Acute pancreatitis associated with omeprazole.

Since their introduction in the late 1980s, proton pump inhibitors (PPI) have demonstrated gastric acid suppression superior to that of histamine H2-receptor blockers. This class of drugs has improved the treatment of various acid-peptic disorders, including gastroesophageal reflux disease, peptic ulcer disease, and nonsteroidal anti-inflammatory drug-induced gastropathy. PPIs have minimal side effects and few significant drug interactions. They are generally considered safe for long-term treatment. We present a rare side effect, acute pancreatitis, occurring in a patient who was treated with the proton pump inhibitor omeprazole.

The distribution and origin of the calretinin-containing innervation of the nucleus accumbens of the rat.

The nucleus accumbens of the rat consists of several subregions that can be distinguished on the basis of histochemical markers. For example, the calcium-binding protein calbindin D28k is a useful marker of the core compartment of the nucleus accumbens. Calretinin, another calcium-binding protein, is found in a dense fibre plexus in the accumbal shell and septal pole regions. The source of the accumbal calretinin innervation is not known. We examined the distribution of calretinin in the nucleus accumbens and used tract-tracing and lesion methods to determine the source of this calretinin innervation. Intense calretinin immunoreactivity was present in the medial shell, but the density of calretinin axons diminished sharply in the ventrolateral shell. Regions of dense calretinin immunostaining and those areas with calbindin-like immunoreactive cell bodies were generally segregated in the nucleus accumbens, although some overlap in the transition region between the core and shell was seen. Small clusters of calretinin-immunoreactive fibres were seen in the core, where they were restricted to calbindin-negative patches. Injections of the anterograde tracer biotinylated dextran amine into the paraventricular thalamic nucleus labelled fibres in calretinin-rich regions of the accumbens. Conversely, injections of Fluoro-gold into the accumbal shell retrogradely labelled numerous cells in the paraventricular thalamic nucleus that were calretinin-immunoreactive. Electrolytic lesions of the paraventricular thalamic nucleus reduced calretinin levels in the shell by approximately 80%. These data indicate that the calretinin innervation of the nucleus accumbens is derived primarily from the thalamic paraventricular nucleus, and marks accumbal territories that are largely complementary to those defined by calbindin.

DOI-Induced activation of the cortex: dependence on 5-HT2A heteroceptors on thalamocortical glutamatergic neurons.

Administration of the hallucinogenic 5-HT(2A/2C) agonist 1-[2, 5-dimethoxy-4-iodophenyl]-2-aminopropane (DOI) induces expression of Fos protein in the cerebral cortex. To understand the mechanisms subserving this action of DOI, we examined the consequences of pharmacological and surgical manipulations on DOI-elicited Fos expression in the somatosensory cortex of the rat. DOI dose-dependently increased cortical Fos expression. Pretreatment with the selective 5-HT(2A) antagonist MDL 100,907 completely blocked DOI-elicited Fos expression, but pretreatment with the 5-HT(2C) antagonist SB 206,553 did not modify DOI-elicited Fos expression. These data suggest that DOI acts through 5-HT(2A) receptors to increase cortical Fos expression. However, we found that DOI did not induce Fos in cortical 5-HT(2A) immunoreactive neurons but did increase expression in a band of neurons spanning superficial layer V to deep III, within the apical dendritic fields of layer V 5-HT(2A)-immunoreactive cells. This band of Fos immunoreactive neurons was in register with anterogradely labeled axons from the ventrobasal thalamus, which have previously been shown to be glutamatergic and express the 5-HT(2A) transcript. The effects of DOI were markedly reduced in animals pretreated with the AMPA/KA antagonist GYKI 52466, and lesions of the ventrobasal thalamus attenuated DOI-elicited Fos expression in the cortex. These data suggest that DOI activates 5-HT(2A) receptors on thalamocortical neurons and thereby increases glutamate release, which in turn drives Fos expression in cortical neurons through an AMPA receptor-dependent mechanism. These data cast new light on the mechanisms of action of hallucinogens.

Heat shock protein 90-dependent (geldanamycin-inhibited) movement of the glucocorticoid receptor through the cytoplasm to the nucleus requires intact cytoskeleton.

We use here a chimera of the green fluorescent protein (GFP) and the glucocorticoid receptor (GR) to test the notion that the protein chaperone heat shock protein-90 (hsp90) is required for steroid-dependent translocation of the receptor through the cytoplasm along cytoskeletal tracks. The GFP-GR fusion protein undergoes steroid-mediated translocation from the cytoplasm to the nucleus, where it is transcriptionally active. Treatment of 3T3 cells containing steroid-bound GFP-GR with geldanamycin, a benzoquinone ansamycin that binds to hsp90 and disrupts its function, inhibits dexamethasone-dependent translocation from the cytoplasm to the nucleus. The t1/2 for translocation in the absence of geldanamycin is approximately 5 min, and the t1/2 in the presence of geldanamycin is approximately 45 min. In cells treated for 1 h with the cytoskeletal disrupting agents colcemid, cytochalasin D, and beta,beta'-iminodipropionitrile to completely disrupt the microtubule, microfilament, and intermediate filament networks, respectively, the GFP-GR still translocates rapidly to the nucleus in a strictly dexamethasone-dependent manner but translocation is no longer affected by geldanamycin. After withdrawal of the cytoskeletal disrupting agents for 3 h, normal cytoskeletal architecture is restored, and geldanamycin inhibition of dexamethasone-dependent GFP-GR translocation is restored. We suggest that in cells without an intact cytoskeletal system, the GFP-GR moves through the cytoplasm by diffusion. However, under physiological conditions in which the cytoskeleton is intact, diffusion is limited, and the GFP-GR utilizes a movement machinery that is dependent upon hsp90 chaperone activity. In contrast to the GR, GFP-STAT5B, a signaling protein that is not complexed with hsp90, undergoes GH-dependent translocation to the nucleus in a manner that is not dependent upon hsp90 chaperone activity.

Evidence that the E2-isoprostane, 15-E2t-isoprostane (8-iso-prostaglandin E2) is formed in vivo.

D2/E2-isoprostanes are prostaglandin D2/E2-like compounds that are produced in vivo as non-enzymatic products of free radical catalyzed peroxidation of arachidonic acid. One E2-isoprostane that should be formed is 15-E2t-isoprostane (8-iso-prostaglandin E2). 15-E2t-isoprostane has been shown to exert potent biological activity but proof that it is formed in vivo is lacking. Evidence is now presented that 15-E2t-isoprostane is formed in vivo by demonstrating that an endogenous E2-isoprostane with a retention time on capillary GC identical with that of 15-E2t-isoprostane co-chromatographs through four high resolving HPLC purification procedures with authentic radiolabeled 15-E2t-isoprostane.

Shock-induced Analgesia in the cockroach (Periplaneta americana).

For 3 consecutive days cockroaches (Periplaneta americana) received escapable, inescapable, or no shock in an escape task. 24 hr. later minimum shock which initiated movement was identified. Reliably higher shocks were needed to initiate movement in the inescapably shocked roaches. In a second experiment the analgesia induced by inescapable shock was blocked by the opiate antagonist naloxone. The results are discussed in relation to the escape deficit and analgesia commonly seen following exposure to inescapable shock in a variety of species.

Route of absorption of drug and ointment after application to the eye.

Chloramphenicol, tetracycline hydrochloride, sodium sulfacetamide, and fluorescein sodium prepared in both aqueous solutions and ointments were placed in the conjunctival sac of humans. Each drug soon was tasted in the back of the mouth with no difference being noticed with the use of aqueous solution or ointment. Tetracycline and fluorescein studies showed that systemic absorption were similar regardless of whether solution or ointment were used. Furthermore, it was found that the ointment passed through the lacrimal drainage system and into the nose and throat. The ocular contact time of ointment with the eye is greater than that of water, and ointment is much more slowly absorbed via the lacrimal drainage system. Both the drugs and the ointment base applied topically to the eye travel through the nasolacrimal system as the way of elimination when given in the small volumes that are held by the conjunctival sac.