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Understanding Brain Delivery
Published in Carla Vitorino, Andreia Jorge, Alberto Pais, Nanoparticles for Brain Drug Delivery, 2021
Joana Bicker, Ana Fortuna, Gilberto Alves, Amílcar Falcäo
Drug delivery to the CNS through the BCSFB has been discouraged due to the larger surface area of the BBB, little mixing within the CSF, high CSF turnover and larger diffusion distance from the CSF to brain tissue than between brain capillaries [3, 45, 46]. It has also been referred that drugs injected into the CSF by the intrathecal route distribute to the blood and superficial brain areas but do not reach deep brain parenchyma [45]. However, Pizzo et al. [47] achieved the delivery of a macromolecule (immunoglobulin G [IgG]) into deep brain regions following intrathecal infusion in rats. The distribution occurred along perivascular spaces, probably through stomata on leptomeningeal cells in the subarachnoid space. This discovery created another possible route for drug delivery into the CNS.
The Role of Plasminogen Activator Inhibitor Type 1 (PAI-1) in the Clinical Setting, Including Deep Vein Thrombosis
Published in Pia Glas-Greenwalt, Fibrinolysis in Disease Molecular and Hemovascular Aspects of Fibrinolysis, 2019
Another American family thought to have inherited high PAI-1 levels was first described in 1983 by Stead et al.95 On the basis of low t-PA activity levels after a 5-min venous occlusion test, the authors concluded that t-PA release was deficient. In 1986 this family was restudied by Pizzo et al., who found an abnormal level of PAI-1 in the proband.96 The same family was again studied in 1993 by Bolan et al., who greatly extended the investigation.97 They examined 28 family members, of which 15 exhibited a deficiency of protein S. There was a clear correlation between protein S deficiency and idiopathic thrombosis, but not between PAI-1 levels and thrombosis.
Unexplained Fever In Hematologic Disorders
Published in Benedict Isaac, Serge Kernbaum, Michael Burke, Unexplained Fever, 2019
Fever is a well-known symptom in patients with acute leukemia (AL).79 Pizzo et al.20 have prospectively examined 1001 febrile episodes registered in their cancer patients during a 5-year period. The risk of developing a fever in pediatric and young adult patients with acute lymphoblastic leukemia (ALL) receiving cytotoxic therapy was 31 % and that of acute myeloblastic leukemia (AML)—45% . Boggs reports that fever was registered in about 25% of 5169 hospitalization days in 70 ALL patients.80 Fifty-three AML patients had fever in more than 40% of 2463 hospitalization days.
Early discontinuation of empirical antibacterial therapy in febrile neutropenia: the ANTIBIOSTOP study
Published in Infectious Diseases, 2018
Lenaïg Le Clech, Jean-Philippe Talarmin, Marie-Anne Couturier, Jean-Christophe Ianotto, Christophe Nicol, Ronan Le Calloch, Stéphanie Dos Santos, Pascal Hutin, Didier Tandé, Virginie Cogulet, Christian Berthou, Gaëlle Guillerm
Infections cause significant morbidity and mortality in haematological patients, in particular during chemotherapy-induced neutropenia, and immediate initiation of empirical antibiotherapy is mandatory in patients with febrile neutropenia [1,2]. This approach has been applied since the 1970s following publications by Pizzo and Schimpff which demonstrated benefits on infection-related mortality [3,4]. Subsequent studies endeavoured to define the best empirical treatment, leading to specific guidelines [2,5–9]. Broad-spectrum antibiotics are frequently administered until symptoms and neutropenia subside. This long-term exposure can trigger side effects like allergies, renal or hepatic toxicity, and bacterial resistance due to selective antimicrobial pressure. The latest 4th European Conference on Infections in Leukaemia (ECIL-4) guidelines advocate to stopping antibiotics in patients with fever of unknown origin (FUO) after apyrexia for 48 h or more, irrespective of neutrophil count or expected duration of neutropenia [2]. The possibility of earlier discontinuation of antibiotics, if patients remain febrile, has rarely been studied [10–12]. It is not recommended to stop antibiotics in patients with a clinically and/or microbiologically documented infection due to excessive mortality.
Silver nanoparticles inhibit neural induction in human induced pluripotent stem cells
Published in Nanotoxicology, 2018
Shigeru Yamada, Daiju Yamazaki, Yasunari Kanda
We demonstrated that ERK phosphorylation mediated the inhibitory effects of AgNPs on the levels of OTX2. (Figures 1 and 4). A previous report indicates that Mfn1 directly binds to Ras and Raf, resulting in the inhibition of the Ras–Raf–ERK signaling pathway by the biochemical analysis (Chen et al. 2004, 2014). Mfn1 reduction by AgNPs may reverse the ERK-mediated signaling inhibition. Mobilization of Ca2+ from intracellular stores, including mitochondria, was reported to result in phosphorylation of MAPKs, as the process was suppressed by chelation of intracellular Ca2+ in human T lymphoblastoid cells (Yu et al. 2000). As mitochondria are known to uptake into the matrix of any Ca2+ that has accumulated in the cytosol, dependent on MMP (Pizzo et al. 2012), mitochondrial dysfunction by AgNPs may cause an overload of Ca2+ in the cytosol, resulting in ERK activation. Moreover, ERK signaling inhibits neural induction by PAX6 silencing via upregulation of the stemness factors NANOG and OCT4, and downregulation of the homeobox transcription factor OTX2 (Greber et al. 2011). Thus, AgNP-induced ERK phosphorylation can downregulate PAX6 expression by the suppression of OTX2, thereby resulting in neurodevelopmental toxicity in iPSCs. Additionally, AgNP-induced ERK signaling may affect the expression of other PAX6 regulatory factors, such as NANOG and OCT4. While there is a correlation of decreased neural gene expression and aberrant Mfn1/ERK activities, a direct effect (e.g. decreased Mfn1 or increased ERK phosphorylation) on neural induction was not shown. In future, we should perform the recovery experiment of Mfn1 activity, and further investigate the effect of AgNPs on neural differentiation (including expression of other factors and morphologic maturation) via ERK.
Impact of low tacrolimus exposure and high tacrolimus intra-patient variability on the development of de novo anti-HLA donor-specific antibodies in kidney transplant recipients
Published in Expert Review of Clinical Immunology, 2019
Aleixandra Mendoza Rojas, Dennis A. Hesselink, Nicole M. van Besouw, Carla C. Baan, Teun van Gelder
Pizzo et al. studied 37 biopsies from 23 pediatric renal transplant patients on combined sirolimus and low-dose tacrolimus immunosuppression [62]. A high IPV of tacrolimus was associated with the formation of dnDSAs, graft rejection, and medication non-adherence. Of the biopsies with both high sirolimus and tacrolimus CV, no less than 67% developed dnDSA.