Mineralocorticoid receptor function in patients with posttraumatic stress disorder

OBJECTIVE: The study examined whether enhanced limbic mineralocorticoid receptor activity resulting in negative glucocorticoid feedback could contribute to the diminished basal and stress-induced cortisol output reported in patients with posttraumatic stress disorder (PTSD). METHOD: The effects of acute antimineralocorticoid (spironolactone) versus placebo pretreatment on levels of plasma cortisol at baseline and after stimulations with corticotropin-releasing hormone (CRH) and on adrenocorticotropic hormone (ACTH) level were measured in 12 PTSD patients and 12 healthy comparison subjects. RESULTS: Spironolactone significantly elevated basal cortisol and ACTH concentrations as well as cortisol secretion after CRH stimulation, but no differential effect between PTSD patients and comparison subjects was detected. CONCLUSIONS: The results indicate intact, but not enhanced, mineralocorticoid receptor function in PTSD. The study's experimental conditions did not allow determination of whether other compensatory factors might have masked the putative mineralocorticoid receptor changes.     

Hydrodynamic contributions to multimodal guidance of prey capture behavior in fish

Water movements, of both abiotic and biotic origin, provide a wealth of information of direct relevance to the guidance of prey capture behavior. To gather hydrodynamic information, fish have sensors of two basic types: those scattered over the surface of the body known as superficial neuromasts and similar sensors embedded in subdermal lateral line canals. Recently, the anatomical dichotomy between superficial and canal neuromasts has been matched by demonstrations of a corresponding functional dichotomy. Prey detection and localization are evidently mediated by canal neuromasts, whereas superficial neuromasts are more sensitive to water flows over the surface of the fish and participate in the orientation to water currents, a behavior known as rheotaxis. However, rheotaxis in combination with chemosensory inputs can also guide fish to their prey. Thus there is evidence that both lateral line sub-modalities either alone or in concert with other senses play a role in prey capture. Are there circumstances where prey capture requires integration of information from both lateral line sub- modalities? Recent evidence shows that fish are capable of tracking other fish on the basis of the hydrodynamic trails left behind by their swimming motion. Pharmacological and physical ablation of lateral line end organs shows that indeed integration of information from both sub-modalities is required for the complex hydrodynamic task of natural prey capture in the dark. Furthermore, these experiments provide an excellent demonstration of the integration of hydrodynamic, chemosensory, tactile and visual information for the multimodal guidance of prey capture behavior.     

Restricted islet-cell reactive T cell repertoire of early pancreatic islet infiltrates in NOD mice

The mechanisms responsible for initiating autoimmune diabetes remain obscure. Here, we describe a method for identifying both the alpha- and beta-chains of the T cell receptor (TCR) from individual pancreatic islet-infiltrating T cells at the earliest stages of disease in nonobese diabetic mice (NOD). Analysis of the TCR repertoire of these early islet infiltrates reveals enrichment for a small subset of TCR sequences. Reconstitution of these TCR in vitro demonstrates that these receptors confer reactivity to islet cells but not to the well characterized autoantigens, glutamic acid decarboxylase (GAD65) and insulin. Thus, autoimmune diabetes in NOD may be initiated by a limited number of antigens distinct from GAD65 and insulin.     

Ethanol-enhanced cytotoxicity of alkylating agents

BACKGROUND: Although ethanol itself is not genotoxic, chronic alcohol consumption increases the risk of neoplastic disease. The mechanism by which ethanol exerts a cocarcinogenic effect is not well established, and the aim of this study was to determine whether exposure to ethanol increased the cytotoxicity of known carcinogens. METHODS: To assess cell survival, the ability of Chinese hamster A10 cells, which express alcohol dehydrogenase, to form colonies was determined after exposure to ethanol and other substances, including both genotoxicants and non-DNA-reactive cytotoxic agents. RESULTS: 1-Methyl-3-nitro-1-nitrosoguanidine (MNNG) is an alkylating agent that forms covalent bonds with DNA. The cytotoxicity of MNNG at concentrations of 0.17 to 0.68 microM was markedly enhanced when cells were also treated with 50 mM ethanol. When combined with 0.34 microM MNNG, concentrations of ethanol as low as 2 mM exacerbated the toxicity of this alkylating agent. When these experiments were repeated in the presence of 4-methylpyrazole, an inhibitor of alcohol dehydrogenase, pretreatment with ethanol did not affect the toxicity of MNNG. When ethanol treatment was combined with exposure to other carcinogens, as well as agents that do not directly damage DNA, the cytotoxicity of the DNA-reactive agents 4-nitroquinoline-N-oxide, mitomycin C, and 6-chloro-9-(3-[2-chloroethyl]aminopropylamino)-2-methoxyacridine was modestly enhanced, and that of a second alkylating agent, ethyl methanesulfonate, was markedly increased. CONCLUSIONS: The results are consistent with impairment of DNA repair processes, particularly base excision repair, by acetaldehyde, as a mechanism by which ethanol increases the genotoxicity of certain genotoxic agents.