Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer's disease model.

Many risk genes for the development of Alzheimer's disease (AD) are exclusively or highly expressed in myeloid cells. Microglia are dependent on colony-stimulating factor 1 receptor (CSF1R) signaling for their survival. We designed and synthesized a highly selective brain-penetrant CSF1R inhibitor (PLX5622) allowing for extended and specific microglial elimination, preceding and during pathology development. We find that in the 5xFAD mouse model of AD, plaques fail to form in the parenchymal space following microglial depletion, except in areas containing surviving microglia. Instead, Aβ deposits in cortical blood vessels reminiscent of cerebral amyloid angiopathy. Altered gene expression in the 5xFAD hippocampus is also reversed by the absence of microglia. Transcriptional analyses of the residual plaque-forming microglia show they exhibit a disease-associated microglia profile. Collectively, we describe the structure, formulation, and efficacy of PLX5622, which allows for sustained microglial depletion and identify roles of microglia in initiating plaque pathogenesis

The effect of scoliotic deformity on spine kinematics in adolescents

Background While adolescent idiopathic scoliosis (AIS) produces well characterized deformation in spinal form, the effect on spinal function, namely mobility, is not well known. Better understanding of scoliotic spinal mobility could yield better treatment targets and diagnoses. The purpose of this study was to characterize the spinal mobility differences due to AIS. It was hypothesized that the AIS group would exhibit reduced mobility compared to the typical adolescent (TA) group. Methods Eleven adolescents with right thoracic AIS, apices T6-T10, and eleven age- and gender-matched TAs moved to their maximum bent position in sagittal and coronal plane bending tasks. A Trakstar (Ascension Technologies Burlington, VT) was used to collect position data. The study was approved by the local IRB. Using MATLAB (MathWorks, Natick, MA) normalized segmental angles were calculated for upper thoracic (UT) from T1-T3, mid thoracic (MT) from T3-T6, lower thoracic (LT) from T6-T10, thoracolumbar (TL) from T10-L1, upper lumbar (UL) from L1-L3, and thoracic from T1-L1 by subtracting the standing position from the maximum bent position and dividing by number of motion units in each segment. Mann Whitney tests (α = 0.05) were used to determine mobility differences. Results The findings indicated that the AIS group had comparatively increased mobility in the periapical regions of the spine. The AIS group had an increase of 1.2° in the mid thoracic region (p = 0.01) during flexion, an increase of 1.0° in the mid thoracic region (p = 0.01), 1.5° in the thoracolumbar region (p = 0.02), and 0.7° in thoracic region (p = 0.04) during left anterior-lateral flexion, an increase of 6.0° in the upper lumbar region (p = 0.02) during right anterior-lateral flexion, and an increase of 2.2° in the upper lumbar region during left lateral bending (p < 0.01). Conclusions Participants with AIS did not have reduced mobility in sagittal or coronal motion. Contrarily, the AIS group often had a greater mobility, especially in segments directly above and below the apex. This indicates the scoliotic spine is flexible and may compensate near the apex

Retinoids regulate TGFβ signaling at the level of Smad2 phosphorylation and nuclear accumulation

AbstractIndirect regulation of transforming growth factor (TGF)-β signaling by retinoids occurs on a long-term timescale, secondary to transcriptional events. Studies by our group show loss of retinoid X receptor (RXR) alpha results in increased TGFβ2 in the midgestational heart, which may play a role in the cardiac defects seen in this model [S.W. Kubalak, D.R. Hutson, K.K. Scott and R.A. Shannon, Elevated transforming growth factor beta2 enhances apoptosis and contributes to abnormal outflow tract and aortic sac development in retinoic X receptor alpha knockout embryos, Development 129 (2002) 733–746.]. Acute and direct interactions between retinoid and TGFβ signaling, however, are not clearly understood. Treatment of dispersed hearts and NIH3T3 cells for 1 h with TGFβ and retinoids (dual treatment) resulted in increased phosphorylated Smad2 and Smad3 when compared to treatment with TGFβ alone. Of all dual treatments, those with the RXR agonist Bexarotene, resulted in the highest level of phosphorylated Smad2, a 7-fold increase over TGFβ2 alone. Additionally, during dual treatment phosphorylation of Smad2 occurs via the TGFβ type I receptor but not by increased activation of the receptor. As loss of RXRα results in increased levels of Smad2 phosphorylation in response to TGFβ treatment and since nuclear accumulation of phosphorylated Smad2 is decreased during dual treatment, we propose that RXRα directly regulates the activities of Smad2. These data show retinoid signaling influences the TGFβ pathway in an acute and direct manner that has been unappreciated until now

Breast cancer instructs dendritic cells to prime interleukin 13–secreting CD4+ T cells that facilitate tumor development

We previously reported (Bell, D., P. Chomarat, D. Broyles, G. Netto, G.M. Harb, S. Lebecque, J. Valladeau, J. Davoust, K.A. Palucka, and J. Banchereau. 1999. J. Exp. Med. 190: 1417–1426) that breast cancer tumors are infiltrated with mature dendritic cells (DCs), which cluster with CD4+ T cells. We now show that CD4+ T cells infiltrating breast cancer tumors secrete type 1 (interferon γ) as well as high levels of type 2 (interleukin [IL] 4 and IL-13) cytokines. Immunofluorescence staining of tissue sections revealed intense IL-13 staining on breast cancer cells. The expression of phosphorylated signal transducer and activator of transcription 6 in breast cancer cells suggests that IL-13 actually delivers signals to cancer cells. To determine the link between breast cancer, DCs, and CD4+ T cells, we implanted human breast cancer cell lines in nonobese diabetic/LtSz-scid/scid β2 microglobulin–deficient mice engrafted with human CD34+ hematopoietic progenitor cells and autologous T cells. There, CD4+ T cells promote early tumor development. This is dependent on DCs and can be partially prevented by administration of IL-13 antagonists. Thus, breast cancer targets DCs to facilitate its development

Bed of roses? The role of garden space in older people’s well-being

The purpose of this research was to investigate the role of outdoor housing environment (OHE), including front and back gardens, yards, courtyards, patios and balconies, in older people’s well-being. Descriptions of their OHEs were collected from 2558 individuals living in 526 distinct housing developments using a postal questionnaire. A large range of background variables were measured, mainly through the questionnaire. Characteristics of respondents’ immediate neighbourhood environments were measured from digital maps and satellite/bird’s-eye images. Among the OHE variables, statistically significant predictors of well-being were having one’s own patio (as opposed to shared or none), and having a green view from one’s living area (a positive effect on well-being). The authors conclude that it would be beneficial for older people’s housing to include private patio space, where possible, as well as a large amount of greenery. The research supports the claim that older people benefit from green space as much by viewing it from inside as spending time in it. If older people have no or very little garden space, a green street environment is likely to increase their well-being, especially if it can be seen from their home

A Moving Target: How We Define Avoidant/Restrictive Food Intake Disorder Can Double Its Prevalence

OBJECTIVE: The DSM-5 criteria for avoidant/restrictive food intake disorder (ARFID) include ambiguities. Diagnostic criteria that allow for clinical judgment are essential for clinical practice. However, ambiguities can have major implications for treatment access and comparability and generalizability of research studies. The purpose of this study was to determine the degree to which distinct operationalizations of the diagnostic criteria for ARFID contribute to differences in the frequency of individuals who are eligible for the ARFID diagnosis. METHODS: Because criteria B, C, and D are rule-outs, we focused on criterion A, identified 19 potential operational definitions, and determined the extent to which these different methods impacted the proportion of individuals who met criteria for ARFID in a sample of children, adolescents, and young adults (n = 80; September 2016–February 2020) enrolled in an avoidant/restrictive eating study. RESULTS: Within each criterion, the proportion of individuals meeting diagnostic criteria differed significantly across the methodologies (all P values < .008). Using the strictest definition of each criterion, 50.0% (n = 40) of participants met criteria for ARFID. In contrast, under the most lenient definition of each criterion, the number nearly doubled, resulting in 97.5% (n = 78) meeting ARFID criteria. CONCLUSIONS: Comparison of diagnostic definitions for ARFID among children, adolescents, and young adults confirmed a broad range of statistically distinct proportions within a single sample. Our findings support the need for additional contextual support and consensus among disciplines on operationalization in both research and clinical settings

BMQ

BMQ: Boston Medical Quarterly was published from 1950-1966 by the Boston University School of Medicine and the Massachusetts Memorial Hospitals