Adenoviral low density lipoprotein receptor attenuates progression of atherosclerosis and decreases tissue cholesterol levels in a murine model of familial hypercholesterolemia

Familial hypercholesterolemia is an autosomal codominant disease characterized by high concentrations of pro-atherogenic lipoproteins and premature atherosclerosis secondary to low density lipoprotein receptor (LDLr) deficiency. In the current study, the effects of gene transfer with 5 x 10(10) particles of E1E3E4-deleted adenoviral vectors expressing the LDLr (AdLDLr) or VLDLr (AdVLDLr) under control of the hepatocyte-specific human alpha(1)-antitrypsin promoter and 4 copies of the human apo E enhancer in C57BL/6 LDLr(-/-) mice were investigated. Evaluation was performed in both sexes and in mice fed either standard chow or an atherogenic diet containing 0.2% cholesterol and 10% coconut oil. Compared to control mice, AdLDLr and AdVLDLr persistently decreased plasma non-HDL cholesterol in both sexes and on both diets. Six months after LDLr gene transfer in mice fed the atherogenic diet, average intimal area was 2.5-fold (p<0.01) and 3.2-fold (p<0.001) lower in male and female mice, respectively, compared to controls. In mice fed standard chow, intimal area was reduced 22-fold (p<0.001) and 21-fold (p<0.001) after LDLr gene transfer in male and female mice, respectively. We show that non-HDL lipoproteins are more atherogenic in female mice, independent of sex differences of plasma HDL cholesterol levels, and that saturated fat does not have an effect on atherosclerosis independent of plasma cholesterol levels. Finally, quantification of tissue cholesterol levels indicates that AdLDLr does not induce cholesterol accumulation in the liver and reduces cholesterol content in the myocardium, quadriceps muscle and kidney. In conclusion, hepatocyte-specific LDLr gene transfer significantly improves cholesterol homeostasis in LDLr(-/-) mice.     

Salt loading affects cortisol metabolism in normotensive subjects: relationships with salt sensitivity

We studied cortisol metabolism together with insulin sensitivity [homeostatic model assessment (HOMA)] and renal hemodynamics in 19 salt-resistant (sr) and nine salt-sensitive (ss) normotensive subjects after a low- and high-salt diet. Results are described as high- vs. low-salt diet. Sum of urinary cortisol metabolite excretion (sum(metabolites)) increased in sr subjects (3.8 +/- 1.6 vs. 3.1 +/- 1.1 microg/min per square meter, P < 0.05) and decreased in ss subjects (2.3 +/- 1.0 vs. 2.9 +/- 1.1 microg/min per square meter, P < 0.05). Plasma 0830 h cortisol decreased in sr subjects but did not change significantly in ss subjects. In all subjects, the absolute blood pressure change correlated negatively with the percentage change in sum(metabolites) (P < 0.05) and positively with the percentage change in renal vascular resistance (P < 0.05). Sum(metabolites) during high-salt diet correlated negatively with the percentage changes in plasma 0830 h cortisol (P < 0.05) and renal vascular resistance (P = 0.05). HOMA did not change in either group, but the percentage change in HOMA correlated positively with the percentage change in plasma cortisol (P = 0.001) and negatively with the percentage change in sum(metabolites) (P < 0.01). Parameters of 11 beta-hydroxysteroid dehydrogenase activity were not different between groups and did not change. In conclusion, these data suggest that cortisol elimination is affected differently after salt loading in sr and ss subjects. Changes in circulating cortisol might contribute to individual sodium-induced alterations in insulin sensitivity.     

Changes in Plant-Based Diet Indices and Subsequent Risk of Type 2 Diabetes in Women and Men: Three U.S. Prospective Cohorts

OBJECTIVEWe evaluated the associations between changes in plant-based diets and subsequent risk of type 2 diabetes.RESEARCH DESIGN AND METHODSWe prospectively followed 76,530 women in the Nurses’ Health Study (NHS) (1986–2012), 81,569 women in NHS II (1991–2017), and 34,468 men in the Health Professionals Follow-up Study (1986–2016). Adherence to plant-based diets was assessed every 4 years with the overall plant-based diet index (PDI), healthful PDI (hPDI), and unhealthful PDI (uPDI). We used multivariable Cox proportional hazards models to estimate hazard ratios (HRs). We pooled results of the three cohorts using meta-analysis.RESULTSWe documented 12,627 cases of type 2 diabetes during 2,955,350 person-years of follow-up. After adjustment for initial BMI and initial and 4-year changes in alcohol intake, smoking, physical activity, and other factors, compared with participants whose indices remained relatively stable (±3%), participants with the largest decrease (>10%) in PDI and hPDI over 4 years had a 12–23% higher diabetes risk in the subsequent 4 years (pooled HR, PDI 1.12 [95% CI 1.05, 1.20], hPDI 1.23 [1.16, 1.31]). Each 10% increment in PDI and hPDI over 4 years was associated with a 7–9% lower risk (PDI 0.93 [0.91, 0.95], hPDI 0.91 [0.87, 0.95]). Changes in uPDI were not associated with diabetes risk. Weight changes accounted for 6.0–35.6% of the associations between changes in PDI and hPDI and diabetes risk.CONCLUSIONSImproving adherence to overall and healthful plant-based diets was associated with a lower risk of type 2 diabetes, whereas decreased adherence to such diets was associated with a higher risk.     

Combined TCRG and TCRA TREC analysis reveals increased peripheral T-lymphocyte but constant intra-thymic proliferative history upon ageing

T-cell receptor (TCR) repertoire diversity, thymic output, clonal size and peripheral T-lymphocyte numbers largely depend on intra-thymic and post-thymic T-lymphocyte proliferation. However, quantitative insight into thymocyte and T-lymphocyte proliferation is still lacking. We developed a new TCRG-based TCR excision circle (TREC) assay, the Vγ-Jγ TREC assay, which we used together with an adjusted δREC-ψJα TREC assay to quantify the proliferative history of human thymocyte and T-lymphocyte subpopulations from children and adults. This revealed that thymocytes undergo ～6–8 intra-thymic cell divisions from the double negative (DN) 3 developmental stage onwards, which appeared independent of age. Thus thymocyte proliferation after the DN3 developmental stages is stable and therefore not contributing to the reduced thymic output upon ageing. Cord blood naive T lymphocytes had already undergone ～2–3 post-thymic cell divisions, which increased to ～6–7 cell divisions in naive T lymphocytes of middle-aged adults, indicating the importance of homeostatic naive T-lymphocyte proliferation from a young age onwards in the maintenance of peripheral T-lymphocyte numbers. In conclusion, our data provide quantitative insight into the proliferative history of thymocyte and T-lymphocyte subpopulations and alterations herein upon ageing. This novel TREC assay approach could prove valuable in immune status monitoring in a variety of conditions.     

Crocidolite and Mesothelioma

This study reports changes in the frequency of detection of various asbestos fiber types between 1982 and 2005. Crocidolite is increasingly detected in U.S. mesothelioma patients. The percentage of crocidolite fibers detected in lung tissue has risen from 4 to 10%, and the percentage of cases in which crocidolite was detected increased from 19 to 37%. Meanwhile, the frequency of detection of amosite and chrysotile has decreased. The authors performed a detailed analysis of cases in which crocidolite was identified in the absence of amosite. Most of such cases were identified in recent years, a finding of concern since crocidolite is considered the most potent fiber type with respect to the pathogenesis of mesothelioma.     

Specific order impairment in arabic number writing: A case‐study

The present study examines the transitory deficit in transcoding verbal to Arabic numbers in an aphasic patient, TM. She showed a mild syntactic impairment in syntactic comprehension of verbal numbers, with preserved performance in comprehension of Arabic numbers, in access to semantic representation, as well as in reading of Arabic numbers, but she committed 75% of errors when required to write numbers in the Arabic format to dictation. In conformity to the previous literature on transcoding deficits, the majority of her errors were syntactic (60%). However, most of them were unusual “order errors” (50%) in which lexical digits (e.g., 1 to 9) were written on the left and zeros on the right of the number, which contained in the majority of the cases the correct number of digits. A similar type of errors has been reported in only one previous case study (Delazer & Denes, 1998), but not specifically studied. We discuss hypotheses concerning its origins as stemming from a syntactic disorder within existing models of transcoding (McCloskey, Caramazza, & Basili, 1985; Power & Dal Martello, 1990). We also report kinematic assessment of the patient's handwriting before and after recovery. At time of the second examination, results show that her pattern of movement fluency parallels that of healthy subjects and supports a distinction between two types of zeros within Arabic numbers, in relation to the verbal code and the rules required to produce them. This paper thus also highlights the potential usefulness of using a digitising tablet in the study of transcoding deficits.     

NK cells – Versatile tools for viral defense and cancer treatment

About 150 NK cell researchers met at the German Cancer Research Center (DKFZ) in Heidelberg, Germany from 26–28 September 2012 for the Natural Killer Cell Symposium which was organized by the NK cell study group of the German Society for Immunology (DGfI) and sponsored by the European Journal of Immunology (EJI), the European Federation of Immunological Societies (EFIS) and the DGfI. The meeting was a forum for the discussion of the function and regulation of these fascinating innate immune cells and the opportunities for the transfer of this knowledge to cancer immunotherapy.     

Human and Animal Isolates of Yersinia enterocolitica Show Significant Serotype-Specific Colonization and Host-Specific Immune Defense Properties

Yersinia enterocolitica is a human pathogen that is ubiquitous in livestock, especially pigs. The bacteria are able to colonize the intestinal tract of a variety of mammalian hosts, but the severity of induced gut-associated diseases (yersiniosis) differs significantly between hosts. To gain more information about the individual virulence determinants that contribute to colonization and induction of immune responses in different hosts, we analyzed and compared the interactions of different human- and animal-derived isolates of serotypes O:3, O:5,27, O:8, and O:9 with murine, porcine, and human intestinal cells and macrophages. The examined strains exhibited significant serotype-specific cell binding and entry characteristics, but adhesion and uptake into different host cells were not host specific and were independent of the source of the isolate. In contrast, survival and replication within macrophages and the induced proinflammatory response differed between murine, porcine, and human macrophages, suggesting a host-specific immune response. In fact, similar levels of the proinflammatory cytokine macrophage inflammatory protein 2 (MIP-2) were secreted by murine bone marrow-derived macrophages with all tested isolates, but the equivalent interleukin-8 (IL-8) response of porcine bone marrow-derived macrophages was strongly serotype specific and considerably lower in O:3 than in O:8 strains. In addition, all tested Y. enterocolitica strains caused a considerably higher level of secretion of the anti-inflammatory cytokine IL-10 by porcine than by murine macrophages. This could contribute to limiting the severity of the infection (in particular of serotype O:3 strains) in pigs, which are the primary reservoir of Y. enterocolitica strains pathogenic to humans.