Improved diabetes control and pancreatic function in a type 2 diabetic after omeprazole administration.

A 43-year-old man with type 2 diabetes, opposed to insulin use and poorly responsive to oral agents added sequentially over 6 years, was placed on 40 mg omeprazole twice daily. A linear decline in daily fasting blood glucose was observed over the first two-month treatment, and his hemoglobin A1c was reduced from 11.9% to 8.2%, then sustained at 8.1% after four months. Glucose, insulin, and C-peptide response to a 2-hour glucose tolerance test were consistently improved across this time period, and calculated beta-cell mass increased by 67%. We believe these responses are consistent with activation or neogenesis of pancreatic beta cells, possibly through a gastrin-mediated mechanism.

Facile oxidative decarboxylation of 3,4-dihydroxyphenylacetic acid catalyzed by copper and manganese ions.

Under physiological conditions, we observed the rapid, pH- and temperature-dependent, oxidative decarboxylation and hydration of 3,4-dihydroxyphenylacetic acid (DOPAC) to form 3,4-dihydroxybenzyl alcohol (DBAlc). This product was oxidized and underwent tautomerization to form 3,4-dihydroxybenzaldehyde (DBAld). This reaction did not occur in the presence of EDTA, was catalyzed by copper (CuI, CuII) and manganese (MnII) and was oxygen dependent. A variety of mono- and dihydroxyphenyl carboxylic acids were tested and the reaction producing DBAlc as an intermediate was observed to be unique to DOPAC. 3.4-Dihydroxymandelic acid (DOMA) was rapidly oxidatively decarboxylated to form DBAld directly. The substrate and catalyst selectivity of this reaction suggest that this may have physiological relevance in the neurotoxic consequences of manganese and copper to the dopaminergic system in man.

Hippocampal 5-HT1A receptor binding site densities, 5-HT1A receptor messenger ribonucleic acid abundance and serotonin levels parallel the activity of the hypothalamo-pituitary-adrenal axis in rats.

We have previously demonstrated that susceptibility of the Lewis rat to inflammatory disease, compared to the relatively resistant Fischer F344 rat, is related to a hyporesponsive hypothalamopituitary adrenal axis to inflammatory and other stress mediators. Since 5-HT and the 5HT1A receptor are important stimulators of this axis, we have investigated the levels of 5-HT1A receptor binding sites and encoding mRNA, 5-HT and 5-hydroxyindole acetic acid in various brain regions of Lewis, Harlan Sprague Dawley and Fischer F344 rats. Lewis rats expressed significantly less hippocampal and frontal cortical 5-HT1A receptor binding sites and mRNA than Harlan Sprague-Dawley and Fischer F344 rats. Adrenalectomy increased the number of 5HT1A receptor binding sites and mRNA expression in the hippocampus of all three strains. The levels of hippocampal 5-HT in Fischer F344 rats were significantly greater than levels detected in the same regions for the other two strains. Hypothalamic 5-HT and 5-hydroxyindole acetic acid levels in Harlan Sprague-Dawley rats were higher than the same area from the other two strains. Adrenalectomy increased the levels of 5-hydroxyindole acetic acid in the hypothalamus of all three strains. We conclude that hippocampal 5-HT1A receptor densities and 5-HT levels in the rat parallel the the activity and responsiveness of the hypthalamopituitary-adrenal axis. We have published these data in an earlier report.

Cerebrospinal fluid monoamine metabolites in boys with attention-deficit hyperactivity disorder.

Cerebrospinal fluid (CSF), plasma, and urinary monoamine metabolites were determined for 29 boys, aged 6-12, with attention-deficit hyperactivity disorder (ADHD). Levels of CSF 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA), and 3-methoxy-4-hydroxyphenylglycol (MHPG), the metabolites of serotonin, dopamine, and norepinephrine, respectively, correlated significantly with behavioral measures of aggression and impulsivity/hyperactivity. However, these correlations were in the unexpected direction; for example, CSF 5-HIAA correlated positively with the Brown-Goodwin Lifetime History of Aggression Scale. HVA in CSF was positively correlated with several measures of hyperactivity. The replicability of these findings, as well as possible socioenvironmental effects, and the predictive value of CSF monoamines in prepubertal hyperactivity are the subjects of ongoing study.

Hippocampal 8-[3H]hydroxy-2-(di-n-propylamino) tetralin binding site densities, serotonin receptor (5-HT1A) messenger ribonucleic acid abundance, and serotonin levels parallel the activity of the hypothalamopituitary-adrenal axis in rat.

We have previously demonstrated that susceptibility of the Lewis rat to inflammatory disease, compared with the relatively resistant Fischer F344/N rat, is related to a hyporesponsive hypothalamopituitary-adrenal axis to inflammatory and other stress mediators. Because serotonin (5-HT) and the 5-HT1A receptor are important stimulators of this axis, we have investigated the levels of 8-[3H]-hydroxy-2,3-(di-n-propylamino)tetralin binding sites, 5-HT1A mRNA, 5-HT, and 5-hydroxyindoleacetic acid in various brain regions of Lewis, outbred Harlan Sprague Dawley, and Fischer F344/N rats. Lewis rats expressed significantly fewer hippocampal and frontal cortical 8-[3H]-hydroxy-2,3-(di-n-propylamino)tetralin binding sites and less 5-HT1A mRNA than Harlan Sprague Dawley and Fischer F344/N rats. Adrenalectomy increased the number of 8-[3H]hydroxy-2,3-(di-n-propylamino)tetralin binding sites and 5-HT1A mRNA expression in the hippocampus of all three strains. Levels of hippocampal 5-HT in Fischer F344/N rats were significantly greater than levels detected in the same regions from Lewis and Harlan Sprague Dawley rats. Hypothalamic 5-HT and 5-hydroxyindoleacetic acid levels in Harlan Sprague Dawley rats were higher than the same area from the other two strains. Adrenalectomy increased the levels of 5-hydroxyindoleacetic acid in the hypothalamus of all three strains. We conclude that hippocampal 5-HT1A receptor densities and 5-HT levels in the rat parallel the activity and responsiveness of the hypothalamopituitary-adrenal axis.

Repeated coronary artery spasm in a young woman with the eosinophilia-myalgia syndrome.

We report a case of repeated coronary artery spasm with myocardial injury in a 37-year-old woman with the eosinophilia-myalgia syndrome. This patient did not have a medical history of cardiac-related illness or risk factors for coronary artery disease. The presence of eosinophil granule major basic protein in otherwise normal-appearing myocardial tissue, along with normal plasma levels of tryptophan metabolites, suggests that the mechanism of vasospasm in this patient might involve toxic eosinophil proteins or focal myocardial lesions, but not the production of excess tryptophan metabolites.

Quantitative examination of tissue concentration profiles associated with microdialysis.

Spatial solute concentration profiles resulting from in vivo microdialysis were measured in rat caudate-putamen by quantitative autoradiography. Radiolabeled sucrose was included in the dialysate, and the tissue concentration profile measured after infusions of 14 min and 61.5 min in an acute preparation. In addition, the changes in sucrose extraction fraction over time were followed in vivo and in a simple in vitro system consisting of 0.5% agarose. These experimental results were then compared with mathematical simulations of microdialysis in vitro and in vivo. Simulations of in vitro microdialysis agreed well with experimental results. In vivo, the autoradiograms of the tissue concentration profiles showed clear evidence of substantial differences between 14 and 61.5 min, even though the change in extraction fraction was relatively small over that period. Comparison with simulated results showed that the model substantially underpredicted the observed extraction fraction and overall amount of sucrose in the tissue. A sensitivity analysis of the various model parameters suggested a tissue extracellular volume fraction of approximately 40% following probe implantation. We conclude that the injury from probe insertion initially causes disruption of the blood-brain barrier in the vicinity of the probe, and this disruption leads to an influx of water and plasma constituents, causing a vasogenic edema.

Cytokine-induced activation of the neuroendocrine stress axis persists in endotoxin-tolerant mice.

Chronic administration of lipopolysaccharide (LPS) to mice markedly reduced activation of the neuroendocrine stress axis elicited by an acute challenge dose of LPS. LPS-induced elevation in norepinephrine turnover in the hypothalamus showed complete tolerance whereas elevation of plasma corticosterone showed only partial tolerance. Challenge-induced increased turnover of dopamine in hypothalamus persisted in LPS-tolerant animals. Neuroendocrine activation persisted following acute challenge with interleukin-1 and tumor necrosis factor following chronic LPS exposure.

Quantitative microdialysis: analysis of transients and application to pharmacokinetics in brain.

The behavior of a microdialysis probe in vivo is mathematically described. A diffusion-reaction model is developed that not only accounts for transport of substances through tissues and probe membranes but also accounts for transport across the microvasculature and metabolism. Time-dependent equations are presented both for the effluent microdialysate concentration and for concentration profiles about the probe. The analysis applies either to measuring the tissue pharmacokinetics of drugs administered systemically, or for sampling of endogenously produced substances from tissue. In addition, an expression is developed for the transient concentration about the probe when it is used as an infusion device. All mathematical expressions are found to be a sum of an algebraic and an integral term. Theoretical prediction of time-dependent probe behavior in brain has been compared with experimental data for acetaminophen administered at 15 mg/kg to rats by intravenous bolus. Plasma and whole striatal tissue samples were used to describe plasma kinetics and to estimate a capillary permeability-area product of 0.07 min-1. Theoretical prediction of transient effluent dialysate concentrations exhibited close agreement with experimental data over 60 min. Terminal decline of the dialysate effluent concentration was slightly overestimated but theoretical concentrations still lay within the 95% confidence interval of the experimental data at 112 min. Microvasculature transport and metabolism play major roles in determining microdialysate transient responses. Extraction fraction (recovery) has been shown to be a declining function in time for five probe operating conditions. High rates of metabolism and/or capillary transport affect the time required to approach steady-state extraction, shortening the time as the rates increase. Conversely, for substances characterized by low permeabilities and negligible metabolism, experimental situations exist that are predicted to have very slow approaches to microdialysis steady state.

Plasma catecholamines and their metabolites in obsessive-compulsive disorder.

Plasma catecholamines and their metabolites were sampled in 13 medication-free patients with obsessive-compulsive disorder (OCD) and 29 normal controls. In addition to severe OCD symptoms, the patients had significantly higher anxiety, tension, and resting pulse rates than the controls. Nonetheless, mean plasma concentrations of norepinephrine (NE) and epinephrine (E), the catecholamine metabolites 3-methoxy-4-hydroxyphenylglycol (MHPG) and homovanillic acid (HVA), and the stress-related hormone cortisol did not differ between OCD patients and normal controls. When the patients and control populations were combined and average plasma NE and E levels calculated over 35 min, subjects with a higher mean NE output (greater than 1.1 pm/ml) had higher Profile of Mood States depression scores than subjects with a low NE output (less than 1.1 pm/ml). Altogether, these results indicate that elevated plasma catecholamine measures are not likely to be associated with the pathophysiology of OCD.

Lithium effects on noradrenergic-linked adenylate cyclase activity in intact rat brain: an in vivo microdialysis study.

The effects of chronic lithium treatment on adenylate cyclase activity in intact rat brain were examined using in vivo microdialysis. Basal extracellular cyclic adenosine monophosphate (AMP) increased in a dose-dependent manner after norepinephrine was added to the perfusate. Chronic lithium treatment increased basal brain extracellular fluid cyclic AMP levels, while decreasing the magnitude of the cyclic AMP response to stimulation with 100 microM norepinephrine.

Effects of morphine administration on catecholamine levels in rat brain; specific reduction of epinephrine concentration in hypothalamus.

The effects of morphine administration on concentrations of epinephrine, norepinephrine and dopamine were examined in the rat brain. Morphine injection reduced the epinephrine level only in the hypothalamus, while the norepinephrine level was reduced in the hypothalamus, medulla, and locus coeruleus. The dopamine concentration was elevated in all regions examined. These changes were blocked by administration of naloxone. Repeated injection of morphine for 14 days did not affect any catecholamine level. In naloxone-induced withdrawal, epinephrine was most markedly depleted in hypothalamus. These observations suggest that the epinephrine level in hypothalamus is affected by morphine acting on opioid receptors.

Biogenic amines distribution in the brain of nervous and normal pointer dogs. A genetic animal model of anxiety.

Nervous pointer dogs have been suggested as an animal model for pathological anxiety. In order to study possible disturbances in neurotransmitter functions in this animal model, we measured brain biogenic amines (norepinephrine, dopamine, and serotonin) and their metabolites in both nervous and normal dogs. Eight nervous and six normal dogs were behaviorally tested and later anesthetized and killed. Brains were removed and dissected while frozen using a punch technique. Samples were assayed using high-performance liquid chromatography (HPLC) with electrochemical detection. The nervous dogs had higher [NE] in the reticular formation and lower serotonin, and its metabolite 5-hydroxyindoleacetic acid, in the septal nuclei, indicating possible important differences in noradrenergic and serotonergic functions in the nervous dogs. There was a trend for lower [HVA] and [DOPAC] levels and a significantly lower [DOPAC]/[DA] ratio in the nervous dogs, suggesting decreased dopaminergic function.

Stimulant drug treatment of hyperactivity: biochemical correlates.

To compare the effects of the stimulant drugs dextroamphetamine and methylphenidate on urinary and plasma monoamines and metabolites within the same clinical sample, thirty-one children with attention-deficit disorder with hyperactivity were treated with dextroamphetamine (up to 1.5 mg/kg/day), methylphenidate (up to 3.0 mg/kg/day), and placebo in an 11-week double-blind crossover trial. As expected, both drugs showed striking clinical efficacy, and within a subsample of the group, earlier findings were confirmed, that dextroamphetamine but not methylphenidate lowered urinary and plasma 3-methoxy-4-hydroxyphenylglycol and whole body norepinephrine turnover, and that urinary and plasma concentration of homovanillic acid was unaltered by either drug. Methylphenidate but not dextroamphetamine increased plasma norepinephrine. Urinary epinephrine and metanephrine were increased with both drugs, but this increase did not correlate significantly with clinical improvement.

A cerebrospinal fluid study of the pathophysiology of panic disorder associated with alcoholism.

In order to investigate the neurochemistry of panic disorder in alcoholics, we measured various cerebrospinal fluid (CSF) parameters in subjects with both conditions and compared them with an age- and sex-matched population of alcoholics and normal controls. When height, age and weight were covaried, subjects with panic disorder had higher levels of B-endorphin in CSF. There were no differences in other CSF measures between the groups. Alcoholics with panic disorder had higher plasma MHPG concentrations compared with alcoholics without panic disorder but these were not statistically different from controls.

Neurotensin and cholecystokinin microinjected into the ventral tegmental area modulate microdialysate concentrations of dopamine and metabolites in the posterior nucleus accumbens.

Neurotensin and cholecystokinin, neuropeptides which coexist with dopamine in many ventral tegmental neurons, were microinjected into the ventral tegmental area during in vivo microdialysis in the posterior nucleus accumbens. Neurotensin significantly elevated concentrations of dopamine and its metabolites at doses of 10 pmol, 1 nmol, and 10 nmol, while cholecystokinin significantly elevated dopamine metabolite concentrations only at a dose of 10 nmol. These data suggest that neurotensin potently mediates the release of dopamine from the mesolimbic pathway via direct actions on the cell body.

Increased ratio of quinolinic acid to kynurenic acid in cerebrospinal fluid of D retrovirus-infected rhesus macaques: relationship to clinical and viral status.

Increased concentrations of excitotoxin quinolinic acid in cerebrospinal fluid (CSF) are associated with infection with the human immunodeficiency virus (HIV-1) and have been implicated in the pathogenesis of the acquired immune deficiency syndrome (AIDS) dementia complex. In the present study, inoculation of macaques with D/1/California, an immunosuppressive serotype 1 type D retrovirus, was associated with acute and chronic increases in CSF and serum quinolinic acid concentrations in macaques that had developed SAIDS, a simian disease analogous to AIDS in humans--particularly macaques with demonstrable opportunistic infections. Kynurenic acid, an antagonist of excitatory amino acid receptors as well as the excitotoxic effects of quinolinic acid, was also increased in the CSF of SAIDS macaques, but to a significantly lesser degree than was quinolinic acid (kynurenic acid, 1.8-fold; quinolinic acid, 15.6-fold). CSF quinolinic acid, but not kynurenic acid, was also increased in viremic macaques with SAIDS-related complex (2.4-fold) and asymptomatic virus positive carriers (3.4-fold). Macaques that had recovered from D/1/California infection and were antibody positive and virus negative had normal CSF quinolinic acid and kynurenic acid concentrations. Increased activity of indoleamine-2,3-dioxygenase, the first enzyme of the kynurenine pathway, was indicated in the macaques with SAIDS by reduced serum L-tryptophan and elevated serum L-kynurenine concentrations. Macaques infected with D/1/California may provide a primate model for investigation of the mechanisms involved in increases in CSF quinolinic acid in retrovirus and other infectious diseases, including HIV-1. It remains to be determined whether the increased CSF quinolinic acid concentrations and the increased ratio of quinolinic acid to kynurenic acid have neurological significance or are a useful "marker" of infection.

Increased biogenic amine release in mouse hypothalamus following immunological challenge: antagonism by indomethacin.

Stimulation of the acute-phase response in mice by lipopolysaccharide, pokeweed mitogen, concanavalin A or interleukin-1 was associated with increased release of biogenic amines, serotonin and norepinephrine in the hypothalamus as indexed by their primary metabolites, 5-hydroxyindoleacetic acid and 3-methoxy-4-hydroxyphenylglycol, respectively. The increases in norepinephrine and serotonin turnover observed 4 h following systemic administration of interleukin-1 were antagonized by concurrent administration of indomethacin, a potent inhibitor of cyclooxygenase. These data suggest that the increase in norepinephrine and serotonin release in mouse hypothalamus during the acute-phase response to infection is partially mediated by the actions of arachidonic acid metabolites.

Effects of different semipermeable membranes on in vitro and in vivo performance of microdialysis probes.

The in vitro and in vivo performance of three different semipermeable microdialysis membranes was compared: a proprietary polycarbonate-ether membrane made by Carnegie Medecin; cuprophan, a regenerated cellulose membrane; and polyacrylonitrile. When microdialysis probes were tested in a stirred in vitro solution, large and statistically significant differences among the three membranes in extraction of acid metabolites (3,4-dihydroxyphenylacetic acid, 5-hydroxyindoleacetic acid, and homovanillic acid) and acetaminophen were found. Polyacrylonitrile had the highest extractions in vitro. In contrast, when microdialysis probes were implanted in vivo (in rat striatum), extraction of acid metabolites and acetaminophen did not differ significantly among the different membranes. These results are consistent with predictions made by a mathematical model of microdialysis and can be explained by the fact that in vitro the main factor limiting extraction is membrane resistance to diffusion, whereas tissue resistance to diffusion plays a more dominant role in vivo. These findings suggest that (aside from differences in surface area), the choice of semipermeable membrane will generally have little effect on in vivo microdialysis results. Furthermore, in vitro measurements of microdialysis probe extractions are not a reliable way of calibrating in vivo performance.