CD19 + CD21lo/neg cells are increased in systemic sclerosis-associated interstitial lung disease

Interstitial lung disease (ILD) represents a significant cause of morbidity and mortality in systemic sclerosis (SSc). The purpose of this study was to examine recirculating lymphocytes from SSc patients for potential biomarkers of interstitial lung disease (ILD). Peripheral blood mononuclear cells (PBMCs) were isolated from patients with SSc and healthy controls enrolled in the Vanderbilt University Myositis and Scleroderma Treatment Initiative Center cohort between 9/2017–6/2019. Clinical phenotyping was performed by chart abstraction. Immunophenotyping was performed using both mass cytometry and fluorescence cytometry combined with t-distributed stochastic neighbor embedding analysis and traditional biaxial gating. This study included 34 patients with SSc-ILD, 14 patients without SSc-ILD, and 25 healthy controls. CD21^lo/neg cells are significantly increased in SSc-ILD but not in SSc without ILD (15.4 ± 13.3% vs. 5.8 ± 0.9%, p = 0.002) or healthy controls (5.0 ± 0.5%, p < 0.0001). While CD21^lo/neg B cells can be identified from a single biaxial gate, tSNE analysis reveals that the biaxial gate is comprised of multiple distinct subsets, all of which are increased in SSc-ILD. CD21^lo/neg cells in both healthy controls and SSc-ILD are predominantly tBET positive and do not have intracellular CD21. Immunohistochemistry staining demonstrated that CD21^lo/neg B cells diffusely infiltrate the lung parenchyma of an SSc-ILD patient. Additional work is needed to validate this biomarker in larger cohorts and longitudinal studies and to understand the role of these cells in SSc-ILD.

     

A literature-based treatment algorithm for low-grade neuroendocrine liver metastases

BackgroundThe optimal timing of treatment of liver metastases from low-grade neuroendocrine tumors (LG-NELM) varies significantly due to numerous treatment modalities and the literature supporting various treatment(s). This study sought to create and validate a literature-based treatment algorithm for LG-NELM.MethodsA treatment algorithm to maximize overall survival (OS) was designed using peer-reviewed articles evaluating treatment of LG-NELM. This algorithm was retrospectively applied to patients treated for LG-NELM at our institution. Deviation was determined based on whether or not a patient received treatment consistent with that recommended by the algorithm. Patients who did and did not deviate from the algorithm were compared with respect to OS and number of treatments.ResultsApplying our algorithm to a 149-patient cohort, 57 (38%) deviated from recommended treatment. Deviation occurred in the form of alternative (28, 49%) versus additional procedures (29, 51%). Algorithm deviators underwent significantly more procedures than non-deviators (median 1 vs. 2, p < 0.001). Cox model indicated no difference in OS associated with algorithm deviation (HR 1.19, p = 0.58) when controlling for age and tumor characteristics.ConclusionThis literature-based algorithm helps standardize treatment protocols in patients with LG-NELM and can reduce cost and risk by minimizing unnecessary procedures. Prospective implementation and validation is required.     

A Conformationally Gated Model of Methadone and Loperamide Transport by P-Glycoprotein

P-glycoprotein (Pgp) is a multidrug resistance transporter that limits the penetration of a wide range of neurotherapeutics into the brain including opioids. The diphenylpropylamine opioids methadone and loperamide are structurally similar, but loperamide has about a 4-fold higher Pgp-mediated transport rate. In addition to these differences, they showed significant differences in their effects on Pgp-mediated adenosine triphosphate (ATP) hydrolysis. The activation of Pgp-mediated ATP hydrolysis by methadone was monophasic, whereas loperamide activation of ATP hydrolysis was biphasic implying methadone has a single binding site and loperamide has 2 binding sites on Pgp. Quenching of tryptophan fluorescence with these drugs and digoxin showed competition between the opioids and that loperamide does not compete for the digoxin-binding site. Acrylamide quenching of tryptophan fluorescence to probe Pgp conformational changes revealed that methadone- and loperamide-induced conformational changes were distinct. These results were used to develop a model for Pgp-mediated transport of methadone and loperamide where opioid binding and conformational changes are used to explain the differences in the opioid transport rates between methadone and loperamide.     

Effect of Cardiorespiratory Fitness on Academic Achievement is Stronger in High‐SES Elementary Schools Compared to Low

BACKGROUND

Academic achievement is influenced by factors at the student, school, and community levels. We estimated the effect of cardiorespiratory fitness performance on academic performance at the school level in Georgia elementary schools and examined effect modification by sociodemographic factors.

METHODS

This study is a repeat cross‐sectional analysis of Georgia elementary schools between 2011 and 2014 (approximately 1138 schools per year). Multivariable beta regression estimated the effect of the proportion of 4th and 5th graders meeting cardiorespiratory fitness standards on the proportion of 5th graders passing standardized tests for Reading, English and Language Arts, Mathematics, Science, and Social Studies and considered potential interaction by school‐level socioeconomic status (SES), racial composition, and urbanity.

RESULTS

There was a 0.15 higher estimated odds (OR: 1.15 (1.09, 1.22)) of passing the mathematics standardized test for every 10‐percentage‐point increase in school‐level cardiorespiratory fitness among high‐SES schools and 0.04 higher odds (OR: 1.04 (1.02, 1.05)) for low‐SES schools. This pattern was similar for other academic subjects. No effect modification by racial composition or urbanity was observed for any academic subject.

CONCLUSIONS

Promoting physical fitness may be effective in improving academic performance among high‐SES schools, but additional strategies may be needed among lower‐SES schools.

     

Effects of plane of nutrition and arginine on ovarian follicles in non-pregnant sheep: Cell proliferation,and expression of endothelial nitric oxide and its receptor

The aim of this study was to investigate the role of the nitric oxide (NO) system in ovarian function, by determining if arginine (Arg) supplementation impacts follicle number, cell proliferation, and expression of the NO system members in nutritionally compromised ewes. Ewes were randomly assigned into maintenance (C, 100% requirements), excess (O; 2xC), or restricted (U; 0.6xC) diets 8 weeks prior to Arg treatment. Ewes were individually fed twice daily with pelleted diets. Ewes from each nutritional group were randomly assigned to one of two treatments: saline or Arg, which was initiated on day 0 of the estrous cycle and administered 3 times per day. Ovaries were collected at the early-luteal, mid-luteal and late-luteal/follicular phases of the estrous cycle to determine 1) the number of surface follicles, 2) follicle cell proliferation marked by Ki67 protein expression, and 3) expression of endothelial nitric oxide (eNOS; NOS3) and soluble guanylyl cyclase beta (sGC; GUCY1B3) protein and mRNA in granulosa (G) and theca (T) layers using immunohistochemistry followed by image analysis and qPCR, respectively. During nutritional treatment, C maintained body weight, O gained 6±1.2 kg, and U lost 14±1.3 kg. Our data show that: 1) Ki67 was expressed in all ovarian compartments, eNOS protein was detected in blood vessels of T and stroma, and sGC protein was detected in T cells, and blood vessels of T layer and other ovarian compartments; 2) plane of nutrition affected the number of surface follicles, and thus folliculogenesis, cell proliferation in the T layer, eNOS and sGC protein expression in T, and NOS3 and GUCY1B3 mRNA expression in G; 3) Arg treatment affected cell proliferation in G and T, eNOS and sGC protein expression in T, mRNA expression of NOS3 in T in all groups, and GUCY1B3 in G depending on the stage of the estrous cycle; and 4) G and T cell proliferation, and expression of eNOS and sGC protein in T was affected by the stage of the estrous cycle. Our data demonstrated that plane of nutrition and Arg are involved in the regulation of follicular functions in non-pregnant sheep.     

Extraordinary grip strength and specialized myology in the hyper‐derived hand of Perodicticus potto?

Previous behavioral reports of the African lorisid, Perodicticus potto, have speculated that these animals have an extraordinary grip strength. This ability is hypothesized to be facilitated by a range of anatomical features within the forelimb, ranging from the presence of a retia mirabilia in its wrist to the hyper‐abduction of its pollex. Despite numerous behavioral reports, however, this claim of extraordinary grip strength has not been empirically substantiated. This study quantifies the physiological cross‐sectional area of the digital flexor muscles within P. potto. These data are compared with a broad primate sample, including several similarly sized strepsirrhines. Contrary to expectation, we found that P. potto actually has relatively below‐average digital flexor PCSA. However, we identified other myological characteristics in the upper limb of P. potto that were unexpected, including the largest brachioradialis muscle (an elbow flexor) among our primate sample, and – despite P. potto having only a vestigial second digit – an independent digital extensor indicis that is absent in almost a quarter of our primate sample.     

Influence of biochemical composition on endplate cartilage tensile properties in the human lumbar spine

Endplate cartilage integrity is critical to spine health and is presumably impaired by deterioration in biochemical composition. Yet, quantitative relationships between endplate biochemical composition and biomechanical properties are unavailable. Using endplate cartilage harvested from human lumbar spines (six donors, ages 51–67 years) we showed that endplate biochemical composition has a significant influence on its equilibrium tensile properties and that the presence of endplate damage associates with a diminished composition–function relationship. We found that the equilibrium tensile modulus (5.9 ± 5.7 MPa) correlated significantly with collagen content (559 ± 147 µg/mg dry weight, r² = 0.35) and with the collagen/GAG ratio (6.0 ± 2.1, r² = 0.58). Accounting for the damage status of the adjacent cartilage improved the latter correlation (r² = 0.77) and indicated that samples with adjacent damage such as fissures and avulsions had a diminished modulus–collagen/GAG relationship (p = 0.02). Quasi‐linear viscoelastic relaxation properties (C, τ₁, and τ₂) did not correlate with biochemical composition. We conclude that reduced matrix quantity decreases the equilibrium tensile modulus of human endplate cartilage and that characteristics of biochemical composition that are independent of matrix quantity, that is, characteristics related to matrix quality, may also be important. © 2013 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 32:245–252, 2014.