Tissue-, sex-, and age-specific DNA methylation of rat glucocorticoid receptor gene promoter and insulin-like growth factor 2 imprinting control region.

Tissue-, sex-, and age-specific epigenetic modifications such as DNA methylation are largely unknown. Changes in DNA methylation of the glucocorticoid receptor gene (NR3C1) and imprinting control region (ICR) of IGF2 and H19 genes during the lifespan are particularly interesting since these genes are susceptible to epigenetic modifications by prenatal stress or malnutrition. They are important regulators of development and aging. Methylation changes of NR3C1 affect glucocorticoid receptor expression, which is associated with stress sensitivity and stress-related diseases predominantly occurring during aging. Methylation changes of IGF2/H19 affect growth trajectory and nutrient use with risk of metabolic syndrome. Using a locus-specific approach, we characterized DNA methylation patterns of different Nr3c1 promoters and Igf2/H19 ICR in seven tissues of rats at 3, 9, and 24 mo of age. We found a complex pattern of locus-, tissue-, sex-, and age-specific DNA methylation. Tissue-specific methylation was most prominent at the shores of the Nr3c1 CpG island (CGI). Sex-specific differences in methylation peaked at 9 mo. During aging, Nr3c1 predominantly displayed hypomethylation mainly in females and at shores, whereas hypermethylation occurred within the CGI. Igf2/H19 ICR exhibited age-related hypomethylation occurring mainly in males. Methylation patterns of Nr3c1 in the skin correlated with those in the cortex, hippocampus, and hypothalamus. Skin may serve as proxy for methylation changes in central parts of the hypothalamic-pituitary-adrenal axis and hence for vulnerability to stress- and age-associated diseases. Thus, we provide in-depth insight into the complex DNA methylation changes of rat Nr3c1 and Igf2/H19 during aging that are tissue and sex specific.

Transfer of maternal psychosocial stress to the fetus.

Psychosocial maternal stress experienced during different vulnerable periods throughout gestation is thought to increase the individual's risk to develop neuropsychiatric, cardiovascular and metabolic disease in later life. Cortisol has generally been identified as the major mediator of maternal stress transfer to the fetus. Its lipophilic nature allows a trans-placental passage and thus excessive maternal cortisol could persistently impair the development of the fetal hypothalamic-pituitary-adrenal axis (HPAA). However, cortisol alone cannot fully explain all effects of maternal stress especially during early to mid pregnancy before maturation of the fetal HPAA has even begun and expression of fetal glucocorticoid receptors is limited. This review focuses on mediators of maternal fetal stress transfer that in addition to cortisol have been proposed as transmitters of maternal stress: catecholamines, cytokines, serotonin/tryptophan, reactive-oxygen-species and the maternal microbiota. We propose that the effects of psychosocial maternal stress on fetal development and health and disease in later life are not a consequence of a single pathway but are mediated by multiple stress-transfer mechanisms acting together in a synergistic manner.

Cerebral involvement in a patient with Goodpasture's disease due to shortened induction therapy: a case report.

INTRODUCTION: Goodpasture's disease is a rare immunological disease with formation of pathognomonic antibodies against renal and pulmonary basement membranes. Cerebral involvement has been reported in several cases in the literature, yet the pathogenetic mechanism is not entirely clear. CASE PRESENTATION: A 21-year-old Caucasian man with Goodpasture's disease and end-stage renal disease presented with two generalized seizures after a period of mild cognitive disturbance. Blood pressure and routine laboratory tests did not exceed the patient's usual values, and examination of cerebrospinal fluid was unremarkable. Cerebral magnetic resonance imaging (MRI) revealed multiple cortical and subcortical lesions on fluid-attenuated inversion recovery sequences. Since antiglomerular basement membrane antibodies were found to be positive with high titers, plasmapheresis was started. In addition, cyclophosphamide pulse therapy was given on day 13. Encephalopathy and MRI lesions disappeared during this therapy, and antiglomerular basement membrane antibodies were significantly reduced. Previous immunosuppressive therapy was performed without corticosteroids and terminated early after 3 months. The differential diagnostic considerations were cerebral vasculitis and posterior reversible encephalopathy syndrome. Vasculitis could be seen as an extrarenal manifestation of the underlying disease. Posterior reversible encephalopathy syndrome, on the other hand, can be triggered by immunosuppressive therapy and may appear without a hypertensive crisis. CONCLUSION: A combination of central nervous system symptoms with a positive antiglomerular basement membrane test in a patient with Goodpasture's disease should immediately be treated as an acute exacerbation of the disease with likely cross-reactivity of antibodies with the choroid plexus. In our patient, a discontinuous strategy of immunosuppressive therapy may have favored recurrence of Goodpasture's disease.

Distribution spectrum of paraoxonase activity in HDL fractions.

BACKGROUND: Paraoxonase (PON1) associated with HDL can be regarded as a cardio- and vasoprotective enzyme. However, because HDL is not a homogeneous fraction, it is important to investigate in which subgroups of HDL active PON1 is located. It would also be useful to determine density profiles of the HDL apolipoproteins (Apo) E and J. METHODS: We investigated the density range of HDL (rho = 1.063-1.256 kg/L) in healthy individuals, using the ultracentrifugation reference method and a newly introduced automated fractionation method. Profiles of PON1 activity and ApoA-I, ApoA-II, ApoE, ApoJ, and cholesterol concentrations were obtained by use of various density gradients. RESULTS: PON1 activity was highest in the more dense HDL(3) and VHDL fractions where PON1 was not dissociated from the particles during centrifugation. The fraction in density range 1.175-1.185 kg/L showed not only the highest PON1 activity, but also the highest specific activity (activity per HDL particle). This fraction was the least-dense fraction containing both ApoE and ApoJ. Only the Q192R polymorphism had an effect on the distribution profile of PON1 activity. In contrast, L55M and the T(-107)C polymorphisms (determined by a novel nonradioactive method) were without effect on the density distribution of PON1 activity. CONCLUSION: The HDL(3) fraction, which is important in reverse cholesterol transport, also carries the highest PON1 activity.