Platelet-derived growth factor receptor-α promotes lymphatic metastases in papillary thyroid cancer

Lymph node metastases are common in papillary thyroid cancer (PTC) and can be resistant to surgical extirpation or radioiodine ablation. We examined the role of platelet‐derived growth factor receptor (PDGFR) in mediating lymph node metastases in PTC. Clinical specimens of PTC (n = 137) were surveyed in a tissue array and by western blots to examine the relationship between expression of the α and β subunits of PDGFR and lymph node metastases. PDGFR‐α was found at high levels in primary tumours with known lymphatic metastases but not in those tumours lacking nodal involvement (p < 0.0001). However, PDGFR‐β expression was not linked to metastatic disease (p = 0.78) as it was found in virtually all PTC specimens. A matching analysis in fresh PTC specimens (n = 13) confirmed that PDGFR‐α expression was strongly linked to metastatic spread (p = 0.0047). PDGFR‐α and ‐β were not found in normal thyroid tissue (p < 0.0001). PTC cell lines selectively expressing PDGFR‐α or ‐β were assessed for invasive potential and activation of downstream signal transduction pathways. PTC cell lines expressing PDGFR‐α responded to PDGF‐BB stimulation with increased invasive potential and this process can be blocked by the tyrosine kinase receptor inhibitor sunitinib (p < 0.009). Cell lines with only PDGFR‐β, or no PDGFR, did not show significant changes in invasive potential. Activation of PDGFR‐α led to downstream up‐regulation of both the MAPK/ERK and PI3K/Akt pathways and disruption of either pathway is sufficient to block PDGFR‐mediated increases in invasive potential. Thus, PDGFR‐α is associated with lymph node metastases in papillary thyroid carcinoma and PDGFR‐α promotes increased invasive potential in PTC cell lines. PDGFR‐α is a strong candidate for a diagnostic biomarker to identify patients at risk of nodal metastases. Our results also strengthen the rationale for selection of tyrosine kinase receptor inhibitors that target PDGFR in the treatment of progressive, metastatic PTC. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Interactions between an N-methyl-D-aspartate antagonist and low-efficacy opioid receptor agonists in assays of schedule-controlled responding and thermal nociception

A growing body of literature has implicated N-methyl-d-aspartate (NMDA) receptor mechanisms in the acute antinociceptive effects of morphine; however, the nature of this interaction has not been thoroughly quantified. Moreover, it is not clear whether NMDA/morphine interactions extend to less efficacious opioids. Therefore, the present study examined the effects of morphine and various low-efficacy opioid agonists in combination with the NMDA antagonist (-)-6-phosphonomethyl-deca-hydroisoquinoline-3-carboxylic acid (LY235959) in two different assays: schedule-controlled responding and thermal nociception. Data were examined with dose-addition analysis to provide a quantitative assessment of the drug interactions. LY235959 and the opioid agonists morphine, buprenorphine, butorphanol, and nalbuphine all decreased rates of schedule-controlled responding. LY235959/morphine and LY235959/buprenorphine mixtures produced additive or subadditive effects in this assay, whereas LY235959/butorphanol and LY235959/nalbuphine mixtures produced additive or supra-additive effects, depending on the relative proportions of each drug in mixture. Morphine, buprenorphine, butorphanol, and nalbuphine also produced dose-dependent antinociception in the assay of thermal nociception, whereas LY235959 failed to produce an effect. In this assay, LY235959 potentiated the antinociceptive effects of morphine and each of the low-efficacy opioids tested. These results suggest that LY235959 may selectively increase the antinociceptive effects of morphine and some low-efficacy opioid receptor agonists without increasing their rate-altering effects. In addition, these data confirm that the behavioral effects of drug mixtures depend on the relative concentrations of the drugs in the mixture and on the endpoint under study.     

Preemptive transplantation for patients with diabetes-related kidney disease

BACKGROUND: Preemptive kidney transplantation (PreKT) before initiation of chronic dialysis has been examined recently with favorable results as the most effective treatment for kidney failure. Given that few of these studies are disease specific, the present analyses investigated the outcomes of PreKT by transplantation option and diabetes type. METHODS: The impact of PreKT on posttransplantation mortality and graft failure was examined in 23 238 adults with type 1 and type 2 diabetes mellitus (DM), receiving either living or deceased donor kidneys or undergoing simultaneous pancreas-kidney (SPK) transplantation between January 1, 1997, and December 31, 2002. RESULTS: The PreKTs were provided to 14.4% of patients with type 1 DM and 6.7% of patients with type 2 DM. Cox regression models were used to estimate the effect of PreKT on the adjusted risk ratio (RR) of graft failure and mortality. After adjusting for multiple factors, PreKT in this era was associated with lower RR of mortality only among type 1 and type 2 diabetic recipients of transplants from living donors and SPK transplant recipients with type 1 DM (RR, 0.50-0.65; P<.007 for each). The effect on graft failure was less pronounced, significant only for preemptive SPK transplant recipients (RR, 0.79; P=.01 vs nonpreemptive SPK transplant recipients). CONCLUSIONS: These analyses suggest that PreKT has significant benefits for subsets of patients with types 1 and 2 DM and end-stage renal disease. It also suggests a time trend toward less benefit from preemptive transplants from deceased donors in more recent years compared with the early 1990s. This observation and the discrepancies between RR of graft loss and RR of mortality deserve further study.     

High-resolution video monitoring of hematopoietic stem cells cultured in single-cell arrays identifies new features of self-renewal

To search for new indicators of self-renewing hematopoietic stem cells (HSCs), highly purified populations were isolated from adult mouse marrow, micromanipulated into a specially designed microscopic array, and cultured for 4 days in 300 ng/ml Steel factor, 20 ng/ml IL-11, and 1 ng/ml flt3-ligand. During this period, each cell and its progeny were imaged at 3-min intervals by using digital time-lapse photography. Individual clones were then harvested and assayed for HSCs in mice by using a 4-month multilineage repopulation endpoint (>1% contribution to lymphoid and myeloid lineages). In a first experiment, 6 of 14 initial cells (43%) and 17 of 61 clones (28%) had HSC activity, demonstrating that HSC self-renewal divisions had occurred in vitro. Characteristics associated with HSC activity included longer cell-cycle times and the absence of uropodia on a majority of cells within the clone during the final 12 h of culture. Combining these criteria maximized the distinction of clones with HSC activity from those without and identified a subset of 27 of the 61 clones. These 27 clones included all 17 clones that had HSC activity; a detection efficiency of 63% (2.26 times more frequently than in the original group). The utility of these characteristics for discriminating HSC-containing clones was confirmed in two independent experiments where all HSC-containing clones were identified at a similar 2- to 3-fold-greater efficiency. These studies illustrate the potential of this monitoring system to detect new features of proliferating HSCs that are predictive of self-renewal divisions.     

U-Shaped Pillows and Sleep-Related Infant Deaths,United States, 2004–2015

Maternal and Child Health Journal - To describe infant deaths where a u-shaped pillow was under or around an infant and to describe cases classified as Explained Suffocation. We examined...     

Pneumocystis carinii induction of tumor necrosis factor-alpha by alveolar macrophages: modulation by pentamidine isethionate.

Pneumocystis carinii, and the inflammatory response it provokes, together contribute to irreversible lung damage in immunocompromised patients. P. carinii cysts were found to be capable of inducing tumor necrosis factor-alpha (TNF) release from alveolar macrophages in a concentration-dependent manner. At physiologically achievable concentrations, pentamidine isethionate (pentamidine) substantially reduces such production. Pretreatment of alveolar macrophages (AM phi) with interferon-gamma (IFN-gamma) synergizes with P. carinii to produce increased levels of TNF, a condition which pentamidine was also able to antagonize. Pentamidine treatment did not interfere with the phagocytic ability of AM phi. Considering clinical reduction of TNF could lessen P. carinii pneumonia (PCP) induced inflammation, the efficacy of pentamidine in the treatment of PCP may be partially associated with its ability to inhibit the release of inflammatory mediators such as TNF.     

A role for MHC class II antigen processing in B cell development

For mature B cells, the encounter with foreign antigen results in the selective expansion of the cells and their differentiation into antibody secreting cells or memory B cells. The response of mature B cells to antigen requires not only antigen binding to and signaling through the B cell antigen receptor (BCR) but also the processing and presentation of the BCR bound antigen to helper T cells. Thus, in mature B cells, the ability to process and present antigen to helper T cells plays a critical role in determining the outcome of antigen encounter. In immature B cells, the binding of antigen results in negative selection of the B cell, inducing apoptosis, anergy or receptor editing. Negative selection of immature B cells requires antigen induced signaling through the BCR, analogous to the signaling function of the BCR in mature B cells. However, the role of class II antigen processing and presentation in immature B cells is less well understood. Current evidence indicates that the ability to process and present antigen bound to the BCR is a late acquisition of developing B cells, suggesting that during negative selection B cells may not present BCR bound antigen and interact with helper T cells. However, the expression of class II molecules is an early acquisition of B cells and recent evidence indicates that the expression of class II molecules early in development is required for the generation of long lived mature B cells. Here we review our current understanding of the processing and presentation of antigen by mature B cells and the role for antigen processing and class II expression during B cell development.     

Spontaneous fungal peritonitis: Micro-organisms,management and mortality in liver cirrhosis-A systematic review

BACKGROUND Spontaneous peritonitis is an infection of ascitic fluid without a known intraabdominal source of infection. spontaneous fungal peritonitis(SFP) is a potentially fatal complication of decompensated cirrhosis, defined as fungal infection of ascitic fluid in the presence of ascitic neutrophil count of greater than250 cells/mL.AIM To determine the prevalence of fungal pathogens, management and outcomes(mortality) of SFP in critically ill cirrhotic patients.METHODS Studies were identified using PubMed, EMBASE, Cochrane Central Register of Controlled Trials and Scopus databases until February 2019. Inclusion criteria included intervention trials and observation studies describing the association between SFP and cirrhosis. The primary outcome was in-hospital, 1-mo, and 6-mo mortality rates of SFP in cirrhotic patients. Secondary outcomes were fungal microorganisms identified and in hospital management by anti-fungal medications. The National Heart, Lung and Blood Institute quality assessment tools were used to assess internal validity and risk of bias for each included study.RESULTS Six observational studies were included in this systematic review. The overall quality of included studies was good. A meta-analysis of results could not be performed because of differences in reporting of outcomes and heterogeneity of the included studies. There were 82 patients with SFP described across all the included studies. Candida species, predominantly Candida albicans was the fungal pathogen in majority of the cases(48%-81.8%) followed by Candida krusei(15%-25%) and Candida glabrata(6.66%-20%). Cryptococcus neoformans(53.3%) was the other major fungal pathogen. Antifungal therapy in SFP patients was utilized in33.3% to 81.8% cases. The prevalence of in hospital mortality ranged from 33.3%to 100%, whereas 1-mo mortality ranged between 50% to 73.3%.CONCLUSION This systematic review suggests that SFP in end stage liver disease patient is associated with high mortality both in the hospital and at 1-mo, and that antifungal therapy is currently underutilized.     

Reduced skeletal muscle satellite cell number alters muscle morphology after chronic stretch but allows limited serial sarcomere addition

Introduction: Muscles add sarcomeres in response to stretch, presumably to maintain optimal sarcomere length. Clinical evidence from patients with cerebral palsy, who have both decreased serial sarcomere number and reduced satellite cells (SCs), suggests a hypothesis that SCs may be involved in sarcomere addition. Methods: A transgenic Pax7‐DTA mouse model underwent conditional SC depletion, and their soleii were then stretch‐immobilized to assess the capacity for sarcomere addition. Muscle architecture, morphology, and extracellular matrix (ECM) changes were also evaluated. Results: Mice in the SC‐reduced group achieved normal serial sarcomere addition in response to stretch. However, muscle fiber cross‐sectional area was significantly smaller and was associated with hypertrophic ECM changes, consistent with fibrosis. Conclusions: While a reduced SC population does not hinder serial sarcomere addition, SCs play a role in muscle adaptation to chronic stretch that involves maintenance of both fiber cross‐sectional area and ECM structure. Muscle Nerve 55 : 384–392, 2017