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Adrenoleukodystrophy (ALD) is an X-linked peroxisomal disease caused by a mutation in the ABCD1 gene, producing mutations in the very long chain fatty acid transporter, ALD protein. Cerebral ALD (cALD) is a severe phenotype of ALD with neuroinflammation and neurodegeneration. Elevated levels of Glycoprotein Nonmetastatic Melanoma Protein B (GNMPB) have been recently documented in neurodegenerative diseases such as Alzheimer’s disease, Multiple Sclerosis and Amyotrophic Lateral Sclerosis. Our objective was to measure the levels cerebral spinal fluid (CSF) GNMPB in cALD patients to determine if GNMPB could be a potential biomarker in tracking cALD disease progression. CSF GNMPB levels were significantly higher in cALD patients versus controls (2407 ± 1672 pg/mL vs. 639.5 ± 404 pg/mL, p = 0.0009). We found a positive correlation between CSF GNMPB and MRI disease severity score levels (R2 = 0.3225, p p = 0.0204). Boys with more severe neurologic deficits also had higher levels of CSF GNMPB (p 2 = 0.2512, p = 0.0244). These data show that GNMPB could be a potential biomarker of cALD disease state and further studies should evaluate it as a predictor of the disease progression.

Hematopoietic cell homing after hematopoietic cell transplant (HCT) is governed by several pathways involving marrow niche cells that are evoked after pre-HCT conditioning. To understand the factors that play a role in homing, we performed expression analysis on zebrafish marrow niche cells following conditioning. We determined that the noncollagenous protein extracellular matrix related protein dermatopontin (Dpt) was upregulated sevenfold in response to irradiation. Studies in mice revealed DPT induction with radiation and lipopolysaccharide exposure. Interestingly, we found that coincubation of zebrafish or murine hematopoietic cells with recombinant DPT impedes hematopoietic stem and progenitor cell homing by 50% and 86%, respectively. Similarly, this translated into a 24% reduction in long-term engraftment (vs control; P = .01). We found DPT to interact with VLA-4 and block hematopoietic cell–endothelial cell adhesion and transendothelial migration. Finally, a DPT-knockout mouse displayed a 60% increase in the homing of hematopoietic cells vs wild-type mice (P = .03) with a slight improvement in long-term lin−SCA1+cKIT+-SLAM cell engraftment (twofold; P = .04). These data show that the extracellular matrix–related protein DPT increases with radiation and transiently impedes the transendothelial migration of hematopoietic cells to the marrow.

We compared the Cox model with the Fine-Gray model when assessing the risk of low-trauma re-fractures. The risk of re-fracture was consistently higher when using the Cox model compared with the Fine-Gray model. The Fine-Gray model more accurately assesses the risk of re-fracture when a competing risk is present. Compared with the Kaplan-Meier and Cox model, the Fine-Gray competing risk model was developed to take competing risks into account, which provides a better estimation for the risk of the main outcome of interest when one or more competing risks are presented. To date, it remains underused. This study aims to use a case study to illustrate why and how the Fine-Gray model should be used and interpreted, especially when a competing risk is present. Using a cohort of patients who presented to a NSW hospital with a non-trauma-related fracture between 2013/2014 and 2017/2018, the cumulative incidence and rate of re-fracture were estimated by the Kaplan-Meier and the Cox model, and by the Fine-Gray model when deaths present as competing events. The cumulative incidence of re-fracture at day 1825 (5 years) was 20.7% when using the Kaplan-Meier model and was 17.7% when using the Fine-Gray model. The estimations of cumulative incidence or rate of re-fracture were consistently higher by traditional survival analyses (Kaplan-Meier or Cox) compared with the Fine-Gray model. For patients aged 90 years and older, the re-fracture incidence at year 5 was estimated to be 66% vs. 28% whereas patients with a history of osteoporosis were 44% vs. 31%. Similarly, compared with patients without osteoporosis history, the estimated re-fracture rate for those with osteoporosis was 9.2 times higher by the Cox model but only 2.6 times higher by the Fine-Gray model. The Fine-Gray model more accurately estimates the cumulative incidence of re-fracture and the effect of covariates on the hazard rate than the Kaplan-Meier and Cox models in the presence of a competing risk. This accuracy improves the larger the rate of a competing event.

Ketosis is a prevalent periparturient metabolic disorder and we hypothesize that lipopolysaccharide (LPS) infiltration may play a key role in its etiology. Study objectives were to characterize biomarkers of inflammation during the transition period in healthy and clinically diagnosed ketotic cows. Cows were retrospectively categorized into one of two groups: healthy and clinically diagnosed ketotic. Two data sets were utilized; the first dataset (Study A) was obtained as a subset of cows (n=16) enrolled in a larger experiment conducted at the Iowa State University Dairy utilizing Holstein cows (8 healthy; 8 ketotic), and the second dataset (Study B; 22 healthy; 22 ketotic) was obtained from a commercial farm. For both experiments, blood samples were collected prior to and following calving. Ketotic cows in both studies had reduced milk production compared to healthy cows (P0.01). Post-calving, ketotic cows had increased serum amyloid A (4.2 and 1.8 fold in studies A and B, respectively; P=0.03 and P=0.04), haptoglobin (6 fold and ~4 fold; P=0.04 and P=0.03), and lipopolysaccharide binding protein (66 and 45%; P0.01 and P=0.02) compared with their healthy counterparts. Antepartum circulating LPS in ketotic cows was increased (2.3 fold; P=0.01) compared to healthy cows in Study B. In summary, increased biomarkers of inflammation appear to be closely associated with ketosis in transition dairy cows.

The metabolic consequences of heat stress (HS) are atypical (i.e. hyperinsulinemia) considering the animal's nutritional status and a compromised intestinal barrier may initiate the pathophysiologi...

Low‐frequency sine tones can have large interaural time differences, but high‐frequency tones cannot. If listeners estimate the lateral positions of tones of different frequency, using a fixed lateralization response scale, the estimates may depend on the experimental blocking of the tones. A context where all frequencies appear equally often (mixed) serves as a standard. It was hypothesized that a context with tones blocked on frequency would lead to abnormally large lateral position estimates for high‐frequency tones because of a tendency to use the entire response scale in any stimulus‐range context. Four listeners estimated the lateral positions of sine tones with frequencies 200, 500, 750, and 1,000 Hz having all possible interaural phase differences (IPD) spaced by 30 deg. Fixed‐frequency blocks were done first, then mixed. Very little trace of the hypothesized effect was observed, either in the overall range of responses or in the slope of the response‐IPD function for small IPD values. The same listeners matched the laterality of the same tones using the interaural level difference (ILD) of a narrow noise band. Relative slopes of the ILD‐IPD functions agreed with slopes of the lateral position estimates. [Work supported by the NIDCD.]