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We describe two patients with subarachnoid haemorrhage due to a ruptured intracranial aneurysm and severe symptomatic vasospasm. The aneurysm was occluded with detachable coils followed by intra-arterial infusion of papaverine to treat vasospasm as an one-stage procedure. There was significant resolution of the vasospasm. The long-term clinical outcome in one patient was excellent, the other still has minor deficits. Combined endovascular aneurysm therapy followed by intra-arterial spasmolysis with papaverine is a technically feasible therapeutic alternative in patients with symptomatic vasospasm.

We report on a case of a giant aneurysm of the internal carotid artery in a 11-year old boy presenting with gradual unilateral visual loss, combined with slight headache and retro-orbital pain. Endovascular balloon occlusion of the internal carotid artery combined with monitoring of somatosensory evoked potentials was performed. Follow-up MR imaging six months after balloon occlusion revealed complete thrombosis and considerable retraction of the aneurysm. However, visual loss persisted, since therapy was initiated too late and optic nerve atrophy had already occurred. It is important to emphasize that visual disturbance should be considered as an emergency, and, although rare, aneurysms do occur in the pediatric population.

The difficulty of introducing foreign genes into a target tissue such as liver prompted us to explore the method of direct injection of DNA into this organ. In this article we examine whether direct hepatic injection of DNA enables the liver to express a transgene controlled by a mammalian promoter. The construct pS14CAT, composed of the rat S14 gene promoter coupled to CAT, was directly injected into rat liver. Hepatic expression of the pS14CAT transgene mimicked expression of the endogenous S14 gene, characterized by a low level of basal expression that increased markedly after exposure to thyroid hormone or a high sucrose diet. This effect was specific, since similar treatments had no effect on activity of a control transgene, pSV2CAT, which is under the direction of the viral SV40 promoter/enhancer. Dexamethasone treatment enhanced the activity of both pS14CAT or pSV2CAT transgenes, an effect likely mediated by both transcriptional and nontranscriptional pathways. In summary, our study demonstrates the feasibility of using direct DNA injection to study transcriptional regulation of hepatic gene promoters in vivo.

Iodixanol is a new nonionic dimer, isotonic with blood at all clinically relevant concentrations. Iodixanol (270 mg I/ml) was compared in a double-blind, randomized, parallel-group, phase-III study to the monomeric nonionic iohexol (300 mg I/ml) for evaluation of safety, tolerability and radiographic efficacy during cerebral CT. One hundred adult patients scheduled to undergo contrast-enhanced cerebral CT were randomly allocated to receive either iodixanol or iohexol. All completed the trial. Safety was evaluated by recording discomfort and other adverse events, tolerance by assessing intensity and incidence of discomfort. Radiographic efficacy was assessed from the diagnostic information and the radiographic density. No serious adverse events occurred. One patient (2 %) in the iodixanol group and one patient (2 %) in the iohexol group experienced a transient reddening at the neck and lower neck-line, respectively. Both contrast agents were well tolerated. One patient (2 %) in the iodixanol group and two patients (4 %) in the iohexol group experienced a sensation of warmth (discomfort) in connection with the injection. No difference between the two contrast media were noted radiographically. This comparison between iodixanol and iohexol showed both contrast media to be safe, well-tolerated and efficacious for use in cerebral CT.

Major improvements have been achieved in endovascular treatment of cerebral aneurysms during the last twenty years. Initial techniques of selective balloon occlusion were progressively replaced by controlled packing of the aneurysmal sac with soft detachable platinum-coils (GDC). In some patients with large or giant aneurysms of the cavernous portion of the internal carotid artery endovascular parent vessel occlusion therapy with balloons is still necessary. In aneurysms of the proximal paraclinoidal segment of the internal carotid artery a combined endovascular and microneurosurgical approach, the "evacuation-trapping"-technique might be helpful. In patients with symptomatic cerebral vasospasm in whom conservative therapy has failed or is not possible balloon angioplasty and or the intra-arterial infusion of papaverine has become a valuable therapeutic alternative. Further follow-up studies are necessary to assess the value and long-term results of endovascular strategies.

To understand whether the NO-dependent vasodilator L-arginine was effective upon a chronically hypertensive cerebral capillary endothelium, dynamic susceptibility contrast MRI was used to measure the relative cerebral blood volume (rCBV) changes in nonischemic spontaneously hypertensive rats (SHRs). rCBV was measured in 11 rats at 4.7 T using fast gradient echo imaging with intravenous injection of Gd-DTPA. Images were acquired before, immediately after, and up to 90 min after the infusion of 300 mg/kg L-arginine (n = 7) or of an equivalent volume of saline (n = 4). L-arginine increased rCBV in cortex beginning 10 min after infusion and reached significance after 30 min (P < 0.01), reached a peak of 1.24 +/- 0.06 (mean +/- SEM) times pre-injection level after 50 min, and was sustained throughout the 90 min observation period. In contrast, the rCBV in the deeper gray matter (striatum) showed no statistically significant change over the 90 min observation period. While this is consistent with previous studies showing that L-arginine infusion can directly modulate vascular tone and cerebral hemodynamics, it demonstrates that the effect is present only in cortex, and that it can occur also in the setting of a disturbed capillary endothelium.

The pivotal role of apolipoprotein AI (Apo AI) in mediating reverse cholesterol transport has lead us to the study of transcription factors that influence the expression of this gene. Previous studies show that rat HNF-4 enhances the activity of a cis-acting site C in the rat Apo AI promoter. Since sites C and A share 80% homology, we have examined whether HNF-4 binds to and modulates the transcriptional activity of the A-motif. Results show that HNF-4 binds to site A. The transcriptional activity of site A in a human hepatoma cell line, HuH-7, increases 2-2.5-fold in the presence of antisense HNF-4, but the sense construct has no effect on the activity of the reporter template. The lack of an effect of HNF-4 on site A activity may be due to high endogenous levels of the factor in HuH-7 cells. However, in BHK cells HNF-4 clearly inhibits the transcriptional activity of site A. Together these findings suggest that in contrast to the enhancing effects of HNF-4 on site C, the same factor inhibits site A activity. Since hepatocytes normally contain the T3 receptor and this nuclear factor increases site A action, cotransfection of T3 receptor along with antisense HNF-4 further augments the activity of p5'A.CAT. In summary, rat HNF-4 binds to site A from rat Apo AI DNA, and this factor suppresses site A activity. HNF-4 interferes with the enhancer role of the T3 receptor and thus contributes negatively to the net expression of the Apo AI gene.

The observation that glucocorticoids increase the abundance of apolipoprotein A-I led us to a search for potential underlying mechanism(s). In this report, we show that the synthetic glucocorticoid, dexamethasone, injected into rats increases serum levels of apoA-I protein, hepatic mRNA and "run-on' transcription of the gene by 3-, 5-, and 2-fold, respectively. Results of transient transfection studies of the rat apoA-I promoter reveal that effects of dexamethasone are mediated by a cis-acting site B (-170 to -145). Dexamethasone treatment of hepatoma cells enhances the DNA binding activity of nuclear factors that bind this site. Unexpectedly, site B does not contain a consensus glucocorticoid receptor recognition motif nor binds to bacterially expressed glucocorticoid receptor. These results indicate that the actions of glucocorticoids on site B involve indirect mechanisms. Site B is comprised of a direct repeat of a nonanucleotide and mutation of either one abolishes the effect of glucocorticoid. Additionally, the transcriptional activity of site B in response to dexamethasone is amplified by a 5' sequence called site S (-186 to -171). Dexamethasone has no effect on site S in the absence of site B. In summary, our data show that dexamethasone increases rat apoA-I gene expression by an indirect mechanism.

Diabetes decreases transcription of the albumin gene. The role of hyperglycemia in mediating this suppression of albumin gene activity is unclear. To study the effect of glucose in vivo, we treated diabetic rats with phlorizin or vanadate, two agents that ameliorate hyperglycemia without increasing the levels of circulating insulin. When glucose was normalized in diabetic rats with either agent, the hepatic levels of albumin mRNA became indistinguishable from those in nondiabetic animals. In light of our previous observation that diabetes decreases the abundance of hepatocyte nuclear factor 1 (HNF1), the predominant factor increasing albumin gene transcription, we wondered whether glucose normalization in diabetes would alter HNF1. Both the levels and DNA binding activity of HNF1 were restored to control values when phlorizin or vanadate was administered to diabetic rats. These findings suggest that hyperglycemia is integrally involved in mediating the suppression of albumin gene expression in diabetes. The effect of hyperglycemia on HNF1 suggests that glucose affects albumin expression at the level of transcription.

Brain MR signal has been observed to decrease during cessation of breathing due to the increase of deoxyhemoglobin in the blood. However, for both animal and human studies, we have demonstrated that if the subjects breathed 100% oxygen in advance of apnea for a short time, T2*-weighted MR brain signal increased when breathing was stopped for a period of 30-60 s. This demonstrates the possibility of measuring responses to hemodynamic change throughout the entire brain with a single respiratory perturbation in a rapid, reliable, and robust manner.

Substantial evidence for involvement of the APUD system in the normal reproductive tract is limited to the prostate gland and uterine cervix. Most supportive data simply documents the presence of neuro-endocrine cells in these tissues. A biological product(s) or role(s) remains to be discovered, but appears likely in the prostate. Tumors possessing cells with APUD characteristics have been described in many reproductive tissues including the prostate, cervix, endometrium, ovary, and testes. These tumors are generally aggressive in behavior, and optimum therapy needs to be determined.

Diabetes mellitus (DM) has been shown previously to decrease hepatic synthesis of both albumin and albumin mRNA. These findings prompted us to ask whether decreased albumin expression is due to changes in the rate of gene transcription. A cell-free in vitro transcription assay demonstrated that activity of the albumin promoter in hepatonuclear extracts was diminished 3- to 4-fold in diabetic compared with control animals. This decrease was abolished in extracts prepared from diabetic animals treated with insulin. The potential mechanisms for diminished activity were examined by mixing extracts from normal and diabetic animals prior to incubation with DNA templates. In the presence of limited amounts of albumin promoter DNA, addition of diabetic to control extract caused a reduction in promoter activity, suggesting that an inhibitor or inhibitors of albumin promoter activity is/are present in the liver of diabetic rats.

We investigated the effect of surgical castration of male rats on the binding of [Tyr(125I)10]VIP to receptors on the anterior pituitary gland, superior mesenteric artery, brain, liver, and prostate gland. In anterior pituitary membranes the maximum number of VIP binding sites was increased whereas binding affinity was decreased 24 hours following castration. In particular, the high affinity equilibrium dissociation constant (KD) increased from 0.13 +/- 0.02 nM (mean +/- SEM) to 0.67 +/- 0.07 nM and the maximum number of high affinity binding sites (Bmax) increased from 71 +/- 9 to 470 +/- 112 fmol/mg protein. No significant change was observed in the other tissues. Anesthesia or sham operation did not alter the anterior pituitary VIP receptor binding parameters. The changes in the VIP receptor 24 hours after castration were prevented by prior injection of testosterone. These findings demonstrate tissue-selective alterations to the anterior pituitary VIP receptor by castration that are likely mediated by withdrawal of testosterone.

The regulation of female rat anterior pituitary vasoactive intestinal peptide (VIP) receptors was examined during postnatal development and lactation. VIP receptor binding to anterior pituitary membranes from 1- to 60-week-old rats and lactating rats was examined using HPLC purified [Tyr(125I)10]VIP. Nonlinear regression of competitive binding studies indicated the presence of 2 VIP binding sites in 3-week and older animals, whereas only 1 site was identified in 1- and 2-week-old rats. The single site did not differ significantly in affinity or number when compared to the low affinity site of older animals. The guanine nucleotide, GTP-gamma-S, decreased the specific binding of VIP by 60-80% in 3-week and older animals, but not in younger animals. Compared with adult nonlactating animals, the number of high affinity binding sites decreased significantly during lactation, with no change in receptor binding affinity.

Vasoactive intestinal peptide (VIP) has been implicated as a physiological PRL-releasing factor; however, characterization of VIP receptors on normal pituitaries using radioligand-binding methods has been problematic. In this study we demonstrated specific receptors for VIP in anterior pituitary glands of female rats using HPLC-purified monoiodinated [Tyr(125I)10]VIP. Binding of VIP was reversible, saturable to receptor and radioligand, regulated by guanine nucleotides, and dependent on time and temperature. Scatchard analysis of competitive binding studies indicated high and low affinity binding sites, with equilibrium dissociation constants (Kd) of 0.19 +/- 0.03 and 28 +/- 16 nM, respectively. The corresponding maximum numbers of binding sites were 158 +/- 34 fmol/mg and 11.7 +/- 6.9 pmol/mg. Binding was specific, as peptides with structural homology to VIP were less than 100th as potent as VIP. The rank order of potency of the peptides tested was VIP greater than rat (r) peptide histidine isoleucine = human (h) PHI greater than rGRF greater than bovine GRF = porcine PHI = VIP-(10-28) greater than hGRF greater than secretin greater than apamin greater than glucagon. Radioligand binding was associated primarily with lactotrope-enriched fractions prepared by unit gravity sedimentation of dispersed anterior pituitary cells. VIP stimulated PRL release from cultured rat anterior pituitary cells, with an ED50 of 1 nM. These results, comprising the first identification of specific VIP receptors in normal rat anterior pituitary tissue using radioligand-binding methods, provide additional support for a biological role of VIP in lactotrope function.