy-dependent, lysosomal type of cell death in GBM cells with possible implications for GBM therapy. One oncoprotein that is often overactivated in these tumors and associated with a particularly dismal prognosis is Signal Transducer and Activator of Transcription 3 (STAT3). Here, we used isogenic human and murine GBM knockout cell lines, advanced fluorescence microscopy, transcriptomic analysis and FACS-based assessment of cell viability to show that STAT3 has an underappreciated, context-dependent role in drug-induced cell death. Specifically, we demonstrate that depletion of STAT3 significantly enhances cell survival after treatment with Pimozide, suggesting that STAT3 confers a particular vulnerability to GBM. Furthermore, we show that active STAT3 has no major influence on the early steps of the autophagy pathway, but exacerbates drug-induced lysosomal membrane permeabilization (LMP) and release of cathepsins into the cytosol. Collectively, our findings support the concept of exploiting the pro-death functions of autophagy and LMP for GBM therapy and to further determine whether STAT3 can be employed as a treatment predictor for highly apoptosis-resistant, but autophagy-proficient cancers.
Kashefiolasl, Sepide ; Wagner, Marlies ; Brawanski, Nina ; Seifert, Volker ; Wanderer, Stefan ; Andereggen, Lukas ; Konczalla, Jürgen
The efficacy of statin-treatment in aneurysmal subarachnoid hemorrhage (SAH) remains controversial. We aimed to investigate the effects of statin-treatment in non-aneurysmal (na)SAH in accordance with animal research data illustrating the pathophysiology of naSAH. We systematically searched PubMed using PRISMA-guidelines and selected experimental studies assessing the statin-effect on SAH. Detecting the accordance of the applied experimental models with the pathophysiology of naSAH, we analyzed our institutional database of naSAH patients between 1999 and 2018, regarding the effect of statin treatment in these patients and creating a translational concept. Patient characteristics such as statin-treatment (simvastatin 40 mg/d), the occurrence of cerebral vasospasm (CVS), delayed infarction (DI), delayed cerebral ischemia (DCI), and clinical outcome were recorded. In our systematic review of experimental studies, we found 13 studies among 18 titles using blood-injection-animal-models to assess the statin-effect in accordance with the pathophysiology of naSAH. All selected studies differ on study-setting concerning drug-administration, evaluation methods, and neurological tests. Patients from the Back to Bedside project, including 293 naSAH-patients and 51 patients with simvastatin-treatment, were recruited for this analysis. Patients under treatment were affected by a significantly lower risk of CVS (p < 0.01; OR 3.7), DI (p < 0.05; OR 2.6), and DCI (p < 0.05; OR 3). Furthermore, there was a significant association between simvastatin-treatment and favorable-outcome (p < 0.05; OR 3). However, dividing patients with statin-treatment in pre-SAH (n = 31) and post-SAH (n = 20) treatment groups, we only detected a tenuously significant higher chance for a favorable outcome (p < 0.05; OR 0.05) in the small group of 20 patients with statin post-SAH treatment. Using a multivariate-analysis, we detected female gender (55%; p < 0.001; OR 4.9), Hunt&Hess ≤III at admission (p < 0.002; OR 4), no anticoagulant-therapy (p < 0.0001; OR 0.16), and statin-treatment (p < 0.0001; OR 24.2) as the main factors improving the clinical outcome. In conclusion, we detected a significantly lower risk for CVS, DCI, and DI in naSAH patients under statin treatment. Additionally, a significant association between statin treatment and favorable outcome 6 months after naSAH onset could be confirmed. Nevertheless, unified animal experiments should be considered to create the basis for developing new therapeutic schemes.
Verboket, René ; Mühlenfeld, Nils ; Sterz, Jasmina ; Störmann, Philipp ; Marzi, Ingo ; Balcik, Yunus ; Rosenow, Felix ; Strzelczyk, Adam ; Willems, Laurent Maximilian
Hintergrund: Die Analyse krankheitsspezifischer Kosten gewinnt in einem zunehmend ökonomisch ausgerichteten Gesundheitssystem an Relevanz, wobei vor allem chronische Erkrankungen aufgrund der langen Krankheitsdauer sowie häufiger Hospitalisierung und Arztbesuche von besonderem Interesse sind. Epilepsien stellen eine häufige neurologische Erkrankung dar, welche mit paroxysmal auftretenden epileptischen Anfällen und häufig hiermit assoziierten Verletzungen einhergeht und alle Altersgruppen betrifft.
Ziel: Ziel der Arbeit ist die Aufarbeitung der stationären Behandlungskosten anfallsbedingter Verletzungen sowie die Analyse hinsichtlich relevanter kostenverursachender Faktoren. Mittels alternativer Kalkulation der Versorgungskosten soll zusätzlich der Frage nach potenziellen Vergütungsproblemen im aktuellen DRG-System („diagnosis related groups“) nachgegangen werden.
Methoden: Grundlage dieser monozentrischen, retrospektiven Analyse ist der tatsächliche Erlös der stationären Behandlung von 62 Patienten, die zwischen 01/2010 und 01/2018 im Universitätsklinikum Frankfurt aufgrund von Verletzungen im Rahmen epileptischer Anfälle erfolgte. Die Analyse potenzieller kostenverursachender Faktoren bezog sich auf relevante soziodemographische und klinische Aspekte, die alternative Kalkulation der Versorgungskosten wurde mit gängigen gesundheitsökonomischen Methoden durchgeführt.
Ergebnisse: Der mittlere DRG-Erlös betrug 7408 € (±8993 €, Median 5086 €, Spanne 563–44.519 €), die mittleren kalkulierten Kosten 9423 € (±11.113 €, 5626 €, Spanne 587–49.830 €). Als signifikant kostenverursachender Faktor konnte eine Liegedauer ≥7 Tage (p = 0,014) identifiziert werden. Aufgrund des signifikanten Unterschieds (p < 0,001) zwischen Erlös und kalkulierten Kosten erfolgte eine Analyse nach Faktoren für potenzielle Vergütungsprobleme, welche für eine Aufenthaltsdauer von ≥7 Tagen (p = 0,014) sowie für eine Behandlung auf Intensivstation (p = 0,019) signifikant verblieb.
Schlussfolgerung: Die stationären Versorgungskosten von Patienten mit Frakturen aufgrund epileptischer Anfälle sind hoch und daher gesundheitsökonomisch relevant. Generell scheint die auf Fallpauschalen basierende Vergütung nach G‑DRG die tatsächlichen Kosten zu decken, bei Patienten mit einer langen Liegedauer oder einen Aufenthalt auf Intensivstation können jedoch Vergütungsprobleme bestehen.