Associations between asthma trigger reports, mental health conditions, and asthma morbidity among world trade center rescue and recovery workers.

Aim: There is limited information regarding asthma triggers in World Trade Center (WTC) rescue and recovery workers (RRW) or how mental health conditions affect the perception of triggers. Methods: We included 372 WTC workers with asthma. The Asthma Trigger Inventory (ATI) assessed triggers along five domains: psychological, allergens, physical activity, infection, and pollution. We administered the Structured Clinical Interview to diagnose post-traumatic stress disorder (PTSD), major depression and panic disorder (PD). The Asthma Control Questionnaire (ACQ) and Mini Asthma Quality of Life Questionnaire (AQLQ) measured asthma control and quality of life, respectively. Linear regression models were fitted to examine the association of ATI total and subdomain scores with mental health conditions as well as the percent of ACQ and AQLQ variance explained by ATI subscales. Results: The most common triggers were air pollution (75%) and general allergens (68%). PTSD was significantly associated with psychological triggers (partial r2=0.05, p < 0.01), physical activity (partial r2=0.03, p < 0.01) and air pollution (partial r2=0.02, p = 0.04) subscales while PD was significantly associated with air pollution (partial r2=0.03, p = 0.03) and general allergens (partial r2=0.02, p = 0.03). ATI subscales explained a large percentage of variance in asthma control (r2=0.37, p < 0.01) and quality of life scores (r2=0.40, p < 0.01). Psychological subscale scores explained the largest portion of the total variability in ACQ (partial r2= 0.11, p = 0.72) and AQLQ (partial r2=0.14, p = 0.64) scores. Conclusion: RRW with mental health conditions reported more asthma triggers and these triggers were associated with asthma morbidity. These data can help support interventions in RRW with asthma.

Methamphetamine-induced insulin release.

Administration of methamphetamine or amphetamine to rats and mice produces a rapid increase in the level of immunoassayable plasma insulin not attributable to hyperglycemia. While in the mouse this release of insulin is followed consistently by a profound hypoglycemia, in the rat this response is variable. Studies in vitro demonstrate that insulin is released by a direct effect of methamphetamine on the pancreas.

Failure of indomethacin to inhibit growth of the R3230AC mammary tumor in rats.

The relationship between the dietary lipid-induced growth of the R3230AC mammary tumor and prostaglandin E2 (PGE2) levels as well as the effect of the prostaglandin synthetase inhibitor indomethacin (Ind) on these parameters was examined. F344 rats fed a high-fat (HF) diet containing 20% corn oil demonstrated more rapid tumor growth and higher tumor and plasma PGE2 levels than rats fed a 20% hydrogenated cottonseed oil (HCTO) diet. Addition of 0.004% Ind to the HF diet markedly reduced tumor and plasma PGE2 levels. However, Ind had no effect on tumor growth. Neither the fatty acid composition nor the insulin-binding capacity of the tumor plasma membranes was affected by Ind. Membranes from animals fed HF diets with or without Ind bound more 125I-labeled insulin than membranes from HCTO-fed rats. The results suggest that, for the R3230AC mammary tumor, reduction in both tumor and plasma PGE2 levels by Ind did not result in reduced tumor growth in animals fed diets high in polyunsaturated fatty acids.

A role of estrogens and insulin binding in the dietary lipid alteration of R3230AC mammary carcinoma growth in rats.

The importance of estrogens in the dietary lipid alteration of R3230AC mammary carcinoma growth and insulin binding was studied. Animals were divided into three groups [intact, ovariectomized, and ovariectomized treated with estradiol valerate (EV)] and were fed diets containing either 0% fat (fat free), 0.5% corn oil (low fat), or 20% corn oil (high fat). An alteration of tumor burden between animals fed high-fat versus either low-fat or fat-free diets was observed and appeared to be influenced by the estrogen status of the animal. The difference in tumor burden attributed to dietary lipid seen in intact rats was less in ovariectomized rats and greater in ovariectomized rats treated with EV, despite the fact that absolute tumor burden was reduced by this treatment. A similar relationship was observed for dietary lipid-induced differences in insulin binding to plasma membranes from these tumors. Reduction of tumor growth resulting from estrogen treatment was greater in low-fat- and fat-free-fed animals than in high-fat-fed rats. Again, tumor growth behavior appeared to be related to the reduction of insulin binding induced by estrogen treatment; insulin binding to plasma membranes from animals fed a low unsaturated lipid diet was decreased to a greater extent by EV treatment than in membranes from high-fat-fed rats. Altered tumor growth and membrane insulin binding, resulting from dietary perturbations and/or EV treatment, were not invariably related to serum insulin levels, nor to differences in membrane preparation, as reflected by 5'-nucleotidase activity, nor to membrane fatty acid composition or uptake of proline. Taken together, these results suggest a potential role of estrogens and insulin receptors as mediators of the dietary lipid alterations of growth of the R3230AC mammary carcinoma.

Effect of estradiol-17 beta on glucose and proline uptake in plasma membrane vesicles from the R3230AC rat mammary carcinoma.

Purified plasma membrane vesicles isolated from R3230AC rat mammary tumors displayed carrier-mediated and stereospecific uptake. Uptake was shown to be proportional to protein concentration, sensitive to increasing osmolarity, and inhibited only by substrates entering by the same carrier. Carrier-mediated glucose uptake was inhibited rapidly by estradiol-17 beta and phloretin in a dose-dependent manner, whereas proline uptake was not affected by estradiol-17 beta. The data suggest that the inhibition of glucose by estradiol and phloretin, originally observed in whole cells, occurs by an interaction of the steroid with a component on the plasma membrane. In contrast, the lack of effects of estradiol on proline transport into vesicles implies that intracellular components may have mediated the estrogen-induced effects observed in whole cells.

Species variation in pancreatic islet monoamine uptake and action.

There are conflicting data in the literature regarding the role of monamines in the secretion of insulin. In order to clarify the contribution that species variation may make to these divergent results, the uptake of serotinin (5-HT), dopamine (DA), and their precursor amino acids, 5-hydroxytryptophan (5-HTP) and L-dopa, into islets was studied. Islets from golden hamsters, rabbits, guinea pigs, and obese, hyperglycemic mice were isolated by the collagenase technique. The islets were incubated in Krebs-Ringer buffer in the presence of 14C-labeled monamines or their precursors. At 30-minute intervals after initiating the study, the incubation mixture was passed through a Millipore filter. The retained islets were disrupted by sonication and the radioactivity counted. The ratio of the uptake of 5-HTP to 5-HT was at least 3:1 in the hamster, guinea pig, and mouse. In the rabbit the ratio was 1:1. A similar relationship was noted for the uptake of L-dopa and DA. The in-vitro results were confirmed by the in-vivo studies, in which hamsters were injected with 14C5-HT or 5-HTP, followed by isolation of the islets. We conclude that there is significant species variation inthe uptake of these monoamines and their precursors.

Glucose intolerance in the carcinoid syndrome.

We assayed glucose tolerance and insulin secretion in ten patients with metastatic carcinoid tumors and the carcinoid syndrome ("active tumors") and in seven patients with metastatic carcinoid tumors without the carcinoid syndrome ("inactive tumors"). The patients with "active tumors" had elevated serum serotonin levels while the patients with "inactive tumors" had normal serum serotonin levels. Of the ten patients with "active tumors," five had diabetic and three had borderline intravenous glucose disposal rate constants (KG = 0.88 +/- 0.07, M. +/- S.E.M.). Their KG was significantly lower (p less than 0.01) than a group of age-matched normals. All of the patients with "inactive tumors" had normal KG values (KG = 1.67 +/- 0.24). Their KG did not differ from that of age-matched normal subjects. Both groups of carcinoid patients had a comparable decrease in their insulinogenic index. Two days' administration of the serotonin antagonist cyproheptadine (Cypro) to eight of the patients with "active tumors" resulted in a significant increase in the "insulinogenic index" (50%) but a nonsignificant increase in the KG (12%). Administration of p-chlorophenylalanine, a compound that blocks serotonin synthesis, resulted in an increase in both the KG (60%) and the "insulinogenic index" (55%). The insulin half-life (t1/2) of patients with "active tumors" (6.1 +/- 0.4 min.) did not differ from the t1/2 of normal subjects (6.6 +/- 0.4 min.), suggesting that the decreased plasma insulin levels following intravenous glucose were due to impaired insulin secretion rather than accelerated insulin destruction. Seven of the patients received treatment with the antitumor agent streptozotocin (Strepto). The patients received cumulative doses of from 70 to 300 mg. of Strepto per kilogram body weight with no impairment in glucose tolerance or insulin secretion. We conclude that there is high incidence of glucose intolerance (80%) and impaired insulin secretion in patients with the carcinoid syndrome and that serotonin plays a role in producing these alterations.

Treatment of metastatic pheochromocytoma with streptozocin.

A 58-year-old man who had a malignant pheochromocytoma with hepatic metastasis was treated with 2 g/mo of intravenous streptozocin for 18 months. There was a reduction in his urinary excretion of dopamine (from 33,840 to 731 micrograms/24 hr), homovanillic acid (from 48 to 8 mg/24 hr), and vanillylmandelic acid (from 350 to 74 mg/24 hr). There also was a reduction in the size of his hepatic metastasis (50%) and a right adrenal mass (25%), as well as a marked clinical improvement in his condition. Based on this evidence, I believe further attempts to treat patients with metastatic pheochromocytoma with streptozocin seem warranted.

Histaminuria from histamine-rich foods.

Using a highly specific and sensitive assay, the histamine content of foodstuffs and the effect of ingesting these foodstuffs on urinary histamine excretion were measured. Certain vegetables (spinach, eggplant), cheeses (Parmesan, blue, Roquefort), and red wines (Chianti and Burgundy) had a high content of histamine. Although only 0.21% of the ingested histamine was excreted unchanged in the urine, the histamine content of some of the foods was so high (Parmesan cheese, 185 micrograms/g; spinach, 60 micrograms/g; baked eggplant, 26 micrograms/g) that they caused histaminuria. Patients collecting urine for analysis for 24-hour histamine excretion for diagnosis of systemic mastocytosis or carcinoid syndrome should avoid intake of these foods and beverages on the day of the urine collection.

Plasma norepinephrine response to standing in patients with pheochromocytoma or medullary carcinoma of the thyroid.

We determined the effect of a lying/standing test on 22 patients with medullary carcinoma of the thyroid (MCT), seven patients with pheochromocytoma (six of whom also had MCT), six healthy first-degree family members of patients with MCT, and nine normal subjects who did not have a family history of MCT. The purpose of the study was to determine if the patients with MCT had an altered noradrenergic response to standing and to determine if this test would be useful in screening MCT patients for the presence of pheochromocytoma. All of the patients with MCT, as well as all of the healthy family members, had normal urinary excretion of catecholamines and their metabolites. Plasma norepinephrine (NE) concentrations, plasma cortisol levels, and blood pressure (BP) were determined during the lying/standing test. The plasma NE concentration showed the expected increase with a change in posture; the plasma cortisol concentration did not change. There was no significant difference in the plasma NE, plasma cortisol, and BP response in the four study groups. Only one of the seven patients with pheochromocytoma had a hypertensive episode in response to standing. We conclude that there is probably a normal noradrenergic response to standing in patients with MCT, and the standing/lying test, as performed in this study, is of limited value in screening for the presence of pheochromocytoma.

Iodine 131-labeled metaiodobenzylguanidine scintigraphy and biochemical analyses in suspected pheochromocytoma.

Detection of abnormal catecholamine levels and localization of tumor mass are important factors in the diagnosis and treatment of pheochromocytoma. Iodine 131-labeled metaiodobenzylguanidine scintigraphy was performed in 64 patients with suspected pheochromocytoma if their urinary catecholamine levels were borderline or elevated, or if the clinical suspicion for pheochromocytoma was high in spite of normal urinary catecholamine determinations. The 131I-metaiodobenzylguanidine scans were evaluated for abnormal localization of tracer. Twenty-four-hour urine collections were analyzed for vanillylmandelic acid, homovanillic acid, dopamine, epinephrine, and norepinephrine. Thirty of the 64 patients had pheochromocytomas. The 131I-metaiodobenzylguanidine scan had a sensitivity and a specificity of 88%. The 24-hour urine vanillylmandelic acid and norepinephrine measurements had the best sensitivity (97%), while the vanillylmandelic acid and homovanillic acid measurements had the best specificity (91%). In patients in whom the vanillylmandelic acid measurement and the 131I-metaiodobenzylguanidine scan were normal, no pheochromocytomas were found. In patients in whom the vanillylmandelic acid measurement and 131I-metaiodobenzylguanidine scan were abnormal, a pheochromocytoma was always present. The 131I-metaiodobenzylguanidine scan often documents the presence or absence of a pheochromocytoma and provides localization of the tumor in the preoperative evaluation of these patients.

Golden hamster pancreatic islets: a tissue rich in monoamine oxidase.

We compared the steady state monoamine oxidase (MAO) activity of collagenase-isolated pancreatic islets of the golden hamster with the steady state MAO activity of liver, kidney, median eminence, pituitary, acinar pancreas, and cerebral cortex. The MAO activity of the islets (5384 +/- 412 pmol/mg protein . min) was 3-fold greater than the activity of the next highest tissue (liver) and 12.5 times greater than the activity of the acinar pancreas. This high MAO activity was not due to collagenase exposure. The islet MAO was mainly of the so-called type B, although there was also some type A activity in this tissue. By assaying the formation of new islet MAO after the irreversible activation of MAO by the MAO inhibitor pargyline, we found that the t 1/2 of islet MAO (5.9 days with 95% confidence limits of 4.1-10.5 days) did not differ from the t 1/2 of MAO in tissues with lower steady state MAO activities. This suggested that the high steady state MAO activity in golden hamster islets is due to a high rate of synthesis rather than to a lower rate of degradation. Although rats, Chinese hamsters, guinea pigs, mice, and rabbits had substantial MAO activity in their pancreatic islets, their levels, at most, were only 16% that of the golden hamster. When the MAO activity of golden hamster islets was inhibited by the administration of pargyline plus clorgyline, there was a 3-fold increase in islet serotonin concentration, with no increase in islet norepinephrine concentration, suggesting that islet MAO activity plays a role in regulating islet serotonin concentration.

Effect of oral contraceptives on platelet monoamine oxidase, monoamine excretion, and adrenocortical function.

Studies with animals indicate that there are cyclical changes in the monoamine oxidase (MAO) activity of brain and uterus, and that these changes may be due to changes in estrogen and progesterone levels. To determine if oral contraceptives (OC) alter the tissue MAO activity of healthy women, we measured platelet MAO activity in 7 control women and in 7 women who were receiving combination estrogen-progesterone OC. The platelet MAO of the control women and the women receiving OC did not differ with the use of tryptamine and serotonin as MAO substrates. The two groups did not differ with respect to the following: serum serotonin, plasma tryptophan, plasma tyrosine, and the urinary excretion of tryptamine, tyramine, serotonin, 5-hydroxyindoleacetic acid, creatinine, 17-hydroxycorticosteroids, 17-ketosteroids, and urinary free cortisol. The subjects receiving OC had higher plasma cortisol concentrations than the controls. Two women in the seventh month of uncomplicated pregnancy, who underwent these studies, had higher plasma cortisol and urinary 17-ketosteroid excretion than control subjects. In the remaining tests the results of pregnant subjects did not differ from those of control subjects. We conclude that tissue MAO activity is not altered by OC or pregnancy.

Serotonin content of foods: effect on urinary excretion of 5-hydroxyindoleacetic acid.

Using a highly specific radioenzymatic assay we determined the serotonin concentration in 80 types of foods. The following fruits had a high serotonin concentration (mean +/- SEM) expressed in micrograms/g weight: plantain 30.3 +/- 7.5; pineapple 17.0 +/- 5.1; banana 15.0 +/- 2.4; Kiwi fruit 5.8 +/- 0.9; plums 4.7 +/- 0.8; and tomatoes 3.2 +/- 0.6. Only nuts in the walnut or hickory family had a high serotonin concentration expressed in micrograms/g weight; butternuts 398 +/- 90; black walnuts 304 +/- 46; English walnuts 87 +/- 20; shagbark hickory nuts 143 +/- 23; mockernut hickory nuts 67 +/- 13; pecans 29 +/- 4; and sweet pignuts 25 +/- 8. Ingestion of these fruits and nuts resulted in an increase in urinary 5-hydroxyindoleacetic acid excretion with no change in platelet serotonin concentration. The above foods should not be eaten while a urine is being collected for 5-hydroxyindoleacetic acid analysis.

Review of glyburide after one year on the market.

After one year on the American market, glyburide, a second-generation sulfonylurea, seems well accepted by physicians. If the hyperglycemia of patients with type II diabetes mellitus is not corrected by diet and exercise, glyburide can be used as adjunctive therapy. The drug is comparable in efficacy to the first-generation sulfonylurea chlorpropamide, but it has fewer reported side effects. Additionally, glyburide does not appear to interact with other medications and is well absorbed from the gastrointestinal tract. Although the drug had been reported to produce hypoglycemia, increased clinical experience--along with use of judicious dosages in appropriate patients--has decreased the incidence of hypoglycemia. Although still in the investigational stage, combination insulin/glyburide therapy may also benefit subgroups of type II diabetic patients. Glyburide is a useful and rational addition to therapy in properly selected patients with type II diabetes mellitus.

The pharmacology of sulfonylureas.

In this report we review the pharmacology of the hypoglycemic sulfonylurea drugs. The early work with sulfonylureas is briefly described. The pharmacokinetics of first-generation sulfonylureas, such as tolbutamide, chlorpropamide, acetohexamide and tolazamide, are described. The first-generation sulfonylureas are compared with second-generation sulfonylureas such as glyburide, glipizide and glibornuride. These latter drugs have a more nonpolar or lipophilic side chain, which results in a marked increase in their hypoglycemic potency. Because of the low serum concentration required for effective therapy, it is necessary to measure the serum concentration of second-generation sulfonylureas by gas-liquid chromatography or radioimmunoassay. The second-generation sulfonylureas do not produce facial flushing after ethanol ingestion (Antabuse effect) and are not uricosuric. Glyburide (but not glipizide or glibornuride) has been evaluated for its effect on water excretion. Glyburide not only does not increase water retention but in fact also increases free water clearance. The second-generation sulfonylureas bind to human serum albumin by nonionic forces in contrast with tolbutamide and chlorpropamide which bind by ionic forces. Thus, anionic drugs such as phenylbutazone, warfarin and salicylate do not displace glyburide from albumin as they displace tolbutamide and chlorpropamide. Therefore, it may be safer to administer the second-generation sulfonylureas than the more polar sulfonylureas when concurrent administration of other pharmacologic agents is likely. The sulfonylurea drugs lower plasma glucose concentrations in diabetic patients by stimulating insulin secretion and by potentiating the biologic effect of the insulin on such tissues as skeletal muscle, fat and liver. The mechanism of the latter so-called extra-pancreatic effect may be activated by increasing the deficient numbers of insulin receptors on muscle, fat or liver cells.

Role of neuropeptides and serotonin in the diagnosis of carcinoid tumors.

The plasma concentrations of neuropeptides (neurotensin, substance P, motilin, somatostatin, vasoactive intestinal peptide and gastrin-releasing peptide), the urinary excretion of 5-hydroxyindoleacetic acid and serotonin, and the platelet concentration of serotonin were compared in 133 patients who could be assigned to one of four groups. These groups were as follows: carcinoid tumors present; history of carcinoid tumors; miscellaneous tumors present; and non-tumor diseases. The test with the most sensitivity (i.e., patients with carcinoid tumors labeled positive) and the test with the most specificity (i.e., patients without carcinoid tumors labeled negative) for the presence of carcinoid tumors was determined. Urinary 5-hydroxyindoleacetic acid excretion had a sensitivity of 73 percent and a specificity of 100 percent; the plasma concentration of substance P had a sensitivity of 32 percent and a specificity of 85 percent; and the plasma concentration of neurotensin had a sensitivity of 41 percent and a specificity of 60 percent. Even when basal plasma concentrations of substance P and neurotensin were elevated, there was no additional increase of these neuropeptides prior to ethanol-induced facial flushing. Although measurements of plasma neuropeptide levels may be helpful in occasional patients with carcinoid tumors, it is concluded that measurements of serotonin overproduction--such as 5-hydroxyindoleacetic acid excretion--are of more general value.

Iodine-131-metaiodobenzylguanidine uptake in metastatic carcinoid tumor to the orbit.

Metastatic tumor is one of several etiologies of space-occupying masses in the orbit that accounts for 1%-13% of all orbital masses (1). In the adult patient population, breast cancer is the most common tumor to metastasize to the orbit followed by metastases from the lung, prostate and gastrointestinal tract (2). It is rare for carcinoid tumors to metastasize to the eye or to the orbit. Carcinoid tumors arise from Kulchitsky cells that originate in the neural crest. Histologically, these tumors resemble, but are not as aggressive as, adenocarcinomas. Most carcinoids arise in the gastrointestinal tract or the lung. The most common site for carcinoid metastases is the liver. On anatomical imaging studies, such as CT and magnetic resonance imaging, metastatic orbital carcinoid tumors appear as nonspecific tumor masses. Carcinoid tumors have an affinity for uptake of the radiopharmaceutical 131I-metaiodobenzylguanidine (MIBG) (3). We report a case of a patient with a known carcinoid tumor who developed a left orbital mass that demonstrated abnormal uptake of 131I-MIBG indicative of metastatic carcinoid tumor to the orbit.

Iodine-131 metaiodobenzylguanidine scintigraphy of carcinoid tumors.

Iodine-131 metaiodobenzylguanidine ([131I]MIBG) is concentrated in pheochromocytomas and can be detected by external imaging. We administered [131I]MIBG to 23 patients with carcinoid tumors to determine if it would be useful in scanning patients with these tumors. The carcinoid tumors of 14 of the 23 patients (61%) were visualized. Iodine-131 MIBG was concentrated most avidly by tumors of midgut origin (ileum, cecum); it was concentrated less avidly by some tumors of foregut origin (pancreas, stomach); it was not significantly concentrated by other tumors of foregut origin (bronchus). We conclude that 131I is a useful imaging agent for carcinoid tumors.

Predictors of outcome of tricuspid valve replacement in carcinoid heart disease.

The cardiac valvular surgical experience of patients in the Duke Carcinoid Database was reviewed to assess operative outcome. Of the 604 patients in the database, 19 patients with carcinoid heart disease were identified by cardiac catheterization or echocardiography, or both. Eight of these underwent tricuspid valve replacement surgery with bioprostheses (2 also had open pulmonic valvuloplasty). Compared with patients medically managed, surgically treated patients were similar with the exception that they had higher right atrial mean (17 +/- 6 vs 9 +/- 4 mm Hg, p = 0.03) and v-wave (27 +/- 6 vs 17 +/- 7 mm Hg, p = 0.04) pressures. Of the 8 surgical patients, 5 (63%) died within 30 days. Causes of death included tricuspid valve thrombosis, cerebral vascular accident, coagulopathy, renal failure, and intractable right heart failure. High comorbidity was present in all 8 patients. There was a weak trend (p = 0.17) toward lower Charlson comorbidity indexes in survivors (6.7 +/- 0.6) compared with nonsurvivors (7.6 +/- 0.9). Age was significantly lower (p = 0.036) in survivors (46 +/- 13 years) compared with nonsurvivors (69 +/- 4 years). Extended follow-up revealed 2 patients who survived beyond a decade. Review of 47 carcinoid valve replacement cases (Duke Carcinoid Database and 39 published cases) revealed a 30-day mortality of 56% for patients > 60 years of age, and 0% for those < or = 60 years of age (p < 0.0001). Although valve replacement surgery can afford prolonged palliation from carcinoid heart disease, it is associated with a significant mortality risk. Careful preoperative risk stratification by age and comorbidity may provide a means for optimal selection of surgical candidates.