The catalytic enantioselective intramolecular ring-opening of oxetanes with alcohols is catalyzed by (salen)Co(III) complexes. Either a monomeric or oligomeric catalyst can be used successfully in ...this transformation, providing 3-substituted tetrahydrofurans in both high yield and enantioselectivity. This methodology extends the range of electrophiles that can be activated toward highly enantioselective addition reactions by (salen)metal catalysts to an important new class.
Distinct subsets of resident tissue macrophages are important in hematopoietic stem cell niche homeostasis and erythropoiesis. We used a myeloid reporter gene (Csf1r-eGFP) to dissect the persistence ...of bone marrow and splenic macrophage subsets following lethal irradiation and autologous hematopoietic stem cell transplantation in a mouse model. Multiple recipient bone marrow and splenic macrophage subsets survived after autologous hematopoietic stem cell transplantation with organ-specific persistence kinetics. Short-term persistence (5 weeks) of recipient resident macrophages in spleen paralleled the duration of extramedullary hematopoiesis. In bone marrow, radiation-resistant recipient CD169+ resident macrophages and erythroid-island macrophages self-repopulated long-term after transplantation via autonomous cell division. Posttransplant peak expansion of recipient CD169+ resident macrophage number in bone marrow aligned with the persistent engraftment of phenotypic long-term reconstituting hematopoietic stem cells within bone marrow. Selective depletion of recipient CD169+ macrophages significantly compromised the engraftment of phenotypic long-term reconstituting hematopoietic stem cells and consequently impaired hematopoietic reconstitution. Recipient bone marrow resident macrophages are essential for optimal hematopoietic stem cell transplantation outcomes and could be an important consideration in the development of pretransplant conditioning therapies and/or chemoresistance approaches.
•Recipient macrophages persist in hematopoietic tissues and self-repopulate via in situ proliferation after syngeneic transplantation.•Targeted depletion of recipient CD169+ macrophages after transplant impaired long-term bone marrow engraftment of hematopoietic stem cells.
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The microenvironment, or niche, surrounding a stem cell largely governs its cellular fate. Two anatomical niches for hematopoietic stem cells (HSCs) have been reported in the bone marrow, but a ...distinct function for each of these niches remains unclear. Here we report a new role for the adhesion molecule E-selectin expressed exclusively by bone marrow endothelial cells in the vascular HSC niche. HSC quiescence was enhanced and self-renewal potential was increased in E-selectin knockout (Sele(-/-)) mice or after administration of an E-selectin antagonist, demonstrating that E-selectin promotes HSC proliferation and is a crucial component of the vascular niche. These effects are not mediated by canonical E-selectin ligands. Deletion or blockade of E-selectin enhances HSC survival threefold to sixfold after treatment of mice with chemotherapeutic agents or irradiation and accelerates blood neutrophil recovery. As bone marrow suppression is a severe side effect of high-dose chemotherapy, transient blockade of E-selectin is potentially a promising treatment for the protection of HSCs during chemotherapy or irradiation.
The nature and function of macrophages at the center of erythroblastic islands is not fully understood. This review discusses novel findings on the phenotypic and molecular characterization of ...erythroblastic island macrophages, and their role in regulating normal and pathological erythropoiesis.
The phenotype to prospectively isolate erythroblastic island macrophages from mouse bone marrow has been identified. In-vivo depletion of erythroblastic island macrophages causes blockade of erythroblast maturation and delays erythropoietic recovery following chemical insults. The cytokine granulocyte colony-stimulating factor arrests medullary erythropoiesis by depleting erythroblastic island macrophages from the bone marrow. In-vivo ablation of macrophages improves anemia associated with β-thalassemia and reduces red blood cell counts in the mouse model of polycythemia vera. The role of cell adhesion molecules regulating interactions between erythroblastic island macrophages and erythroblasts has been clarified, and mechanisms of pyrenocyte engulfment by erythroblastic island macrophages have been demonstrated to involve Mer tyrosine kinase receptor.
Prospective isolation of mouse erythroblastic island macrophages together with new genetic mouse models to specifically target erythroblastic island macrophages will enable molecular studies to better define their role in controlling erythroblast maturation. These studies have revealed the key role of erythroblastic island macrophages in regulating normal erythropoiesis and could be interesting targets to treat β-thalassemia or polycythemia vera.
Similarly to other tissues, the bone marrow contains subsets of resident tissue macrophages, which are essential to maintain bone formation, functional hematopoietic stem cell (HSC) niches, and ...erythropoiesis. Pharmacologic doses of granulocyte colony-stimulating factor (G-CSF) mobilize HSC in part by interfering with the HSC niche-supportive function of BM resident macrophages. Because bone marrow macrophages are key to both maintenance of HSC within their niche and erythropoiesis, we investigated the effect of mobilizing doses of G-CSF on erythropoiesis in mice. We now report that G-CSF blocks medullar erythropoiesis by depleting the erythroid island macrophages we identified as co-expressing F4/80, vascular cell adhesion molecule-1, CD169, Ly-6G, and the ER-HR3 erythroid island macrophage antigen. Both broad macrophage depletion, achieved by injecting clodronate-loaded liposomes, and selective depletion of CD169+ macrophages, also concomitantly depleted F4/80+ VCAM-1+ CD169+ ER-HR3+ Ly-6G+ erythroid island macrophages and blocked erythropoiesis. This more precise phenotypic definition of erythroid island macrophages will enable studies on their biology and function in normal settings and on diseases associated with anemia. Finally, this study further illustrates that macrophages are a potent relay of innate immunity and inflammation on bone, hematopoietic, and erythropoietic maintenance. Agents that affect these macrophages, such as G-CSF, are likely to affect these three processes concomitantly.
The cytokines granulocyte colony-stimulating factor (G-CSF) and Flt3 ligand (Flt3-L) mobilize hematopoietic stem and progenitor cells into the peripheral blood of primates, humans, and mice. We ...recently reported that G-CSF administration causes a transient blockade of medullar erythropoiesis by suppressing erythroblastic island (EI) macrophages in the bone marrow. In the study described here, we investigated the effect of mobilizing doses of Flt3-L on erythropoiesis in mice in vivo. Similar to G-CSF, Flt3-L caused whitening of the bone marrow with significant reduction in the numbers of EI macrophages and erythroblasts. This was compensated by an increase in the numbers of EI macrophages and erythroblasts in the spleen. However, unlike G-CSF, Flt3-L had an indirect effect on EI macrophages, as it was not detected at the surface of EI macrophages or erythroid progenitors.
Adapting evidence-based interventions (EBIs) guided by implementation science frameworks is a promising way to bridge the gap between research and practice and advance effective sexual violence ...prevention in schools.
Abstract
Psychosocial guidelines recommend routine screening of depressive symptoms in adolescents and young adults (AYA) with diabetes. Best practices for screening in routine care and patient characteristics associated with depressive symptoms require further investigation. The purpose of this study was to examine psychometric properties of the Patient Health Questionnaire (PHQ-2 and PHQ-9); document rates of depressive symptoms and related clinical actions; and evaluate associations with patient characteristics. The Patient Health Questionnaire (PHQ-2 or PHQ-9) was administered at five pediatric academic medical centers with 2,138 youth with type 1 diabetes. Screening was part of routine clinical care; retrospective data from electronic health records were collected for the first screening date as well as 12 months prior. The PHQ demonstrated good psychometric properties. Evaluation of item-level PHQ-9 data identified 5.0% of AYA with at least moderate depressive symptoms who would not have been flagged for further screening using the PHQ-2 only. On the PHQ-9, 10.0% of AYA with type 1 diabetes endorsed elevated depressive symptoms and 7.0% endorsed thoughts of self-harm. Patients with moderate or greater depressive symptoms had a 43.9% documented referral rate for mental health treatment. Higher BMI, older age, public insurance, shorter diabetes duration, higher HbA1C, and a diabetic ketoacidosis (DKA) event in the past year were associated with depressive symptoms. The PHQ-9 identified AYA with elevated depressive symptoms that would not have been identified using the PHQ-2. Depressive symptoms were associated with negative diabetes indicators. To improve referral rates, standardized methods for provision and documentation of referrals are needed.
Our aim was to evaluate self-reported depressive symptoms and clinical outcomes during routine screening for adolescents and young adults with type 2 diabetes (T2D), and examine associations among ...depressive symptoms and demographic and clinical characteristics.
The Patient Health Questionnaire (PHQ) was administered to 197 adolescents and young adults with T2D using the PHQ-2 or PHQ-9 in routine pediatric diabetes care at 4 academic medical centres. Data from electronic health records were extracted from the screening date and 12 months earlier.
Adolescents and young adults with T2D (mean age, 16.85 years; 57% male; 77.2% non-Caucasian) completed the PHQ as part of routine diabetes care. On the PHQ, 19.3% of adolescents and young adults endorsed elevated depressive symptoms (PHQ score ≥10) and, among a subsample with item-level data (n=53), 18.9% endorsed thoughts of self-harm. Subsequently, 50.0% of those with depressive symptoms had a documented referral for mental health treatment in the electronic health record after the positive screening outcome. Older age, shorter diabetes duration, higher glycated hemoglobin level, being non-Hispanic white, more blood glucose checks per day and being prescribed oral medications were significantly associated with more depressive symptoms.
Screening for depressive symptoms identifies individuals in need of referral for mental health treatment. A focus on self-harm assessment, standardized methods for documentation of symptoms and mental health referrals and increased referral resources are needed.
Notre objectif était d’évaluer les symptômes de dépression autodéclarés et les résultats cliniques lors du dépistage systématique des adolescents et des jeunes adultes atteints du diabète de type 2 (DT2), et d’examiner l’association des symptômes dépressifs aux données démographiques et aux caractéristiques cliniques.
Nous avons fait passer un questionnaire sur la santé du patient (PHQ, soit le QSP-2 ou le QSP-9) à 197 adolescents et jeunes adultes atteints du DT2 lors des soins courants en diabète pédiatrique dans 4 centres universitaires qui offrent des soins médicaux. Nous avons extrait les données des dossiers médicaux électroniques à la date du dépistage et des 12 mois précédents.
Les adolescents et les jeunes adultes atteints du DT2 (âge moyen, 16,85 ans; 57 % de sexe masculin; 77,2 % non-Caucasiens) ont rempli le PHQ dans le cadre de soins courants en diabète. Au QSP, 19,3 % des adolescents et des jeunes adultes reconnaissaient avoir un nombre élevé de symptômes de dépression (score au QSP ≥ 10) et, dans un sous-échantillon de données (n = 53), 18,9 % reconnaissaient avoir pensé à l’automutilation. Par la suite, 50,0 % de ceux qui avaient des symptômes de dépression avaient une demande de consultation en santé mentale consignée dans les dossiers médicaux électroniques après les résultats positifs au dépistage. Le fait d’avoir un âge plus avancé, un diabète depuis moins longtemps, des concentrations plus élevées de l’hémoglobine glyquée, d’être un Blanc non hispanique, de faire des vérifications quotidiennes plus fréquentes de la glycémie et de recevoir des ordonnances de médicaments par voie orale était significativement associé à un nombre plus élevé de symptômes de dépression.
Le dépistage des symptômes de dépression permet de repérer les individus qui ont besoin d’être dirigés vers des services en santé mentale. Il est essentiel d’accorder une attention particulière à l’évaluation de l’automutilation, aux méthodes normalisées de consignation des symptômes et des demandes de consultation en santé mentale, et à l’accroissement des ressources pour l’orientation des patients.
Objective: To document rates of elevated depressive symptoms endorsed during routine screening for adolescents and young adults (AYA) with type 2 diabetes (T2D), review clinical actions taken in ...response to screening results, and evaluate associations of depressive symptoms with AYA characteristics.
Research Design and Methods: The Patient Health Questionnaire (PHQ) was administered to 218 AYA with T2D using the PHQ-2 or PHQ-9 in routine pediatric diabetes care at 4 academic medical centers. Data from electronic health records were collected from the screening date and 12 months prior.
Results: The mean age was 16.77 (SD 2.10 years); 56% male; 74% non-Hispanic White; Mean T2D duration 3.48 (SD 2.51 years). On the PHQ, 21.6% of AYA with T2D endorsed elevated depressive symptoms (PHQ score≥10) and 15.2% endorsed thoughts of self-harm. Older age, shorter T2D duration, not on insulin, and more blood glucose checks per day were significantly associated with more depressive symptoms. Of those AYAs endorsing the harm-to-self item, 8.3% were in mental health treatment. For AYAs expressing harm-to-self who were not in treatment (91.7%),18.2% did not have a documented referral for mental health treatment in the medical record.
Conclusions: Screening for depressive symptoms identifies individuals in need of referral for mental health treatment; however, a focus on self-harm assessment, standardized methods for documentation of symptoms, mental health referrals and increased referral resources are needed.
Disclosure
J.Y. Stone: None. S.A. Mulvaney: None. C.A. Mara: None. J.C. Kichler: None. S. Majidi: Advisory Panel; Self; Companion Medical. K.A. Driscoll: None. S.C. Westen: None. A. Rawlinson: None. L.M. Jacobsen: None. K.K. Hood: Research Support; Self; Dexcom, Inc. Speaker’s Bureau; Self; LifeScan, Inc., MedIQ. M. Monaghan: Research Support; Self; American Diabetes Association. R.N. Adams: Employee; Self; Virta Health Corp.
Funding
National Center for Advancing Translational Sciences (UL1TR002243, UL1TR001427)
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