Universal DNA methylation age across mammalian tissues.

Aging, often considered a result of random cellular damage, can be accurately estimated using DNA methylation profiles, the foundation of pan-tissue epigenetic clocks. Here, we demonstrate the development of universal pan-mammalian clocks, using 11,754 methylation arrays from our Mammalian Methylation Consortium, which encompass 59 tissue types across 185 mammalian species. These predictive models estimate mammalian tissue age with high accuracy (r > 0.96). Age deviations correlate with human mortality risk, mouse somatotropic axis mutations and caloric restriction. We identified specific cytosines with methylation levels that change with age across numerous species. These sites, highly enriched in polycomb repressive complex 2-binding locations, are near genes implicated in mammalian development, cancer, obesity and longevity. Our findings offer new evidence suggesting that aging is evolutionarily conserved and intertwined with developmental processes across all mammals.

High Oestradiol Replacement Reverses Response Memory Bias in Ovariectomised Female Rats Regardless of Dopamine Levels in the Dorsal Striatum.

Oestrogens influence memory system bias in female rats such that high levels of oestrogen are associated with place (or spatial) memory use, and low oestrogen levels with response (or habitual) memory use. Moreover, striatal-dependent response memory is sensitive to dopamine transmission in the dorsal striatum, and oestrogens have been shown to affect dopamine release in that brain area. In the present study, the effects of oestrogens and dopamine transmission on multiple memory system bias were explored in ovariectomised rats receiving low or high 17ß-oestradiol replacement under saline, autoreceptor-activating doses of the dopamine D2 receptor agonist, apomorphine (50 and 80 µg/kg), or amphetamine (0.5 mg/kg) administration. Furthermore, dorsal striatal dopamine release was measured after administration of the same drug conditions using in vivo microdialysis. As expected, high oestradiol rats predominantly used place memory, whereas the opposite pattern was observed in low oestradiol rats. However, the high apomorphine dose statistically significantly altered memory bias in high oestradiol rats from predominant place to predominant response memory, with a similar trend in the low apomorphine dose and the amphetamine group. There was no effect of drugs on memory bias in low oestradiol rats. Rats with high oestradiol replacement receiving amphetamine exhibited greater dorsal striatal dopamine release than low oestradiol replacement rats, and this difference was amplified in the right hemisphere. Furthermore, a logistic regression analysis revealed that oestradiol, but not dorsal striatal dopamine levels, significantly predicted response memory bias. These findings provide further evidence that oestradiol modulates memory system bias, and also that memory bias is changed by systemic apomorphine administration. However, although oestradiol affects dopamine transmission in the dorsal striatum in a lateralised manner, this does not predict memory system bias.

The neural substrates for the rewarding and dopamine-releasing effects of medial forebrain bundle stimulation have partially discrepant frequency responses.

Midbrain dopamine neurons have long been implicated in the rewarding effect produced by electrical brain stimulation of the medial forebrain bundle (MFB). These neurons are excited trans-synaptically, but their precise role in intracranial self-stimulation (ICSS) has yet to be determined. This study assessed the hypothesis that midbrain dopamine neurons are in series with the directly stimulated substrate for self-stimulation of the MFB and either perform spatio-temporal integration of synaptic input from directly activated MFB fibers or relay the results of such integration to efferent stages of the reward circuitry. Psychometric current-frequency trade-off functions were derived from ICSS performance, and chemometric trade-off functions were derived from stimulation-induced dopamine transients in the nucleus accumbens (NAc) shell, measured by means of fast-scan cyclic voltammetry. Whereas the psychometric functions decline monotonically over a broad range of pulse frequencies and level off only at high frequencies, the chemometric functions obtained with the same rats and electrodes are either U-shaped or level off at lower pulse frequencies. This discrepancy was observed when the dopamine transients were recorded in either anesthetized or awake subjects. The lack of correspondence between the psychometric and chemometric functions is inconsistent with the hypothesis that dopamine neurons projecting to the NAc shell constitute an entire series stage of the neural circuit subserving self-stimulation of the MFB.

Is a good perioperative echocardiographic result predictive of durability in ischemic mitral valve repair?

BACKGROUND: Chronic ischemic mitral regurgitation is associated with poor long-term survival. Despite the increasing popularity of valve repair, its durability and long-term outcome for ischemic mitral regurgitation have recently been questioned. METHODS: Seventy-eight patients underwent repair for ischemic mitral regurgitation between 1996 and 2002 at our institution. Of these patients, 73 had complete clinical and echocardiographic follow-up. Preoperative, intraoperative, and postoperative clinical data were obtained, and the results of echocardiograms were reviewed to assess the rate of recurrence of regurgitation after repair and to identify predictive factors. RESULTS: The mean preoperative mitral regurgitation grade, New York Heart Association class, and left ventricular ejection fraction were 2.72, 2.65, and 39.4%, respectively. Mortality was 12.3% at 30 days and 30.1% at a mean follow-up of 39 +/- 25 months. Immediate postoperative echocardiography showed absent or mild mitral regurgitation in 89.4% of patients and showed moderate mitral regurgitation in 10.6%. Freedom from reoperation was 93.2%. Recurrent moderate mitral regurgitation (2+) was present in 36.7% of patients, and severe mitral regurgitation (3+ to 4+) was present in 20.0% at mean follow-up of 28.1 +/- 22.5 months. Only age (P = .0130) and less marked preoperative posterior tethering (P = .0362) were predictive of recurrent mitral regurgitation. Patients with a preoperative New York Heart Association class greater than II and recurrent mitral regurgitation greater than 2+ had decreased survival (P = .0152 and P = .0450, respectively). CONCLUSIONS: Significant recurrent mitral regurgitation occurs following repair for ischemic mitral regurgitation, despite good early results. This finding raises questions about the need for improved repair techniques, better patient selection, or eventual mitral valve replacement in selected patients.

Characterization of the subventricular zone of the adult human brain: evidence for the involvement of Bcl-2.

The subventricular zone (SVZ) is an embryonic remnant that persists and remains mitotically active throughout adulthood. The rodent SVZ harbors neuronal precursors, principally in its anterior part, and generates neuroblasts that migrate tangentially into the olfactory bulb, thus forming the so-called rostral migratory stream. This study aimed at characterizing the SVZ in the human brain. Antibodies raised against the widely used SVZ molecular markers nestin, glial fibrillary acidic protein, beta-tubulin-III and polysialylated neural cell adhesion molecule, have allowed us to characterize in detail a zone similar to the rodent SVZ in humans. Virtually all portions of the lateral ventricle, as well as the ventral (hypothalamic) sector of the third ventricle, displayed immunoreactivity for most of the molecular markers. The midline region of the septum (septal recess) and the ventral portion of the SVZ displayed a particularly intense immunostaining for all SVZ markers. These two regions may represent zones of adult neurogenesis that are unique to primates. Furthermore, the anti-apoptotic protein Bcl-2 was found to be actively synthesized and co-expressed with all the other markers throughout the entire SVZ. This study reveals that a well-developed SVZ exists in the adult human brain and suggests that Bcl-2 might play an important role in the functional organization of such a system.

Dopaminergic innervation of human basal ganglia.

This paper summarises the results of some of our recent tyrosine hydroxylase (TH) immunohistochemical studies of the dopaminergic innervation of the human basal ganglia. It also reports new findings on the presence of TH-immunoreactive (ir) neurons in the striatum. Our data show the existence of nigrostriatal TH-ir axons that provide collaterals arborizing in the globus pallidus and subthalamic nucleus. These thin and varicose collaterals emerge from thick and smooth axons that course along the main output pathways of the basal ganglia, including the ansa lenticularis, the lenticular fasciculus and Wilson's pencils. We postulate that this extrastriatal innervation, which allows nigral dopaminergic neurons to directly affect the pallidum and subthalamic nucleus, plays a critical role in the functional organisation of human basal ganglia. The TH-ir fibres that reach the striatum arborize according to a highly heterogeneous pattern. At rostral striatal levels, numerous small TH-poor zones embedded in a TH-rich matrix correspond to calbindin-poor striosomes and calbindin-rich extrastriosomal matrix, respectively. At caudal striatal levels, in contrast, striosomes display a TH immunostaining that is more intense than that of the matrix. A significant number of small, oval, aspiny TH-ir neurons scattered throughout the rostrocaudal extent of the caudate nucleus and putamen, together with a few larger, multipolar, spiny TH-ir neurons lying principally within the ventral portion of the putamen, were disclosed in human. This potential source of intrinsic striatal dopamine might play an important role in the functional organisation of the human striatum, particularly in case of Parkinson's disease.

Extrastriatal dopaminergic innervation of human basal ganglia.

A tyrosine-hydroxylase immunohistochemical analysis of the brains of normal human individuals has revealed nigrostriatal axons providing collaterals that arborize in the pallidum and subthalamic nucleus. These thin and varicose collaterals emerge from thick and smooth axons that course backward along the main output pathways of the basal ganglia, including the ansa lenticularis, the lenticular fasciculus and Wilson's pencils. Many of these fibers run within pallidal medullary laminae before reaching the putamen, whereas others climb along the reticular thalamic nucleus to reach the caudate nucleus. This extrastriatal innervation, which allows nigral dopaminergic neurons to directly affect the pallidum and subthalamic nucleus, may play a crucial role in the functional organization of human basal ganglia, in both health and disease.

Comparison of anthropometric measures of men with HIV: asymptomatic, symptomatic, and AIDS.

OBJECTIVE: Anthropometric measures were performed to determine differences in estimated fat mass, lean body mass, and body weight among three groups of men infected with human immunodeficiency virus (HIV). DESIGN: This study was cross-sectional. SETTING: Local centers of community services and support groups for persons infected with HIV in the province of Quebec, Canada. SUBJECTS: Thirty-seven HIV-positive men were recruited; 11 were asymptomatic (T helper cells [CD4+ count] > 400 cells/mm3), 8 were symptomatic (CD4+ < 400 cells/mm3), and 17 were clinically stable but met the criteria of the Centers for Disease Control and Prevention for acquired immunodeficiency syndrome (AIDS). MAIN OUTCOME MEASURES: Self-reported usual weight, actual weight, body mass index, midarm circumference, and triceps and subscapular skinfolds were recorded. From those we derived the percentage of body fat, the midarm muscle, and fat areas. Daily energy and protein intakes were determined from a 7-day food record. Clinical signs and symptoms were assessed by a structured questionnaire. STATISTICAL ANALYSES PERFORMED: For statistical comparisons, analysis of variance was used, with P < .05 being significant. RESULTS: We found a trend toward a decrease in body weight and in the fat mass indicators as the disease progressed. Lower energy intakes were observed among symptomatic and AIDS groups. The number of nutrition-related clinical signs and symptoms experienced by each individual correlated with the magnitude of weight loss (P < .0004, r = -.69). APPLICATIONS: The findings suggest that anthropometric measures can be used in routine clinical practice to assess changes in body weight and in estimated fat mass among men infected with HIV. Symptoms and energy intakes should be assessed to identify subjects at high risk of greater weight loss.

Human thymic dendritic cells. Characterization, isolation and functional assays.

The phenotypic analysis of human thymic dentritic cells (DC) in culture and in purified suspensions has been studied with light and electron microscopic (EM) immunolabelling techniques. Using a series of monoclonal antibodies (mAb) and a protein A-gold technique, we demonstrated that DR- and T6-positive cultured DC strongly bind the 9.3F10 mAb, an anti-DR-related antibody produced against human blood DC, and weakly express the T4 antigen, a membrane marker shared by Langerhan's cells (LC). On the other hand, thymic-cultured DC are negative for the other T-cell and monocyte-macrophage antigens. These results support the hypothesis that human thymic DC may be related to blood DC and epidermal LC. Moreover DC, unlike thymic macrophages, do not phagocytose latex particles, opsonized sheep red blood cells (SRBC) or Candida albicans. An efficient two-step technique of isolation, using a Percoll density gradient followed by an indirect panning technique, yields a purified (70-80%) thymic DC population, OKIa1-, 9.3F10- and OKT6-positive and esterase-negative. Immunolabelling and electron microscopy confirm that these isolated DC present similar phenotypic and ultrastructural features to human thymic DC in situ and in culture. Purified DC, used as stimulator cells in mixed leucocyte reaction (MLR), induce stronger proliferative responses than peripheral blood monocytes used as a control; blocking assays with OKIa1 mAb plus complement greatly reduced this stimulatory potency. These functional assays demonstrate that we obtained a purified typical DC population that can be used in immunological functional studies to elucidate the specific role of DC in human thymus.