Breast Cancer Research and Treatment

Oral or intravenous vinorelbine plus capecitabine in heavily pretreated HER2 negative metastatic breast cancer; similar effect or quality of life?

Correction to: Anti-tumor and anti-metastasis efficacy of E6201, a MEK1 inhibitor, in preclinical models of triple-negative breast cancer Unfortunately in the original publication of the article, the author's funding support has been mentioned incorrectly. The correct funding statement should read as "This work was supported by the Morgan Welch Inflammatory Breast Cancer Research Program, the State of Texas Rare and Aggressive Breast Cancer Research Program, MD Anderson's Cancer Center Support Grant (P30CA016672, used the Characterized Cell Line Core Facility and Flow Cytometry and Cellular Imaging Facility), and Spirita Oncology, LLC." The first affiliations was incorrect in the original article. The correct information is given below.

Classifying sarcopenia: using median value or cut-off values?

Correction to: Second International Consensus Conference on lesions of uncertain malignant potential in the breast (B3 lesions) The article Second International Consensus Conference on lesions of uncertain malignant potential in the breast (B3 lesions), written by Christoph J Rageth, Elizabeth AM O'Flynn, Katja Pinker, Rahel A Kubik-Huch, Alexander Mundinger, Thomas Decker, Christoph Tausch, Florian Dammann, Pascal A. Baltzer, Eva Maria Fallenberg, Maria P Foschini, Sophie Dellas, Michael Knauer, Caroline Malhaire, Martin Sonnenschein, Andreas Boos, Elisabeth Morris, Zsuzsanna Varga, was originally published electronically on the publisher's internet portal (currently SpringerLink) on November 30, 2018 without open access.

Impact of invasive lobular carcinoma on long-term outcomes in Mexican breast cancer patients Abstract Purpose The aim of this study was to compare the difference in disease-free survival (DFS) and overall survival (OS) between invasive lobular carcinoma (ILC) and invasive ductal carcinoma (IDC) in our Hispanic population with breast cancer (BC). Methods We retrospectively analyzed a database of 4533 non-metastatic BC patients treated for BC at the National Cancer Institute in Mexico (INCan) between 2006 and 2016. We compared clinical characteristics, treatment and survival between women with invasive ductal and invasive lobular BC. We evaluated differences between survival curves with the log-rank test and used Cox's proportional hazards model for the multivariate analysis. Results Median follow-up time was 42.13 months (IQ25 25.2–IQ75 72.06). The median age was 50.9 years (IQ25 43.5–IQ75 59.8). DFS at 5 years was 80.8% for IDC versus 76.2% for ILC. 5 years OS was 88.7% for IDC versus 84.3% for ILC. Multivariate analysis showed that factors that negatively affected the 5-year DFS include: clinical stage III [hazard ratio (HR) 4.2, 95% CI 3.36–5.35; p < 0.001], triple negative phenotype (HR 1.4, 95% CI 1.08–1.81; p = 0.009), Ki67 ≥ 18 (HR 1.6, 95% CI 1.28–2.11; p < 0.001), and lobular histological type (HR 1.6, 95% CI 1.09–2.49; p = 0.017). Factors associated with a negative impact on OS were: clinical stage III (HR 4.5, 95% CI 3.15–6.54; p < 0.001), triple negative phenotype (HR 2.4, 95% CI 1.69–3.48; p < 0.001), and Ki67 ≥ 18% (HR 1.9, 95% CI 1.27–2.92; p = 0.02). Conclusion Our results highlight the different biology of ILC and show that long-term prognosis in terms of DFS is not as favorable as previously reported.

miR-106b-5p and miR-17-5p could predict recurrence and progression in breast ductal carcinoma in situ based on the transforming growth factor-beta pathway Abstract Purpose Ductal carcinoma in situ (DCIS) is well-known precursor of invasive ductal carcinoma (IDC). Parts of patients show recurrence as DCIS or IDC after local treatment, but there are no established markers predicting relapse. We analyzed changes in miRNA and oncogene expression during DCIS progression/evolution to identify potential markers predicting recurrence. Methods Forty archival tissues diagnosed as primary or recurrent DCIS and DCIS adjacent to IDC were analyzed. MiRNA hierarchical clustering showed up-regulation of miR-17-5p and miR-106b-5p in recurrent DCIS and DCIS adjacent to IDC. Target genes were predicted based on pre-formed miRNA databases and PanCancer Pathway panel. MiRNAs were transfected into MCF-10A and MCF-7 cells; western blot analysis was performed with MCF-7 cell line to evaluate the effects on TGF-β downstream pathway. Results miRNA hierarchical clustering showed 17 dysregulated miRNAs, including miR-17-5p and miR-106b-5p. Based on miRNA database and nCounter Pancancer pathway analysis, TGFβRII was selected as target of miR-106b-5p and miR-17-5p. MiR-106b-5p- and miR-17-5p-transfected MCF-7 cells showed decreased expression of TGFβRII, especially in cells transfected with both miRNAs. Conclusion miR-106b-5p and miR-17-5p might have a role in breast cancer recurrence and progression by suppressing TGF-β activity, leading to early breast cancer carcinogenesis.

The influence of neoadjuvant chemotherapy on complications of immediate DIEP flap breast reconstructions Abstract Purpose The impact of neoadjuvant chemotherapy on the surgical outcomes of immediate breast reconstruction remains controversial. The aim of this study was to analyze the incidence of complications of immediate deep inferior epigastric artery perforator (DIEP) flap breast reconstructions in patients who received neoadjuvant chemotherapy compared to patients without neoadjuvant chemotherapy prior to surgery. Methods A multicenter, retrospective cohort study was conducted of all patients who underwent immediate DIEP flap breast reconstruction between January 2010 and June 2017. Patients were divided in two groups as breast reconstructions with or without neoadjuvant chemotherapy, respectively. The primary outcome was the incidence of postoperative flap re-explorations, recipient-site complications and donor-site complications. Results In total 432 immediate DIEP flap breast reconstructions in 326 patients were included. Forty-eight patients (n = 67 flaps) received neoadjuvant chemotherapy prior to immediate breast reconstruction and 278 patients (n = 365 flaps) did not. No statistically significant differences for any major (4.5% vs. 10.4%; p = 0.175) or minor (16.4% vs. 24.7%; p = 0.191) recipient-site complication were observed. Donor-site complications were recorded in 9 (18.8%) and 62 (22.2%) patients, respectively (p = 0.587). There was no difference in need for flap re-exploration between groups (3.0% vs. 8.5%; p = 0.139). Correction for potential confounding variables did not result in significant differences. Conclusions This study demonstrated similar complication rates for patients with and without neoadjuvant chemotherapy prior to immediate breast reconstruction, indicating that it is safe to perform an immediate DIEP flap breast reconstruction after neoadjuvant chemotherapy.

Prognostic role of body mass index is different according to menopausal status and tumor subtype in breast cancer patients Abstract Purpose Although controversial, obesity and underweight may have a negative impact on breast cancer outcome. However, the relationship between body mass index (BMI) and breast cancer outcomes according to tumor subtype and menopausal status remains unclear. Methods This study investigated the association between BMI and breast cancer outcome in stage I–III breast cancer patients. The relationships were further evaluated according to tumor subtype and menopausal status. Results A total of 5919 patients, 3475 (58.7%) hormone receptor (HR)(+) human epidermal growth factor receptor 2 (HER2)(–), 608 (10.3%) HR(+)HER2(+), 621 (10.5%) HR(–)HER2(+), and 1079 (18.2%) HR(–)HER2(–) were included. Underweight and obesity had a negative impact on relapse-free survival but did not affect overall survival. Importantly, the prognostic role of BMI was different according to tumor subtype and menopausal status. In HR(+)HER2(–) patients, underweight was associated with poor relapse-free survival and overall survival in pre-menopausal women. In contrast, obesity had negative impact on relapse-free survival and overall survival in HR(+)HER2(–) post-menopausal patients. Underweight may have a negative prognostic role in HR(+)HER2(+) patients. However, BMI did not impact the outcome of HR(–)HER2(+) and HR(–)HER2(–) patients. Conclusions The impact of BMI on breast cancer outcome was dependent on tumor subtype and menopausal status. In HR(+)HER2(–) patients, underweight and obesity had a negative prognostic role in pre-menopausal and post-menopausal women, respectively. These findings in Asian population should be further evaluated and compared in Western population.

Examining the cost-effectiveness of baseline left ventricular function assessment among breast cancer patients undergoing anthracycline-based therapy Abstract Background There is a lack of consensus to guide which breast cancer patients require left ventricular function assessment (LVEF) prior to anthracycline therapy; the cost-effectiveness of screening this patient population has not been previously evaluated. Methods We performed a retrospective analysis of the Yale Nuclear Cardiology Database, including 702 patients with baseline equilibrium radionuclide angiography (ERNA) scan prior to anthracycline and/or trastuzumab therapy. We sought to examine associations between abnormal baseline LVEF and potential cardiac risk factors. Additionally, we designed a Markov model to determine the incremental cost-effectiveness ratio (ICER) of ERNA screening for women aged 55 with stage I–III breast cancer from a payer perspective over a lifetime horizon. Results An abnormal LVEF was observed in 2% (n = 14) of patients. There were no significant associations on multivariate analysis performed on self-reported risk factors. Our analysis showed LVEF screening is cost-effective with ICER of $45,473 per QALY gained. For a willingness-to-pay threshold of $100,000/ QALY, LVEF screening had an 81.9% probability of being cost-effective. Under the same threshold, screening was cost-effective for non-anthracycline cardiotoxicity risk of RR ≤ 0.58, as compared to anthracycline regimens. Conclusions Age, preexisting cardiac risk factors and coronary artery disease did not predict a baseline abnormal LVEF. While the prevalence of an abnormal baseline LVEF is low in patients with breast cancer, our results suggest that cardiac screening prior to anthracycline is cost-effective.

Temporal trends and regional variation in the utilization of low-value breast cancer care: has the Choosing Wisely campaign made a difference? Abstract Purpose Since 2012, about 80 specialty societies have released Choosing Wisely (CW) recommendations aimed at reducing the use of low-value, unproven, or ineffective medical services. The extent to which these recommendations have influenced the behavior of physicians and patients remains largely unknown. Methods Using MarketScan Commercial Claims and Medicare Supplemental and Coordination of Benefits databases, we identified annual cohorts of women with incident, early-stage breast cancer and estimated the prevalence of four initial treatment and six surveillance metrics deemed as low-value breast cancer care by CW. Multivariable logistic regressions were subsequently used to estimate temporal trends and regional variation in the use of these metrics, with a special focus on the year of CW's publication. Results There were 122,341 women identified as undergoing treatment for incident breast cancer between 2010 and 2014. Two of the four low-value initial treatment metrics and four of the six low-value surveillance metrics declined significantly over time. The temporal trend of declining use, however, preceded the release of CW's guidelines. Declines ranged from 11.0% for follow-up mammography to 40.6% for receipt of surgical biopsy without an attempted needle biopsy. There were marked regional differences in use of low-value breast cancer care for all metrics, much of which persisted after publication of CW. Conclusions With two notable exceptions, use of low-value breast cancer care has declined steadily since 2010. The declines, however, were not accelerated by the publication of CW recommendations.

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

Inflammation

Under inflammatory stimuli mesenteric mesothelial cells transdifferentiate into macrophages and produce pro-inflammatory cytokine IL-6 Abstract Objective Inflammatory stimuli inducing epithelial-to-mesenchymal transition (EMT) can transdifferentiate mesenteric mesothelial cells into macrophages. Methods Sprague Dawley rat mesenteric mesothelial cells were used as a model. 1 ml Freund adjuvant was injected into the peritoneal cavity of rat and GM-CSF treatment was used to induce inflammation. IL-10 and IL-6 expression were studied by immunocytochemistry and Western blot analysis both in vivo and in vitro. Results Control mesothelial cell express anti-inflammatory IL-10, but no pro-inflammatory IL-6 expression could be detected in them. By the time of inflammation, IL-6 expression increased (reached the maximum level at the fifth day of inflammation), parallel to this the IL-10 entirely disappeared from these cells. In vitro GM-CSF treatment resulted in similar changes. As the mesothelial cells started to recover (at the eighth day of inflammation) IL-6 expression decreased and IL-10 level started to increase again. Conclusion These data show that under inflammatory stimuli mesothelial cells—like macrophages—can produce pro-inflammatory cytokines.

Lung infection caused by Pseudomonas aeruginosa in a CD26/DPP4 deficient F344 rat model Abstract Background Pseudomonas aeruginosa (PA) is the most important opportunistic pathogen in causing nosocomial infections and, furthermore, poses a permanent threat for severe chronic infections in patients with cystic fibrosis or COPD. The transmembrane protein CD26 with dipeptidyl peptidase-4 (DPP4) activity shows an increased expression in inflamed tissue. We tested whether CD26/DPP4 deficiency leads to reduced inflammation and decreased structural damage when infected with PA. Methods CD26/DPP4+ and CD26/DPP4− rats were instilled intratracheally with NaCl (controls) or with PA. Six hours later, bacterial distribution was detected with the in vivo imaging system 200 (IVIS). Lungs were then processed for molecular biology, light and electron microscopy and analyzed qualitatively, quantitatively and stereologically. Bacterial numbers were determined in homogenized lungs. Results Compared to saline treated controls, in both infected groups (1) the acinar airspace was significantly increased, (2) the volume density of the alveolar epithelium was significantly decreased, (3) the septal thickness was significantly reduced, (4) more than 40% of the alveolar epithelial surface was damaged, and up to 36% of the epithelial surface was covered with edema. In infected CD26− rats, the increase in lung weight was significantly less pronounced, the portion of edematous alveolar airspace was significantly lower and the part of edema interspersed with PA was decreased significantly. Conclusions CD26/DPP4 deficiency resulted in reduced pulmonary edema under sublethal PA infection, implicating a role for CD26 in infection progression. The partly pronounced structural damage may mask further possible influences of CD26 on the inflammatory response.

The incretin enhancer, sitagliptin, exacerbates expression of hepatic inflammatory markers in rats fed a high-cholesterol diet Abstract Objective Hypercholesterolemia is associated with the development of a pro-inflammatory state and is a documented risk factor for progression to insulin resistance, nonalcoholic fatty liver and cardiovascular diseases. Sitagliptin is an incretin enhancer that improves glucose tolerance by inhibiting dipeptidyl peptidase-4, but it also has reported anti-inflammatory effects. The current study was thus undertaken to examine the interactions of dietary Cholesterol (Cho) and sitagliptin on markers of inflammation. Methods Male Sprague–Dawley rats were provided diets high in Cho and gavaged with vehicle or an aqueous suspension of sitagliptin (100 mg/kg/day) from day 10 through day 35. Molecular methods were used to analyze the lipid profile and inflammatory markers in liver and serum samples. H&E-stained liver sections were used for histopathological evaluation. Hepatic influx of mononuclear cells and necrosis were assessed by immunohistochemistry. Results Sitagliptin reduced triglyceride and Cho levels in serum of rats on the control diet but these effects were abrogated in rats on the high-Cho diet. Sitagliptin produced a significant increase in the expression of hepatic inflammatory markers (Tnfa, Il1b, and Mcp1) and a corresponding increase in serum TNFα and IL-1β in rats on the high-Cho diet, but it had no effect on rats on the control diet. Additionally, sitagliptin had no effect on liver morphology in rats on the control diet, but it produced hepatic histopathological changes indicative of necrosis and mononuclear cell infiltration in rats on the high-Cho diet. These mononuclear cells were identified as macrophages and T cells. Conclusion When provided in the context of a high-Cho diet, these findings reveal previously unrecognized hepato-inflammatory effects of sitagliptin that are accompanied by evidence of hepatic necrosis and mononuclear cell infiltration.

Chrysophanol, an anthraquinone from AST2017-01, possesses the anti-proliferative effect through increasing p53 protein levels in human mast cells Abstract Objective Natural products are well known as the source of drugs in the treatment of allergic inflammation. Chrysophanol, an anthraquinone from the AST2017-01 extract, showed a beneficial anti-inflammatory effect on activated human mast cells in our previous study. However, a regulatory effect of AST2017-01 and chrysophanol on mast cell proliferation induced by thymic stromal lymphopoietin (TSLP) remains unclear. The present study determined the anti-proliferative effect and the fundamental mechanism of AST2017-01 and chrysophanol in mast cells. Methods We evaluated an anti-proliferative effect of AST2017-01 and chrysophanol in TSLP-stimulated human mast cell line, HMC-1. Results Without cytotoxicity, AST2017-01 and chrysophanol decreased mast cells growth and Ki67 mRNA expression increased by TSLP. AST2017-01 and chrysophanol enhanced expressions of p53 and Bax, whereas inhibited expression of Bcl-2. AST2017-01 and chrysophanol restored caspase-3 activity which was decreased by TSLP. AST2017-01 and chrysophanol suppressed expressions of murine double minute-2 protein and phosphorylated-signal transducer and activator of transcription six which are associated with the regulation of p53 protein. AST2017-01 and chrysophanol decreased levels of interleukin (IL)-13, IL-6, and tumor necrosis factor-α. Moreover, AST2017-01 and chrysophanol reduced mRNA expressions of TSLP receptor and IL-7 receptor α. Conclusions Therefore, this study proposes that AST2017-01 and chrysophanol may be promising candidates for the development of potent anti-inflammatory or health functional foods.

TNF-α/calreticulin dual signaling induced NLRP3 inflammasome activation associated with HuR nucleocytoplasmic shuttling in rheumatoid arthritis Abstract Objective The present study was undertaken to validate whether TNF-α and calreticulin (CRT) serve as dual signaling to activate nucleotide-binding oligomerization domain-, leucine-rich repeat- and pyrin domain-containing 3 (NLRP3) inflammasome in rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLS) and HUVECs. The effect of human antigen R (HuR) in NLRP3 inflammasome activation was also explored in RA FLS. Methods Immunofluorescence was used to determine the expression of NLRP3 and adaptor protein apoptosis associated speck-like protein containing a CARD (ASC) in RA synovial tissue and HuR location in RA FLS. Western blot and quantitative real-time PCR were employed to measure the priming effect of NLRP3 inflammasome in cells and HuR expression in synovial tissue. The concentrations of IL-1β and IL-18 were detected by enzyme linked immunosorbent assay. Immunohistochemistry was used to visualize the expression of HuR in synovial tissue. HuR knockdown in RA FLS was achieved by siRNA-mediated gene silencing. Results Higher expression of NLRP3 and ASC in RA synovial tissue than those in osteoarthritis was detected. The staining of NLRP3, ASC and cleaved IL-1β were observed in FLS and vascular endothelial cells in RA synovium. Expression of NLRP3 and pro-IL-1β in RA FLS and HUVECs treated with TNF-α was increased. The pro-IL-18 expression was also enhanced in HUVECs, but not in RA FLS. TNF-α/CRT dual stimulation of cells gave rise to caspase-1 p20 expression and the secretion of IL-1β. The secreted IL-18 was also elevated in HUVECs but not in RA FLS. HuR expression was significantly elevated in RA synovial tissue. TNF-α initiated the nucleocytoplasmic shuttling of HuR in both FLS and HUVECs. The knockdown of HuR in FLS incubated with TNF-α led to reduced caspase-1 p20 protein expression and further resulted in decreased secretion of IL-1β in the presence of CRT. Conclusions TNF-α/CRT dual signaling induced NLRP3 inflammasome activation, which could be suppressed by HuR knockdown presumably due to the block of HuR translocating from nucleus to cytoplasma.

Adoptive transfer of IFN-γ-induced M-MDSCs promotes immune tolerance to allografts through iNOS pathway Abstract Aim and objective Efficient production of monocytic myeloid-derived suppressor cells (M-MDSCs) with stable immunosuppressive function is crucial for immunomodulatory cell therapy for many diseases such as transplant rejection, graft-versus-host disease and autoimmune diseases. Methods We used M-CSF as growth factor for myeloid progenitor cell differentiation and activated them with IFN-γ during early stage in vitro to produce M-MDSCs. The cell phenotypes were determined using flow cytometry, the immunosuppressive function and mechanisms were determined by skin grafted mouse models and genetic modified mice. Results IFN-γ treatment endows these cell strong immunosuppressive function by inhibition of T cell proliferation and cytokine productions. The phenotype of these cells also changed towards M-MDSCs. IFN-γ significantly upregulated iNOS expression in these M-MDSCs and inhibition of this molecule significantly reversed their immune regulatory function. The functional stability of induced M-MDSCs by IFN-γ was tested in vivo by transferring them to alloskin-grafted mice. Adoptive transfer of these cells significantly prolonged allograft survival and promoted immune tolerance, whereas iNOS deficiency in these cells reversed this effect. Conclusions We established one M-MDSCs-inducting protocol with the combination of M-CSF and IFN-γ in vitro. M-CSF+IFN-γ-induced M-MDSCs are promising to prevent graft rejection by immune regulation.

Proinflammatory and anti-inflammatory cytokine profiles in psoriasis: use as laboratory biomarkers and disease predictors Abstract Objective The objectives of this study were to delineate the pro and anti-inflammatory cytokine profiles of psoriasis and cytokine profile models that externally validate the diagnosis. Subjects and Methods This study recruited 70 patients with psoriasis and 76 healthy controls. Cytokine profiles were evaluated, including pro-inflammatory M1 (IL-1 + IL-6 + TNF-α), Th1 (IL-2 + IL-12 + IFN-γ), Th17 (IL-6 + IL-17), and immune-inflammatory response system (IRS = M1 + Th1 + Th17) profiles. Moreover, the anti-inflammatory potential included Th2 (IL-4), Th2 + T regulatory (Th2 + Treg, namely IL-4 + IL-10 + TGF-β), anti-inflammatory (Th2 + Treg + adiponectin), and the pro-inflammatory/anti-inflammatory index. Results There was a highly significant association between psoriasis and cytokine levels with an effect size of 0.829 and a particularly strong impact on IL-2 (0.463), IL-12 (0.451), IL-10 (0.532) and adiponectin (0.401). TGF-β and adiponectin were significantly lower while all other cytokines (except IFN-γ) were significantly higher in psoriasis than in controls. In addition, M1, Th1, Th17, Th2 + Treg, and IRS/Anti-inflammatory index were significantly higher in psoriasis patients than in controls. The IRS index, Th2 + Treg, and adiponectin predicted psoriasis with 97.1% sensitivity and 94% specificity. Conclusion In conclusion, psoriasis is characterized by increased M1, Th1, Th2 and Th17 profiles together with lowered TGF-β and adiponectin. In addition, we propose a model based on a higher IRS and Th2 + Treg index coupled with lower adiponectin values, which may be used to externally validate the diagnosis of psoriasis. The most important single biomarker of psoriasis is adiponectin. Because the latter may play a role in the modulation of the chronic inflammatory response in psoriasis, adiponectin could be a new drug target to treat psoriasis.

N -Pyrazoloyl and N -thiopheneacetyl hydrazone of isatin exhibited potent anti-inflammatory and anti-nociceptive properties through suppression of NF-κB, MAPK and oxidative stress signaling in animal models of inflammation Abstract Background Hydrazide derivatives constitute an important class of compounds for new drug development as they are reported to possess good anti-inflammatory and analgesic activity. The present study was aimed to investigate the role of newly synthesized hydrazide derivatives N-pyrazoloyl hydrazone of isatin (PHI) and N-thiopheneacetyl hydrazone of isatin (THI) in acute and chronic inflammatory pain models induced by carrageenan and complete Freud's adjuvant (CFA). Materials PHI and THI (0.1, 1 and 10 mg/kg) pretreatments were provided intraperitoneally to male BALB/c mice prior to inflammatory inducers. Behavioral responses to inflammation and pain were evaluated by assessment of paw edema, mechanical allodynia, mechanical and thermal hyperalgesia. Cytokines production and NF-κB levels were evaluated by ELISA. Western blot analysis was performed for the detection of IκBα, p38, JNK and ERK. Hematoxylin and eosin (H&E) staining and radiographic analysis were performed to evaluate the effect of PHI and THI treatment on bone and soft tissues. Oxidative stress was determined by reduced glutathione, glutathione-S-transferase and catalase assays. Evans blue dye was used to monitor vascular protein leakage. Result PHI and THI dose dependently (0.1, 1 and 10 mg/kg) reduced inflammation and pain in mice, however, the dose of 10 mg/kg exhibited significant activity. The anti-inflammatory and analgesic effects were attributed to suppression of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6) production levels. PHI and THI significantly blocked CFA-induced activation of NF-κB and MAPK signaling pathways. Oxidative stress and plasma nitrite levels were reduced remarkably. The PHI and THI (10 mg/kg) treatment did not exhibit any apparent toxicity on the liver, kidney, muscles strength, and motor co‐ordination in mice. Conclusion Both PHI and THI possess significant anti-inflammatory and analgesic activity via inhibition of inflammatory mediators.

Neferine inhibits LPS-ATP-induced endothelial cell pyroptosis via regulation of ROS/NLRP3/Caspase-1 signaling pathway Abstract Background Oxidative stress-induced endothelial dysfunction and pyroptosis play an important role during chronic kidney disease (CKD) progression. Neferine, which is an alkaloid ingredient from the lotus seed embryo, has many biological actions such as anti-inflammatory, anticancer and antioxidant. However, the role of neferine in endothelial cell pyroptosis and the involved mechanism remain obscure. The aim is to probe the protective effects of neferine on cell pyroptosis and the involved underlying mechanism. Methods After the HUVECs were primed with neferine treatment for 2 h prior to LPS and ATP exposure for 24 h, the cell proliferation was determined by BrdU; the cell LDH release was detected by LDH kits; the levels of intracellular ROS, MDA and SOD were tested by detection kits; Caspase-1 activity kit was used to determine caspase-1 activity; the contents of NLRP3, ASC, caspase-1, IL-1β, IL-18 and GSDMD were tested by RT-PCR and western blot. Results We found that neferine could inhibit LPS-ATP-induced oxidative stress and the activation of NLRP3 inflammasome signaling, and increased the endothelial cell viability and SOD production. siRNA which mediated the knockdown of NLRP3 promoted the neferine-induced inhibition effects of cell pyroptosis. Furthermore, these neferine-induced effects were reversed by the over-expression of NLRP3. Conclusions Our findings indicated neferine may reduce ROS by anti-oxidation and inhibit LPS-ATP-induced endothelial cell pyroptosis via blocking ROS/NLRP3/Caspase-1 signaling pathway, which provides the evidence for therapeutic effect in CKD.

Anti-inflammatory activity of extensively hydrolyzed casein is mediated by granzyme B Abstract Objective Nutritional factors such as extensively hydrolyzed casein (eHC) have been proposed to exert anti-inflammatory activity and affect clinical outcomes such as tolerance development in cow's milk allergy. Granzyme B (GrB) induces apoptosis in target cells and also controls the inflammatory response. Whether eHC could affect the activity of granzyme B and play a role in GrB-mediated inflammatory responses in vitro was unknown. Methods The activity of GrB was measured using the substrate Ac-IEPD-pNA. Inflammatory responses were induced with GrB in HCT-8 and THP-1 cells, and pro-inflammatory cytokines were determined at the transcriptional and protein level. Results GrB could induce the expression of IL-1β in HCT-8 cells, and IL-8 and MCP-1 in THP-1 cells, respectively. Interestingly, GrB acted synergistically on LPS-induced inflammation in HCT-8 cells and eHC reduced pro-inflammatory responses in both GrB and LPS-mediated inflammation. Further analyses revealed that eHC could inhibit the biological activities and cytotoxic activities of GrB and then could reduce GrB-mediated inflammatory response. Conclusion The results from the current study suggest that anti-inflammatory activity of extensively hydrolyzed casein is, to a certain extent, mediated through modulation of granzyme B activity and responses.

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

Micropaléontologie

Factors controlling the deformation of benthic foraminifera in the Manzala lagoon, Egypt Publication date: June 2019 Source: Revue de Micropaléontologie, Volume 63 Author(s): A.M. Badr-El Din, A.A. El-Badry, O.H. Orabi Abstract Morphological deformations among hyaline and porcelaneous benthic foraminiferal were observed at stations with high contents of trace metals within the Manzala Lagoon. Energy Dispersive X-ray Analyses (EDX) were conducted on deformed and non-deformed specimens of this population. Deformed Adelosina sp. specimens show high sulfur, magnesium, iron and low copper content. The deformed Ammonia tepida show high aluminum, chloride, calcite and copper in the shell. Analyses of non-deformed foraminifera tests at unpolluted localities show that A. tepida displays high calcium content only, whereas Adelosina sp. shows calcium and magnesium. It is worth mentioning that the non-deformed tests of both species are free from copper and sulfur. We conclude that the low salinity and/or high trace metals in the western and southern regions of the Manzala Lagoon are the main cause for the reduction in overall size of the foraminiferal shells. Porcelaneous Adelosina sp. is very rare (0 to 2%) and mainly found on the northern side, where salinity increases, whereas hyaline A. tepida is the most dominant species in the lagoon and covers more than 97% of the total benthic foraminifera.

Eocene larger benthic foraminifera (alveolinids, nummulitids, and orthophragmines) from the eastern Alborz region (NE Iran): Taxonomy and biostratigraphy implications Publication date: June 2019 Source: Revue de Micropaléontologie, Volume 63 Author(s): Mehdi Hadi, György Less, Mohammad Vahidinia Abstract Shallow marine Eocene successions are described and illustrated with major focus on the systematics and biostratigraphic interpretation of larger benthic foraminifera in two stratigraphic sections (Mojen & Kalateh) of the Ziarat Formation from the eastern Alborz zone (Iran). Based on the larger benthic foraminifera assemblages, six shallow benthic zones (SBZ8-SBZ10 and SBZ16?-SBZ17-SBZ18b) during the middle Ilerdian-early Cuisian and Late Lutetian?-Bartonian interval are identified for the first time. The Mojen section is mainly composed of Alveolina horizons as index markers, such as Alveolina decipiens (Schwager), A. tumida (Hottinger), A. ilerdensis (Hottinger), A. sp. cf. A. ilerdensis, A. laxa (Hottinger), A. citrea (Drobne), A. trempina (Hottinger), A. fornasinii (Checchia-Rispoli), A. canavarii (Checchia-Rispoli), A. cf. canavarii and A. aff. cayrazensis, which are consistent with the SBZ8 to SBZ10 interval, whilst the exact age of the top of the interval was not distinctly recognizable. The studied interval of the Kalateh section was assigned to the SBZ16?-SBZ17-SBZ18b with identifications of larger hyaline-lamellar foraminifera represented by Nummulites cf. deshayesi, N. lyelli (D'Archiac & Haime), Orbitoclypeus zitteli (Checchia-Rispoli) and Asterocyclina stella stella (Gümbel).

Dynamics of development of the small foraminiferal biota during early Kungurian (Permian) as evidenced from the Chikali section, Middle Urals, Russia Publication date: June 2019 Source: Revue de Micropaléontologie, Volume 63 Author(s): Tatiana V. Filimonova, Tatiana N. Isakova Abstract The study of taxonomic diversity and dynamics of development of the small foraminifera (SF) at the Artinskian/Kungurian transition in the Chikali section, one of the typical Kungurian successions, revealed four stratigraphically successive SF assemblages. The lowermost assemblage corresponds to the upper part of the Artinskian and three younger assemblages characterize the Kungurian interval. It is shown that the stratigraphic potential of SF makes possible their use for detailed subdivision of a typical Kungurian succession (Chikali section) and interregional correlation of sedimentary successions. The taxa common for Urals, North and North-East Russia include Hemigordius permicus, H. longus, Midiella ovata minima, Omoloniella prima, small specimens of Howchinella (H. semiovalis, H. breggeri, H. impolita), Nodosinelloides mirabilis, N. bella, N. shiknanica, N. cubanicus elongatus, N. pugioidea, Geinitzina chapmani sylvae, G. postcarbonica, G. ex gr. spandeli, Pachyphloia angulata irregularis and Lateenoglobivalvulina ovalis. New comprehensive description of the characteristic species of the early Kungurian Saranian Horizon such as Hemigordius permicus and Midiella ovata minima are given based the study of topotypical material.

Lectotype designation for Alveolina boscii and Fabularia discolites (Foraminifera) from the rediscovered part of the Defrance collection Publication date: June 2019 Source: Revue de Micropaléontologie, Volume 63 Author(s): Jérôme Tréguier, François Le Coze, Roch-Alexandre Benoit Abstract Five lots of Foraminifera, belonging to the Marin Defrance (1758–1850) collection, were discovered in the collection of the Musée des Sciences in Laval (Mayenne, France). The original material used by Defrance to describe Alveolina boscii (Defrance in Bronn, 1825) and Fabularia discolites Defrance in Bronn, 1825 was identified among them, allowing the designation of a lectotype and paralectotypes for those two species. The systematic description of A. boscii and F. discolites is reviewed. The presence of these specimens in the museum collections is still puzzling, since the complete Defrance's collection was thought to have been lost during World War II.

Terrestrial plant microfossils in palaeoenvironmental studies, pollen, microcharcoal and phytolith. Towards a comprehensive understanding of vegetation, fire and climate changes over the past one million years Publication date: June 2019 Source: Revue de Micropaléontologie, Volume 63 Author(s): Anne-Laure Daniau, Stéphanie Desprat, Julie C. Aleman, Laurent Bremond, Basil Davis, William Fletcher, Jennifer R. Marlon, Laurent Marquer, Vincent Montade, César Morales-Molino, Filipa Naughton, Damien Rius, Dunia H. Urrego Abstract The Earth has experienced large changes in global and regional climates over the past one million years. Understanding processes and feedbacks that control those past environmental changes is of great interest for better understanding the nature, direction and magnitude of current climate change, its effect on life, and on the physical, biological and chemical processes and ecosystem services important for human well-being. Microfossils from terrestrial plants – pollen, microcharcoal and phytoliths – preserved in terrestrial and marine sedimentary archives are particularly useful tools to document changes in vegetation, fire and land climate. They are well-preserved in a variety of depositional environments and provide quantitative reconstructions of past land cover and climate. Those microfossil data are widely available from public archives, and their spatial coverage includes almost all regions on Earth, including both high and low latitudes and altitudes. Here, we (i) review the laboratory procedures used to extract those microfossils from sediment for microscopic observations and the qualitative and quantitative information they provide, (ii) highlight the importance of regional and global databases for large-scale syntheses of environmental changes, and (iii) review the application of terrestrial plant microfossil records in palaeoclimatology and palaeoecology using key examples from specific regions and past periods.

Editorial Board Publication date: June 2019 Source: Revue de Micropaléontologie, Volume 63 Author(s):

Palynostratigraphic, palynofacies, organic geochemical and palaeoenvironmental analysis of the Silurian Tanezzuft Formation in the Ghadames Basin of north-west Libya Publication date: March 2019 Source: Revue de Micropaléontologie, Volume 62, Issue 1 Author(s): Waleed Shukry El Diasty, Salah Youssef El Beialy, Fadeel Ibrahim Fadeel, David J. Batten Abstract Two palynofacies associations are documented from the Silurian Tanezzuft Formation in the Ghadames Basin. These are characteristic of the basal 'Hot Shale' and the overlying deposits, referred to here as the Cold Shale. The former reflects deposition in distal suboxic anoxic conditions and is dominated by highly oil-prone amorphous organic matter (AOM) typical of deposition in generally anoxic, restricted marine basins. Only a few acritarchs, prasinophyte algae and chitinozoans occur in association: virtually no spores or cryptospores were recorded. Thick-walled prasinophytes are most numerous in this part of the Tanezzuft Formation in both the Ghadames and Murzuq basins, suggesting enhanced surface water productivity. Deposition took place after the melting of the Late Ordovician ice sheets, which led to a major marine transgression. The palynofacies recorded from the overlying 'Cold Shale' deposits indicate deposition in distal shelf and basin conditions that were also relatively anoxic. They contain more palynomorphs, especially acritarchs, and generally less AOM. The phytoplankton assemblages are dominated by simple and thin-walled prasinophyte algae (leiospheres), suggesting dysoxic–anoxic conditions. Overall the middle and the upper parts of the Tanezzuft Formation are regarded as being deposited in distal dysoxic–anoxic shelf, distal dysoxic–oxic shelf and distal suboxic–anoxic basin respectively. Because chitinozoans are very rare, age determinations of the samples investigated are based mainly on acritarchs. The Hot Shale is dated as early-mid Rhuddanian (early Llandovery) whereas the rest of the formation is considered to late Rhuddanian–Telychian in age. As documented previously from other samples of the Tanezzuft Formation in both the Ghadames and Murzuq basins, the Hot Shale has a very high TOC content and excellent source potential for liquid hydrocarbons, whereas rest of the formation is less rich in organic matter with larger terrestrial and oxidized components and hence reduced potential for sourcing hydrocarbons (both oil and gas).

Benthic foraminiferal assemblages in the severely polluted coastal environment of Drapetsona-Keratsini, Saronikos Gulf (Greece) Publication date: March 2019 Source: Revue de Micropaléontologie, Volume 62, Issue 1 Author(s): Margarita D. Dimiza, Alexandra Ravani, Vasilios Kapsimalis, Ioannis P. Panagiotopoulos, Elisavet Skampa, Maria V. Triantaphyllou Abstract Surface sediments were collected from the coastal zone of Drapetsona–Keratsini (Saronikos Gulf, Greece) in December 2012 for determining the local benthic foraminiferal community, identifying their spatial distribution patterns, and evaluating the response of foraminiferal species to geochemical composition through the hierarchical cluster analysis, principal component analysis and Spearman's rho correlation. Foraminifera can be classified into three distinct assemblages associated with the granulometry, elemental geochemistry, particulate organic carbon content and degree of sediment contamination. A relatively low-diversity assemblage, dominated by stress-tolerant taxa with Ammonia tepida Bolivina spathulata and Bulimina elongata being the prevailing species, is characteristic of the silty seabed of the main part of Drapetsona coastal zone and the Keratsini Port central basin, where organic carbon content, aliphatic and polycyclic aromatic hydrocarbons concentrations and trace metal loads are greatly elevated. On the sandy bottom of the investigated area, relatively high frequencies of miliolids prevail. An epiphytic rotaliid-dominated assemblage is recorded in the slightly-polluted sedimentary bottom of the inner and western part of the Keratsini Port.

Paleobiogeographic implications of the Middle Eocene ostracods from Cairo–Suez district, Egypt Publication date: March 2019 Source: Revue de Micropaléontologie, Volume 62, Issue 1 Author(s): Sherif M. El Baz, Mohamed M. Khalil Abstract The main targets of this paper are to examine the Middle Eocene ostracod assemblages collected from a succession exposed in the Cairo–Suez district, Egypt and to detect their paleobiogeographical implications. The studied succession is subdivided into two rock units: the Observatory and Qurn formations, in ascending order. The analysis of the ostracod assemblages led to the identification of 18 species, none of which is new. Three local biozones are established, Digmocythere ismaili - Xestoleberis kenawyi Assemblage Zone, Grinioneis moosi - Loxoconcha pseudopunctatella Assemblage Zone and Cativella qurnenis - Soudanella triangulataAssemblage Zone. The multivariate analyses indicate that there are three distinct bioprovinces, one of them represents the North Africa bioprovince, including Egypt, Libya, and Tunisia. The second bioprovince represents the Middle East, including Jordan and Israel. The third represents the West Africa bioprovince, including Senegal, Togo, Ivory Coast and Nigeria. Therefore, this deduction supports a migration of Eocene ostracods along the southern Tethys.

New insights in late Miocene lower Chelif basin biostratigraphy based on planktonic foraminifera (Algeria) Publication date: March 2019 Source: Revue de Micropaléontologie, Volume 62, Issue 1 Author(s): Mostapha Benzina, Hakim Hebib, Mustapha Bensalah Abstract Quantitative and qualitative analyses based on planktonic foraminifera of two sections (Oued Derdoussa and Djebel Meni) from lower Chelif basin (northern Algeria) enable us to identify for the first time a sequence of bioevents calibrated with the geomagnetic polarity time scale. The identified bioevents of late Miocene formations are useful for a high-resolution correlation in the whole western Mediterranean at local and regional scales. In particular, this work reveals that the sequence covers an interval of time that extends from the upper Tortonian up to the pre-evaporite Messinian period. Indeed, the base of the succession starts with a change in the coiling direction (from dextral to sinistral) of Neogloboquadrina acostaensis as the first bioevent. This later corresponds to the bioevent (1–8) assigned to the Tortonian sediments. This period is marked by the presence of Globorotalia menardii in sinistral coiled form that was substituted gradually with dextral coiled. The Tortonian/Messinian (T/M) boundary coincides to some extent with a sharp replacement of G. menardii group (I and II) with the first common occurrence (FCO) of Globorotalia miotumida plexus few meters below the development of the Tripoli diatomite formation (bioevent 9). This later is dominated mainly by highly convex species (G. miotumidaplexus) marked by the presence of Globorotalia mediterranea in contrast with the marly formation at the base of the section. In this part, the recorded bioevents (10 to 17) are assigned to the Messinian sediments. Thus, the Tripoli formation shows the influx of Globorotalia nicolae and a small incursion of the dextrally coiled of Globorotalia scitula at the top of Oued Derdoussa section as a local bioevent that may be related to the local palaeoenvironment. We notice the absence of the change in the coiling from sinistral to dextral of N. acostaensis during the upper Messinian, this may be due to the coincidence of this bioevent with the barren levels.

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

Dysphagia

Can We Reduce Frame Rate to 15 Images per Second in Pediatric Videofluoroscopic Swallow Studies? Abstract Videofluoroscopic Swallow studies (VFSS) are useful radiological examinations to explore swallowing disorders but which require ionizing radiation. The aim of our study was to evaluate the comparability of pediatric VFSS at 15 frames per second (fps) with 30 fps. Fifty-five loops including 190 swallowings of VFSS at 30 fps performed on 32 consecutive pediatric patients in a University Hospital Center were retrospectively modified by a software to delete one image out of two to obtain secondary loops with a frame rate of 15 fps. An otorhinolaryngologist-phonatrician and a radiologist reviewed all swallowings blindly and randomly using the penetration and aspiration scale (PAS). In case of discordance, they concluded a consensual interpretation. Fifteen girls and seventeen boys were included. The median age was 4 years and 8 months (range = 4 months–16 yr.). 144 swallowings were normal. Swallowing disorder was confirmed in 46 swallowings, (23 supraglottic penetrations and 23 aspirations). Considering each swallowing at 15 fps, sensitivity and specificity were, respectively, 93% (CI 0.82–0.98) and 98% (CI 0.94–0.99). The Cohen'Kappa coefficient between each interpretation at 15 and 30 fps was "almost perfect" (κ = 0.95; CI 0.88–0.99). Considering each loop, conclusion was identical. Reducing frame rate at 15 fps during pediatric VFSS seemed to be acceptable with comparable diagnostic performances without clinical impact compared to 30 fps, while being an efficient way to reduce the ionizing radiation exposition in children. We would suggest reconsidering the possibility of using VFSS with a 15 fps in a pediatric population.

High-Resolution Pharyngeal Manometry and Impedance: Protocols and Metrics—Recommendations of a High-Resolution Pharyngeal Manometry International Working Group Abstract High-resolution manometry has traditionally been utilized in gastroenterology diagnostic clinical and research applications. Recently, it is also finding new and important applications in speech pathology and laryngology practices. A High-Resolution Pharyngeal Manometry International Working Group was formed as a grass roots effort to establish a consensus on methodology, protocol, and outcome metrics for high-resolution pharyngeal manometry (HRPM) with consideration of impedance as an adjunct modality. The Working Group undertook three tasks (1) survey what experts were currently doing in their clinical and/or research practice; (2) perform a review of the literature underpinning the value of particular HRPM metrics for understanding swallowing physiology and pathophysiology; and (3) establish a core outcomes set of HRPM metrics via a Delphi consensus process. Expert survey results were used to create a recommended HRPM protocol addressing system configuration, catheter insertion, and bolus administration. Ninety two articles were included in the final literature review resulting in categorization of 22 HRPM-impedance metrics into three classes: pharyngeal lumen occlusive pressures, hypopharyngeal intrabolus pressures, and upper esophageal sphincter (UES) function. A stable Delphi consensus was achieved for 8 HRPM-Impedance metrics: pharyngeal contractile integral (CI), velopharyngeal CI, hypopharyngeal CI, hypopharyngeal pressure at nadir impedance, UES integrated relaxation pressure, relaxation time, and maximum admittance. While some important unanswered questions remain, our work represents the first step in standardization of high-resolution pharyngeal manometry acquisition, measurement, and reporting. This could potentially inform future proposals for an HRPM-based classification system specifically for pharyngeal swallowing disorders.

Variations in Healthy Swallowing Mechanics During Various Bolus Conditions Using Computational Analysis of Swallowing Mechanics (CASM) Abstract Bolus properties such as volume, consistency, and density have been shown to influence swallowing through the analysis of kinematics and timing in both normal and disordered swallowing. However, inherent intra- and inter-person variability of swallowing cloud interpretation of group data. Computational analysis of swallow mechanics (CASM) is an established methodology that uses coordinate tracking to map structural movements during swallowing and yields statistically powerful analyses at both the group and individual levels. In this study, the CASM method was used to determine how different bolus properties (volume, consistency, and density) altered swallow mechanics in healthy young adults at the group and individual levels. Videofluoroscopic swallow studies of 10 (4 females) healthy young adults were analyzed using CASM. Five bolus types were administered in each study (3 × 5 ml 40% w/v nectar, 3 × 5 ml 22% w/v thin, 3 × 5 ml 40% w/v thin, 3 × 10 ml 22% w/v thin, and 3 × 20 ml 22% w/v thin). Canonical variate analyses demonstrated that bolus condition did not affect swallowing mechanics at the group level, but bolus condition did affect pharyngeal swallow mechanics at the individual level. Functional swallow adaptations (e.g., hyoid movement) to bolus conditions were not uniform across participants, consistent with the nonsignificant group finding. These results suggest that individual swallowing systems of healthy young individuals vary in how they respond to bolus different conditions, highlighting the intrinsic variability of the swallow mechanism and the importance of individually tailored evaluation and treatment of swallowing. Findings warrant further investigation with different bolus conditions and aging and disordered populations.

The Penetration–Aspiration Scale: Adaptation to Open Partial Laryngectomy and Reliability Analysis Abstract A standard for assessing swallowing function after open partial horizontal laryngectomy (OPHL) is still not established. The variability in the measures used to investigate swallowing functional outcomes after OPHL limits the communication among clinicians and the possibility to compare and combine results from different studies. The study aims to adapt the PAS to the altered anatomy after OPHLs using fiberoptic endoscopic evaluation of swallowing (FEES) and to test its reliability. To adapt the PAS, two landmarks were identified: the entry of the laryngeal vestibule and the neoglottis. Ninety patients who underwent an OPHL were recruited (27 type I, 31 type II and 32 type III). FEES was performed and video-recorded. Two speech and language therapists (SLTs) independently rated each FEES using the PAS adapted for OPHL (OPHL-PAS). FEES recordings were rated for a second time by both SLTs at least 15 days from the first video analysis. Inter- and intra-rater agreement was assessed using unweighted Cohen's kappa. Overall, inter-rater agreement of the OPHL-PAS was k = 0.863, while intra-rater agreement was k = 0.854. Concerning different OPHL types, inter- and intra-rater agreement were k = 0.924 and k = 0.914 for type I, k = 0.865 and k = 0.790 for type II, and k = 0.808 and k = 0.858 for type III, respectively. The OPHL-PAS is a reliable scale to assess the invasion of lower airway during swallowing in patients with OPHL using FEES. The study represents the first attempt to define standard tools to assess swallowing functional outcome in this population.

Letter to the Editor

Tongue-Strengthening Exercises in Healthy Older Adults: Does Exercise Load Matter? A Randomized Controlled Trial Abstract Tongue-strengthening exercises (TSE) are based on the principles of exercise and motor learning, including intensity. Intensity is manipulated by gradually adjusting the resistive load. This randomized controlled trial (RCT) investigates the effect of three different values resistive load during TSE in healthy older adults. Sixty subjects completed 8 weeks of TSE while exercising with Iowa Oral Performance Instrument (IOPI). They were randomly distributed to 4 different treatment arms: 3 exercise groups (EG1: n = 15; EG2: n = 16, EG3: n = 16) and 1 control group performing lip-strengthening exercises (CG: n = 13). Values of resistive load for EG1, EG2, and EG3 were 100, 80, and 60% 1RM, respectively. Anterior and posterior maximal isometric pressures (MIPA, MIPP) were measured at baseline, after 4 and 8 weeks of training and 4 weeks post-training. MIPA and MIPP in the EG were significantly higher than in the CG at all time points, except baseline. No significant differences between EG were found, but some trends were observable. Anteriorly, the higher the resistive load, the higher the increase in MIP. Posteriorly, 100% 1RM caused the highest values, followed by 60% and 80% 1RM. No detraining effects were measured. The degree of exercise load had a significant negative effect on the registered success rate. This RCT confirms the efficacy of TSE in healthy older adults. For MIPA and MIPP, TSE at a resistive load of 100% 1RM are the most efficient choice in this population, while lowering the resistive load will lead to an increased success rate. No detraining effects were registered.

Does the Hebrew Eating Assessment Tool-10 Correlate with Pharyngeal Residue, Penetration and Aspiration on Fiberoptic Endoscopic Examination of Swallowing? Abstract The Eating Assessment Tool-10 (EAT-10) is a 10-item patient-reported outcome measure (PROM) for dysphagia patients. The objective of this study was to translate and validate the EAT-10Heb and to test for a correlation between its score and residue, penetration and aspiration on Fiberoptic Endoscopic Examination of Swallowing (FEES). 136 patients visiting two specialized dysphagia clinics and undergoing FEES between April 2015 and August 2017, filled the EAT-10Heb. 23 patients refilled the EAT-10Heb during a 2-week period following their first visit. FEES were scored for residue (1 point per consistency, maximum 3 points) and penetration and aspiration (1 point for penetration, 2 points for aspiration per consistency, maximum 6 points). 51 healthy volunteers also filled the EAT-10Heb. Internal consistency and test–retest reproducibility were examined for reliability testing. Validity was established by comparing EAT-10Heb scores of dysphagia patients to healthy controls. The EAT-10Heb score was then correlated with the FEES score. Internal consistency of the EAT-10Heb was high (Cronbach's alpha = 0.925) as was the test–retest reproducibility (Spearman's correlation coefficient = 0.82, p < 0.0001). The median EAT-10Heb score was significantly higher in the dysphagia group compared to healthy controls (13, IQR 7–22 points for dysphagia patients compared to 0, IQR 0–0 points for healthy controls, p < 0.0001). A weak correlation was found between the EAT-10Heb scores and the FEES score (Pearson's correlation coefficient = 0.376, p < 0.0001). While the EAT-10Heb was found to be a reliable and valid PROM, it only weakly correlates with the pathological findings on FEES examination.

Dysphagia Research Society 26th Anniversary Annual Meeting March 15–17, 2018 Renaissance Baltimore Harborplace Hotel, Baltimore, Maryland

Effects of Tongue-Hold Swallows on Suprahyoid Muscle Activation According to the Relative Tongue Protrusion Length in the Elderly Individuals Abstract This study investigated differences in suprahyoid muscle activity in elderly adults during tongue-hold swallowing (THS) according to tongue protrusion length to determine the most effective tongue protrusion length during THS. A total of 52 healthy participants (34 females and 18 males) aged 69–92 years were included. Changes in suprahyoid muscle activation during normal swallowing and THS with 1/3rd and 2/3rd tongue protrusions using surface electromyography were observed. Suprahyoid muscle activation significantly increased with the increasing tongue protrusion length (p < 0.05). Depending on the responses of the participants based on tongue protrusion length, participants were categorized into the increase group [increased suprahyoid muscle activity with tongue protrusion, n = 36 (1/3rd THS compared to normal swallowing) or 38 (2/3rd THS compared to normal swallowing)] or decrease group [decreased suprahyoid muscle activity with tongue protrusion, n = 16 (1/3rd THS compared to normal swallowing) or 14 (2/3rd THS compared to normal swallowing)]. The functional reserve of the increase group was significantly higher than that of the decrease group (p < 0.05). Many elderly people were found to have increased activation of the suprahyoid muscle during THS; however, others showed the opposite. Therefore, it is necessary to confirm the degree of suprahyoid muscle activation during THS so that the patient can perform the exercise at the tongue protrusion length that can maximize the effect of the exercise. For individuals who cannot overcome even a small amount of tongue protrusion (e.g., 1/3rd MTPL), replacing THS with another exercise may be considered.

The Relationship Between Hiatal Hernia and Cricopharyngeus Muscle Dysfunction Abstract Although the precise etiology of cricopharyngeus muscle (CPM) dysfunction (CPMD) is uncertain, many have hypothesized that a hypertrophied CPM may develop as a protective compensation against gastroesophageal reflux disease (GERD). The purpose of this investigation was to evaluate the association between CPMD and the presence of hiatal hernia (HH) in an attempt to elucidate the potential etiology of CPMD. The charts of individuals who underwent video fluoroscopic esophagrams between 01/01/14 and 10/30/16 were reviewed from an electronic database. A group of 50 subjects with reported HH were identified and age- and gender-matched to an individual without HH. The prevalence of CPMD was compared between groups. The mean (± SD) age of the HH cohort was 64 (± 13.4) years and 64 (± 12.8) years for the group without HH (p > 0.05). Thirty-eight percent was male. The frequency of CPMD in the HH group was 78% versus 58% in the non-HH group (p < 0.05). Individuals with a HH were 2.57 times more likely to have evidence of CPMD (95% CI 1.07– 6.15). Although these data suggest an association between GERD and CPMD, further research is required before a causal relationship can be presumed.

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

Endocrine

Plasma renin levels are associated with cardiac function in primary adrenal insufficiency Abstract Background Despite adequate glucocorticoid (GC) and mineralocorticoid (MC) replacement therapy, primary adrenal insufficiency (AI) is associated with an increased mortality, mainly due to cardiovascular disease. The role of MC replacement is not known. Therefore, we assessed whether renin concentrations during routine GC and MC substitution therapy are associated with heart function and morphology. Methods Thirty two patients with primary AI were included in a cross-sectional case–control study. In total, 17 patients and 34 healthy controls (age: 48 ± 12 vs. 46 ± 18 years; BMI: 23 ± 3 vs. 24 ± 3 kg/m2) underwent magnetic resonance spectroscopy and imaging measurements to assess cardiac function, morphology, ectopic lipids, and visceral/subcutaneous fat mass. Patients were divided according to their actual plasma renin concentration at the study visit (Actual-Reninlow vs. Actual-Reninhigh) and their median plasma renin concentration of previous visits (Median-Reninlow vs. Median-Reninhigh). Results Ejection fraction was higher (67 ± 5 vs. 55 ± 3%; p = 0.001) and left ventricular mass was lower (60 ± 9 vs. 73 ± 10 g/m2; p = 0.025) in Actual-Reninhigh. Median-Reninhigh was associated with lower cardiac mass (64 ± 9 vs. 76 ± 11 g/m2; p = 0.029). Blood pressure, glucose, and lipid metabolism, as well as ectopic lipid content, pericardial fat mass, and visceral/subcutaneous fat were not different between the groups. Compared with controls, ejection fraction was significantly lower in patients with AI (56 ± 4 vs. 63 ± 8%; p = 0.019). No differences were found in patients with ≤20 mg compared with >20 mg of hydrocortisone per day. Conclusions Higher renin concentrations are associated with more favorable cardiac function and morphology in patients with primary AI.

Uremic leontiasis ossea

Alterations in atrial ion channels and tissue structure promote atrial fibrillation in hypothyroid rats Abstract Purpose It is well known that hyperthyroidism is associated with atrial fibrillation (AF); however, the relationship between hypothyroidism and AF remains controversial. Methods Hypothyroidism was established in rats by two methods: methimazole-induced (MMI) and thyroidectomy (TX). MMI model includes control (n = 10), MMI (n = 10), and MMI + L-thyroxine (T4, n = 10). Methimazole was given intragastrically in MMI and MMI + T4 for 12 weeks, and T4 was added intragastrically in MMI + T4 at week 5. TX model includes sham (n = 10), TX (n = 10), and TX + T4 (n = 10). Four weeks after surgery, rats in TX + T4 received T4 for 8 weeks. Triiodothyronine (T3), T4, and thyroid-stimulating hormone (TSH) were measured. Electrophysiology, tissue structure and function, and protein levels of potassium and L-type calcium channels were assessed in the atria. Results Severe changes in the atrial structure of hypothyroid rats were observed. Compared with euthyroid rats, atrial effective refractory period (AERP) in hypothyroid rats was significantly shortened; accordingly, inducibility and duration of AF were considerably increased. Protein levels of minK, Kv1.5, Kv4.2, Kv4.3, Kv7.1, and Cav1.2 were upregulated in hypothyroid rats, whereas there was only a tendency toward increased Kir2.1. Kv11.1 was statistically upregulated in the MMI model and had an increasing tendency in the TX model. Conversely, Kir3.1 and Kir3.4 were downregulated in hypothyroid rats. The above changes could be partially inhibited by T4 treatment. Conclusions AERP shortening due to altered protein levels of ion channels and atrial structural changes increased the susceptibility to AF in hypothyroidism. Thyroid replacement therapy could prevent electrical and structural remodeling under hypothyroid condition.

Reply to "Methodological issues in meta-analysis of the metformin effects on simple obesity"

Abnormal expression of Pappa2 gene may indirectly affect mouse hip development through the IGF signaling pathway Abstract Introduction Developmental dysplasia of the hip (DDH) is a major cause of disability in children, and the genetic mechanism of this disease remains unclear. In our previous study, we found that pregnancy-associated plasma protein-A2 (PAPP-A2) was associated with DDH significantly. Objectives The aim of this study was to investigate the insulin-like growth factor (IGF) expression and collagen synthesis as well as cartilage proliferation-related proteins in the case of abnormal expression of Pappa2 in mice to research the relationship between PAPP-A2 and the pathological changes of DDH. Methods In vivo animal experiments, the mice were directly injected with 50 µl of Cas9/PAPP-A2 sgRNA lentiviruses around the hip to downregulate the Pappa2 gene expression and injected with control lentiviruses on the other side, then to observe the expression and localization of related proteins. And in an in vitro experiment, mice fibroblasts and primary chondrocytes were cultured with insulin-like growth factor binding protein-5 (IGFBP-5) protein, PAPP-A2 protein and Cas9/PAPP-A2 sgRNA lentiviruses to detect of related proteins and mRNA expression. Results Cartilage proliferation-related proteins demonstrated a significant decrease in the PAPP-A2 knockdown hips acetabulum and femoral head cartilage, meanwhile the IGF expression was also downregulated in the soft tissue around the acetabulum compared with the control hips. Furthermore, the role PAPP-A2 played in chondrocytes and fibroblasts was the same as in the in vivo experiments, downregulation of PAPP-A2 expression or upregulation of IGFBP-5 expression can reduce collagen synthesis and cartilage proliferation. Conclusions PAPP-A2 may be involved in the development of the mouse hip joint by interfering the fibrous and cartilaginous metabolism via IGF pathway-associated proteins pathway.

Long-term control of Paget's disease of bone with low-dose, once-weekly, oral bisphosphonate preparations, in a "real world" setting

Lineage-dependent role of miR-410-3p as oncomiR in gonadotroph and corticotroph pituitary adenomas or tumor suppressor miR in somatotroph adenomas via MAPK, PTEN/AKT, and STAT3 signaling pathways Abstract Purpose miR-410-3p plays opposite roles in different cancers and may act as an oncomiR or tumor suppressor miR. The purpose of this study was to assess the role of miR-410-3p in somatotroph, gonadotroph, and corticotroph pituitary adenomas. Methods Tissue samples were obtained from 75 patients with pituitary adenoma. miR-410-3p expression was assessed using qRT-PCR performed on RNA isolated from fresh frozen samples. In vitro experiments were performed on cell lines derived from somatotroph (GH3), gonadotroph (RC-4B/C), and corticotroph (AtT-20) pituitary tumors. Cells were transfected with synthetic mimic of miR-410-3p or non-targeting scrambled-miR control. Subsequently, proliferation assays and transwell invasion assays were performed. The expression of cyclin D1, E1, and B1 in cells after transfection was determined using qRT-PCR. The activation of MAPK, PTEN/AKT and STAT3 signaling pathways were assessed using western blot. Results We have found that the level of expression of miR-410-3p differs in particular types of pituitary adenomas. miR-410-3p significantly upregulates proliferation and invasiveness of RC-4B/C and AtT-20 cells, while inhibiting GH3 cells. We observed that the levels of cyclin B1 upon transfection with miR-410-3p mimic were increased in RC-4B/C and AtT-20, yet decreased in GH3 cells. We have shown that miR-410-3p promoted the activation of MAPK, PTEN/AKT, and STAT3 signaling pathways in RC-4B/C and AtT-20 cells, but suppressed their activity in GH3 cells. Conclusions miR-410-3p acts as an oncomiR in gonadotroph and corticotroph adenoma cells, while as a tumor suppressor miR in somatotroph adenoma cells.

Development of a metabolic syndrome severity score and its association with incident diabetes in an Asian population—results from a longitudinal cohort in Singapore Abstract Purpose Metabolic syndrome (MetS) is a constellation of clinical factors that indicates elevated risk of diabetes. It is diagnosed based on three or more abnormalities in its components. This does not take into account that MetS can likely present as a continuum of risk. We aim to develop a MetS severity score and assess its association with incident diabetes. Methods In total, 4149 subjects without baseline diabetes participated in a community screening programme in 2013–2017. MetS was defined according to International Diabetes Federation criteria. A MetS severity z-score was derived from standardised loading coefficients of a confirmatory factor analysis for waist circumference, triglycerides, HDL-cholesterol, blood pressure and fasting plasma glucose (FPG). Multivariable cox proportional hazards regression model was used to assess the risk of diabetes by the score with adjustment for demographics and MetS components. Results Diabetes occurred in 130 subjects. Quintile 5 of the baseline MetS severity z-score was significantly associated with development of diabetes even in fully adjusted model with HR 2.63 (95% CI: 1.04–6.64; p = 0.040). The relationship between MetS and incident diabetes became attenuated and non-significant in fully adjusted model with HR 0.67 (95% CI: 0.34–1.29; p = 0.228). Mediation analysis showed that MetS severity z-score accounted 61.0% of the association between increasing body mass index and development of diabetes (p < 0.001). Conclusions The MetS severity z-score is an inexpensive and clinically-available continuous measure of MetS to identify individuals at high risk of diabetes.

High dose of linagliptin induces thermogenic beige adipocytes in the subcutaneous white adipose tissue in diet-induced obese C57BL/6 mice Abstract Purpose To verify whether the treatment with linagliptin induces the browning of the subcutaneous WAT (sWAT) and thermogenesis in murine diet-induced obesity (DIO) model. Methods Forty animals were randomly assigned to receive a control diet (C, 10% lipids as energy) or a high-fat diet (HF, 50% lipids as energy) for 10 weeks. Each group was re-divided to begin the 5-week treatment, totalizing four experimental groups: C, C-L (C plus linagliptin, 30 mg/kg body mass; BM), HF, and HF-L (HF plus linagliptin, 30 mg/kg BM). The drug was mixed with diet. Results HF animals showed overweight, glucose intolerance, and a greater cross-sectional area of adipocytes. The treatment with linagliptin was able to normalize the BM, restore the glucose tolerance and the cross-sectional area of adipocytes. These observations comply with the observation of UCP1-positive multilocular adipocytes in the sWAT of treated animals. Both treated groups (C-L and HF-L) showed high expression of thermogenic and type 2 cytokines genes, which agree with the enhanced body temperature and the lower respiratory exchange ratio, implying enhanced thermogenesis with the use of lipids as fuel. Conclusions The reduced BM, the enhanced body temperature, and the presence of positive UCP1 beige cells in the sWAT point to the activation of the browning cascade on the sWAT of linagliptin-treated mice, and hence, linagliptin could induce the thermogenic pathway as a pleiotropic effect that can have translational potential.

Long-term control of Paget's disease of bone with low-dose, once-weekly, oral bisphosphonate preparations, in a "real world" setting

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com