Identification of prognostic factors in advanced epithelial ovarian carcinoma.

OBJECTIVE: The Gynecologic Oncology Group (GOG) has demonstrated that age, tumor grade, and size and number of residual lesions after primary cytoreductive surgery are significant prognostic factors in advanced ovarian carcinoma. Recent studies have reported numerous other clinical features as having prognostic value. We sought to identify the independent prognostic factors for survival in a cohort of patients with advanced ovarian cancer. METHODS: We performed a retrospective chart review of all patients with stage III and IV ovarian carcinoma who received their primary treatment at our institution between 1987 and 1994. RESULTS: A total of 295 patients were identified, 282 of whom were evaluable. Of these 282 patients, 214 (76%) have died of disease or other causes. The median follow-up is 32 months (range: 1-139). Eighteen factors were evaluated for prognostic significance. Significant factors in univariate analysis included patient age, gravidity (0 vs > 0), parity (0 vs > 0), preoperative albumin level, preoperative total protein level, ascites (presence vs absence), disease stage (IIIA/IIIB vs IIIC vs IV), number of residual lesions (< or =20 vs >20), and diameter of largest residual tumor nodule (< or = 1 cm vs 1-2 cm vs > 2 cm). However, on multivariate analysis, only patient age (P < 0.001), ascites (P = 0.001), and size of residual disease (P = 0.005) retained prognostic significance. Substage of disease was of borderline significance (P = 0.086). CONCLUSION: Although numerous clinical variables have recently been reported to have prognostic value in advanced ovarian carcinoma, only patient age, presence or absence of ascites, and diameter of the largest residual tumor nodule proved to be of statistical significance in our analysis.

Catechol and indole metabolism in rostral ventrolateral medulla change synchronously with changing blood pressure.

Catechol and indole metabolism in rostral ventrolateral medulla (RVLM or C1) was studied in response to changes in blood pressure across different rat strains. Sprague-Dawley, Wistar Kyoto normotensive and spontaneously hypertensive rats were anesthetized with urethane and had a 250 mu carbon paste in vivo electrochemical electrode implanted in RVLM area. Two electrochemical peaks were detected in this region. The first was at 0.12 V and the second at 0.28 V. To identify the electrochemical peaks, inhibitors of monoamine metabolism were administrated. alpha-Methylparatyrosine (tyrosine hydroxylase inhibitor), fusaric acid (dopamine-beta-hydroxylase inhibitor), pargyline (monoamine oxidase inhibitor) and LY 134046 (phenylethanolamine-N-methyltransferase inhibitor) showed that the first peak measured in the RVLM is likely to have multiple components including epinephrine, norepinephrine and 3,4-dihydroxyphenylacetic acid. The second peak most likely represents 5-hydroxyindole acetic acid. Phenylephrine or nitroprusside was infused to increase or decrease the blood pressure. Phenylephrine-induced hypertension reduced the catechol peak and increased the indole peak. By contrast, nitroprusside-induced hypotension produced reciprocal results. Hypotension led to an increase in the catechol peak and a reduction in the indole peak. The same pattern was observed in all three rat strains. We conclude that catechol and serotonin metabolism in RVLM changes in close relation to changes in blood pressure.

Plasma osmolality predicts extracellular fluid catechol concentrations in the lateral hypothalamus.

The lateral hypothalamus has an important role in regulating food and water intake. We have investigated the endogenous release of monoamines from the lateral hypothalamus during manipulations of plasma osmolality and circulating volume. Adult male Sprague-Dawley rats implanted with carbon paste in vivo electrochemical (EC) electrodes in the lateral hypothalamus were placed on a 72-h water deprivation schedule. Although the carbon paste EC electrode has an intrinsically ambiguous signal in which changes in ascorbic acid may appear as changes in catechol concentrations, pharmacologic studies in lateral hypothalamus indicated that the electrode most likely measured norepinephrine and possibly epinephrine. On the test day, the EC electrodes were scanned with linear sweep voltammetry from -0.2 to +0.4 V at a rate of 5 mV/s. Semiderivative signal processing showed catechol and hydroxyindole peaks at +0.11 and +0.23 V, respectively. Baseline recordings were made prior to rats drinking distilled water, 10% sucrose, 5% dextrose, 0.30% NaCl, 0.90% NaCl, or 10% d-mannitol. To control for the act of drinking, other implanted dehydrated rats were intraperitoneally injected with 5% dextrose, 0.30% NaCl, or 0.90% NaCl. To dissociate the effects of osmolality and circulating volume on the EC response, hydrated rats implanted with EC electrodes were subcutaneously injected with 12% NaCl or intraperitoneally injected with 35% polyethylene glycol. Other rats subjected to water deprivation and osmotic challenges were decapitated and trunk blood was collected for measurements of plasma osmolality and hematocrit. Similar experiments were conducted using homozygous Brattleboro rats which lack arginine vasopressin (AVP) but which preserve normal plasma osmolality with prodigious drinking.(ABSTRACT TRUNCATED AT 250 WORDS)

Changes in neurotransmitter turnover in locus coeruleus produced by changes in arterial blood pressure.

The effect of drug-induced hypertension and hypotension on neurotransmitter metabolism in the locus coeruleus (LC) of urethane anesthetized rats was studied using in vivo electrochemical methods. Peaks were seen at +0.15 V and +0.28 V. Studies with alpha-methylparatyrosine, fusaric acid and pargyline showed the first peak was produced by extracellular fluid dihydroxyphenylacetic acid (DOPAC) while the second peak was 5-hydroxyindoleacetic acid (5-HIAA). Phenylephrine was infused intravenously to raise the blood pressure by 50 mmHg, nitroprusside IV was used to reduce the blood pressure by 20 mmHg. During phenylephrine hypertension, the electrochemical signal for DOPAC showed an initial small reduction followed by a later significant increase which persisted even after the infusion was stopped. The signal for 5-HIAA rose with the onset of hypertension and remained elevated. Nitroprusside hypotension did not change the DOPAC peak but did lead to an immediate and persistent increase in the electrochemical 5-HIAA peak. To confirm the electrochemical findings, other groups of rats were decapitated during and after hypertensive and hypotensive drug infusions and the LC was assayed for norepinephrine, dopamine, DOPAC, serotonin, and 5-HIAA using HPLC with electrochemical detection. Changes in tissue DOPAC and 5-HIAA concentrations supported the electrochemical electrode observations. The effect of clonidine on the electrochemical recordings from LC was also studied. Clonidine reduced the catechol peak. No change was observed in the 5-HIAA peak during the infusion, but the 5-HIAA peak went up after the infusion was stopped. These experiments show that hypertension, hypotension, and alpha-2 agonists lead to changes in catecholamine and indoleamine metabolism in LC.

Changes in arterial blood pressure lead to baroreceptor-mediated changes in norepinephrine and 5-hydroxyindoleacetic acid in rat nucleus tractus solitarius.

Catecholamine and indoleamine metabolism in nucleus tractus solitarius were studied during drug-induced hypertension and hypotension. Urethane-anesthetized normotensive male Sprague-Dawley rats implanted with a 250-mu carbon paste in vivo electrochemical electrode were infused with phenylephrine to raise blood pressure 50 mm Hg. Other animals were given nitroprusside to lower pressure 20 mm Hg. Phenylephrine-induced hypertension was associated with a 30% reduction in the electrochemical peak corresponding to norepinephrine. The electrochemical peak which was identified as 5-hydroxyindoleacetic acid (5-HIAA) was increased 25% with the onset of hypertension and remain elevated after the phenylephrine infusion was stopped. Nitroprusside-induced hypotension resulted in a 20% reduction in the norepinephrine peak during the infusion followed by an additional 10% reduction after the infusion. 5-HIAA concentration did not change during the hypotensive phase but showed a 40% increase after the nitroprusside was stopped as blood pressure rebounded to levels higher than the control period. Direct tissue assays of norepinephrine and 5-HIAA confirmed the electrochemical findings. These experiments were repeated in rats which had undergone sinoaortic denervation. The electrochemical changes in norepinephrine and 5-HIAA associated with hypertension and hypotension were attenuated in these animals indicating that the brain neurotransmitter changes were a consequence of baroreceptor input to the brain. We conclude that 5-HIAA in nucleus tractus solitarius appears to be a marker for elevated blood pressure, whereas norepinephrine falls with either an increase or a decrease in pressure.

Nucleus tractus solitarius: an evaluation by in vivo voltammetry.

Nucleus tractus solitarius (NTS) is a brainstem nucleus known to play an important role in baroreceptor mediated cardiovascular regulation. As part of our study of the role of monoamines in the function of NTS, we have characterized pharmacologically the in vivo electrochemical signal recorded from the nucleus using carbon paste electrodes and linear sweep voltammetry with semiderivative signal processing in awake, freely moving rats. Two peaks were recorded by these techniques, one at 0.14 V and a second at 0.28 V. The tyrosine hydroxylase inhibitor alpha-methyl-p-tyrosine led to a significant reduction in the peak recorded at 0.14 V whereas it had no effect on the higher potential peak at 0.28 V. The dopamine-beta-hydroxylase inhibitor fusaric acid resulted in a large reduction in the 0.14 V peak and led to a 30% increase in the 0.28 V peak height. Pargyline, a monoamine oxidase inhibitor, did not change the low potential peak but did significantly reduce the 0.28 V peak. Tissue assays provided further support for the interpretation of in vivo electrochemical recordings. Norepinephrine concentration was reduced with fusaric acid. Tissue serotonin was not affected by any of the drugs while the 5-HIAA content was increased with fusaric acid and reduced with pargyline. These experimental findings lead to the conclusion that the first peak in the voltammogram most likely represents norepinephrine with a possible contribution by dopamine but not by DOPAC. The second peak appears to be 5-HIAA.

Effect of hypophosphatemia on brain catecholamines content in the rat.

Phosphate depletion is associates with abnormalities of the central nervous system (CNS) and of the cardiovascular system. Since alterations of catecholamines content in the CNS may contribute to these abnormalities, we studied the effect of phosphate depletion on catecholamine content of various areas of CNS in rat. Phosphate-depleted rats showed significant reduction in both dopamine and nonrepinephrine concentrations of medulla oblongata, hypothalamus, striatum and midbrain. However, epinephrine levels were significantly reduced only in the hypothalamus and not in any other regions studied. Dopamine content of cerebral cortex, cerebellum and norepinephrine content of cerebellum were not affected. These changes could contribute to the CNS abnormalities observed in phosphate depletion, but they may also be a consequence of altered energy metabolism coupled with hypotensive effect seen in phosphate-depleted animals.

Brain serotonin and blood pressure regulation: studies using in vivo electrochemistry and direct tissue assay.

Hypotensive responses to tryptophan and 5-hydroxytryptophan infusions were studied in normotensive male Sprague-Dawley rats. Results showed that 5-hydroxytryptophan but not tryptophan lowered pressure in a dose dependent way in direct relation to the production of brain serotonin and 5-HIAA. Intrinsic release of serotonin from brain was also studied during periods of induced hypertension and hypotension. Brain monoamine responses to blood pressure changes induced by intravenous phenylephrine and nitroprusside were measured in dorsal raphe nucleus and nucleus tractus solitarius by in vivo electrochemistry. Results showed that 5-HIAA was increased during drug induced hypertension and during reflex hypertension which followed a period of hypotension. These changes were blocked by sinoaortic denervation indicating that these central serotonergic neurons are responding to increased pressure sensed by baroreceptors. Therefore, serotonin has a role in blood pressure regulation as a pharmacologic agent and as a neurotransmitter in homeostatic control of pressure.

Murine regional brain monoamine oxidase activity: time- and age-dependent response to inhibitors.

The inhibitory effect of procaine hydrochloride and Gerovital-H3 on monoamine oxidase (MAO) activity in the rat brain was studied at six time points during the 24-hour cycle. It was found that the percent inhibition is time dependent. Both drugs showed maximum inhibition when the MAO activity was at the lowest values during the 24-hour period. In addition to time dependence, these drugs are also age dependent because the MAO activity varies with age.

Circadian variations in the monoamine levels and monoamine oxidase activity in different regions of the rat brain as a function of age.

Time-related changes in the levels of norepinephrine (NE), dopamine (DA), 5-hydroxytryptamine (5-HT) and monoamine oxidase (EC 1.4.3.4, MAO) activity have been studied in the cerebral cortex, cerebellum, medulla oblongata, hypothalamus, striatum and midbrain of 21 day, 3, 6, 12 and 24 month old rats maintained at 12 hours of light and 12 hours of dark condition. Maximum NE level was seen during the dark phase in all the regions of 3, 6, 12 and 24 month old rats, whereas in 21 day old, the maximum NE level occurred during the light phase. In the cerebral cortex and in the cerebellum of 21 day old rat DA was absent at all times. In all the other age groups, the maximum DA level was seen during the dark phase, while for 5-HT higher level was during the light phase in all the age groups. MAO activity of 3, 6, 12 and 24 month old rats showed the peak activity at the beginning of the light phase (06:00 hours), whereas cerebral cortex, cerebellum and medulla oblongata of 21 day old rat had its peak MAO activity at 14:00 hours and at 22:00 hours in other regions.

Effect of phase shift on monoamine oxidase activity in different regions of the rat brain as a function of age.

The effect of reversed light-dark cycle on the monoamine oxidase activity of different regions of the rat brain in various age groups was studied. Twenty-one-day-old rats showed an irregular pattern of shift in the appearance of the peak activity. In the case of 3-, 6-, and 12-month-old rats, all the regions of the brain became synchronized to the altered environmental condition, and the peak MAO activity was shifted by 180 degrees. In the cerebral cortex of 24-month-old rats the peak was shifted by only 60 degrees, whereas a 120 degrees shift was observed for all the other regions. The present study suggests that the synchronizing effect of the light-dark cycle is age dependent.

Monoamine levels and monoamine oxidase activity in different regions of rat brain as a function of age.

The levels of norepinephrine, dopamine, 5-hydroxytryptamine and the activity of monoamine oxidase were estimated in cerebral cortex, cerebellum, medulla oblongata, hypothalamus, striatum and midbrain of 21-day-old, 3-, 6-, 12- and 24-month-old male albino rats of Wistar strain. No significant change with age was found in the levels of all the three amines in cerebral cortex and cerebellum, while medulla oblongata showed a significant decrease of all the amines by 24 months of age. Hypothalamic norepinephrine, dopamine and striatal dopamine showed a highly significant decrease by 24 months of age, whereas 5-hydroxytryptamine in hypothalamus, norepinephrine and 5-hydroxytryptamine in striatum and dopamine in midbrain did not show any appreciable change with age. Monoamine oxidase activity in all the regions except cerebellum showed a significant increase by 24 months of age compared to 3- and 6-month-old rats.