Stress, glucocorticoids, and aging

Attention has long been focused on the relationship between stress and aging, both under the guise of stress as an accelerator of normal aging and of aging as a time of impaired ability to cope with stress. This review examines the considerable amount of evidence in support of these views. We address these ideas with respect to glucocorticoids, the adrenal steroid hormones secreted during stress. In particular, we concentrate on three model systems: 1) programmed senescence in marsupial mice and semelparous fish as mediated by glucocorticoid excess; 2) glucocorticoid hypersecretion in rats and its role in damaging the aging brain; and 3) potential human and primate adrenocortical dysfunction during aging. We discuss physical and cognitive consequences of adrenocortical dysfunction in these systems, and how they may relate to human aging.     

Gene transfer of calbindin D28k cDNA via herpes simplex virus amplicon vector decreases cytoplasmic calcium ion response and enhances neuronal survival following glutamatergic challenge but not following cyanide

Excitatory amino acid overstimulation of neurons can lead to a marked rise in cytoplasmic Ca2+ concentration ([Ca2+])i) and be followed by neuron death from hours to days later. If the rise in [Ca2+]i is prevented, either by removing Ca2+ from the extracellular environment or by placing Ca2+ chelators in the cytosol of the stimulated cells, the neurotoxicity associated with excitotoxins can be ameliorated. We have recently shown that neurons infected with a herpes simplex virus amplicon vector expressing cDNA for calbindin D28k responded to hypoglycemia with decreased [Ca2+]i and increased survival relative to controls. We now report that vector-infected neurons respond to glutamatergic insults with lower [Ca2+]i than controls and with increased survival. Infected neurons exposed to sodium cyanide did not respond with lower [Ca2+]i than controls, nor did they demonstrate increased survival postinsult. We examine these results in light of our earlier report and in the context of the potential of vectors like this for neuronal gene therapy.     

Inducible gene expression from defective herpes simplex virus vectors using the tetracycline-responsive promoter system

Herpes simplex virus-based amplicon vectors have been used for gene transfer into cultured neurons and the adult CNS. Since constitutive expression of a foreign gene or overexpression of an endogenous gene may have deleterious effects, the ability to control temporal expression would be advantageous. To achieve inducible gene expression, we have incorporated the tetracycline-responsive promoter system into amplicon vectors and showed, both in vitro and in vivo, that expression can be modulated by tetracycline. Using the firefly luciferase as the reporter gene, maximal repression by tetracycline in hippocampal cultures was about 50-fold. Withdrawal of tetracycline derepressed gene expression, reaching maximal levels within 10-12 h. In contrast, addition of tetracycline to cultures without prior tetracycline exposure inhibited gene expression rapidly; luciferase activity was reduced to less than 8% within 24 h. In adult rat hippocampus, vectors expressing luciferase or the Escherichia coli lacZ were repressed by tetracycline 9- and 60-fold, respectively. Maximum gene expression from the vectors occurred 2-3 days post-infection and declined thereafter. Such decline impeded further induction of expression by withdrawing tetracycline. This study demonstrates the feasibility of incorporating a powerful inducible promoter system into HSV vectors. The development of such an inducible viral vector system for gene transfer into the adult CNS might prove to be of experimental and therapeutic value.     

An effort at studying Rorschach content symbolism: The frog response.

The conception was advanced that a frog response on the Rorschach Test constituted a symbolic representation of unconscious cloacal birth and oral impregnation fantasies. It was hypothesized that a group of frog responders would display more eating disturbances than would a comparison group. A group of 31 psychiatric patients, giving frog responses in their Rorschach protocols, was compared with a matched control group. A chisquare test corrected for continuity proved significant beyond the .001 level of confidence for a 2-tailed test. This was interpreted as lending support to a conception of interpreting Rorschach responses as symbolic communications. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Gene therapy with HSP72 is neuroprotective in rat models of stroke and epilepsy

Brain areas damaged by stroke and seizures express high levels of the 72-kd heat shock protein (HSP72). Whether HSP72 represents merely a marker of stress or plays a role in improving neuron survival in these cases has been debated. Some induced tolerance experiments have provided correlative evidence for a neuroprotective effect, and others have documented neuroprotection in the absence of HSP72 synthesis. We report that gene transfer therapy with defective herpes simplex virus vectors overexpressing hsp72 improves neuron survival against focal cerebral ischemia and systemic kainic acid administration. HSP72 overexpression improved striatal neuron survival from 62.3 to 95.4% in rats subjected to 1 hour of middle cerebral artery occlusion, and improved survival of hippocampal dentate gyrus neurons after systemic kainic acid administration, from 21.9 to 64.4%. We conclude that HSP72 may participate in processes that enhance neuron survival during transient focal cerebral ischemia and excitotoxin-induced seizures.     

Effect of interpersonal relationships upon verbal conditioning.

"Two conditioning experiments were conducted in which E used 'mmm-hmm' to reinforce sentences which S began with pronouns 'I' or 'We.' Experiment I relied upon instructions to create a condition of either High- or Low-Attraction between S and E. Experiment II utilized… [a] scale to establish Compatible and Incompatible groups in terms of interpersonal needs… . Ss who were incompatible, or not attracted to E, suppressed the effects of reinforcement until removed from E's presence. The implications of these findings for generalizing from verbal conditioning situations to the patient-therapist relationship in clinical settings was discussed." (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Augmented ACTH responses to stress in adrenalectomized rats replaced with constant, physiological levels of corticosterone are partially normalized by acute increases in corticosterone

Adrenalectomized rats replaced with constant, physiological levels of corticosterone via a subcutaneous pellet (Pellet) have normal basal morning ACTH but exhibit enhanced and prolonged ACTH responses to stress vs. sham-operated (Sham) rats. It has not been determined if the lack of either stress-induced or circadian increases in corticosterone, both of which are missing in Pellet rats, may account for this enhanced response. To test the extent to which stress-associated increases in corticosterone alone can normalize stress-induced hypersecretion of ACTH, we approximated endogenous secretion by injecting additional corticosterone in Pellet rats via an indwelling subcutaneous cannula, 5 min before hypoxia stress (10% O2). A corticosterone dose of 666 micrograms/kg (Pellet+B), but not 333 micrograms/kg (Pellet+Low B), produced plasma corticosterone levels comparable to those in Shams and normalized stress-induced but not post-stress plasma ACTH. Administration of the type II corticosteroid receptor antagonist RU 38486 30 min before corticosterone reversed this inhibition. We conclude that enhanced ACTH responses to stress in Pellet rats result in large part from lack of type II receptor-mediated feedback inhibition by corticosterone increases during stress, although prior circadian increases in corticosterone may also be required.     

Relationship between patient-doctor compatibility, mutual perception, and outcome of treatment.

An investigation was designed to study the effects of patient-doctor Fundamental Interpersonal Relations Orientation Behavior (FIRO-B) scale compatibility upon outcome of hospital treatment and upon perceptions developed of each other in the dyadic relationship. The latter variable was measured by administration of a Semantic Differential Scale under differing instructonal "sets." A total of 25 voluntarily hospitalized female patients and 3 psychiatric residents participated. The degree of compatibility existing between patient and doctor was found to have been positively correlated with outcome of treatment. This effect upon outcome of treatment appeared to have occurred through the differential effect the compatibility variable had upon the way the resident was perceived by the patient. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Glucocorticoids may enhance oxygen radical-mediated neurotoxicity

Modern populations are constantly exposed to a variety of compounds in the workplace and the environment that promote formation of reactive oxygen species (ROS) within susceptible tissues. Due to its high oxygen consumption, the brain may be particularly vulnerable to oxidative damage and degeneration. Agents that impact cellular oxidative homeostasis would therefore be expected to alter the toxicity of ROS generating compounds. We are testing this hypothesis using endogenous stress hormones, glucocorticoids, to perturb neuronal homeostasis, and adriamycin to generate ROS. Glucocorticoids (GCs) are hormones secreted by the adrenals in response to stress, and are also prescribed clinically to control inflammatory and autoimmune disorders in millions of people annually. Therefore, high GC levels may not be uncommon in individuals exposed to low levels of toxic compounds. Also, GCs appear to act on cellular pathways relevant to ROS as seen by their potentiation of neurodegeneration following insults such as stroke, hypoglycemia and seizure. Using rat primary neuronal culture, we determined neuronal susceptibility to adriamycin toxicity by cell counting (using MAP-2 staining). Dichlorofluorescein fluorescence confirmed ROS generation after adriamycin administration. Physiological levels of GCS (up to mM concentrations) in the culture media exacerbated both adriamycin toxicity and ROS generation. We hypothesize that GCs may exacerbate the toxicity of three neurotoxins whose mechanisms of action overlap GC pathways.     

A comparative analysis of distinctive features of yeast protein sequences

The recently published sequence of yeast chromosome III (YCIII) provides the longest continuous stretch of a eukaryotic DNA molecule sequenced to date (315 kb). The sequence contains 116 distinct AUG-initiated open reading frames of at least 200 codons in length, more than 50 of which had not been described previously nor bear significant similarity to known proteins. We have analysed the YCIII known and putative-protein sequences with respect to significant statistical features which might reflect on structural and functional characteristics. The YCIII proteins have striking similarities and differences in their sequence attribute distributions compared to the corresponding distributions for all available yeast sequences and other protein collections. Nine examples of YCIII proteins with distinctive sequence features are discussed in detail.