22 research outputs found
Mycophenolate pharmacokinetics and pharmacodynamics in belatacept treated renal allograft recipients – a pilot study
<p>Abstract</p> <p>Background</p> <p>Mycophenolic acid (MPA) is widely used as part of immunosuppressive regimens following allograft transplantation. The large pharmacokinetic (PK) and pharmacodynamic (PD) variability and narrow therapeutic range of MPA provide a potential for therapeutic drug monitoring. The objective of this pilot study was to investigate the MPA PK and PD relation in combination with belatacept (2<sup>nd </sup>generation CTLA4-Ig) or cyclosporine (CsA).</p> <p>Methods</p> <p>Seven renal allograft recipients were randomized to either belatacept (n = 4) or cyclosporine (n = 3) based immunosuppression. Samples for MPA PK and PD evaluations were collected predose and at 1, 2 and 13 weeks posttransplant. Plasma concentrations of MPA were determined by HPLC-UV. Activity of inosine monophosphate dehydrogenase (IMPDH) and the expressions of two <it>IMPDH </it>isoforms were measured in CD4+ cells by HPLC-UV and real-time reverse-transcription PCR, respectively. Subsets of T cells were characterized by flow cytometry.</p> <p>Results</p> <p>The MPA exposure tended to be higher among belatacept patients than in CsA patients at week 1 (P = 0.057). Further, MPA concentrations (AUC<sub>0–9 h </sub>and C<sub>0</sub>) increased with time in both groups and were higher at week 13 than at week 2 (P = 0.031, n = 6). In contrast to the postdose reductions of IMPDH activity observed early posttransplant, IMPDH activity within both treatment groups was elevated throughout the dosing interval at week 13. Transient postdose increments were also observed for <it>IMPDH1 </it>expression, starting at week 1. Higher MPA exposure was associated with larger elevations of <it>IMPDH1 </it>(r = 0.81, P = 0.023, n = 7 for MPA and <it>IMPDH1 </it>AUC<sub>0–9 h </sub>at week 1). The maximum <it>IMPDH1 </it>expression was 52 (13–177)% higher at week 13 compared to week 1 (P = 0.031, n = 6). One patient showed lower MPA exposure with time and did neither display elevations of IMPDH activity nor <it>IMPDH1 </it>expression. No difference was observed in T cell subsets between treatment groups.</p> <p>Conclusion</p> <p>The significant influence of MPA on <it>IMPDH1 </it>expression, possibly mediated through reduced guanine nucleotide levels, could explain the elevations of IMPDH activity within dosing intervals at week 13. The present regulation of IMPDH in CD4+ cells should be considered when interpreting measurements of IMPDH inhibition.</p
DNA glycosylase Neil3 regulates vascular smooth muscle cell biology during atherosclerosis development.
BACKGROUND AND AIMS: Atherogenesis involves a complex interaction between immune cells and lipids, processes greatly influenced by the vascular smooth muscle cell (VSMC) phenotype. The DNA glycosylase NEIL3 has previously been shown to have a role in atherogenesis, though whether this is due to its ability to repair DNA damage or to other non-canonical functions is not yet clear. Hereby, we investigate the role of NEIL3 in atherogenesis, specifically in VSMC phenotypic modulation, which is critical in plaque formation and stability. METHODS: Chow diet-fed atherosclerosis-prone Apoe-/- mice deficient in Neil3, and NEIL3-abrogated human primary aortic VSMCs were characterized by qPCR, and immunohistochemical and enzymatic-based assays; moreover, single-cell RNA sequencing, mRNA sequencing, and proteomics were used to map the molecular effects of Neil3/NEIL3 deficiency in the aortic VSMC phenotype. Furthermore, BrdU-based proliferation assays and Western blot were performed to elucidate the involvement of the Akt signaling pathway in the transdifferentiation of aortic VSMCs lacking Neil3/NEIL3. RESULTS: We show that Neil3 deficiency increases atherosclerotic plaque development without affecting systemic lipids. This observation was associated with a shift in VSMC phenotype towards a proliferating, lipid-accumulating and secretory macrophage-like cell phenotype, without changes in DNA damage. VSMC transdifferentiation in Neil3-deficient mice encompassed increased activity of the Akt signaling pathway, supported by cell experiments showing Akt-dependent proliferation in NEIL3-abrogated human primary aortic VSMCs. CONCLUSIONS: Our findings show that Neil3 deficiency promotes atherosclerosis development through non-canonical mechanisms affecting VSMC phenotype involving activation of the Akt signaling pathway
Association of CLEC16A with human common variable immunodeficiency disorder and role in murine B cells
Common variable immunodeficiency disorder (CVID) is the most common symptomatic primary immunodeficiency in adults, characterized by B-cell abnormalities and inadequate antibody response. CVID patients have considerable autoimmune comorbidity and we therefore hypothesized that genetic susceptibility to CVID may overlap with autoimmune disorders. Here, in the largest genetic study performed in CVID to date, we compare 778 CVID cases with 10, 999 controls across 123, 127 single-nucleotide polymorphisms (SNPs) on the Immunochip. We identify the first non-HLA genome-wide significant risk locus at CLEC16A (rs17806056, P = 2.0 x 10(-9)) and confirm the previously reported human leukocyte antigen (HLA) associations on chromosome 6p21 (rs1049225, P = 4.8 x 10(-16)). Clec16a knockdown (KD) mice showed reduced number of B cells and elevated IgM levels compared with controls, suggesting that CLEC16A may be involved in immune regulatory pathways of relevance to CVID. In conclusion, the CLEC16A associations in CVID represent the first robust evidence of non-HLA associations in this immunodeficiency condition
Loss-of-function mutations in SLC30A8 protect against type 2 diabetes.
Neðst á síðunni er hægt að nálgast greinina í heild sinni með því að smella á hlekkinn View/OpenLoss-of-function mutations protective against human disease provide in vivo validation of therapeutic targets, but none have yet been described for type 2 diabetes (T2D). Through sequencing or genotyping of ~150,000 individuals across 5 ancestry groups, we identified 12 rare protein-truncating variants in SLC30A8, which encodes an islet zinc transporter (ZnT8) and harbors a common variant (p.Trp325Arg) associated with T2D risk and glucose and proinsulin levels. Collectively, carriers of protein-truncating variants had 65% reduced T2D risk (P = 1.7 × 10(-6)), and non-diabetic Icelandic carriers of a frameshift variant (p.Lys34Serfs*50) demonstrated reduced glucose levels (-0.17 s.d., P = 4.6 × 10(-4)). The two most common protein-truncating variants (p.Arg138* and p.Lys34Serfs*50) individually associate with T2D protection and encode unstable ZnT8 proteins. Previous functional study of SLC30A8 suggested that reduced zinc transport increases T2D risk, and phenotypic heterogeneity was observed in mouse Slc30a8 knockouts. In contrast, loss-of-function mutations in humans provide strong evidence that SLC30A8 haploinsufficiency protects against T2D, suggesting ZnT8 inhibition as a therapeutic strategy in T2D prevention.US National Institutes of Health (NIH) Training
5-T32-GM007748-33
Doris Duke Charitable Foundation
2006087
Fulbright Diabetes UK Fellowship
BDA 11/0004348
Broad Institute from Pfizer, Inc.
NIH
U01 DK085501
U01 DK085524
U01 DK085545
U01 DK085584
Swedish Research Council
Dnr 521-2010-3490
Dnr 349-2006-237
European Research Council (ERC)
GENETARGET T2D
GA269045
ENGAGE
2007-201413
CEED3
2008-223211
Sigrid Juselius Foundation
Folkh lsan Research Foundation
ERC
AdG 293574
Research Council of Norway
197064/V50
KG Jebsen Foundation
University of Bergen
Western Norway Health Authority
Lundbeck Foundation
Novo Nordisk Foundation
Wellcome Trust
WT098017
WT064890
WT090532
WT090367
WT098381
Uppsala University
Swedish Research Council and the Swedish Heart- Lung Foundation
Academy of Finland
124243
102318
123885
139635
Finnish Heart Foundation
Finnish Diabetes Foundation, Tekes
1510/31/06
Commission of the European Community
HEALTH-F2-2007-201681
Ministry of Education and Culture of Finland
European Commission Framework Programme 6 Integrated Project
LSHM-CT-2004-005272
City of Kuopio and Social Insurance Institution of Finland
Finnish Foundation for Cardiovascular Disease
NIH/NIDDK
U01-DK085545
National Heart, Lung, and Blood Institute (NHLBI)
National Institute on Minority Health and Health Disparities
N01 HC-95170
N01 HC-95171
N01 HC-95172
European Union Seventh Framework Programme, DIAPREPP
Swedish Child Diabetes Foundation (Barndiabetesfonden)
5U01DK085526
DK088389
U54HG003067
R01DK072193
R01DK062370
Z01HG000024info:eu-repo/grantAgreement/EC/FP7/20201
Rare and low-frequency coding variants alter human adult height
Height is a highly heritable, classic polygenic trait with ~700 common associated variants identified so far through genome - wide association studies . Here , we report 83 height - associated coding variants with lower minor allele frequenc ies ( range of 0.1 - 4.8% ) and effects of up to 2 16 cm /allele ( e.g. in IHH , STC2 , AR and CRISPLD2 ) , >10 times the average effect of common variants . In functional follow - up studies, rare height - increasing alleles of STC2 (+1 - 2 cm/allele) compromise d proteolytic inhibition of PAPP - A and increased cleavage of IGFBP - 4 in vitro , resulting in higher bioavailability of insulin - like growth factors . The se 83 height - associated variants overlap genes mutated in monogenic growth disorders and highlight new biological candidates ( e.g. ADAMTS3, IL11RA, NOX4 ) and pathways ( e.g . proteoglycan/ glycosaminoglycan synthesis ) involved in growth . Our results demonstrate that sufficiently large sample sizes can uncover rare and low - frequency variants of moderate to large effect associated with polygenic human phenotypes , and that these variants implicate relevant genes and pathways
Challenges in the Management of Kidney Allograft Herniation With a Single-stage Pedicled Anterolateral Thigh Flap
Wound complications are the most common surgical complication after kidney allograft transplantation. Total wound rupture exposing the entire kidney is a rare and not well-described event. We present a successful treatment of this complication in a patient admitted to our unit. A single-stage procedure was performed combining debridement and reconstruction with a pedicled anterolateral thigh flap and an iliotibial band transferring. A short literature review is performed comparing the different treatment strategies and results
Real-World Experiences With Facilitated Subcutaneous Immunoglobulin Substitution in Patients With Hypogammaglobulinemia, Using a Three-Step Ramp-Up Schedule
Immunoglobulin replacement therapy with facilitated subcutaneous immunoglobulin (fSCIg) can be self-administrated at home and given at longer intervals compared to subcutaneous immunoglobulin (SCIg) therapy, but real-word experience of home-based fSCIg therapy is limited. Herein we present our real-word clinical experiences with home-based fSCIg therapy using a three-step ramp-up schedule. We registered data from all patients with immunodeficiency starting fSCIg from 01.01.2017 to 31.12.2019. For comparison we also included patients starting conventional SCIg training. Fifty-four patients followed for a median of 18 months (IQR 12, range 0–40), received fSCIg training, and 84 patients received conventional SCIg training. Out of 54 patients starting with fSCIg, 41 patients had previous experience with conventional SCIg therapy, and the main reason for starting fSCIg was ‘longer intervals between therapies’ (n=48). We found an increase in training requirement for fSCIg (3 ± 1 [2-9] days) compared to conventional SCIg (2 ± 0 [1-7] days), P &lt; 0.001 (median ± IQR, [range]). For fSCIg training, IgG levels were stable from baseline (8.9 ± 2.3 g/L), 3-6 months (10.2 ± 2.2 g/L) and 9-12 months (9.9 ± 2.3 g/L), P = 0.11 (mean ± SD). The most common side-effect was: ‘rubor around injection site’ (n=48, 89%). No patients experienced severe adverse events (grade 3-4). Thirteen patients (24%) discontinued fSCIg therapy due to local adverse events (n=9), cognitive/psychological difficulties (n=6) and/or systemic adverse events (n=3). In conclusion, fSCIg training using a three-step ramp-up schedule is safe and well tolerated by the majority of patients, but requires longer training time compared to conventional SCIg