Effects of Mobile Stroke Unit dispatch on blood pressure management and outcomes in patients with intracerebral haematoma: Results from the Berlin_Prehospital Or Usual Care Delivery in acute Stroke (B_PROUD) controlled intervention study.

INTRODUCTION: In patients with acute intracerebral haemorrhage (ICH) and elevated systolic blood pressure (BP), guidelines suggest that systolic BP reduction to <140 mmHg should be rapidly initiated. Compared with conventional care, Mobile Stroke Units (MSUs) allow for earlier ICH diagnosis through prehospital imaging and earlier BP lowering. PATIENTS AND METHODS: ICH patients were prospectively evaluated as a cohort of the controlled B_PROUD-study in which MSU availability alone determined MSU dispatch in addition to conventional ambulance. We used inverse probability of treatment weighting to adjust for confounding to estimate the effect of additional MSU dispatch in ICH patients. Outcomes of interest were 7-day mortality (primary), systolic BP (sBP) at hospital arrival, dispatch-to-imaging time, largest haematoma volume, anticoagulation reversal, length of in-hospital stay, 3-month functional outcome. RESULTS: Between February 2017 and May 2019, MSUs were dispatched to 95 (mean age: 72 ± 13 years, 45% female) and only conventional ambulances to 78 ICH patients (mean age: 71 ± 12 years, 44% female). After adjusting for confounding, we found shorter dispatch-to-imaging time (mean difference: -17.75 min, 95% CI: -27.16 to -8.21 min) and lower sBP at hospital arrival (mean difference = -16.31 mmHg, 95% CI: -30.64 to -6.19 mmHg) in the MSU group. We found no statistically significant difference for the other outcomes, including 7-day mortality (adjusted odds ratio: 1.43, 95% CI: 0.68 to 3.31) or favourable outcome (adjusted odds ratio = 0.67, 95% CI: 0.27 to 1.67). CONCLUSIONS: Although MSU dispatch led to sBP reduction and lower dispatch-to-imaging time compared to conventional ambulance care, we found no evidence of better outcomes in the MSU dispatch group.

Follow-up of Patients With Stroke Based on Opt-out Choice: Potential Approach for Acute Care Quality Registries or Observational Studies.

BACKGROUND AND OBJECTIVES: Restricting follow-up assessment of both interventional and observational studies to patients who provide informed consent introduces relevant selection bias-particularly by underrepresenting patients with neurologic communication deficits and impaired capacity to consent. Many patients who are initially unable to give consent may be willing to do so after recovery. Informing patients on study purposes and procedures with offering them the option of nonparticipation but not requesting explicit consent is called "opt-out" approach. We investigated whether an opt-out strategy yields meaningful follow-up rates in an acute stroke registry with an embedded controlled study. METHODS: The citywide Berlin-SPecific Acute Treatment in Ischemic or hAemorrhagic Stroke With Long Term Follow-up (B-SPATIAL) registry was designed to provide reliable information on process indicators and outcomes of specific acute stroke treatments to inform health care providers about quality of care and best practice strategies including the effects of a mobile stroke unit implementation. Because this information was regarded of high public interest, Berlin data protection authorities permitted data sampling without prior informed consent, using instead follow-up assessment on an "opt-out" basis. Patients were included if they had neurologic symptoms at ambulance or hospital arrival within 6 hours of onset and had a final diagnosis of stroke or TIA. Information on data collection and outcome assessment was sent by letter to patients 1 month before follow-up. RESULTS: From February 1, 2017, to January 31, 2020, a total of 10,597 patients were assessed. Thirty-one (0.3%) patients declined any data use, whereas 578 (5.5%) opted out of follow-up assessment. Of those not opting out (n = 9,988), functional outcome (modified Rankin Scale) was collected in 8,330 patients (83.4%) and vital status in 9,741 patients (97.5%). We received no complaints regarding data collection procedures. DISCUSSION: Opt-out-based follow-up collection offers a way to achieve high follow-up rates along with respecting patients' preferences.

Effects of metal salophene and saldach complexes on lymphoma and leukemia cells.

Schiff base transition metal complexes are an important class of compounds with great potential for therapeutic interventions. However, data on antileukemic and antilymphoma effects of these complexes are limited. The activity of N,N'-bis(salicylidene)-1,2-phenylenediamine (salophene, 1), its iron(II/III) and manganese(II/III) complexes as well as rac-trans-N,N'-bis(salicylidene)-1,2-cyclohexanediamine (saldach, 2) and its respective iron(II/III) complexes was evaluated against U-937 non-Hodgkin's lymphoma and the HL-60, SUP-B15, and K-562 leukemia cell lines. The free ligands induced in all cell lines, if at all, only marginal, concentration-dependent growth inhibitory effects, and did not trigger Cu/Zn superoxide dismutase (Cu/Zn SOD) release or induce apoptosis. [Fe(II) (salophene)] (3) and [Fe(III) (salophene)Cl] (4) blocked cellular growth, caused a strong release of Cu/Zn SOD and induced apoptosis. In contrast, the manganese analogs [Mn(II) (salophene)] (5) and [Mn(III) (salophene)OAc] (6) inhibited cell growth, caused the programmed cell death only at higher concentrations and did not provoke release of Cu/Zn SOD in any of the four cell lines. Weaker cell death-promoting effects were observed when the salophene moiety of 3 and 4 was replaced with saldach (complexes 7 and 8), indicating the influence exerted by the ligand structure. In conclusion, Schiff base transition metal complexes induce strong inhibitory effects on human lymphoma and leukemia cells.

[Fe(III)(salophene)Cl], a potent iron salophene complex overcomes multiple drug resistance in lymphoma and leukemia cells.

We demonstrate the cytotoxic potential of the Schiff base iron complex [Fe(III)(salophene)Cl] in vitro and ex vivo and illustrate its ability to overcome multiple drug resistance in vincristine and daunorubicine resistant leukemic cells (Nalm-6). Treatment of lymphoma cells (BJAB) with [Fe(III)(salophene)Cl] led to the exclusion of unspecific necrosis, a concentration-dependent inhibition of proliferation and a specific apoptotic cell death. We further detected a significant loss of the mitochondrial membrane potential in lymphoma cells and an up- and downregulation of various apoptosis relevant genes, respectively, indicating the involvement of the intrinsic mitochondrial pathway.

Influence of methoxy groups on the antiproliferative effects of [Fe(III)(salophene-OMe)Cl] complexes.

We synthesized methoxy-substituted iron(III)-salophene complexes ([Fe(III)(OMe-salophene)Cl] with salophene = N,N'-bis(salicylidene)-1,2-phenylenediamine) and analyzed their biological activity in MCF-7 and MDA-MB-231 breast cancer as well as in HT-29 colon carcinoma cells. The results obtained in a time-dependent chemosensitivity test clearly demonstrated the correlation between the cytotoxicity of the complexes and the position of methoxy substituents in the salicylidene moieties: 3-OCH(3) (4) < 5-OCH(3) (8) < H (2) < 4-OCH(3) (6) = 6-OCH(3) (10). Compounds 6 and 10 caused cytocidal effects already at a concentration of 0.5 µM. Both lead compound 2 and complex 8 showed similar time response curves, however, with a 5-fold lower activity compared to 6 and 10, respectively. Referring to [Fe(III)(salophene)Cl] (2), methoxy substitution was accompanied with the loss of tumor cell selectivity. Moreover, the free ligands (1, 3, 5, 7, and 9) were inactive.

[NiII(3-OMe-salophene)]: a potent agent with antitumor activity.

In this study, we investigated the anticancer properties of methoxy-substituted nickel(II)(salophene) derivatives. We demonstrated that the most active complex [NiII(3-OMe-salophene)] is not necrotic in Burkitt-like lymphoma cells (BJAB) and human B-cell precursor cells (Nalm-6). [NiII(3-OMe-salophene)] inhibited proliferation and induced apoptosis in a concentration dependent manner, giving evidence for the involvement of CD95 receptor-mediated, extrinsic pathway. Furthermore, [NiII(3-OMe-salophene)] overcame vincristine drug resistance in BJAB and Nalm-6 cells.

Relationship between anticancer activity and stereochemistry of saldach ligands and their iron(III) complexes.

(R,R)-, (S,S)- and (R,S)-N,N'-bis(salicylidene)-1,2-diaminocyclohexane (saldach) and their iron(III) complexes were screened for anticancer activity against MCF-7 and MDA-MB 231 breast cancer as well as HT-29 colon carcinoma cells. Antiproliferative effects depended on the presence of the central atom iron but were independent on the configuration at the saldach ligand. While the free ligands were inactive, the iron(III) derivatives displayed anticancer activity within a concentration range of 1 to 5 microM irrespective of the used cell line. At 5 microM they were even more active than cis-platin. A mode of action comparable to cis-platin can be excluded because it is very likely that the DNA is not the primary target of [Fe(III) (saldach)] complexes.

[N,N'-Bis(salicylidene)-1,2-phenylenediamine]metal complexes with cell death promoting properties.

We developed N,N'-bis(salicylidene)-1,2-phenylenediamine (salophene, 1) as a chelating agent for metal ions such as Mn(II/III), Fe(II/III), Co(II), Ni(II), Cu(II), and Zn(II). The resulting complexes, from which owing to the carrier ligand a selective mode of action is assumed, were tested for antiproliferative effects on the MCF-7 breast cancer cell line. The cytotoxicity in this assay depended on the nature of the transition metal used. Iron complexes in oxidation states +II and +III (3, 4) strongly reduced cell proliferation in a concentration-dependent manner, whereas, e.g., the manganese analogues 5 and 6 were only marginally active. Therefore, the [N,N'-bis(salicylidene)-1,2-phenylenediamine]iron(II/III) complexes 3 and 4 were selected for studies on the mode of action. Both complexes possessed high activity against various tumor cells, for instance, MDA-MB-231 mammary carcinoma cells as well as HT-29 colon carcinoma cells. They were able to generate reactive oxygen species, showed DNA binding, and induced apoptosis. Exchange of 1 by N,N'-bis(salicylidene)-1,2-cyclohexanediamine (saldach, 2) yielding complexes 7 and 8 reduced the in vitro effects drastically. An unequivocal mode of action cannot be deduced from these results, but it seems to be very likely that cell death is caused by interference with more than one intracellular target.