Everolimus immunosuppression in de novo heart transplant recipients: What does the evidence tell us now?

The efficacy of everolimus with reduced cyclosporine in de novo heart transplant patients has been demonstrated convincingly in randomized studies. Moreover, everolimus-based immunosuppression in de novo heart transplant recipients has been shown in two randomized trials to reduce the increase in maximal intimal thickness based on intravascular ultrasound, indicating attenuation of cardiac allograft vasculopathy (CAV). Randomized trials of everolimus in de novo heart transplantation have also consistently shown reduced cytomegalovirus infection versus antimetabolite therapy. In maintenance heart transplantation, conversion from calcineurin inhibitors to everolimus has demonstrated a sustained improvement in renal function. In de novo patients, a renal benefit may only be achieved if there is an adequate reduction in exposure to calcineurin inhibitor therapy. Delayed introduction of everolimus may be appropriate in patients at high risk of wound healing complications, e.g. diabetic patients or patients with ventricular assist device. The current evidence base suggests that the most convincing reasons for use of everolimus from the time of heart transplantation are to slow the progression of CAV and to lower the risk of cytomegalovirus infection. A regimen of everolimus with reduced-exposure calcineurin inhibitor and steroids in de novo heart transplant patients represents a welcome addition to the therapeutic armamentarium.     

causing amyloid angiopathy and brain hemorrhage - clinical genetics in Iceland

Firstly, we review investigations of hereditary cystatin C amyloid angiopathy, which is caused by a mutation in the cystatin C gene. Symptoms of brain haemorrhages, which lead to death in young adults, are the hallmark of this disorder. The mutation can now be detected by the RFLP method using Alu I restriction enzyme and cystatin C cDNA probe. Secondly, we give an overview of other clinical genetic studies in Iceland with emphasis on activities initiated or sponsored by the Genetical Committee of the University of Iceland. The list of references covers most publications on genetic studies of Icelanders.     

Genetic evidence for three unique components in primary cell-wall cellulose synthase complexes in Arabidopsis

In higher plants, cellulose is synthesized at the plasma membrane by the cellulose synthase (CESA) complex. The catalytic core of the complex is believed to be composed of three types of CESA subunits. Indirect evidence suggests that the complex associated with primary wall cellulose deposition consists of CESA1, -3, and -6 in Arabidopsis thaliana. However, phenotypes associated with mutations in two of these genes, CESA1 and -6, suggest unequal contribution by the different CESAs to overall enzymatic activity of the complex. We present evidence that the primary complex requires three unique types of components, CESA1-, CESA3-, and CESA6-related, for activity. Removal of any of these components results in gametophytic lethality due to pollen defects, demonstrating that primary-wall cellulose synthesis is necessary for pollen development. We also show that the CESA6-related CESAs are partially functionally redundant.     

Dietary Polyunsaturated Fatty Acids Increase Survival and Decrease Bacterial Load during Septic Staphylococcus aureus Infection and Improve Neutrophil Function in Mice

Severe infection, including sepsis, is an increasing clinical problem that causes prolonged morbidity and substantial mortality. At present, antibiotics are essentially the only pharmacological treatment for sepsis. The incidence of resistance to antibiotics is increasing; therefore, it is critical to find new therapies for sepsis. Staphylococcus aureus is a major cause of septic mortality. Neutrophils play an important role in the defense against bacterial infections. We have shown that a diet with high levels of dietary saturated fatty acids decreases survival in septic mice, but the mechanisms behind this remain elusive. The aim of the present study was to investigate how the differences in dietary fat composition affect survival and bacterial load after experimental septic infection and neutrophil function in uninfected mice. We found that, after S. aureus infection, mice fed a polyunsaturated high-fat diet (HFD-P) for 8 weeks had increased survival and decreased bacterial load during sepsis compared with mice fed a saturated high-fat diet (HFD-S), similar to mice fed a low-fat diet (LFD). Uninfected mice fed HFD-P had a higher frequency of neutrophils in bone marrow than mice fed HFD-S. In addition, mice fed HFD-P had a higher frequency of neutrophils recruited to the site of inflammation in response to peritoneal injection of thioglycolate than mice fed HFD-S. Differences between the proportion of dietary protein and carbohydrate did not affect septic survival at all. In conclusion, polyunsaturated dietary fat increased both survival and efficiency of bacterial clearance during septic S. aureus infection. Moreover, this diet increased the frequency and chemotaxis of neutrophils, key components of the immune response to S. aureus infections.     

Circulating oxidized low-density lipoprotein is associated with echolucent plaques in the femoral artery independently of hsCRP in 61-year-old men

OBJECTIVES: The aim of the study was to test the hypothesis that circulating markers of inflammation (high-sensitive C-reactive protein, hsCRP) and oxidative modification of lipids (oxidized low-density lipoprotein, oxLDL) were associated with the occurrence of echolucent rather than echogenic femoral artery plaques in a cross-sectional population based cohort of 513, 61-year-old men. BACKGROUND: The relationships between circulating oxLDL, hsCRP and the occurrence of echolucent plaques in the femoral artery have not previously been investigated. METHODS: The levels of circulating oxLDL and hsCRP were determined in plasma by ELISA. Plaque occurrence, size and echogenicity were measured by B-mode ultrasound in the right femoral artery. Assessment of plaque echogenicity was based on the classification (grades 1-4) proposed by Gray-Weale et al. RESULTS: A higher frequency of echolucent femoral plaques was observed in subjects with the metabolic syndrome and current smokers (p=0.01 and p<0.001, respectively) as well as with increasing levels of oxLDL and hsCRP (p=0.002 and p=0.005, respectively). In a multiple logistic regression analysis oxLDL and current smokers turned out to be independent associated with the presence of echolucent femoral artery plaques. CONCLUSIONS: The results of the present study support our hypothesis that circulating oxLDL is a marker of an unstable echolucent plaque phenotype in the femoral artery in man.     

Restoration of muscle volume and shape induced by electrical stimulation of denervated degenerated muscles: qualitative and quantitative measurement of changes in rectus femoris using computer tomography and image segmentation

Abstract:  This study demonstrates in a novel way how volume and shape are restored to denervated degenerated muscles due to a special pattern of electrical stimulation. To this purpose, Spiral Computer Tomography (CT) and special image processing tools were used to develop a method to isolate the rectus femoris from other muscle bellies in the thigh and monitor growth and morphology changes very accurately. During 4 years of electrical stimulation, three-dimensional (3D) reconstructions of the rectus femoris muscles from patients with long-term flaccid paraplegia were made at different points in time. The growth of the muscle and its changes through the time period are seen in the 3D representation and are measured quantitatively. Furthermore, changes in shape are compared with respect to healthy muscles in order to estimate the degree of restoration. The results clearly show a slow but continuing muscle growth induced by electrical stimulation; the increase of volume is accompanied by the return of a quasi-normal muscle shape. This technique allows a unique way of monitoring which provides qualitative and quantitative information on the denervated degenerated muscle behavior otherwise hidden.     

Metabolic markers in relation to nutrition and growth in healthy 4-y-old children in Sweden

BACKGROUND: The worldwide increase in overweight and obesity probably involves dietary factors, and early indicators of risk must be identified. OBJECTIVE: We aimed to analyze metabolic markers in relation to dietary intake and anthropometry in healthy 4-y-old children. DESIGN: A cross-sectional study of nutritional intake was performed in 95 children by use of 7-d food records. Fasting blood samples were analyzed for glucose, insulin, and lipids. RESULTS: The study population was representative of Swedish children except that more parents than the average had a university education. The boys' mean energy intake was higher (6.6 +/- 0.75 MJ) than the girls' (5.7 +/- 0.79 MJ). Significant associations were found between the percentage of energy from carbohydrates and that from fat (r = -0.91) and sucrose (r = 0.59). High body mass index was associated with a low percentage of energy from fat (r = -0.32). Serum triacylglycerol, insulin, and the HOMA (homeostatic model assessment) index were higher in girls than in boys. In girls, HOMA beta-cell function was significantly negatively associated with fat intake and serum fasting insulin, and HOMA insulin resistance indexes were significantly associated with the increment in z scores for height and weight from birth to age 4 y. Compared with children with fasting insulin concentrations below the group mean + SD, the children with concentrations above that value were smaller as newborns and had larger increments in growth z scores from birth to age 4 y. CONCLUSION: In healthy Swedish 4-y-olds from well-educated families, low fat intake was related to high body mass index. Upward weight and height percentile crossings were related to insulin resistance, especially in girls.