Forebrain glucocorticoid receptor overexpression increases environmental reactivity and produces a stress-induced spatial discrimination deficit.

Reactivity to environmental stressors influences vulnerability to neurological and psychiatric illnesses, but little is known about molecular mechanisms that control this reactivity. Since mice with forebrain-specific glucocorticoid receptor overexpression (GRov mice) display anxiety-like behaviors in novel environments and have difficulty adjusting to change in memory tasks, we hypothesized that these may be facets of a broader phenotype of altered reactivity to environmental demands. Male GRov and wild-type mice were tested in a multiple-trial object interaction test comprising environmental and object habituation and spatial and object novelty trials. Half the mice received restraint stress before testing. GRov mice exhibited more locomotor activity and, without stress, more object interaction than wild-type mice. Following acute stress, GRov mice no longer showed increased object exploration. While stress dampened responses to object novelty in both groups, GRov mice were particularly impaired in discrimination of spatial novelty post-stress. These data demonstrate that GRov leads to increased environmental reactivity, responsiveness to salience, and vulnerability to stress-induced cognitive deficits. They implicate forebrain glucocorticoid receptor (GR) in fine-tuning interactions with the environment and the interplay of emotional salience, coping abilities, and cognitive function.

Genetic modifiers of the Kv beta2-null phenotype in mice.

Shaker-type potassium (K+) channels are composed of pore-forming alpha subunits associated with cytoplasmic beta subunits. Kv beta2 is the predominant Kv beta subunit in the mammalian nervous system, but its functions in vivo are not clear. Kv beta2-null mice have been previously characterized in our laboratory as having reduced lifespans, cold swim-induced tremors and occasional seizures, but no apparent defect in Kv alpha-subunit trafficking. To test whether strain differences might influence the severity of this phenotype, we analyzed Kv beta2-null mice in different strain backgrounds: 129/SvEv (129), C57BL/6J (B6) and two mixed B6/129 backgrounds. We found that strain differences significantly affected survival, body weight and thermoregulation in Kv beta2-null mice. B6 nulls had a more severe phenotype than 129 nulls in these measures; this dramatic difference did not reflect alterations in seizure thresholds but may relate to strain differences we observed in cerebellar Kv1.2 expression. To specifically test whether Kv beta1 is a genetic modifier of the Kv beta2-null phenotype, we generated Kv beta1.1-deficient mice by gene targeting and bred them to Kv beta2-null mice. Kv beta1.1/Kv beta2 double knockouts had significantly increased mortality compared with either single knockout but still maintained surface expression of Kv1.2, indicating that trafficking of this alpha subunit does not require either Kv beta subunit. Our results suggest that genetic differences between 129/SvEv and C57Bl/6J are key determinants of the severity of defects seen in Kv beta2-null mice and that Kv beta1.1 is a specific although not strain-dependent modifier.

A study of the association between epistaxis and the severity of hypertension.

Hypertension (HTN) has frequently been cited as a general risk factor for epistaxis. However, studies dealing with this association have yielded equivocal results. In this study, a sample of 121 hypertensives (blood pressure > or = 140/90 mmHg) was selected to evaluate the association between the severity of HTN and a previous history of epistaxis. Patients with an average blood pressure > or = 160/100 mmHg were classified as suffering from a more severe form of HTN and were compared with those with a less severe form of the disease (160/100 mm Hg < or = blood pressure > or = 140/90 mm Hg). The frequency of epistaxis did not differ among patients categorized by the severity of HTN. Users of aspirin were found to be twice as likely to have a history of epistaxis. In addition, there was a statistical tendency for an association between a history of epistaxis and the duration of hypertension. We conclude that the severity of HTN and a history of epistaxis were not associated in a cohort of hypertensive patients. The identification of other risk factors for epistaxis, including the duration of HTN, deserves further study.

Novel prostanoid thromboxane A2 agonists.

The chemistry and biology of novel TXA2(TP)-receptor agonists based on the prostanoid skeleton is described and structure-activity-relationships are discussed. One compound,(5Z,13E), (9R,15R)-9-fluoro-15-hydroxy-16-phenoxy-17,18,19,20-tetranor- 5,13-prostadienoic acid (33), was identified which is 10 times more potent than the standard TP-receptor against U 46619.