Influence of body condition and dietary energy supply on lipolysis, ketogenesis and immune system of periparturient dairy cows with special regard to dipeptidyl peptidase-4

The increased energy requirements and the decreased dry matter intake during late gestation and early lactation, in particular relative to the requirement, cause a catabolic state in the dairy cow, characterized by a distinct negative energy balance (NEB). During NEB increased concentrations in blood of non-esterified fatty acids (NEFA) are detectable. Subsequently, ketone bodies are produced in the liver. β-hydroxybutyrate (BHB) is the most stable ketone body in blood, therefore it is usually used to define a ketotic status, with 1.2 mM BHB in serum suggested as cut-off point for subclinical ketosis. The aim of the present dissertation was to induce subclinical ketosis in lactating cows to test potential therapeutical or prophylactic measures. Owing to a body condition score (BCS) of at least 3.0 six weeks before calving, a high energy diet ante partum (concentrate proportion of 60%) and a decreased energy supply post partum, 80% of the cows developed ketosis (81% subclinical, 19% clinical ketosis). The success of the animal model allowed for a well-controlled observation of different variables, related to metabolism and the immune system. Cows of subclinical ketosis had higher blood concentrations of NEFA, BHB and liver function enzymes, as well as higher liver lipid contents (e.g. 154 mg/g in the 2nd week post partum) than cows which were fed adequately and stayed metabolically healthy during the experimental trial. Moreover, subclinically ketotic cows had higher milk yields (Δ = 4.4 kg/day) and a fat:protein ratio in milk > 1.5, which also coincides a high lipolysis. Variables about immune function were slightly influenced by the ketotic metabolism. In in vitro tests peripheral blood mononuclear cells (PBMC) of cows not pre-stressed by ketosis in vivo responded more sensitively to increased concentrations of BHB as evidenced by both, the proliferative capability and the increased release of nitric oxide in the PBMC supernatant. The results indicate that even slightly diminished immune cell reactions might imply an immunosuppression during periparturient period and confirmed statements that beside NEFA, BHB also elicits effects on immune cells. For further investigations and in relation to find new possibilities for ketosis therapy, a dipeptidyl peptidase-4 (DPP4) inhibitor (BI 14332) was tested. The inhibition of DPP4 via specific inhibitors is known to result in improved insulin sensitivity and decreased accumulation of hepatic fat in rodents and type II diabetic human patients. With first occurrence of serum BHB concentrations ≥ 1.2 mM BI 14332 was administered daily for 7 days (intravenous, 0.3 mg/kg body weight). The treatment did not alter the main markers of ketosis (BHB, liver lipid content), but NEFA and triglyceride concentrations in blood were decreased after the treatment. Therefore, a positive impact on the pathways of energy metabolism, resulting in a reduced NEB-induced lipolysis may be assumed. Furthermore, the results suggest that the DPP4 inhibition acts also at cellular level. The increase in the lymphocyte CD4+/CD8+ ratio for treated versus untreated cows was less strong and indicated that the peripartal immune dysregulation of ketotic cows may be positively modulated by BI 14332. A moderate correlation between NEFA and the CD4+/CD8+ ratio (r = 0.40) clarified how close changes at the biochemical level are connected to immune dysregulation.Einfluss der Körperkondition und der Energieversorgung auf die Lipolyse, die Ketogenese und das Immunsystem peripartaler Milchkühe unter besonderer Berücksichtigung der Dipeptidylpeptidase-4 Während der Transitphase weisen Milchkühe einen erhöhten Energiebedarf auf, wobei die Futteraufnahme gleichzeitig gesenkt ist. Es kommt verstärkt zum Abbau von Körperreserven, insbesondere von Depotfett. Die resultierende negative Energiebilanz (NEB) ist gekennzeichnet durch hohe Konzentrationen an nicht-veresterten Fettsäuren (NEFA) im Blut. Mit steigenden NEFA-Konzentrationen werden diese in der Leber oxidiert (β-Oxidation) und über das dabei entstehende Acetyl-CoA in Ketonkörper umgewandelt (Ketogenese). Ketonkörper werden von der Leber in den Blutkreislauf abgegeben und stellen eine Energiequelle für verschiedene Organe (z.B. das Gehirn) dar. β-Hydroxybutyrat (BHB) gilt als bedeutendster „Ketonkörper“ und als Indikator für subklinische (BHB im Blut > 1.2 mM) und klinische Ketosen (BHB im Blut ≥ 3.0 mM). Ziel der vorliegenden Dissertation war die Schaffung einer Tiermodells zur Induktion subklinischer Ketosen bei der Milchkuh, um so unter kontrollierten Bedingungen den ketotischen Stoffwechsel und mögliche Auswirkungen auf die Immunantwort zu untersuchen. Dabei wurden Kühe mit einer Körperkondition (BCS) von mindestens 3.0 für die letzten 6 Wochen der Trächtigkeit mit einer hochenergetischen Futterration versorgt (7.7 MJ NEL/kg Trockenmasse). Post partum erfolgte eine verzögerte Steigerung der Energiezufuhr um die postpartale Lipolyse zusätzlich zu stimulieren. Insgesamt wiesen 80% der Kühe eine Ketose auf (81% subklinisch, 19% klinisch) und zeigten höhere Blutkonzentrationen an BHB, NEFA und ausgewählten Leberenzymen als gesunde, normalkonditionierte Kühe der Kontrollgruppe. Subklinische Kühe gaben zudem mehr Milch (Δ = 4.4 kg/Tag), wobei der Fett/Protein-Quotient der Milch über 1.5 lag, was auf eine übermäßige Lipolyse hinweist. Gravierende Auswirkungen auf immunologische Parameter konnten nicht gezeigt werden, jedoch ließ sich aus den durchgeführten in vitro-Untersuchungen ableiten, dass bereits eine subklinische Ketose die Immunzellreaktionen vermindert und so das Risiko von Folgeerkrankungen erhöht sein kann. Mit dem Ziel neue Therapiemaßnahmen bei Ketose zu entwickeln, wurde erstmalig der Einsatz eines Dipeptidylpeptidase-4 (DPP4) Inhibitors (BI 14332) getestet. Untersuchungen bei Nagern und Diabetes-Typ II-Patienten zeigen, dass durch eine DPP4-Inhibierung die Insulinsensitivität verbessert werden kann, während es in der Leber gleichzeitig zu reduzierten Fetteinlagerungen kommt. In der vorliegenden Dissertation wurden subklinisch ketotische Kühe über 7 Tage (1 x täglich) mit dem DPP4-Inhibitor behandelt (intravenös, 0.3 mg/kg Lebendmasse). Durch die Behandlung konnte der Gehalt an BHB im Blut und der Leberfettgehalt der Kühe nicht beeinflusst werden, jedoch waren die Konzentrationen an NEFA und Triglyceriden mit Behandlungsende reduziert. Die BI 14332-Behandlung lässt einen positiven Einfluss auf den Energiestoffwechsel vermuten, so dass die durch die NEB induzierte Lipolyse leicht reduziert war. Auch Einflüsse auf zellulärer Ebene sind vorstellbar. So weist ein weniger starker Anstieg des CD4+/CD8+-Quotienten bei T-Lymphozyten auf eine verbesserte Immunregulation im peripartalen Zeitraum hin. Letztlich verdeutlicht der positive Zusammenhang der NEFA-Konzentration im Blut mit dem CD4+/CD8+-Quotienten (r = 0.40) wie eng biochemische Veränderungen auch mit Dysregulationen des Immunsystem einhergehen und umgekehrt

A Search for H2O in the Strongly Lensed QSO MG 0751+2716 at z=3.2

We present a search for 183 GHz H_2O(3_13-2_20) emission in the infrared-luminous quasar MG 0751+2716 with the NRAO Very Large Array (VLA). At z=3.200+/-0.001, this water emission feature is redshifted to 43.6 GHz. As opposed to the faint rotational transitions of HCN (the standard high-density tracer at high-z), H_2O(3_13-2_20) is observed with high maser amplification factors in Galactic star-forming regions. It therefore holds the potential to trace high-density star-forming regions in the distant universe. If indeed all star-forming regions in massively star-forming galaxies at z>3 have similar physical properties as e.g. the Orion or W49N molecular cloud cores, the flux ratio between the maser-amplified H_2O(3_13-2_20) and the thermally excited CO(1-0) transitions may be as high as factor of 20 (but has to be corrected by their relative filling factor). MG 0751+2716 is a strong CO(4-3) emitter, and therefore one of the most suitable targets to search for H_2O(3_13-2_20) at cosmological redshifts. Our search resulted in an upper limit in line luminosity of L'(H_2O) < 0.6 x 10^9 K km/s pc^2. Assuming a brightness temperature of T_b(H_2O) ~= 500 K for the maser emission and CO properties from the literature, this translates to a H_2O(3_13-2_20)/CO(4-3) area filling factor of less than 1%. However, this limit is not valid if the H_2O(3_13-2_20) maser emission is quenched, i.e. if the line is only thermally excited. We conclude that, if our results were to hold for other high-z sources, H_2O does not appear to be a more luminous alternative to HCN to detect high-density gas in star-forming environments at high redshift.Comment: 6 pages, 1 figure, to appear in ApJ (accepted May 19, 2006

Pop-up cavities

Метою роботи є дослідження маловивченого на теперішній час процесу переміщення збережених у приповерхневому вуглепородному масиві Донбасу пустот від місця їхнього первинного розташування до земної поверхні.The object of this paper is research into the understudied for now process of cavities, preserved in the sub-surface coal-bearing strata in the Donets Basin, moving from the places of their original location towards the surface.Целью работы является исследование малоизученного в настоящее время процесса перемещения сохранившихся в приповерхностном углепородном массиве Донбасса пустот от мест их первоначального расположения к земной поверхности. Методика исследования. Проанализированы фактические случаи так называемого всплывания пустот в угледобывающей практике. Выполнен абстрактный расчёт поэтапного всплывания условно сохранившейся выработки (пустоты) в породном массиве различной прочности

787-5 Systemic Effect of Ramipril on Endothelin, but not on Elcosanoid Levels in Patients with Coronary Artery Disease

Study aimNeurohumoral effects of ramipril (R) alone or in combination with isosorbide dinitrate (ISDN) compared to ISDN or placebo.Study designPlacebo-controlled double-blind parallel group trial.Methods32 patients with coronary artery disease (CAD) received placebo, R5mg, ISDN 20mg slow release b.i.d. or R+ISDN for one week. A 24 hour kinetic profile of ramipril and its metabolite, of ace activity (ACE-A) and of related hormones (renin and aldosterone), of endothelin and of prostaglandins (PG), thromboxane B2 (TXB2), PGF2a, 6-keto PGF1a, the stable metabolite of prostacyclin (PGI2-M) was studied after the first dose. Measurements were repeated after 8 days of treatment before and 3 hours after the morning dose.ResultsHormone measurements are presented as means of percent difference of patients treated with R (n=16) vs. those without ace-inhibitor (n=16).Time (hrs)0123468240–83–8Ramipril (mg/l)08543210.417Ramiprilat (mg/l)0611108751214ACE-A (%)-6-78-95-98-98-97-96-80-82-98Aldosteron (%)9-5-31-34-21-27-23-34--Renin (%)-9-771913175332--Endothelin (%)-17-13-25-19-16-15-40--TXB2 (%)41045-5012-3PGF2a (%)101700-8-22-9PGI2-M (%)70-38--59-1-713-=not done; significant differences are printed in italics (two-tailed t-test)A single oral dose of 5mg R reduced ACE activity (p&lt;0.001), decreased aldosterone and increased renin (p&lt;0.1). R did not influence plasma levels of the vasoconstricting (TXB2, PGF2a) or vasodilating (PGI2-M) eicosanoid mediators, but decreased endothelin (p&lt;0.1).ConclusionR, in a dose that results in significant systemic inhibition of the renin angiotensin aldosteron system, does not induce measurable changes of circulating eicosanoid concentrations, but seems to diminish systemic release of endothelin

Digital First: Die Open-Access-Tage 2020 erstmals als Online-Konferenz

Die Open-Access-Tage 2020 hätten wie ihre Vorgänger als Präsenzveranstaltung und mit einem eingeführten Konzept in Bielefeld stattfinden sollen. Die Corona-Pandemie hat die Ausrichtung in der Form jedoch unmöglich gemacht. Um die Tagung nicht absagen zu müssen, haben sich die Veranstalter*innen entschlossen, sie mit kurzer Vorbereitungszeit und wenig Vorerfahrung ausschließlich digital durchzuführen. In diesem Artikel beschreiben wir die Ausgangssituation und die Organisation unter veränderten Rahmenbedingungen sowie unsere Erfahrungen mit dem Online-Format, die für andere, die Ähnliches vorhaben, hilfreich sein könnten

Photo-ionization and fragmentation of Sc3N@C80 following excitation above the Sc K-edge

We have investigated the ionization and fragmentation of a metallo-endohedral fullerene, Sc3N@C80, using ultrashort (10 fs) x-ray pulses. Following selective ionization of a Sc (1s) electron (hν = 4.55 keV), an Auger cascade leads predominantly to either a vibrationally cold multiply charged parent molecule or multifragmentation of the carbon cage following a phase transition. In contrast to previous studies, no intermediate regime of C2 evaporation from the carbon cage is observed. A time-delayed, hard x-ray pulse (hν = 5.0 keV) was used to attempt to probe the electron transfer dynamics between the encapsulated Sc species and the carbon cage. A small but significant change in the intensity of Sc-containing fragment ions and coincidence counts for a delay of 100 fs compared to 0 fs, as well as an increase in the yield of small carbon fragment ions, may be indicative of incomplete charge transfer from the carbon cage on the sub-100 fs time scale

Therapeutic approaches to pediatric COVID-19: an online survey of pediatric rheumatologists

Data on therapy of COVID-19 in immunocompetent and immunosuppressed children are scarce. We aimed to explore management strategies of pediatric rheumatologists. All subscribers to international Pediatric Rheumatology Bulletin Board were invited to take part in an online survey on therapeutic approaches to COVID-19 in healthy children and children with autoimmune/inflammatory diseases (AID). Off-label therapies would be considered by 90.3% of the 93 participating respondents. In stable patients with COVID-19 on oxygen supply (stage I), use of remdesivir (48.3%), azithromycin (26.6%), oral corticosteroids (25.4%) and/or hydroxychloroquine (21.9%) would be recommended. In case of early signs of 'cytokine storm' (stage II) or in critically ill patients (stage III) (a) anakinra (79.5% stage II; 83.6% stage III) or tocilizumab (58.0% and 87.0%, respectively); (b) corticosteroids (oral 67.2% stage II, intravenously 81.7% stage III); (c) intravenous immunoglobulins (both stages 56.5%); or (d) remdesivir (both stages 46.7%) were considered. In AID, &amp;gt; 94.2% of the respondents would not support a preventive adaptation of the immunomodulating therapy. In case of mild COVID-19, more than 50% of the respondents would continue pre-existing treatment with immunoglobulins (100%), hydroxychloroquine (94.2%), anakinra (79.2%) or canakinumab (72.5%), or tocilizumab (69.8%). Long-term corticosteroids would be reduced by 26.9% (&amp;lt; = 2 mg/kg/d) and 50.0% (&amp;gt; 2 mg/kg/day), respectively, with only 5.8% of respondents voting to discontinue the therapy. Conversely, more than 75% of respondents would refrain from administering cyclophosphamide and anti-CD20-antibodies. As evidence on management of pediatric COVID-19 is incomplete, continuous and critical expert opinion and knowledge exchange is helpful

Walk well:a randomised controlled trial of a walking intervention for adults with intellectual disabilities: study protocol

Background - Walking interventions have been shown to have a positive impact on physical activity (PA) levels, health and wellbeing for adult and older adult populations. There has been very little work carried out to explore the effectiveness of walking interventions for adults with intellectual disabilities. This paper will provide details of the Walk Well intervention, designed for adults with intellectual disabilities, and a randomised controlled trial (RCT) to test its effectiveness. Methods/design - This study will adopt a RCT design, with participants allocated to the walking intervention group or a waiting list control group. The intervention consists of three PA consultations (baseline, six weeks and 12 weeks) and an individualised 12 week walking programme. A range of measures will be completed by participants at baseline, post intervention (three months from baseline) and at follow up (three months post intervention and six months from baseline). All outcome measures will be collected by a researcher who will be blinded to the study groups. The primary outcome will be steps walked per day, measured using accelerometers. Secondary outcome measures will include time spent in PA per day (across various intensity levels), time spent in sedentary behaviour per day, quality of life, self-efficacy and anthropometric measures to monitor weight change. Discussion - Since there are currently no published RCTs of walking interventions for adults with intellectual disabilities, this RCT will examine if a walking intervention can successfully increase PA, health and wellbeing of adults with intellectual disabilities

Prognostic Integrated Image-Based Immune and Molecular Profiling in Early-Stage Endometrial Cancer

Optimum risk stratification in early-stage endometrial cancer (EC) combines clinicopathological factors and the molecular EC classification defined by The Cancer Genome Atlas (TCGA). It is unclear whether analysis of intratumoral immune infiltrate improves this. We developed a machine-learning image-based algorithm to quantify density of CD8+ and CD103+ immune cells in tumor epithelium and stroma in 695 stage I endometrioid ECs from the PORTEC-1&amp;-2 trials. The relationship between immune cell density and clinicopathological/molecular factors was analyzed by hierarchical clustering and multiple regression. The prognostic value of immune infiltrate by cell type and location was analyzed by univariable and multivariable Cox regression, incorporating the molecular EC classification. Tumor-infiltrating immune cell density varied substantially between cases, and more modestly by immune cell type and location. Clustering revealed three groups with high, intermediate and low densities, with highly significant variation in the proportion of molecular EC subgroups between them. Univariable analysis revealed intraepithelial CD8+ cell density as the strongest predictor of EC recurrence; multivariable analysis confirmed this was independent of pathological factors and molecular subgroup. Exploratory analysis suggested this association was not uniform across molecular subgroups, but greatest in tumors with mutant p53 and absent in DNA mismatch repair deficient cancers. Thus, this work identified that quantification of intraepithelial CD8+ cells improved upon the prognostic utility of the molecular EC classification in early-stage EC

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy