Intranasal (i.n.) drug application is a widely known and low-invasive route of administration that may be able to achieve rapid symptom control in terminally ill patients. According to the German S3 ...guideline "Palliative care for patients with incurable cancer", benzodiazepines, such as midazolam, are recommended for the treatment of terminal agitation. To the best of our knowledge there is no evidence for i.n. midazolam in terminally ill patients. We aim to assess the use of i.n. midazolam as an alternative to subcutaneous administration of the drug.
In this monocentric, randomised, controlled, open-label investigator initiated trial, n = 60 patients treated at the palliative care unit of a University Hospital will be treated with 5 mg midazolam i.n. versus 5 mg subcutaneous (s.c.) midazolam in the control arm when terminal agitation occurs (randomly assigned 1:1). The estimated recruitment period is 18 months. Treatment efficacy is defined as an improvement on the Richmond Agitation Sedation Scale (Palliative Version) (RASS-PAL) and a study specific numeric rating scale (NRS) before and after drug administration. Furthermore, plasma concentration determinations of midazolam will be conducted at t
= 0 min, t
= 5 min, and t
= 20 min using liquid chromatography/mass spectrometry (LC-MS). The primary objective is to demonstrate non-inferiority of midazolam i.n. in comparison to midazolam s.c. for the treatment of agitation in terminally ill patients.
Midazolam i.n. is expected to achieve at least equivalent reduction of terminal agitation compared to s.c. administration. In addition, plasma concentrations of midazolam i.n. are not expected to be lower than those of midazolam s.c. and the dynamics of the plasma concentration with an earlier increase could be beneficial.
German Clinical Trials Registry DRKS00026775, registered 07.07.2022, Eudra CT No.: 2021-004789-36.
A set of unimodal criteria for a tunable matching network is presented to make the objective function of the matching network to be unimodal, which leads to the finding of the global optimum point. ...Furthermore, the proposed unimodal criteria are extended to the lossy matching network.
Context.
Carbon is one of the most abundant components in the Universe. While silicates have been the main focus of solid phase studies in protoplanetary discs (PPDs), little is known about the solid ...carbon content especially in the planet-forming regions (~0.1–10 au). Fortunately, several refractory carbonaceous species present C-H bonds (such as hydrogenated nano-diamond and amorphous carbon as well as polycyclic aromatic hydrocarbons), which generate infrared (IR) features that can be used to trace the solid carbon reservoirs. The new mid-IR instrument MATISSE, installed at the Very Large Telescope Interferometer (VLTI), can spatially resolve the inner regions (~1–10 au) of PPDs and locate, down to the au-scale, the emission coming from carbon grains.
Aims.
Our aim is to provide a consistent view on the radial structure, down to the au-scale, as well as basic physical properties and the nature of the material responsible for the IR continuum emission in the inner disk region around HD 179218.
Methods.
We implemented a temperature-gradient model to interpret the disk IR continuum emission, based on a multiwavelength dataset comprising a broadband spectral energy distribution and VLTI
H
-,
L
-, and
N
-bands interferometric data obtained in low spectral resolution. Then, we added a ring-like component, representing the carbonaceous
L
-band features-emitting region, to assess its detectability in future higher spectral resolution observations employing mid-IR interferometry.
Results.
Our temperature-gradient model can consistently reproduce our dataset. We confirmed a spatially extended inner 10 au emission in
H
- and
L
-bands, with a homogeneously high temperature (~1700 K), which we associate with the presence of stochastically heated nano-grains. On the other hand, the
N
-band emitting region presents a ring-like geometry that starts at about 10 au with a temperature of 400 K. Moreover, the existing low resolution MATISSE data exclude the presence of aromatic carbon grains (i.e., producing the 3.3 μm feature) in close proximity tothe star (≲1 au). Future medium spectral resolution MATISSE data will confirm their presence at larger distances.
Conclusions.
Our best-fit model demonstrates the presence of two separated dust populations: nano-grains that dominate the near- to mid-IR emission in the inner 10 au region and larger grains that dominate the emission outward. The presence of such nano-grains in the highly irradiated inner 10 au region of HD 179218 requires a replenishment process. Considering the expected lifetime of carbon nano-grains from The Heterogeneous dust Evolution Model for Interstellar Solids (THEMIS model), the estimated disk accretion inflow of HD 179218 could significantly contribute to feed the inner 10 au region in nano-grains.Moreover, we also expect a local regeneration of those nano-grains by the photo-fragmentation of larger aggregates.
Infusion of endothelial progenitor cells (EPC), but not of mature endothelial cells, promotes neovascularization after ischemia. We performed gene expression profiling of EPC and endothelial cells to ...identify genes that might be important for the neovascularization capacity of EPC. Notably, the protease cathepsin L (CathL) was highly expressed in EPC as opposed to endothelial cells and was essential for matrix degradation and invasion by EPC in vitro. CathL-deficient mice showed impaired functional recovery following hind limb ischemia, supporting the concept of a crucial role for CathL in postnatal neovascularization. Infused CathL-deficient progenitor cells neither homed to sites of ischemia nor augmented neovascularization. Forced expression of CathL in mature endothelial cells considerably enhanced their invasive activity and sufficed to confer their capacity for neovascularization in vivo. We concluded that CathL has a critical role in the integration of circulating EPC into ischemic tissue and is required for EPC-mediated neovascularization.
Adult and embryonic stem cells hold great promise for regenerative medicine. Expression profiling of stem cells revealed a characteristic imprint of genes, so-called “stemness” genes, providing ...resistance to stress. Circulating progenitor cells with an endothelial phenotype (EPCs) can be isolated from peripheral blood and contribute to neovascularization and endothelial regeneration. We investigated whether EPCs are equipped with an antioxidative defense to provide resistance against oxidative stress. EPCs exhibited a significantly lower basal reactive oxygen species (ROS) concentration as compared with mature umbilical vein endothelial cells (HUVECs). Incubation with H2O2 (500 μM) or the redox cycler LY-83583 (10 μM) profoundly increased the ROS concentration to 3- and 4-fold and induced apoptosis in HUVECs. In contrast, H2O2 and LY-83583 induced only a minor increase in intracellular ROS levels and apoptosis in EPCs. Consistently, the expression of the intracellular antioxidative enzymes catalase, glutathione peroxidase and manganese superoxide dismutase (MnSOD), was significantly higher in EPCs versus HUVECs and human microvascular endothelial cells. In accordance, combined inhibition of these antioxidative enzymes increased ROS levels in EPCs and impaired EPC survival and migration. Taken together, EPCs reveal a higher expression of antioxidative enzymes and, thus, are exquisitely equipped to be protected against oxidative stress consistent with their progenitor cell character.
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