The phenotype of some late-flowering mutants is enhanced by a locus on chromosome 5 that is not effective in the Landsberg erecta wild-type

Late-flowering mutants that have been described in ecotypes other than Landsberg erecta (Ler) have been found to be dominant alleles of the FRI locus located on chromosome 4, which determines lateness in many very late ecotypes. The extreme lateness of dominant FRI alleles depends on dominant alleles at the FLC locus that maps on the top of chromosome 5. FLC alleles with this effect have been found in all ecotypes tested (Col, Ws, S96, Est and Li) except Ler. Most likely the same locus confers lateness to the luminidependens (ld) mutant. Genotypes with a dominant FRI allele and the monogenic recessive ld mutant are only slightly later with recessive Ler alleles at the FLC locus. Genotypes where the dominant FLC alleles are combined with FRI or with the ld mutant, are strongly responsive to vernalization, which is much less effective in the FLC-Ler background.     

Endogenous cholesterol synthesis is associated with VLDL-2 apoB-100 production in healthy humans

Subjects with high plasma cholesterol levels exhibit a high production of VLDL apolipoprotein B-100 (apoB-100), suggesting that cholesterol is a mediator for VLDL production. The objective of the study was to examine whether endogenous cholesterol synthesis, reflected by the lathosterol-cholesterol ratio (L-C ratio), affects the secretory rates of different VLDL subfractions. Ten healthy subjects were studied after overnight fasting. During a 10 h primed, constant infusion of 13C-valine (15 micromol/kg/h), enrichment was determined in apoB-100 from ultracentrifugally isolated VLDL-1 and VLDL-2 by gas chromatography mass spectrometry. The synthesis rates of VLDL-1 apoB-100 and VLDL-2 apoB-100, catabolism, and transfer were estimated by compartmental analysis. Mean VLDL-1 apoB-100 pool size was 90 +/- 15 mg, and mean VLDL-2 apoB-100 pool size was 111 +/- 14 mg. Absolute synthesis rate of VLDL-1 apoB-100 was 649 +/- 127 mg/day and 353 +/- 59 mg/day for VLDL-2 apoB-100. There was a strong association between the absolute synthesis rate of VLDL-2 apoB-100 and L-C ratio (r 2 = 0.61, P < 0.01). In contrast, no correlation was observed between L-C ratio and absolute synthesis rate of VLDL-1 apoB-100 (r 2 = 0.302, P = 0.09). In conclusion, these data provide additional support for an independent regulation of VLDL-1 apoB-100 and VLDL-2 apoB-100 production.Endogenous cholesterol synthesis is correlated only with the VLDL-2 apoB-100 production.     

CT Coronary Angiography Is Feasible for the Assessment of Coronary Artery Disease in Chronic Dialysis Patients,Despite High Average Calcium Scores

Purpose

Significant obstructive coronary artery disease (CAD) is common in asymptomatic dialysis patients. Identifying these high risk patients is warranted and may improve the prognosis of this vulnerable patient group. Routine catheterization of incident dialysis patients has been proposed, but is considered too invasive. CT-angiography may therefore be more appropriate. However, extensive coronary calcification, often present in this patient group, might hamper adequate lumen evaluation. The objective of this study was to assess the feasibility of CT-angiography in this patient group.

Methods

For this analysis all patients currently participating in the ICD2 trial (ISRCTN20479861), with no history of PCI or CABG were included. The major epicardial vessels were evaluated on a segment basis (segment 1–3, 5–8, 11 and 13) by a team consisting of an interventional and an imaging specialist. Segments were scored as not significant, significant and not interpretable.

Results

A total of 70 dialysis patients, with a mean age of 66±8 yrs and predominantly male (70%) were included. The median calcium score was 623 [79, 1619].Over 90% of the analyzed segments were considered interpretable. The incidence of significant CAD on CT was 43% and was associated with cardiovascular events during follow-up. The incidence of cardiovascular events after 2-years follow-up: 36% vs. 0% in patients with no significant CAD (p<0.01).

Conclusion

Despite the high calcium scores CT-angiography is feasible for the evaluation of the extent of CAD in dialysis patients. Moreover the presence of significant CAD on CT was associated with events during follow-up.     

Identification of Free Nitric Oxide Radicals in Rat Bone Marrow: Implications for Progenitor Cell Mobilization in Hypertension

Nitric oxide (NO) has been implicated in matrix metallopeptidase 9 (MMP9)-dependent mobilization of hematopoietic stem and progenitor cells from bone marrow (BM). However, direct measurement of NO in the BM remained elusive due to its low in situ concentration and short lifetime. Using NO spin trapping and electron paramagnetic resonance (EPR) spectroscopy we give the first experimental confirmation of free NO radicals in rodent BM. NO production was quantified and attributed to enzymatic activity of NO synthases (NOS). Although endothelial NOS (eNOS) accounts for most (66%) of basal NO, we identified a significant contribution (23%) from inducible NOS (iNOS). Basal NO levels closely correlate with MMP9 bioavailability in BM of both hypertensive and control rats. Our observations support the hypothesis that inadequate mobilization of BM-derived stem and progenitor cells in hypertension results from impaired NOS/NO/MMP9 signalling in BM, a condition that may be corrected with pharmacological intervention.     

Optical coherence tomography to detect acute esophageal radiation‐induced damage in mice: A validation study

Radiation therapy for patients with non‐small‐cell lung cancer is hampered by acute radiation‐induced toxicity in the esophagus. This study aims to validate that optical coherence tomography (OCT), a minimally invasive imaging technique with high resolution (~10 μm), is able to visualize and monitor acute radiation‐induced esophageal damage (ARIED) in mice. We compare our findings with histopathology as the gold standard. Irradiated mice receive a single dose of 40 Gy at proximal and distal spots of the esophagus of 10.0 mm in diameter. We scan mice using OCT at two, three, and seven days post‐irradiation. In OCT analysis, we define ARIED as a presence of distorted esophageal layering, change in backscattering signal properties, or change in the esophageal wall thickness. The average esophageal wall thickness is 0.53 mm larger on OCT when ARIED is present based on histopathology. The overall sensitivity and specificity of OCT to detect ARIED compared to histopathology are 94% and 47%, respectively. However, the overall sensitivity of OCT to assess ARIED is 100% seven days post‐irradiation. We validate the capability of OCT to detect ARIED induced by high doses in mice. Nevertheless, clinical studies are required to assess the potential role of OCT to visualize ARIED in humans.      

Differential kinetics of antigen-specific CD4+ and CD8+ T cell responses in the regression of retrovirus-induced sarcomas

Despite the accepted role for CD4+ T cells in immune control, little is known about the development of Ag-specific CD4+ T cell immunity upon primary infection. Here we use MHC class II tetramer technology to directly visualize the Ag-specific CD4+ T cell response upon infection of mice with Moloney murine sarcoma and leukemia virus complex (MoMSV). Significant numbers of Ag-specific CD4+ T cells are detected both in lymphoid organs and in retrovirus-induced lesions early during infection, and they express the 1B11-reactive activation-induced isoform of CD43 that was recently shown to define effector CD8+ T cell populations. Comparison of the kinetics of the MoMSV-specific CD4+ and CD8+ T cell responses reveals a pronounced shift toward CD8+ T cell immunity at the site of MoMSV infection during progression of the immune response. Consistent with an important early role of Ag-specific CD4+ T cell immunity during MoMSV infection, CD4+ T cells contribute to the generation of virus-specific CD8+ T cell immunity within the lymphoid organs and are required to promote an inflammatory environment within the virus-infected tissue.     

The ethics of euthanasia: advocates' perspectives

The Netherlands is currently the only country in the world in which euthanasia is legally permissible. More specifically, Dutch law (briefly explained) allows that a doctor terminates the life of a patient of hers on his voluntary, well-considered and sustained request, if he is suffering unbearably and hopelessly. The aim of this paper is to reconstruct the Dutch debate on the moral permissibility of euthanasia so as to clarify and strengthen the various views that can be advanced in support of euthanasia. On the one view, The Pure Autonomy View (TPAV), the justification of euthanasia rests solely on the principle of respect for autonomy. That is, the reason for performing and permitting euthanasia is the patient's voluntary, well-considered and sustained, in one word: autonomous, request for euthanasia. On the alternative view, The Joint View (TJV), the principle of respect for autonomy and the principle of beneficence morally justify euthanasia together . That is, euthanasia is ethical if and partly because, since the patient is suffering unbearably and hopelessly, euthanasia is in his interest. According to this paper, there is no easy argument for one of these views rather than the other. Instead, as yet both TPAV and TJV seem inherently problematic. TPAV is unable to give a doctor a reason for performing euthanasia that appeals to her in her capacity as a doctor, such as relief of suffering. And TJV begs the question – for example, if a state were to legalize euthanasia on grounds of TJV, it would force the view upon its citizens that it may be in a person's interest to die.