Single-cell spatial proteomic imaging for human neuropathology.

Neurodegenerative disorders are characterized by phenotypic changes and hallmark proteopathies. Quantifying these in archival human brain tissues remains indispensable for validating animal models and understanding disease mechanisms. We present a framework for nanometer-scale, spatial proteomics with multiplex ion beam imaging (MIBI) for capturing neuropathological features. MIBI facilitated simultaneous, quantitative imaging of 36 proteins on archival human hippocampus from individuals spanning cognitively normal to dementia. Customized analysis strategies identified cell types and proteopathies in the hippocampus across stages of Alzheimer's disease (AD) neuropathologic change. We show microglia-pathologic tau interactions in hippocampal CA1 subfield in AD dementia. Data driven, sample independent creation of spatial proteomic regions identified persistent neurons in pathologic tau neighborhoods expressing mitochondrial protein MFN2, regardless of cognitive status, suggesting a survival advantage. Our study revealed unique insights from multiplexed imaging and data-driven approaches for neuropathologic analysis and serves broadly as a methodology for spatial proteomic analysis of archival human neuropathology. TEASER: Multiplex Ion beam Imaging enables deep spatial phenotyping of human neuropathology-associated cellular and disease features.

Self-report of symptoms in children with cancer younger than 8 years of age: a systematic review.

OBJECTIVE: The study's objective was to summarize the psychometric evaluation of self-report symptom instruments used in children with cancer younger than 8 years of age. METHODS: We conducted electronic searches of Ovid Medline, EMBASE, PsycInfo, Science Citation, Social Science Citation (Web of Science), and CINAHL. We included studies of children with cancer in which their self-report symptoms had been quantified and in which results were described for those younger than 8 years of age. The search was restricted to publications in English. Two reviewers screened studies and abstracted all data in duplicate. Descriptive analysis of reliability and validity was performed. RESULTS: Thirteen studies were included. Only one study recruited children <8 years alone. Most studies described reliability and validity in a wider age range cohort in which most children were older than 8 years of age. Of the eight studies that evaluated reliability within the younger age group, six raised concerns about poor internal consistency with Cronbach's alpha <0.7 in at least one dimension. Concerns about test re-test reliability and inter-rater reliability were also observed. None of the studies evaluated validity. CONCLUSIONS: We failed to demonstrate that currently available instruments to measure self-report symptoms are reliable or valid specifically for children with cancer younger than 8 years of age. Development of psychometrically robust instruments for younger children should be a priority.

Glucagon-like peptide-1 receptor expression on human eosinophils and its regulation of eosinophil activation.

BACKGROUND: Glucagon-like peptide-1 (GLP-1) and its receptor are part of the incretin family of hormones that regulate glucose metabolism. GLP-1 also has immune modulatory roles. OBJECTIVES: To measure the expression of the GLP-1 receptor (GLP-1R) on eosinophils and neutrophils in normal and asthmatic subjects and evaluate effects of a GLP-1 analog on eosinophil function. METHODS: Peripheral blood samples were taken from 10 normal and 10 allergic asthmatic subjects. GLP-1R expression was measured on eosinophils and neutrophils. Subsequently, the asthmatic subjects underwent allergen and diluent inhalation challenges, and GLP-1R expression was measured. Purified eosinophils, collected from mild asthmatic subjects, were stimulated with lipopolysaccharide (LPS) and a GLP-1 analog to evaluate eosinophil cell activation markers CD11b and CD69 and cytokine (IL-4, IL-5, IL-8 and IL-13) production. RESULTS: Glucagon-like peptide-1 receptor is expressed on human eosinophils and neutrophils. Eosinophil, but not neutrophil, expression of GLP-1R is significantly higher in normal controls compared to allergic asthmatics. The expression of GLP-1R did not change on either eosinophils or neutrophils following allergen challenge. A GLP-1 analog significantly decreased the expression of eosinophil-surface activation markers following LPS stimulation and decreased eosinophil production of IL-4, IL-8 and IL-13, but not IL-5. CONCLUSION AND CLINICAL RELEVANCE: Glucagon-like peptide-1 receptor is expressed on human eosinophils and neutrophils. A GLP-1 analog attenuates LPS-stimulated eosinophil activation. GLP-1 agonists may have additional adjunctive indications in treating persons with concomitant type 2 diabetes mellitus and asthma.

Percent improvement in renal pelvis antero-posterior diameter (PI-APD): Prospective validation and further exploration of cut-off values that predict success after pediatric pyeloplasty supporting safe monitoring with ultrasound alone.

INTRODUCTION: Renograms are frequently obtained post-pyeloplasty in patients with residual hydronephrosis to confirm adequate drainage. Recent evidence suggests that percent improvement in antero-posterior diameter (PI-APD) ≥38 is predictive of success. We sought to further explore PI-APD ranges that would allow identification of patients who would benefit from ultrasound (US) monitoring alone vs. post-operative renal scan, and those more likely to develop recurrent ureteropelvic junction obstruction (rUPJO). METHODS: A single-center prospectively-collected pyeloplasty database (2008-2015) was queried (n = 151). Only patients with both pre- and post-operative APD measurements were included (n = 138). PI-APD was divided into 3 categories: <20%; 20-39%; ≥40%. The following variables were collected post-operatively: patients monitored with US alone, renogram and US, rUPJO and minimal or resolved hydronephrosis (SFU ≤2; UTD ≤1; APD ≤15 mm). RESULTS: Mean age at first and last follow-up were 4.8 (median 4.0; range 0-60) months and 26.6 (median 20.5; range 1-77) months, respectively. Of 138 patients, 84 (61%) had US alone, 54 (39%) had a renogram and US post-operatively, and 6 (4%) developed rUPJO. Of 84 patients who had US alone, 71 (84%; p < 0.01) demonstrated ≥40% PI-APD. Of 54 patients with renogram and US 46 (85%; p < 0.01) had ≥40 PI-APD. Of the 6 patients who developed rUPJO, all were in the <20 PI-APD group (100%; p < 0.01). Resolution of hydronephrosis according to SFU, UTD and APD occurred in 96/138 (70%), 89/138 (64%) and 113/138 (82%) patients respectively. Of these, 87 (91%), 81 (91%), and 108 (95%) occurred in >40% PI-APD group. CONCLUSION: ≥40% PI-APD at the first post-operative visit strongly predicts pyeloplasty success, as up to 82% of these patients showed resolved hydronephrosis and 61% underwent non-invasive monitoring by US alone. Our data suggests that up to 85% of renograms may have been unnecessary. Finally, <20% PI-APD permitted identification of all rUPJO cases. Stratification of patients based in PI-APD is a promising strategy for further minimizing radiation exposure while safely detecting children at risk for rUPJO.

Transient lipoprotein deficiency at birth: a cause of low levels of vitamin E in the newborn.

In newborns, the level of vitamin E in blood is very low as compared to that of placental intervillous blood and maternal blood. In our attempt to investigate the role of placenta in the transfer of vitamin E from the maternal to the newborn circulation, we have discovered that vitamin E is able to enter placental blood but is not being efficiently transferred from the placental to the newborn circulation. It appears from our preliminary study that the most limiting factor in the transfer of vitamin E from the placental to the newborn circulation is the transient deficiency of prebeta lipoprotein in the newborn blood at birth. A transient lipoprotein deficiency is implicated as a cause of low levels of vitamin E in the newborn.