Thyroid hormones (THs) play a pivotal role in the regulation of metabolic activity throughout all life stages. Cross-talk with other hormone systems permits THs to coordinate metabolic changes as ...well as modifications in growth and maintenance in response to changing environmental conditions. The scope of this review is to explain the relevant basics of TH endocrinology, highlight pertinent topics that have been investigated so far, and offer guidance on measuring THs in non-invasively collected matrices.
The first part of the review provides an overview of TH biochemistry, which is necessary to understand and interpret the findings of existing studies and to apply non-invasive TH monitoring. The second part focuses on the role of THs in mammalian ecology, and the third part highlights the role of THs in growth and maintenance. The fourth part deals with the advantages and difficulties of measuring THs in non-invasively collected samples. This review concludes with a summary that considers future directions in the study of THs.
•Thyroid hormones (TH) are useful biomarkers to study mammalian ecology and growth•This article focuses on THs in healthy mammals, highlighting relationships between TH levels and environmental conditions•Urine and fecal samples allow long-term and non-invasive monitoring of TH levels in wild-living mammals•Considerations for extraction- and validation steps for using urine and fecal samples to measure THs are presented
The application of deep learning for automated segmentation (delineation of boundaries) of histologic primitives (structures) from whole slide images can facilitate the establishment of novel ...protocols for kidney biopsy assessment. Here, we developed and validated deep learning networks for the segmentation of histologic structures on kidney biopsies and nephrectomies. For development, we examined 125 biopsies for Minimal Change Disease collected across 29 NEPTUNE enrolling centers along with 459 whole slide images stained with Hematoxylin & Eosin (125), Periodic Acid Schiff (125), Silver (102), and Trichrome (107) divided into training, validation and testing sets (ratio 6:1:3). Histologic structures were manually segmented (30048 total annotations) by five nephropathologists. Twenty deep learning models were trained with optimal digital magnification across the structures and stains. Periodic Acid Schiff-stained whole slide images yielded the best concordance between pathologists and deep learning segmentation across all structures (F-scores: 0.93 for glomerular tufts, 0.94 for glomerular tuft plus Bowman’s capsule, 0.91 for proximal tubules, 0.93 for distal tubular segments, 0.81 for peritubular capillaries, and 0.85 for arteries and afferent arterioles). Optimal digital magnifications were 5X for glomerular tuft/tuft plus Bowman’s capsule, 10X for proximal/distal tubule, arteries and afferent arterioles, and 40X for peritubular capillaries. Silver stained whole slide images yielded the worst deep learning performance. Thus, this largest study to date adapted deep learning for the segmentation of kidney histologic structures across multiple stains and pathology laboratories. All data used for training and testing and a detailed online tutorial will be publicly available.
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Heterogeneity in disease course and treatment response among patients with MCD/FSGS necessitates a granular evaluation of kidney tissue features. This study aimed to identify histologic and ...ultrastructural descriptors of structural changes most predictive of clinical outcomes in the Nephrotic Syndrome Study Network (NEPTUNE).
Forty-eight histologic (37 glomerular, 9 tubulointerstitial, 2 vascular) and 20 ultrastructural descriptors were quantified by applying the NEPTUNE Digital Pathology Scoring System to NEPTUNE kidney biopsies. Outcomes included time from biopsy to disease progression, first complete remission of proteinuria, and treatment response. Relative importance of pathology and clinical predictors was obtained from random forest models, and predictive discrimination was assessed.
Among 224 participants (34% Black, 24% Hispanic), model performance was excellent, with predictive discrimination of 0.9 for disease progression, 0.85 for complete remission, and 0.81 for treatment response. The most predictive descriptors of outcomes included both conventional-
, global sclerosis or segmental sclerosis and interstitial fibrosis/tubular atrophy-and novel features, including adhesion, interstitial foam cells, deflation, periglomerular fibrosis, mononuclear white blood cells, endothelial cell abnormalities, microvillous transformation, and acute tubular injury.
The most predictive descriptors of clinical outcomes among MCD/FSGS patients reflected structural changes in multiple renal compartments. Reporting these descriptors should be standardized to guide prognostication of proteinuric glomerular diseases.
Unfiltered seawater samples from vertical profiles collected at 60 stations within the California Current during four summer cruises spanning a two-year period from 2014 to 2015, were analyzed for ...elemental mercury (Hg°), monomethyl mercury (MMHg), dimethyl mercury (DMHg) and total mercury (THg). Fog water samples, taken at sea and throughout a network of land based stations were also analyzed for MMHg and THg. Vertical profiles indicate that midwater regions around 300 m are associated with concentration maxima in methylated species. Cyclonic mesoscale eddies were shown to be strong sources of the gaseous mercury species to the lower atmosphere and a likely source of these species to fog. Calculated evasive flux of Hg0 and DMHg were greatest in these regions (34 and 11 pmol m−2 d−1, respectively), whereas anticyclonic eddies support little or no sea-air evasion. Incubation experiments showed that DMHg is stable over short time scales at natural seawater pH (7.8–8.2) but degrades rapidly to MMHg at low pH. Demethylation of only a small percent of the evading DMHg, on acidic marine aerosols associated with fog condensation nuclei, can account for over 100% of the MMHg observed in fog. The surface microlayer, enriched in MMHg (by 30 ×), may also contribute to sea-air flux through aerosol production. Neither shelf sediments nor oxygen minimum zones appear to be a major source of methylated mercury in the California Current.
The current classification system for focal segmental glomerulosclerosis (FSGS) and minimal change disease (MCD) does not fully capture the complex structural changes in kidney biopsies nor the ...clinical and molecular heterogeneity of these diseases.
Prospective observational cohort study.
221 MCD and FSGS patients enrolled in the Nephrotic Syndrome Study Network (NEPTUNE).
The NEPTUNE Digital Pathology Scoring System (NDPSS) was applied to generate scores for 37 glomerular descriptors.
Time from biopsy to complete proteinuria remission, time from biopsy to kidney disease progression (40% estimated glomerular filtration rate eGFR decline or kidney failure), and eGFR over time.
Cluster analysis was used to group patients with similar morphologic characteristics. Glomerular descriptors and patient clusters were assessed for associations with outcomes using adjusted Cox models and linear mixed models. Messenger RNA from glomerular tissue was used to assess differentially expressed genes between clusters and identify genes associated with individual descriptors driving cluster membership.
Three clusters were identified: X (n = 56), Y (n = 68), and Z (n = 97). Clusters Y and Z had higher probabilities of proteinuria remission (HRs of 1.95 95% CI, 0.99-3.85 and 3.29 95% CI, 1.52-7.13, respectively), lower hazards of disease progression (HRs of 0.22 95% CI, 0.08-0.57 and 0.11 95% CI, 0.03-0.45, respectively), and lower loss of eGFR over time compared with X. Cluster X had 1,920 genes that were differentially expressed compared with Y+Z; these reflected activation of pathways of immune response and inflammation. Six descriptors driving the clusters individually correlated with clinical outcomes and gene expression.
Low prevalence of some descriptors and biopsy at a single time point.
The NDPSS allows for categorization of FSGS/MCD patients into clinically and biologically relevant subgroups, and uncovers histologic parameters associated with clinical outcomes and molecular signatures not included in current classification systems.
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Apolipoprotein L1 (APOL1)-associated focal segmental glomerulosclerosis (FSGS) is the dominant form of FSGS in Black individuals. There are no targeted therapies for this condition, in part because ...the molecular mechanisms underlying APOL1’s pathogenic contribution to FSGS are incompletely understood. Studying the transcriptomic landscape of APOL1 FSGS in patient kidneys is an important way to discover genes and molecular behaviors that are unique or most relevant to the human disease. With the hypothesis that the pathology driven by the high-risk APOL1 genotype is reflected in alteration of gene expression across the glomerular transcriptome, we compared expression and co-expression profiles of 15,703 genes in 16 Black patients with FSGS at high-risk vs 14 Black patients with a low-risk APOL1 genotype. Expression data from APOL1-inducible HEK293 cells and normal human glomeruli were used to pursue genes and molecular pathways uncovered in these studies. We discovered increased expression of APOL1 and nine other significant differentially expressed genes in high-risk patients. This included stanniocalcin, which has a role in mitochondrial and calcium-related processes along with differential correlations between high- and low-risk APOL1 and metabolism pathway genes. There were similar correlations with extracellular matrix- and immune-related genes, but significant loss of co-expression of mitochondrial genes in high-risk FSGS, and an NF-κB-down regulating gene, NKIRAS1, as the most significant hub gene with strong differential correlations with NDUF family (mitochondrial respiratory genes) and immune-related (JAK-STAT) genes. Thus, differences in mitochondrial gene regulation appear to underlie many differences observed between high- and low-risk Black patients with FSGS.
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Steroids, the mainstay of treatment for nephrotic syndrome in children, have multiple adverse effects including growth suppression.
Anthropometric measurements in children < 18 years enrolled in the ...Nephrotic Syndrome Study Network (NEPTUNE) were collected. The longitudinal association of medication exposure and nephrotic syndrome characteristics with height z-score and growth velocity was determined using adjusted Generalized Estimating Equation regression and linear regression.
A total of 318 children (57.2% males) with a baseline age of 7.64 ± 5.04 years were analyzed. The cumulative steroid dose was 216.4 (IQR 61.5, 652.7) mg/kg (N = 233). Overall, height z-scores were not significantly different at the last follow-up compared to baseline (- 0.13 ± 1.21 vs. - 0.23 ± 1.71, p = 0.21). In models adjusted for age, sex, and eGFR, greater cumulative steroid exposure (β - 7.5 × 10
, CI - 1.2 × 10
, - 3 × 10
, p = 0.001) and incident cases of NS (vs. prevalent) (β - 1.1, CI - 2.22, - 0.11, p = 0.03) were significantly associated with lower height z-scores over time. Rituximab exposure was associated with higher height z-scores (β 0.16, CI 0.04, 0.29, p = 0.01) over time.
Steroid dose was associated with lower height z-score, while rituximab use was associated with higher height z-score.
In order to accommodate the ever increasing diversity and specialization of the practice of pharmacy, the University of Toledo College of Pharmacy (UTCP) Externship program has for over the past five ...years offered specialized externship experiences to selected students. UTCP has made a commitment to develop specific specialized objectives for each of the unique rotational experiences it offers. One specific area that met with a great deal of success over the past four years has been the experiences within the ever expanding long term care pharmacy environment. During the Winter Quarter of 1985, an opportunity to offer an externship experience with an independent consultant in the long term care field arose. The development of the specific objectives and the experiences that resulted from this externship rotation are described.
A 60-year-old man developed a subcutaneous mass in the right lower eyelid 2 1/2 years after enucleation of the left eye for a mixed-cell-type choroidal melanoma. Excision of the subcutaneous eyelid ...mass revealed the tumor to be a malignant melanoma composed of spindle B cells similar to those in the intraocular tumor. The patient's systemic evaluation, including liver enzymes, has remained normal, with no signs of further metastasis and no evidence of another primary melanoma for 14 months of postexcision follow-up. The significance of the rare occurrence of isolated metastatic melanoma from the choroid of one eye to the eyelid of the other is discussed.
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