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- Arora, Satish, et al.
(författare)
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Virtual Histology Assessment of Cardiac Allograft Vasculopathy Following Introduction of Everolimus—Results of a Multicenter Trial
- 2012
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Ingår i: American Journal of Transplantation. - : Wiley-Blackwell. - 1600-6135 .- 1600-6143. ; 12:10, s. 2700-2709
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Tidskriftsartikel (refereegranskat)abstract
- In this 12-month multicenter Scandinavian study, 78 maintenance heart transplant (HTx) recipients randomized to everolimus with reduced calcineurin inhibitor (CNI) exposure or continued standard CNI-therapy underwent matched virtual histology (VH) examination to evaluate morphological progression of cardiac allograft vasculopathy (CAV). Parallel measurement of a range of inflammatory markers was also performed. A similar rate of quantitative CAV progression was observed in the everolimus (n = 30) and standard CNI group (n = 48) (plaque index 1.9 +/- 3.8% and 1.6 +/- 3.9%, respectively; p = 0.65). However, VH analysis revealed a significant increase in calcified (2.4 +/- 4.0 vs. 0.3 +/- 3.1%; p = 0.02) and necrotic component (6.5 +/- 8.5 vs. 1.1 +/- 8.6%; p = 0.01) among everolimus patients compared to controls. The increase in necrotic and calcified components was most prominent in everolimus patients with time since HTx andgt;5.1 years and was accompanied by a significant increase in levels of von Willebrand (vWF) factor (p = 0.04) and vascular cell adhesion molecule (VCAM) (p = 0.03). Conversion to everolimus and reduced CNI is associated with a significant increase in calcified and necrotic intimal components and is more prominent in patients with a longer time since HTx. A significant increase in vWF and VCAM accompanied these qualitative changes and the prognostic implication of these findings requires further investigation.
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- Chisalita, Simona I., 1972-
(författare)
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Expression and function of IGF-I and insulin receptors in human micro- and macrovascular cells
- 2008
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Insulin-like growth factor and insulin are phylogenetically closely related polypeptides and have large structural and biological similarities. Low circulating insulin-like growth factor-I (IGF-I), diabetes as well as insulin resistance have been implicated in the pathogenesis of cardiovascular disease, but the mechanisms involved are still not clear. Furthermore, little is known about direct effects of insulin-like growth factor-I (IGF-I) and insulin on human micro- and macrovascular cells.In these studies we investigated the expression and function of insulin-like growth factor-I receptors (IGF-IR) and insulin receptors (IR) in human micro- and macrovascular endothelial cells and in human coronary artery smooth muscle cells.Our results showed expression of both IGF-IR and IR in human dermal microvascular (HMVEC), aortic (HAEC) umbilical vein (HUVEC) and coronary artery (HCAEC) endothelial cells as well as in human coronary artery smooth muscle cells (HASMC). The gene expression of IGF-IR was several times more abundant than that of IR. Ligand binding studies confirmed that the IGF-IR was severalfold more abundant than the IR. It also demonstrated that insulin and glargine interacted with the IGF-IR with thousand- and hundredfold, respectively, less potency than IGF-I itself. The presence of IGF-IR and IR proteins and activation of their β-subunits was revealed by immunoprecipitation and Western blot analysis in human macrovascular endothelial cells and in coronary artery smooth muscle cells. At physiological concentrations (≤10-9 M) IGF-I and insulin activated their cognate receptors. The presence of hybrid IR/IGF-IR was shown through detection of the β-subunit for IGF-IR and IR on the same membrane by Western blot after immunoprecipitation with specific antibodies against either IGF-IR or IR, implying coprecipitation of the IGF-IR β-subunit and the IR β-subunit. The inability of physiological concentrations of insulin to phosphorylate IR β-subunit immunoprecipitated with IGF-IR antibodies and that IGF-I at physiological concentration activates the IR β-subunit is another evidence for the presence of the hybrid IR/IGF-IR. At physiological concentrations (≤10-9 M) IGF-I stimulated DNA synthesis and glucose incorporation into human coronary artery smooth muscle cells (HCASMC) and DNA synthesis in microvascular endothelial cells (HMVEC), but not in human macrovascular endothelial cells (HCAEC or HUVEC). No effect of insulin was found. Although physiological concentrations of insulin (≤10-9 M) were able to activate IR, insulin had no biological effects on the vascular cells studied. A possible explanation is that the insulin receptor signalling is too attenuated due to the presence of hybrid IR/IGF-IR and low number of IR expressed in the cells studied. Regarding the safety in the use of glargine, we show that glargine has 10-fold higher affinity for IGF-IR than human insulin. However, the glargine concentrations obtained in vivo during diabetes treatment is too low to affect the IGF-IR.In conclusions our studies provide experimental evidence that human micro- and macrovascular endothelial and vascular smooth muscle cells express both IGF-IR and IR. Our in vitro data suggest that the cells studied are sensitive to IGF-I, but insensitive to insulin and this is due to the preponderance of IGF-IR and presence of hybrid IR/IGF-IR.
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- Hanås, Ragnar, 1951, et al.
(författare)
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Indwelling catheters used from the onset of diabetes decrease injection pain and pre-injection anxiety
- 2002
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Ingår i: J Pediatr. - : Elsevier BV. - 0022-3476 .- 0022-3476 .- 1097-6833. ; 140:3, s. 315-20
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: To investigate the use of indwelling catheters as injection aids at diabetes onset to reduce injection pain and pre-injection anxiety. STUDY DESIGN: Forty-one patients aged 8.1 +/- 3.7 years (range, 1-15) participated in this open, controlled randomized study. A 10-cm VAS with faces was used for scoring. A local anesthetic cream was used before all insertions. The control group used insulin pens with standard needles. After one week, the indwelling catheter group could choose regular injections but were included in the "intention to treat" analysis. RESULTS: Injection pain and anxiety decreased from day 1 to 15 in both groups (average, 4.1 injections/day). Pain was significantly lower for indwelling catheter injections when scored by parents (median, 1.2 cm vs 2.7 cm; P =.002), children/teenagers (0.8 cm vs 1.5 cm; P =.006), and nurses (1.4 cm vs 3.0 cm; P =.002). Parental pre-injection anxiety was also lower (1.2 cm vs 2.9 cm; P =.016). Taking injections, including inserting catheters, was found to be less problematic with an indwelling catheter (1.6 cm vs 3.3 cm;P =.009). During the 6-month follow-up, injection pain and injection problems were significantly lower in the catheter group. Mean catheter indwelling time was 3.7 days. Median pain for catheter insertion was 2.1 cm and for glucose testing was 0.9 cm. Sixteen of 20 patients continued to use indwelling catheters after 2 weeks, and 9 of 20 after 6 months. CONCLUSIONS: We found an evident relief of pre-injection anxiety and injection pain when using indwelling catheters for introducing insulin injections at the onset of diabetes.
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- I. Fernlund, Eva, et al.
(författare)
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Novel Genetic Variants in BAG3 and TNNT2 in a Swedish Family with a History of Dilated Cardiomyopathy and Sudden Cardiac Death
- 2017
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Ingår i: Pediatric Cardiology. - : Springer Science and Business Media LLC. - 0172-0643 .- 1432-1971. ; 38:6, s. 1262-1268
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Tidskriftsartikel (refereegranskat)abstract
- Familial dilated cardiomyopathy is a rare cause of dilated cardiomyopathy (DCM), especially in childhood. Our aim was to describe the clinical course and the genetic variants in a family where the proband was a four-month-old infant presenting with respiratory problems due to DCM. In the family, there was a strong family history of DCM and sudden cardiac death in four generations. DNA was analyzed initially from the deceased girl using next-generation sequencing including 50 genes involved in cardiomyopathy. A cascade family screening was performed in the family after identification of the TNNT2 and the BAG3 variants in the proband. The first-degree relatives underwent clinical examination including biochemistry panel, cardiac ultrasound, Holter ECG, exercise stress test, and targeted genetic testing. The index patient presented with advanced DCM. After a severe clinical course, the baby had external left ventricular assist as a bridge to heart transplantation. 1.5 months after transplantation, the baby suffered sudden cardiac death (SCD) despite maximal treatment in the pediatric intensive care unit. The patient was shown to carry two heterozygous genetic variants in the TNNT2 gene [TNNT2 c.518G>A(p.Arg173Gln)] and BAG3 [BAG3 c.785C>T(p.Ala262Val)]. Two of the screened individuals (two females) appeared to carry both the familial variants. All the individuals carrying the TNNT2 variant presented with DCM, the two adult patients had mild or moderate symptoms of heart failure and reported palpitations but no syncope or presyncopal attacks prior to the genetic diagnosis. The female carriers of TNNT2 and BAG3 variants had more advanced DCM. In the family history, there were three additional cases of SCD due to DCM, diagnosed by autopsy, but no genetic analysis was possible in these cases. Our findings suggest that the variants in TNNT2 and BAG3 are associated with a high propensity to life-threatening cardiomyopathy presenting from childhood and young adulthood.
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- Jansson, Desirée, et al.
(författare)
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Intestinal spirochaetes (genus Brachyspira) colonise wild birds in the southern Atlantic region and Antarctica
- 2015
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Ingår i: Infection Ecology & Epidemiology. - : Informa UK Limited. - 2000-8686 .- 2000-8686. ; 5
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: The genus Brachyspira contains well-known enteric pathogens of veterinary significance, suggested agents of colonic disease in humans, and one potentially zoonotic agent. There are recent studies showing that Brachyspira are more widespread in the wildlife community than previously thought. There are no records of this genus in wildlife from the southern Atlantic region and Antarctica. Our aim was therefore, to determine whether intestinal spirochaetes of genus Brachyspira colonise marine and coastal birds in this region.METHOD: Faecal samples were collected from marine and coastal birds in the southern Atlantic region, including sub-Antarctic islands and Antarctica, in 2002, 2009, and 2012, with the aim to isolate and characterise zoonotic agents. In total, 205 samples from 11 bird species were selectively cultured for intestinal spirochaetes of genus Brachyspira. To identify isolates to species level, they were subjected to phenotyping, species-specific polymerase chain reactions, sequencing of partial 16S rRNA, NADH oxidase (nox), and tlyA genes, and phylogenetic analysis. Antimicrobial susceptibility tests were performed.RESULTS: Fourteen unique strains were obtained from 10 birds of three species: four snowy sheathbills (Chionis albus), three kelp geese (Chloephaga hybrida subsp. malvinarum), and three brown skua (Stercorarius antarcticus subsp. lonnbergi) sampled on the Falkland Islands, Tierra del Fuego in Argentina, South Georgia, South Shetland Islands, and the Antarctic Peninsula. Five Brachyspira strains were closely related to potentially enteropathogenic Brachyspira sp. of chickens: B. intermedia (n=2, from snowy sheathbills), and B. alvinipulli (n=3, from a kelp goose and two snowy sheathbills). Three strains from kelp geese were most similar to the presumed non-pathogenic species 'B. pulli' and B. murdochii, whereas the remaining six strains could not be attributed to currently known species. No isolates related to human strains were found. None of the tested strains showed decreased susceptibility to tiamulin, valnemulin, doxycycline, tylvalosin, lincomycin, or tylosin.CONCLUSIONS: This is the first report of intestinal spirochaetes from this region. Despite limitations of current diagnostic methods, our results, together with earlier studies, show that Brachyspira spp., including potentially pathogenic strains, occur globally among free-living avian hosts, and that this genus encompasses a higher degree of biodiversity than previously recognised.
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