Infant feeding experiences and concerns among caregivers early in the COVID‐19 State of Emergency in Nova Scotia,Canada

The global emergency caused by the novel coronavirus (COVID‐19) pandemic has impacted access to goods and services such as health care and social supports, but the impact on infant feeding remains unclear. Thus, the objective of this study was to explore how caregivers of infants under 6 months of age perceived changes to infant feeding and other food and health‐related matters during the COVID‐19 State of Emergency in Nova Scotia, Canada. Four weeks after the State of Emergency began, between 17 April and 15 May 2020, caregivers completed this online survey, including the Perceived Stress Scale. Participants (n = 335) were 99% female and mostly White (87%). Over half (60%) were breastfeeding, and 71% had a household income over CAD$60,000. Most participants (77%) received governmental parental benefits before the emergency, and 59% experienced no COVID‐19‐related economic changes. Over three quarters of participants (77%) scored moderate levels of perceived stress. Common themes of concern included social isolation, COVID‐19 infection (both caregiver and infant), and a lack of access to goods, namely, human milk substitutes (‘infant formula’), and services, including health care, lactation support, and social supports. Most COVID‐19‐related information was sought from the internet and social media, so for broad reach, future evidence‐based information should be shared via online platforms. Although participants were experiencing moderate self‐perceived stress and shared numerous concerns, very few COVID‐19‐related changes to infant feeding were reported, and there were few differences by socio‐economic status, likely due to a strong economic safety net in this Canadian setting.     

Hypothermia and Occlusive Skin Wrap in the Low Birth Weight Premature Infant: An Evidentiary Review

Low-birth-weight (LBW) premature infants are born without the adaptive mechanisms needed for survival outside of the womb. These fragile infants require thermoprotective interventions that begin in the delivery room. Current heat preservation interventions such as a pre-warmed delivery room, warm blankets/towels, drying, radiant warmer tables, and skin-to-skin with mother are not as effective in preserving heat in the smallest of infants. Despite the use of current heat preservation strategies, LBW premature infants remain vulnerable to hypothermia and associated morbidities and mortality. The use of an occlusive skin wrap has been studied since the late 1960's as a method for heat loss prevention in infants at birth. This evidentiary review will explore the most recent research on occlusive skin wrap in the delivery room for heat preservation in the LBW premature infant and propose a guideline for use.     

Marine alkaloid Monanchocidin a overcomes drug resistance by induction of autophagy and lysosomal membrane permeabilization

Monanchocidin A (MonA) is a novel alkaloid recently isolated from the marine sponge Monanchora pulchra. The compound reveals cytotoxic activity in genitourinary cancers including cisplatin-sensitive and -resistant germ cell tumor (GCT) cell lines, hormone-sensitive and castration-resistant prostate carcinoma cell lines and different bladder carcinoma cell lines. In contrast, non-malignant cells were significantly less sensitive. MonA is highly synergistic with cisplatin in GCT cells. Induction of autophagy at lower and lysosomal membrane permeabilization (LMP) at higher concentrations were identified as the dominating modes of action. Cytotoxicity and protein degradation could be inhibited by 3-methyladenine, an inhibitor of autophagy. LMP was confirmed by loss of acridine orange staining of lysosoms and by release of cathepsin B. In conclusion, MonA exerts cytotoxiс activity by mechanisms different from “classical” apoptosis, and could be a promising new compound to overcome resistance to standard therapies in genitourinary malignancies.     

Double-Binding Botulinum Molecule with Reduced Muscle Paralysis: Evaluation in In Vitro and In Vivo Models of Migraine

With a prevalence of 15%, migraine is the most common neurological disorder and among the most disabling diseases, taking into account years lived with disability. Current oral medications for migraine show variable effects and are frequently associated with intolerable side effects, leading to the dissatisfaction of both patients and doctors. Injectable therapeutics, which include calcitonin gene–related peptide–targeting monoclonal antibodies and botulinum neurotoxin A (BoNT/A), provide a new paradigm for treatment of chronic migraine but are effective only in approximately 50% of subjects. Here, we investigated a novel engineered botulinum molecule with markedly reduced muscle paralyzing properties which could be beneficial for the treatment of migraine. This stapled botulinum molecule with duplicated binding domain—binary toxin-AA (BiTox/AA)—cleaves synaptosomal-associated protein 25 with a similar efficacy to BoNT/A in neurons; however, the paralyzing effect of BiTox/AA was 100 times less when compared to native BoNT/A following muscle injection. The performance of BiTox/AA was evaluated in cellular and animal models of migraine. BiTox/AA inhibited electrical nerve fiber activity in rat meningeal preparations while, in the trigeminovascular model, BiTox/AA raised electrical and mechanical stimulation thresholds in Aδ- and C-fiber nociceptors. In the rat glyceryl trinitrate (GTN) model, BiTox/AA proved effective in inhibiting GTN-induced hyperalgesia in the orofacial formalin test. We conclude that the engineered botulinum molecule provides a useful prototype for designing advanced future therapeutics for an improved efficacy in the treatment of migraine.Supplementary InformationThe online version contains supplementary material available at 10.1007/s13311-020-00967-7.Key Words: Migraine, botulinum, trigeminal, trigeminovascular, glyceryl trinitrate model, multivalent, neuronal delivery     

Glucocorticoid-Related Molecular Signaling Pathways Regulating Hippocampal Neurogenesis

Stress and glucocorticoid hormones regulate hippocampal neurogenesis, but the molecular mechanisms underlying their effects are unknown. We, therefore, investigated the molecular signaling pathways mediating the effects of cortisol on proliferation, neuronal differentiation, and astrogliogenesis, in an immortalized human hippocampal progenitor cell line. In addition, we examined the molecular signaling pathways activated in the hippocampus of prenatally stressed rats, characterized by persistently elevated glucocorticoid levels in adulthood. In human hippocampal progenitor cells, we found that low concentrations of cortisol (100 nM) increased proliferation (+16%), decreased neurogenesis into microtubule-associated protein 2 (MAP2)-positive neurons (−24%) and doublecortin (Dcx)-positive neuroblasts (−21%), and increased differentiation into S100β-positive astrocytes (+23%). These effects were dependent on the mineralocorticoid receptor (MR) as they were abolished by the MR antagonist, spironolactone, and mimicked by the MR-agonist, aldosterone. In contrast, high concentrations of cortisol (100 μM) decreased proliferation (−17%) and neuronal differentiation into MAP2-positive neurons (−22%) and into Dcx-positive neuroblasts (−27%), without regulating astrogliogenesis. These effects were dependent on the glucocorticoid receptor (GR), blocked by the GR antagonist RU486, and mimicked by the GR-agonist, dexamethasone. Gene expression microarray and pathway analysis showed that the low concentration of cortisol enhances Notch/Hes-signaling, the high concentration inhibits TGFβ-SMAD2/3-signaling, and both concentrations inhibit Hedgehog signaling. Mechanistically, we show that reduced Hedgehog signaling indeed critically contributes to the cortisol-induced reduction in neuronal differentiation. Accordingly, TGFβ-SMAD2/3 and Hedgehog signaling were also inhibited in the hippocampus of adult prenatally stressed rats with high glucocorticoid levels. In conclusion, our data demonstrate novel molecular signaling pathways that are regulated by glucocorticoids in vitro, in human hippocampal progenitor cells, and by stress in vivo, in the rat hippocampus.     

The protein tyrosine kinase inhibitor SU5614 inhibits FLT3 and induces growth arrest and apoptosis in AML-derived cell lines expressing a constitutively activated FLT3

Activating mutations of the protein tyrosine kinase (PTK) FLT3 can be found in approximately 30% of patients with acute myeloid leukemia (AML), thereby representing the most frequent single genetic alteration in AML. These mutations occur in the juxtamembrane (FLT3 length mutations; FLT3-LMs) and the second tyrosine kinase domain of FLT3-TKD and confer interleukin 3 (IL-3)-independent growth to Ba/F3 cells. In the mouse bone marrow transplantation model, FLT3-LMs induce a myeloproliferative syndrome stressing their transforming activity in vivo. In this study, we analyzed the pro-proliferative and antiapoptotic potential of FLT3 in FLT3-LM/TKD-mutation-transformed Ba/F3 cells and AML-derived cell lines. The PTK inhibitor SU5614 has inhibitory activity for FLT3 and selectively induces growth arrest, apoptosis, and cell cycle arrest in Ba/F3 and AML cell lines expressing a constitutively activated FLT3. In addition, the compound reverts the antiapoptotic and pro-proliferative activity of FLT3 ligand (FL) in FL-dependent cells. No cytotoxic activity of SU5614 was found in leukemic cell lines that express a nonactivated FLT3 or no FLT3 protein. At the biochemical level, SU5614 down-regulated the activity of the hyperphosphorylated FLT3 receptor and its downstream targets, signal transducer and activator of (STAT) 3, STAT5, and mitogen-activated protein kinase (MAPK), and the STAT5 target genes BCL-X(L) and p21. Our results show that SU5614 is a PTK inhibitor of FLT3 and has antiproliferative and proapoptotic activity in AML-derived cell lines that endogenously express an activated FLT3 receptor. The selective and potent cytotoxicity of FLT3 PTK inhibitors support a clinical strategy of targeting FLT3 as a new molecular treatment option for patients with FLT3-LM/TKD-mutation(+) AML.     

Mutations in the tyrosine kinase domain of FLT3 define a new molecular mechanism of acquired drug resistance to PTK inhibitors in FLT3-ITD-transformed hematopoietic cells

Activating mutations in the juxtamembrane domain (FLT3-length mutations, FLT3-LM) and in the protein tyrosine kinase domain (TKD) of FLT3 (FLT3-TKD) represent the most frequent genetic alterations in acute myeloid leukemia (AML) and define a molecular target for therapeutic interventions by protein tyrosine kinase (PTK) inhibitors. We could show that distinct activating FLT3-TKD mutations at position D835 mediate primary resistance to FLT3 PTK inhibitors in FLT3-transformed cell lines. In the presence of increasing concentrations of the FLT3 PTK inhibitor SU5614, we generated inhibitor resistant Ba/F3 FLT3-internal tandem duplication (ITD) cell lines (Ba/F3 FLT3-ITD-R1-R4) that were characterized by a 7- to 26-fold higher IC50 (concentration that inhibits 50%) to SU5614 compared with the parental ITD cells. The molecular characterization of ITD-R1-4 cells demonstrated that specific TKD mutations (D835N and Y842H) on the ITD background were acquired during selection with SU5614. Introduction of these dual ITD-TKD, but not single D835N or Y842H FLT3 mutants, in Ba/F3 cells restored the FLT3 inhibitor resistant phenotype. Our data show that preexisting or acquired mutations in the PTK domain of FLT3 can induce drug resistance to FLT3 PTK inhibitors in vitro. These findings provide a molecular basis for the evaluation of clinical resistance to FLT3 PTK inhibitors in patients with AML.     

Cytotoxic Activity of Salicylic Acid-Containing Drug Models with Ionic and Covalent Binding

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Cutting Forces and Tool Wear Investigation during Turning of Sintered Nickel-Cobalt Alloy with CBN Tools

This article describes issues related to the machining of parts made of sintered nickel-cobalt alloy. Longitudinal turning with a CBN (cubic boron nitride) tool was analyzed. The results of experiments showed the influence of cutting parameters in the field of finishing machining on the values of cutting forces and specific cutting force, taking into account the wear of the cutting edge. Measurements and analysis of the topography and roughness parameters of the machined surface, as well as the cutting tool wear, were presented. The microscopic examination showed that the average grain size of the sintered nickel-cobalt alloy was 3.22 ± 0.1 (μm). The presence of the hardening state variability of the material during machining, as well as the value of the cutting force fluctuation as a function of the tool wear VB, were stated. The specific cutting force values increased to a small degree for the tool wear in the range of VB = 0–0.2 mm, and reached similar values in the range k_c = 5500–7500 N/mm². The specific cutting force values increased significantly for wear VB > 0.2 mm and were characterized by a large variability. The occurring phenomena were analyzed and several explanations were proposed. A recommendation was developed for the machining of parts made of sintered nickel-cobalt alloy. The Taguchi method was used in the experiment methodology.