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1
Jorgačević, B., D. Mladenović, M. Ninković, V. Prokić, MN Stanković, V. Aleksić, I. Cerović, et al. "Dynamics of oxidative/nitrosative stress in mice with methionine–choline-deficient diet-induced nonalcoholic fatty liver disease." Human & Experimental Toxicology 33, no. 7 (October 15, 2013): 701–9. http://dx.doi.org/10.1177/0960327113506723.
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Insulin resistance, oxidative stress, and proinflammatory cytokines play a key role in pathogenesis of nonalcoholic fatty liver disease (NAFLD). The aim of our study was to investigate the dynamics of oxidative/nitrosative stress in methionine–choline-deficient (MCD) diet -induced NAFLD in mice. Male C57BL/6 mice were divided into following groups: group 1: control group on standard diet; group 2: MCD diet for 2, 4, and 6 weeks (MCD2, MCD4, and MCD6, respectively). After treatment, liver and blood samples were taken for histopathology, alanine- and aspartate aminotransferase, acute phase reactants, and oxidative/nitrosative stress parameters. Liver malondialdehyde level was higher in all MCD-fed groups versus control group ( p < 0.01), while nitrites + nitrates level showed a progressive increase. The activity of total superoxide dismutase and its isoenzymes was significantly lower in all MCD-fed groups ( p < 0.01). Although catalase activity was significantly lower in MCD-fed animals at all intervals ( p < 0.01), the lowest activity of this enzyme was evident in MCD4 group. Liver content of glutathione was lower in MCD4 ( p < 0.05) and MCD6 group ( p < 0.01) versus control.Ferritin and C-reactive protein serum concentration were significantly higher only in MCD6 group. Our study suggests that MCD diet induces a progressive rise in nitrosative stress in the liver. Additionally, the most prominent decrease in liver antioxidative capacity is in the fourth week, which implies that application of antioxidants would be most suitable in this period, in order to prevent nonalcoholic steatohepatitis but not the initial NAFLD phase.
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Fongsamut, Kanokkarn, Monsit Tanasittikosol, and Mingkhuan Phaksunchai. "Effectiveness of the simulation-based learning (SBL) assisted with scaffolding approach to address students’ misconceptions about projectile motion." Physics Education 58, no. 2 (December 14, 2022): 025002. http://dx.doi.org/10.1088/1361-6552/aca57d.
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Abstract This research studied the effectiveness of the simulation-based learning assisted with scaffolding approach to address students’ misconceptions (MCs) about projectile motion. The five MCs were related to the direction of the force acting on an object (MC1), the acceleration of an object at the top of the trajectory (MC2), the directions of velocity and acceleration during projectile motion (MC3), the time of flight of objects (MC4), and the relationship between the range of projectile motion and angle of projection (MC5). This study was a pre-experimental design using both quantitative and qualitative data. The sample comprised 35 tenth-grade Thai high school students who were chosen using the cluster sampling technique. The teaching method consisted of three steps: a briefing, simulation, and debriefing. Each step was assisted with scaffolding to guide and help the students. The MCs tests consisted of five multiple-choice questions with a four-tier diagnostic test, and the tests were used as a pre-test, end-of-class test, and end-of-topic test. Six semi-structured interview questions were used to obtain in-depth data. The results indicated that MC1, MC2, MC3, MC4, and MC5 were addressed by 11.1%, 85.7%, 57.2%, 57.2%, and 61.5%, respectively, at the end-of-topic test. Students who had MCs in the pre-test changed their understanding of the concepts in MC2, MC3, MC4, and MC5 by 57.1%, 14.3%, 28.6%, and 53.8%, respectively. None of the MC students in MC1 understood the concept at the end-of-topic test. Nevertheless, the overall results showed increased students’ understanding of all conceptions.
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Abdellah, Marwa Mahmoud, Hatem Gamal Ammar, Mohamed Anbar, Engy Mohammed Mostafa, Mahmoud Mohamed Farouk, Khulood Sayed, Alahmady Hammad Alsmman, and Mohamed Gamal Elghobaier. "Corneal Endothelial Cell Density and Morphology in Healthy Egyptian Eyes." Journal of Ophthalmology 2019 (February 24, 2019): 1–8. http://dx.doi.org/10.1155/2019/6370241.
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Purpose. To evaluate the corneal endothelial cell density and morphology in normal Egyptian eyes. Methods. In total, 568 healthy eyes of 568 Egyptian volunteers aged 20 to 85 years were examined using noncontact specular microscopy for the central corneal thickness (CCT), mean endothelial cell density (MCD), coefficient of variation (CV) in cell area, mean cell area (MCA), and hexagonal cell (Hex) percentage. Variables were compared between sexes and between different age groups. Results. The mean CCT, MCD, and MCA were 514.45 ± 43.04 μm, 2647.50 ± 382.62 cells/mm2, and 390.59 ± 149.94 μm2, respectively. MCD and MCA showed no significant differences between men and women (P=0.171 and 0.099, respectively), whereas CV (%) and Hex (%) showed significant differences (P=0.024 and 0.015, respectively). CCT (P=0.007, r = −0.113) and MCD (P<0.001, r = −0.357) exhibited a significant negative correlation with age, whereas CV (%) (P<0.001, r = 0.341) and MCA (P=0.008, r = 0.111) exhibited a significant positive correlation. The mean rate of endothelial cell loss from 20 to 85 years of age was 0.3% per year. Conclusions. Our results provide normative data for the corneal endothelium in healthy Egyptian eyes, thus increasing the knowledge base for corneal endothelial cell parameters in healthy Egyptian eyes. Furthermore, our findings can be used as baseline values for comparisons between Egyptian and other populations and for studies of the endothelial cell reserve and capacity for intraocular surgery and corneal transplantation.
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Uski, P., A. Ellman, I. Laine, L. Hillman, and J. Nieminen. "Model-Based Definition Accelerates Product Life Cycle in Manufacturing and Inspection Phase – Experiment of Machined One-Off Production." Proceedings of the Design Society 2 (May 2022): 643–52. http://dx.doi.org/10.1017/pds.2022.66.
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AbstractThe paper focuses on comparative experiment on manufacturing and inspection of two different prismatic one-off parts, which have different complexity. Our experiment shows that transforming product definition method from the Drawing Centric Definition (DCD) to the Model Centric Definition (MCD) enables 28%-29% time savings in manufacturing and inspection phases of machined one-off part's life cycle. Furthermore, transition from MCD to Model-Based Definition (MBD) enables 5%-9% time savings, respectively. Applying of MBD enables more time savings in complex part compared to a less complex part.
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Arıcı, Ceyhun, Osman Sevki Arslan, and Funda Dikkaya. "Corneal Endothelial Cell Density and Morphology in Healthy Turkish Eyes." Journal of Ophthalmology 2014 (2014): 1–5. http://dx.doi.org/10.1155/2014/852624.
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Purpose. To describe the normative values of corneal endothelial cell density, morphology, and central corneal thickness in healthy Turkish eyes.Methods. Specular microscopy was performed in 252 eyes of 126 healthy volunteers (M : F, 42 : 84). Parameters studied included mean endothelial cell density (MCD), mean cell area (MCA), coefficient of variation (CV) in cell size, percentage of hexagonal cells, and central corneal thickness (CCT).Results. The mean age of volunteers was44.3±13.5(range, 20 to 70) years. There was a statistically significant decrease in MCD (P<0.001; correlation, −0.388) and percentage of hexagonal cells, (P<0.001; correlation, −0.199) with age. There was also a statistically significant increase in MCA (P<0.001; correlation, 0.363) with increasing age. There was no statistically significant difference in MCD, MCA, CV in cell size, percentage of hexagonal cells, and CCT between genders and there was also no significant difference in these parameters between fellow eyes of subjects.Conclusions. Normotive data for the endothelium in the Turkish population are reported. Endothelial cell density in the Turkish eyes is less than that described in the Japanese, American, Chinese, and Filipino eyes and higher than that described in Indian, Thai, and Iranian eyes.
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Cho, Won-Hee, Seon-Hwa Park, Seul-Ki Choi, Su Woong Jung, Kyung Hwan Jeong, Yang-Gyun Kim, Ju-Young Moon, et al. "Characterization of IgA Deposition in the Kidney of Patients with IgA Nephropathy and Minimal Change Disease." Journal of Clinical Medicine 9, no. 8 (August 12, 2020): 2619. http://dx.doi.org/10.3390/jcm9082619.
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Approximately 5% of patients with IgA nephropathy (IgAN) exhibit mild mesangial lesions with acute onset nephrotic syndrome and diffuse foot process effacement representative of minimal change disease (MCD). It is not clear whether these unusual cases of IgAN with MCD (IgAN-MCD) are variant types of IgAN or coincidental deposition of IgA in patients with MCD. In a retrospective multicenter cohort study of 18 hospitals in Korea, we analyzed 46 patients with IgAN-MCD. Patients with endocapillary proliferation, segmental sclerosis, and crescent were excluded, and the clinical features and prognosis of IgAN-MCD were compared with those of pure MCD. In addition, we performed galactose-deficient IgA1 (KM55) staining to characterize IgAN-MCD. Among the 21,697 patients with glomerulonephritis enrolled in the database, 46 patients (0.21%) were diagnosed with IgAN-MCD, and 1610 patients (7.4%) with pure MCD. The 46 patients with IgAN-MCD accounted for 0.6% of primary IgAN patients (n = 7584). There was no difference in prognosis between patients with IgAN-MCD and those with only MCD. IgA and KM55 showed double positivity in all patients with IgAN-MCD (n = 4) or primary IgAN (n = 5) under double immunofluorescent staining. However, in four patients with lupus nephritis, mesangial IgA was deposited, but galactose-deficient-IgA1 (Gd-IgA1) was not. These findings suggest that IgAN-MCD is a dual glomerulopathy in which MCD was superimposed on possibly indolent IgAN. We confirmed by KM55 staining that IgAN-MCD is true IgAN, enabling better characterizations of the disease. Furthermore, IgAN-MCD shows a good prognosis when treated according to the usual MCD treatment modality.
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Vesković, Milena, Milica Labudović-Borović, Ivan Zaletel, Jelena Rakočević, Dušan Mladenović, Bojan Jorgačević, Danijela Vučević, and Tatjana Radosavljević. "The Effects of Betaine on the Nuclear Fractal Dimension, Chromatin Texture, and Proliferative Activity in Hepatocytes in Mouse Model of Nonalcoholic Fatty Liver Disease." Microscopy and Microanalysis 24, no. 2 (January 19, 2018): 132–38. http://dx.doi.org/10.1017/s1431927617012806.
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AbstractThe effects of betaine on hepatocytes chromatin architecture changes were examined by using fractal and gray-level co-occurrence matrix (GLCM) analysis in methionine/choline-deficient (MCD) diet-induced, nonalcoholic fatty liver disease (NAFLD). Male C57BL/6 mice were divided into groups: (1) Control: standard diet; (2) BET: standard diet and betaine supplementation through drinking water (solution 1.5%); (3) MCD group: MCD diet for 6 weeks; (4) MCD+BET: fed with MCD diet + betaine for 6 weeks. Liver tissue was collected for histopathology, immunohistochemistry, and determination of fractal dimension and GLCM parameters. MCD diet induced diffuse micro- and macrovesicular steatosis accompanied with increased Ki67-positive hepatocyte nuclei. Steatosis and Ki67 immunopositivity were less prominent in the MCD+BET group compared with the MCD group. Angular second moment (ASM) and inverse difference moment (IDM) (textural homogeneity markers) were significantly increased in the MCD+BET group versus the MCD group (p<0.001), even though no difference between the MCD and the control group was evident. Heterogeneity parameters, contrast, and correlation were significantly increased in the MCD group versus the control (p<0.001). On the other hand, betaine treatment significantly reduced correlation, contrast, and entropy compared with the MCD group (p<0.001). Betaine attenuated MCD diet-induced NAFLD by reducing fat accumulation and inhibiting hepatocyte proliferation. Betaine supplementation increased nuclear homogeneity and chromatin complexity with reduction of entropy, contrast, and correlation.
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Vesković, Milena, Milica Labudović-Borović, Dušan Mladenović, Jelena Jadžić, Bojan Jorgačević, Dušan Vukićević, Danijela Vučević, and Tatjana Radosavljević. "Effect of Betaine Supplementation on Liver Tissue and Ultrastructural Changes in Methionine–Choline-Deficient Diet-Induced NAFLD." Microscopy and Microanalysis 26, no. 5 (August 12, 2020): 997–1006. http://dx.doi.org/10.1017/s1431927620024265.
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AbstractNonalcoholic fatty liver disease (NAFLD) represents a hepatic manifestation of metabolic syndrome. The aim of this study was to examine the effect of betaine on ultrastructural changes in the mouse liver with methionine- and choline-deficient (MCD) diet-induced NAFLD. Male C57BL/6 mice were divided into groups: Control—fed with standard chow, BET—standard chow supplemented with betaine (1.5% w/v drinking water), MCD—fed with MCD diet, and MCD + BET—MCD diet with betaine supplementation for 6 weeks. Liver samples were taken for pathohistology and transmission electron microscopy. The MCD diet-induced steatosis, inflammation, and balloon-altered hepatocytes were alleviated by betaine. MCD diet induced an increase in mitochondrial size versus the control group (p < 0.01), which was decreased in the betaine-treated group. In the MCD diet-fed group, the total mitochondrial count decreased versus the control group (p < 0.01), while it increased in the MCD + BET group versus MCD (p < 0.01). Electron microscopy showed an increase in the number of autophagosomes in the MCD and MCD + BET group versus control, and a significant difference in autophagosomes number was detected in the MCD + BET group by comparison with the MCD diet-treated group (p < 0.05). Betaine decreases the number of enlarged mitochondria, alleviates steatosis, and increases the number of autophagosomes in the liver of mice with NAFLD.
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Young, Martin E., Gary W. Goodwin, Jun Ying, Patrick Guthrie, Christopher R. Wilson, Frank A. Laws, and Heinrich Taegtmeyer. "Regulation of cardiac and skeletal muscle malonyl-CoA decarboxylase by fatty acids." American Journal of Physiology-Endocrinology and Metabolism 280, no. 3 (March 1, 2001): E471—E479. http://dx.doi.org/10.1152/ajpendo.2001.280.3.e471.
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Malonyl-CoA decarboxylase (MCD) catalyzes the degradation of malonyl-CoA, an important modulator of fatty acid oxidation. We hypothesized that increased fatty acid availability would increase the expression and activity of heart and skeletal muscle MCD, thereby promoting fatty acid utilization. The results show that high-fat feeding, fasting, and streptozotocin-induced diabetes all significantly increased the plasma concentration of nonesterified fatty acids, with a concomitant increase in both rat heart and skeletal muscle MCD mRNA. Upon refeeding of fasted animals, MCD expression returned to basal levels. Fatty acids are known to activate peroxisome proliferator-activated receptor-α (PPARα). Specific PPARα stimulation, through Wy-14643 treatment, significantly increased the expression of MCD in heart and skeletal muscle. Troglitazone, a specific PPARγ agonist, decreased MCD expression. The sensitivity of MCD induction by fatty acids and Wy-14643 was soleus > extensor digitorum longus > heart. High plasma fatty acids consistently increased MCD activity only in solei, whereas MCD activity in the heart actually decreased with high-fat feeding. Pressure overload-induced cardiac hypertrophy, in which PPARα expression is decreased (and fatty acid oxidation is decreased), resulted in decreased MCD mRNA and activity, an effect that was dependent on fatty acids. The results suggest that fatty acids induce the expression of MCD in rat heart and skeletal muscle. Additional posttranscriptional mechanisms regulating MCD activity appear to exist.
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DYCK, Jason R. B., Luc G. BERTHIAUME, Panakkezhum D. THOMAS, Paul F. KANTOR, Amy J. BARR, Rick BARR, Dyal SINGH, et al. "Characterization of rat liver malonyl-CoA decarboxylase and the study of its role in regulating fatty acid metabolism." Biochemical Journal 350, no. 2 (August 23, 2000): 599–608. http://dx.doi.org/10.1042/bj3500599.
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In the liver, malonyl-CoA is central to many cellular processes, including both fatty acid biosynthesis and oxidation. Malonyl-CoA decarboxylase (MCD) is involved in the control of cellular malonyl-CoA levels, and functions to decarboxylate malonyl-CoA to acetyl-CoA. MCD may play an essential role in regulating energy utilization in the liver by regulating malonyl-CoA levels in response to various nutritional or pathological states. The purpose of the present study was to investigate the role of liver MCD in the regulation of fatty acid oxidation in situations where lipid metabolism is altered. A single MCD enzyme of molecular mass 50.7kDa was purified from rat liver using a sequential column chromatography procedure and the cDNA was subsequently cloned and sequenced. The liver MCD cDNA was identical to rat pancreatic β-cell MCD cDNA, and contained two potential translational start sites, producing proteins of 50.7kDa and 54.7kDa. Western blot analysis using polyclonal antibodies generated against rat liver MCD showed that the 50.7kDa isoform of MCD is most abundant in heart and liver, and of relatively low abundance in skeletal muscle (despite elevated MCD transcript levels in skeletal muscle). Tissue distribution experiments demonstrated that the pancreas is the only rat tissue so far identified that contains both the 50.7 kDa and 54.7kDa isoforms of MCD. In addition, transfection of the full-length rat liver MCD cDNA into COS cells produced two isoforms of MCD. This indicated either that both initiating methionines are functionally active, generating two proteins, or that the 54.7kDa isoform is the only MCD protein translated and removal of the putative mitochondrial targeting pre-sequence generates a protein of approx. 50.7kDa in size. To address this, we transiently transfected a mutated MCD expression plasmid (second ATG to GCG) into COS-7 cells and performed Western blot analysis using our anti-MCD antibody. Western blot analysis revealed that two isoforms of MCD were still present, demonstrating that the second ATG may not be responsible for translation of the 50.7kDa isoform of MCD. These data also suggest that the smaller isoform of MCD may originate from intracellular processing. To ascertain the functional role of the 50.7kDa isoform of rat liver MCD, we measured liver MCD activity and expression in rats subjected to conditions which are known to alter fatty acid metabolism. The activity of MCD was significantly elevated under conditions in which hepatic fatty acid oxidation is known to increase, such as streptozotocin-induced diabetes or following a 48h fast. A 2-fold increase in expression was observed in the streptozotocin-diabetic rats compared with control rats. In addition, MCD activity was shown to be enhanced by alkaline phosphatase treatment, suggesting phosphorylation-related control of the enzyme. Taken together, our data demonstrate that rat liver expresses a 50.7kDa form of MCD which does not originate from the second methionine of the cDNA sequence. This MCD is regulated by at least two mechanisms (only one of which is phosphorylation), and its activity and expression are increased under conditions where fatty acid oxidation increases.
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Chen, Rongrong, De Zhou, Lulu Wang, Lixia Zhu, and Xiujin Ye. "MYD88L265P and CD79B double mutations type (MCD type) of diffuse large B-cell lymphoma: mechanism, clinical characteristics, and targeted therapy." Therapeutic Advances in Hematology 13 (January 2022): 204062072110728. http://dx.doi.org/10.1177/20406207211072839.
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MYD88/CD79B-mutated (MCD) genotype is a genetic subgroup of diffuse large B-cell lymphoma (DLBCL) with the co-occurrence of MYD88L265P and CD79B mutations. MCD genotype is characterized by poor prognosis and extranodal involvement especially in immune-privileged sites. MCD model is dominated by activated B-cell (ABC)-like subtype of DLBCLs. It is generally accepted that the pathogenesis of MCD DLBCL mainly includes chronic active B-cell receptor (BCR) signaling and oncogenic MYD88 mutations, which drives pathological nuclear factor kappa B (NF-κB) activation in MCD lymphoid malignancies. CD79B and MYD88L265P mutations are frequently and contemporaneously founded in B-cell malignancies. The collaboration of the two mutations may explain the unique biology of MCD. Meanwhile, standard immunochemotherapy combine with different targeted therapies worth further study to improve the prognosis of MCD, according to genetic, phenotypic, and clinical features of MCD type. In this review, we systematically described mechanism, clinical characteristics, and targeted therapy of MCD DLBCL.
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Vrouenraets, Lieke Josephina Jeanne Johanna, Laura A. Hartman, Irma M. Hein, Annelou L. C. de Vries, Martine C. de Vries, and Bert A. C. Molewijk. "Dealing with Moral Challenges in Treatment of Transgender Children and Adolescents: Evaluating the Role of Moral Case Deliberation." Archives of Sexual Behavior 49, no. 7 (June 26, 2020): 2619–34. http://dx.doi.org/10.1007/s10508-020-01762-3.
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Abstract Treatment teams providing affirmative medical transgender care to young people frequently face moral challenges arising from the care they provide. An adolescent’s capacity to consent, for example, could raise several issues and challenges. To deal with these challenges more effectively, several Dutch treatment teams started using a relatively well-established form of clinical ethics support (CES) called Moral Case Deliberation (MCD). MCD is a facilitator-led, collective moral inquiry based on a real case. This study’s purpose is to describe the teams’ perceived value and effectiveness of MCD. We conducted a mixed methods evaluation study using MCD session reports, individual interviews, focus groups, and MCD evaluation questionnaires. Our results show that Dutch transgender care providers rated MCD as highly valuable in situations where participants were confronted with moral challenges. The health care providers reported that MCD increased mutual understanding and open communication among team members and strengthened their ability to make decisions and take action when managing ethically difficult circumstances. However, the health care providers also expressed criticisms of MCD: some felt that the amount of time spent discussing individual cases was excessive, that MCD should lead to more practical and concrete results, and that MCD needed better integration and follow-up in the regular work process. We recommend future research on three matters: studying how MCD contributes to the quality of care, involvement of transgender people themselves in MCD, and integration of CES into daily work processes.
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Samokhvalov, Victor, John R. Ussher, Natasha Fillmore, Ian K. G. Armstrong, Wendy Keung, Daniel Moroz, David G. Lopaschuk, John Seubert, and Gary D. Lopaschuk. "Inhibition of malonyl-CoA decarboxylase reduces the inflammatory response associated with insulin resistance." American Journal of Physiology-Endocrinology and Metabolism 303, no. 12 (December 15, 2012): E1459—E1468. http://dx.doi.org/10.1152/ajpendo.00018.2012.
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We previously showed that genetic inactivation of malonyl-CoA decarboxylase (MCD), which regulates fatty acid oxidation, protects mice against high-fat diet-induced insulin resistance. Development of insulin resistance has been associated with activation of the inflammatory response. Therefore, we hypothesized that the protective effect of MCD inhibition might be caused by a favorable effect on the inflammatory response. We examined if pharmacological inhibition of MCD protects neonatal cardiomyocytes and peritoneal macrophages against inflammatory-induced metabolic perturbations. Cardiomyocytes and macrophages were treated with LPS to induce an inflammatory response, in the presence or absence of an MCD inhibitor (CBM-301106, 10 μM). Inhibition of MCD attenuated the LPS-induced inflammatory response in cardiomyocytes and macrophages. MCD inhibition also prevented LPS impairment of insulin-stimulated glucose uptake in cardiomyocytes and increased phosphorylation of Akt. Additionally, inhibition of MCD strongly diminished LPS-induced activation of palmitate oxidation. We also found that treatment with an MCD inhibitor prevented LPS-induced collapse of total cellular antioxidant capacity. Interestingly, treatment with LPS or an MCD inhibitor did not alter intracellular triacylglycerol content. Furthermore, inhibition of MCD prevented LPS-induced increases in the level of ceramide in cardiomyocytes and macrophages while also ameliorating LPS-initiated decreases in PPAR binding. This suggests that the anti-inflammatory effect of MCD inhibition is mediated via accumulation of long-chain acyl-CoA, which in turn stimulates PPAR binding. Our results also demonstrate that pharmacological inhibition of MCD is a novel and promising approach to treat insulin resistance and its associated metabolic complications.
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Eikrem, Øystein, Bjørnar Lillefosse, Nicolas Delaleu, Philipp Strauss, Tarig Osman, Bjørn Egil Vikse, Hanna Debiec, et al. "Network-Based Assessment of Minimal Change Disease Identifies Glomerular Response to IL-7 and IL-12 Pathways Activation as Innovative Treatment Target." Biomedicines 11, no. 1 (January 16, 2023): 226. http://dx.doi.org/10.3390/biomedicines11010226.
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Background: Minimal change disease (MCD), a major cause of nephrotic syndrome, is usually treated by corticosteroid administration. MCD unresponsiveness to therapy and recurrences are nonetheless frequently observed, particularly in adults. To explore MCD-related pathogenetic mechanisms and to identify novel drug targets ultimately contributing to novel therapeutic avenues with a certain specificity for MCD, we compared glomerular transcriptomes from MCD with membranous nephropathy (MN) patients and healthy controls. Methods: Renal biopsies from adult patients with MCD (n = 14) or MN (n = 12), and non-diseased controls (n = 8) were selected from the Norwegian Kidney Biopsy Registry. RNA for 75 base-pair paired-end RNASeq were obtained from laser capture micro-dissected (LCM) glomeruli from FFPE sections. Transcriptional landscapes were computed by combining pathway-centered analyses and network science methodologies that integrate multiple bioinformatics resources. Results: Compared to normal glomeruli, cells from MCD displayed an inflammatory signature apparently governed by the IL1 and IL7 systems. While enrichment of IL1 production and secretion was a shared feature of MCD and MN compared to normal tissue, responses involving IL7 pathway activation were unique to MCD. Indeed, IL7R expressed by glomeruli was the most upregulated gene of the interleukin family in MCD versus normal controls. IL7 pathway activation was paralleled by significant enrichment in adaptive immune system processes and transcriptional regulation and depletion in pathways related to energy metabolism and transcription. Downregulation of these organ function-related themes again occurred predominately in MCD and was significantly less pronounced in MN. Immunofluorescence and immunohistochemistry, respectively, confirmed the expression of phosphorylated IL-7 receptor alpha (IL7RA, CD127) and IL12 receptor beta 1 (IL12RB1) proteins. Conclusions: Gene expression profiling of archival FFPE-biopsies identifies MCD-specific signatures with IL7RA and IL12RB1 as novel targets for MCD treatment.
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Zhao, Bing, Hui Han, Junhui Zhen, Xiaowei Yang, Jin Shang, Liang Xu, and Rong Wang. "CD80 and CTLA-4 as diagnostic and prognostic markers in adult-onset minimal change disease: a retrospective study." PeerJ 6 (August 3, 2018): e5400. http://dx.doi.org/10.7717/peerj.5400.
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Background Minimal change disease (MCD) is a form of idiopathic nephrotic syndrome. Compared to children, adult-onset MCD patients are reported to have delayed responses to glucocorticoid treatment. Several studies of children have suggested detecting urinary CD80 levels to diagnose MCD. There are no effective diagnostic methods to distinguish steroid-sensitive MCD from steroid-resistant MCD unless treatments are used. Methods In a total of 55 patients with biopsy-proven MCD and 26 patients with biopsy-proven idiopathic membranous nephropathy, CD80 and cytotoxic T-lymphocyte antigen-4 (CTLA-4) levels in serum, urine and renal tissue were analyzed. Results Steroid-sensitive MCD patients in remission had lower urinary CD80 levels and higher CTLA-4 levels than patients in relapse (156.65 ± 24.62 vs 1066.40 ± 176.76 ng/g creatinine; p < 0.0001), (728.73 ± 89.93 vs 151.70 ± 27.01 ng/g creatinine; p < 0.0001). For MCD patients in relapse, mean urinary CD80 level was higher, and CTLA-4 level was lower for those who were steroid-sensitive than those who were steroid-resistant (1066.40 ± 176.76 vs. 203.78 ± 30.65 ng/g creatinine; p < 0.0001), but the mean urinary CTLA-4 level was lower (151.70 ± 27.01 vs. 457.83 ± 99.45 ng/g creatinine; p < 0.0001). CD80 expression in glomeruli was a sensitive marker to diagnose MCD. The absent or minimal expression of CTLA-4 in glomeruli could distinguish steroid-sensitive MCD from steroid-resistant MCD. Conclusions Glucocorticoid treatment may result in complete remission for only MCD patients with strongly positive CD80 expression and negative CTLA-4 expression in glomeruli, or higher urinary CD80 level and lower CTLA-4 level.
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Chen, Ping, Yan Chen, Maoqing Jiang, Yijun Mo, Huanhuan Ying, Xun Tang, and Jun Zhang. "Usefulness of the cytokines expression of Th1/Th2/Th17 and urinary CD80 excretion in adult-onset minimal change disease." PeerJ 8 (September 8, 2020): e9854. http://dx.doi.org/10.7717/peerj.9854.
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Background Minimal change disease (MCD) is a common form of nephrotic syndrome in adults. However, the molecular mechanism underlying the pathogenesis of MCD remains incompletely understood. In this study, we aimed to investigate the role of the cytokines expression of Th1/Th2/Th17 and urinary CD80 excretion in adult-onset MCD patients. Methods The lymphocyte subsets, 34 cytokine levels of Th1/Th2/Th17, serum and urine concentrations of CD80, and expression of CD80 in glomeruli were analyzed in 28 cases (15 males and 13 females; average age: 34.1 years, age range: 18–56 years), including 10 patients with MCD in relapse, nine patients with MCD in remission and nine healthy controls. Results There was no significant difference of CD3+CD4+ cells proportion among patients with MCD in relapse, MCD in remission and healthy controls (P = 0.802). The cytokine levels of GM-CSF and tumor necrosis factor (TNF)-related activation-induced cytokine (TRANCE) in patients with MCD in relapse increased 1.5 times higher than those in remission. An evident increase in the excretion of urinary CD80 was found in patients with relapsed MCD compared with those in remission (598.4 ± 115.8 vs 81.78 ± 7.04 ng/g creatinine, P < 0.001) and healthy controls (598.4 ± 115.8 vs 67.44 ± 8.94 ng/g creatinine, P < 0.001). CD80 expression was observed in podocyte of MCD patient in relapse by immunofluorescence technique. Conclusions The cytokines GM-CSF and TRANCE are increased and the urinary CD80 levels are elevated in adult-onset MCD patients in relapse, indicating a disorder of Th1/Th2/Th17 balance and that the elevated excretion of CD80 may underlie the pathogenesis and development of adult-onset MCD.
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Henkel, Anne S., Amanda M. Dewey, Kristy A. Anderson, Shantel Olivares, and Richard M. Green. "Reducing endoplasmic reticulum stress does not improve steatohepatitis in mice fed a methionine- and choline-deficient diet." American Journal of Physiology-Gastrointestinal and Liver Physiology 303, no. 1 (July 1, 2012): G54—G59. http://dx.doi.org/10.1152/ajpgi.00052.2012.
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Endoplasmic reticulum (ER) stress has been implicated in the pathogenesis of nonalcoholic steatohepatitis. The ER stress response is activated in the livers of mice fed a methionine- and choline-deficient (MCD) diet, yet the role of ER stress in the pathogenesis of MCD diet-induced steatohepatitis is unknown. Using chemical chaperones on hepatic steatosis and markers of inflammation and fibrosis in mice fed a MCD diet, we aim to determine the effects of reducing ER stress. C57BL/6J mice were fed a MCD diet with or without the ER chemical chaperones 4-phenylbutyric acid (PBA) and tauroursodeoxycholic acid (TUDCA) for 2 wk. TUDCA and PBA effectively attenuated the ER stress response in MCD diet-fed mice, as evidenced by reduced protein levels of phosphorylated eukaryotic initiation factor 2α and phosphorylated JNK and suppression of mRNA levels of CCAAT/enhancer binding protein homologous protein, glucose-regulated protein 78 kDa, and X-box binding protein 1. However, PBA and TUDCA did not decrease MCD diet-induced hepatic steatosis. MCD diet-induced hepatic inflammation, as evidenced by increased plasma alanine aminotransferase and induction of hepatic TNFα expression, was also not reduced by PBA or TUDCA. PBA and TUDCA did not attenuate MCD diet-induced upregulation of the fibrosis-associated genes tissue inhibitor of metalloproteinase-1 and matrix metalloproteinase-9. ER chemical chaperones reduce MCD diet-induced ER stress, yet they do not improve MCD diet-induced hepatic steatosis, inflammation, or activation of genes associated with fibrosis. These data suggest that although the ER stress response is activated by the MCD diet, it does not have a primary role in the pathogenesis of MCD diet-induced steatohepatitis.
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Kounatidis, Dimitris, Dimitra Rontogianni, Dimitrios Sampaziotis, Maria Vardaka, Chara Giatra, Christodoulos Dolapsakis, Evangelia Margellou, and Natalia G. Vallianou. "An HHV-8 Positive HIV Negative Multicentric Castleman’s Disease, who Responded well to Rituximab Alone." Cardiovascular & Hematological Disorders-Drug Targets 20, no. 1 (February 26, 2020): 84–86. http://dx.doi.org/10.2174/1871529x19666190227185318.
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Background: Multicentric Castleman Disease (MCD) presents with enlarged lymph nodes in multiple regions and systemic inflammatory symptoms, due to the dysregulation of cytokines, most commonly interleukin-6 (IL-6). Human herpes virus-8 (HHV-8) is strongly related to MCD (HHV-8-associated MCD) and is being implicated in cytokine dysregulation in patients, the majority of whom are HIV positive or immunosuppressed. Preferred treatment of HHV-8- associated MCD depends on the presence or not of concurrent Kaposi sarcoma and on whether the patient has life-threatening organ failure or poor performance status thought to be related to HHV- 8-associated MCD. Case Presentation: Herein, we describe a female patient with HHV-8 positive, HIV negative MCD, who responded well to the administration of rituximab once weekly for four weeks alone for three cycles. Conclusion: HHV-8 positive, HIV negative MCD treatment modalities are only anecdotal due to the rarity of this form of MCD. Administration of rituximab alone seems to be beneficial among patients with good performance status and the absence of life-threatening organ failure in cases of HHV-8 positive, HIV negative MCD.
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van der Dam, S., TA Abma, AC Molewijk, MJM Kardol, JMGA Schols, and GAM Widdershoven. "Organizing moral case deliberation Experiences in two Dutch nursing homes." Nursing Ethics 18, no. 3 (May 2011): 327–40. http://dx.doi.org/10.1177/0969733011400299.
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Moral case deliberation (MCD) is a specific form of clinical ethics, aiming to stimulate ethical reflection in daily practice in order to improve the quality of care. This article focuses on the implementation of MCD in nursing homes and the questions how and where to organize MCD. The purpose of this study was to evaluate one way of organizing MCD in two Dutch nursing homes. In both of these nursing homes the MCD groups had a heterogeneous composition and were organized apart from existing institutional communication structures. As part of a naturalistic evaluation, systematic observations, interviews and focus groups were completed. The findings indicate that the heterogeneous composition and MCD meetings separate from existing structures have benefits. However, the participants also reported negative experiences. This gives rise to the question whether a mixed MCD group which meets separately is an effective way to embed MCD as an instrument for reflection on moral issues in daily practice. We conclude that there is no single answer to that question. In the end, the two implementation strategies (i.e. within existing communication structures and a mixed MCD group) can be complementary to each other.
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Carpino, Guido, Diletta Overi, Paolo Onori, Antonio Franchitto, Vincenzo Cardinale, Domenico Alvaro, and Eugenio Gaudio. "Effect of Calcium-Sulphate-Bicarbonate Water in a Murine Model of Non-Alcoholic Fatty Liver Disease: A Histopathology Study." International Journal of Molecular Sciences 23, no. 17 (September 2, 2022): 10065. http://dx.doi.org/10.3390/ijms231710065.
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The progression of nonalcoholic fatty liver disease (NAFLD) is associated with alterations of the gut–liver axis. The activation of toll-like receptor 4 (TLR4) pathways by endotoxins, such as lipopolysaccharide (LPS), contributes to liver injury. The aim of the present study was to evaluate the possible beneficial effects of a calcium-sulphate-bicarbonate natural mineral water on the gut–liver axis by evaluating liver and terminal ileum histopathology in a murine model of NAFLD. NAFLD was induced in mice by administrating a methionine-choline-deficient (MCD) diet. The following experimental groups were evaluated: controls (N = 10); MCD+Tap water (MCD; N = 10); MCD+Calcium-sulphate-bicarbonate water (MCD/Wcsb; N = 10). Mice were euthanised after 4 and 8 weeks. Liver and terminal ileum samples were collected. Samples were studied by histomorphology, immunohistochemistry, and immunofluorescence. In mice subjected to the MCD diet, treatment with mineral water improved inflammation and fibrosis, and was associated with a reduced number of activated hepatic stellate cells when compared to MCD mice not treated with mineral water. Moreover, MCD/Wcsb mice showed lower liver LPS localization and less activation of TLR4 pathways compared to the MCD. Finally, Wcsb treatment was associated with improved histopathology and higher occludin positivity in intestinal mucosa. In conclusion, calcium-sulphate-bicarbonate water may exert modulatory activity on the gut–liver axis in MCD mice, suggesting potential beneficial effects on NAFLD.
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Okubo, Hirofumi, Yusuke Nakatsu, Hideyuki Sakoda, Akifumi Kushiyama, Midori Fujishiro, Toshiaki Fukushima, Yasuka Matsunaga, et al. "Mosapride citrate improves nonalcoholic steatohepatitis with increased fecal lactic acid bacteria and plasma glucagon-like peptide-1 level in a rodent model." American Journal of Physiology-Gastrointestinal and Liver Physiology 308, no. 2 (January 15, 2015): G151—G158. http://dx.doi.org/10.1152/ajpgi.00198.2014.
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Several lines of evidence have suggested a role of gut microbiota in the etiology of nonalcoholic steatohepatitis (NASH). NASH subjects reportedly showed a prolonged orocecal transit time coexistent with small intestinal bacterial overgrowth. We considered the possibility that enhanced gastrointestinal motility would influence gut microbiota and thus investigated the effects of the gastroprokinetic agent mosapride citrate (MC) on gut microbiota and the development of NASH using a methionine-choline deficient (MCD) diet-fed rodent model. Mice were divided into three groups, given the normal chow diet (NCD), the MCD diet, or the MCD diet containing 10 mg·kg−1·day−1 of MC (MCD plus MC) for 6 wk. NASH development was evaluated based on hepatic histochemical findings, serum parameters and various mRNA and/or protein expression levels. MC treatment suppressed MCD diet-induced NASH development, with reduced serum lipopolysaccharide and increased plasma glucagon-like peptide-1 (GLP-1) concentrations. Calculation of the relative abundance of each strain based on gut microbiota analyses indicated lactic acid bacteria specifically, such as Bifidobacterium and Lactobacillus, in feces to be decreased in the MCD, compared with the NCD group. Interestingly, the reduction in lactic acid bacteria in the MCD diet group was reversed in the MCD plus MC group. In addition, colon inflammation observed in the MCD diet group was reduced in the MCD plus MC group. Therefore, MC showed a protective effect against MCD diet-induced NASH development in our rodent model, with possible involvements of increased fecal lactic acid bacteria, protection against colon inflammation and elevated plasma GLP-1.
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Kaiser, H. J., U. Cremerius, O. Sabri, M. Schreckenberger, P. Reinartz, U. Büll, and M. Zimny. "F-18-FDG Positron Imaging in Oncological Patients: Gamma Camera Coincidence Detection versus Dedicated PET." Nuklearmedizin 38, no. 04 (1999): 108–14. http://dx.doi.org/10.1055/s-0038-1632201.
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Summary Aim of the present study was to investigate the feasibility of 2-[fluorine-18]-fluoro-2-deoxy-D-glucose (FDG) imaging in oncological patients with a dual head gamma camera modified for coincidence detection (MCD). Methods: Phantom studies were done to determine lesion detection at various lesion-to-background ratios, system sensitivity and spatial resolution. Thirty-two patients with suspected or known malignant disease were first studied with a dedicated full-ring PET system (DPET) applying measured attenuation correction and subsequently with an MCD system without attenuation correction. MCD images were first interpreted without knowledge of the DPET findings. In a second reading, MCD and DPET were evaluated simultaneously. Results: The phantom studies revealed a comparable spatial resolution for DPET and MCD (5.9 × 6.3 × 4.2 mm vs. 5.9 × 6.5 × 6.0 mm). System sensitivity of MCD was less compared to DPET (91 cps/Bq/ml/cmF0V vs. 231 cps/ Bq/ml/cmFOv). At a lesion-to-background ratio of 4:1, DPET depicted a minimal phantom lesion of 1.0 cm in diameter, MCD a minimal lesion of 1.6 cm. With DPET, a total of 91 lesions in 27 patients were classified as malignant. MCD without knowledge of DPET results revealed increased FDG uptake in all patients with positive DPET findings. MCD detected 72 out of 91 DPET lesions (79.1 %). With knowledge of the DPET findings, 11 additional lesions were detected (+12%). MCD missed lesions in six patients with relevance for staging in two patients. All lesions with a diameter above 18 mm were detected. Conclusion: MCD FDG imaging yielded results comparable to dedicated PET in most patients. However, a considerable number of small lesions clearly detectable with DPET were not detected by MCD alone. Therefore, MCD cannot yet replace dedicated PET in all oncological FDG studies. Further technical refinement of this new method is needed to improve image quality (e.g. attenuation correction).
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Soulier, J., L. Grollet, E. Oksenhendler, P. Cacoub, D. Cazals-Hatem, P. Babinet, MF d'Agay, et al. "Kaposi's sarcoma-associated herpesvirus-like DNA sequences in multicentric Castleman's disease [see comments]." Blood 86, no. 4 (August 15, 1995): 1276–80. http://dx.doi.org/10.1182/blood.v86.4.1276.bloodjournal8641276.
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Multicentric Castleman's disease (MCD) is an atypical lymphoproliferative disorder defined using clinical and pathologic criteria. A characteristic of the MCD is a close association with Kaposi's sarcoma (KS), which occurs during the clinical course of most human immunodeficiency virus (HIV)-associated MCD cases and also, but less frequently, in HIV-negative patients. Recently, sequences of a putative new Herpesvirus (KSHV) have been isolated and further detected in almost all the acquired immunodeficiency syndrome (AIDS) KS and in most of the non-AIDS KS samples. In this study, we searched for these Herpesvirus-like sequences in MCD samples of 31 patients. KSHV sequences were detected in 14 of 14 cases of HIV-associated MCD, including 5 cases without detectable KS. Moreover, KSHV was detected in 7 of 17 MCD cases in HIV-negative patients, including 1 case associated with a cutaneous KS. In 34 non-MCD reactive lymph nodes (follicular and/or interfollicular hyperplasia) in HIV-negative patients, KSHV was detected in only 1 case. In 1 HIV-negative case of MCD, KSHV was found in both the lymph node and peripheral blood samples. These data suggest that KSHV could play a role in the pathogenesis of MCD, especially in HIV-infected patients.
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Nielsen, E., N. Bonsu, L. M. Andras, and R. Y. Goldstein. "The effect of canal fill on paediatric femur fractures treated with titanium elastic nails." Journal of Children's Orthopaedics 12, no. 1 (February 2018): 15–19. http://dx.doi.org/10.1302/1863-2548.12.170083.
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Purpose Traditional teaching for fixation of paediatric femur fractures recommends 80% nail diameter/medullary canal diameter ratio (ND/MCD) for successful maintenance of reduction. Prior studies have investigated this with stainless steel Enders nails. Our aim was to assess the impact of ND/MCD on maintenance of reduction and malunion rates in paediatric femur fractures treated with flexible intramedullary nails (FINs). Methods Retrospective data was collected on all paediatric patients treated with FINs for diaphyseal femur fractures at a single tertiary care institution over a ten-year period. Patients with co-morbidities affecting bone quality were excluded. Patients were subdivided into groups based on ND/MCD. Results A total of 66 patients met inclusion criteria. Mean ND/MCD was 76.3% (32.9% to 98.8%, SD 14.3). In all, 50% (n = 33/66) of patients had > 80% ND/MCD, and only 13.6% (n = 9/66) of patients had less than 60% ND/MCD. When controlling for fracture stability, ND/MCD had no correlation with mean shortening (p = 0.07) There was no correlation between ND/MCD and angulation in the sagittal (p = 0.96) or coronal plane (p = 0.20). Three patients fit malunion criteria. ND/MCD for these patients were 40%, 67% and 79%. Conclusion There was no correlation between ND/MCD and shortening or malangulation. The majority of patients in this series with less than 80% fill with FIN healed within acceptable parameters. Level of Evidence III
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VANDE WALLE, JOHAN G. J., RAYMOND A. DONCKERWOLCKE, and HEIN A. KOOMANS. "Pathophysiology of Edema Formation in Children with Nephrotic Syndrome Not Due to Minimal Change Disease." Journal of the American Society of Nephrology 10, no. 2 (February 1999): 323–31. http://dx.doi.org/10.1681/asn.v102323.
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Abstract. It has been shown that children with nephrotic syndrome due to minimal change disease (MCD) can present with avid salt retention and stimulated vasoactive hormones, as well as with stable edema. The present study examines these conditions in children with nephrotic syndrome not due to MCD (non-MCD). In six children with hypovolemic symptoms (congenital nephrotic syndrome in four), strong sodium retention (fractional sodium excretion, FENa, 0.2 ± 0.2%) was found. Lithium clearance (FELi) and maximal water excretion (Vmax) were suppressed, suggesting avid sodium reabsorption throughout the nephron. Aldosterone, renin, and norepinephrine were elevated. Sixteen other children with non-MCD had stable edema. FENa was 1.8 ± 1.1%, whereas FELi, Vmax, and hormones were normal, and not different from data in 35 nonproteinuric children. In children with MCD, 12 presented with hypovolemic symptoms and strong sodium retention (FENa 0.3 ± 0.3%), whereas 15 were stable (FENa 1.1 ± 0.7%). Regarding tubular sodium handling and hormones, the same distinction could be made as for the children with non-MCD. However, hypoproteinemia differed. In the children with non-MCD lesions, plasma colloid osmotic pressure was significantly lower in the hypovolemic types (4.2 ± 0.4 mmHg) than in those with stable edema (13.0 ± 3.8 mmHg; P < 0.05); in MCD, no such difference existed (respectively, 8.1 ± 3.0 and 9.9 ± 2.2 mmHg). In summary, children with nephrotic syndrome may present with pathophysiologic pictures of decreased effective circulating volume or of stable edema, regardless of whether they have non-MCD or MCD. The pathogenesis of the hypovolemic picture seems to be different, since it is associated with extreme hypoproteinemia only in the children with non-MCD.
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Guan, Yu Lan, Wen Qi Dai, Lin Jun Wang, Jian Huang, Jian Ming Lai, Ke Tang, and Yi Ben Xia. "Investigation of Nano/Microcrystalline Diamond Composite Films for Thermal Applications." Materials Science Forum 610-613 (January 2009): 563–66. http://dx.doi.org/10.4028/www.scientific.net/msf.610-613.563.
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A newly developed nano/microcrystalline diamond composite film for thermal applications was prepared in this investigation. A microcrystalline diamond (MCD) film was deposited onto silicon substrate by hot filament chemical vapor deposition (HFCVD) method, and then a nanocrystalline diamond (NCD) film was grown onto this MCD film to obtain a NCD/MCD composite film. The root-mean-square (RMS) value of surface roughness for the composite film estimated from the atomic force microscope image was 42.7nm. Compared with 85.9nm for the MCD film. And it was also found that the thermal diffusivity increased from 32.61mm2/s to 37.63mm2/s by further growing a NCD film. Results indicated that the deposition of NCD film reduced the rough surface of the MCD film with grain sizes of the order of microns, and thus increased the efficiency of diamond films as thermal spreading device. It was found that the NCD/MCD composite film had a smoother surface and a higher thermal diffusivity compared with MCD film.
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Roh, Eul Hee. "Analysis of multiple chronic disease characteristics in South Koreans by age groups using association rules analysis." Health Informatics Journal 28, no. 1 (January 2022): 146045822110702. http://dx.doi.org/10.1177/14604582211070208.
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The prevalence of MCD (multiple chronic disease) is increasing due to increased life expectancies and aging populations. Individual and socioeconomic burdens of MCD are also increasing. To reduce these burdens, it is necessary to establish policies to prevent MCD; therefore, it is important to understand the characteristics of MCD in the current population. In this study, the combinations of MCD that affect hypertension, which has the highest prevalence, were examined according to different age groups. The combinations of diseases were identified utilizing association rules analysis, using the Community Health Survey as the raw data. Two association rules were determined in young adult group, 18 in the middle-aged group, and 30 in the senior group, showing that the number of rules increases with age. Association rules of this study mean that combined chronic diseases are highly associated with hypertension. Then logistic regression analysis was performed on the MCD combinations with highest lift value in each age group to identify relationships between health behavior and MCD combinations. Especially, alcohol consumption was found to be a common factor affecting MCD prevalence in three combinations. On the contrary, sleep habit did not have a statistically significant influence on any combination.
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Spronk, Benita. "Op onbekend terrein?" Religie & Samenleving 12, no. 2/3 (October 1, 2017): 230–48. http://dx.doi.org/10.54195/rs.12120.
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This article investigates the role of moral case deliberation (MCD) in dealing with tragic situations. It focuses on experiences of care givers involved in the treatment of a pregnant woman with a brain tumour, and their evaluation of a series of MCD meetings in which the dilemmas around care were discussed. A case study design is used by conducting semi-structured interviews (n=10) with health care professionals who both played a role in the treatment of the patient and attended the MCD. The results show that MCD helps people to deal with tragic situations. An important element of MCD in this respect is making explicit the dilemma and the damage, demonstrating that there is no simple solution. MCD prompts participants to formulate and share personal experiences with one another and thus helps to create a shared perception of the situation as tragic. The article concludes that MCD contributes to the sharing of tragic experiences, and fosters mutual interaction during a tragedy. The ability of spiritual caregivers with their substantive knowledge of life questions can support the moral deliberation on a tragic case. This substantive knowledge brings the spiritual caregiver into familiar territory. The knowledge of methodology and structure of MCD and the handling of values determined in experiences of contingency in MCD are, however, competencies that can be more developed by the spiritual caregiver.
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CUI, YU-XIAO, YUANPING HE, CHUNHUI JI, BIN LIN, and DAWEI ZHANG. "ANTI-WEAR PERFORMANCE OF POLISHED MICROCRYSTALLINE DIAMOND FILMS SLIDING AGAINST Si3N4 UNDER WATER LUBRICATION." Surface Review and Letters 27, no. 11 (July 27, 2020): 2050008. http://dx.doi.org/10.1142/s0218625x20500080.
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In this work, aiming at enhancing the tribological behavior of chemical vapor-deposited (CVD) diamond and Si3N4 tribo-pair, mechanical polishing is performed on CVD microcrystalline diamond (MCD) films. The tribological performance of as-fabricated polished MCD (MCD-p) films is investigated by ball-on-plate reciprocating friction tests with Si3N4 ceramic balls as the counterparts under water lubrication, where the as-grown MCD films, nanocrystalline diamond (NCD) films and Si3N4 ceramic plate are employed as the contrast specimens. Under a normal load of 10 N and at a reciprocating frequency of 30 Hz for 2-mm distance, the as-fabricated MCD, NCD and MCD-p films exhibit similar steady friction coefficients after run-in state, which are 0.036, 0.032 and 0.035, respectively. Nevertheless, the wear rate of Si3N4 counterparts varies. Due to the plowing effect of as-grown MCD and NCD films, severe abrasion of Si3N4 counterparts can be observed after sliding for 20[Formula: see text]min. For the MCD-p specimen, however, the Si3N4 counterpart exhibits 2–3 orders of magnitude lower wear rate than those sliding against the as-grown MCD or NCD specimen. On the other hand, due to the reciprocating motion failing to form fluid film between the contact surfaces, high friction coefficient (0.092) and rather severe abrasion are observed for the self-mated Si3N4 ceramic contact.
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Ramaswami, Ramya, Kathryn Lurain, Mark N. Polizzotto, Irene Ekwede, Kirsta Waldon, Seth M. Steinberg, Ralph Mangusan, et al. "Characteristics and outcomes of KSHV-associated multicentric Castleman disease with or without other KSHV diseases." Blood Advances 5, no. 6 (March 15, 2021): 1660–70. http://dx.doi.org/10.1182/bloodadvances.2020004058.
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Abstract Kaposi sarcoma (KS)-associated herpesvirus (KSHV)–associated multicentric Castleman disease (MCD) is a relapsing and remitting systemic lymphoproliferative disorder characterized by severe inflammatory symptoms most common among people living with HIV (PLWH). Patients with KSHV-MCD may present with concurrent KSHV-associated diseases, such as KS and/or primary effusion lymphoma (PEL). We evaluated clinical and immunologic characteristics, the effects of concurrent KSHV malignancies, and treatments from the largest prospective natural history study of participants with KSHV-MCD within the United States. Treatment options administered at investigator discretion included high-dose zidovudine with valganciclovir (AZT/VGC), rituximab, or rituximab with liposomal doxorubicin (R-Dox) during KSHV-MCD flares. Survival analyses and prognostic factors were explored for all participants. Sixty-two participants with HIV were enrolled, including 20 with KSHV-MCD alone, 34 with KSHV-MCD and KS, 1 with KSHV-MCD and PEL, and 7 with all KSHV-associated diseases. Forty-four percent of KSHV-MCD diagnoses were made at our institution. Forty-four participants received rituximab-based therapies, 20 of whom had maintenance AZT/VGC or interferon. Participants receiving R-Dox and then maintenance AZT/VGC had the highest 5-year progression-free survival (89%). Cytokine profiles during KSHV-MCD flares did not differ by the presence of concurrent KSHV-associated diseases. The 10-year survival was 71% (95% confidence interval [CI], 56% to 82%) for all participants. A concurrent diagnosis of PEL negatively impacted survival (PEL hazard ratio, 5.4; 95% CI, 1.8 to 16.8). KSHV-MCD is an underdiagnosed condition among PLWH, including those with KS. KSHV-MCD has an excellent prognosis with appropriate treatment. Physicians should be alert for patients with multiple KSHV diseases, which impact optimal treatment and survival outcomes. This study was registered at www.clinicaltrials.gov as #NCT00099073.
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Wolkove, Norman, Marc A. Baltzan, Hany Kamel, and Michael Rotaple. "A Randomized Trial to Evaluate the Sustained Efficacy of a Mucus Clearance Device in Ambulatory Patients with Chronic Obstructive Pulmonary Disease." Canadian Respiratory Journal 11, no. 8 (2004): 567–72. http://dx.doi.org/10.1155/2004/828591.
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OBJECTIVE:To determine whether a mucus clearance device (MCD) (Flutter; Axcan Scandipharm, USA) could consistently improve the bronchodilator response and exercise performance in patients with chronic obstructive pulmonary disease (COPD) when used in an ambulatory setting over a one-week period.SUBJECTS:Fifteen patients with severe COPD (mean age 71±10 years) were studied.METHODS:A randomized crossover design compared an MCD with a sham MCD (SMCD), in which each were tested for one week. At the beginning and end of each study week, forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) were measured before and after MCD or SMCD. A bronchodilator aerosol (ipratropium bromide and salbutamol sulphate) was then given, and FEV1and FVC were remeasured 30 min, 60 min and 120 min later. A 6 min walk test (6MWT) was also performed.RESULTS:FEV1improved significantly (P<0.05) after bronchodilator administration with both the SMCD and MCD. The improvement was always greater with MCD use than with SMCD. At the baseline measure, 120 min postbronchodilator administration, the mean FEV1improved by 24±24% with SMCD use and 60±28% with MCD use (P<0.05). After one week of use, the corresponding values at 120 min were 19±24% and 43±26% (P<0.05). Similar findings were obtained for FVC. 6MWT distances increased by 29±12 m (P<0.05) after one week of MCD use, whereas it decreased slightly (by 16±18 m) after SMCD. The decline in saturation with the 6MWT was smaller with MCD use than with SMCD use. After one week, the decline in saturation with MCD use was similar to baseline levels, although patients were walking farther. After one week, dyspnea was lower on walking with MCD use than with SMCD use.CONCLUSION:Patients with COPD had an increased response to bronchodilator therapy after use of the MCD compared with SMCD use. The increase persisted after one week of use, and was associated with improved exercise performance as measured by the 6MWT.
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Guerreiro, Marilisa M. "Malformations of cortical development." Arquivos de Neuro-Psiquiatria 67, no. 2b (June 2009): 570–74. http://dx.doi.org/10.1590/s0004-282x2009000300041.
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Malformations of cortical development (MCD) have been increasingly identified. The purpose of this presentation is to review the current knowledge of the MCD. Before we address this issue, we will briefly present a review of cortical development. The second part of this presentation will address the most important MCD. Finally, the last part of this presentation will address the correlation between MCD and epilepsy.
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Teh, Yoong Mond, Soo Kun Lim, Norhana Jusoh, Kahar Osman, and Siti Aisyah Mualif. "CD80 Insights as Therapeutic Target in the Current and Future Treatment Options of Frequent-Relapse Minimal Change Disease." BioMed Research International 2021 (January 6, 2021): 1–17. http://dx.doi.org/10.1155/2021/6671552.
Full textAbstract:
Minimal change disease (MCD) is the most common cause of idiopathic nephrotic syndrome in children, and it is well known for its multifactorial causes which are the manifestation of the disease. Proteinuria is an early consequence of podocyte injury and a typical sign of kidney disease. Steroid-sensitive patients react well with glucocorticoids, but there is a high chance of multiple relapses. CD80, also known as B7-1, is generally expressed on antigen-presenting cells (APCs) in steroid-sensitive MCD patients. Various glomerular disease models associated with proteinuria demonstrated that the detection of CD80 with the increase of urinary CD80 was strongly associated closely with frequent-relapse MCD patients. The role of CD80 in MCD became controversial because one contradicts finding. This review covers the treatment alternatives for MCD with the insight of CD80 as a potential therapeutic target. The promising effectiveness of CD20 (rituximab) antibody and CD80 inhibitor (abatacept) encourages further investigation of CD80 as a therapeutic target in frequent-relapse MCD patients. Therapeutic-based antibody towards CD80 (galiximab) had never been investigated in MCD or any kidney-related disease; hence, the role of CD80 is still undetermined. A new therapeutic approach towards MCD is essential to provide broader effective treatment options besides the general immunosuppressive agents with gruesome adverse effects.
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Zhang, Kaiyue, Wenjuan Sun, Lai Zhang, Xuefang Xu, Jidong Wang, and Yan Hong. "miR-499 Ameliorates Podocyte Injury by Targeting Calcineurin in Minimal Change Disease." American Journal of Nephrology 47, no. 2 (2018): 94–102. http://dx.doi.org/10.1159/000486967.
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Background: Podocyte injury is a hallmark of minimal change disease (MCD). Calcineurin inhibitors have been widely used in the current treatment of MCD, and miR-499 may target calcineurin. We aimed to study the function of miR-499 in MCD and test whether miR-499 delivery can improve MCD. Methods: An MCD mouse model was generated using puromycin aminonucleoside (PAN). MiR-499 was delivered using lentiviruses. Biochemical indicators including serum albumin, triglyceride, cholesterol, and 24-h urine protein were determined. Targets of miR-499 were confirmed using reporter gene activity assays. The ultrastructure of podocytes was analyzed using transmission electron microscopy. Results: MiR-499 significantly improved MCD-related symptoms and signs. Foot-process effacement was caused by PAN and partially reversed by miR-499. We identified that both CnAα and CnAβ were targets of miR-499, and were overexpressed in the presence of PAN. However, miR-499 reduced the expression of CnAα and CnAβ, leading to a decreased activity of calcineurin signaling in mouse podocytes in vitro and in vivo. In addition, miR-499 recovered PAN-induced reduction of cell viability. Conclusions: MiR-499 ameliorated podocyte injury by targeting CnAα and CnAβ in a PAN-induced MCD mouse model. Delivery of miR-499 can be a novel strategy for MCD treatment.
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Dispenzieri, Angela, and David C. Fajgenbaum. "Overview of Castleman disease." Blood 135, no. 16 (April 16, 2020): 1353–64. http://dx.doi.org/10.1182/blood.2019000931.
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Abstract Castleman disease (CD) describes a group of at least 4 disorders that share a spectrum of characteristic histopathological features but have a wide range of etiologies, presentations, treatments, and outcomes. CD includes unicentric CD (UCD) and multicentric CD (MCD), the latter of which is divided into idiopathic MCD (iMCD), human herpes virus-8 (HHV8)-associated MCD (HHV8-MCD), and polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma cell disorder, skin changes (POEMS)-associated MCD (POEMS-MCD). iMCD can be further subclassified into iMCD–thrombocytopenia, ascites, reticulin fibrosis, renal dysfunction, organomegaly (iMCD-TAFRO) or iMCD–not otherwise specified (iMCD-NOS). Advances in diagnosis, classification, pathogenesis, and therapy are substantial since the original description of UCD by Benjamin Castleman in 1954. The advent of effective retroviral therapy and use of rituximab in HHV8-MCD have improved outcomes in HHV8-MCD. Anti–interleukin-6–directed therapies are highly effective in many iMCD patients, but additional therapies are required for refractory cases. Much of the recent progress has been coordinated by the Castleman Disease Collaborative Network (CDCN), and further progress will be made by continued engagement of physicians, scientists, and patients. Progress can also be facilitated by encouraging patients to self-enroll in the CDCN’s ACCELERATE natural history registry (#NCT02817997; www.CDCN.org/ACCELERATE).
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Hunsberger, Monica, Che Henry Ngwa, Mamtuti Panneh, Gabriele Eiben, and Maja Rosén. "Milk Cereal Drink Feeding Practices: A Descriptive Study Among Swedish Cohort of the IDEFICS Family Study." SDRP Journal of Food Science & Technology 6, no. 1 (2021): 293–98. http://dx.doi.org/10.25177/jfst.6.1.ra.10692.
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Background: Childhood overweight is an increasing public health concern and has recently been associated with the consumption of a traditional Swedish milk cereal drink (MCD). This study aimed to describe the consumption pattern of MCD among study participants in relation to the recommendations by the National Food Agency of Sweden. Method: A cross-sectional study among the Swedish cohort of the IDEFICS.Family (I.Family) study was conducted in 2013/2014. Swedish participants completed a questionnaire aimed at understanding the prevalence of consumption, timing, frequency, feeding modality and rationale for offering MCD. Results: Most children (74.7%) reportedly consumed MCD. Of those who consumed MCD, a large part of the participants consumed MCD two or more times a day with a high proportion of participants (87%) stating a preference for bottle-feeding. Keywords: Milk cereal drink, Obesity, Complementary food, Feeding practice, I. Family Study, Sweden.
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Jagdale, Deepali M., and Ramaa C. S. "QUANTITATIVE STRUCTURE-ACTIVITY RELATIONSHIP ANALYSIS OF NOVEL PYRAZOLINE DERIVATIVES USING K NEAREST NEIGHBOUR MOLECULAR FIELD ANALYSIS METHOD." International Journal of Pharmacy and Pharmaceutical Sciences 9, no. 12 (December 1, 2017): 87. http://dx.doi.org/10.22159/ijpps.2017v9i12.19401.
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Objective: Malonyl CoA decarboxylase (MCD) enzyme plays important role in fatty acid and glucose oxidation. Inhibition of MCD might turn to a novel approach to treat ischemia. The main objective of this research article was to develop a novel pharmacophore for enhanced activity.Methods: Three-dimensional quantitative structure-activity relationships (3D-QSAR) was performed for pyrazoline derivatives as MCD inhibitors using VLife MDS 4.6 software. The QSAR model was developed using the stepwise 3D-QSAR kNN-MFA method.Results: The statistical results generated from kNN-MFA method indicated the significance and requirements for better MCD inhibitory activity. The information rendered by 3D-QSAR model may render to better understanding and designing of novel MCD inhibitors.Conclusion: 3D-QSAR is an important tool in understanding the structural requirements for the design of novel and potent MCD inhibitors. It can be employed to design new drug discovery.
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Casper, Corey, W. Garrett Nichols, Meei-Li Huang, Lawrence Corey, and Anna Wald. "Remission of HHV-8 and HIV-associated multicentric Castleman disease with ganciclovir treatment." Blood 103, no. 5 (March 1, 2004): 1632–34. http://dx.doi.org/10.1182/blood-2003-05-1721.
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Abstract Multicentric Castleman disease (MCD) is a lymphoproliferative disorder associated with human herpesvirus 8 (HHV-8) infection among persons with human immunodeficiency virus (HIV) infection. Treatment often includes chemotherapy, and progression to non-Hodgkin lymphoma frequently occurs. MCD is characterized in part by active HHV-8 replication, and many of the symptoms of MCD may be attributable to viral gene products. We describe the effect of ganciclovir on the clinical and virologic course of MCD in a series of 3 case reports. Two patients experienced a reduction in the frequency of episodic flares of MCD and detectable HHV-8 DNA with intravenous or oral ganciclovir, whereas the third patient recovered from an acute episode of renal and respiratory failure with intravenous ganciclovir therapy. These data provide in vivo evidence for the utility of antiviral agents against HHV-8 in the management of MCD.
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Zhang, Jianguo, Yigao Yuan, and Jinjiang Zhang. "Cutting Performance of Microcrystalline, Nanocrystalline and Dual-Layer Composite Diamond Coated Tools in Drilling Carbon Fiber Reinforced Plastics." Applied Sciences 8, no. 9 (September 13, 2018): 1642. http://dx.doi.org/10.3390/app8091642.
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The drilling of carbon fiber reinforced plastics (CFRP) is a significant topic for the aircraft industry. However, CFRP are materials which are difficult to cut due to their unique properties. This paper studies tools with excellent cutting performance in machining CFRP. The microcrystalline diamond (MCD), nanocrystalline diamond (NCD), and dual-layer composite MCD/NCD coatings are deposited on Co-cemented tungsten carbide (WC-Co) drills. The morphology of MCD shows pyramidal grains and the NCD and MCD/NCD coatings present cauliflower-like morphology. The cutting performances of coated tools are checked in CFRP drilling tests by the drilling force and tool wear. According to the results, the dual-layer composite MCD/NCD coated tools present the best cutting performance with the lowest drilling force. Meanwhile, the MCD/NCD coated tools display high resistance to wear and adhesive strength.
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Sethuraman, A., E. Kontaki, E. Gaynor, K. Jones, A. Cherian, V. Zamvar, and F. Kiparissi. "P206 Paediatric Genital Crohn’s Disease: Presentation and Treatment, a combined case series." Journal of Crohn's and Colitis 15, Supplement_1 (May 1, 2021): S267—S268. http://dx.doi.org/10.1093/ecco-jcc/jjab076.332.
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Abstract Background Metastatic Crohn’s Disease (MCD) affecting the genitalia is a rare condition, characterised by granulomatous inflammation of the genital tract. Only few paediatric cases have been described in the literature with a female preponderance. Paucity of literature is noted with regards to treatment and outcome. Methods: Aim To describe the clinical presentation, associated features, and response to treatment in a cohort of paediatric patients diagnosed as genital metastatic Crohn’s disease (MCD). Methods All cases of paediatric genital MCD were retrospectively collected from two centres at Great Ormond Street Hospital for Children and Leeds Children’s Hospital for the past 20 years (January 2001 to January 2021). Medical history, symptoms at presentation, histological characteristics, results of investigations and response to treatment were reviewed. Results A total of 12 patients (7 male and 5 female) were diagnosed with genital MCD. The mean age at presentation of genital MCD symptoms was 8.9 years of age (1.5–14 years). Generalised swelling of the genital region was the most common presentation. 5/12 (42%) children had luminal Crohn’s disease (CD) before development of Genital MCD whereas 4/12 (33%) children developed luminal CD after Genital MCD presentation. 3/12 (25%) children after evaluation were found to have only Genital MCD with no luminal pathology of CD. Genital MCD was the first presentation of Crohn’s disease in 7/12 children (58.3%) in our cohort. 6/12(50%) children were seen to have perianal disease. All children were extensively investigated endoscopically and radiologically. Genital biopsy was done in 6/12(50%) patients showing non caseating granulomatous inflammation. 11/12 patients received dual therapy at some point in their treatment with azathioprine and infliximab. Switch of infliximab to adalimumab was seen in 7/12 (58.3%) patients mostly in view of escalating treatment to control luminal CD. Initiation of treatment since first symptoms of genital MCD appeared to be prolonged, perhaps due to delay in diagnosis via referral pathways from local paediatrician via urologist to paediatric gastroenterologist. Improvement of genital MCD was seen in most children with dual therapy of azathioprine and infliximab. Conclusion Genital MCD can be the first presentation of Crohn’s disease and may not be associated with GI symptoms or luminal CD. All children with MCD do benefit from histological as well as radiological and endoscopic evaluation. Formal MDT discussions with the urologist, radiologist and gastroenterologist may help in early diagnosis and treatment. A retrospective multi-centre case reviews will help to identify the prevalence of genital MCD in children and also help develop a national pathway.
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Zhou, Jing, Honggui Li, Yuli Cai, Linqiang Ma, Destiny Matthews, Bangchao Lu, Bilian Zhu, et al. "Mice lacking adenosine 2A receptor reveal increased severity of MCD-induced NASH." Journal of Endocrinology 243, no. 3 (December 2019): 199–209. http://dx.doi.org/10.1530/joe-19-0198.
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Adenosine 2A receptor (A2AR) exerts a protective role in obesity-related non-alcoholic fatty liver disease. Here, we examined whether A2AR protects against non-alcoholic steatohepatitis (NASH). In C57BL/6J mice, feeding a methionine- and choline-deficient diet (MCD) resulted in significant weight loss, overt hepatic steatosis, and massive aggregation of macrophages in the liver compared with mice fed a chow diet. MCD feeding also significantly increased the numbers of A2AR-positive macrophages/Kupffer cells in liver sections although decreasing A2AR amount in liver lysates compared with chow diet feeding. Next, MCD-induced NASH phenotype was examined in A2AR-disrupted mice and control mice. Upon MCD feeding, A2AR-disruptd mice and control mice displayed comparable decreases in body weight and fat mass. However, MCD-fed A2AR-disrupted mice revealed greater liver weight and increased severity of hepatic steatosis compared with MCD-fed control mice. Moreover, A2AR-disupted mice displayed increased severity of MCD-induced liver inflammation, indicated by massive aggregation of macrophages and increased phosphorylation states of Jun-N terminal kinase (JNK) p46 and nuclear factor kappa B (NFκB) p65 and mRNA levels of tumor necrosis factor alpha, interleukin-1 beta, and interleukin-6. In vitro, incubation with MCD-mimicking media increased lipopolysaccharide (LPS)-induced phosphorylation states of JNK p46 and/or NFκB p65 and cytokine mRNAs in control macrophages and RAW264.7 cells, but not primary hepatocytes. Additionally, MCD-mimicking media significantly increased lipopolysaccharide-induced phosphorylation states of p38 and NFκB p65 in A2AR-deficient macrophages, but insignificantly decreased lipopolysaccharide-induced phosphorylation states of JNK p46 and NFκB p65 in A2AR-deficient hepatocytes. Collectively, these results suggest that A2AR disruption exacerbates MCD-induced NASH, which is attributable to, in large part, increased inflammatory responses in macrophages.
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Maina, Virginia, Salvatore Sutti, Irene Locatelli, Matteo Vidali, Cristina Mombello, Cristina Bozzola, and Emanuele Albano. "Bias in macrophage activation pattern influences non-alcoholic steatohepatitis (NASH) in mice." Clinical Science 122, no. 11 (February 10, 2012): 545–54. http://dx.doi.org/10.1042/cs20110366.
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In humans, there is large inter-individual variability in the evolution of NAFLD (non-alcoholic fatty liver disease) to NASH (non-alcoholic steatohepatitis). To investigate this issue, NASH was induced with an MCD (methionine–choline-deficient) diet in C57BL/6 and Balb/c mice that are characterized by different biases in Th1/Th2 and macrophage (M1/M2) responses. Following 4 weeks on the MCD diet, steatosis and lobular inflammation were prevalent in C57BL/6 (Th1, M1 oriented) than in Balb/c (Th2, M2 oriented) mice. Consistently, hepatic TNFα (tumour necrosis factor α) mRNA expression and circulating TNFα levels were higher in MCD-fed C57BL/6 than in MCD-fed Balb/c mice. The Th1/Th2 bias did not account for the increased NASH severity, as in both strains MCD feeding did not significantly modify the liver mRNA expression of the Th1 markers IFNγ (interferon γ) and T-bet or that of the Th2 markers IL-4 (interleukin 4) and GATA-3. Conversely, MCD-fed C57BL/6 mice displayed higher liver mRNAs for the macrophage M1 activation markers iNOS (inducible NO synthase), IL-12p40 and CXCL10 (CXC chemokine ligand 10) than similarly treated Balb/c mice, without effects on the M2 polarization markers IL-10 and MGL-1 (macrophage galactose-type C-type lectin-1). Circulating IL-12 was also higher in MCD-fed C57BL/6 than in MCD-fed Balb/c mice. The analysis of macrophages isolated from the livers of MCD-fed animals confirmed an enhanced expression of M1 markers in C57BL/6 mice. Among all of the MCD-treated mice, liver iNOS, IL-12p40 and CXCL10 mRNA levels positively correlated with the frequency of hepatic necro-inflammatory foci. We concluded that the macrophage M1 bias in C57BL/6 mice may account for the increased severity of NASH in this strain, suggesting macrophage responses as important contributors to NAFLD progression.
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Denize, Thomas, Subrina Farah, Alessia Cimadamore, Abdallah Flaifel, Emily Walton, Maura A. Sticco-Ivins, Chris Labaki, et al. "Biomarkers of Angiogenesis and Clinical Outcomes to Cabozantinib and Everolimus in Patients with Metastatic Renal Cell Carcinoma from the Phase III METEOR Trial." Clinical Cancer Research 28, no. 4 (December 16, 2021): 748–55. http://dx.doi.org/10.1158/1078-0432.ccr-21-3088.
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Abstract Purpose: Antiangiogenic VEGF receptor (VEGFR) inhibitors are approved for metastatic clear cell renal cell carcinoma (mccRCC) and their efficacy is higher in high angiogenic tumors. As cabozantinib inhibits multiple tyrosine kinase receptors, including VEGFRs, we tested whether markers of angiogenesis, including microvascular density (MVD) and mast cell density (MCD), could predict benefit from cabozantinib versus everolimus, using RCC samples from the METEOR (NCT01865747) trial. Experimental Design: MVD and MCD were studied in 430 patients (cabozantinib = 216, everolimus = 214) by double immunohistochemistry for CD31 (vascular marker) and tryptase (mast cell marker) coupled with automated image analysis. Results from evaluable cases (MVD = 360, MCD = 325) were correlated with progression-free survival (PFS), overall survival (OS), and objective response rate (ORR). Results: MVD was positively correlated with MCD. In the whole cohort, high MVD and high MCD were associated with longer PFS; improved PFS was most evident in patients with high levels of both MCD and MVD. Cabozantinib was associated with improved PFS, OS, and ORR compared with everolimus, irrespective of MVD levels. Cabozantinib was also associated with improved ORR compared with everolimus, irrespective of MCD levels. For PFS and OS, the treatment effect for cabozantinib versus everolimus tended to be greater in tumors with low MCD. Conclusions: High MVD and high MCD are associated with improved outcome in mccRCC but do not predict efficacy to cabozantinib versus everolimus. The high efficacy of cabozantinib in low angiogenic tumors allows us to speculate that its antitumor activity is not exclusively mediated by VEGFR inhibition.
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de Snoo-Trimp, Janine. "Moral Competence, Moral Teamwork, Moral Action – Outcomes of Moral Case Deliberation in the Euro-MCD 2.0 For Evaluating Clinical Ethics Support." Studia Universitatis Babeş-Bolyai Bioethica 66, Special Issue (September 9, 2021): 67. http://dx.doi.org/10.24193/subbbioethica.2021.spiss.38.
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"Background: For Moral Case Deliberation (MCD), like any form of Clinical ethics support (CES), it is important to know whether it reaches its presumed goal of supporting healthcare professionals in their ethical challenges. Evaluation is needed to gain insight in the value of MCD. Therefore, the Euro-MCD instrument was developed to assess outcomes of MCD, and has now been revised. The aim of this presentation is to present the revised Instrument: the Euro-MCD 2.0. Methods: The revision process was an iterative dialogue in which field study findings were integrated with theoretical reflections and expert-input. Results: The Euro-MCD 2.0 has three domains: 1) Moral Competence, 2) Moral Teamwork and 3) Moral Action. Moral Competence includes items on moral sensitivity, analytical skills and a virtuous attitude, like ‘I speak up in ethically difficult situations’. Moral Teamwork refers to open dialogue and supportive relationships, for example ‘We feel secure to share emotions in ethically difficult situations’. Moral Action includes items about moral decision-making and responsible care, like ‘We are able to explain and justify our care towards patients and their families’. Discussion: The Euro-MCD 2.0 is shorter and more strongly substantiated by empirical data and theoretical reflections. At the conference, we will reflect on the revision process and the underlying foundations of the domains. The revised instrument helps to get insight in the MCD related outcomes for healthcare professionals in their daily practice. Our research can further improve implementation of MCD and contribute to the research field of evaluation of CES in general. "
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Riordan, F. Andrew I., Laura Jones, and Julia Clark. "Validation of two algorithms for managing children with a non-blanching rash." Archives of Disease in Childhood 101, no. 8 (March 16, 2016): 709–13. http://dx.doi.org/10.1136/archdischild-2015-309451.
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BackgroundPaediatricians are concerned that children who present with a non-blanching rash (NBR) may have meningococcal disease (MCD). Two algorithms have been devised to help identify which children with an NBR have MCD.AimTo evaluate the NBR algorithms’ ability to identify children with MCD.MethodsThe Newcastle-Birmingham-Liverpool (NBL) algorithm was applied retrospectively to three cohorts of children who had presented with NBRs. This algorithm was also piloted in four hospitals, and then used prospectively for 12 months in one hospital. The National Institute for Health and Care Excellence (NICE) algorithm was validated retrospectively using data from all cohorts.ResultsThe cohorts included 625 children, 145 (23%) of whom had confirmed or probable MCD. Paediatricians empirically treated 324 (52%) children with antibiotics. The NBL algorithm identified all children with MCD and suggested treatment for a further 86 children (sensitivity 100%, specificity 82%). One child with MCD did not receive immediate antibiotic treatment, despite this being suggested by the algorithm. The NICE algorithm suggested 382 children (61%) who should be treated with antibiotics. This included 141 of the 145 children with MCD (sensitivity 97%, specificity 50%).ConclusionsThese algorithms may help paediatricians identify children with MCD who present with NBRs. The NBL algorithm may be more specific than the NICE algorithm as it includes fewer features suggesting MCD. The only significant delay in treatment of MCD occurred when the algorithms were not followed.
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Grishina, D. A., and A. B. Lokshina. "Mild Cognitive Impairment: Some Aspects of Diagnosis and Therapy." Doctor.Ru 20, no. 5 (2021): 21–25. http://dx.doi.org/10.31550/1727-2378-2021-20-4-21-25.
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Objective of the Paper: To describe the modern approaches to diagnosis and management of moderate cognitive disorders (MCD). Key Points. MCD is a transition between normal characteristics of cognitive functions and dementia. Prevalence of MCD is extremely high; with improper diagnosis and management, the condition can develop to dementia. Currently there are no generally accepted recommendations on MCD medications. We have used an example of a MCD patient to demonstrate cognitive defect stabilisation within 1 year with memantine therapy. The use of the medicine at pre-dementia stage of Alzheimer's disease is discussed. Conclusion. Timely diagnosis and proper management of MCD syndrome are very important taking into account a high risk of their progression to dementia. Memantine is a promising medication possessing neuroprotective activity and prolonging the period of patient independence. Clinical studies of memantine for non-dementia cognitive disorders should be conducted, where the duration of therapy is sufficient to assess its neuroprotective effects. Keywords: cognitive disorders, moderate cognitive disorders, memantine.
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Cattaneo, Chiara, Emanuela Vaccher, Alessandro Re, Salvatore Casari, Erika Borlenghi, Michele Spina, Umberto Tirelli, and Giuseppe Rossi. "HAART Does Not Improve the Outcome of HIV-Related Multicentric Castleman Disease: Results of a Multicentric Retrospective Study." Blood 118, no. 21 (November 18, 2011): 4918. http://dx.doi.org/10.1182/blood.v118.21.4918.4918.
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Abstract Abstract 4918 Background. Multicentric Castleman Disease (MCD) is a rare lymphoproliferative disorder, strictly related to Kaposi Sarcoma (KS) as both associated to HHV-8 infection. Like other HIV-related diseases, such as Non Hodgkin Lymphoma (NHL) and Primary Central Nervous System Lymphoma, MCD prevalence is known to be increased in HIV-pos subjects. However, limited case series among this subset of patients (pts) are reported and data regarding epidemiological variations in the pre and post HAART era are often non conclusive. In order to evaluate possible differences between pre- and post-HAART era, we retrospectively evaluated epidemiological and clinical characteristics of all pts affected by HIV-pos MCD afferent to two Italian Institutions. Patients and Methods. Data concerning biological, clinical and prognostic factors of HIV-pos MCD pts were collected and reported on a database. Pts were grouped according to the date of diagnosis in pre- (before 1997) and post-HAART (after 1997) era. Results. During a 21-year period (1990-2011), 35 HIV-pos MCD pts were observed at our Institutions, nine in the pre- and 26 in the post-HAART era. Male/Female ratio was 30/5; median age 37y (23-65). Histological subtype in 34 evaluable cases was hyaline-vascular in 6, plasmacytic in 20 and mixed cellularity in 8. Median time interval from HIV-pos detection to MCD diagnosis was 24 months (range 0–157) and CD4 count at MCD diagnosis 233/mcL (26-839). All these MCD baseline characteristics were not statistically different between pre- and post-HAART era. A concomitant diagnosis of KS was made in 18/35 (51.4%) cases, all but one in the post-HAART era. NHL was diagnosed concurrently with MCD in 2/35 (5.7%) pts (1 Primary Effusion Lymphoma, PEL, and 1 Plasmablastic Lymphoma, PBL); in 8/35 (22.8%) cases NHL developed after MCD diagnosis (2 PEL, 1 PBL, 2 Diffuse Large Cell, DLC, 1 unspecified, respectively). Median time from MCD to NHL was 19 mo (0-71). Evolution toward NHL was observed in 3 (33%) cases in the pre-HAART era and in 5 (19%) in the post-HAART era (p=0.39, Fisher's exact test). Six pts did not receive any type of treatment, 6 were treated with HAART only and 23 with different therapies, including antivirals, steroids, chemotherapy and rituximab (alone in 1 pt, in combination with chemotherapy in 5). Nineteen/23 pts received HAART together with other therapies. Two pts treated with rituximab developed NHL (1 PEL and 1 DLC). A complete or partial radiological response, together with clinical improvement was observed in 19/25 of evaluable pts (76%). Thirty pts were evaluable for relapse/progression, mainly in the post-HAART era. Overall, 19/30 pts showed MCD progression or transformation to NHL; median PFS was 15 months. Nineteen pts died and 5 were lost to follow-up. Overall survival (OS) of the entire series was 28 months, without significant differences between pre and post-HAART era (18 and 28 months, OR 0.643 [CI 0.2406–1.045], median follow-up 18 and 9 months, respectively). Causes of death were evaluable in 18 cases: NHL (7), MCD (6), opportunistic infections (1), liver cyrrhosis (1), acute myocardial infarction (1), KS (1) and therapy-related toxicity (1). NHL and MCD were the most frequent cause of death in the post-HAART era (4 and 5 of the 10 cases, respectively). Although no differences in OS between MCD pts without or with NHL were seen (19 vs 28 months, OR 0.6786 [CI 0.2763–1.081], median follow-up 13 and 23 months, respectively), eight/10 pts with NHL died, in comparison with 11/21 pts without NHL evaluable for outcome and median time from NHL diagnosis to death was 2 months (0-31). Conclusions. Our data confirm that the prognosis of HIV-related MCD remains poor even after the advent of HAART. Unlike other lymphoproliferative disorders, HAART did not impact on outcome of HIV-related MCD, suggesting that MCD can “escape” immune reconstitution. A concomitant diagnosis of NHL and uncontrolled MCD seem to be the main reason for an unfavourable outcome, particularly in the post-HAART era. New therapeutic approaches, including rituximab, should therefore aim at avoiding NHL transformation and controlling “MCD-related cytokine storm”. Disclosures: No relevant conflicts of interest to declare.
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Ni, Xi-Ping, Aditi Bhargava, David Pearce, and Michael H. Humphreys. "Modulation by dietary sodium intake of melanocortin 3 receptor mRNA and protein abundance in the rat kidney." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 290, no. 3 (March 2006): R560—R567. http://dx.doi.org/10.1152/ajpregu.00279.2005.
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γ-Melanocyte stimulating hormone (γ-MSH) is a circulating natriuretic peptide hormone derived from proopiomelanocortin (POMC); its concentration in plasma and pituitary POMC mRNA abundance, increase in rats ingesting a high-sodium diet (HSD, 8% NaCl) compared with a low-sodium diet (LSD, 0.07% NaCl). RT-PCR of rat kidney RNA demonstrated reaction products of the expected size in both cortex and medulla for MC3-R, MC4-R, and MC5-R mRNA; no signal for MC1-R or MC2-R was detected. Relative to β-actin or cyclophilin, abundance of the three receptor transcripts after 1 wk of the LSD was approximately equal in both cortex and medulla. After 1 wk of the HSD, mRNA abundance of MC4-R and MC5-R was unchanged, whereas that of MC3-R in medulla more than doubled, the ratio of MC3-R/β-actin signal increasing from 0.38 ± 0.04 on LSD to 0.84 ± 0.04 on HSD ( P < 0.001). No significant increase occurred in the cortex. The increase in MC3-R expression induced by dietary sodium was observed in inner medullary collecting duct (IMCD) cells isolated from the kidneys of HSD rats, suggesting that these cells were the major site of receptor expression in the medulla. Immunoblots of whole medullary and IMCD cell homogenates detected MC3-R immunoreactive protein; its expression was twice as great in samples from HSD vs. LSD rat kidneys, paralleling the increase in MC3-R mRNA abundance on the HSD. No changes in MC4-R or MC5-R protein expression were observed. Incubation of IMCD cell suspensions with increasing concentrations of γ2-MSH led to increased cAMP accumulation, with values from rats on the HSD being roughly double the values from LSD rats. Intrarenal infusion of γ2-MSH (500 fmol/min) increased sodium and cAMP excretion from the infused but not contralateral kidney of HSD rats, while having no effect in LSD rats. These data show that MC3-R is expressed in rat IMCD cells in a manner modulated by dietary sodium intake. Because MC3-R is the receptor with which γ-MSH interacts, our findings suggest the existence of a sodium-regulating system, activated in response to a HSD, which increases urinary sodium excretion to balance the high-sodium intake.
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Guihot, Amélie, Eric Oksenhendler, Lionel Galicier, Anne-Geneviève Marcelin, Laura Papagno, Anne-Sophie Bedin, Félix Agbalika, et al. "Multicentric Castleman disease is associated with polyfunctional effector memory HHV-8–specific CD8+ T cells." Blood 111, no. 3 (February 1, 2008): 1387–95. http://dx.doi.org/10.1182/blood-2007-03-080648.
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AbstractMulticentric Castleman disease (MCD) is a devastating human herpesvirus 8 (HHV-8)–related lymphoproliferative disorder that occurs in immunocompromised persons. To determine the role of immune responses in MCD, we studied the frequency, antigenic repertoire, differentiation, and functional profile of HHV-8–specific CD8+ T cells in MCD patients and in human immunodeficiency virus–coinfected asymptomatic HHV-8 carriers (AC). Screening CD8+ T-cell responses with ELISpot interferon-γ (IFN-γ) assays using 56 peptides on 6 latent and lytic HHV-8 proteins showed that MCD and AC patients had responses of similar magnitude and antigenic repertoire and identified a new 10-mer human leukocyte antigen B7 CD8 epitope in K15. Intracellular IFN-γ staining showed significantly more CD45RA−CCR7−CD27− CD8+IFN-γ+ cells (late phenotype) and significantly fewer CCR7−CD27+CD45RA− cells (early and intermediate phenotype) in MCD than in AC patients. This phenotypic shift was not found for Epstein-Barr virus–specific CD8+ T cells tested as controls. HHV-8 viral loads were negatively correlated with early and intermediate effector memory cells. HHV-8–specific T cells were polyfunctional (secretion of IFN-γ, tumor necrosis factor-α, macrophage inflammatory protein-1β, and/or CD107a) in both MCD and AC patients. In conclusion, MCD is not associated with a lack of HHV-8–specific CD8+ T cells or limitation of their functional profile. Their differentiation increases with HHV-8 viral load. These results offer new insight into the pathophysiology of MCD.
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Hsiao, Ching-Chung, Kun-Hua Tu, Chun-Yih Hsieh, Cheng-Chia Lee, Chih-Hsiang Chang, Pei-Chun Fan, Ya-Chung Tian, and Ji-Tseng Fang. "Immunoglobulin E and G Levels in Predicting Minimal Change Disease before Renal Biopsy." BioMed Research International 2018 (November 11, 2018): 1–6. http://dx.doi.org/10.1155/2018/3480309.
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Purpose. The diagnosis of minimal change disease in adults relies mainly on renal biopsy, but this procedure is not without complications. Despite the advancements in technique of percutaneous renal biopsy, biopsy-related complications still occur. Bleeding is one of the major complications, which may lead to hemodynamic instability and, sometimes, even death. Thus, we developed a model to predict MCD for high-risk patients unsuitable for renal biopsy. Methods. We enrolled 142 patients with nephrotic syndrome who received renal biopsy between October 2007 and April 2011 at one tertiary medical center in this study. Demographic, clinical, and prebiopsy laboratory variables were retrospectively recorded and analyzed. Results. The overall prevalence of MCD was 26.8%. Age, hemoglobin levels, 24-hour urine protein, immunoglobulin (Ig) G, and IgE differed significantly between the MCD and non-MCD groups. Logistic regression analysis showed a significant increase in the risk of developing MCD as the number of Ig risk factors, namely, IgG < 450 mg/dl and IgE > 110 mg/dl, increased. Having both risk factors significantly increased the chances of receiving a diagnosis of MCD (by 31.84-fold, P =.007) compared with having neither. Combining the aforementioned clinical model and the 2 Ig risk factors was the best in predicting the diagnosis of MCD, with the area under a receiver-operating characteristic curve of 0.91. Conclusions. Combining clinical model and this 2 Ig risk factors provides physicians simple and valuable clinical markers to diagnose MCD.