Adaptive response to inflammation contributes to sustained myelopoiesis and confers a competitive advantage in myelodysplastic syndrome HSCs.

Despite evidence of chronic inflammation in myelodysplastic syndrome (MDS) and cell-intrinsic dysregulation of Toll-like receptor (TLR) signaling in MDS hematopoietic stem and progenitor cells (HSPCs), the mechanisms responsible for the competitive advantage of MDS HSPCs in an inflammatory milieu over normal HSPCs remain poorly defined. Here, we found that chronic inflammation was a determinant for the competitive advantage of MDS HSPCs and for disease progression. The cell-intrinsic response of MDS HSPCs, which involves signaling through the noncanonical NF-κB pathway, protected these cells from chronic inflammation as compared to normal HSPCs. In response to inflammation, MDS HSPCs switched from canonical to noncanonical NF-κB signaling, a process that was dependent on TLR-TRAF6-mediated activation of A20. The competitive advantage of TLR-TRAF6-primed HSPCs could be restored by deletion of A20 or inhibition of the noncanonical NF-κB pathway. These findings uncover the mechanistic basis for the clonal dominance of MDS HSPCs and indicate that interfering with noncanonical NF-κB signaling could prevent MDS progression.

Pediatric Gnathic Bony and Mesenchymal Tumors.

Evaluation of bone pathology within the head and neck region, particularly the gnathic bonesis is complex, demonstrating unique pathologic processes. In part, this variation is due to odontogenesis and the embryological cells that may be involved, which can contribute to disease development and histologic variability. As with any boney pathosis, the key is to have clinical correlation, particularly with radiographic imaging prior to establishing a definitive diagnosis. This review will cover those entities that have a predilection for the pediatric population, and while it is not all inclusive, it should serve as a foundation for the pathologist who is evaluating bony lesions involving the craniofacial skeleton.

Pediatric Odontogenic Tumors.

Odontogenic tumors are rare tumors of the jaws that arise from remnants of the tooth forming apparatus. Some odontogenic tumors demonstrate strong predilection for pediatric patients including the unicystic ameloblastoma, adenomatoid odontogenic tumor, ameloblastic fibroma, ameloblastic fibro-odontoma, odontoma, and primordial odontogenic tumor. In this review, we discuss the clinical, radiographic, histopathologic, and molecular characteristics of select odontogenic tumors that demonstrate pediatric predilection and review management.

Genomic landscape of Epstein-Barr virus-positive extranodal marginal zone lymphomas of mucosa-associated lymphoid tissue.

Epstein-Barr virus (EBV)-positive extranodal marginal zone lymphomas of mucosa-associated lymphoid tissue (MALT lymphomas) were initially described in solid organ transplant recipients, and, more recently, in other immunodeficiency settings. The overall prevalence of EBV-positive MALT lymphomas has not been established, and little is known with respect to their genomic characteristics. Eight EBV-positive MALT lymphomas were identified, including 1 case found after screening a series of 88 consecutive MALT lymphomas with EBER in situ hybridization (1%). The genomic landscape was assessed in 7 of the 8 cases with a targeted high throughput sequencing panel and array comparative genomic hybridization. Results were compared to published data for MALT lymphomas. Of the 8 cases, 6 occurred post-transplant, 1 in the setting of primary immunodeficiency, and 1 case was age-related. Single pathogenic/likely pathogenic mutations were identified in 4 of 7 cases, including mutations in IRF8, BRAF, TNFAIP3, and SMARCA4. Other than TNFAIP3, these genes are mutated in <3% of EBV-negative MALT lymphomas. Copy number abnormalities were identified in 6 of 7 cases with a median of 6 gains and 2 losses per case, including 4 cases with gains in regions encompassing several IRF family or interacting genes (IRF2BP2, IRF2, and IRF4). There was no evidence of trisomies of chromosomes 3 or 18. In summary, EBV-positive MALT lymphomas are rare and, like other MALT lymphomas, are usually genetically non-complex. Conversely, while EBV-negative MALT lymphomas typically show mutational abnormalities in the NF-κB pathway, other than the 1 TNFAIP3-mutated case, no other NF-κB pathway mutations were identified in the EBV-positive cases. EBV-positive MALT lymphomas often have either mutations or copy number abnormalities in IRF family or interacting genes, suggesting that this pathway may play a role in these lymphomas.

Fatty acid composition and N2 solubility in triacylglycerol-rich adipose tissue: the likely importance of intact molecular structure.

Diving tetrapods (sea turtles, seabirds and marine mammals) are a biologically diverse group, yet all are under similar constraints: oxygen limitation and increased hydrostatic pressure at depth. Adipose tissue is important in the context of diving because nitrogen gas (N2) is five times more soluble in fat than in blood, creating a potential N2 sink in diving animals. Previous research demonstrates that unusual lipid composition [waxes and short-chained fatty acids (FA)] in adipose tissue of some whales leads to increased N2 solubility. We evaluated the N2 solubility of adipose tissue from 12 species of diving tetrapods lacking these unusual lipids to explore whether solubility in this tissue can be linked to lipid structure. Across all taxonomic groups, the same eight FA accounted for 70-80% of the entire lipid profile; almost all adipose tissues were dominated by monounsaturated FA (40.2-67.4 mol%). However, even with consistent FA profiles, there was considerable variability in N2 solubility, ranging from 0.051±0.003 to 0.073±0.004 ml N2 ml-1 oil. Interestingly, differences in N2 solubility could not be attributed to taxonomic group (P=0.06) or FA composition (P>0.10). These results lead to two main conclusions: (1) in triacylglycerol-only adipose tissues, the FA pool itself may not have a strong influence on N2 solubility; and (2) samples with similar FA profiles can have different N2 solubility values, suggesting that 3D arrangement of individual FA within a triacylglycerol molecule may have important roles in determining N2 solubility.

Microvessel density, lipid chemistry and N2 solubility in human and pig adipose tissue.

Decompression sickness (DCS) occurs when nitrogen gas (N2) comes out of solution too quickly, forming bubbles in the blood and tissues. These bubbles can be a serious condition; thus it is of extreme interest in the dive community to model DCS risk. Diving models use tissue compartments to calculate tissue partial pressures, often using data obtained from other mammalian species (i.e., pigs). Adipose tissue is an important compartment in these models because N2 is five times more soluble in fat than in blood; at any blood/tissue interface N2 will diffuse into the fat and can lead to bubble formation on ascent. Little is known about many characteristics of adipose tissue relevant to diving physiology. Therefore, we measured microvessel density and morphology, lipid composition, and N2 solubility in adipose tissue from humans and pigs. Human adipose tissue has significantly higher microvascular density (1.79 ± 0.04 vs. 1.21 ± 0.30%), vessel diameter (10.25 ± 0.28 vs. 6.72 ± 0.60 µm), total monounsaturated fatty acids (50.1 vs. 41.2 mol%) and N2 solubility (0.061 ± 0.003 vs. 0.054 ± 0.004 mL N2 mL⁻ ¹ oil) compared to pig tissue. Pig adipose tissue has significantly higher lipid content (76.1 ± 4.9 vs. 64.6 ± 5.1%) and total saturated fatty acids (38.8 vs. 29.5 mol%). Though two important components in gas kinetics within adipose tissue during diving (blood flow rates and degree of perfusion) are not well understood, our results indicate differences between the adipose tissue of humans and pigs. This suggests data from swine may not exactly predict gas dynamics for estimating DCS in humans.

Medication use and medical history of 155 patients with oral lichenoid lesions: a retrospective study.

Several medications have been reported as possible etiologic factors for oral lichen planus (OLP) and oral lichenoid lesions (OLLs). This study investigated the medication profile and medical history of patients with biopsy-proven OLP or OLLs, also classified by the clinically nonspecific term oral lichenoid mucositis (OLM), in a busy oral medicine clinic. The University of Florida College of Dentistry records from 2009 to 2014 were searched retrospectively for all patients with a biopsy-proven diagnosis of OLP, OLLs, or OLM. Patients were excluded if dysplasia or carcinoma was diagnosed concurrently at the same biopsy site. The demographics, clinical parameters, systemic diseases, histologic diagnosis, and direct immunofluorescence testing results were recorded. Medication category use was recorded based on both commonly used medications and those that have been reportedly linked to lichenoid disease in the literature. A total of 155 patients with an average age of 63.6 years were included. The majority of patients were women (76.8%) and Caucasian (91.8%). Most of the lesions were multifocal and mixed (white-red) in appearance. The most common systemic conditions were hypertension (n = 80; 51.6%) followed by thyroid disease (n = 52; 33.5%) and diabetes (n = 26; 16.8%). Antihypertensives were the most common medication category followed by, in descending order, nonsteroidal anti-inflammatory drugs, cholesterol-lowering medications, psychiatric medications, and thyroid replacement drugs. The records revealed that 87.7% of the patients took at least 1 medication from 1 of the categories studied. Medication use is common in patients with biopsy-proven OLP or OLLs. Although causation cannot be assessed from the results of this study, the clinician should consider the possibility of medication as a complicating factor in patients with OLP or OLLs.

Does It Pay to Penalize Hospitals for Excess Readmissions? Intended and Unintended Consequences of Medicare's Hospital Readmissions Reductions Program.

To incentivize hospitals to provide better quality care at a lower cost, the Affordable Care Act of 2010 included the Hospital Readmissions Reduction Program (HRRP), which reduces payments to hospitals with excess 30-day readmissions for Medicare patients treated for certain conditions. We use triple difference estimation to identify the HRRP's effects in Virginia hospitals; this method estimates the difference in changes in readmission over time between patients targeted by the policy and a comparison group of patients and then compares those difference-in-differences estimates in patients treated at hospitals with readmission rates above the national average (i.e., those at risk for penalties) and patients treated at hospitals with readmission rates below or equal to the national average (those not at risk). We find that the HRRP significantly reduced readmission for Medicare patients treated for acute myocardial infarction (AMI). We find no evidence that hospitals delay readmissions, treat patients with greater intensity, or alter discharge status in response to the HRRP, nor do we find changes in the age, race/ethnicity, health status, and socioeconomic status of patients admitted for AMI. Future research on the specific mechanisms behind reduced AMI readmissions should focus on actions by healthcare providers once the patient has left the hospital. Copyright © 2016 John Wiley & Sons, Ltd.

Pharmacological Modulation of Photoreceptor Outer Segment Degradation in a Human iPS Cell Model of Inherited Macular Degeneration.

Degradation of photoreceptor outer segments (POS) by retinal pigment epithelium (RPE) is essential for vision, and studies have implicated altered POS processing in the pathogenesis of some retinal degenerative diseases. Consistent with this concept, a recently established hiPSC-RPE model of inherited macular degeneration, Best disease (BD), displayed reduced rates of POS breakdown. Herein we utilized this model to determine (i) if disturbances in protein degradation pathways are associated with delayed POS digestion and (ii) whether such defect(s) can be pharmacologically targeted. We found that BD hiPSC-RPE cultures possessed increased protein oxidation, decreased free-ubiquitin levels, and altered rates of exosome secretion, consistent with altered POS processing. Application of valproic acid (VPA) with or without rapamycin increased rates of POS degradation in our model, whereas application of bafilomycin-A1 decreased such rates. Importantly, the negative effect of bafilomycin-A1 could be fully reversed by VPA. The utility of hiPSC-RPE for VPA testing was further evident following examination of its efficacy and metabolism in a complementary canine disease model. Our findings suggest that disturbances in protein degradation pathways contribute to the POS processing defect observed in BD hiPSC-RPE, which can be manipulated pharmacologically. These results have therapeutic implications for BD and perhaps other maculopathies.

iPS cell modeling of Best disease: insights into the pathophysiology of an inherited macular degeneration.

Best disease (BD) is an inherited degenerative disease of the human macula that results in progressive and irreversible central vision loss. It is caused by mutations in the retinal pigment epithelium (RPE) gene BESTROPHIN1 (BEST1), which, through mechanism(s) that remain unclear, lead to the accumulation of subretinal fluid and autofluorescent waste products from shed photoreceptor outer segments (POSs). We employed human iPS cell (hiPSC) technology to generate RPE from BD patients and unaffected siblings in order to examine the cellular and molecular processes underlying this disease. Consistent with the clinical phenotype of BD, RPE from mutant hiPSCs displayed disrupted fluid flux and increased accrual of autofluorescent material after long-term POS feeding when compared with hiPSC-RPE from unaffected siblings. On a molecular level, RHODOPSIN degradation after POS feeding was delayed in BD hiPSC-RPE relative to unaffected sibling hiPSC-RPE, directly implicating impaired POS handling in the pathophysiology of the disease. In addition, stimulated calcium responses differed between BD and normal sibling hiPSC-RPE, as did oxidative stress levels after chronic POS feeding. Subcellular localization, fractionation and co-immunoprecipitation experiments in hiPSC-RPE and human prenatal RPE further linked BEST1 to the regulation and release of endoplasmic reticulum calcium stores. Since calcium signaling and oxidative stress are critical regulators of fluid flow and protein degradation, these findings likely contribute to the clinical picture of BD. In a larger context, this report demonstrates the potential to use patient-specific hiPSCs to model and study maculopathies, an important class of blinding disorders in humans.

Bitter taste function-related genes are implicated in the behavioral association between taste preference and ethanol preference in male mice.

Alcohol use disorder in humans is highly heritable, and as a term is synonymous with alcoholism, alcohol dependence, and alcohol addiction. Defined by the NIAAA as a medical condition characterized by an impaired ability to stop or control alcohol use despite adverse social, occupational, or health consequences, the genetic basis of alcohol dependence is much studied. However, an intriguing component to alcohol acceptance exists outside of genetics or social factors. In fact, mice of identical genetic backgrounds without any prior experience of tasting ethanol display widely varying preferences to it, far beyond those seen for typical taste solutions. Here, we hypothesized that a preference for ethanol, which tastes both bitter and sweet to humans, would be influenced by taste function. Using a mouse model of taste behavior, we tested preferences for bitter and sweet in mice that, without training or previous experience, either preferred or avoided ethanol solutions in consumption trials. Data showed clear sex differences, in which male mice that preferred ethanol also preferred a bitter quinine solution, whereas female mice that preferred ethanol also preferred a sweet sucralose solution. Male mice preferring ethanol also exhibited lower expression levels of mRNA for genes encoding the bitter taste receptors T2R26 and T2R37, and the bitter transducing G-protein subunit GNAT3, suggesting that the higher ethanol preference observed in the male mice may be due to bitter signaling, including that arising from ethanol, being weaker in this group. Results further support links between ethanol consumption and taste response, and may be relevant to substance abuse issues in human populations.

Legislative Differences Governing Exotic Animal Practice.

Laws regulating exotic animal ownership vary throughout the world. While some differences regarding the legal status and use of exotic companion animals are associated with cultural differences and public perception, some differences may result in different outcome, which could be of interest for other parts of the world. This article provides a general overview of relevant laws pertaining to exotic companion animals in certain developed countries.

Influence of differing levels of concentrate on circulating cytokine concentrations in beef heifers.

Components of the immune system (e.g., cytokines and chemokines) can influence reproductive efficiency. Characterizing the influence nutrition has on shifts in circulating cytokine concentrations will allow for a better understanding of reproductive efficiency in beef cattle. This study aimed to determine the effect of diet composition on circulating cytokine concentrations of beef heifers. Using a 3 × 3 Latin square design, pubertal Bos taurus-influenced rumen-cannulated heifers (n = 15) were fed a diet based on different concentrate percentages. The treatment period consisted of 28-d feeding periods with a washout interval of 21 d. Treatment groups were fed 100% grass hay (high forage; HF), 60% grass hay with 40% corn-based concentrate (intermediate; INT), and 25% grass hay with 75% corn-based concentrate (high grain; HG). Heifers were offered 2% of their body weight in feed daily. Blood was collected on days 0 and 28 of the treatment period for cytokine analysis. Plasma cytokine concentrations were quantified using RayBiotech Quantibody Bovine Cytokine Array Q1 kit according to manufacturer instructions. Concentrations of interferon gamma-induced protein 10 (IP10) linearly decreased with an increased concentrate diet (P = 0.037). Concentrations of IP10 differed for heifers consuming HF diet vs. HG diet (3,069.52 vs. 1,001.84 ±â€…669.01 pg/mL, respectively) and heifers consuming INT diet vs. HG diet (2,886.77 vs. 1,001.84 ±â€…669.01 pg/mL, respectively); however, there were no significant differences in IP10 concentrations between HF and INT heifers. There was a tendency for interleukin-1 family member 5 (IL1F5) concentrations to be lower for heifers consuming the HG diet compared to INT diet (P = 0.08). Results suggest that heifers consuming a high-concentrate diet have lower concentrations of IP10 and IL1F5. Additional research is necessary to better understand the dietary influence on the immune system in developing heifers.

Maternal versus environmental contributions to the piglet pioneer microbiome.

The pioneer microbiome is the initial colonization and establishment of microorganisms within the neonate. The objective of this project was to quantify maternal and environmental contributions to the piglet's pioneer microbiome. Sterile swabs were used to collect samples from the gilt's rectum, the farrowing crate before and after gilts were moved in, the gilt's birth canal during farrowing, and the piglet's rectum on days 0 (prior to suckling), 3, and 10 post-farrowing and at weaning (21.6 ± 1.0 days post-farrowing). During farrowing, colostrum was collected from each gilt from a representative sample of teats into a single sterile collection cup. Bacterial DNA extraction and sequencing targeted the V4 hypervariable region of the 16S rRNA gene. The relative abundance of Lactobacillus in the piglet microbiome was lower on day 3 compared to day 0, 10, and at weaning (P < 0.05). For alpha diversity, piglet samples exhibited distinct clustering for bacterial richness by day (P < 0.01). Multiple regression analyses indicated that the birth canal explained 51.6% of the variation observed in the piglet day 0 microbiome (P < 0.0001) and 6.5% of the variation in the piglet day 10 microbiome (P = 0.013). The day 10 microbiome explained 58.6% of the variation observed in the piglet microbiome at weaning (P < 0.0001). Bacterial communities of the farrowing crate and colostrum did not impact the piglet microbiome for any day (P > 0.10). Results indicate that the piglet pioneer microbiome is largely influenced by the microbiome of the birth canal.

Sourdough starter culture microbiomes influence physical and chemical properties of wheat bread.

Sourdough fermentation is an ancient leavening method that uses wild yeasts to produce carbon dioxide, contributing to bread rise, and bacteria which produce organic acids. Sourdough starter cultures are known to be diverse in terms of the microorganisms they comprise and while specific genera and species of microorganisms have been identified from starters and associated with specific attributes, overarching relationships between sourdough starter culture microbiomes and bread quality are not well understood. The objective of this study was to characterize differences in the physical and chemical properties of breads produced with sourdough starter cultures with unique microbiomes. Sourdough starter cultures (n = 20) of known microbial populations were used to produce wheat-based dough and bread, which were analyzed for chemical and physical properties then compared to their microbial populations in order to identify relationships between microbial profiles and dough/bread qualities. All samples were also compared to bread produced only with Saccharomyces cerevisiae (baker's yeast). Significant differences among pH, titratable acidity, loaf volume, crumb firmness, crust color, free amino acids, and organic acids were observed when comparing sourdough breads to the yeast-only control (p ≤ 0.05). Furthermore, bacterial diversity of sourdough starter cultures was correlated with lactic acid and free amino acid in the dough and loaf volume and crumb firmness of baked breads. No significant correlations were found between fungal diversity and measured outcomes. These data demonstrate the importance of considering sourdough starter microbiomes as an ingredient in baked goods and they contribute to quality and safety outcomes in bread production. PRACTICAL APPLICATION: Sourdough starter cultures have diverse and dynamic populations of bacteria and yeasts, which contribute to the production of bread products. These populations can influence the physical and chemical properties of sourdough fermentation and final breads. Understanding of the relationship between sourdough starter microbiomes and bread quality parameters can lead to targeted development of sourdough bread products with specific physical and chemical properties.

Reticular Myxoid Odontogenic Neoplasm with Novel STRN::ALK Fusion: Report of 2 Cases in 3-Year-Old Males.

Odontogenic tumors represent a collection of entities ranging from hamartomas to destructive benign and malignant neoplasms. Occasionally, pathologists encounter gnathic lesions which clearly exhibit an odontogenic origin but do not fit within the confines of established diagnoses. Here, we describe two such odontogenic tumors, both affecting 3-year-old males. Each case presented as a destructive, radiolucent mandibular lesion composed of mesenchymal cells, some with unique multi-lobed nuclei, frequently arranged in a reticular pattern and supported by a myxoid stroma with focal laminations. Production of odontogenic hard tissues was also seen. Because of their unique microscopic features, both cases were investigated by next-generation sequencing and found to harbor the same STRN::ALK oncogene fusion. To our knowledge, these cases represent the first report of an odontogenic tumor with a STRN::ALK gene rearrangement. We propose the possibility that this neoplasm could be separate from other known odontogenic tumors. Both patients were treated with surgical resection and reconstruction. The prognosis of patients with this entity is currently uncertain but shall become more apparent over time as more cases are identified and followed.

The primary care extension program: a catalyst for change.

The Affordable Care Act authorized, but did not fund, the Primary Care Extension Program (PCEP). Much like the Cooperative Extension Program of the US Department of Agriculture sped the modernization of farming a century ago, the PCEP could speed the transformation of primary care. It could also help achieve other goals such as integrating primary care with public health and translating research into practice. The urgency of these goals and their importance to achieving the Triple Aim for health care should increase interest in rapidly building the PCEP, much as the need to feed the country did a century ago.

A double-blind, randomized, placebo-controlled trial of adalimumab in the treatment of cutaneous sarcoidosis.

BACKGROUND: Many medications, including tumor necrosis factor antagonists, have been anecdotally reported to be effective in treating cutaneous sarcoidosis, but controlled study is lacking. OBJECTIVE: We sought to determine if adalimumab is a safe and effective treatment for cutaneous sarcoidosis. METHODS: Adalimumab or placebo was administered to 10 and 6 patients, respectively, in double-blind, randomized fashion for 12 weeks, followed by open-label treatment for an additional 12 weeks, followed by 8 weeks of no treatment. Assessments were made of cutaneous lesions, quality-of-life issues, laboratory findings, pulmonary function, and radiographic findings. RESULTS: At the end of the 12-week, double-blind phase, there was improvement in a number of cutaneous findings in the adalimumab-treated patients (group 1) relative to placebo recipients (group 2), most notably in target lesion area (P = .0203). At the end of the additional 12-week open-label phase, significant improvement relative to baseline was found for target lesion area (P = .0063), target lesion volume (P = .0225), and Dermatology Life Quality Index score (P = .0034). No significant changes were seen in pulmonary function tests, radiographic findings, or laboratory studies. After 8 weeks off treatment, there was some loss of this improvement. LIMITATIONS: Standardized, validated measures for cutaneous sarcoidosis are lacking. There may be observer bias in the open-label portion of this study. The small size of this study makes it difficult to generalize results. CONCLUSIONS: Adalimumab, at the dose and duration of treatment used in this study, is likely to be an effective and relatively safe suppressive treatment for cutaneous sarcoidosis.