Optimisation of BACE1 inhibition of tripartite structures by modification of membrane anchors, spacers and pharmacophores – development of potential agents for the treatment of Alzheimer's disease

Systematic variation of membrane anchor, spacer and pharmacophore building blocks leads to an optimisation of the inhibitory effect of tripartite structures towards BACE1-induced cleavage of the amyloid precursor protein (APP).Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich

A Novel Tandem Mass Spectrometry Method for Rapid Confirmation of Medium- and Very Long-Chain acyl-CoA Dehydrogenase Deficiency in Newborns

BACKGROUND:Newborn screening for medium- and very long-chain acyl-CoA dehydrogenase (MCAD and VLCAD, respectively) deficiency, using acylcarnitine profiling with tandem mass spectrometry, has increased the number of patients with fatty acid oxidation disorders due to the identification of additional milder, and so far silent, phenotypes. However, especially for VLCADD, the acylcarnitine profile can not constitute the sole parameter in order to reliably confirm disease. Therefore, we developed a new liquid chromatography tandem mass spectrometry (LC-MS/MS) method to rapidly determine both MCAD- and/or VLCAD-activity in human lymphocytes in order to confirm diagnosis. METHODOLOGY:LC-MS/MS was used to measure MCAD- or VLCAD-catalyzed production of enoyl-CoA and hydroxyacyl-CoA, in human lymphocytes. PRINCIPAL FINDINGS:VLCAD activity in controls was 6.95+/-0.42 mU/mg (range 1.95 to 11.91 mU/mg). Residual VLCAD activity of 4 patients with confirmed VLCAD-deficiency was between 0.3 and 1.1%. Heterozygous ACADVL mutation carriers showed residual VLCAD activities of 23.7 to 54.2%. MCAD activity in controls was 2.38+/-0.18 mU/mg. In total, 28 patients with suspected MCAD-deficiency were assayed. Nearly all patients with residual MCAD activities below 2.5% were homozygous 985A>G carriers. MCAD-deficient patients with one other than the 985A>G mutation had higher MCAD residual activities, ranging from 5.7 to 13.9%. All patients with the 199T>C mutation had residual activities above 10%. CONCLUSIONS:Our newly developed LC-MS/MS method is able to provide ample sensitivity to correctly and rapidly determine MCAD and VLCAD residual activity in human lymphocytes. Importantly, based on measured MCAD residual activities in correlation with genotype, new insights were obtained on the expected clinical phenotype

Plasma octanoyl-carnitine (C8:0) concentrations determined in dried blood spots during initial newborn screening and subsequent follow-up from patients carrying two confirmed <i>ACADM</i> mutations.

<p>Plasma octanoyl-carnitine (C8:0) concentrations determined in dried blood spots during initial newborn screening and subsequent follow-up from patients carrying two confirmed <i>ACADM</i> mutations.</p

Octanoyl-CoA oxidation, plasma medium-chain acylcarnitine levels and gene analysis of both <i>ACADM</i> alleles in subjects with suspected MCAD-deficiency.

<p>Case 1 to 18 were identified in NBS, with the exception of 4 and 8.</p>1<p>Relative residual MCAD enzyme activities are presented as a percentage of the mean of lymphocytes from healthy control (2.38 nmol · min⁻¹ · mg⁻¹, n = 6).</p>2<p>First octanoylcarnitine specimen (C8:0 I) obtained on day 2–5 of life and subsequent repeat specimen (C8:0 II) are shown in µmol · L⁻¹, cut-off was set at 0.30.</p>3<p>Parents of 12.</p>4<p>Parents of 16.</p>5<p>Intervening sequences: IVS2-32C>G, IVS3+10T>C, IVS5+32C>G, IVS7-22C>A.</p>6<p>Intervening sequences: IVS2-32C>G, IVS3+10T>C, IVS5+32C>G, IVS6-14A>G and IVS7-22C>A.</p>7<p>subjects with clinical suspicion of MCADD.</p

Multiple Reactant Monitoring (MRM) chromatograms of quenched VLCAD assay samples.

<p>C16:OH-CoA, m/z 1022.4 → 515.2 (A and B) and C16:1-CoA, m/z 1004.4 → 497.2 (C and D) after 0 (A and C) and 5 (B and D) min. of incubation.</p

Does lithium reduce acute suicidal ideation and behavior? : a protocol for a randomized, placebo-controlled multicenter trial of lithium plus Treatment As Usual (TAU) in patients with suicidal major depressive episode

Background: Lithium has proven suicide preventing effects in the long-term treatment of patients with affective disorders. Clinical evidence from case reports indicate that this effect may occur early on at the beginning of lithium treatment. The impact of lithium treatment on acute suicidal thoughts and/or behavior has not been systematically studied in a controlled trial. The primary objective of this confirmatory study is to determine the association between lithium therapy and acute suicidal ideation and/or suicidal behavior in inpatients with a major depressive episode (MDE, unipolar and bipolar disorder according to DSM IV criteria). The specific aim is to test the hypothesis that lithium plus treatment as usual (TAU), compared to placebo plus TAU, results in a significantly greater decrease in suicidal ideation and/or behavior over 5 weeks in inpatients with MDE. Methods/Design: We initiated a randomized, placebo-controlled multicenter trial. Patients with the diagnosis of a moderate to severe depressive episode and suicidal thoughts and/or suicidal behavior measured with the Sheehan-Suicidality-Tracking Scale (S-STS) will be randomly allocated to add lithium or placebo to their treatment as usual. Change in the clinician administered S-STS from the initial to the final visit will be the primary outcome. Discussion: There is an urgent need to identify treatments that will acutely decrease suicidal ideation and/or suicidal behavior. The results of this study will demonstrate whether lithium reduces suicidal ideation and behavior within the first 5 weeks of treatment

The role of passive immunization in the age of SARS-CoV-2: an update

The rapid spread of the corona virus pandemic is an existential problem for many people in numerous countries. So far, there is no effective vaccine protection or proven therapy available against the SARS-CoV-2 virus. In this review, we describe the role of passive immunization in times of the corona virus. Passive immunization could be a bridging technology to improve the immune defense of critically ill patients until better approaches with effective medications are available

Correction to:The role of passive immunization in the age of SARS-CoV-2: an update

An amendment to this paper has been published and can be accessed via the original article