329 results on '"TYPE-1"'
Search Results
52. Alphaherpesvirus US3 protein-mediated inhibition of the m6A mRNA methyltransferase complex
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Robert J.J. Jansens, Ruth Verhamme, Aashiq H. Mirza, Anthony Olarerin-George, Cliff Van Waesberghe, Samie R. Jaffrey, and Herman W. Favoreel
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EXPRESSION ,Adenosine ,HERPES-SIMPLEX-VIRUS ,SINGLE GENES ,METHYLATION ,Genetics and Molecular Biology ,Methyltransferases ,PSEUDORABIES VIRUS ,Methylation ,General Biochemistry, Genetics and Molecular Biology ,HERPESVIRUSES ,Viral Proteins ,General Biochemistry ,Medicine and Health Sciences ,KINASE ,INACTIVATION ,Veterinary Sciences ,RNA, Messenger ,N-6-METHYLADENOSINE MODIFICATION ,TYPE-1 - Abstract
Chemical modifications of mRNA, the so-called epitranscriptome, represent an additional layer of post -tran-scriptional regulation of gene expression. The most common epitranscriptomic modification, N6-methylade-nosine (m6A), is generated by a multi-subunit methyltransferase complex. We show that alphaherpesvirus kinases trigger phosphorylation of several components of the m6A methyltransferase complex, including METTL3, METTL14, and WTAP, which correlates with inhibition of the complex and a near complete loss of m6A levels in mRNA of virus-infected cells. Expression of the viral US3 protein is necessary and sufficient for phosphorylation and inhibition of the m6A methyltransferase complex. Although m6A methyltransferase complex inactivation is not essential for virus replication in cell culture, the consensus m6A methylation motif is under-represented in alphaherpesvirus genomes, suggesting evolutionary pressure against methylation of viral transcripts. Together, these findings reveal that phosphorylation can be associated with inactivation of the m6A methyltransferase complex, in this case mediated by the viral US3 protein.
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- 2021
53. A base-line cellular antiviral state is maintained by cGAS and its most frequent naturally occurring variant rs610913
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Jacques Fellay, Jenny Jansen, Xiaoyi Zhou, Katinka Doehner, Roman Fedorov, Carina Elsner, Aurélie Ducroux, Christian W. Thorball, Markus W. Loeffler, Beate Sodeik, Julia Kazmierski, Shuting Xu, Alexander N.R. Weber, Fabian Pott, Ole Zeymer, and Christine Goffiner
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type-1 ,Innate immune system ,pathway ,Immunology ,Medizin ,dna ,Biology ,Peripheral blood mononuclear cell ,Virology ,infection ,Virus ,capsids ,herpes-simplex-virus ,chemistry.chemical_compound ,chemistry ,In vivo ,Polymorphism (computer science) ,2nd-messenger ,transport ,Immunology and Allergy ,progression ,Binding site ,reveals ,Gene ,DNA - Abstract
Upon recognition of aberrantly located DNA, the innate immune sensor cGAS activates STING/IRF-3-driven antiviral responses. Here we characterized the ability of a specific variant of the cGAS-encoding gene MB21D1, rs610913, to alter cGAS-mediated DNA sensing and viral infection. rs610913 is a frequent G>T polymorphism resulting in a P261H exchange in the cGAS protein. Data from the International Collaboration for the Genomics of HIV suggested that rs610913 nominally associates with HIV-1 acquisition in vivo. Molecular modeling of cGAS(P261H) hinted towards the possibility for an additional binding site for a potential cellular co-factor in cGAS dimers. However, cGAS(WT) or cGAS(P261H)-reconstituted THP-1 cGAS KO cells shared steady-state expression of interferon-stimulated genes (ISGs), as opposed to cells expressing the enzymatically inactive cGAS(G212A/S213A). Accordingly, cGAS(WT) and cGAS(P261H) cells were less susceptible to lentiviral transduction and infection with HIV-1, HSV-1, and Chikungunya virus as compared to cGAS KO- or cGAS(G212A/S213A) cells. Upon DNA challenge, innate immune activation appeared to be mildly reduced upon expression of cGAS(P261H) compared to cGAS(WT). Finally, DNA challenge of PBMCs from donors homozygously expressing rs610913 provoked a trend towards a slightly reduced type I IFN response as compared to PBMCs from GG donors. Taken together, the steady-state activity of cGAS maintains a base-line antiviral state rendering cells more refractory to ISG-sensitive viral infections. Even though rs610913 failed to grossly differ phenotypically from the wild-type gene, its expression potentially results in a slightly altered susceptibility to viral infections in vivo.
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- 2021
54. Impact of Genotype, Serum Bile Acids, and Surgical Biliary Diversion on Native Liver Survival in FIC1 Deficiency
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Liting Li, Jian-She Wang, Ozlem Durmaz, Felipe Ordonez, Wikrom Karnsakul, Seema Alam, Cristina Targa Ferreira, Natural Course, Bettina E. Hansen, Kyung Mo Kim, Etienne Sokal, Ryan T. Fischer, Valerie Sency, Estella M. Alonso, Simon Horslen, Elisa de Carvalho, Piotr Czubkowski, Emanuele Nicastro, Nanda Kerkar, Dieter C. Broering, Björn Fischler, Dorothee Krebs-Schmitt, Kathleen M. Loomes, Dominique Debray, Marianne Hørby Jørgensen, Benjamin L. Shneider, Emmanuel Gonzales, Cigdem Arikan, Nathalie Rock, Antal Dezsőfi, Tassos Grammatikopoulos, Steffen Hartleif, Mara Cananzi, Talal Algoufi, Ronald J. Sokol, Jan B F Hulscher, Carolina Jimenez-Rivera, Emmanuel Jacquemin, Anne Spraul, Henkjan J. Verkade, Patryk Lipiński, Daan B E van Wessel, Nejat Mazhar, Maria Rogalidou, Deirdre Kelly, Alexandre Fabre, Daniele Serranti, Pier Luigi Calvo, Yael Mozer-Glassberg, Richard J. Thompson, Cristina Goncalves, Yumirle P. Turmelle, Jesus Quintero Bernabeu, Agustina Kadaristiana, Florence Lacaille, Loreto Hierro, Mohammad Shagrani, Patrick J. McKiernan, Girish S. Rao, Gema Muñoz Bartolo, Huey-Ling Chen, Wendy L. van der Woerd, Irena Jankowska, Amer Azaz, Philip J. Rosenthal, Frederick J. Suchy, Jernej Brecelj, Gabriella Nebbia, Noemie Laverdure, Henrik Arnell, Binita M. Kamath, Heng Wang, Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de pédiatrie multidisciplinaire [Hôpital de la Timone Enfants - APHM], Hôpital de la Timone [CHU - APHM] (TIMONE), Arıkan, Çiğdem (ORCID 0000-0002-0794-2741 & YÖK ID 240198), van Wessel, D. B. E., Thompson, R. J., Gonzales, E., Jankowska, I., Shneider, B. L., Sokal, E., Grammatikopoulos, T., Kadaristiana, A., Jacquemin, E., Spraul, A., Lipiński, P., Czubkowski, P., Rock, N., Shagrani, M., Broering, D., Algoufi, T., Mazhar, N., Nicastro, E., Kelly, D., Nebbia, G., Arnell, H., Fischler, B., Hulscher, J. B. F., Serranti, D., Debray, D., Lacaille, F., Goncalves, C., Hierro, L., Muñoz Bartolo, G., Mozer-Glassberg, Y., Azaz, A., Brecelj, J., Dezsőfi, A., Luigi Calvo, P., Krebs-Schmitt, D., Hartleif, S., van der Woerd, W. L., Wang, J. S., Li, L. T., Durmaz, Ö., Kerkar, N., Hørby Jørgensen, M., Fischer, R., Jimenez-Rivera, C., Alam, S., Cananzi, M., Laverdure, N., Ferreira, C. T., Ordonez, F., Wang, H., Sency, V., Kim, K. M., Chen, H. L., Carvalho, E., Fabre, A., Quintero Bernabeu, J., Alonso, E. M., Sokol, R. J., Suchy, F. J., Loomes, K. M., McKiernan, P. J., Rosenthal, P., Turmelle, Y., Rao, G. S., Horslen, S., Kamath, B. M., Rogalidou, M., Karnsakul, W. W., Hansen, B., Verkade, H. J., Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM), School of Medicine, Center for Liver, Digestive and Metabolic Diseases (CLDM), UCL - SSS/IREC/PEDI - Pôle de Pédiatrie, and UCL - (SLuc) Service de gastro-entérologie et hépatologie pédiatrique
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0301 basic medicine ,Male ,[SDV]Life Sciences [q-bio] ,CHILDREN ,Compound heterozygosity ,Gastroenterology ,PFIC1 ,DISEASE ,0302 clinical medicine ,Genotype ,Medicine ,Prospective Studies ,Prospective cohort study ,Child ,ComputingMilieux_MISCELLANEOUS ,Adenosine Triphosphatases ,ATP8B1 GENE ,Bile acid ,Progressive familial intrahepatic cholestasis ,Prognosis ,Treatment Outcome ,Codon, Nonsense ,Child, Preschool ,Cohort ,030211 gastroenterology & hepatology ,Female ,Original Article ,EXPRESSION ,medicine.medical_specialty ,Adolescent ,medicine.drug_class ,Cholestasis, Intrahepatic ,Risk Assessment ,Frameshift mutation ,Bile Acids and Salts ,03 medical and health sciences ,Young Adult ,FAMILIAL INTRAHEPATIC CHOLESTASIS ,Internal medicine ,Humans ,ABCB11 MUTATIONS ,Survival analysis ,TYPE-1 ,ATP8B1 ,FIC1 deficiency ,Serum bile acids ,Surgical biliary diversion ,Retrospective Studies ,[SDV.GEN]Life Sciences [q-bio]/Genetics ,Hepatology ,business.industry ,Infant ,Original Articles ,medicine.disease ,Survival Analysis ,Liver Transplantation ,SALT EXPORT PUMP ,030104 developmental biology ,Bile Ducts, Intrahepatic ,Autoimmune, Cholestatic and Biliary Disease ,business ,[SDV.MHEP]Life Sciences [q-bio]/Human health and pathology ,Follow-Up Studies - Abstract
Mutations in ATP8B1 can lead to familial intrahepatic cholestasis type 1 (FIC1) deficiency, or progressive familial intrahepatic cholestasis type 1 (PFIC1). The rarity of FIC1 deficiency has largely prevented a detailed analysis of its natural history, effects of predicted protein truncating mutations (PPTMs), and possible associations of serum bile acid (sBA) concentrations and surgical biliary diversion (SBD) with long-term outcome. We aimed to provide novel insights by using the largest genetically defined cohort of FIC1 deficiency patients to date. This multicenter, combined retrospective and prospective study included 130 patients with compound heterozygous or homozygous predicted pathogenic ATP8B1 variants. Patients were categorized according to the number of PPTMs (i.e., splice site, frameshift due to deletion or insertion, nonsense, duplication); FIC1-A (n=67; no PPTM), FIC1-B (n=29; one PPTM) or FIC1-C (n=34; two PPTMs). Survival analysis showed an overall native liver survival (NLS) of 44% at age 18y. NLS was comparable between FIC1-A, FIC1-B, and FIC1-C (%NLS at age 10y: 67%, 41%, and 59%, respectively; P=0.12), despite FIC1-C undergoing SBD less often (%SBD at age 10y: 65%, 57%, and 45%, respectively; P=0.03). sBAs at presentation were negatively associated with NLS (NLS at age 10y; sBAs, University of Colorado; Baylor College of Medicine; Children’s Hospital of Philadelphia; Children’s Hospital of Pittsburgh; St Louis Children’s Hospital; Riley Hospital for Children; Seattle Children’s Hospital; M.D./Ph.D. Scholarship from the University of Groningen; European Society for Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) Networking Grant 2019; ChilDReN National Institutes of Health Grants; Ann & Robert H. Lurie Children’s Hospital; Albireo and Mirum Pharmaceuticals
- Published
- 2021
55. Fasting and post-oral-glucose-load levels of methylglyoxal are associated with microvascular, but not macrovascular, disease in individuals with and without (pre)diabetes: The Maastricht Study
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Hanssen, N. M. J., Hanssen, N. M. J., Scheijen, J. L. J. M., Houben, A. J. H. M., van de Waarenburg, M, Berendschot, T. T. J. M., Webers, C. A. B., Reesink, K D, van Greevenbroek, M M J, van der Kallen, C, Schaper, N C, Schram, M T, Henry, R M A, Stehouwer, C D A, Schalkwijk, C G, Hanssen, N. M. J., Hanssen, N. M. J., Scheijen, J. L. J. M., Houben, A. J. H. M., van de Waarenburg, M, Berendschot, T. T. J. M., Webers, C. A. B., Reesink, K D, van Greevenbroek, M M J, van der Kallen, C, Schaper, N C, Schram, M T, Henry, R M A, Stehouwer, C D A, and Schalkwijk, C G
- Abstract
AIMS: Reactive dicarbonyl compounds, such as methylglyoxal (MGO), rise during an oral glucose tolerance test (OGTT), particularly in (pre)diabetes. Fasting MGO levels are associated with chronic kidney disease (CKD) and cardiovascular disease (CVD) in patients with poorly controlled type 2 diabetes mellitus (T2DM). Yet, whether fasting or post-OGTT plasma MGO levels are associated with vascular disease in people with (pre)diabetes is unknown.METHODS: Subjects with normal glucose metabolism (n=1796; age: 57.9±8.2 years; 43.3% men), prediabetes (n=478; age: 61.6±7.6 years; 54.0% men) and T2DM (n=669; age: 63.0±7.5 years; 67.0% men) from the Maastricht Study underwent OGTTs. Plasma MGO levels were measured at baseline and 2h after OGTT by mass spectrometry. Prior CVD was established via questionnaire. CKD was reflected by estimated glomerular filtration rate (eGFR) and albuminuria; retinopathy was assessed using retinal photographs. Data were analyzed using logistic regression adjusted for gender, age, smoking, systolic blood pressure, total-to-HDL cholesterol ratio, triglycerides, HbA1c, BMI and medication use. Odd ratios (ORs) were expressed per standard deviation of LN-transformed MGO.RESULTS: Fasting and post-OGTT MGO levels were associated with higher ORs for albuminuria ≥30mg/24h [fasting: 1.12 (95% CI: 0.97-1.29); post-OGTT: 1.19 (1.01-1.41)], eGFR<60mL/min/1.73 m2 [fasting: 1.58 (95% CI: 1.38-1.82), post-OGTT: 1.57 (1.34-1.83)] and retinopathy [fasting: 1.59 (95% CI: 1.01-2.53), post-OGTT: 1.38 (0.77-2.48)]. No associations with prior CVD were found.CONCLUSION: Fasting and post-OGTT MGO levels were associated with microvascular disease, but not prior CVD. Thus, therapeutic strategies directed at lowering MGO levels may prevent microvascular disease.
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- 2021
56. MCPIP1 is a novel link between diabetogenic conditions and impaired insulin secretory capacity
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Tyka, Karolina, Joerns, Anne, Dunst, Alessia, Tang, Yadi, Bryde, Tenna Holgersen, Mehmeti, Ilir, Walentinsson, Anna, Marselli, Lorella, Cnop, Miriam, Tyrberg, Bjorn, Marzec, Michal T., Gurgul-Convey, Ewa, Tyka, Karolina, Joerns, Anne, Dunst, Alessia, Tang, Yadi, Bryde, Tenna Holgersen, Mehmeti, Ilir, Walentinsson, Anna, Marselli, Lorella, Cnop, Miriam, Tyrberg, Bjorn, Marzec, Michal T., and Gurgul-Convey, Ewa
- Abstract
During diabetes development insulin production and glucose-stimulated insulin secretion (GSIS) are defective due to inflammation-related, yet not fully understood mechanisms. MCPIP1 (monocyte chemotactic protein-induced protein-1) is a strong regulator of inflammation, and acts predominantly as a specific RNase. The impact of MCPIP1 on insulin secretory capacity is unknown.We show that the expression of the ZC3H12A gene, which encodes MCPIP1, was induced by T1DM- and by T2DM-simulating conditions, with a stronger effect of cytokines. The number of MCPIP1-positive pancreatic islet-cells, including beta-cells, was significantly higher in diabetic compared to nondiabetic individuals. In the 3' UTR regions of mRNAs coding for Pdx1 (pancreatic and duodenal homeobox 1), FoxO1 (forkhead box protein O1), and of a novel regulator of insulin handling, Grp94 (glucose-regulated protein 94), MCPIP1-target structures were detected. Overexpression of the wild type MCPIP1(wt), but not of the mutant MCPIP1(D141N) (lacking the RNase activity), decreased the expression of genes involved in insulin production and GSIS. Additionally INS1-E-MCPIP1(wt) cells exhibited a higher Ire1 (inositol-requiring enzyme 1) expression. MCPIP1(wt) overexpression blunted GSIS and glucose-mediated calcium influx with no deleterious effects on glucose uptake or glucokinase activity.We identify MCPIP1 as a new common link between diabetogenic conditions and beta-cell failure. MCPIP1 may serve as an interesting target for novel beta-cell protective approaches.
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- 2021
57. The Role of Pancreatic Alpha Cells and Endothelial Cells in the Reduction of Oxidative Stress in Pseudoislets
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Fredrik C. Wieland, Mireille M.J.P.E. Sthijns, Thomas Geuens, Clemens A. van Blitterswijk, Vanessa L.S. LaPointe, CBITE, RS: MERLN - Cell Biology - Inspired Tissue Engineering (CBITE), and FSE Campus Venlo
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Histology ,human umbilical vein endothelial cell line ,Biomedical Engineering ,Alpha (ethology) ,Incretin ,pseudoislet ,030209 endocrinology & metabolism ,Bioengineering ,Enteroendocrine cell ,Oxidative phosphorylation ,medicine.disease_cause ,Alpha cell ,ROS - reactive oxygen species ,PROTECTS ,03 medical and health sciences ,0302 clinical medicine ,HUVEC ,BETA-CELLS ,medicine ,oxidative stress ,VASCULARIZATION ,Beta (finance) ,HUVEC - human umbilical vein endothelial cell line ,TYPE-1 ,Original Research ,030304 developmental biology ,reactive oxygen species ,0303 health sciences ,Chemistry ,alpha TC1 clone 6 ,Pancreatic islets ,Bioengineering and Biotechnology ,INS1E cells ,GLP-1 - glucagon-like peptide-1 ,ROS ,DYSFUNCTION ,3. Good health ,Cell biology ,medicine.anatomical_structure ,glucagon-like peptide-1 ,ISLETS ,GLP-1 ,Oxidative stress ,TP248.13-248.65 ,Biotechnology - Abstract
Pancreatic beta cells have inadequate levels of antioxidant enzymes, and the damage induced by oxidative stress poses a challenge for their use in a therapy for patients with type 1 diabetes. It is known that the interaction of the pancreatic endocrine cells with support cells can improve their survival and lead to less vulnerability to oxidative stress. Here we investigated alpha (alpha TC-1), beta (INS1E) and endothelial (HUVEC) cells assembled into aggregates known as pseudoislets as a model of the pancreatic islets of Langerhans. We hypothesised that the coculture of alpha, beta and endothelial cells would be protective against oxidative stress. First, we showed that adding endothelial cells decreased the percentage of oxidative stress-positive cells. We then asked if the number of endothelial cells or the size (number of cells) of the pseudoislet could increase the protection against oxidative stress. However, no additional benefit was observed by those changes. On the other hand, we identified a potential supportive effect of the alpha cells in reducing oxidative stress in beta and endothelial cells. We were able to link this to the incretin glucagon-like peptide-1 (GLP-1) by showing that the absence of alpha cells in the pseudoislet caused increased oxidative stress, but the addition of GLP-1 could restore this. Together, these results provide important insights into the roles of alpha and endothelial cells in protecting against oxidative stress.
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- 2021
58. Short Duration Alagebrium Chloride Therapy Prediabetes Does Not Inhibit Progression to Autoimmune Diabetes in an Experimental Model
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Anthony W. Purcell, Casper G. Schalkwijk, Rochelle Ayala, David Briskey, Jean L.J.M. Scheijen, Josephine M. Forbes, Raymond J. Steptoe, Kai Lin Giam, Sherman Leung, Domenica A. McCarthy, Brooke E. Harcourt, Micheal S. Ward, Peta L. S. Reeves, Amelia K. Fotheringham, Pouya Faridi, Danielle J. Borg, Nadine L. Dudek, MUMC+: MA Alg Onderzoek Interne Geneeskunde (9), Interne Geneeskunde, RS: Carim - V01 Vascular complications of diabetes and metabolic syndrome, and MUMC+: MA Alg Interne Geneeskunde (9)
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0301 basic medicine ,EXPRESSION ,medicine.medical_specialty ,immunopeptidome ,type 1 diabetes ,Endocrinology, Diabetes and Metabolism ,cross-link breaker ,030209 endocrinology & metabolism ,MIN6N8 cell line ,Major histocompatibility complex ,Microbiology ,Biochemistry ,INSULIN-SECRETION ,DENDRITIC CELLS ,autoimmune diabetes ,Article ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Antigen ,Internal medicine ,MHC class I ,medicine ,Prediabetes ,Molecular Biology ,TYPE-1 ,Type 1 diabetes ,LYMPH-NODES ,biology ,RECEPTOR ,business.industry ,advanced glycation end products ,medicine.disease ,QR1-502 ,RAGE ,3. Good health ,030104 developmental biology ,Endocrinology ,biology.protein ,T-CELLS ,business ,GLYCATION END-PRODUCTS ,Insulitis ,alagebrium chloride ,CD8 ,BETA-CELL DYSFUNCTION ,NOD mouse - Abstract
Mechanisms by which advanced glycation end products (AGEs) contribute to type 1 diabetes (T1D) pathogenesis are poorly understood. Since life-long pharmacotherapy with alagebrium chloride (ALT) slows progression to experimental T1D, we hypothesized that acute ALT therapy delivered prediabetes, may be effective. However, in female, non-obese diabetic (NODShiLt) mice, ALT administered prediabetes (day 50–100) did not protect against experimental T1D. ALT did not decrease circulating AGEs or their precursors. Despite this, pancreatic β-cell function was improved, and insulitis and pancreatic CD45.1+ cell infiltration was reduced. Lymphoid tissues were unaffected. ALT pre-treatment, prior to transfer of primed GC98 CD8+ T cell receptor transgenic T cells, reduced blood glucose concentrations and delayed diabetes, suggesting islet effects rather than immune modulation by ALT. Indeed, ALT did not reduce interferon-γ production by leukocytes from ovalbumin-pre-immunised NODShiLt mice and NODscid recipients given diabetogenic ALT treated NOD splenocytes were not protected against T1D. To elucidate β-cell effects, NOD-derived MIN6N8 β-cell major histocompatibility complex (MHC) Class Ia surface antigens were examined using immunopeptidomics. Overall, no major changes in the immunopeptidome were observed during the various treatments with all peptides exhibiting allele specific consensus binding motifs. As expected, longer MHC Class Ia peptides were captured bound to H-2Db than H-2Kb under all conditions. Moreover, more 10–12 mer peptides were isolated from H-2Db after AGE modified bovine serum albumin (AGE-BSA) treatment, compared with bovine serum albumin (BSA) or AGE-BSA+ALT treatment. Proteomics of MIN6N8 cells showed enrichment of processes associated with catabolism, the immune system, cell cycling and presynaptic endocytosis with AGE-BSA compared with BSA treatments. These data show that short-term ALT intervention, given prediabetes, does not arrest experimental T1D but transiently impacts β-cell function.
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- 2021
59. Shoulder pain and functional disability in type 1 diabetic patients: A cross-sectional survey
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Aqsa Mehmood, Muhammad Nazim Farooq, Fatima Amjad, and Jaweria Syed
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medicine.medical_specialty ,business.industry ,Cross-sectional study ,Shoulder pain ,Significant difference ,General Medicine ,Disease ,Creative commons ,Type-1 ,medicine.disease ,Tertiary care ,Diabetes mellitus ,Risk factors ,Functional disability ,Internal medicine ,Female patient ,Prevalence ,medicine ,Original Article ,business - Abstract
Objective: To assess the prevalence of shoulder pain and functional disability (SPFD) in Type-1 diabetic patients, and to explore its association with duration of the disease, age and gender. Methods: A cross-sectional survey was carried out on previously diagnosed patients with Type-1 diabetes mellitus between April 2019 and March 2020. Data was collected from six hospitals including three tertiary care hospitals of Islamabad and Rawalpindi. Three hundred and twenty-eight patients were recruited through convenience sampling. Shoulder Pain and Disability Index was used to determine SPFD among participants. Point-biserial and Pearson correlation coefficients were calculated to find out the correlation between the variables. Independent t-test was used to determine the difference in the mean scores between the variables. Results: The prevalence of SPFD was found 85.7%. A significant correlation was found of the SPFD with age (r = 0.332, p < 0.001), duration of the diabetes mellitus (r = 0.154, p = 0.005) and gender (rpb = 0.171, p = 0.002). A significant difference was found in SPFD mean scores between female and male patients (female patients = 43.42±22.80, male patients = 35.31±22.91, p = 0.002). Conclusion: SPFD seems prevalent among Type-1 diabetic patients. Increasing age, long history of diabetes mellitus and female gender appear the associated risk factors for the shoulder pain and disability. doi: https://doi.org/10.12669/pjms.37.4.3401 How to cite this:Farooq MN, Mehmood A, Amjad F, Syed J. Shoulder pain and functional disability in type 1 diabetic patients: A cross-sectional survey. Pak J Med Sci. 2021;37(4):1211-1214. doi: https://doi.org/10.12669/pjms.37.4.3401 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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- 2021
60. Age at Seroconversion, HLA Genotype, and Specificity of Autoantibodies in Progression of Islet Autoimmunity in Childhood
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Attila Gyenesei, Mikael Knip, Minna Kiviniemi, Taina Härkönen, Riitta Veijola, Witold Bauer, Jorma Ilonen, Johanna Lempainen, Jorma Toppari, Diabetes and Obesity Research Program, Staff Services, HUS Children and Adolescents, Research Programs Unit, Children's Hospital, University of Helsinki, and Research Group Knip
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Male ,GENETIC SUSCEPTIBILITY ,Insulin Antibodies ,Endocrinology, Diabetes and Metabolism ,Clinical Biochemistry ,CHILDREN ,Autoimmunity ,Kaplan-Meier Estimate ,medicine.disease_cause ,Biochemistry ,APPEARANCE ,Cohort Studies ,0302 clinical medicine ,Endocrinology ,Longitudinal Studies ,Child ,RISK ,0303 health sciences ,geography.geographical_feature_category ,Glutamate Decarboxylase ,Age Factors ,Islet ,INSULIN ,3. Good health ,POSITIVITY ,Seroconversion ,Child, Preschool ,Disease Progression ,Female ,medicine.medical_specialty ,Adolescent ,Genotype ,RELATIVES ,PHENOTYPES ,030209 endocrinology & metabolism ,Context (language use) ,Human leukocyte antigen ,03 medical and health sciences ,HLA-DQ Antigens ,Internal medicine ,Diabetes mellitus ,medicine ,Humans ,Genetic Predisposition to Disease ,TYPE-1 ,Autoantibodies ,Proportional Hazards Models ,030304 developmental biology ,geography ,Type 1 diabetes ,business.industry ,Biochemistry (medical) ,Autoantibody ,Infant ,HLA-DR Antigens ,ALLELES ,medicine.disease ,Diabetes Mellitus, Type 1 ,3121 General medicine, internal medicine and other clinical medicine ,Immunology ,3111 Biomedicine ,business - Abstract
Context Children with initial autoantibodies to either insulin (IAA) or glutamic acid decarboxylase (GADA) differ in peak age of seroconversion and have different type 1 diabetes (T1D) risk gene associations, suggesting heterogeneity in the disease process. Objective To compare the associations of age at seroconversion, HLA risk, and specificity of secondary autoantibodies with the progression of islet autoimmunity between children with either IAA or GADA as their first autoantibody. Design and methods A cohort of 15,253 children with HLA-associated increased risk of T1D participated in a follow-up program in which islet autoantibodies were regularly measured. The median follow-up time was 6.7 years. Spearman correlation, Kaplan-Meier survival plots, and Cox proportional-hazard models were used for statistical analyses. Results Persistent positivity for at least one of the tested autoantibodies was detected in 998 children; 388 of children progressed to clinical T1D. Young age at initial seroconversion was associated with a high probability of expansion of IAA-initiated autoimmunity and progression to clinical diabetes, whereas expansion of GADA-initiated autoimmunity and progression to diabetes were not dependent on initial seroconversion age. The strength of HLA risk affected the progression of both IAA- and GADA-initiated autoimmunity. The simultaneous appearance of two other autoantibodies increased the rate of progression to diabetes compared with that of a single secondary autoantibody among subjects with GADA-initiated autoimmunity but not among those with IAA as the first autoantibody. Conclusions Findings emphasize the differences in the course of islet autoimmunity initiated by either IAA or GADA supporting heterogeneity in the pathogenic process.
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- 2019
61. Circulating type-1 anti-tumor CD4+ T cells are preferentially pro-apoptotic in cancer patients
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Amy K. Wesa, Maja eMandic, Jennifer L. Taylor, Stergios eMoschos, John M. Kirkwood, William W. Kwok, James Harold Finke, and Walter J. Storkus
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Apoptosis ,CD4+ T cells ,tumor ,Peripheral Blood ,Type-1 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Melanoma patients frequently exhibit a deficiency in Type-1 (but not Type-2 or regulatory) CD4+ T cell responses against tumor-associated antigens (TAA), which may limit protection against cancer progression or responsiveness to immunotherapy in these individuals. Since such deficiency was acutely evident in patients with active disease, where chronic stimulation of anti-tumor CD4+ T cells would be expected and activation-induced cell death may be prevalent, we employed MHC Class II-peptide tetramers to characterize the frequency and apoptotic status of TAA- vs. influenza (FluM1) virus-specific CD4+ T cells in the peripheral blood of HLA-DR*0401+ patients with melanoma or renal cell carcinoma (RCC). We observed that Flu-specific CD4+ T cells ranged from 0.17 to 3.89%, while up to approximately 1% of CD4+ T cells reacted against individual TAA epitopes derived from the EphA2 or MAGE-6 proteins. The frequencies of EphA2 and MAGE-6-specific CD4+ T cells in patients were significantly correlated with active disease and patient gender (i.e. females > males), while frequencies of Flu-specific CD4+ T cells were distributed within a normal range in all patients. Notably, patient CD4+ T cells reactive with MHC class II-TAA (but not MHC class II-Flu) tetramers were significantly enriched for a pro-apoptotic (Annexin-V+) phenotype, particularly amongst the Th1 (T-bet+) subset. These results suggest that the preferential sensitivity of TAA (but not viral)-specific CD4+ Th1 cells to apoptosis in melanoma patients with active disease will need to be overcome for optimal clinical benefit of immunotherapeutic approaches to be realized.
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- 2014
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62. WHO-5 and BDI-II are acceptable screening instruments for depression in people with diabetes
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A. C. T. M. Peeters, Maya J. Schroevers, K. A. Tovote, Joke Fleer, Paul M. G. Emmelkamp, N. L. Rauwerda, Robbert Sanderman, Psychology, Health & Technology, Clinical Psychology and Experimental Psychopathology, and Lifelong Learning, Education & Assessment Research Network (LEARN)
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Agreeableness ,Adult ,Male ,Endocrinology, Diabetes and Metabolism ,UT-Hybrid-D ,EMOTIONAL-PROBLEMS ,030209 endocrinology & metabolism ,Logistic regression ,World Health Organization ,behavioral disciplines and activities ,law.invention ,Diabetes Complications ,03 medical and health sciences ,0302 clinical medicine ,Endocrinology ,Randomized controlled trial ,law ,Surveys and Questionnaires ,Internal Medicine ,Diabetes Mellitus ,MANAGEMENT ,Medicine ,Health Status Indicators ,Humans ,Mass Screening ,ANXIETY ,030212 general & internal medicine ,Depression (differential diagnoses) ,TYPE-1 ,Aged ,Netherlands ,Response rate (survey) ,Psychiatric Status Rating Scales ,Depressive Disorder ,business.industry ,Depression ,Beck Depression Inventory ,Middle Aged ,n/a OA procedure ,PREVALENCE ,Psychotherapy ,Mood ,Anxiety ,WELL-BEING INDEX ,Female ,medicine.symptom ,business ,OUTPATIENTS ,Clinical psychology - Abstract
Aims: To investigate the acceptability of two questionnaires, the five item WHO Well-being Index (WHO-5) and the Beck Depression Inventory II (BDI-II), which differ in length and focus, by comparing three screening groups: (1) WHO-5, (2) BDI-II and (3) WHO-5 and BDI-II. Methods: A total of 699 individuals with diabetes were approached to participate in the study, of whom 95 completed the WHO-5, 254 completed the BDI-II and 350 completed both the WHO-5 and the BDI-II questionnaires. Five facets of acceptability were compared, including objective aspects (response rate and completion level) and subjective aspects (appreciation, agreeableness and accuracy of the screening questionnaire). Data were analysed using logistic regression analysis and (multivariate) analysis of covariance. Results: The overall response rate was 65% (453 out of 699). No differences between the three groups were found with respect to the response rate (WHO-5: 66%; BDI-II: 63%; WHO-5 and BDI-II: 66%; P ≥ 0.19) and completion level (WHO-5: 99.5%; BDI-II: 97.8%; WHO-5 and BDI-II: 98.7%; P=0.45). The three groups did differ significantly in their scores on two of the three subjective indicators (P
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- 2018
63. No evidence of the role of early chemical exposure in the development of β-cell autoimmunity
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Harri M. Salo, Outi Vaarala, Jorma Ilonen, Panu Rantakokko, Hannu Kiviranta, Suvi M. Virtanen, Jani Koponen, Jarno Honkanen, Mikael Knip, Vallo Tillmann, and Taina Härkönen
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Male ,Health, Toxicology and Mutagenesis ,Breastfeeding ,Physiology ,Autoimmunity ,CHILDREN ,010501 environmental sciences ,medicine.disease_cause ,01 natural sciences ,Cohort Studies ,Pregnancy ,Risk Factors ,Insulin-Secreting Cells ,cell autoimmunity ,Child ,biology ,General Medicine ,FINLAND ,Fetal Blood ,Pollution ,3. Good health ,Breast Feeding ,Type 1 diabetes ,PERFLUORINATED COMPOUNDS ,Child, Preschool ,Prenatal Exposure Delayed Effects ,Cord blood ,Environmental Pollutants ,Female ,Antibody ,Research Article ,Human ,β-cell autoimmunity ,IMMUNITY ,PERFLUOROALKYL ACIDS ,Diabetes mellitus ,medicine ,Humans ,Environmental Chemistry ,TYPE-1 ,Autoantibodies ,0105 earth and related environmental sciences ,Fetus ,business.industry ,Infant, Newborn ,Autoantibody ,Infant ,DIABETES-MELLITUS ,medicine.disease ,Diet ,CYTOKINE ,Diabetes Mellitus, Type 1 ,13. Climate action ,Case-Control Studies ,ANTIBODIES ,Chemical exposure ,T-CELLS ,biology.protein ,business - Abstract
Exposure to environmental chemicals can modulate the developing immune system, but its role in the pathogenesis of type 1 diabetes is largely unexplored. Our objective was to study the levels of circulating concentrations of environmental pollutants during the first years of life and their associations with the later risk of diabetes-predictive autoantibodies. From two birth-cohort studies including newborn infants with HLA-conferred susceptibility to type 1 diabetes (FINDIA and DIABIMMUNE), we identified case children with at least one biochemical diabetes-associated autoantibody (n = 30–40) and from one to four autoantibody-negative controls per each case child matched for age, gender, diabetes-related HLA-risk, delivery hospital, and, in FINDIA, also dietary intervention group. Plasma levels of 13 persistent organic pollutants and 14 per- and polyfluorinated substances were analyzed in cord blood and plasma samples taken at the age of 12 and 48 months. Both breastfeeding and the geographical living environment showed association with circulating concentrations of some of the chemicals. Breastfeeding-adjusted conditional logistic regression model showed association between decreased plasma HBC concentration at 12-month-old children and the appearance of diabetes-associated autoantibodies (HR, 0.989; 95% Cl, 0.978–1.000; P = 0.048). No association was found between the plasma chemical levels and the development of clinical type 1 diabetes. Our results do not support the view that exposure to the studied environmental chemicals during fetal life or early childhood is a significant risk factor for later development of β-cell autoimmunity and type 1 diabetes. Electronic supplementary material The online version of this article (10.1007/s11356-018-3659-6) contains supplementary material, which is available to authorized users.
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- 2018
64. CRISPR/Cas9-Constructed Pseudorabies Virus Mutants Reveal the Importance of UL13 in Alphaherpesvirus Escape from Genome Silencing
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Esteban A. Engel, Orkide O. Koyuncu, Jolien Van Cleemput, Lynn W. Enquist, and Kathlyn Laval
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U(L)13 PROTEIN-KINASE ,Swine ,animal diseases ,viruses ,Pseudorabies ,EFFICIENT ,Alphaherpesvirinae ,medicine.disease_cause ,Axonal Transport ,Medicine and Health Sciences ,CRISPR ,PHOSPHORYLATION ,Cells, Cultured ,Neurons ,0303 health sciences ,LATENCY ,virus diseases ,Viral tegument ,Herpesvirus 1, Suid ,Cell biology ,Virus Latency ,Capsid ,PNS neurons ,AXON TRANSPORT ,alphaherpesvirus ,EXPRESSION ,Immunology ,Genome, Viral ,Biology ,Protein Serine-Threonine Kinases ,Microbiology ,Virus ,03 medical and health sciences ,Viral Proteins ,herpesvirus ,Virology ,medicine ,Gene silencing ,Animals ,Gene Silencing ,Gene ,TYPE-1 ,latency ,030304 developmental biology ,030306 microbiology ,HERPES-SIMPLEX-VIRUS ,Biology and Life Sciences ,biochemical phenomena, metabolism, and nutrition ,biology.organism_classification ,pseudorabies virus ,GENE ,Herpes simplex virus ,Insect Science ,Mutation ,Pathogenesis and Immunity ,CRISPR-Cas Systems - Abstract
Alphaherpesviruses have mastered various strategies to persist in an immunocompetent host, including the induction of latency and reactivation in peripheral nervous system (PNS) ganglia. We recently discovered that the molecular mechanism underlying escape from latency by the alphaherpesvirus pseudorabies virus (PRV) relies on a structural viral tegument protein., Latent and recurrent productive infection of long-living cells, such as neurons, enables alphaherpesviruses to persist in their host populations. Still, the viral factors involved in these events remain largely obscure. Using a complementation assay in compartmented primary peripheral nervous system (PNS) neuronal cultures, we previously reported that productive replication of axonally delivered genomes is facilitated by pseudorabies virus (PRV) tegument proteins. Here, we sought to unravel the role of tegument protein UL13 in this escape from silencing. We first constructed four new PRV mutants in the virulent Becker strain using CRISPR/Cas9-mediated gene replacement: (i) PRV Becker defective for UL13 expression (PRV ΔUL13), (ii) PRV where UL13 is fused to eGFP (PRV UL13-eGFP), and two control viruses (iii and iv) PRV where VP16 is fused with mTurquoise at either the N terminus (PRV mTurq-VP16) or the C terminus (PRV VP16-mTurq). Live-cell imaging of PRV capsids showed efficient retrograde transport after axonal infection with PRV UL13-eGFP, although we did not detect dual-color particles. However, immunofluorescence staining of particles in mid-axons indicated that UL13 might be cotransported with PRV capsids in PNS axons. Superinfecting nerve cell bodies with UV-inactivated PRV ΔUL13 failed to efficiently promote escape from genome silencing compared to UV-PRV wild type and UV-PRV UL13-eGFP superinfection. However, UL13 does not act directly in the escape from genome silencing, as adeno-associated virus (AAV)-mediated UL13 expression in neuronal cell bodies was not sufficient to provoke escape from genome silencing. Based on this, we suggest that UL13 may contribute to initiation of productive infection through phosphorylation of other tegument proteins. IMPORTANCE Alphaherpesviruses have mastered various strategies to persist in an immunocompetent host, including the induction of latency and reactivation in peripheral nervous system (PNS) ganglia. We recently discovered that the molecular mechanism underlying escape from latency by the alphaherpesvirus pseudorabies virus (PRV) relies on a structural viral tegument protein. This study aimed at unravelling the role of tegument protein UL13 in PRV escape from latency. First, we confirmed the use of CRISPR/Cas9-mediated gene replacement as a versatile tool to modify the PRV genome. Next, we used our new set of viral mutants and AAV vectors to conclude the indirect role of UL13 in PRV escape from latency in primary neurons, along with its spatial localization during retrograde capsid transport in axons. Based on these findings, we speculate that UL13 phosphorylates one or more tegument proteins, thereby priming these putative proteins to induce escape from genome silencing.
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- 2021
65. Diabetes and fractures: new evidence of atypical femoral fractures?
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Rasmussen, N H, Rasmussen, N H, Dal, J, de Vries, F, van den Bergh, J P, Jensen, M H, Vestergaard, P, Rasmussen, N H, Rasmussen, N H, Dal, J, de Vries, F, van den Bergh, J P, Jensen, M H, and Vestergaard, P
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Patients with diabetes have an increased risk of fractures. In this study, subtrochanteric and femoral shaft fractures were increased in patients with type 1 diabetes compared with the general population. In the light of this, more evidence points towards an association between diabetes and atypical femoral fractures.INTRODUCTION: Patients with diabetes have an increased risk of femoral fractures, but little is known about the risk of atypical femoral fractures (AFFs). The aim of this study was to identify the risk of subtrochanteric and femoral shaft (ST/FS) fractures and estimate the risk of AFFs in patients with type 1 (T1D) and type 2 diabetes (T2D).METHODS: From the nationwide Danish National Patient Register, we identified patients with T1D (n = 19,896), T2D (n = 312,188), and sex- and aged-matched controls without diabetes (n = 996,252) from the general population and all ST/FS fractures (n = 7509). Data were analyzed using a Cox proportional-hazards model and the incidence rate and rate ratio of ST/FS fractures were estimated.RESULTS: The incidence rate of ST/FS fractures in T1D was 52.14 events per 100,000 person years and 73.21 per 100,000 person years in T2D. T1D was associated with an increased risk of ST/FS (HR 2.07 (95% CI 1.68-2.56)), whereas T2D was not (HR 0.99 (95% CI 0.94-1.10)). Previous ST/FS fractures were associated with an increased risk of subsequent ST/FS fractures (HR 6.95 (95% CI 6.00-8.05)) and the use of bisphosphonates with an increased risk of ST/FS fractures (HR 1.72 (95% CI 1.54-1.91)).CONCLUSION: Patients with T1D have a higher risk of ST/FS fractures compared with sex- and age-matched controls. Since a proportion of ST/FS fractures are classified as AFFs, this could point towards the fact that AFFs also are increased in patients with T1D, but not T2D.
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- 2020
66. Characterization of pre-transplant psychosocial burden in an integrated national islet transplant program
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Liew, Aaron Y. L., Holmes-Truscott, Elizabeth, Flatt, Anneliese J. S., Bennett, Denise, Crookston, Robert, Pimkova, Mirka, Birtles, Linda, Casey, John, Pernet, Andrew, Wood, Ruth C., Choudhary, Pratik, Forbes, Shareen, Rutter, Martin K., Rosenthal, Miranda, Johnson, Paul, Shaw, James A. M., Speight, Jane, Liew, Aaron Y. L., Holmes-Truscott, Elizabeth, Flatt, Anneliese J. S., Bennett, Denise, Crookston, Robert, Pimkova, Mirka, Birtles, Linda, Casey, John, Pernet, Andrew, Wood, Ruth C., Choudhary, Pratik, Forbes, Shareen, Rutter, Martin K., Rosenthal, Miranda, Johnson, Paul, Shaw, James A. M., and Speight, Jane
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- 2020
67. Mitophagy protects beta cells from inflammatory damage in diabetes
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Sidarala, Vaibhav, Pearson, Gemma L., Parekh, Vishal S., Thompson, Benjamin, Christen, Lisa, Gingerich, Morgan A., Zhu, Jie, Stromer, Tracy, Ren, Jianhua, Reck, Emma C., Chai, Biaoxin, Corbett, John A., Mandrup-Poulsen, Thomas, Satin, Leslie S., Soleimanpour, Scott A., Sidarala, Vaibhav, Pearson, Gemma L., Parekh, Vishal S., Thompson, Benjamin, Christen, Lisa, Gingerich, Morgan A., Zhu, Jie, Stromer, Tracy, Ren, Jianhua, Reck, Emma C., Chai, Biaoxin, Corbett, John A., Mandrup-Poulsen, Thomas, Satin, Leslie S., and Soleimanpour, Scott A.
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Inflammatory damage contributes to beta cell failure in type 1 and 2 diabetes (T1D and T2D, respectively). Mitochondria are damaged by inflammatory signaling in beta cells, resulting in impaired bioenergetics and initiation of proapoptotic machinery. Hence, the identification of protective responses to inflammation could lead to new therapeutic targets. Here, we report that mitophagy serves as a protective response to inflammatory stress in both human and rodent beta cells. Utilizing in vivo mitophagy reporters, we observed that diabetogenic proinflammatory cytokines induced mitophagy in response to nitrosative/oxidative mitochondrial damage. Mitophagy-deficient II cells were sensitized to inflammatory stress, leading to the accumulation of fragmented dysfunctional mitochondria, increased beta cell death, and hyperglycemia. Overexpression of CLEC16A, a T1D gene and mitophagy regulator whose expression in islets is protective against T1D, ameliorated cytokine-induced human beta cell apoptosis. Thus, mitophagy promotes ti cell survival and prevents diabetes by countering inflammatory injury. Targeting this pathway has the potential to prevent beta cell failure in diabetes and may be beneficial in other inflammatory conditions.
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- 2020
68. Distinct alterations of gut morphology and microbiota characterize accelerated diabetes onset in nonobese diabetic mice
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Simon, Marie-Christine, Reinbeck, Anna Lena, Wessel, Corinna, Heindirk, Julia, Jelenik, Tomas, Kaul, Kirti, Arreguin-Cano, Juan, Strom, Alexander, Blaut, Michael, Backhed, Fredrik, Burkart, Volker, Roden, Michael, Simon, Marie-Christine, Reinbeck, Anna Lena, Wessel, Corinna, Heindirk, Julia, Jelenik, Tomas, Kaul, Kirti, Arreguin-Cano, Juan, Strom, Alexander, Blaut, Michael, Backhed, Fredrik, Burkart, Volker, and Roden, Michael
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The rising prevalence of type 1 diabetes (T1D) over the past decades has been linked to lifestyle changes, but the underlying mechanisms are largely unknown. Recent findings point to gut-associated mechanisms in the control of T1D pathogenesis. In nonobese diabetic (NOD) mice, a model of T1D, diabetes development accelerates after deletion of the Toll-like receptor 4 (TLR4). We hypothesized that altered intestinal functions contribute to metabolic alterations, which favor accelerated diabetes development in TLR4-deficient (TLR4(?/?)) NOD mice. In 70?90-day-old normoglycemic (prediabetic) female NOD TLR4(+/+) and NOD TLR4(?/?) mice, gut morphology and microbiome composition were analyzed. Parameters of lipid metabolism, glucose homeostasis, and mitochondrial respiratory activity were measured in vivo and ex vivo. Compared with NOD TLR4(+/+) mice, NOD TLR4(?/?) animals showed lower muscle mass of the small intestine, higher abundance of Bacteroidetes, and lower Firmicutes in the large intestine, along with lower levels of circulating short-chain fatty acids (SCFA). These changes are associated with higher body weight, hyperlipidemia, and severe insulin and glucose intolerance, all occurring before the onset of diabetes. These mice also exhibited insulin resistance?related abnormalities of energy metabolism, such as lower total respiratory exchange rates and higher hepatic oxidative capacity. Distinct alterations of gut morphology and microbiota composition associated with reduction of circulating SCFA may contribute to metabolic disorders promoting the progression of insulin-deficient diabetes/T1D development.
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- 2020
69. Hypoglycaemia and cardiac arrhythmias in diabetes
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Andersen, Andreas, Jørgensen, Peter G., Knop, Filip K., Vilsbøll, Tina, Andersen, Andreas, Jørgensen, Peter G., Knop, Filip K., and Vilsbøll, Tina
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Hypoglycaemia remains an inevitable risk in insulin-treated type 1 diabetes and type 2 diabetes and has been associated with multiple adverse outcomes. Whether hypoglycaemia is a cause of fatal cardiac arrhythmias in diabetes, or merely a marker of vulnerability, is still unknown. Since a pivotal report in 1991, hypoglycaemia has been suspected to induce cardiac arrhythmias in patients with type 1 diabetes, the so-called 'dead-in-bed syndrome'. This suspicion has subsequently been supported by the coexistence of an increased mortality and a three-fold increase in severe hypoglycaemia in patients with type 2 diabetes receiving intensive glucose-lowering treatment in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. Studies have investigated the association between hypoglycaemia-induced cardiac arrhythmias. In a rat-model, severe hypoglycaemia resulted in a specific pattern of cardiac arrhythmias including QT-prolongation, ventricular tachycardia, second- and third-degree AV block and ultimately cardiorespiratory arrest. In clinical studies of experimentally induced hypoglycaemia, QTc-prolongation, a risk factor of ventricular arrhythmias, is an almost consistent finding. The extent of QT-prolongation seems to be modified by several factors, including antecedent hypoglycaemia, diabetes duration and cardiac autonomic neuropathy. Observational studies indicate diurnal differences in the pattern of electrocardiographic alterations during hypoglycaemia with larger QTc-prolongations during daytime, whereas the risk of bradyarrhythmias may be increased during sleep. Daytime periods of hypoglycaemia are characterized by shorter duration, increased awareness and a larger increase in catecholamines. The counterregulatory response is reduced during nightly episodes of hypoglycaemia, resulting in prolonged periods of hypoglycaemia with multiple nadirs. An initial sympathetic activity at plasma glucose nadir is replaced by increased vagal activity, which re
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- 2020
70. New Insights into the Genetics of Latent Autoimmune Diabetes in Adults
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Andersen, Mette K. and Andersen, Mette K.
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Purpose of Review Diabetes is a spectrum of clinical manifestations, including latent autoimmune diabetes in adults (LADA). However, it has been questioned whether LADA exists or simply is a group of misclassified type 1 diabetes (T1D) and type 2 diabetes (T2D) patients. This review will provide an updated overview of the genetics of LADA, highlight what genetics tell us about LADA as a diabetes subtype, and point to future directions in the study of LADA. Recent Findings Recent studies have verified the genetic overlap between LADA and both T1D and T2D and have contributed identification of a novel LADA-specific locus, namely,PFKFB3, and subtype-specific signatures in the HLA region. Genetic risk scores comprising T1D-risk variants have been shown to be a promising tool for discriminating diabetes subtypes and identifying patients rapidly progressing to insulin dependence. Genetic data support the existence of LADA, but further studies are needed to fully determine the place of LADA in the diabetes spectrum.
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- 2020
71. Sweet dreams or bitter nightmare: A narrative review of 25 years of research on the role of sleep in diabetes and the contributions of behavioural science
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Nefs, G., Bazelmans, E., Donga, E., Tack, C. J., de Galan, B. E., Nefs, G., Bazelmans, E., Donga, E., Tack, C. J., and de Galan, B. E.
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The aim of this review was to provide an overview of developments, clinical implications and gaps in knowledge regarding the relationship between diabetes and sleep over the past 25 years, with special focus on contributions from the behavioural sciences. Multiple prospective observational and experimental studies have shown a link between suboptimal sleep and impaired glucose tolerance, decreased insulin sensitivity and the development of type 2 diabetes. While prevalence rates of suboptimal sleep vary widely according to definition, assessment and sample, suboptimal subjective sleep quality appears to be a common reality for one-third of people with type 1 diabetes and over half of people with type 2 diabetes. Both physiological and psychosocial factors may impair sleep in these groups. In turn, suboptimal sleep can negatively affect glycaemic outcomes directly or indirectly via suboptimal daytime functioning (energy, mood, cognition) and self-care behaviours. Technological devices supporting diabetes self-care may have both negative and positive effects. Diabetes and its treatment also affect the sleep of significant others. Research on the merits of interventions aimed at improving sleep for people with diabetes is in its infancy. Diabetes and sleep appear to be reciprocally related. Discussion of sleep deserves a central place in regular diabetes care. Multi-day, multi-method studies may shed more light on the complex relationship between sleep and diabetes at an individual level. Intervention studies are warranted to examine the potential of sleep interventions in improving outcomes for people with diabetes.
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- 2020
72. Empowering native adolescents: Responsibility for their health behaviors
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Anne Kenney, Marissa Begay, Rachel Chambers, Novalene Goklish, Dane Hautala, Leonela Nelson, Dike van de Mheen, Melissa L. Walls, Allison Barlow, Jennifer Richards, Nicole Neault, Raymond Reid, Summer Rosenstock, Verslaving, and Tranzo, Scientific center for care and wellbeing
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Gerontology ,Male ,AUTONOMY ,obesity ,Health (social science) ,Diabetes risk ,genetic structures ,Social Psychology ,Adolescent ,IMPACT ,health promotion ,Health Behavior ,CHILDREN ,Type 2 diabetes ,Young Adult ,Native Americans ,Diabetes mellitus ,Surveys and Questionnaires ,medicine ,Humans ,Baseline (configuration management) ,Child ,American Indian or Alaska Native ,TYPE-1 ,OVERWEIGHT ,diabetes ,Public Health, Environmental and Occupational Health ,YOUTH EMPOWERMENT ,medicine.disease ,adolescent health ,Obesity ,INSULIN ,Latent class model ,MANAGEMENT PROGRAM ,Health promotion ,Caregivers ,Diabetes Mellitus, Type 2 ,Empowerment ,Female ,Psychology ,DIABETES PREVENTION ,Adolescent health - Abstract
Objectives: In this study, we assess the impact of a home-based diabetes prevention program, Together on Diabetes (TOD), on adolescent responsibility-taking for tasks related to diabetes risk. Methods: Participants were Native American youth ages 10-19 with or at risk of type 2 diabetes who participated in a 12-session, 6-month diabetes prevention program with an adult caretaker. Assessments completed at baseline, 6-month, and 12-month follow-up include demographics and the Diabetes and Obesity Task Sharing (DOTS) Questionnaire. We used latent class analysis (LCA) at baseline to examine heterogeneity in DOTS responses. We identified 3 classes (adolescent, shared, caretaker). We used latent transition analysis to examine stability and change in latent status at baseline, 6- and 12-month follow-up. Results: At baseline, the mean age of participants was 13.6 years and 55.9% were boys. From baseline to 6-month follow-up, the adolescent class was most stable, whereas the shared and caretaker classes were less stable. For participants who transition from the adolescent class, most transition to shared class compared to caretaker class. Conclusions: TOD helps to empower Native American adolescents to take responsibility for their health and engage with their caregivers in these decisions.
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- 2021
73. Safety of alemtuzumab in a nationwide cohort of Finnish multiple sclerosis patients
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Juha Matti Seppä, Sakari Simula, Auli Verkkoniemi-Ahola, Marge Kartau, Riitta Ahmasalo, Liisa Luostarinen, Ilkka Pieninkeroinen, Hanna Kuusisto, Jukka T Saarinen, Tero Tapiola, M. Ukkonen, Anne M. Remes, Marianne Männikkö, Ilkka Rauma, Mervi Ryytty, Tiina Mustonen, Jussi O.T. Sipilä, Tampere University, Department of Neurosciences and Rehabilitation, Seinäjoen keskussairaala VA, Kanta-Häme Central Hospital Hämeenlinna, University of Helsinki, Neurologian yksikkö, HUS Neurocenter, HYKS erva, and Päijät-Häme Welfare Consortium
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Pediatrics ,medicine.medical_specialty ,Thrombotic thrombocytopenic purpura ,Autoimmunity ,3121 Internal medicine ,THERAPY ,3124 Neurology and psychiatry ,Drug-related side effects and adverse reactions ,Multiple sclerosis ,03 medical and health sciences ,Multiple Sclerosis, Relapsing-Remitting ,0302 clinical medicine ,medicine ,Humans ,030212 general & internal medicine ,Adverse effect ,AUTOIMMUNE-DISEASE ,Alemtuzumab ,Finland ,TYPE-1 ,Retrospective Studies ,Hemophagocytic lymphohistiocytosis ,Original Communication ,business.industry ,Incidence (epidemiology) ,Incidence ,3112 Neurosciences ,medicine.disease ,EFFICACY ,3. Good health ,Neurology ,Cohort ,Neurology (clinical) ,Safety ,business ,FOLLOW-UP ,030217 neurology & neurosurgery ,medicine.drug ,Case series - Abstract
Background Alemtuzumab is an effective disease-modifying therapy (DMT) for highly active multiple sclerosis (MS). However, safety concerns limit its use in clinical practice. Objectives To evaluate the safety of alemtuzumab in a nationwide cohort of Finnish MS patients. Methods In this retrospective case series study, we analyzed the data of all but two MS patients who had received alemtuzumab in Finland until 2019. Data were systematically collected from patient files. Results Altogether 121 patients were identified, most of whom had received previous DMTs (82.6%). Median follow-up time after treatment initiation was 30.3 months and exceeded 24 months in 78 patients. Infusion-associated reactions (IARs) were observed in 84.3%, 57.3%, and 57.1% of patients during alemtuzumab courses 1–3, respectively. Serious adverse events (SAEs) were observed in 32.2% of patients, serious IARs in 12.4% of patients, and SAEs other than IARs in 23.1% of patients. Autoimmune adverse events were observed in 30.6% of patients. One patient died of hemophagocytic lymphohistiocytosis, and one patient died of pneumonia. A previously unreported case of thrombotic thrombocytopenic purpura was documented. Conclusions SAEs were more frequent in the present cohort than in previous studies. Even though alemtuzumab is a highly effective therapy for MS, vigorous monitoring with a long enough follow-up time is advised.
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- 2021
74. Protein phosphatase 1 regulates atypical mitotic and meiotic division in Plasmodium sexual stages
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Mathieu Bollen, Rita Tewari, Ravish Rashpa, Mohammad Zeeshan, Andrew R. Bottrill, Arnab Pain, Anthony A. Holder, Amit Kumar Subudhi, David J. P. Ferguson, Sue Vaughan, Gursimran Kaur, Rajan Pandey, David S. Guttery, Raushan Nugmanova, Declan Brady, and Mathieu Brochet
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Life Sciences & Biomedicine - Other Topics ,Cell biology ,Plasmodium ,QH301-705.5 ,Molecular biology ,Protozoan Proteins ,Medicine (miscellaneous) ,Library science ,Mitosis ,FALCIPARUM ,Mosquito Vectors ,General Biochemistry, Genetics and Molecular Biology ,Article ,03 medical and health sciences ,0302 clinical medicine ,Political science ,Protein Phosphatase 1 ,parasitic diseases ,REVEALS ,BINDING ,CELL-CYCLE ,Biology (General) ,PHOSPHORYLATION ,Biology ,PP1-MEDIATED DEPHOSPHORYLATION ,TYPE-1 ,030304 developmental biology ,Cell Proliferation ,ddc:616 ,0303 health sciences ,Life Cycle Stages ,Science & Technology ,KINASES ,fungi ,3. Good health ,Malaria ,Multidisciplinary Sciences ,Meiosis ,MITOSIS ,Science & Technology - Other Topics ,GROWTH ,Core laboratory ,General Agricultural and Biological Sciences ,Life Sciences & Biomedicine ,030217 neurology & neurosurgery - Abstract
PP1 is a conserved eukaryotic serine/threonine phosphatase that regulates many aspects of mitosis and meiosis, often working in concert with other phosphatases, such as CDC14 and CDC25. The proliferative stages of the malaria parasite life cycle include sexual development within the mosquito vector, with male gamete formation characterized by an atypical rapid mitosis, consisting of three rounds of DNA synthesis, successive spindle formation with clustered kinetochores, and a meiotic stage during zygote to ookinete development following fertilization. It is unclear how PP1 is involved in these unusual processes. Using real-time live-cell and ultrastructural imaging, conditional gene knockdown, RNA-seq and proteomic approaches, we show that Plasmodium PP1 is implicated in both mitotic exit and, potentially, establishing cell polarity during zygote development in the mosquito midgut, suggesting that small molecule inhibitors of PP1 should be explored for blocking parasite transmission., Zeeshan et al. used real-time live-cell and ultrastructural imaging, conditional gene knockdown, RNA-seq and proteomic approaches to implicate Plasmodium PP1 in both mitotic exit and, potentially, establishing cell polarity during zygote development in the mosquito midgut. They suggest that small molecule inhibitors of PP1 should be explored for blocking parasite transmission.
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- 2021
75. An Unbiased Approach to Mapping the Signaling Network of the Pseudorabies Virus US3 Protein
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Herman W. Favoreel, Sandra Marmiroli, and Robert J. J. Jansens
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Microbiology (medical) ,Alphaherpesvirus ,Kinase ,Mass spectrometry ,Phosphoproteome ,PRV ,Pseudorabies virus ,US3 ,kinase ,viruses ,SINGLE GENES ,lcsh:Medicine ,macromolecular substances ,Biology ,Article ,ACTIN ,MAP1B PHOSPHORYLATION ,LAMIN A/C ,Gene expression ,Immunology and Allergy ,Veterinary Sciences ,Protein kinase A ,Molecular Biology ,Protein kinase B ,TYPE-1 ,mass spectrometry ,General Immunology and Microbiology ,ALPHAHERPESVIRUS ,IDENTIFICATION ,AKT ,lcsh:R ,Phosphoproteomics ,phosphoproteome ,pseudorabies virus ,Cell biology ,APOPTOSIS ,Infectious Diseases ,Viral replication ,Phosphorylation ,Lamin ,alphaherpesvirus - Abstract
The US3 serine/threonine protein kinase is conserved among the alphaherpesvirus family and represents an important virulence factor. US3 plays a role in viral nuclear egress, induces dramatic alterations of the cytoskeleton, represses apoptosis, enhances gene expression and modulates the immune response. Although several substrates of US3 have been identified, an unbiased screen to identify US3 phosphorylation targets has not yet been described. Here, we perform a shotgun and phosphoproteomics analysis of cells expressing the US3 protein of pseudorabies virus (PRV) to identify US3 phosphorylation targets in an unbiased way. We identified several cellular proteins that are differentially phosphorylated upon US3 expression and validated the phosphorylation of lamin A/C at serine 404, both in US3-transfected and PRV-infected cells. These results provide new insights into the signaling network of the US3 protein kinase and may serve as a basis for future research into the role of the US3 protein in the viral replication cycle.
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- 2020
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76. CirculatingType-1 anti-tumor CD4+ T cells are preferentially pro-apoptotic in cancer patients.
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Mandic, Maja, Taylor, Jennifer L., Wesa, Amy K., Storkus, Walter J., Moschos, Stergios, Kirkwood, John M., Kwok, William W., and Finke, James Harold
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CANCER patients ,T cells ,IMMUNOTHERAPY ,MELANOMA ,RENAL cell carcinoma ,PATIENTS - Abstract
Cancer patients frequently exhibit a deficiency in Type-1 (but not Type-2 or regulatory) CD4
+ T cell responses against tumor-associated antigens (TAA), which may limit protection against disease progression or responsiveness to immunotherapy in these individuals. Since such deficiency was acutely evident in patients with active disease (AD), where chronic stimulation of anti-tumor CD4+ T cells would be expected and activation-induced cell death may be prevalent, we employed MHC Class II-peptide tetramers to characterize the frequency and apoptotic status of TAA- vs. influenza (FluM1) virus-specific CD4+ T cells in the peripheral blood of HLA-DR*0401C patients with melanoma or renal cell carcinoma. We observed that Flu-specific CD4+ T cells ranged from 0.17 to 3.89%, while up to approximately 1% of CD4+ T cells reacted against individual TAA epitopes derived from the EphA2 or MAGE-6 proteins. The frequencies of EphA2 and MAGE-6-specific CD4+ T cells in patients were significantly correlated with AD and gender of the patient (i.e., females>males), while frequencies of Flu-specific CD4+ T cells were distributed within a normal range in all patients. Notably, patient CD4+ T cells reactive with MHC class II-TAA (but not MHC class II-Flu) tetramers were significantly enriched for a proapoptotic (Annexin-V+ ) phenotype, particularly amongst the Th1 (T-bet+ ) subset. These results suggest that the preferential sensitivity of TAA (but not viral)-specific CD4+ Th1 cells to apoptosis in melanoma patients with AD will need to be overcome for optimal clinical benefit of immunotherapeutic approaches to be realized. [ABSTRACT FROM AUTHOR]- Published
- 2014
- Full Text
- View/download PDF
77. Known-key distinguishers on type-1 Feistel scheme and near-collision attacks on its hashing modes.
- Author
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Dong, Le, Wu, Wenling, Wu, Shuang, and Zou, Jian
- Abstract
We present some known-key distinguishers for a type-1 Feistel scheme with a permutation as the round function. To be more specific, the 29-round known-key truncated differential distinguishers are given for the 256-bit type-1 Feistel scheme with an SP (substitution-permutation) round function by using the rebound attack, where the S -boxes have perfect differential and linear properties and the linear diffusion layer has a maximum branch number. For two 128-bit versions, the distinguishers can be applied on 25-round structures. Based on these distinguishers, we construct near-collision attacks on these schemes with MMO (Matyas-Meyer-Oseas) and MP (Miyaguchi-Preneel) hashing modes, and propose the 26-round and 22-round near-collision attacks for two 256-bit schemes and two 128-bit schemes, respectively. We apply the near-collision attack on MAME and obtain a 26-round near-collision attack. Using the algebraic degree and some integral properties, we prove the correctness of the 31-round known-key integral distinguisher proposed by Sasaki et al. We show that if the round function is a permutation, the integral distinguisher is suitable for a type-1 Feistel scheme of any size. [ABSTRACT FROM AUTHOR]
- Published
- 2014
- Full Text
- View/download PDF
78. Postprandial Glucose Spikes, an Important Contributor to Cardiovascular Disease in Diabetes?
- Subjects
GLUCAGON-LIKE PEPTIDE-1 ,hyperglyacemia ,hematopoeis ,diabete ,inflammation ,RISK-FACTOR ,HYPERGLYCEMIA ,GLYCEMIC CONTROL ,HUMAN ATHEROSCLEROTIC PLAQUES ,GLYCATION END-PRODUCTS ,FOLLOW-UP ,PLASMA-LEVELS ,RAGE (receptor for advanced glycation end products) ,TYPE-1 ,ALL-CAUSE MORTALITY - Abstract
Clinical trials investigating whether glucose lowering treatment reduces the risk of CVD in diabetes have thus far yielded mixed results. However, this doesn't rule out the possibility of hyperglycemia playing a major causal role in promoting CVD or elevating CVD risk. In fact, lowering glucose appears to promote some beneficial long-term effects, and continuous glucose monitoring devices have revealed that postprandial spikes of hyperglycemia occur frequently, and may be an important determinant of CVD risk. It is proposed that these short, intermittent bursts of hyperglycemia may have detrimental effects on several organ systems including the vasculature and the hematopoietic system collectively contributing to the state of elevated CVD risk in diabetes. In this review, we summarize the potential mechanisms through which hyperglycemic spikes may increase atherosclerosis and how new and emerging interventions may combat this.
- Published
- 2020
79. Postprandial Glucose Spikes, an Important Contributor to Cardiovascular Disease in Diabetes?
- Author
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Andrew J. Murphy, Michael J Kraakman, Prabhakara R Nagareddy, Nordin M J Hanssen, Michelle C Flynn, and Casper G. Schalkwijk
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0301 basic medicine ,lcsh:Diseases of the circulatory (Cardiovascular) system ,Inflammation ,Disease ,Review ,030204 cardiovascular system & hematology ,Cardiovascular Medicine ,Bioinformatics ,03 medical and health sciences ,0302 clinical medicine ,hematopoeis ,RISK-FACTOR ,HYPERGLYCEMIA ,Diabetes mellitus ,GLYCEMIC CONTROL ,Medicine ,HUMAN ATHEROSCLEROTIC PLAQUES ,PLASMA-LEVELS ,Organ system ,TYPE-1 ,Uncategorized ,ALL-CAUSE MORTALITY ,Glucose lowering ,GLUCAGON-LIKE PEPTIDE-1 ,business.industry ,Continuous glucose monitoring ,medicine.disease ,Clinical trial ,hyperglyacemia ,030104 developmental biology ,Postprandial ,lcsh:RC666-701 ,diabete ,inflammation ,medicine.symptom ,Cardiology and Cardiovascular Medicine ,business ,GLYCATION END-PRODUCTS ,FOLLOW-UP ,RAGE (receptor for advanced glycation end products) - Abstract
Clinical trials investigating whether glucose lowering treatment reduces the risk of CVD in diabetes have thus far yielded mixed results. However, this doesn't rule out the possibility of hyperglycemia playing a major causal role in promoting CVD or elevating CVD risk. In fact, lowering glucose appears to promote some beneficial long-term effects, and continuous glucose monitoring devices have revealed that postprandial spikes of hyperglycemia occur frequently, and may be an important determinant of CVD risk. It is proposed that these short, intermittent bursts of hyperglycemia may have detrimental effects on several organ systems including the vasculature and the hematopoietic system collectively contributing to the state of elevated CVD risk in diabetes. In this review, we summarize the potential mechanisms through which hyperglycemic spikes may increase atherosclerosis and how new and emerging interventions may combat this.
- Published
- 2020
80. Mitophagy protects beta cells from inflammatory damage in diabetes
- Author
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John A. Corbett, Emma C. Reck, Scott A. Soleimanpour, Biaoxin Chai, Morgan A. Gingerich, Benjamin Thompson, Lisa Christen, Thomas Mandrup-Poulsen, Vishal S. Parekh, Gemma L. Pearson, Vaibhav Sidarala, Leslie S. Satin, Jianhua Ren, Jie Zhu, and Tracy Stromer
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0301 basic medicine ,Male ,Cell ,Regulator ,lcsh:Medicine ,Apoptosis ,Mitochondrion ,MITOCHONDRIAL ,Mice ,0302 clinical medicine ,Endocrinology ,Insulin-Secreting Cells ,Mitophagy ,Medicine ,TRANSCRIPTION ,Chemistry ,Diabetes ,General Medicine ,Cell biology ,Mitochondria ,medicine.anatomical_structure ,ISLETS ,030220 oncology & carcinogenesis ,AUTOPHAGY ,Female ,medicine.symptom ,Research Article ,Signal Transduction ,Programmed cell death ,CLEC16A ,Monosaccharide Transport Proteins ,Cell Survival ,Primary Cell Culture ,Inflammation ,Oxidative phosphorylation ,Protective Agents ,MECHANISMS ,Proinflammatory cytokine ,Diabetes Complications ,03 medical and health sciences ,Diabetes mellitus ,Diabetes Mellitus ,Animals ,Humans ,Lectins, C-Type ,TYPE-1 ,ELIMINATION ,NITRIC-OXIDE ,business.industry ,lcsh:R ,medicine.disease ,Apoptosis survival pathways ,Mice, Inbred C57BL ,Disease Models, Animal ,Oxidative Stress ,030104 developmental biology ,Diabetes Mellitus, Type 1 ,Diabetes Mellitus, Type 2 ,Cancer research ,MORPHOLOGY ,business - Abstract
Inflammatory damage contributes to β-cell failure in type 1 and 2 diabetes (T1D and T2D). Mitochondria are damaged by inflammatory signaling in β-cells, resulting in impaired bioenergetics and initiation of pro-apoptotic machinery. Hence, the identification of protective responses to inflammation could lead to new therapeutic targets. Here we report that mitophagy serves as a protective response to inflammatory stress in both human and rodent β-cells. Utilizingin vivomitophagy reporters, we observed that diabetogenic pro-inflammatory cytokines induced mitophagy in response to nitrosative/oxidative mitochondrial damage. Mitophagy-deficient β-cells were sensitized to inflammatory stress, leading to the accumulation of fragmented dysfunctional mitochondria, increased β-cell death, and hyperglycemia. Overexpression ofCLEC16A, a T1D gene and mitophagy regulator whose expression in islets is protective against T1D, ameliorated cytokine-induced human β-cell apoptosis. Thus, mitophagy promotes β-cell survival and prevents diabetes by countering inflammatory injury. Targeting this pathway has the potential to prevent β-cell failure in diabetes and may be beneficial in other inflammatory conditions.
- Published
- 2020
81. Using Person-Reported Outcomes (PROs) to Motivate Young People with Diabetes
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Maartje de Wit, Judith Versloot, Eveline R. Goethals, and Ian Zenlea
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Blood Glucose ,Person-reported outcomes ,Adolescent ,Endocrinology, Diabetes and Metabolism ,media_common.quotation_subject ,030209 endocrinology & metabolism ,Context (language use) ,Psychosocial Aspects (SS Jaser, Section Editor) ,Endocrinology & Metabolism ,03 medical and health sciences ,PROMs ,0302 clinical medicine ,Nursing ,QUALITY-OF-LIFE ,Diabetes mellitus ,ADOLESCENTS ,IMPLEMENTATION ,Internal Medicine ,medicine ,Diabetes Mellitus ,Humans ,Conversation ,030212 general & internal medicine ,Patient Reported Outcome Measures ,Clinical care ,PERSPECTIVE ,TYPE-1 ,Glycemic ,media_common ,Type 1 diabetes ,Motivation ,Science & Technology ,business.industry ,Outcome measures ,RANDOMIZED CONTROLLED-TRIAL ,CARE ,EFFICACY ,medicine.disease ,Life domain ,WELL ,Self Care ,PROs ,Young people ,business ,Life Sciences & Biomedicine ,INTERVENTION - Abstract
Purpose of ReviewThis manuscript describes how person-reported outcomes (PROs) can be utilized in care for young people with diabetes in the context of motivation.Recent FindingsThe use of person-reported outcome measures (PROMS) in clinical care is feasible and acceptable, and helps focus the clinical encounter on life domains important to the person with diabetes. Results with regard to impact on self-management and glycemic outcomes are limited. Motivation is an important factor for self-management. Based on self-determination theory, autonomy-supportive, person-centered, and collaborative communication by diabetes care providers is associated with better outcomes. PROMs can facilitate this conversation.SummaryUnderstanding of youth motivation for maintaining or improving self-management behaviors requires a person-centered approach. PROMs can be used to facilitate an autonomy-supportive and person-centered conversation in clinical care. Training diabetes care providers in autonomy-supportive, person-centered conversation skills to discuss PROs might help to tap into youth’s motivation, but further research is needed.
- Published
- 2020
82. Can Stem Cells Beat COVID-19: Advancing Stem Cells and Extracellular Vesicles Toward Mainstream Medicine for Lung Injuries Associated With SARS-CoV-2 Infections
- Author
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Wojciech Chrzanowski, Sally Yunsun Kim, and Lana McClements
- Subjects
0301 basic medicine ,medicine.medical_treatment ,02 engineering and technology ,Disease ,CORONAVIRUS ,Bioinformatics ,THERAPY ,stem cell therapy ,0903 Biomedical Engineering ,Medicine ,Bioengineering and Biotechnology ,Stem-cell therapy ,021001 nanoscience & nanotechnology ,Multidisciplinary Sciences ,Perspective ,Science & Technology - Other Topics ,Stem cell ,0210 nano-technology ,extracellular vesicles ,Life Sciences & Biomedicine ,Biotechnology ,Histology ,lcsh:Biotechnology ,0699 Other Biological Sciences ,Biomedical Engineering ,Bioengineering ,MESENCHYMAL STROMAL CELLS ,03 medical and health sciences ,lcsh:TP248.13-248.65 ,TYPE-1 ,SARS ,Science & Technology ,business.industry ,SARS-CoV-2 ,1004 Medical Biotechnology ,Coronavirus (2019-nCoV) ,Mesenchymal stem cell ,COVID-19 ,medicine.disease ,Microvesicles ,Review article ,lung injuries ,Clinical trial ,Coronavirus ,stem cell ,030104 developmental biology ,Biotechnology & Applied Microbiology ,0699 Other Biological Sciences, 0903 Biomedical Engineering, 1004 Medical Biotechnology ,business ,Cytokine storm ,ACUTE RESPIRATORY SYNDROME - Abstract
A number of medicines are currently under investigation for the treatment of COVID-19 disease including anti-viral, anti-malarial, and anti-inflammatory agents. While these treatments can improve patient's recovery and survival, these therapeutic strategies do not lead to unequivocal restoration of the lung damage inflicted by this disease. Stem cell therapies and, more recently, their secreted extracellular vesicles (EVs), are emerging as new promising treatments, which could attenuate inflammation but also regenerate the lung damage caused by COVID-19. Stem cells exert their immunomodulatory, anti-oxidant, and reparative therapeutic effects likely through their EVs, and therefore, could be beneficial, alone or in combination with other therapeutic agents, in people with COVID-19. In this review article, we outline the mechanisms of cytokine storm and lung damage caused by SARS-CoV-2 virus leading to COVID-19 disease and how mesenchymal stem cells (MSCs) and their secreted EVs can be utilized to tackle this damage by harnessing their regenerative properties, which gives them potential enhanced clinical utility compared to other investigated pharmacological treatments. There are currently 17 clinical trials evaluating the therapeutic potential of MSCs for the treatment of COVID-19, the majority of which are administered intravenously with only one clinical trial testing MSC-derived exosomes via inhalation route. While we wait for the outcomes from these trials to be reported, here we emphasize opportunities and risks associated with these therapies, as well as delineate the major roadblocks to progressing these promising curative therapies toward mainstream treatment for COVID-19.
- Published
- 2020
83. Dried blood spot versus venous blood sampling for phenylalanine and tyrosine
- Author
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Wiggert G. van Ginkel, Esther van Dam, Martijn Koehorst, Hermi A. Kingma, Francjan J. van Spronsen, Kimber van Vliet, Pim de Blaauw, M. Rebecca Heiner-Fokkema, and Center for Liver, Digestive and Metabolic Diseases (CLDM)
- Subjects
0301 basic medicine ,Tandem mass spectrometry ,Phenylalanine ,lcsh:Medicine ,INFANTS ,030105 genetics & heredity ,behavioral disciplines and activities ,Tyrosinemia ,03 medical and health sciences ,Dried blood spots ,Phenylketonurias ,medicine ,Humans ,Pharmacology (medical) ,Tyrosine ,Bland–Altman plot ,Amino Acids ,TANDEM MASS-SPECTROMETRY ,PHENYLKETONURIA ,Genetics (clinical) ,TYPE-1 ,Chromatography ,Chemistry ,Research ,lcsh:R ,General Medicine ,Heparin ,Venous blood ,medicine.disease ,EDTA plasma ,Dried blood spot ,nervous system diseases ,030104 developmental biology ,surgical procedures, operative ,nervous system ,Dried Blood Spot Testing ,ION-EXCHANGE CHROMATOGRAPHY ,Lithium heparin plasma ,Blood drawing ,medicine.drug - Abstract
Background This study investigated the agreement between various dried blood spot (DBS) and venous blood sample measurements of phenylalanine and tyrosine concentrations in Phenylketonuria (PKU) and Tyrosinemia type 1 (TT1) patients. Study design Phenylalanine and tyrosine concentrations were studied in 45 PKU/TT1 patients in plasma from venous blood in lithium heparin (LH) and EDTA tubes; venous blood from LH and EDTA tubes on a DBS card; venous blood directly on a DBS card; and capillary blood on a DBS card. Plasma was analyzed with an amino acid analyzer and DBS were analyzed with liquid chromatography-mass spectrometry. Agreement between different methods was assessed using Passing and Bablok fit and Bland Altman analyses. Results In general, phenylalanine concentrations in LH plasma were comparable to capillary DBS, whereas tyrosine concentrations were slightly higher in LH plasma (constant bias of 6.4 μmol/L). However, in the low phenylalanine range, most samples had higher phenylalanine concentrations in DBS compared to LH plasma. Remarkably, phenylalanine and tyrosine in EDTA plasma were higher compared to all other samples (slopes ranging from 7 to 12%). No differences were observed when comparing capillary DBS to other DBS. Conclusions Overall agreement between plasma and DBS is good. However, bias is specimen- (LH vs EDTA), and possibly concentration- (low phenylalanine) dependent. Because of the overall good agreement, we recommend the use of a DBS-plasma correction factor for DBS measurement. Each laboratory should determine their own factor dependent on filter card type, extraction and calibration protocols taking the LH plasma values as gold standard.
- Published
- 2020
84. Stable Monomeric Insulin Formulations Enabled by Supramolecular PEGylation of Insulin Analogues
- Author
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Anton A. A. Smith, Joseph L. Mann, Caitlin L. Maikawa, Lei Zou, Eric A. Appel, Matthew J. Webber, and Catherine M. Meis
- Subjects
MECHANISM ,insulin ,medicine.medical_treatment ,Supramolecular chemistry ,Pharmaceutical Science ,Medicine (miscellaneous) ,Excipient ,AQUEOUS-SOLUTION ,Article ,THERAPIES ,chemistry.chemical_compound ,Diabetes mellitus ,medicine ,Pharmacology (medical) ,polymers ,TYPE-1 ,Genetics (clinical) ,Pharmacology ,chemistry.chemical_classification ,diabetes ,STABILITY ,Chemistry ,Insulin ,Biochemistry (medical) ,PEGylation ,RECOGNITION ,PEPTIDES ,medicine.disease ,Combinatorial chemistry ,SELF-ASSOCIATION ,Amino acid ,Monomer ,drug delivery ,Drug delivery ,FIBRILLATION ,PRAMLINTIDE ,supramolecular ,medicine.drug - Abstract
Current "fast-acting" insulin analogues contain amino acid modifications meant to inhibit dimer formation and shift the equilibrium of association states toward the monomeric state. However, the insulin monomer is highly unstable and current formulation techniques require insulin to primarily exist as hexamers to prevent aggregation into inactive and immunogenic amyloids. Insulin formulation excipients have thus been traditionally selected to promote insulin association into the hexameric form to enhance formulation stability. This study exploits a novel excipient for the supramolecular PEGylation of insulin analogues, including aspart and lispro, to enhance the stability and maximize the prevalence of insulin monomers in formulation. Using multiple techniques, it is demonstrated that judicious choice of formulation excipients (tonicity agents and parenteral preservatives) enables insulin analogue formulations with 70-80% monomer and supramolecular PEGylation imbued stability under stressed aging for over 100 h without altering the insulin association state. Comparatively, commercial "fast-acting" formulations contain less than 1% monomer and remain stable for only 10 h under the same stressed aging conditions. This simple and effective formulation approach shows promise for next-generation ultrafast insulin formulations with a short duration of action that can reduce the risk of post-prandial hypoglycemia in the treatment of diabetes.
- Published
- 2020
85. Fungal Dysbiosis and Intestinal Inflammation in Children With Beta-Cell Autoimmunity
- Author
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Jarno Honkanen, Arja Vuorela, Daniel Muthas, Laura Orivuori, Kristiina Luopajärvi, Mysore Vishakante Gowda Tejesvi, Anton Lavrinienko, Anna Maria Pirttilä, Christopher L. Fogarty, Taina Härkönen, Jorma Ilonen, Terhi Ruohtula, Mikael Knip, Janne J. Koskimäki, Outi Vaarala, HUS Children and Adolescents, Clinicum, Faculty of Medicine, University of Helsinki, Children's Hospital, Helsinki University Hospital Area, HUS Internal Medicine and Rehabilitation, HUS Abdominal Center, CAMM - Research Program for Clinical and Molecular Metabolism, Research Services, and Research Group Knip
- Subjects
Male ,0301 basic medicine ,beta-Defensins ,type 1 diabetes ,suolistomikrobisto ,Autoimmunity ,Gut flora ,medicine.disease_cause ,autoimmuniteetti ,Feces ,0302 clinical medicine ,autoimmuunisairaudet ,Insulin-Secreting Cells ,HLA-DQ beta-Chains ,Immunology and Allergy ,Medicine ,Child ,Finland ,Original Research ,Candida ,2. Zero hunger ,RISK ,MUCOSA ,tulehdus ,biology ,GUT MICROBIOTA ,dysbiosis ,Fungal antigen ,3. Good health ,Child, Preschool ,gut ,CATHELICIDIN LL-37 ,Female ,medicine.symptom ,lcsh:Immunologic diseases. Allergy ,Adolescent ,Immunology ,Inflammation ,IMMUNITY ,03 medical and health sciences ,mycobiome ,Saccharomyces ,SEROCONVERSION ,Humans ,PERMEABILITY ,Antibodies, Fungal ,TYPE-1 ,Autoantibodies ,Type 1 diabetes ,business.industry ,nuoruustyypin diabetes ,Autoantibody ,medicine.disease ,biology.organism_classification ,Diabetes Mellitus, Type 1 ,030104 developmental biology ,Mycoses ,hiivasienet ,inflammation ,3121 General medicine, internal medicine and other clinical medicine ,ANTIBODIES ,ONSET ,3111 Biomedicine ,Calprotectin ,business ,lcsh:RC581-607 ,Dysbiosis ,030215 immunology - Abstract
Although gut bacterial dysbiosis is recognized as a regulator of beta-cell autoimmunity, no data is available on fungal dysbiosis in the children at the risk of type 1 diabetes (T1D). We hypothesized that the co-occurrence of fungal and bacterial dysbiosis contributes to the intestinal inflammation and autoimmune destruction of insulin-producing beta-cells in T1D. Fecal and blood samples were collected from 26 children tested positive for at least one diabetes-associated autoantibody (IAA, GADA, IA-2A or ICA) and matched autoantibody-negative children with HLA-conferred susceptibility to T1D (matched for HLA-DQB1 haplotype, age, gender and early childhood nutrition). Bacterial 16S and fungal ITS2 sequencing, and analyses of the markers of intestinal inflammation, namely fecal human beta-defensin-2 (HBD2), calprotectin and secretory total IgA, were performed. Anti-Saccharomyces cerevisiae antibodies (ASCA) and circulating cytokines, IFNG, IL-17 and IL-22, were studied. After these analyses, the children were followed for development of clinical T1D (median 8 years and 8 months). Nine autoantibody positive children were diagnosed with T1D, whereas none of the autoantibody negative children developed T1D during the follow-up. Fungal dysbiosis, characterized by high abundance of fecal Saccharomyces and Candida, was found in the progressors, i.e., children with beta-cell autoimmunity who during the follow-up progressed to clinical T1D. These children showed also bacterial dysbiosis, i.e., increased Bacteroidales and Clostridiales ratio, which was, however, found also in the non-progressors, and is thus a common nominator in the children with beta-cell autoimmunity. Furthermore, the progressors showed markers of intestinal inflammation detected as increased levels of fecal HBD2 and ASCA IgG to fungal antigens. We conclude that the fungal and bacterial dysbiosis, and intestinal inflammation are associated with the development of T1D in children with beta-cell autoimmunity.
- Published
- 2020
86. 17β-Hydroxysteroid dehydrogenase 1:2 and breast cancer recurrence:a Danish population-based study
- Author
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Sinna Pilgaard Ulrichsen, Henrik Toft Sørensen, Lauren E. McCullough, Michael Goodman, Kristina B. Christensen, Kristina Lystlund Lauridsen, Per Damkier, Rami Yacoub, Lance A. Waller, Timothy L. Lash, Thomas P. Ahern, Bent Ejlertsen, Deirdre Cronin-Fenton, Peer Christiansen, Lindsay J Collin, and Stephen Hamilton-Dutoit
- Subjects
Oncology ,Denmark ,030218 nuclear medicine & medical imaging ,Estradiol Dehydrogenases ,0302 clinical medicine ,Hydroxysteroid dehydrogenase ,skin and connective tissue diseases ,ESTRADIOL ,Breast cancer recurrence ,Incidence ,Incidence (epidemiology) ,Hematology ,General Medicine ,Middle Aged ,Prognosis ,PREDICTS ,ESTROGEN ,030220 oncology & carcinogenesis ,Female ,hormones, hormone substitutes, and hormone antagonists ,medicine.drug ,Adult ,EXPRESSION ,medicine.medical_specialty ,endocrine system ,Antineoplastic Agents, Hormonal ,medicine.drug_class ,Breast Neoplasms ,Malignancy ,Article ,03 medical and health sciences ,Breast cancer ,Internal medicine ,Biomarkers, Tumor ,medicine ,Humans ,Radiology, Nuclear Medicine and imaging ,TAMOXIFEN ,TYPE-1 ,Aged ,ENDOCRINE THERAPY ,business.industry ,Case-control study ,medicine.disease ,Tamoxifen ,Estrogen ,COOPERATIVE GROUP DBCG ,Case-Control Studies ,DEHYDROGENASES ,Neoplasm Recurrence, Local ,business ,Follow-Up Studies - Abstract
BACKGROUND: Approximately 20–40% of patients diagnosed with breast cancer will experience a recurrence up to 20 years after their original diagnosis. 17?-hydroxysteroid dehydrogenase 1 and 2 (HSD17B1 and HSD17B2, respectively) regulate intratumoral concentrations of oestradiol, which promotes growth and proliferation of hormone dependent tumours. Breast carcinomas with increased HSD17B1, without a corresponding increase in HSD17B2, expression may become resistant to tamoxifen therapy by producing locally higher concentrations of oestradiol, which compete with tamoxifen and its metabolites for binding to the oestrogen receptor (ER). MATERIALS AND METHODS: In this population-based case-control study, we included women diagnosed with stage I–III breast cancer between 1985 and 2001, aged 35–69 years, registered in the Danish Breast Cancer Group. We identified 541 cases of breast cancer recurrence among women with ER positive disease who were treated with tamoxifen for at least 1 year (ER+TAM+). We also enrolled 300 breast cancer recurrence cases among women with ER negative disease, not treated with tamoxifen, who survived at least 1 year (ER?/TAM?). Controls were recurrence-free breast cancer patients at the time of case diagnosis, matched to recurrence cases on ER/TAM status, date of surgery, menopausal status, stage, and county or residence. Expression of HSD17B1 and HSD17B2 were measured by immunohistochemistry on tissue microarrays. We fit logistic regression models to compute odds ratios (ORs) and 95% confidence intervals (CIs) associating the HSD17B1:HSD17B2 ratio (>1 vs. ?1)—and each enzyme’s independent expression—with recurrence. RESULTS: We found no association between the HSD17B1:HSD17B2 ratio and breast cancer recurrence in either ER/TAM stratum (ER+/TAM+: OR=1.03, 95% CI: 0.78, 1.40; ER?/TAM?: OR=1.02, 95% CI: 0.77, 1.19). Associations for expression of each individual enzyme were also near null. CONCLUSION: The ratio of HSD17B1 expression to HSD17B2 expression was not associated with breast cancer recurrence in this study.
- Published
- 2020
87. Tryptophan Trimers and Tetramers Inhibit Dengue and Zika Virus Replication by Interfering with Viral Attachment Processes
- Author
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Dominique Schols, Antonios Fikatas, Peter Vervaeke, Olaia Martí-Marí, María-José Camarasa, Christophe Pannecouque, Belén Martínez-Gualda, Eef Meyen, Sam Noppen, Ana San-Félix, Research Foundation - Flanders, Ministerio de Economía y Competitividad (España), Ministerio de Ciencia, Innovación y Universidades (España), and Consejo Superior de Investigaciones Científicas (España)
- Subjects
MECHANISM ,SPR, Zika, antivirals, dengue, envelope protein, virus attachme ,SPR ,Dengue virus ,Virus Replication ,medicine.disease_cause ,DISEASE ,Dengue fever ,Zika virus ,antivirals ,0302 clinical medicine ,Viral Envelope Proteins ,DOMAIN-III ,Chlorocebus aethiops ,HISTORY ,DENDRIMERS ,Pharmacology (medical) ,Pharmacology & Pharmacy ,030212 general & internal medicine ,Host cell membrane ,0303 health sciences ,biology ,Chemistry ,Tryptophan ,Infectious Diseases ,HUMAN-IMMUNODEFICIENCY-VIRUS ,Life Sciences & Biomedicine ,TRANSMISSION ,Serogroup ,Antiviral Agents ,Microbiology ,SEQUENCE ,Virus ,Structure-Activity Relationship ,03 medical and health sciences ,Zika ,Viral envelope ,Human Umbilical Vein Endothelial Cells ,medicine ,Animals ,Humans ,Vero Cells ,TYPE-1 ,030304 developmental biology ,Pharmacology ,Science & Technology ,HIV ,Zika Virus ,Dengue Virus ,medicine.disease ,biology.organism_classification ,dengue ,Virology ,In vitro ,envelope protein ,virus attachment - Abstract
Here, we report a class of tryptophan trimers and tetramers that inhibit (at low micromolar range) dengue and Zika virus infection in vitro. These compounds (AL family) have three or four peripheral tryptophan moieties directly linked to a central scaffold through their amino groups; thus, their carboxylic acid groups are free and exposed to the periphery. Structure-activity relationship (SAR) studies demonstrated that the presence of extra phenyl rings with substituents other than COOH at the N1 or C2 position of the indole side chain is a requisite for the antiviral activity against both viruses. The molecules showed potent antiviral activity, with low cytotoxicity, when evaluated on different cell lines. Moreover, they were active against laboratory and clinical strains of all four serotypes of dengue virus as well as a selected group of Zika virus strains. Additional mechanistic studies performed with the two most potent compounds (AL439 and AL440) demonstrated an interaction with the viral envelope glycoprotein (domain III) of dengue 2 virus, preventing virus attachment to the host cell membrane. Since no antiviral agent is approved at the moment against these two flaviviruses, further pharmacokinetic studies with these molecules are needed for their development as future therapeutic/prophylactic drugs., This work was supported by KU Leuven and the Fonds Wetenschappelijk Onder-zoek (FWO grant PF/10/018), the Spanish MINECO (projects SAF2015-64629-C2-1-Rand SAF2015-64629-C2-2-R [MINECO/FEDER]), and the Spanish Agencia EstatalConsejo Superior de Investigaciones Científicas (CSIC; projects CSIC201680E079 and201980E028). The Spanish MEC/MINECO is also acknowledged for grants to B.M.-G.and O.M.-M
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- 2020
88. A Mobile App for Longterm Monitoring of Narcolepsy Symptoms: Design, Development, and Evaluation
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Laury Quaedackers, Merel M. van Gilst, Sigrid Pillen, Panos Markopoulos, Sebastiaan Overeem, Nikolaos Batalas, Gert Jan Lammers, Jan de Wit, Language, Communication and Cognition, Future Everyday, Signal Processing Systems, Eindhoven MedTech Innovation Center, Biomedical Diagnostics Lab, EAISI High Tech Systems, and EAISI Health
- Subjects
medicine.medical_specialty ,Cataplexy ,DISORDERS ,Excessive daytime sleepiness ,Health Informatics ,Information technology ,03 medical and health sciences ,0302 clinical medicine ,DEFICITS ,Surveys and Questionnaires ,medicine ,Humans ,SLEEPINESS ,PROM ,SCALE ,TYPE-1 ,Narcolepsy ,Original Paper ,Sleep disorder ,patient-related outcome measure ,outcome measure ,business.industry ,ATTENTION ,Panic ,Cognition ,medicine.disease ,T58.5-58.64 ,Mobile Applications ,030228 respiratory system ,mHealth ,Physical therapy ,hypersomnia ,Anxiety ,medicine.symptom ,Public aspects of medicine ,RA1-1270 ,Sleep ,business ,BURDEN ,CATAPLEXY ,symptom monitoring ,Sleep paralysis ,030217 neurology & neurosurgery - Abstract
BackgroundNarcolepsy is a chronic sleep disorder with a broad variety of symptoms. Although narcolepsy is primarily characterized by excessive daytime sleepiness and cataplexy (loss of muscle control triggered by emotions), patients may suffer from hypnagogic hallucinations, sleep paralysis, and fragmented night sleep. However, the spectrum of narcolepsy also includes symptoms not related to sleep, such as cognitive or psychiatric problems. Symptoms vary greatly among patients and day-to-day variance can be considerable. Available narcolepsy questionnaires do not cover the whole symptom spectrum and may not capture symptom variability. Therefore, there is a clinical need for tools to monitor narcolepsy symptoms over time to evaluate their burden and the effect of treatment.ObjectiveThis study aimed to describe the design, development, implementation, and evaluation of the Narcolepsy Monitor, a companion app for long-term symptom monitoring in narcolepsy patients.MethodsAfter several iterations during which content, interaction design, data management, and security were critically evaluated, a complete version of the app was built. The Narcolepsy Monitor allows patients to report a broad spectrum of experienced symptoms and rate their severity based on the level of burden that each symptom imposes. The app emphasizes the reporting of changes in relative severity of the symptoms. A total of 7 patients with narcolepsy were recruited and asked to use the app for 30 days. Evaluation was done by using in-depth interviews and user experience questionnaire.ResultsWe designed and developed a final version of the Narcolepsy Monitor after which user evaluation took place. Patients used the app on an average of 45.3 (SD 19.2) days. The app was opened on 35% of those days. Daytime sleepiness was the most dynamic symptom, with a mean number of changes of 5.5 (SD 3.7) per month, in contrast to feelings of anxiety or panic, which was only moved 0.3 (SD 0.7) times per month. Mean symptom scores were highest for daytime sleepiness (1.8 [SD 1.0]), followed by lack of energy (1.6 [SD 1.4]) and often awake at night (1.5 [SD 1.0]). The personal in-depth interviews revealed 3 major themes: (1) reasons to use, (2) usability, and (3) features. Overall, patients appreciated the concept of ranking symptoms on subjective burden and found the app easy to use.ConclusionsThe Narcolepsy Monitor appears to be a helpful tool to gain more insight into the individual burden of narcolepsy symptoms over time and may serve as a patient-reported outcome measure for this debilitating disorder.
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- 2020
89. Hypoglycaemia and cardiac arrhythmias in diabetes
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Andreas Andersen, Peter Godsk Jørgensen, Filip K. Knop, and Tina Vilsbøll
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Diabetes duration ,Bradycardia ,medicine.medical_specialty ,endocrine system diseases ,type 1 diabetes ,Endocrinology, Diabetes and Metabolism ,BED SYNDROME ,Type 2 diabetes ,Review ,Ventricular tachycardia ,lcsh:Diseases of the endocrine glands. Clinical endocrinology ,NOCTURNAL HYPOGLYCEMIA ,Internal medicine ,Diabetes mellitus ,medicine ,In patient ,cardiovascular diseases ,Risk factor ,GLUCOSE CONTROL ,TYPE-1 ,RISK ,Type 1 diabetes ,lcsh:RC648-665 ,business.industry ,nutritional and metabolic diseases ,diabetes complications ,REPOLARIZATION ,medicine.disease ,INSULIN ,cardiac arrhythmias ,CARDIOVASCULAR-DISEASE ,QT INTERVAL PROLONGATION ,Cardiology ,cardiovascular system ,type 2 diabetes ,medicine.symptom ,business ,FOLLOW-UP ,hormones, hormone substitutes, and hormone antagonists ,hypoglycaemia - Abstract
Hypoglycaemia remains an inevitable risk in insulin-treated type 1 diabetes and type 2 diabetes and has been associated with multiple adverse outcomes. Whether hypoglycaemia is a cause of fatal cardiac arrhythmias in diabetes, or merely a marker of vulnerability, is still unknown. Since a pivotal report in 1991, hypoglycaemia has been suspected to induce cardiac arrhythmias in patients with type 1 diabetes, the so-called ‘dead-in-bed syndrome’. This suspicion has subsequently been supported by the coexistence of an increased mortality and a three-fold increase in severe hypoglycaemia in patients with type 2 diabetes receiving intensive glucose-lowering treatment in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. Studies have investigated the association between hypoglycaemia-induced cardiac arrhythmias. In a rat-model, severe hypoglycaemia resulted in a specific pattern of cardiac arrhythmias including QT-prolongation, ventricular tachycardia, second- and third-degree AV block and ultimately cardiorespiratory arrest. In clinical studies of experimentally induced hypoglycaemia, QTc-prolongation, a risk factor of ventricular arrhythmias, is an almost consistent finding. The extent of QT-prolongation seems to be modified by several factors, including antecedent hypoglycaemia, diabetes duration and cardiac autonomic neuropathy. Observational studies indicate diurnal differences in the pattern of electrocardiographic alterations during hypoglycaemia with larger QTc-prolongations during daytime, whereas the risk of bradyarrhythmias may be increased during sleep. Daytime periods of hypoglycaemia are characterized by shorter duration, increased awareness and a larger increase in catecholamines. The counterregulatory response is reduced during nightly episodes of hypoglycaemia, resulting in prolonged periods of hypoglycaemia with multiple nadirs. An initial sympathetic activity at plasma glucose nadir is replaced by increased vagal activity, which results in bradycardia. Here, we provide an overview of the existing literature exploring potential mechanisms for hypoglycaemia-induced cardiac arrhythmias and studies linking hypoglycaemia to cardiac arrhythmias in patients with diabetes.
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- 2020
90. Management of Latent Autoimmune Diabetes in Adults: A Consensus Statement From an International Expert Panel
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Raffaella Buzzetti, Zhiguang Zhou, Tiinamaija Tuomi, Massimo Pietropaolo, Richard David Leslie, Paolo Pozzilli, Didac Mauricio, Centre of Excellence in Complex Disease Genetics, HUS Abdominal Center, Institute for Molecular Medicine Finland, Research Programs Unit, CAMM - Research Program for Clinical and Molecular Metabolism, and University of Helsinki
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0301 basic medicine ,Latent autoimmune diabetes of adults ,Male ,Endotype ,Endocrinology, Diabetes and Metabolism ,Consensus Development Conferences as Topic ,International Cooperation ,LADA CHINA ,Type 2 diabetes ,METABOLIC-CONTROL ,LADA ,law.invention ,0302 clinical medicine ,Randomized controlled trial ,law ,C-Peptide ,Glutamate Decarboxylase ,C-PEPTIDE SECRETION ,Middle Aged ,3. Good health ,Practice Guidelines as Topic ,Female ,GENE VARIANTS ,Algorithms ,Adult ,medicine.medical_specialty ,030209 endocrinology & metabolism ,INSULIN REQUIREMENT ,03 medical and health sciences ,Therapeutic approach ,GLUTAMIC-ACID DECARBOXYLASE ,BETA-CELL FUNCTION ,Diabetes mellitus ,Internal medicine ,therapeutic approach ,C-peptide ,Internal Medicine ,medicine ,Humans ,Hypoglycemic Agents ,Genetic Predisposition to Disease ,Latent Autoimmune Diabetes in Adults ,TYPE-1 ,Aged ,Type 1 diabetes ,business.industry ,medicine.disease ,Clinical trial ,030104 developmental biology ,Sulfonylurea Compounds ,Diabetes Mellitus, Type 2 ,3121 General medicine, internal medicine and other clinical medicine ,ONSET ,Perspectives in Diabetes ,AUTOANTIBODIES ,business - Abstract
A substantial proportion of patients with adult-onset diabetes share features of both type 1 diabetes (T1D) and type 2 diabetes (T2D). These individuals, at diagnosis, clinically resemble T2D patients by not requiring insulin treatment, yet they have immunogenetic markers associated with T1D. Such a slowly evolving form of autoimmune diabetes, described as latent autoimmune diabetes of adults (LADA), accounts for 2–12% of all patients with adult-onset diabetes, though they show considerable variability according to their demographics and mode of ascertainment. While therapeutic strategies aim for metabolic control and preservation of residual insulin secretory capacity, endotype heterogeneity within LADA implies a personalized approach to treatment. Faced with a paucity of large-scale clinical trials in LADA, an expert panel reviewed data and delineated one therapeutic approach. Building on the 2020 American Diabetes Association (ADA)/European Association for the Study of Diabetes (EASD) consensus for T2D and heterogeneity within autoimmune diabetes, we propose “deviations” for LADA from those guidelines. Within LADA, C-peptide values, proxy for β-cell function, drive therapeutic decisions. Three broad categories of random C-peptide levels were introduced by the panel: 1) C-peptide levels 0.7 nmol/L: suggests a modified ADA/EASD algorithm as for T2D but allowing for the potentially progressive nature of LADA by monitoring C-peptide to adjust treatment. The panel concluded by advising general screening for LADA in newly diagnosed non–insulin-requiring diabetes and, importantly, that large randomized clinical trials are warranted.
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- 2020
91. Safety issues associated with dietary management in patients with hepatic glycogen storage disease
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Thomas A. H. Steunenberg, Carolina Fischinger Moura de Souza, Terry G J Derks, Foekje de Boer, Irene J Hoogeveen, Helen Mundy, John J. Mitchell, David A. Weinstein, Charlotte M A Lubout, Fabian Peeks, and Center for Liver, Digestive and Metabolic Diseases (CLDM)
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0301 basic medicine ,Adult ,Male ,Pediatrics ,medicine.medical_specialty ,Complications ,SYMPTOMS ,Adolescent ,Diet therapy ,Endocrinology, Diabetes and Metabolism ,CHILDREN ,Disease ,030105 genetics & heredity ,Hypoglycemia ,GUIDELINES ,Biochemistry ,03 medical and health sciences ,Young Adult ,Endocrinology ,Hepatic glycogen storage ,Surveys and Questionnaires ,Genetics ,medicine ,Glycogen storage disease ,Humans ,In patient ,Child ,Molecular Biology ,TYPE-1 ,Aged ,Safety management ,business.industry ,Acute complication ,IA ,Dietary management ,Infant ,III DIAGNOSIS ,Middle Aged ,medicine.disease ,Diet ,CORNSTARCH THERAPY ,Liver ,Child, Preschool ,Female ,Safety ,business - Abstract
Introduction Hepatic glycogen storage diseases (GSDs) are a group of inherited disorders of carbohydrate metabolism for which dietary management is the cornerstone. Safety and acute complications associated with dietary management have been poorly documented. We hypothesized that safety issues and complications associated with dietary management are prevalent amongst patients with these ultra-rare disorders.Methods: A questionnaire was developed consisting of 40 questions and was distributed via eight GSD patient organizations from multiple countries. Respondents were (caregivers of) patients with self-reported hepatic GSD.Results: 249 GSD patients from 26 countries responded with a median age of 14.8 years (range: 0.5-66.1). Although management was considered safe by 71% of patients, 51% reported at least one acute complication associated with dietary management, with a total number of 425 reported complications. Most frequently reported causes were: not waking up by an alarm clock (n = 70), forgetting a meal (n = 57) and infections (n = 43). Most frequently reported complications were: hypoglycemia (n = 112), hospital admissions (n = 79) and drowsiness (n = 74). Most complications occurred before the age of 12 years (82%; 637/ 774 total number of reported events) and during night time (63%; 340/536). Only 61% (152/249) of the GSD patients reported using a written emergency protocol.Conclusions: Safety issues and complications associated with dietary management are prevalently reported by (caregivers of) 249 GSD patients. A discrepancy has been observed between the patient's perspective on safety of dietary management and occurrence of complications as a result of dietary management.
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- 2018
92. The biology of cutaneous neurofibromas
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Lu Q. Le, Jaishri O. Blakeley, Robert M. Lavker, Pierre Wolkenstein, Sharad K. Verma, Jean-Philippe Brosseau, Vincent M. Riccardi, Eric H. Legius, Dominique C. Pichard, and Isaac Brownell
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0301 basic medicine ,SCHWANN-CELLS ,Neurofibromatosis 1 ,Skin Neoplasms ,Consensus Development Conferences as Topic ,GENOTYPE-PHENOTYPE CORRELATION ,Clinical Neurology ,Cutaneous neurofibroma ,03 medical and health sciences ,Tumor Microenvironment ,Animals ,Humans ,TYPE-1 ,Science & Technology ,Neurofibroma ,Cellular composition ,MUTATIONS ,ORIGIN ,Management science ,Research ,NF1 GENE ,030104 developmental biology ,Neurology ,MAST-CELLS ,Neurosciences & Neurology ,Neurology (clinical) ,MESSENGER-RNA ,Topic areas ,Life Sciences & Biomedicine ,PLEXIFORM NEUROFIBROMAS ,SKIN - Abstract
ObjectiveA group of experts in dermatology, genetics, neuroscience, and regenerative medicine collaborated to summarize current knowledge on the defined factors contributing to cutaneous neurofibroma (cNF) development and to provide consensus recommendations for future research priorities to gain an improved understanding of the biology of cNF.MethodsThe group members reviewed published and unpublished data on cNF and related diseases via literature search, defined a set of key topic areas deemed critical in cNF pathogenesis, and developed recommendations in a series of consensus meetings.ResultsFive specific topic areas were identified as being relevant to providing an enhanced understanding of the biology of cNF: (1) defining the human cells of origin; (2) understanding the role of the microenvironment, focusing on neurons, mast cells, and fibroblasts; (3) defining the genetic and molecular differences between the cNFs, focusing on size and number; (4) understanding if sex hormones are critical for cNF development or progression; and (5) identifying challenges in establishing in vitro and in vivo models representing human cNF.ConclusionsThe complexity of cNF biology stems from its heterogeneity at multiple levels including genetic, spatial involvement, temporal development, and cellular composition. We propose a unified working model for cNF that builds a framework to address the key questions about cNF that, when answered, will provide the necessary understanding of cNF biology to allow meaningful development of therapies.
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- 2018
93. A preliminary study of telemedicine for patients with hepatic glycogen storage disease and their healthcare providers: from bedside to home site monitoring
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Tom J. de Koning, Francjan J. van Spronsen, Foekje de Boer, Terry G J Derks, Robert Jan Zandvoort, Sebastiaan te Boekhorst, Irene J Hoogeveen, Fabian Peeks, Charlotte M A Lubout, Rob Burghard, Center for Liver, Digestive and Metabolic Diseases (CLDM), and Movement Disorder (MD)
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0301 basic medicine ,Blood Glucose ,Male ,CLINICAL-COURSE ,CHILDREN ,Pilot Projects ,030105 genetics & heredity ,Glycogen Storage Disease Type I ,METABOLIC-CONTROL ,THERAPY ,Health care ,Prospective Studies ,Child ,Genetics (clinical) ,System usability scale ,Second opinion ,Disease Management ,Middle Aged ,Glycogen Storage Disease ,Mobile Applications ,Telemedicine ,Rare diseases ,Child, Preschool ,Female ,Medical emergency ,Hepatic glycogen storage diseases ,Adult ,congenital, hereditary, and neonatal diseases and abnormalities ,Monitoring ,Adolescent ,Health Personnel ,Mobile application ,03 medical and health sciences ,Young Adult ,Genetics ,medicine ,MANAGEMENT ,Humans ,Medical prescription ,Dietary management ,TYPE-1 ,Monitoring, Physiologic ,CARDIOMYOPATHY ,business.industry ,III DIAGNOSIS ,nutritional and metabolic diseases ,Usability ,medicine.disease ,Clinical trial ,business - Abstract
BackgroundThe purpose of this project was to develop a telemedicine platform that supports home site monitoring and integrates biochemical, physiological, and dietary parameters for individual patients with hepatic glycogen storage disease (GSD).Methods and resultsThe GSD communication platform (GCP) was designed with input from software developers, GSD patients, researchers, and healthcare providers. In phase 1, prototyping and software design of the GCP has occurred. The GCP was composed of a GSD App for patients and a GSD clinical dashboard for healthcare providers. In phase 2, the GCP was tested by retrospective patient data entry. The following software functionalities were included (a) dietary registration and prescription module, (b) emergency protocol module, and (c) data import functions for continuous glucose monitor devices and activity wearables. In phase 3, the GSD App was implemented in a pilot study of eight patients with GSD Ia (n=3), GSD IIIa (n=1), and GSD IX (n=4). Usability was measured by the system usability scale (SUS). The mean SUS score was 64/100 [range: 38-93].ConclusionsThis report describes the design, development, and validation process of a telemedicine platform for patients with hepatic GSD. The GCP can facilitate home site monitoring and data exchange between patients with hepatic GSD and healthcare providers under varying circumstances. In the future, the GCP may support cross-border healthcare, second opinion processes and clinical trials, and could possibly also be adapted for other diseases for which a medical diet is the cornerstone.
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- 2018
94. Overweight, obesity and the risk of LADA: results from a Swedish case–control study and the Norwegian HUNT Study
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B. Rasouli, Anders Rosengren, Emma Ahlqvist, Leif Groop, Sofia Carlsson, Rebecka Hjort, Valdemar Grill, Tiinamaija Tuomi, Bjørn Olav Åsvold, Per-Ola Carlsson, Mats Martinell, Institute for Molecular Medicine Finland, Centre of Excellence in Complex Disease Genetics, Diabetes and Obesity Research Program, Research Programs Unit, Department of Medicine, Tiinamaija Tuomi Research Group, Clinicum, Endokrinologian yksikkö, and HUS Abdominal Center
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Male ,HUNT Study ,Endocrinology, Diabetes and Metabolism ,PROGRESSION ,Type 2 diabetes ,Overweight ,LADA ,Body Mass Index ,0302 clinical medicine ,Risk Factors ,Insulin-Secreting Cells ,Odds Ratio ,HETEROGENEITY ,030212 general & internal medicine ,Prospective Studies ,Body mass index ,ESTRID ,INSULIN-RESISTANCE ,Norway ,Case-control study ,Middle Aged ,3. Good health ,Endokrinologi och diabetes ,Female ,medicine.symptom ,ANDiU ,NORD-TRONDELAG HEALTH ,Adult ,medicine.medical_specialty ,EUROPE ,Case–control study ,030209 endocrinology & metabolism ,Endocrinology and Diabetes ,AUTOIMMUNE-DISEASES ,Article ,03 medical and health sciences ,Young Adult ,Insulin resistance ,Diabetes mellitus ,Internal medicine ,Internal Medicine ,medicine ,Humans ,ACID DECARBOXYLASE AUTOANTIBODIES ,Obesity ,Risk factor ,Prospective study ,Latent Autoimmune Diabetes in Adults ,TYPE-1 ,ANDIS ,Aged ,Autoantibodies ,ADULTS LADA ,Sweden ,Latent autoimmune diabetes in adults ,business.industry ,medicine.disease ,Diabetes Mellitus, Type 2 ,3121 General medicine, internal medicine and other clinical medicine ,Case-Control Studies ,ONSET ,Insulin Resistance ,business - Abstract
Aims/hypothesis Excessive weight is a risk factor for type 2 diabetes, but its role in the promotion of autoimmune diabetes is not clear. We investigated the risk of latent autoimmune diabetes in adults (LADA) in relation to overweight/obesity in two large population-based studies. Methods Analyses were based on incident cases of LADA (n = 425) and type 2 diabetes (n = 1420), and 1704 randomly selected control participants from a Swedish case–control study and prospective data from the Norwegian HUNT Study including 147 people with LADA and 1,012,957 person-years of follow-up (1984–2008). We present adjusted ORs and HRs with 95% CI. Results In the Swedish data, obesity was associated with an increased risk of LADA (OR 2.93, 95% CI 2.17, 3.97), which was even stronger for type 2 diabetes (OR 18.88, 95% CI 14.29, 24.94). The association was stronger in LADA with low GAD antibody (GADA
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- 2018
95. HIV Activates the Tyrosine Kinase Hck to Secrete ADAM Protease-Containing Extracellular Vesicles
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Tapio Kesti, Thomas Harrer, A.S. Baur, B. Simon, Jung-Hyun Lee, Kalle Saksela, Heiko Bruns, Christian Ostalecki, Zhe Zhao, Medicum, Department of Virology, University of Helsinki, Infection Biology Research Program, Kalle Saksela / Principal Investigator, and HUSLAB
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0301 basic medicine ,Male ,HIV Core Protein p24 ,lcsh:Medicine ,HIV Infections ,LIVER FIBROSIS ,SH3 domain ,ANTIRETROVIRAL THERAPY ,SH3 DOMAIN ,lcsh:R5-920 ,INFECTED PATIENTS ,ADAM17 ,Chronic HIV infection ,Hck ,Chemistry ,Effector ,GOLGI ,virus diseases ,Translation (biology) ,General Medicine ,3. Good health ,Cell biology ,Liver ,HUMAN-IMMUNODEFICIENCY-VIRUS ,Myeloid cells ,Host-Pathogen Interactions ,symbols ,Proto-Oncogene Proteins c-hck ,lcsh:Medicine (General) ,Tyrosine kinase ,Research Paper ,Proteases ,IMMUNE ,Plasma extracellular vesicles ,Context (language use) ,ADAM17 Protein ,General Biochemistry, Genetics and Molecular Biology ,Cell Line ,03 medical and health sciences ,symbols.namesake ,Extracellular Vesicles ,Humans ,Secretion ,nef Gene Products, Human Immunodeficiency Virus ,TYPE-1 ,Nef ,lcsh:R ,Golgi apparatus ,030104 developmental biology ,3121 General medicine, internal medicine and other clinical medicine ,Case-Control Studies ,CELLS ,Hepatocytes ,3111 Biomedicine - Abstract
HIV-Nef activates the myeloid cell-typical tyrosine kinase Hck, but its molecular role in the viral life cycle is not entirely understood. We found that HIV plasma extracellular vesicles (HIV pEV) containing/10 proteases and Nef also harbor Hck, and analyzed its role in the context of HIV pEV secretion. Myeloid cells required Hck for the vesicle-associated release of ADAM17. This could be induced by the introduction of Nef and implied that HIV targeted Hck for vesicle-associated ADAM17 secretion from a myeloid compartment. The other contents of HIV-pEV, however, including miRNA and effector protein profiles, as well as the presence of haptoglobin suggested hepatocytes as a possible cellular source. HIV liver tissue analysis supported this assumption, revealing induction of Hck translation, evidence for ADAM protease activation and HIV infection. Our findings suggest that HIV targets Hck to induce pro-inflammatory vesicles release and identifies hepatocytes as a possible host cell compartment., Highlights • Hck is found along with HIV Nef and ADAM17 in plasma extracellular vesicles (pEV) from HIV-infected individuals. • Hck is required for the secretion of ADAM17 via pEV from myeloid cells and hepatocytes. • Liver tissue from HIV infected individuals revealed induction of Hck expression and presence of Nef.
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- 2018
96. Ex vivo and in vitro assessment of anti-inflammatory activity of seed β-conglutin proteins from Lupinus angustifolius
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Juan de Dios Alché, Sonia Morales-Santana, Victor Alché, José Carlos Jiménez-López, Rhonda C. Foley, Kadambot H. M. Siddique, Su Melser, Elena Lima-Cabello, Karam B. Singh, [Lima-Cabello, Elena] CSIC, Estn Expt Zaidin, Dept Biochem Cell & Mol Biol Plants, Prof Albareda 1, E-18008 Granada, Spain, [Alche, Juan D.] CSIC, Estn Expt Zaidin, Dept Biochem Cell & Mol Biol Plants, Prof Albareda 1, E-18008 Granada, Spain, [Jimenez-Lopez, Jose C.] CSIC, Estn Expt Zaidin, Dept Biochem Cell & Mol Biol Plants, Prof Albareda 1, E-18008 Granada, Spain, [Morales-Santana, Sonia] Univ Hosp San Cecilio, Biomed Res Inst Granada IBS Granada, CIBER Fragil & Hlth Aging CIBERFFS, Endocrinol Unit,Endocrinol Div, Dr Oloriz 16, E-18012 Granada, Spain, [Morales-Santana, Sonia] Univ Hosp San Cecilia, Biomed Res Inst Granada IBS Granada, Proteom Res Serv, Dr Oloriz 16, E-18012 Granada, Spain, [Foley, Rhonda C.] CSIRO, CELS, Agr & Food, 147 Underwood Ave, Wembly, WA 6014, Australia, [Singh, Karam B.] CSIRO, CELS, Agr & Food, 147 Underwood Ave, Wembly, WA 6014, Australia, [Melser, Su] Univ Bordeaux, INSERM, NeuroCtr Magendie, Team Endocannabinoids & Neuroadaptat,U1215, 146 Rue Leo Saignat, F-33076 Bordeaux, France, [Alche, Victor] Hlth Ctr Villanueva De Las Torres, Andalusian Hlth Syst, E-18539 Granada, Spain, [Siddique, Kadambot H. M.] Univ Western Australia, UWA Inst Agr, 35 Stirling Highway, Nedlands, WA 6009, Australia, [Singh, Karam B.] Univ Western Australia, UWA Inst Agr, 35 Stirling Highway, Nedlands, WA 6009, Australia, [Jimenez-Lopez, Jose C.] Univ Western Australia, UWA Inst Agr, 35 Stirling Highway, Nedlands, WA 6009, Australia, [Siddique, Kadambot H. M.] Univ Western Australia, Sch Agr & Environm, 35 Stirling Highway, Nedlands, WA 6009, Australia, [Singh, Karam B.] Univ Western Australia, Sch Agr & Environm, 35 Stirling Highway, Nedlands, WA 6009, Australia, [Jimenez-Lopez, Jose C.] Univ Western Australia, Sch Agr & Environm, 35 Stirling Highway, Nedlands, WA 6009, Australia, European Research Program MARIE CURIE, Spanish Ministry of Economy, Industry and Competitiveness, Ministerio de Economía, Industria y Competitividad (España), Consejo Superior de Investigaciones Científicas (España), and European Commission
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0301 basic medicine ,Chemokine ,chemokine CCL5 ,medicine.drug_class ,beta-conglutins ,Activation ,Medicine (miscellaneous) ,030209 endocrinology & metabolism ,Anti-inflammatory proteins ,Lupinus angustifolius ,Pharmacology ,Type-1 ,Anti-inflammatory ,β-conglutins ,Nitric oxide ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Nutraceutical ,Nitric-oxide ,Functional food ,IL-1 beta ,medicine ,TX341-641 ,Alpha ,Nutrition and Dietetics ,biology ,Nutrition. Foods and food supply ,Chemistry ,biology.organism_classification ,In vitro ,3. Good health ,Islet inflammation ,iNOS ,030104 developmental biology ,Vicilin ,IL-1β ,biology.protein ,Cytokines ,Antioxidant ,Ex vivo ,Food Science - Abstract
The development of functional food ingredients using legume seed proteins has potential for nutraceutical use. We purified recombinant β-conglutin proteins (rβ1 to rβ4, and rβ6) from narrow-leafed lupin using affinity–chromatography, and evaluated their anti-inflammatory activity using ex vivo and in vitro systems. rβ1, rβ3, and rβ6 produced lower levels of pro-inflammatory mediators such as nitric oxide (about –34.0–fold in all cases), iNOS mRNA (−7.15, −7.97, −7.41–fold), interleukin 1β (−12.05, −11.64, −12.16–fold), chemokine CCL5 (−16.0, −18.0, −19.0–fold), and cytokines including TNF-α INF-γ IL-1β IL-2, IL-6, IL-8, and IL-12 (β1: −28, −100, −8, −2, −49, −45, −127–fold; β3: −22, −400, −9, −3, −33, −10, −2.54–fold; β6: −72, −122, −11, −3, −2000, −13, −338–fold). These results suggest that the β1, β3, and β6 conglutins have potential as functional food components in nutraceuticals and that can provide alternative therapies for the prevention and treatment of inflammatory-related diseases., This work was partially supported by the European Research Program MARIE CURIE (FP7-PEOPLE-24 2011-IOF) through the grant ref. number PIOF-GA-2011-301550 to JCJ-L, KBS and JDA. JCJ-L thanks the Spanish Ministry of Economy, Industry and Competitiveness for the grant ref. RYC-2014-16536 (Ramon y Cajal Research Program), and the grant ref. BFU2016-77243-P.
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- 2018
97. A randomised controlled trial of cognitive behaviour therapy and motivational interviewing for people with type 1 diabetes mellitus with persistent sub-optimal glycaemic control: A Diabetes and Psychological Therapies (ADaPT) study
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K Ismail, E Maissi, S Thomas, T Chalder, U Schmidt, J Bartlett, A Patel, C Dickens, F Creed, and J Treasure
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diabetes ,hypoglycaemia ,type-1 ,glycated-haemoglobin ,motivational-enhancement-therapy ,cognitive-behaviour-therapy ,Medical technology ,R855-855.5 - Abstract
Objectives: To determine whether (i) motivational enhancement therapy (MET) + cognitive behaviour therapy (CBT) compared with usual care, (ii) MET compared with usual care, (iii) or MET + CBT compared with MET was more effective in improving glycaemic control when delivered by general nurses with additional training in these techniques. Design: A three-arm parallel randomised controlled trial as the gold standard design to test the effectiveness of psychological treatments. Setting: The recruiting centres were diabetes clinics in seven acute trusts in south-east London and Greater Manchester. Participants: Adults (18–65 years) with a confirmed diagnosis of type 1 diabetes for a minimum duration of 2 years and a current glycated (or glycosylated) haemoglobin (HbA1c) value between 8.2% and 15.0%. Interventions: The control arm consisted of usual diabetes care which varied between the hospitals, but constituted at least three monthly appointments to diabetes clinic. The two treatments arms consisted of usual care with MET and usual care with MET + CBT. Main outcome measures: The primary outcome was HbA1c at 12 months from randomisation. Secondary outcome measures were 1-year costs measured by the Client Service Receipt Inventory at baseline, 6 months and 12 months; quality of life-years [quality-adjusted life-years (QALYs)] measured by the SF-36 (Short Form-36 Health Survey Questionnaire) and EQ-5D (European Quality of Life-5 Dimensions) at baseline and 12 months. Results: One thousand six hundred and fifty-nine people with type 1 diabetes were screened and 344 were randomised to MET + CBT (n = 106), MET (n = 117) and to usual care (n = 121). The 12-month follow-up rate for HbA1c was 88% (n = 305). The adjusted mean 12-month HbA1c was 0.45% lower in those treated with MET + CBT [95% confidence interval (CI) 0.16% to 0.79%, p = 0.008] than for usual care; 0.16% lower in those treated with MET (95% CI 0.20% to 0.51%, p = 0.38) than for usual care; and 0.30% lower with MET + CBT than with MET (95% CI –0.07% to 0.66%, p = 0.11). The higher the HbA1c, and the younger the participant at baseline, the greater was the reduction in HbA1c. The interventions had no effect on secondary outcomes such as depression and quality of life. The economic evaluation was inconclusive. Both interventions were associated with increased health care costs than for usual care alone. There was no significant difference in social costs. Cost effectiveness ratios, up to one year, varied considerably according to whether QALY estimates were based on EQ-5D or SF-36 and whether imputed or complete data were used in the analyses. Conclusions: A combination of MET and CBT may be useful for patients with persistent sub-optimal diabetic control. MET alone appears less effective than usual care. Economic evaluation was inconclusive. Trial registration: Current Controlled Trials ISRCTN77044517.
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- 2010
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98. Polar dust obscuration in broad-line active galaxies from the XMM-XXL field
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Denis Burgarella, Médéric Boquien, Patrice Theulé, Yannick Roehlly, Laure Ciesla, Marko Stalevski, V. Buat, Guang Yang, G. Mountrichas, Laboratoire d'Astrophysique de Marseille (LAM), Centre National de la Recherche Scientifique (CNRS)-Institut national des sciences de l'Univers (INSU - CNRS)-Aix Marseille Université (AMU)-Centre National d'Études Spatiales [Toulouse] (CNES), Laboratory of Image Science and Technology [Nanjing] (LIST), Southeast University [Jiangsu]-School of Computer Science and Engineering, Southeast University [Jiangsu], Aix Marseille Université (AMU)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS), Aix-Marseille Université, Agencia Estatal de Investigación (España), Ministerio de Ciencia, Innovación y Universidades (España), Ministry of Education, Science and Technological Development (Serbia), and Republic of Serbia
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GALACTIC NUCLEI ,Active galactic nucleus ,Infrared ,Astrophysics::High Energy Astrophysical Phenomena ,galaxies: active ,Extinction (astronomy) ,nuclei [galaxies] ,FOS: Physical sciences ,Astrophysics::Cosmology and Extragalactic Astrophysics ,Astrophysics ,01 natural sciences ,0103 physical sciences ,data analysis [methods] ,ABSORPTION ,010303 astronomy & astrophysics ,TYPE-1 ,Astrophysics::Galaxy Astrophysics ,Line (formation) ,High Energy Astrophysical Phenomena (astro-ph.HE) ,Physics ,HERSCHEL ,[SDU.ASTR]Sciences of the Universe [physics]/Astrophysics [astro-ph] ,RAY-SELECTED AGN ,extinction ,010308 nuclear & particles physics ,Spectral density ,Astronomy and Astrophysics ,Astrophysics - Astrophysics of Galaxies ,methods: data analysis ,Wavelength ,SPECTRAL ENERGY-DISTRIBUTION ,QUASARS ,Physics and Astronomy ,[SDU]Sciences of the Universe [physics] ,Space and Planetary Science ,Astrophysics of Galaxies (astro-ph.GA) ,active [galaxies] ,X-RAY ,Spectral energy distribution ,Polar ,COVERING FACTOR ,Astrophysics::Earth and Planetary Astrophysics ,dust ,galaxies: nuclei ,Astrophysics - High Energy Astrophysical Phenomena ,EMISSION ,[PHYS.ASTR]Physics [physics]/Astrophysics [astro-ph] - Abstract
[Aims]: Dust is observed in the polar regions of nearby active galactic nuclei (AGN) and it is known to contribute substantially to their mid-IR emission and to the obscuration of their UV to optical emission. We aim to carry out a statistical test to check whether this component is a common feature based on an analysis of the integrated spectral energy distributions of these composite sources., [Methods]: We selected a sample of 1275 broad-line AGN in the XMM-XXL field, with optical to infrared photometric data. These AGN are seen along their polar direction and we expect a maximal impact of dust located around the poles when it is present. We used X-CIGALE, which introduces a dust component to account for obscuration along the polar directions, modeled as a foreground screen, and an extinction curve that is chosen as it steepens significantly at short wavelengths or is much grayer. By comparing the results of different fits, we are able to define subsamples of sources with positive statistical evidence in favor of or against polar obscuration (if present) and described using the gray or steep extinction curve., [Results]: We find a similar fraction of sources with positive evidence for and against polar dust. Applying statistical corrections, we estimate that half of our sample could contain polar dust and among them, 60% exhibit a steep extinction curve and 40% a flat extinction curve; although these latter percentages are found to depend on the adopted extinction curves. The obscuration in the V-band is not found to correlate with the X-ray column density, while AV/NH ratios span a large range of values and higher dust temperatures are found with the flat, rather than with the steep extinction curve. Ignoring this polar dust component in the fit of the spectral energy distribution of these composite systems leads to an overestimation of the stellar contribution. A single fit with a polar dust component described with an SMC extinction curve efficiently overcomes this issue but it fails at identifying all the AGN with polar dust obscuration., The project has received funding from Excellence Initiative of Aix-Marseille University – AMIDEX, a French ‘Investissements d’Avenir’ programme. GM acknowledges support by the Agencia Estatal de Investigacíon, Unidad de Excelencia María de Maeztu, ref. MDM-2017-0765. M.S. acknowledges support by the Ministry of Education, Science and Technological Development of the Republic of Serbia through the contract no. 451-03- 9/2021-14/200002 and by the Science Fund of the Republic of Serbia, PROMIS 6060916, BOWIE.
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- 2021
99. Lessons learned from drug trials in neurofibromatosis: A systematic review
- Author
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Annette Bakker, Angela M. Kaindl, D. Gareth Evans, Marco Nievo, Charlotte Carton, Cornelia Potratz, Rianne Oostenbrink, Edwin van de Ketterij, Britt A.E. Dhaenens, Rosalie E. Ferner, Guenter Heimann, Geesje Hissink, Eric Legius, Pediatrics, and Erasmus MC other
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congenital, hereditary, and neonatal diseases and abnormalities ,medicine.medical_specialty ,Neurofibromatoses ,PROGRESSIVE VESTIBULAR SCHWANNOMA ,MEDLINE ,Psychological intervention ,CHILDREN ,Neurofibromatosis ,OPTIC PATHWAY GLIOMA ,Internal medicine ,YOUNG-ADULTS ,otorhinolaryngologic diseases ,Genetics ,medicine ,Humans ,Neurofibromatosis type 2 ,Schwannomatosis ,TYPE-1 ,Genetics (clinical) ,Genetics & Heredity ,Clinical Trials as Topic ,Science & Technology ,business.industry ,LOW-GRADE GLIOMA ,General Medicine ,medicine.disease ,Systematic review ,Drug development ,Practice Guidelines as Topic ,PATIENT-REPORTED OUTCOMES ,Population study ,VISUAL OUTCOMES ,business ,Life Sciences & Biomedicine ,PHASE-II TRIAL ,PLEXIFORM NEUROFIBROMAS ,Neurofibromatosis type 1 - Abstract
Neurofibromatosis (NF) is the umbrella term for neurofibromatosis type 1 (NF1), neurofibromatosis type 2 (NF2) and schwannomatosis (SWN). EU-PEARL aims to create a framework for platform trials in NF. The aim of this systematic review is to create an overview of recent clinical drug trials in NF, to identify learning points to guide development of the framework. We searched Embase, Medline and Cochrane register of trials on October 1, 2020 for publications of clinical drug trials in NF patients. We excluded publications published before 2010, systematic reviews, secondary analyses and studies with
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- 2021
100. Possible clearance of transfusion-acquired nef/LTR-deleted attenuated HIV-1 infection by an elite controller with CCR5 Delta 32 heterozygous and HLA-B57 genotype
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Zaunders, J, Dyer, WB, Churchill, M, Munier, CML, Cunningham, PH, Suzuki, K, McBride, K, Hey-Nguyen, W, Koelsch, K, Wang, B, Hiener, B, Palmer, S, Gorry, PR, Bailey, M, Xu, Y, Danta, M, Seddiki, N, Cooper, DA, Saksena, NK, Sullivan, JS, Riminton, S, Learmont, J, Kelleher, AD, Zaunders, J, Dyer, WB, Churchill, M, Munier, CML, Cunningham, PH, Suzuki, K, McBride, K, Hey-Nguyen, W, Koelsch, K, Wang, B, Hiener, B, Palmer, S, Gorry, PR, Bailey, M, Xu, Y, Danta, M, Seddiki, N, Cooper, DA, Saksena, NK, Sullivan, JS, Riminton, S, Learmont, J, and Kelleher, AD
- Abstract
Background: Subject C135 is one of the members of the Sydney Blood Bank Cohort, infected in 1981 through transfusion with attenuated nef/3′ long terminal repeat (LTR)-deleted HI V-1, and has maintained undetectable plasma viral load and steady CD4 cell count, in the absence of therapy. Uniquely, C135 combines five factors separately associated with control of viraemia: nef/LTR-deleted HI V-1, HLA -B57, HLA -DR13, heterozygous CCRccr5 Δ32 genotype and vigorous p24-stimulated peripheral blood mononuclear cell (PBMC) proliferation. Therefore, we studied in detail viral burden and immunological responses in this individual.Methods: PBMC and gut and lymph node biopsy samples were analysed for proviral HI V-1 DNA by real-time and nested PCR s, and nef/LTR alleles by nested PCR . HI V-specific antibodies were studied by Western blotting, and CD4+ and CD8+ T lymphocyte responses were measured by proliferation and cytokine production in vitro.Results: PBMC samples from 1996, but not since, showed amplification of nef alleles with gross deletions. Infectious HI V-1 was never recovered. Proviral HI V-1 DNA was not detected in recent PBMC or gut or lymph node biopsy samples. C135 has a consistently weak antibody response and a substantial CD4+ T cell proliferative response to a previously described HLA -DR13-restricted epitope of HI V-1 p24 in vitro, which augmented a CD8+ T cell response to an immunodominant HLA -B57-restricted epitope of p24, while his T cells show reduced levels of CCRccr5.Conclusions: Subject C135’s early PCR and weak antibody results are consistent with limited infection with a poorly replicating nef/LTR-deleted strain of HI V-1. With his HLA -B57-restricted gag-specific CD8 and helper HLA -DR13-restricted CD4 T cell proliferative responses, C135 appears to have cleared his HI V-1 infection 37 years after transfusion.
- Published
- 2019
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