Die Azidose-induzierte Schwellung und intrazelluläre Azidose von Gliazellen - Bedeutung von Anionen und Kalzium

Die vorliegenden Untersuchungen stellen eine Fortsetzung langjähriger Versuche am Institut für Chirurgische Forschung dar, zellbiologische Mechanismen des zytotoxischen Hirnödems zu klären. Bislang konnten in einem in vitro Modell von Gliazellen verschiedene Mediatoren einer Gliazellschwellung im Sinne eines zytotoxischen Hirnödems charakterisiert werden. Darunter unter anderen eine Laktazidose – in Schweregraden wie sie bei Schädel-Hirn-Traumen und zerebralen Ischämien vorkommt. Ursächlich konnten sowohl der Na+/H+-Antiporter wie auch ein Chlorid- und Bikarbonat-abhängiges Transportsystem identifiziert werden die zur Akkumulation osmotisch aktiver Solute (Na+ und Cl-) in der Zelle führen und somit eine Zellschwellung bedingen. In der vorliegenden Arbeit sollten der Azidose-induzierten Schwellung zugrundeliegende Mechanismen, d.h. Membrantransporter und –kanäle weitergehend charakterisiert werden. Dabei wurde ein Schwerpunkt auf Anionentranporter und die Rolle von Kalziumionen gelegt. Die Untersuchungen erfolgten am Modell suspendierter C6 Gliomzellen als Modellzelle für Astrozyten. Durchflusszytometrisch wurde das Zellvolumen bestimmt ebenso der intrazelluläre pH unter Zuhilfenahme des pH-abhängigen Fluoreszenzfarbstoffes BCECF. Die Ergebnisse lassen sich folgendermaßen zusammenfassen: Setzt man C6 Gliomzellen einer Laktazidose von pH 6,2 aus, so kommt es zur prompten Zellschwellung die nach 60 min ihr Maximum bei 125,1 % des Ausgangsvolumens erreicht. Gleichzeitig kommt es zum Absinken des intrazellulären pH (pHi). Analoge Versuche in Chlorid- bzw. Bikarbonat-freiem Medium gingen mit einer deutlichen Hemmung der Azidose-induzierten Schwellung einher. Das Absinken von pHi war ebenfalls geringer ausgeprägt. Ähnliche Ergebnisse ließen sich mit den Inhibitoren des Cl-/HCO3--Antiporters DIDS und Niflumat erzielen. Die Zusammenschau dieser Ergebnisse lässt sie Schlussfolgerung zu, dass im Rahmen der Azidose-induzierten Schwellung der Na+-unabhängige Cl-/HCO3--Antiporter aktiv ist und zur Akkumulation von Chlorid in der Zelle führt und somit zur Zellschwellung beiträgt. Unter physiologischen Bedingungen hingegen ist der Na+-abhängige Cl-/HCO3--Antiporter aktiv und trägt zur Regulierung des ´steady state` pHi bei. In weiteren Versuchen konnte erstmals unter Verwendung der Na+-K+-Cl--Kotransportinhibitoren Bumetanid und Furosemid eine Beteiligung dieses Kotransporters an der Azidose-induzierten Schwellung nachgewiesen werden. Beide Inhibitoren führten zur deutlichen Reduktion der Zellschwellung ohne relevante Einflüsse auf den intrazellulären pH. Die Aktivierung des Transporters in Azidose führt zur Akkumulation der transportierten Ionen Natrium, Kalium und Chlorid in der Zelle, die dort als osmotisch wirksame Teilchen einen Wassereinstrom nach sich ziehen und auf diesem Wege zur Zellschwellung führen. Daneben wurde eine Abhängigkeit der Azidose-induzierten Schwellung von extrazellulären Kalziumionen gefunden. In Kalzium-freiem Medium ist ausschließlich die Zellschwellung deutlich reduziert während der Verlauf des intrazellulärem pH dem der Kontrollgruppe entsprach. Daraus lässt sich schlussfolgern, dass extrazelluläre Kalziumionen für die Aktivierung eines pH-unbeeinflussenden Transporters wie z.B. den Na+-K+-Cl--Kotransport notwendig sind. Die Chelierung intrazellulärer Kalziumionen hatte keinen Effekt auf die Azidose-induzierte Schwellung und den intrazellulären pH. Damit konnten die vorliegenden Untersuchungen die Bedeutung des Cl-/HCO3--Antiporters im Rahmen der Azidose-induzierten Schwellung näher charakterisieren und die Beteiligung des Na+-K+-Cl--Kotransportes erstmals nachweisen. Ebenfalls konnte die Bedeutung extra- nicht jedoch intrazellulärer Kalziumionen für die Azidose-induzierte Schwellung gezeigt werden

Wohnen in Sachsen-Anhalt im demographischen Wandel: wie können Kommunen und Unternehmen auf Ansprüche einer älter werdenden Bewohnerschaft reagieren? ; Handlungsempfehlungen und Befunde aus der Forschung zum demographischen Wandel in Sachsen-Anhalt

Durch den fortschreitenden demographischen Wandel in Sachsen-Anhalt verändern sich zunehmend Wohnquartiere. Aus zwei an der MLU Halle-Wittenberg durchgeführten Forschungsprojekten des Instituts für Geographie wurde deutlich, dass sich einerseits Unternehmen auf altersspezifische Wünsche und Bedürfnisse einstellen müssen, andererseits werden Kommunen gezwungen sein, sich in Zukunft verstärkt mit einer älteren Klientel zu beschäftigen. Als Schnittpunkt werden beispielsweise generationengerechte Infrastruktur- und Dienstleistungsangebote gesehen. Bei einer alternsgerechten Ausrichtung von Kommunen können diese wirtschaftlich profitieren und so den eigentlichen Ortskern im suburbanen Raum wieder stärken. Der klassische suburbane Raum ist momentan kein attraktiver Wohnstandort für Senioren, kann aber z.B. durch Eigeninitiative von Wohneigentümern (Umbaumaßnahmen) und durch politische Entscheidungen (interkommunale Zusammenarbeit) aufgewertet werden. Dazu ist es aber auch notwendig, dass sowohl Unternehmen als auch Politik ältere Bürger stärker als bisher als eine wichtige Zielgruppe identifizieren und entsprechend handeln. (Autorenreferat)The advancing demographic change within Saxony-Anhalt leads to a shift in accommodation realities. Two research projects conducted by the Institute of Geography of the MartinLuther-University Halle-Wittenberg point out that companies need to adjust more to age-specific needs and that municipalities will be under further constraint to deal with an elderly clientele in the near future. A solution can be found by offering infrastructure and services being equally suitable for all generations. By aligning itself better to an aging population, the municipality could profit economically and therefore strengthen the town center of the suburban area, which at the moment is not desirable for elderly people to live in. Improvement may be realized through proactivity by proprietors (remodeling and rebuilding) as well as political decisions (intercommunal cooperation). It is therefore necessary that companies as well as politicians see elderly people as an increasingly important target group and act more appropriately than before. (author's abstract

Kontinuität und Wandel der Zielgebietspräferenzen und Motive älterer Binnenwanderer

Der Vergleich aktueller mit früheren Binnenwanderungsmustern älterer Menschen soll klären, inwieweit deren Zielgebiete und Migrationsmotive angesichts des Strukturwandels des Alters und zunehmender Übergänge von Babyboomern in den Ruhestand eher von Trendfortsetzungen oder -veränderungen geprägt sind. In der Zeitreihenbetrachtung haben sowohl die Standortverbundenheit der Zielgruppe als auch die Distanzempfindlichkeit überregionaler Ruhesitzwanderungen nach wie vor Bestand. Modifizierungen zeigen sich hingegen im Rahmen von interregionalen Verflechtungsanalysen: In Westdeutschland haben sich die ehemaligen Zielgebiete der älteren Fortzügler aus den Metropolen und Großstädten von den angrenzenden Umlandregionen zunehmend in periurbane und ländliche Räume verlagert. Demgegenüber verzeichnen ostdeutsche Städte Wanderungsgewinne, z. T. auch aus Rückwanderungen an den vertrauten Herkunftsort. Mit den wohnbedingten und netzwerkorientierten Motiven behalten die klassischen Umzugsdeterminanten ihren hohen Stellenwert. Im Vergleich zu früheren Untersuchungen weisen sie aktuell jedoch ein deutlich vielfältigeres Begründungsspektrum auf

Decreased Secondary Lesion Growth and Attenuated Immune Response after Traumatic Brain Injury in Tlr2/4(-/-) Mice

Danger-associated molecular patterns are released by damaged cells and trigger neuroinflammation through activation of non-specific pattern recognition receptors, e. g., toll-like receptors (TLRs). Since the role of TLR2 and 4 after traumatic brain injury (TBI) is still unclear, we examined the outcome and the expression of pro-inflammatory mediators after experimental TBI in Tlr2/4(-/-) and wild-type (WT) mice. Tlr2/4(-/-) and WT mice were subjected to controlled cortical injury and contusion volume and brain edema formation were assessed 24 h thereafter. Expression of inflammatory markers in brain tissue was measured by quantitative PCR 15 min, 3 h, 6 h, 12 h, and 24 h after controlled cortical impact (CCI). Contusion volume was significantly attenuated in Tlr2/4(-/-) mice (29.7 +/- 0.7 mm3 as compared to 33.5 +/- 0.8 mm(3) in WT;p < 0.05) after CCI while brain edema was not affected. Only interleukin (IL)-1 beta gene expression was increased after CCI in the Tlr2/4(-/-) relative to WT mice. Inducible nitric oxide synthetase, TNF, IL-6, and COX-2 were similar in injured WT and Tlr2/4(-/-) mice, while the increase in high-mobility group box 1 was attenuated at 6 h. TLR2 and 4 are consequently shown to potentially promote secondary brain injury after experimental CCI via neuroinflammation and may therefore represent a novel therapeutic target for the treatment of TBI

Increasing incidence of spondylodiscitis in England: an analysis of the national health service (NHS) hospital episode statistics from 2012 to 2021

Background Spondylodiscitis is a potentially life-threatening infection of the intervertebral disk and adjacent vertebral bodies, with a mortality rate of 2–20%. Given the aging population, the increase in immunosuppression, and intravenous drug use in England, the incidence of spondylodiscitis is postulated to be increasing; however, the exact epidemiological trend in England remains unknown. Objective The Hospital Episode Statistics (HES) database contains details of all secondary care admissions across NHS hospitals in England. This study aimed to use HES data to characterise the annual activity and longitudinal change of spondylodiscitis in England. Methods The HES database was interrogated for all cases of spondylodiscitis between 2012 and 2019. Data for the length of stay, waiting time, age-stratified admissions, and ‘Finished Consultant Episodes’ (FCEs), which correspond to a patient's hospital care under a lead clinician, were analysed. Results In total, 43135 FCEs for spondylodiscitis were identified between 2012 and 2022, of which 97.1% were adults. Overall admissions for spondylodiscitis have risen from 3 per 100,000 population in 2012/13 to 4.4 per 100,000 population in 2020/21. Similarly, FCEs have increased from 5.8 to 10.3 per 100,000 population, in 2012–2013 and 2020/21 respectively. The highest increase in admissions from 2012 to 2021 was recorded for those aged 70–74 (117% increase) and aged 75-59 (133% increase), among those of working age for those aged 60–64 years (91% increase). Conclusion Population-adjusted admissions for spondylodiscitis in England have risen by 44% between 2012 and 2021. Healthcare policymakers and providers must acknowledge the increasing burden of spondylodiscitis and make spondylodiscitis a research priority

Conservative or surgical treatment of pyogenic spinal infection: a retrospective multicenter binational retrospective cohort study [Abstract]

Spinal Tumors / Infections (Spine Parallel Session v.3), September 27, 2023, 8:30 AM - 10:00 AM Background: The optimal treatment of patients with spinal infections remains a controversial topic. While there is some consensus regarding the indication for surgical intervention in infections with neurologic deficit, significant deformity or progressive disease, other situations remain controversial. Within Europe, fundamentally different therapeutic concepts are found. Therefore, the aim of this study was to compare the outcome of patients who received surgical vs. antibiotic treatment alone for primary pyogenic spondylodiscitis in an international cohort analysis. Methods: The retrospectively compiled databases of tertiary high-volume spine centers served as the baseline for this study. All documented cases of primary spondylodiscitis treated surgically and conservatively in the period of 2017-2022 were included and grouped according to the therapeutic concept: conservative vs. surgical treatment. Independent investigators collected the relevant clinical and radiological data. The primary endpoint of this study was mortality rate; secondary endpoints were relapse rate and persisting neurological deficit. Results: A total of 392 patients were included in the analysis (155 females and 237 males with a mean age of 68 years). Of these, 95 cases were treated conservatively (CoT) and 297 cases were treated surgically (SuT). Most of conservatively treated patients were treated in the United Kingdom (CoT 81/ SuT 7), while most of the surgically treated cases were treated in Germany (CoT 14/ SuT 290). There was no significant difference (p<0.01) related to patient’s disease characteristics: Lumbar was the main location (n=240, CoT 58/ SuT 182, p=0.97) followed by thoracic (n=70, CoT 24/ SuT 46, p=0,03) and cervical (n=47, CoT 7/ SuT 40, p=0.11) region. A multilocular spinal infection was present in 32 patients (CoT 3/ SuT 29, p=0.04). 181 cases (CoT 36/ SuT 145, p=0.06) presented with an epidural abscess. Neurological deficits were recorded in 100 cases (CoT 26/ SuT 74, p=0.63), and septic conditions in 88 cases (CoT 26/ SuT 62, p=0.19). Pre-existing conditions like Diabetes (CoT 20/, SuT 71, p=0.57), renal failure (CoT 19/ SuT 60, p= 0.97), hepatopathy (CoT 4/ SuT 26, p= 0.15), malignoma (CoT 9/ SuT 38, p=0.39) or i.v. drug abuse (CoT 5/, SuT 15, p=0.93) did also not differ between the groups. The mortality rate of all conservatively treated was 24.2% (23 cases) and 6.7% (20 cases) in all surgically treated patients (p<0.001). A follow-up of ≥ 6 weeks was available in 289 cases (CoT 83, SuT 206 ). In this subset of patients relapse of infection occurred in six (7.2%) and 23 (11.2%) cases in the conservative and early surgical treatment group, respectively (p=0.69). Persisting neurological deficit was recorded in 21 (25.3%) of conservatively treated and 51 (24.8%) of surgically treated cases (p=0.92). Conclusions: Whereas relapse rates and persisting neurological deficit were not found to differ significantly, the results of this international data analyses, with their respective limitations, clearly support the growing evidence of a significantly reduced mortality rate after surgical therapy for primary pyogenic spondylodiscitis when compared to conservative treatment regimen

Automated grading of cerebral vasospasm to standardize computed tomography angiography examinations after subarachnoid hemorrhage

Background: Computed tomography angiography (CTA) is frequently used with computed tomography perfusion imaging (CTP) to evaluate whether endovascular vasospasm treatment is indicated for subarachnoid hemorrhage patients with delayed cerebral ischemia. However, objective parameters for CTA evaluation are lacking. In this study, we used an automated, investigator-independent, digital method to detect vasospasm, and we evaluated whether the method could predict the need for subsequent endovascular vasospasm treatment.Methods: We retrospectively reviewed the charts and analyzed imaging data for 40 consecutive patients with subarachnoid hemorrhages. The cerebrovascular trees were digitally reconstructed from CTA data, and vessel volume and the length of the arteries of the circle of Willis and their peripheral branches were determined. Receiver operating characteristic curve analysis based on a comparison with digital subtraction angiographies was used to determine volumetric thresholds that indicated severe vasospasm for each vessel segment. Results: The automated threshold-based volumetric evaluation of CTA data was able to detect severe vasospasm with high sensitivity and negative predictive value for predicting cerebral hypoperfusion on CTP, although the specificity and positive predictive value were low. Combining the automated detection of vasospasm on CTA and cerebral hypoperfusion on CTP was superior to CTP or CTA alone in predicting endovascular vasospasm treatment within 24 h after the examination. Conclusions: This digital volumetric analysis of the cerebrovascular tree allowed the objective, investigator-independent detection and quantification of vasospasms. This method could be used to standardize diagnostics and the selection of subarachnoid hemorrhage patients with delayed cerebral ischemia for endovascular diagnostics and possible interventions

Conservative versus early surgical treatment in the management of pyogenic spondylodiscitis: a systematic review and meta-analysis [Abstract]

Oral e-Poster Presentations - Booth 2: Spine 1 (Trauma&Misc), September 25, 2023, 10:00 AM - 10:40 AM Background: Spondylodiscitis is a prevalent type of spinal infection, with pyogenic spondylodiscitis being the most common subtype. While antibiotic therapy is the standard treatment, some argue that early surgery can aid in infection clearance, improve survival rates, and prevent long-term complications such as deformities. However, others view early surgery as excessively risky. Due to the high mortality rate of up to 20%, it is crucial to determine the most effective treatment. Methods: The primary objective of this study was to compare the mortality rate, relapse rate, and length of hospital stay for conservative and early surgical treatments of pyogenic spondylodiscitis, including determinants of outcomes. The study was registered on PROSPERO with the registration number CRD42022312573. The databases MEDLINE, Embase, Scopus, PubMed, and JSTOR were searched for original studies comparing conservative and early surgical treatments of pyogenic spondylodiscitis. The included studies were assessed using the ROBINS-1 tool, and eligible studies were evaluated using meta-analyses, influence, and regression analyses. Results: The systematic review included 31 studies. The meta-analysis, which had a pooled sample size of 10,954 patients from 21 studies, found that the pooled mortality rate among patients treated with early surgery was 8%, while the rate was 13% for patients treated conservatively. The mean proportion of relapse/failure was 15% for patients treated with early surgery and 21% for those treated conservatively. Furthermore, the analysis concluded that early surgical treatment is associated with a 40% and 39% risk reduction in relapse/failure and mortality rates, respectively, when compared to conservative management. Additionally, early surgical treatment resulted in a 7.75-day reduction in length of hospital stay per patient (p<0.01). The most highly significant predictors of treatment outcome were found to be intravenous drug use, diabetes, the presence of an epidural abscess, positive cultures, location of infection, and age (p<0.001). Conclusions: Overall, early surgical management was found to be consistently significantly more effective than conservative management in terms of relapse/failure and mortality rates when treating pyogenic spondylodiscitis, particularly for non-spinal epidural abscess spondylodiscitis