Genetic dissection reveals diabetes loci proximal to the gimap5 lymphopenia gene

rats are protected from type 1 diabetes (T1D) by 34 Mb of F344 DNA introgressed proximal to the gimap5 lymphopenia gene. To dissect the genetic factor(s) that confer protection from T1D in the DRF. f/f rat line, DRF. f/f rats were crossed to inbred BBDR or DR. lyp/lyp rats to generate congenic sublines that were genotyped and monitored for T1D, and positional candidate genes were sequenced. All (100%) DR. f/f congenic sublines further refined the RNO4 region 1 interval to ϳ670 kb and region 2 to the 340 kb proximal to gimap5. All congenic DRF. f/f sublines were prone to low-grade pancreatic mononuclear cell infiltration around ducts and vessels, but Ͻ20% of islets in nondiabetic rats showed islet infiltration. Coding sequence analysis revealed TCR V␤ 8E, 12, and 13 as candidate genes in region 1 and znf467 and atp6v0e2 as candidate genes in region 2. Our results show that spontaneous T1D is controlled by at least two genetic loci 7 Mb apart on rat chromosome 4. type 1 diabetes; BB rat; T cell receptor; autoimmune CHARACTERISTICS OF TYPE 1 DIABETES (T1D) in both human and the BioBreeding spontaneously diabetes-prone (BBDP) rat include polyuria, hyperglycemia, ketoacidosis, insulitis, and insulin dependency for life. As in human T1D, islets are infiltrated by mononuclear cells at the time of onset with rapid hyperglycemia due to a complete loss of islet ␤-cells (32). The genetic etiology of human T1D remains complex and although the major histocompatibility complex (MHC) (HLA DQ) on chromosome 6 accounts for ϳ40% of T1D risk, the number of non-HLA genetic factors is increasing steadily (2, 7). The BB rat offers a powerful model to dissect both genetic contributions and mechanisms by which immunemediated beta cell killing induces T1D (3, 4, 15, 17-21, 27, 28, 46). As in humans, the major genetic determinant of susceptibility in the BB rat is the MHC (Iddm1) on rat chromosome (RNO) 20. The class II MHC locus RT1B/D. u/u ), an ortholog of human HLA DQ (9), is necessary but not sufficient for T1D in the BBDP rat and other RT1. u/u -related rat strains with spontaneous (24, 47) or induced T1D (8, 43). In BBDP, a null mutation in the gimap5 gene (lyp; Iddm2) on RNO4 (14, 27) causes lymphopenia and is tightly linked to spontaneous T1D development. The DR. lyp/lyp rat with 2 Mb of BBDP DNA encompassing gimap5 introgressed into the genome of related BBDR rats (BioBreeding resistant to spontaneous T1D) are also 100% lymphopenic and 100% spontaneously diabetic (11). With complete T1D penetrance and tight regulation of onset, the congenic DR. lyp/lyp rat line offers distinct advantages in identification of genes responsible for disease progression. It is possible to induce T1D in BBDR rats (32) and related RT1 u/u rats (8) by administration of polyinosinic: polycytidylic acid (poly I:C, an activator of innate immunity), the T reg depleting cytotoxic DS4.23 anti-ART2.1 (formerly RT6) monoclonal antibody or by viral infection (34). This indicates that the BBDR has an underlying genetic susceptibility to T1D. In crosses between WF and either BBDP or BBDR rats, a quantitative trait locus (QTL) important for induced T1D (Iddm14, previously designated Iddm4) was mapped to RNO4 (6, Interestingly, F344 DNA introgressed between D4Rat253 and D4Rhw6 into the congenic DR. lyp/lyp genetic background resulted in a lymphopenic but nondiabetic rat (designated DRF. f/f ) (11). Protection from T1D in the DRF. f/f congenic rat line led us to conclude that spontaneous T1D in the BB rat is controlled, in part, by a diabetogenic factor(s) independent of the gimap5 mutation (76.84 Mb) on RNO4. This congenic interval is encompassed within Iddm14, raising the possibility that the Iddm14 locus could be required for both spontaneous and induced T1D in the BB rat. The aim of this study was to cross the DRF. f/f rat to BBDR and DR. lyp/lyp rats and produce recombinant sublines that could be assessed for both lymphopenia and diabetes and to estimate the number of independent genes on RNO4 that control spontaneous T1D

Estimating risk of encapsulating peritoneal sclerosis accounting for the competing risk of death

Background: Risk of Encapsulating Peritoneal Sclerosis (EPS) is strongly associated with the duration of peritoneal dialysis (PD), such that patients who have been on PD for some time may consider elective transfer to haemodialysis to mitigate risk of EPS. There is a need to determine this risk to better inform clinical decision-making, but previous studies have not allowed for the competing risk of death. Methods: This study included new adult PD patients in either Australia and New Zealand (ANZ 1990-2010) or Scotland (2000-2008) followed until 2012. Age, time on PD, primary renal disease, gender, dataset and diabetic status were evaluated as predictors at start of PD, then at three and five years after starting PD using flexible parametric competing risks models. Results: In 17,396 patients (16,162 ANZ, 1,234 Scotland), EPS was observed in 99 (0.57%) patients less frequently in ANZ patients (n=65, 0.4%) than in Scottish patients (n=34, 2.8%). The estimated risk of EPS was much lower when the competing risk of death was taken into account (1-KM=0.0126, CIF=0.0054). Strong predictors of EPS included age, primary renal disease and time on PD. The risk of EPS was reasonably discriminated at the start of PD (C-statistic = 0.74 to 0.79) and this improved at 3 and 5 years after starting PD (C-statistic = 0.81 to 0.92). Conclusions: EPS risk estimates are lower when calculated using competing risk of death analyses. A patient’s estimated risk of EPS is country-specific, and can be predicted using age, primary renal disease and duration of PD

Can a total knee arthroplasty be both rotationally unconstrained and anteroposteriorly stabilised? A pulsed fluoroscopic investigation

Objectives: Throughout the 20th Century, it has been postulated that the knee moves on the basis of a four-bar link mechanism composed of the cruciate ligaments, the femur and the tibia. As a consequence, the femur has been thought to roll back with flexion, and total knee arthroplasty (TKA) prostheses have been designed on this basis. Recent work, however, has proposed that at a position of between 0° and 120° the medial femoral condyle does not move anteroposteriorly whereas the lateral femoral condyle tends, but is not obliged, to roll back - a combination of movements which equates to tibial internal/femoral external rotation with flexion. The aim of this paper was to assess if the articular geometry of the GMK Sphere TKA could recreate the natural knee movements in situ/in vivo. Methods: The pattern of knee movement was studied in 15 patients (six male: nine female; one male with bilateral TKAs) with 16 GMK Sphere implants, at a mean age of 66 years (53 to 76) with a mean BMI of 30 kg/m2 (20 to 35). The motions of all 16 knees were observed using pulsed fluoroscopy during a number of weight-bearing and non-weight-bearing static and dynamic activities. Results: During maximally flexed kneeling and lunging activities, the mean tibial internal rotation was 8° (standard deviation (SD) 6). At a mean 112° flexion (SD 16) during lunging, the medial and lateral condyles were a mean of 2 mm (SD 3) and 8 mm (SD 4) posterior to a transverse line passing through the centre of the medial tibial concavity. With a mean flexion of 117° (SD 14) during kneeling, the medial and lateral condyles were a mean of 1 mm (SD 4) anterior and 6 mm (SD 4) posterior to the same line. During dynamic stair and pivoting activities, there was a mean anteroposterior translation of 0 mm to 2 mm of the medial femoral condyle. Backward lateral condylar translation occurred and was linearly related to tibial rotation. Conclusion: The GMK Sphere TKA in our study group shows movements similar in pattern, although reduced in magnitude, to those in recent reports relating to normal knees during several activities. Specifically, little or no translation of the medial femoral condyle was observed during flexion, but there was posterior roll-back of the lateral femoral condyle, equating to tibiofemoral rotation. We conclude that the GMK Sphere is anteroposteriorly stable medially and permits rotation about the medial compartment

GDF15 promotes weight loss by enhancing energy expenditure in muscle

Funding Information: We thank R. Seeley for sharing GFRAL-null mice; B. Lowell for sharing β-less mice; and J. Wu for shipping β-less mice to us. G.R.S. was supported by a Diabetes Canada Investigator Award (DI-5-17-5302-GS), a Canadian Institutes of Health Research Foundation Grant (201709FDN-CEBA-116200), a Tier 1 Canada Research Chair in Metabolic Diseases and a J. Bruce Duncan Endowed Chair in Metabolic Diseases; D.W. by Fellowship Grants from the McMaster Institute for Research on Aging (MIRA) at McMaster University; S.R. by a postdoctoral fellowship supported by MITACS and Novo Nordisk; L.K.T. by a CIHR Post-Doctoral Fellowship Award and Michael DeGroote Fellowship Award in Basic Biomedical Science; E.M.D. by a Vanier Canada Graduate Scholarship; G.P.H. by the Natural Sciences and Engineering Research Council of Canada (NSERC: 400362); G.J.D. and S.M.F. by NSERC-CGSM scholarships; L.D. by the Fonds de Recherche du Québec-Santé doctoral training award; D.P.B. by the GSK Chair in Diabetes of Université de Sherbrooke and a FRQS J1 salary award. The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health, and by the NCI, NHGRI, NHLBI, NIDA, NIMH and NINDS. Funding Information: S.B.J. and R.E.K. are employees of Novo Nordisk, a pharmaceutical company producing and selling medicine for the treatment of diabetes and obesity. G.R.S. is a co-founder and shareholder of Espervita Therapeutics. McMaster University has received funding from Espervita Therapeutics, Esperion Therapeutics, Poxel Pharmaceuticals and Nestle for research conducted in the laboratory of G.R.S. S.R. is supported by a MITACS postdoctoral fellowship sponsored by Novo Nordisk. H.C.G. holds the McMaster-Sanofi Population Health Institute Chair in Diabetes Research and Care. G.R.S., G.P. and H.C.G. are inventors listed on a patent for identifying GDF15 as a biomarker for metformin. G.R.S. has received consulting/speaking fees from Astra Zeneca, Eli Lilly, Esperion Therapeutics, Merck, Poxel Pharmaceuticals and Cambrian Biosciences. The other authors declare no competing interests. Publisher Copyright: © 2023, The Author(s).Peer reviewedPublisher PD

Flavonoids in prevention of diseases with respect to modulation of Ca-pump function

Flavonoids, natural phenolic compounds, are known as agents with strong antioxidant properties. In many diseases associated with oxidative/nitrosative stress and aging they provide multiple biological health benefits. Ca2+-ATPases belong to the main calcium regulating proteins involved in the balance of calcium homeostasis, which is impaired in oxidative/nitrosative stress and related diseases or aging. The mechanisms of Ca2+-ATPases dysfunction are discussed, focusing on cystein oxidation and tyrosine nitration. Flavonoids act not only as antioxidants but are also able to bind directly to Ca2+-ATPases, thus changing their conformation, which results in modulation of enzyme activity