ABSTRACT
The genetic control of pubertal timing has been a field of active investigation for the last decade, but remains a fascinating and mysterious conundrum. Self-limited delayed puberty (DP), also known as constitutional delay of growth and puberty, represents the extreme end of normal pubertal timing, and is the commonest cause of DP in both boys and girls. Familial self-limited DP has a clear genetic basis. It is a highly heritable condition, which often segregates in an autosomal dominant pattern (with or without complete penetrance) in the majority of families. However, the underlying neuroendocrine pathophysiology and genetic regulation has been largely unknown. Very recently novel gene discoveries from next generation sequencing studies have provided insights into the genetic mutations that lead to familial DP. Further understanding has come from sequencing genes known to cause GnRH deficiency, next generation sequencing studies in patients with early puberty, and from large-scale genome wide association studies in the general population. Results of these studies suggest that the genetic basis of DP is likely to be highly heterogeneous. Abnormalities of GnRH neuronal development, function, and its downstream pathways, metabolic and energy homeostatic derangements, and transcriptional regulation of the hypothalamic-pituitary-gonadal axis may all lead to DP. This variety of different pathogenic mechanisms affecting the release of the puberty 'brake' may take place in several age windows between fetal life and puberty.
Subject(s)
Gene Expression Regulation, Developmental , Puberty, Delayed/genetics , Humans , Inheritance Patterns/genetics , Models, Biological , Mutation/genetics , Time FactorsABSTRACT
In the current experiment we conducted a multi-level analysis of age-related characteristics in the hippocampus of young adult (3 months), middle-aged (12 months), and old (24 months) Fisher 344xBrown Norway hybrid (FBNF1) rats. We examined the relationships between aging, hippocampus, and memory using a combination of behavioral, non-invasive magnetic resonance imaging and spectroscopy, and postmortem neuroanatomical measures in the same rats. Aging was associated with functional deficits on hippocampus-dependent memory tasks, accompanied by structural alterations observed both in vivo (magnetic resonance imaging-hippocampal volume) and postmortem (dentate gyrus neuronal density and neurogenesis). Neuronal metabolic integrity, assessed by levels of N-acetylaspartate with magnetic resonance spectroscopy, was however, preserved. Further, our results suggest that neurogenesis (doublecortin) seems to be related to both performance deficits on hippocampus-dependent tasks and hippocampal volume reduction. The observed pattern of age-related alterations closely resembles that previously reported in humans and suggests FBNF1 rats to be a useful model of normal human aging.
Subject(s)
Aging/physiology , Hippocampus/cytology , Hippocampus/physiology , Animals , Behavior, Animal/physiology , Bromodeoxyuridine/pharmacokinetics , Discrimination, Psychological/physiology , Doublecortin Domain Proteins , Doublecortin Protein , Female , Hippocampus/drug effects , Immunohistochemistry/methods , Ki-67 Antigen/metabolism , Magnetic Resonance Imaging/methods , Maze Learning/physiology , Microtubule-Associated Proteins/metabolism , Multivariate Analysis , Neuropeptides/metabolism , Phosphopyruvate Hydratase/metabolism , Positron-Emission Tomography/methods , Rats , Rats, Inbred F344 , Spatial Behavior/physiologyABSTRACT
BACKGROUND: An experimental model in rats was developed to investigate the significance of mucosal integrity in abacterial prostatitis. METHODS: Ethanol was instilled into the ventral prostates of male rats to reduce mucosal integrity; dinitrobenzenesulfonic acid (DNBS) was added as an irritant to induce inflammation. Controls received no treatment, ethanol only, DNBS only, or a suspension of bacteria. After various time points, rats were sacrificed, and their prostates were assayed for gross morphology, histological appearance, and cytokine levels. RESULTS: Prostates subjected to ethanol plus DNBS showed significant inflammation, most notably after 12, 24, and 48 hr. Inflammation judged by gross and histological observations and interleukin-1beta levels correlated well at these times. Rats given only ethanol, DNBS, or no treatment, acting as negative controls, displayed little or no inflammation; rats given a bacterial suspension, acting as positive controls, showed inflammation consistent with past studies. Cytokine assays revealed raised interleukin-1beta levels in this model, while tumor necrosis factor-alpha remained at a basal level. CONCLUSIONS: The loss of an intact mucosal surface in the prostate resulted in inflammation caused by an irritant. Interleukin-1beta appears to play a role in this inflammation, while tumor necrosis factor-alpha does not.
