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Prenatal and postnatal experiences associated with epigenetic changes in the adult mouse brain
(2018)
To analyze the influences of early-life history on the brain epigenome, the offspring of mouse dams kept in an enriched or standard environment were exposed postnatally to enriched, standard, or adverse conditions. The methylation patterns of 7 candidate genes (9 loci) involved in developmental programming of stress vulnerability/resilience and psychiatric disease were analyzed in 6 brain regions of adult male and female mice. Exposure to an enriched prenatal environment was associated with widespread epigenetic changes (all of small effect size), affecting 29 of 324 (9%) gene/region-specific methylation patterns. The effects of either adverse or enriched postnatal conditions were tested separately in the two prenatal cohorts. Significant changes were observed in 2 of 324 (0.6%) loci in offspring of dams in a standard environment and 6 of 324 (1.9%) loci in animals that were exposed prenatally to an enriched environment. Prenatal life experiences appear to have a bigger effect on the adult brain epigenome than postnatal experiences. Positive prenatal life experiences may increase epigenetic plasticity of the brain later in life. All observed between-group differences were sex-specific, consistent with largely different developmental trajectories of the male and female brain. Multiple changes of small effect size are consistent with a multifactorial model of developmental programming of adult behavior and disease susceptibility.
Beside its involvement in somatic dysfunctions, altered insulin signalling constitutes a risk factor for the development of mental disorders like Alzheimer’s disease and obsessive-compulsive disorder. While insulin-related somatic and mental disorders are often comorbid, the fundamental mechanisms underlying this association are still elusive. Studies conducted in rodent models appear well suited to help decipher these mechanisms. Specifically, these models are apt to prospective studies in which causative mechanisms can be manipulated via multiple tools (e.g., genetically engineered models and environmental interventions), and experimentally dissociated to control for potential confounding factors. Here, we provide a narrative synthesis of preclinical studies investigating the association between hyperglycaemia – as a proxy of insulin-related metabolic dysfunctions – and impairments in working and spatial memory, and attention. Ultimately, this review will advance our knowledge on the role of glucose metabolism in the comorbidity between somatic and mental illnesses.
Behavioural inflexibility is a symptom of neuropsychiatric and neurodegenerative disorders such as Obsessive-Compulsive Disorder, Autism Spectrum Disorder and Alzheimer’s Disease, encompassing the maintenance of a behaviour even when no longer appropriate. Recent evidence suggests that insulin signalling has roles apart from its regulation of peripheral metabolism and mediates behaviourally-relevant central nervous system (CNS) functions including behavioural flexibility. Indeed, insulin resistance is reported to generate anxious, perseverative phenotypes in animal models, with the Type 2 diabetes medication metformin proving to be beneficial for disorders including Alzheimer’s Disease. Structural and functional neuroimaging studies of Type 2 diabetes patients have highlighted aberrant connectivity in regions governing salience detection, attention, inhibition and memory. As currently available therapeutic strategies feature high rates of resistance, there is an urgent need to better understand the complex aetiology of behaviour and develop improved therapeutics. In this review, we explore the circuitry underlying behavioural flexibility, changes in Type 2 diabetes, the role of insulin in CNS outcomes and mechanisms of insulin involvement across disorders of behavioural inflexibility.
Highlights
• Overview on functional work performed in rodent, zebrafish and fruit fly models of ADHD and its comorbidities.
• Comprehensive search for new genetically modified mouse models to study ADHD-related and comorbid traits.
• Review of behavioral assays available in animal models to test ADHD-related and comorbid traits.
• Animal models to assess environmental effects contributing to the epigenetic mechanisms of ADHD and comorbidities.
Abstract
Attention-deficit/hyperactivity disorder (ADHD) is a highly prevalent neurodevelopmental disorder resulting from the interaction between genetic and environmental risk factors. It is well known that ADHD co-occurs frequently with other psychiatric disorders due, in part, to shared genetics factors. Although many studies have contributed to delineate the genetic landscape of psychiatric disorders, their specific molecular underpinnings are still not fully understood. The use of animal models can help us to understand the role of specific genes and environmental stimuli-induced epigenetic modifications in the pathogenesis of ADHD and its comorbidities. The aim of this review is to provide an overview on the functional work performed in rodents, zebrafish and fruit fly and highlight the generated insights into the biology of ADHD, with a special focus on genetics and epigenetics. We also describe the behavioral tests that are available to study ADHD-relevant phenotypes and comorbid traits in these models. Furthermore, we have searched for new models to study ADHD and its comorbidities, which can be useful to test potential pharmacological treatments.
A recent in-vivo experiment has shown that force can be transmitted between the gastrocnemius and the hamstring muscles due to a direct tissue continuity. However, it remains unclear if this mechanical interaction is affected by the stiffness of the structural connection. This study therefore aimed to investigate the impact of the knee angle on myofascial force transmission across the dorsal knee. A randomized, cross-over study was performed, including n = 56 healthy participants (25.36 ± 3.9 years, 25 females). On two separate days, they adopted a prone position on an isokinetic dynamometer (knee extended or 60° flexed). In each condition, the device moved the ankle three times from maximal plantarflexion to maximal dorsal extension. Muscle inactivity was ensured using EMG. High-resolution ultrasound videos of the semimembranosus (SM) and the gastrocnemius medialis (GM) soft tissue were recorded. Maximal horizontal tissue displacement, obtained using cross-correlation, was examined as a surrogate of force transmission. SM tissue displacement was higher at extended (4.83 ± 2.04 mm) than at flexed knees (3.81 ± 2.36 mm). Linear regression demonstrated significant associations between (1) SM and GM soft tissue displacement (extended: R2 = 0.18, p = 0.001; flexed: R2 = 0.17, p = 0.002) as well as (2) SM soft tissue displacement and ankle range of motion (extended: R2 = 0.103, p = 0.017; flexed: R2 = 0.095, p = 0.022). Our results further strengthen the evidence that local stretching induces a force transmission to neighboring muscles. Resulting remote exercise effects such as increased range of motion, seem to depend on the stiffness of the continuity.
Trial registration: DRKS (Deutsches Register Klinischer Studien), registration number DRKS00024420, first registered 08/02/2021, https://drks.de/search/de/trial/DRKS00024420.
This study investigated the effects of a daily plyometric hopping intervention on running economy (RE) in amateur runners. In a randomized, controlled trial, thirty-four amateur runners (29 ± 7 years, 27 males) were allocated to a control or a hopping exercise group. During the six-week study, the exercise group performed 5 min of double-legged hopping exercise daily. To progressively increase loading, the number of hopping bouts (10 s each) was steadily increased while break duration between sets was decreased. Pre- and post-intervention, RE, peak oxygen uptake (VO2peak), and respiratory exchange ratio (RER) were measured during 4-min stages at three running speeds (10, 12, and 14 km/h). ANCOVAs with baseline values and potential cofounders as cofactors were performed to identify differences between groups. ANCOVA revealed an effect of hopping on RE at 12 km/h (df = 1; F = 4.35; p < 0.05; η2 = 0.072) and 14 km/h (df = 1; F = 6.72; p < 0.05; η2 = 0.098), but not at 10 km/h (p > 0.05). Exercise did not affect VO2peak (p > 0.05), but increased RER at 12 km/h (df = 1; F = 4.26; p < 0.05; η2 = 0.059) and 14 km/h (df = 1; F = 36.73; p < 0.001; η2 = 0.520). No difference in RER was observed at 10 km/h (p > 0.05). Daily hopping exercise is effective in improving RE at high running speeds in amateurs and thus can be considered a feasible complementary training program.
Clinical trial registration German Register of Clinical Trials (DRKS00017373).
Background: Knee osteoarthritis is associated with higher kinetic friction in the knee joint, hence increased acoustic emissions during motion. Decreases in compressive load and improvements in movement quality might reduce this friction and, thus, sound amplitude. We investigated if an exercise treatment acutely affects knee joint sounds during different activities of daily life.
Methods: Eighteen participants with knee osteoarthritis (aged 51.8 ± 7.3 years; 14 females) were included in this randomized crossover trial. A neuromuscular exercise intervention and a placebo laser needle acupuncture treatment were performed. Before and after both interventions, knee joint sounds were measured during three different activities of daily living (standing up/sitting down, walking, descending stairs) by means of vibroarthrography. The mean amplitude (dB) and the median power frequency (MPF, Hz) were assessed at the medial tibial plateau and the patella. Differences in knee acoustic emissions between placebo and exercise interventions were calculated by analyses of covariance.
Results: Controlled for participant's age, knee demanding activity level and osteoarthritis stage, the conditions significantly differed in their impact on the MPF (mean(± SD) pre-post-differences standing up: placebo: 9.55(± 29.15) Hz/ exercise: 13.01(± 56.06) Hz, F = 4.9, p < 0.05) and the amplitude (standing up: placebo:0.75(± 1.43) dB/ exercise: 0.51(± 4.68) dB, F = 5.0, p < 0.05; sitting down: placebo: 0.07(± 1.21) dB/ exercise: -0.16(± .36) dB, F = 4.7, p < 0.05) at the tibia. There were no differences in the MPF and amplitude during walking and descending stairs (p > 0.05). At the patella, we found significant differences in the MPF during walking (placebo 0.08(± 1.42) Hz/ exercise: 15.76(± 64.25) Hz, F = 4.8, p < .05) and in the amplitude during descending stairs (placebo: 0.02 (± 2.72) dB/ exercise: -0.73(± 2.84) dB, F = 4.9, p < 0.05). There were no differences in standing up/ sitting down for both parameters, nor in descending stairs for the MPF and walking for the amplitude (p > 0.05).
Conclusion: The MPF pre-post differences of the exercise intervention were higher compared to the MPF pre-post differences of the placebo treatment. The amplitude pre-post differences were lower in the exercise intervention. In particular, the sound amplitude might be an indicator for therapy effects in persons with knee osteoarthritis.
Trial registration: The study was retrospectively registered in the German Clinical Trials Register (DRKS00022936, date of registry: 26/08/2020).
• Mexican and German populations of L. sericata differ in their development times.
• Mexican L. sericata had a shorter development time at 20°C than German flies.
• At 30 °C, German L. sericata pupariated and eclosed earlier than the Mexican flies.
• Differences in study design make the comparison of developmental studies difficult.
Abstract
The cosmopolitan blow fly Lucilia sericata is often used in forensic case work for estimating the minimum postmortem interval (PMImin). For this, the age of immature specimens developing on the dead body is calculated by measuring the time taken to reach the sampled developmental stage at a given temperature. To test whether regional developmental data of L. sericata is valid on a global scale, the time taken to reach different developmental stages was compared between a population from Mexico and one from Germany at two different constant temperatures.
The German population of L. sericata was collected in Frankfurt/Main, while the Mexican population originated near Oaxaca de Juarez and was transported to Germany in the larval stage. Only the F1 generation was used to avoid adaption of the Mexican flies. Eggs were immediately placed at 20 °C and 30 °C. Five times 30 freshly eclosed larvae per replicate (n = 5) were then transferred to a cup of minced meat in separate containers. The larvae were checked every 8 h for migration, pupariation or emergence of adult flies. The time at which the first individual and 50 % of the specimens per container entered each of these stages, was recorded.
Significant differences in the time of development between the two populations were observed at both temperatures. At 20 °C, the first specimens of the Mexican population reached all developmental stages a little (< 1 day to < 2 days) earlier than the German L. sericata. At 30 °C, the Mexican flies also reached the post-feeding stage slightly earlier (0.2 days). However, at 30 °C, the German flies started pupariation significantly earlier (after 5 days) than the Mexican flies (6.9 days) and the adults from Germany also emerged earlier (10.5 days compared to 13.1 days). The same pattern was observed when looking at 50 % of the total number of specimens per container. A comparison with previously published developmental studies was difficult as the experimental design varied widely between studies. However, the results were within the range of most studies. Our study has shown that age estimation can vary widely depending on the population on which the reference data used for the calculations are based. This highlights the importance of using local and population-specific developmental data for estimating the age of blow flies in case work.
• Mexican and German populations of L. sericata differ in their development times.
• Mexican L. sericata had a shorter development time at 20°C than German flies.
• At 30 °C, German L. sericata pupariated and eclosed earlier than the Mexican flies.
• Differences in study design make the comparison of developmental studies difficult.
Abstract
The cosmopolitan blow fly Lucilia sericata is often used in forensic case work for estimating the minimum postmortem interval (PMImin). For this, the age of immature specimens developing on the dead body is calculated by measuring the time taken to reach the sampled developmental stage at a given temperature. To test whether regional developmental data of L. sericata is valid on a global scale, the time taken to reach different developmental stages was compared between a population from Mexico and one from Germany at two different constant temperatures.
The German population of L. sericata was collected in Frankfurt/Main, while the Mexican population originated near Oaxaca de Juarez and was transported to Germany in the larval stage. Only the F1 generation was used to avoid adaption of the Mexican flies. Eggs were immediately placed at 20 °C and 30 °C. Five times 30 freshly eclosed larvae per replicate (n = 5) were then transferred to a cup of minced meat in separate containers. The larvae were checked every 8 h for migration, pupariation or emergence of adult flies. The time at which the first individual and 50 % of the specimens per container entered each of these stages, was recorded.
Significant differences in the time of development between the two populations were observed at both temperatures. At 20 °C, the first specimens of the Mexican population reached all developmental stages a little (< 1 day to < 2 days) earlier than the German L. sericata. At 30 °C, the Mexican flies also reached the post-feeding stage slightly earlier (0.2 days). However, at 30 °C, the German flies started pupariation significantly earlier (after 5 days) than the Mexican flies (6.9 days) and the adults from Germany also emerged earlier (10.5 days compared to 13.1 days). The same pattern was observed when looking at 50 % of the total number of specimens per container. A comparison with previously published developmental studies was difficult as the experimental design varied widely between studies. However, the results were within the range of most studies. Our study has shown that age estimation can vary widely depending on the population on which the reference data used for the calculations are based. This highlights the importance of using local and population-specific developmental data for estimating the age of blow flies in case work.
Highlights
• Out of the six edible pumpkin seeds found in Cameroonian C. sativus showed most potent anti-proliferative effects on prostate cells.
• Its oil conserved almost all the effects of raw seeds and prevented benign prostatic hyperplasia (BPH).
• It exhibited potent anti-inflammatory activities in rat with BPH.
Abstract
Pumpkin seeds are claimed to treat prostate tumour/cancer. The in vitro (ability to inhibit cell growth through MTT assay) and in vivo (ability to prevent testosterone-induced BPH in rats at the doses of 125, 250, 500 and 1000 mg/kg BW) of six edible pumpkin seeds found in Cameroonian were assessed. The endpoints were cell growth arrest, prostate mass and volume, prostatic epithelium height, prostatic proteins, prostate specific antigen (PSA) and inflammatory cytokines. In vitro, C. sativus seeds exhibited the most potent antiproliferative effects on DU145 and PC3 prostate cancer cells and its oil conserved almost all the effects of raw seeds. Further, it prevented the increased of prostate relative mass and volume, prostate epithelium height, PSA and testosterone dose-dependently compared to normal rats. This effect is thought to be mediated through antiandrogenic, estrogenic and anti-inflammatory activities, evidenced by a decreased in IL-1β, IL-6 and TNFα level. Overall, this results justify its traditional use.
Bedeutung der Retikulozytenbestimmung zur Differenzierung und Behandlungskontrolle der Anämie
(1994)
Die Retikulozytenbestimmung hat eine wesentliche Bedeutung in der Differenzierung und Behandlungskontrolle von Anämien. Dies insbesondere, seitdem die mikroskopische Retikulozytenzählung durch die Bestimmung mit automatisierten Blutzellzählgeräten abgelöst und somit die Retikulozytenzahl mit geringer Impräzision bestimmt werden kann. Somit ist es möglich, die Regeneration derErythropoese gut zu verfolgen. In der Differenzierung der Anämien hat die Retikulozytenbestimmung ihre wesentliche Bedeutung zur Unterscheidung der nprmozytären Anämie formen. Ist bei normozytärer Anämie die Retikulozytenzahl normal oder vermindert, muß eine Knochenmarkpunktion in Erwägung gezogen werden. Bei mikro- und makrozytären Anämien ist die Retikulozytenbestimmung weniger bedeutsam. Für die Behandlungskontrolle der Anämien kann die Retikulozytenzahl ein wichtiger Indikator sowohl für eine beginnende Regeneration der Erythropoese als auch für die erfolgreiche Behandlung einer die Erythrozytenlebenszeit verkürzenden Erkrankung sein.
Das „Seralyzer®-System" (AMES) wird zur quantitativen Bestimmung von Bilirubinkonzentrationen in Erwachsenen- und Neugeborenenplasmen eingesetzt und mit konventionellen Methoden verglichen. Die Präzision in Serie an Humanplasma beträgt im Normalbereich 0,95-8,8896, im erhöhten Konzentrationsbereich 2,64-14,3%, an Kontrollseren 3,20-6,78%, am Neugeborenenplasma 8,60%. Für die Präzision von Tag zu Tag ergibt sich an Humanplasma im Gesamtbereich 10,5-15,3%, an Kalibratoren 4,35-6,17%, an Kontrollseren im Normalbereich 9,27-20,9%, im erhöhten Bereich 9,25-23,5%. Die Wiederfindung deklarierter Werte bei Kalibratoren und Kontrollseren ist befriedigend. Eine Linearität bis 20 mg/dl ist auch bei Neugeborenenplasma erreichbar. Die Speicherdauer der Kalibrierung beträgt mehr als 30 Tage. Die Grenzbedingungen der internen und externen Qualitätskontrolle und des „State of the art" werden einwandfrei erfüllt. Hämoglobin und Matrix-beeinflussende Substanzen interferieren. Aufgrund eines eingehenden Vergleichs von über 3000 Meßwerten mit Literaturdaten kann festgestellt werden, daß die „ Trockenchemie-Analytik" des Seralyzer-Systems für Bilirubin den klinischen Anforderungen genügt.
Zur quantitativen Plasmaproteinbestimmung sind die Immunnephelometrie und die Immunturbidimetrie häufig eingesetzte Bestimmungstechniken. Aufgrund der kürzeren Analysenzeit bei vergleichbarer oder besserer Präzision und Empfindlichkeit haben diese Techniken die radiale Immundiffusion in vielen Laboratorien ersetzt.
Die mechanisierte Plasmaproteinbestimmung erfolgt als Antigen-Antikörper-Reaktion entweder mit Proteinanalyzern oder mit klinisch-chemischen Analysensystemen, an denen normalerweise Enzyme und Substrate bestimmt werden.
Zwischen den verschiedenen Plasmaproteinen im Serum besteht ein bis zu 10.OOOfacher Konzentrationsunterschied und die biologische Varianz des einzelnen Plasmaproteins ist breit Damit die Plasmaproteine mit hoher analytischer Sensitivität über einen weiten Konzentrationsbereich, mit guter Präzision und der erforderlichen Richtigkeit mechanisiert bestimmt werden können, ist eine gute Adaption des Immunreagenzes auf das mechanisierte Analysensystem erforderlich. Diese Übersicht soll dazu Grundlagen vermitteln.
Die Entzündung ist eine Folge von Reaktionen mit der Zielsetzung, die Ausbreitung einer Gewebeschädigung, oder eines Infektionserregers einzudämmen. Zelluläre und humorale Mechanismen interagieren dabei in einem komplexen Netzwerk. In diesem Übersichtsbeitrag zeigen wir die wichtigsten Wege des inflammatorischen Reaktionsgeschehens auf und diskutieren die Bedeutung von Laboratoriumsuntersuchungen für die Diagnostik und das Monitoring von Entzündungen.
Wesentliche Schritte im Ablauf der Entzündungsreaktion sind
- die Synthese von Prostaglandinen aus Arachidonsäure, die durch Phospholipasen A2 (PLA2)-katalysierte Hydrolyse aus Membranphospholipiden gebildet wird;
- Interaktionen zwischen Gefäßendothel und Leukozyten, die Leukozytenextravasation und die Freisetzung freier Sauerstoffradikale und von Elastase im Gewebe;
- die Bildung inflammatorischer Cytokine, ihr Effekt auf Entzündungszellen und ihre systemische Wirkung auf Organe;
- die Synthese von Akute-Phase-Proteinen, deren Plasmakonzentration bei Entzündung als Antwort auf eine Vielfalt von Schädigungen ansteigt.
Zur Diagnostik und Verlaufsbeurteilung entzündlicher Krankheiten hat die Bestimmung des C-reaktiven Proteins den höchsten Stellenwert. Die Elastase hat nur eine begrenzte Bedeutung. Die Bestimmung von PLA2, der 'inflammatorischen Cytokine TNFa, IL-1, IL-6 und des s!L-2R als generelle Entzündungsmarker kann in der Routinediagnostik noch nicht empfohlen werden. Eingehende klinische Untersuchungen zur diagnostischen Bedeutung müssen noch abgewartet werden.
Aufgrund der leichten Handhabung und des Nachweises einer Mortalitätssenkung gilt der Nachweis von okkultem Blut (FOBT) im Stuhl derzeit als das am weitesten verbreitete Screeningverfahren für das kolorektale Karzinom. Als nachteilig erweisen sich allerdings eine unzureichende Sensitivität, insbesondere beim Nachweis früher Stadien und eine nach wie vor geringe Akzeptanz in der Bevölkerung. Vorläufige Daten zum Nachweis von Calprotectin oder der Tumor-M2-PK im Stuhl ließen bessere Screeningeigenschaften erwarten. Aber auch hierschränkt die geringe Sensitivität für frühe Vorstufen und unzureichende Spezifität mit zu erwartenden hohen Folgekosten die Tauglichkeit der Tests deutlich ein. Die kürzlich entwickelten immunologischen FOBTs (I-FOBT)erweisen sich als spezifischer und sensitiver. Sie beruhen auf dem Nachweis von humanem Hämoglobin mittels spezifischer Antikörper und sind somit unabhängig von diätetischen oder medikamentösen Faktoren, was zu einer deutlich besseren Akzeptanz führt. Sie gelten derzeit als kosteneffektivste Verfahren unter den nichtinvasiven Screeningmaßnahmen. Der Nachweis von Tumor-DNA im Stuhl eröffnet eine neue Ära zum frühzeitigen Nachweis kolorektaler Karzinome. Erste kleinere Studien weisen auf eine sehr gute Sensitivität dieser Verfahren hin. Sie lagen für kolorektale Karzinome zwischen 62–91% und für Adenome zwischen 26–73% bei mit 93–100% sehr guter Spezifität. Als nachteilig im Ver-gleich zu den derzeit verfügbaren Screeningtests erweisen sich allerdings die vergleichsweise hohen Kosten.
Given the simplicity of the method and how it can be applied, as well as proof that it lowers the mortality rate, fecal occult blood testing (FOBT) is currently the most commonly used screening method for colorectal cancer (CRC). However, the test suffers from poor sensitivity, particularly with respect to detecting early stages, as well as low acceptance among the population. Preliminary data on detecting calprotectin and tumour-M2-PK in the stool indicated that a better screening performance could be expected. But these tests also suffer from low sensitivity in detecting early stages and from poor specificity, thus limiting the usefulness of the tests as a result of high follow-up costs. Recently developed immunological tests (I-FOBT) demonstrate significantly increased sensitivity and specificity. I-FOBTs use antibodies specific to human hemoglobin and are therefore not affected by diet and drugs, leading to improved patient partipication. At present, I-FOBTs seem to be the most cost-effective approach for non-invasive screening. The detection of tumour-DNA in the stool opens up a new era in early diagnosis of colorectal cancer. Small trials have pointed to a very high sensitivity of these methods: 62–91% for colorectal cancer and between 26% and 73% for adenomas, with a very high level of specificity (93–100%). The major drawback of this type of testing, compared with other screening tests available today, is its high cost.
Es wurde die Seroprävalenz von Erregern mit und ohne Tropismus zu Gefäßendothelzellen, wie Chlamydia (C.) pneumoniae, C. trachomatis, C. psittaci, verschiedene Herpesviren (Cytomegalie-Virus (CMV), Epstein-Barr-Virus (EBV), Herpes simplex Typ l und 2-Virus, Varizella Zoster-Virus (VZV)) sowie Masern- und Mumpsviren, bei Patienten mit koronarer Herzerkrankung (KHK) (n=167) und zwei Kontrollkollektiven ohne Herzerkrankung (n=400, n=108) ermittelt. Die IgG-Antikörperprävalenzen betrugen im KHK-Kollektiv für C. pneumoniae 79,6% bzw. in den Kontrollkollektiven 72,5% und 66,7%, für C. trachomatis 4,8% bzw. 6,8% und 2,8%, für C. psittaci 3% bzw. 3,5% und 6,5%, für CMV 72,9% bzw. 74,3% und 79,2%, für EBV 95,1% bzw. 93.1% und 94%, für Herpes simplex 1/2 91,8% bzw. 87,4% und 91,3%, für Masern 99,2% bzw. 100% und für Mumps 93,4% bzw. 86,5% und 84,8%. Die Prävalenzen der VZV-IgA waren 60,3% bzw. 57,3% und 54%. Bei dieser Untersuchung zeigten sich somit keine signifikanten Unterschiede in den Antikörperprävalenzen zwischen den einzelnen Kollektiven. Wurden kranke, stationäre Patienten aus dem Kontrollkollektiv ausgeschlossen, so fand sich in diesem zweiten Kontrollkollektiv mittels Chi2-Test eine signifikant niedrigere Prävalenz (66,7%) der C. pneumoniae-IgG-Antikörper im Vergleich zu Patienten mit KHK (79,6%), (p=0,02). Die Untersuchung der geschlechtsspezifischen Prävalenzen zeigte für Männer (82,6% bzw. 78,5% und 73,2%) eine höhere Durchseuchung als für Frauen (55,6% bzw. 63% und 59,6%). Beim Vergleich gleichgeschlechtlicher Gruppen fanden sich keine signifikanten Unterschiede. Eine Assoziation von C. pneumoniae oder CMV mit der atherosklerotischen, koronaren Herzerkrankung konnte somit durch unsere* Untersuchung nicht bestätigt werden. Die Wahl der Kontroll-Gruppen kann möglicherweise die Ergebnisse der Metaanalyse früherer Assoziationsstudien beeinflußt haben.
Die Bestimmung von Lipoprotein(a) im Plasma mittels kinetischer Nephelometrie (Beckman Instruments) wurde mit einem immunoradiometrischen Assay (Mercodia) verglichen. Untersucht wurden 182 Proben in frischem Zustand und 18 Proben, die für kurze Zeit bei -25 °C gelagert waren. Die Meßergebnisse zeigen eine gute Übereinstimmung der Median werte (147 mg/1 bzw. 160 mg/1) und eine gute Korrelation bei den frischen und den eingefrorenen Proben (r = 0,971/rs= 0,985 bzw. r = 0,971). Die Variationskoeffizienten der Nephelometrie entsprechen mit 4.2% in der Serie (Intraassay) und 5,5-6,5% von Tag zu Tag (Interassay) den bisherigen Literaturwerten. Entgegen der Empfehlung, nur frisches Probenmaterial für die Nephelometrie einzusetzen, wurde bei einer Probe mit einer hohen Lipoprotein(a) Konzentration (960 mg/1) über 5 Wochen keine bedeutende Abnahme der Meßwerte registriert. Um den Einfluß der Triglyzeridkonzentration auf die Lp(a) Bestimmung zu untersuchen, wurden sechs Plasmaproben mit Triglyzeridwerten > 5,75 mmol/1 ausgewählt und in verschiedenen Verdünnungen mit Triglyzeridkonzentrationen zwischen 3,45-8,05 mmol/1 analysiert. Während 4 Proben keinen Einfluß der Triglyzeridkonzentration zeigten, wurde bei 2 Proben ein geringer Abfall der Lipoprotein(a) Meßwerte mit steigender Triglyzeridkonzentration beobachtet.
Bacterial adhesion to the host is the most decisive step in infections. Trimeric autotransporter adhesins (TAA) are important pathogenicity factors of Gram-negative bacteria. The prototypic TAA Bartonella adhesin A (BadA) from human-pathogenic Bartonella henselae mediates bacterial adherence to endothelial cells (ECs) and extracellular matrix proteins. Here, we determined the interaction between BadA and fibronectin (Fn) to be essential for bacterial host cell adhesion. BadA interactions occur within the heparin-binding domains of Fn. The exact binding sites were revealed by mass spectrometry analysis of chemically cross-linked whole-cell bacteria and Fn. Specific BadA interactions with defined Fn regions represent the molecular basis for bacterial adhesion to ECs and these data were confirmed by BadA-deficient bacteria and CRISPR-Cas knockout Fn host cells. Interactions between TAAs and the extracellular matrix might represent the key step for adherence of human-pathogenic Gram-negative bacteria to the host.
IMPORTANCE Deciphering the mechanisms of bacterial host cell adhesion is a clue for preventing infections. We describe the underestimated role that the extracellular matrix protein fibronectin plays in the adhesion of human-pathogenic Bartonella henselae to host cells. Fibronectin-binding is mediated by a trimeric autotransporter adhesin (TAA) also present in many other human-pathogenic Gram-negative bacteria. We demonstrate that both TAA and host-fibronectin contribute significantly to bacterial adhesion, and we present the exact sequence of interacting amino acids from both proteins. Our work shows the domain-specific pattern of interaction between the TAA and fibronectin to adhere to host cells and opens the perspective to fight bacterial infections by inhibiting bacterial adhesion which represents generally the first step in infections.
The capacity of pathogenic microorganisms to adhere to host cells and avoid clearance by the host immune system is the initial and most decisive step leading to infections. Bacteria have developed different strategies to attach to diverse host surface structures. One important strategy is the adhesion to extracellular matrix (ECM) proteins (e.g., collagen, fibronectin, laminin) that are highly abundant in connective tissue and basement membranes. Gram-negative bacteria express variable outer membrane proteins (adhesins) to attach to the host and to initiate the process of infection. Understanding the underlying molecular mechanisms of bacterial adhesion is a prerequisite for targeting this interaction by “anti-ligands” to prevent colonization or infection of the host. Future development of such “anti-ligands” (specifically interfering with bacteria-host matrix interactions) might result in the development of a new class of anti-infective drugs for the therapy of infections caused by multidrug-resistant Gram-negative bacteria. This review summarizes our current knowledge about the manifold interactions of adhesins expressed by Gram-negative bacteria with ECM proteins and the use of this information for the generation of novel therapeutic antivirulence strategies.
Highlights
• An airport can result in high particle concentrations in a distant residential area.
• The particle size distribution indicated the airport as the main source of particles.
• Lower air traffic during the COVID-19 pandemic lead to lower particle concentrations.
• The particle concentration showed high temporal variations.
Abstract
Exposure to ultrafine particles has a significant influence on human health. In regions with large commercial airports, air traffic and ground operations can represent a potential particle source. The particle number concentration was measured in a low-traffic residential area about 7 km from Frankfurt Airport with a Condensation Particle Counter in a long-term study. In addition, the particle number size distribution was determined using a Fast Mobility Particle Sizer.
The particle number concentrations showed high variations over the entire measuring period and even within a single day. A maximum 24 h-mean of 24,120 cm−3 was detected. Very high particle number concentrations were in particular measured when the wind came from the direction of the airport. In this case, the particle number size distribution showed a maximum in the particle size range between 5 and 15 nm. Particles produced by combustion in jet engines typically have this size range and a high potential to be deposited in the alveoli. During a period with high air traffic volume, significantly higher particle number concentrations could be measured than during a period with low air traffic volume, as in the COVID-19 pandemic.
A large commercial airport thus has the potential to lead to a high particle number concentration even in a distant residential area. Due to the high particle number concentrations, the critical particle size, and strong concentration fluctuations, long-term measurements are essential for a realistic exposure analysis.
Voraussetzung zur Diagnostik und Verlaufsbeurteilung des Krebses durch die Bestimmung von Tumormarkern ist eine gute Abstimmung zwischen dem klinisch bzw. praktisch tätigen Arzt und dem Labor. Für die Auswahl der Testkits und die Festlegung des Grenzwertes normal/pathologisch muß das Labor vom anfordernden Arzt wissen, ob die Tumormarkerbestimmung eingesetzt wird:
a) zur Verlaufsbeurteilung eines bekannten Krebses, also im Sinne der Longitudinalbeurteilung
b) im Rahmen der Tumordiagnostik, d. h. zur Transversalbeurteilung.
Zum effektiven Einsatz der Tumormarkerbestimmung für die Verlaufsbeurteilung sollte das Labor sicherstellen:
a) Verwendung eines Testkits hoher Nachweisempfindlichkeit
b) Keinen Wechsel des Testkits bei nicht standardisierten Markern vorzunehmen, ohne den anforderndenArzt in Kenntnis zu setzen
c) Patientenbezogenen Kumulativreport liefern, der die relativen Veränderungen zum Vorwert erkennen läßt
d) Aufbewahrung der jeweilig letzten Analysenprobe. Nochmalige Bestimmung mit der neuen Probe in dergleichen Analysenserie, falls der Analysenwert der neuen Probe ein „Ausreißer"zu sein scheint.
Im Rahmen der Tumordiagnostik kann bei symptomatischen Patienten die Bestimmung von AFP beim Leberzellkarzinom und von AFP und HCG bei Keimzelltumoren empfohlen werden. Andere Tumormarker sollten nur zur Diagnostik eingesetzt werden, wenn im Patientenkollektiv des anfordernden Arztes eine hohe Krankheitsprävalenz für den entsprechenden Krebs vorliegt In Kenntnis der Krankheitsprävalenz sollten Labor und anfordernder Arzt unter Auswahl einer optimalen Spezifität (noch vertretbare Zahl falsch positiver Ergebnisse), den Grenzwert normal/pathologisch für die Transversalbeurteilung festlegen.
The clinical diagnosis of neurologicaldiseases can be supported by the use of instructive, case-related reports for interpretation of CSF quantities. By using the knowledge-based System Pro.M.D.-cerebrospinal fluid diagnostics the process of clinical diagnosis can be optimized and standardized, as far as sensible. With the presentation of an exemplary case, the main features of the system are demonstrated.
Die Diagnostik der pathologischen Proteinurie ist im Wandel begriffen. Während zur Zeit noch der Streifentest und die Gesamteiweißbestimmung in der Proteindiagnostik von Nierenerkrankungen im Vordergrund stehen, gewinnt die quantitative Bestimmung von Plasmaproteinen im Harn eine gewisse Bedeutung. Ursachen sind, neben einer mangelnden diagnostischen und analytischen Sensitiv/tat und Spezifität des Streifentests und der Gesamteiweißbestimmungsmethoden, der technische Fortschritt in der mechanisierten immunnephelometrischen oder immunturbidimetrischen Analytik der Plasmaproteine im Harn.
In der vorliegenden Studie wird der Enzymun-Test®-PSA der zweiten Generation mit zwei monoklonalen Antikörpern am ES 700 Analyzer mit drei radioimmunologischen und einem fluorometrischen Verfahren verglichen. Für den Enzymun-Test®-PSA würden an 150 gesunden Probanden (100 Männer und 50 Frauen) die Referenzbereiche ermittelt. Bei den Männern lag die 95 % Perzentile bei 3,8 ng/ml, bei den Frauen bei 0,46 ng/ml. Außerdem wurden mit denselben Methode 50 Patienten mit benignen Prostataerkrankungen und 50 Patienten mit einem Prostatakarzinom untersucht. Der Korrelationskoeffizienl zwischen dem Enzymun-Test®-PSA und der radioimmunologischen Methode Tandem®-R-PSA liegt bei r = 0,99, die analytische Sensitivität von Enzymun-Rest®-R-PSA liegt bei 0,05 ng/ml. Die Stabilität der Serumproben zwischen +2 °C und +8 °C ist über einen Tag garantiert. Über diesen Zeitraum hinaus sollten Serumproben bei —20 °C gelagert werden.
In der vorliegenden Studie wird der mit zwei monoklonalen Antikörpern arbeitende Enzymun-Test® NSE für die Bestimmung der neuronspezifischen Enolase am ES700 Analyzer mit zwei radioimmunologischen, einem fluorometrischen und drei enzymimmunologischen Verfahren verglichen. Für den Enzymun-Test® NSE wurde an 200 gesunden Probanden (100 Männer und 100 Frauen) als Referenzbereich 2,15-15,25 µg/1 ermittelt. Der Median lag bei 6,6 µg/l und der Mittelwert bei 6,92 ± 1,8 µg/l Außerdem wurden mit denselben Methoden Serumproben von 70 Patienten mit benignen Lungenerkrankungen und von 300 Patienten mit verschiedenen Karzinomen untersucht. Der Korrelationskoeffizient zwischen dem Enzymun-Test® NSE und dem NSE-RIA-Pharmacia liegt bei r = 0,96. Die Stabilität der Serumproben bei Lagerung zwischen 2 und 8 °C ist über einen Zeitraum von 24 Stunden nicht gewährleistet.
Bei 70 Patienten mit einem metastasierenden Seminom wurde die neuronspezifische Enolase (NSE) im Serum bestimmt und mit den anerkannten Tumormarkern Alpha-Fetoprotein (AFP) und humanem Choriongonadotropin (HCG) verglichen. Erhöhte NSE-Konzentrationen wurden bei 40 Patienten (58%) gemessen. Nach der durchgeführten Chemotherapie beobachteten wir einen Abfall der NSE-Aktivität in den Normbereich. Die Bestimmungen von NSE wurden mit radioimmunologischen und fluorometrischen DELFIA*-Verfahren durchgeführt.
Vascular guidance is critical in developmental vasculogenesis and pathological angiogenesis. Brain tumors are strongly vascularized, and antiangiogenic therapy was anticipated to exhibit a strong anti-tumor effect in this tumor type. However, vascular endothelial growth factor A (VEGFA) specific inhibition had no significant impact in clinical practice of gliomas. More research is needed to understand the failure of this therapeutic approach. EphrinB2 has been found to directly interact with vascular endothelial growth factor receptor 2 (VEGFR2) and regulate its activity. Here we analyzed the expression of ephrinB2 and EphB4 in human glioma, we observed vascular localization of ephrinB2 in physiology and pathology and found a significant survival reduction in patients with elevated ephrinB2 tumor expression. Induced endothelial specific depletion of ephrinB2 in the adult mouse (efnb2i∆EC) had no effect on the quiescent vascular system of the brain. However, we found glioma growth and perfusion altered in efnb2i∆EC animals similar to the effects observed with antiangiogenic therapy. No additional anti-tumor effect was observed in efnb2i∆EC animals treated with antiangiogenic therapy. Our data indicate that ephrinB2 and VEGFR2 converge on the same pathway and intervention with either molecule results in a reduction in angiogenesis.
Background: The aim of this study was to identify pre-operative parameters able to predict length of stay (LoS) based on clinical data and patient-reported outcome measures (PROMs) from a scorecard database in patients with significant aortic stenosis who underwent TAVI (transfemoral aortic valve implantation). Methods: 302 participants (51.7% males, age range 78.2–84.2 years.) were prospectively recruited. After computing the median LoS value (=6 days, range = 5–8 days), we implemented a decision tree algorithm by setting dichotomized values at median LoS as the dependent variable and assessed baseline clinical variables and PROMs (Clinical Frailty Scale (CFS), EuroQol-5 Dimension-5 Levels (EQ-5D) and Kansas City Cardiomyopathy Questionnaire (KCCQ)) as potential predictors. Results: Among clinical parameters, only peripheral arterial disease (p = 0.029, HR = 1.826) and glomerular filtration rate (GFR, cut-off < 33 mL/min/1.73 m2, p = 0.003, HR = 2.252) were predictive of LoS. Additionally, two PROMs (CFS; cut-off = 3, p < 0.001, HR = 1.324 and KCCQ; cut-off = 30, p = 0.003, HR = 2.274) were strong predictors. Further, a risk score for LoS (RS_LoS) was calculated based on these predictors. Patients with RS_LoS = 0 had a median LoS of 5 days; patients RS_LoS ≥ 3 had a median LoS of 8 days. Conclusions: based on the pre-operative values of the above four predictors, a personalized prediction of LoS after TAVI can be achieved.
Evidence-based clinical guidelines generally consider single conditions, and rarely multimorbidity. We developed an evidence-based guideline for a structured care program to manage polypharmacy in multimorbidity by using a realist synthesis to update the German polypharmacy guideline including the following five methods: formal prioritization in focus groups; systematic guideline review of evidence-based multimorbidity/polypharmacy guidelines; evidence search/synthesis and recommendation development; multidisciplinary consent of recommendations; feasibility test of updated guideline. We identified the need for a better description of the target group, decision support, prioritization of medication, consideration of patient preferences and anticholinergic properties, and of healthcare interfaces. We conducted a systematic guideline review of eight guidelines and extracted and synthesized recommendations using the Ariadne principles. We also included 48 systematic reviews. We formulated and agreed upon 34 recommendations for the revised guideline. During the feasibility test, guideline use enabled 57% of GPs to identify problems, leading to medication changes in 49% and self-assessed improvement in 56% of patients. Although 58% of GPs felt that it was too long, 92% recommended it. Polypharmacy should be systematically reviewed at least annually. Patients, family members, and healthcare professionals should monitor and adjust it using prospective process validation, taking into account patient preferences and agreed treatment goals.
Invasive fungal infections are associated with increased mortality in hematological patients. Despite considerable advances in antifungal therapy, the evaluation of suspected treatment failure is a common clinical challenge requiring extensive diagnostic testing to rule out potential causes, such as mixed infections. We present a 64-year-old patient with secondary AML, diabetes mellitus, febrile neutropenia, and sinusitis. While cultures from nasal tissue grew Aspergillus flavus, a microscopic examination of the tissue was suggestive of concomitant mucormycosis. However, fluorescence in situ hybridization (FISH) using specific probes targeting Aspergillus and Mucorales species ruled out mixed infection. This was confirmed by specific qPCR assays amplifying the DNA of Aspergillus, but not of Mucorales. These results provided a rational basis for step-down targeted therapy, i.e., the patient received posaconazole after seven days of calculated dual therapy with liposomal amphotericin B and posaconazole. Despite clinical response to the antifungal therapy, he died due to the progression of the underlying disease within two weeks after diagnosis of fungal infection. Molecular diagnostics applied to tissue blocks may reveal useful information on the etiology of invasive fungal infections, including challenging situations, such as with mixed infections. A thorough understanding of fungal etiology facilitates targeted therapy that may improve therapeutic success while limiting side effects.
Epoxyeicosatrienoic acids (EETs) are signaling lipids produced by the cytochrome P450-(CYP450)-mediated epoxygenation of arachidonic acid. EETs have numerous biological effects on the vascular system, but aspects including their species specificity make their effects on vascular tone controversial. CYP450 enzymes require the 450-reductase (POR) for their activity. We set out to determine the contribution of endothelial CYP450 to murine vascular function using isolated aortic ring preparations from tamoxifen-inducible endothelial cell-specific POR knockout mice (ecPOR−/−). Constrictor responses to phenylephrine were similar between control (CTR) and ecPOR−/− mice. Contrastingly, sensitivity to the thromboxane receptor agonist U46619 and prostaglandin E2 (PGE2) was increased following the deletion of POR. Ex vivo incubation with a non-hydrolyzable EET (14,15-EE-8(Z)-E, EEZE) reversed the increased sensitivity to U46619 to the levels of CTR. EETs had no effect on vascular tone in phenylephrine-preconstricted vessels, but dilated vessels contracted with U46619 or PGE2. As U46619 acts through RhoA-dependent kinase, this system was analyzed. The deletion of POR affected the expression of genes in this pathway and the inhibition of Rho-GTPase with SAR407899 decreased sensitivity to U46619. These data suggest that EET and prostanoid crosstalk at the receptor level and that lack of EET production sensitizes vessels to vasoconstriction via the induction of the Rho kinase system.
Previous studies towards reduced oxygen availability have mostly focused on changes in total mRNA expression, neglecting underlying transcriptional and post-transcriptional events. Therefore, we generated a comprehensive overview of hypoxia-induced changes in total mRNA expression, global de novo transcription, and mRNA stability in monocytic THP-1 cells. Since hypoxic episodes often persist for prolonged periods, we further compared the adaptation to acute and chronic hypoxia. While total mRNA changes correlated well with enhanced transcription during short-term hypoxia, mRNA destabilization gained importance under chronic conditions. Reduced mRNA stability not only added to a compensatory attenuation of immune responses, but also, most notably, to the reduction in nuclear-encoded mRNAs associated with various mitochondrial functions. These changes may prevent the futile production of new mitochondria under conditions where mitochondria cannot exert their full metabolic function and are indeed actively removed by mitophagy. The post-transcriptional mode of regulation might further allow for the rapid recovery of mitochondrial capacities upon reoxygenation. Our results provide a comprehensive resource of functional mRNA expression dynamics and underlying transcriptional and post-transcriptional regulatory principles during the adaptation to hypoxia. Furthermore, we uncover that RNA stability regulation controls mitochondrial functions in the context of hypoxia.
LFA-1 (Lymphocyte function-associated antigen-1) is a heterodimeric integrin (CD11a/CD18) present on the surface of all leukocytes; it is essential for leukocyte recruitment to the site of tissue inflammation, but also for other immunological processes such as T cell activation and formation of the immunological synapse. Absent or dysfunctional expression of LFA-1, caused by mutations in the ITGB2 (integrin subunit beta 2) gene, results in a rare immunodeficiency syndrome known as Leukocyte adhesion deficiency type I (LAD I). Patients suffering from severe LAD I present with recurrent infections of the skin and mucosa, as well as inflammatory symptoms complicating the clinical course of the disease before and after allogeneic hematopoietic stem cell transplantation (alloHSCT); alloHSCT is currently the only established curative treatment option. With this review, we aim to provide an overview of the intrinsic role of inflammation in LAD I.
Activation of the tumor-associated stroma to support tumor growth is a common feature observed in different cancer entities. This principle is exemplified by cancer-associated fibroblasts (CAFs), which are educated by the tumor to shape its development across all stages. CAFs can alter the extracellular matrix (ECM) and secrete a variety of different molecules. In that manner they have the capability to affect activation, survival, proliferation, and migration of other stromal cells and cancer cell themselves. Alteration of the ECM, desmoplasia, is a common feature of breast cancer, indicating a prominent role for CAFs in shaping tumor development in the mammary gland. In this review, we summarize the multiple roles CAFs play in mammary carcinoma. We discuss experimental and clinical strategies to interfere with CAFs function in breast cancer. Moreover, we highlight the issues arising from CAFs heterogeneity and the need for further research to identify CAFs subpopulation(s) that can be targeted to improve breast cancer therapy.
Germany experienced a 6-month second lockdown (November 2020–April 2021) during the COVID-19 pandemic, which included the closure of all physical activity (PA) facilities. The use of online exercise classes (OECs) was promoted by public health and exercise organizations. Using the present cross-sectional online survey, we assess the use of and opinion towards OECs in Germany during the second lockdown. We used contingency tables and the Chi2 test to calculate the frequency of awareness and use of OECs according to PA status, well-being and demographic data, and conducted a binary logistic regression with OEC awareness or use and dichotomized independent predictors. The associations between opinion and activity status, frequency of use, educational attainment, age and body mass index were calculated using Spearman correlations. A total of 993 datasets were analyzed in detail. Of the 785 (79.1%) participants reporting awareness of OECs, 536 tried them, and 262, 188 and 85 used them <1 per week, 1–2 per week and ≥3 per week, respectively. The users were typically active, female participants with poorer mental well-being. The opinions towards OECs varied according to participant characteristics, such as activity status, BMI and age. Overall, regular OEC use was quite limited, and, as such, cannot replace in-person exercise opportunities. Keeping physical activity facilities open and safe must be prioritized in the ongoing pandemic.
Background: Intraoperative blood salvage (IBS) is regarded as an alternative to allogeneic blood transfusion excluding the risks associated with allogeneic blood. Currently, IBS is generally avoided in tumor surgeries due to concern for potential metastasis caused by residual tumor cells in the erythrocyte concentrate.
Methods: The feasibility, efficacy and safety aspects of the new developed Catuvab procedure using the bispecific trifunctional antibody Catumaxomab was investigated in an ex-vivo pilot study in order to remove residual EpCAM positive tumor cells from the autologous erythrocyte concentrates (EC) from various cancer patients, generated by a IBS device.
Results: Tumor cells in intraoperative blood were detected in 10 of 16 patient samples in the range of 69–2.6 × 105 but no residual malignant cells in the final erythrocyte concentrates after Catuvab procedure. IL-6 and IL-8 as pro-inflammatory cytokines released during surgery, were lowered in mean 28-fold and 52-fold during the Catuvab procedure, respectively, whereas Catumaxomab antibody was detected in 8 of 16 of the final EC products at a considerable decreased and uncritical residual amount (37 ng in mean).
Conclusion: The preliminary study results indicate efficacy and feasibility of the new medical device Catuvab allowing potentially the reinfusion of autologous erythrocyte concentrates (EC) produced by IBS device during oncological high blood loss surgery. An open-label, multicenter clinical study on the removal of EpCAM-positive tumor cells from blood collected during tumor surgery using the Catuvab device is initiated to validate these encouraging results.
Hintergrund: Durch COVID-19 kam es weltweit, insbesondere in den ersten Wochen der Pandemie, zu einer Verschiebung und Absage elektiver Operationen in allen chirurgischen Fachdisziplinen. Eine Beschreibung der spezifischen Situation in gefäßchirurgischen Kliniken in Deutschland während dieser Periode ist bislang nicht erfolgt.
Ziel der Arbeit: Zweck der Befragung war die Erfassung der gefäßchirurgischen Leistungserbringung in der Zeit von März 2020 bis Dezember 2020, sowie von logistischen und infrastrukturellen Veränderungen, die sich durch die pandemische Lage ergeben hatten. Hierbei lag der Fokus der Umfrage auf der möglichst realitätsnahen Abbildung der Versorgungssituation anhand der Einschätzung der leitenden Gefäßchirurg*innen.
Material und Methoden: In Zusammenarbeit mit der Deutschen Gesellschaft für Gefäßchirurgie und Gefäßmedizin (DGG) wurde das leitende ärztliche Personal von gefäßchirurgischen Einrichtungen in Deutschland aufgefordert, an der Umfrage teilzunehmen. Die Beantwortung der Fragen erfolgte anonym.
Ergebnisse: Durch COVID-19 und korrespondierende Maßnahmen kam und kommt es zu relevanten Absagen und Verschiebungen von Operationen, Verlust an Kapazitäten und einer gesteigerten Personalbelastung. Es traten im Beobachtungszeitraum verspätete Versorgungen gefäßchirurgischer Krankheitsbilder und ein gehäuftes Auftreten schwererer klinischer Stadien verglichen mit dem entsprechenden Vorjahreszeitraum auf. Betroffen sind alle Versorgungsstufen, größtenteils dauern diese Veränderungen an.
Diskussion: Um der strukturellen Schwächung und den Einschränkungen in der Patientenversorgung zu begegnen, sind klinische Abläufe, Patientenaufklärung und Priorisierung zu optimieren. Neue Konzepte wie z. B. Telemedizin und engmaschigere klinische Kontrolle sind ggf. sinnvoll. Eine erforderliche Infrastruktur für Notfallmanagement (COVID) darf im Alltag nicht die Versorgungsqualität der gefäßchirurgischen Patient*innen negativ beeinflussen.
Neben einer guten Tanztechnik spielt die Körperform von professionellen Tänzer*innen eine entscheidende Rolle. Im klassischen Tanz gilt eine leptosom-grazile Form mit langen Gliedmaßen bei Frauen als ideal. Dementsprechend ist die Prävalenz von Untergewicht hoch. Dabei ist es nicht ausgeschlossen, dass dieses physische Erscheinungsbild mittels Diäten erreicht wird. Auffällig ist eine höhere Prävalenz von Störungen des Essverhaltens und Essstörungen vor allem bei Tänzerinnen im Vergleich zu nicht tanzenden Vergleichsgruppen. Im Zusammenhang mit dem Untergewicht können hormonelle Störungen, wie Amenorrhoe, Osteoporose oder Leistungseinschränkungen auftreten. Daher ist es wichtig, Tänzer*innen regelmäßig zu untersuchen und präventive Maßnahmen zu ergreifen. Ziel der vorliegenden Übersicht ist die Darstellung der Literatur zu diesem Thema.
Background: Orthodontic root resorptions are frequently investigated in small animals, and micro-computed tomography (μCT) enables volumetric comparison. Despite, due to overlapping histograms from dentine and bone, accurate quantification of root resorption is challenging. The present study aims at (i) validating a novel automated approach for tooth segmentation (ATS), (ii) to indicate that matching of contralateral teeth is eligible to assess orthodontic tooth movement (OTM) and root resorption (RR), (iii) and to apply the novel approach in an animal trial performing orthodontic tooth movement.
Methods: The oral apparatus of three female mice were scanned with a μCT. The first molars of each jaw and animal were segmented using ATS (test) and manually (control), and contralateral volumes were compared. Agreement in root volumes and time efficiency were assessed for method validation. In another n = 14 animals, the left first upper molar was protracted for 11 days at 0.5 N, whereas the contralateral molar served as control. Following ATS, OTM and RR were estimated.
Results: ATS was significantly more time efficient compared to the manual approach (81% faster, P < 0.01), accurate (volume differences: − 0.01 ± 0.04 mm3), and contralateral roots had comparable volumes. Protracted molars had significantly lower root volumes (P = 0.03), whereas the amount of OTM failed to reveal linear association with RR (P > 0.05).
Conclusions: Within the limits of the study, it was demonstrated that the combination of ATS and registration of contralateral jaws enables measurements of OTS and associated RR in μCT scans.
The disruption in blood supply due to myocardial infarction is a critical determinant for infarct size and subsequent deterioration in function. The identification of factors that enhance cardiac repair by the restoration of the vascular network is, therefore, of great significance. Here, we show that the transcription factor Zinc finger E-box-binding homeobox 2 (ZEB2) is increased in stressed cardiomyocytes and induces a cardioprotective cross-talk between cardiomyocytes and endothelial cells to enhance angiogenesis after ischemia. Single-cell sequencing indicates ZEB2 to be enriched in injured cardiomyocytes. Cardiomyocyte-specific deletion of ZEB2 results in impaired cardiac contractility and infarct healing post-myocardial infarction (post-MI), while cardiomyocyte-specific ZEB2 overexpression improves cardiomyocyte survival and cardiac function. We identified Thymosin β4 (TMSB4) and Prothymosin α (PTMA) as main paracrine factors released from cardiomyocytes to stimulate angiogenesis by enhancing endothelial cell migration, and whose regulation is validated in our in vivo models. Therapeutic delivery of ZEB2 to cardiomyocytes in the infarcted heart induces the expression of TMSB4 and PTMA, which enhances angiogenesis and prevents cardiac dysfunction. These findings reveal ZEB2 as a beneficial factor during ischemic injury, which may hold promise for the identification of new therapies.
Background: Tisagenlecleucel, an anti-CD19 chimeric antigen receptor T cell therapy, has demonstrated efficacy in children and young adults with relapsed/refractory B cell acute lymphoblastic leukemia (B-ALL) in two multicenter phase 2 trials (ClinicalTrials.gov, NCT02435849 (ELIANA) and NCT02228096 (ENSIGN)), leading to commercialization of tisagenlecleucel for the treatment of patients up to age 25 years with B-ALL that is refractory or in second or greater relapse.
Methods: A pooled analysis of 137 patients from these trials (ELIANA: n=79; ENSIGN: n=58) was performed to provide a comprehensive safety profile for tisagenlecleucel.
Results: Grade 3/4 tisagenlecleucel-related adverse events (AEs) were reported in 77% of patients. Specific AEs of interest that occurred ≤8 weeks postinfusion included cytokine-release syndrome (CRS; 79% (grade 4: 22%)), infections (42%; grade 3/4: 19%), prolonged (not resolved by day 28) cytopenias (40%; grade 3/4: 34%), neurologic events (36%; grade 3: 10%; no grade 4 events), and tumor lysis syndrome (4%; all grade 3). Treatment for CRS included tocilizumab (40%) and corticosteroids (23%). The frequency of neurologic events increased with CRS severity (p<0.001). Median time to resolution of grade 3/4 cytopenias to grade ≤2 was 2.0 (95% CI 1.87 to 2.23) months for neutropenia, 2.4 (95% CI 1.97 to 3.68) months for lymphopenia, 2.0 (95% CI 1.87 to 2.27) months for leukopenia, 1.9 (95% CI 1.74 to 2.10) months for thrombocytopenia, and 1.0 (95% CI 0.95 to 1.87) month for anemia. All patients who achieved complete remission (CR)/CR with incomplete hematologic recovery experienced B cell aplasia; however, as nearly all responders also received immunoglobulin replacement, few grade 3/4 infections occurred >1 year postinfusion.
Conclusions: This pooled analysis provides a detailed safety profile for tisagenlecleucel during the course of clinical trials, and AE management guidance, with a longer follow-up duration compared with previous reports.
Patients with unilateral hip osteoarthritis show a characteristic gait pattern in which they unload the affected leg and overload the unaffected leg. Information on the gait characteristics of patients with bilateral hip osteoarthritis is very limited. The main purposes of this study were to investigate whether the gait pattern of both legs of patients with bilateral hip osteoarthritis deviates from healthy controls and whether bilateral hip osteoarthritis patients show a more symmetrical joint load compared to unilateral hip osteoarthritis patients. In this prospective study, 26 patients with bilateral hip osteoarthritis, 26 patients with unilateral hip osteoarthritis and 26 healthy controls were included. The three groups were matched for gender, age and walking speed. Patients were scheduled for a unilateral total hip arthroplasty on the more affected/more painful side. All participants underwent a three-dimensional gait analysis. Gait kinematics and gait kinetics of patients and controls were compared using Statistical Parametric Mapping. Corrected for speed, the gait kinematics and kinetics of both legs of patients with bilateral hip osteoarthritis differed from healthy controls. Bilateral patients had symmetrical knee joint loading, in contrast to the asymmetrical knee joint loading in unilateral hip osteoarthritis patients. The ipsilateral leg of the bilateral patients could be included in studies in addition to unilateral hip osteoarthritis patients as no differences were found. Although patients with bilateral hip osteoarthritis show more symmetrical frontal plane knee joint moments, a pathological external knee adduction moment in the second half of stance was present in the ipsilateral leg in patients with unilateral and bilateral hip osteoarthritis. The lateral adjustment of the knee adduction moment may initiate or accelerate progression of degenerative changes in the lateral compartment of the knee.
Um eine gezielte Prophylaxe und Therapie der Urolithiasis zu ermöglichen und um die Rezidivrate zu senken, ist die genaue Kenntnis der Steinzusammensetzung erforderlich. Wegen des hohen Beschaffungspreises sind Röntgendiffraktion und Infrarotspektroskopie nur wenigen Laboratorien vorbehalten, andererseits sollten unspezifisch-chemische Steinanalysenmethoden wegen deren geringeren Sensitivität und Spezifität heute nicht mehr angewendet werden.
In dieser Arbeit wird eine unter dem Mikroskop durchführbare Harnsteinkomponentenanalysenmethode (Harzalith) beschrieben. Es handelt sich um eine mikroskopisch-mikrochemische Harnsteinanalysenmethode. Sie basiert auf der Auswertung mikroskopisch typischer, leicht einprägsamer Farbmuster, die sich je nach Steinzusammensetzung in charakteristischer Weise nach Zugabe des Steinmaterials zum Reagenz innerhalb von Sekunden entwickeln.
Eine Bewertung der mikroskopisch-mikrochemischen Harnsteinkomponentenanalyse gegenüber Röntgendiffraktion, Infrarotspektroskopie und unspezifisch-chemischen Methoden erfolgt anhand von Ergebnissen aus über 10jähriger eigener Anwendungserfahrung.
Folgende Vorteile werden kurz dargestellt:
1. Es werden Steinkomponenten und nicht nur Ionen erfaßt.
2. Es können geringste Steinprobenmengen analysiert werden.
3. Die Ergebnisse der Methode hinsichtlich Richtigkeit, Sensitivität und Spezifität sind in gleicher Größenordnung wie die von Infrarotspektroskopie und Röntgendiffraktion.
4. Die Methode ist einfach zu erlernen, schnell, genau und von leichter Handhabung. Sie ist damit eine echte Alternative gegenüber den anderen apparativ-aufwendigen Harnsteinanalysenverfahren.
Es wird eine neue pH-Indikatormethode zur Harnstoffbestimmung beschrieben. Die Methode zeichnet sich durch gute Präzision und Richtigkeit aus. Der aus 150 Wertepaaren ermittelte Korrelationskoeffizient beträgt mit der DAM-Methode r = 0,9970 und mit der GLDH-Methode r = 0,9971. Die Richtigkeitsversuche charakterisieren die Methode als praxisgerecht. Wegen der schnellen Durchführung ist die Methode auch für Notfall-Laboratorien zu empfehlen.