In vitro 2,3,7,8-tetrachlorodibenzo-p-dioxin interference with the anterior pituitary hormone adrenocorticortropin.

Treatment of male Sprague-Dawley rats with a single oral dose of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) has been shown to increase serum adrenocorticotropin (ACTH) and decrease serum corticosterone. The present in vitro study was designed to assess whether TCDD has a direct effect on the anterior pituitary under basal and stimulated conditions. Primary anterior pituitary cell cultures were prepared from normal 180- to 220-g male Sprague-Dawley rats and the cultures treated with 10(-9)-10(-19) M TCDD. Maximal secretion of ACTH occurred between 10(-11) and 10(-15) M TCDD for both medium (2-fold) and intracellular (1.5-fold) concentrations after 24 h TCDD exposure. TCDD treatment also caused an early (6 h) and persistent (10 days) increase in basal medium (1.4- to 2.8-fold) and intracellular (1.1- to 1.7-fold) ACTH concentrations. However, while stimulation with corticotropin-releasing hormone (CRH) increased intracellular ACTH 1.5- to 1.7-fold in pituitary cells treated for 24 h with 10(-9)-10(-13) M TCDD, ACTH secreted into the media was decreased by 30-50% compared with controls. Lastly, the secretagogue arginine-8-vaso-pressin (AVP), did not increase the amount of ACTH secreted above levels observed with basal TCDD exposure. From this study, it appears that TCDD stimulates in vitro synthesis and secretion of ACTH by the anterior pituitary under basal conditions, but decreases the pituitary's responsiveness to CRH and AVP stimulation.

Some factors associated with mortality in perforated peptic ulcer: a case-control study.

This study examined the associations of individual coexisting illnesses, septicaemia, intra-abdominal abscess, marital status, smoking and alcohol use, with mortality following perforation of peptic ulcer without pre-operative evidence of haemorrhage. Patients who died in hospital following ulcer perforation (cases; n = 300) were compared with patients who survived following ulcer perforation (controls; n = 276). The controls were frequency-matched to the cases on age, sex and perforation site. Data were analysed by logistic regression. Cardiac, respiratory, cerebrovascular, renal, liver and malignant diseases, and septicaemia and intra-abdominal abscess were associated with mortality and the coexisting illnesses were significantly increased in cases compared to controls both on admission and at the end of hospital stay. During hospitalization, the odds of pneumonia decreased in cases, otherwise there was little change in strengths of associations over this period. Being widowed or never married was positively associated with mortality, and moderate alcohol use was negatively associated. In conclusion, this study identifies several coexisting illnesses, septicaemia and intra-abdominal abscess as risk factors for mortality following ulcer perforation. The results suggest that, with little exception, the same level of mortality risk is associated with coexisting illnesses whether the beginning or end of hospital stay is used as the index time point.

A comparative overview of the adverse effects of antiulcer drugs.

During the past 2 decades, great advances have been made in the treatment of ulcer disease. This has involved the development of new drugs that are not only well tolerated, but are relatively inexpensive. The lack of significant adverse effects has revealed a degree of tolerability that, to write a review of the adverse effects, poses a difficult task. Most of the adverse effects are related to an excessive reaction to the relevant pharmacological characteristic that mediates the therapeutic response. The drug dosage can be reduced, freeing the patient of the adverse reaction, but leaving behind a background activity adequate to produce a therapeutically beneficial effect. The adverse effects of H2-antagonists fall into 2 groups. Firstly, there are poorly defined symptoms that have a prevalence similar to that in the community; these include headache, giddiness, dizziness, fatigue, constipation and diarrhoea. Secondly, they may delay the metabolism of drugs metabolised by the the cytochrome P450 system, and rarely be androgenic. Many antacids and the site-protective agent sucralfate contain aluminium, which can be absorbed, producing elevation of serum aluminium levels. In view of the possible association of aluminium with Alzheimer's disease, anxiety has arisen as to whether aluminium from these sources may, in those on prolonged treatment, cause Alzheimer's disease. However, the evidence so far indicates that aluminium is not a risk factor for Alzheimer's disease. The association of gastric cancer with achlorhydria has led to the fear that long term use of potent acid inhibitors may cause cancer. This fear has been accentuated by the observation that some rats, given omeprazole over their lifetime, developed carcinoid tumours of the stomach. However, enthusiastic research, both clinical and epidemiological, indicates that drug-induced achlorhydria is unlikely to be a problem in humans. Site protective agents have a role in certain conditions such as pregnancy where the systemic effect of a drug may produce adverse effects.

Lipid peroxidation in the adrenal glands of male rats exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD).

This study was performed to determine whether TCDD (50 micrograms/kg; single oral dose) could induce adrenal microsomal lipid peroxidation, which might be correlated to decreased levels of cytochrome P-450 and 21-hydroxylase activity. The amount of malondialdehyde (MDA) formed was significantly higher than controls at days 1 through 5 following TCDD treatment. Microsomal cytochrome P-450 levels were depressed after lipid peroxidation at days 1, 3, and 5, and 21-hydroxylase activity decreased at day 5 after TCDD treatment. This study shows that TCDD stimulates adrenal microsomal lipid peroxidation which is associated with decreased cytochrome P-450 levels and 21-hydroxylase activity.

TCDD alters pituitary-adrenal function. I: Adrenal responsiveness to exogenous ACTH.

Plasma ACTH concentrations in 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD)-treated rats (50 micrograms/kg; single, oral dose) were 2.1-, 2.1-, 2.9-, 1.7-, 1.5-, 2.0- and 3.0-fold greater than control values, respectively, at days 1, 3, 5, 7, 10, and 14. At days 1 and 5 plasma corticosterone concentrations were increased 5.1- and 8.0-fold, respectively; whereas, at days 10 and 14 they were depressed to values of 50% and 39% of controls, respectively. Adrenal glands were excised from rats treated with TCDD and corticosterone production was assessed. Basal corticosterone concentrations produced by treated adrenals were depressed to 81%, 72%, and 71% of control values at days 5, 7, and 14, respectively. Corticosterone secretion by ACTH stimulated adrenals was equivalent to controls. These findings suggest that TCDD exposure decreases the bioactivity of the ACTH secreted by the anterior pituitary.

Trends in peptic ulcer mortality in Sydney from 1971 to 1987.

Gastric and duodenal ulcer (GU,DU) mortality in Western countries has varied over time by age and sex. Temporal variation raises the question of whether these ulcers have an environmental etiology. Using death certificate data, we investigated peptic ulcer mortality time trends from 1971 to 1987 in Sydney, Australia, and whether ulcer mortality and overall mortality in Sydney were similar with regard to time trends and associations with demographic and environmental factors. In men in all age groups and in women age < 65, GU and DU mortality decreased. In women age > or = 70, GU mortality remained constant and DU mortality increased. Average age at ulcer death increased: from 1971 to 1987, ulcer deaths at age > or = 70 rose from 52 to 80% of all ulcer deaths. In men who died at age 30-54, GU and DU mortality decreased relative to overall mortality. In women who died at age > or = 55, DU mortality increased relative to overall mortality. Compared with overall mortality, the ulcer mortality rate was affected more adversely by lower social class and lack of the marriage tie, and smoking rates tended to correlate more strongly with GU mortality. The greater-than-expected decrease in GU and DU mortality in younger men and the increase in DU mortality in elderly women suggest important changes in as yet unidentified environmental risk factors for ulcer mortality within the young adult male and elderly female general populations.

Stress and personality in patients with chronic peptic ulcer.

The concept that stress and personality are associated with ulcer is widely held by lay persons and to some extent by the medical community. By means of epidemiological techniques and more precise terminology, the role of psychosomatic factors in ulcer disease has been more clearly defined. Regarding acute stress, the number of events experienced and the change and distress they are purported to produce has been found to be similar in ulcer patients and their controls matched on age, sex, and social class. However, chronic difficulties, i.e., events or circumstances that have persisted for > or = 6 months, are twice as common in duodenal ulcer patients as in controls. Events, either acute or chronic, are more strongly associated with duodenal ulcer if they contain a component involving personal threat or goal frustration. Associations that have been found between acute or chronic stress and duodenal ulcer have been relatively weak, with odds ratios of 2 to 3. For some patients, it is possible that depression and social incongruity may have played some role in initiating ulcer disease. Personality studies have shown that ulcer patients are more neurotic than controls, but the difference is small and there is no evidence to indicate an ulcer personality. As regards both stress and personality, gastric ulcer patients do not differ from duodenal ulcer patients.

A note on sex-specific mortality and social class in Sydney, 1979 to 1983.

Simple indicators such as education, income, occupation, and employment status are often used to adjust for social class in studies of morbidity or mortality. The effect of social class on such outcomes can be different for men and women. In population-based studies, residential area may be the only means of assessing social class. This study investigated sex differences in the association between mortality between 1979 and 1983 and several area indices of social class--percentage with a degree, percentage professional, percentage blue collar, percentage unemployed, percentage with annual income greater than $40,000, and the composite indicator constructed by the Australian Bureau of Statistics. Thirty-seven Sydney statistical local areas were ranked for men and women separately according to the indicators and standardised mortality ratios. Correlations between the indicators and mortality were all negative and stronger for men than for women. The composite indicator and percentage unemployed correlated most strongly with mortality. There was a moderate correlation between the remaining indicators and mortality for men, but only a weak correlation for women. The results suggest that the use of simple area indicators may be inadequate to classify the social class of women, and that the unemployment rate in those over 35 years of age may be a reasonable alternative to the composite indicator for the purpose of social class adjustment in mortality studies.

Perforated peptic ulcer in Hong Kong and New South Wales.

Direct comparisons of ulcer perforation rates and trends between countries have not been made in the past. Data on hospital admissions for perforated peptic ulcer during 1 January 1979 to 31 December 1985 were collected in Hong Kong (5868 perforations) and New South Wales, Australia (1669 perforations). Age and sex specific rates per 100,000 population were calculated. In Hong Kong, annual duodenal ulcer and gastric ulcer perforation rates were 13-16 and under two per 100,000 population respectively. In New South Wales, the corresponding rates were between three and four and under two per 100,000 population, respectively. The male:female ratios for duodenal ulcer perforation were consistently about 5:1 in Hong Kong and 2:1 in New South Wales, and for gastric ulcer perforation about 2:1 and 1:1, respectively. The incidence of perforation increased with age, and there was a statistically significant rise, over time, in duodenal but not gastric ulcer perforation rates in persons aged over 60 years in New South Wales; similar trends were seen in Hong Kong. Thus duodenal ulcer perforation occurs five times more commonly in Hong Kong than in New South Wales and this is largely accountable for by the higher rates of duodenal ulcer perforation in Chinese than in Australian males. Such geographical differences can best be explained by the occurrence of multiple aetiological mechanisms in ulcer perforation. Furthermore, there appears to be an increased susceptibility and an appreciable rising trend for duodenal ulcer perforation to occur in the elderly.

The acute appendicitis syndrome: psychological aspects of the inflamed and non-inflamed appendix.

The aetiological importance of stressful life events and psychological characteristics was assessed amongst 280 appendicectomy patients of whom 80% were classified with 'acutely inflamed' (organic) appendicitis and 20% with 'non-inflamed' (non-organic) appendicitis. Patients were compared with a community comparison group. Specific characteristics of life stressors, namely severe goal frustration for organic patients and severe threat for non-organic patients, were the best predictors of patient outcome. Whilst psychological characteristics were not useful in discriminating between patients, depression in particular, was clearly associated with both conditions, with 38% of non-organic and 28% of organic patients with depression scores in the clinical range. As the patient's clinical depression status failed to modify the effect of the life stress predictors, it was concluded that life stress played an important role in the development of the patients GI symptoms, irrespective of their clinical depression status.

Patterns of dyspepsia during the course of duodenal ulcer.

Dyspepsia patterns during the course of duodenal ulcer (DU) were examined in terms of the number of consecutive months that patients experienced dyspepsia either intermittently or continuously, or were dyspepsia-free. The patients (n = 224) were community-based. After ulcer healing, they were evaluated every 3 months for less than or equal to 7 years. Antiulcer agents were prescribed at the physicians' discretion. We analyzed the data on a patient-month basis using a 2-state Markov chain model. The fitted mean number of consecutive months with dyspepsia and the number of months dyspepsia-free were, respectively, 1.7 and 14 in patients on antiulcer agents, and 1.5 and 9 in patients not taking them. On average, patients experienced dyspepsia during 15% of months studied if they were on antiulcer agents, and during 20% of months if not. Regardless of antiulcer therapy, dyspepsia periods were lengthened by age, especially greater than 60 years; male sex; widowhood/divorce/separation; increasing acetaminophen use; and increasing length of time since initial onset of ulcerlike dyspepsia. Dyspepsia-free periods were lengthened by age greater than 70 years, and shortened by widowhood/divorce/separation and increasing cigarette consumption. These results suggest that dyspepsia occurs for less than or equal to 20% of the time in DU patients on about a yearly basis. The least dyspepsia may be expected in patients neither widowed, divorced, nor separated, in whom length of time since the initial onset of ulcerlike dyspepsia does not exceed 7 years, and who neither smoke nor use analgesics regularly.

Causes of death amongst a population of gastric ulcer patients in New South Wales, Australia.

The purpose of this study was to investigate whether any specific causes of death were more frequent than expected in an Australian group of 305 gastric ulcer patients (131 men, 174 women) who had died in New South Wales between 1 January 1974 and 31 December 1983. The distribution of causes of death among the ulcer population deaths was compared with that among the New South Wales population deaths, after adjusting for sex, 5-year age group, and time period of death (1974-1978, 1979-1983). Causes of death were ascertained from death certificates. Deaths due to peptic ulcer, liver cirrhosis, and diffuse pulmonary disease were more frequent than expected (p less than 0.05). The associations found with these other diseases accord with those found in previous surveys on causes of death in gastric ulcer patients and in studies of living gastric ulcer populations. Overall, the combined evidence suggests that liver cirrhosis and diffuse pulmonary disease are associated with gastric ulcer.

Human chorionic gonadotropin treatment prevents depressed 17 alpha-hydroxylase/C17-20 lyase activities and serum testosterone concentrations in 2,3,7,8-tetrachlorodibenzo-p-dioxin-treated rats.

It is known that administration of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) causes decreased serum testosterone concentrations in the rat. Previous studies in this laboratory have shown that in rats TCDD exposure results in decreased 17 alpha-hydroxylase and C17-20 lyase activities. The decreases in these activities paralleled decreases in testicular microsomal heme and cytochrome P450 contents. As reported herein, neither testicular mitochondrial cytochrome P450 content nor the activity of cholesterol side-chain cleavage was altered in rats exposed to TCDD. Since the production of testosterone in the testis is dependent on LH, it is important to determine the early effects of TCDD on serum LH concentrations in the rat. Male Sprague-Dawley rats were given a single, oral dose of TCDD (50 micrograms/kg). Serum LH concentrations were determined by RIA on Days 1, 2, 3, 5, and 7 following TCDD treatment. Rat serum LH concentrations were decreased to 60% of controls as early as Day 1 and continued to be depressed on Days 2 and 3 at 53% and 59% of control values, respectively. Rat serum LH returned to control values by Day 5 in spite of continued depression of serum testosterone concentrations. The early depression in serum LH levels caused by TCDD may be related to the subsequent androgenic deficiency in the rat. Treatment of rats with hCG was found to be able to prevent the depression of the activities of testicular microsomal 17 alpha-hydroxylase and C17-20 lyase and serum testosterone concentrations caused by TCDD. These data indicate that TCDD decreases serum testosterone by decreasing P450(17 alpha) and C17-20 but not P450sec activities and that hCG treatment prevents the TCDD-induced decrease.

Factors influencing mortality from bleeding peptic ulcers.

The mortality, causes of death, and the factors that are influencing deaths from bleeding acute and chronic peptic ulcers were evaluated retrospectively. During a 2-year period (1986-87) 272 patients were endoscoped for acute gastrointestinal hemorrhage and were found to have bled from a peptic ulcer (chronic gastric ulcers, 90; chronic duodenal ulcers, 114; acute gastroduodenal ulcers, 66; stomal ulcers, 2). The overall mortality was 9.6% (n = 26) (gastric ulcers, 6.7%; duodenal ulcers, 11.4%; acute ulcers, 10.6%). Statistically significant factors adversely affecting prognosis for gastric ulcer were re-bleeding, need for operation and serious intercurrent illness; for duodenal ulcer were units of transfused blood, re-bleeding, signs of recent hemorrhage at endoscopy, need for operation, and serious intercurrent illness; and for acute ulcer were increasing age, shock, units of transfused blood, re-bleeding, and serious intercurrent illness. Multivariate analysis was only attempted for duodenal ulcers because of sample sizes; it suggested that active bleeding or visible vessel at endoscopy, re-bleeding, and serious intercurrent illness were independent factors for mortality. From this study it is apparent that the major determinants of a fatal outcome in bleeding peptic ulcer diseases were serious intercurrent illness and rebleeding. As it must be anticipated that patients with these particular problems are at high risk of a poor outcome, it follows that it is important they have access to skilled treatment as provided by a specialist team in an intensive care ward. It also follows that every effort should be made to keep ulcers in remission to free the ulcer patient of potentially lethal complications.

Phenylthiocarbamide taste sensitivity in chronic peptic ulcer.

Ability to taste phenylthiocarbamide is genetically determined and has been investigated as a possible genetic marker for disease. This study examined phenylthiocarbamide taste sensitivity in gastric and duodenal ulcer disease. The study sample included 164 patients with gastric ulcer, 134 with duodenal ulcer, and 299 community controls. Eight concentrations of phenylthiocarbamide in distilled water were obtained by binary serial dilution. The lowest concentration distinguished by taste from distilled water defined taste threshold. Bimodality of threshold distributions distinguished nontasters from tasters. Comparisons of patients with controls gave odds ratios of nontaste in gastric ulcer and duodenal ulcer of, respectively, 0.7 (P greater than 0.1) and 1.3 (P greater than 0.03). The power of detecting at least a twofold difference between patients and controls in the odds of nontaste was 80%. Nontaste was more common in duodenal than in gastric ulcer patients (odds ratio = 2.0, P = 0.02). Taste sensitivity was unassociated with other genetic factors related to ulcer--ABO blood group, secretor status, and serum pepsinogen 1 level. The difference between gastric and duodenal ulcer patients in the ability to taste phenylthiocarbamide may be genetic; however, this study's inability, despite substantial power, to detect at least a twofold difference between patients and controls suggests that if phenylthiocarbamide taste sensitivity is a genetic factor in peptic ulcer, the relationship is weak.

Cost-effectiveness of cimetidine maintenance therapy in chronic gastric and duodenal ulcer.

The effects of cimetidine maintenance therapy on the socioeconomic life of patients with peptic ulcers in the 3 years after healing and the extent to which treatment was cost-effective were studied. Three hundred eleven patients with healed ulcers (184 gastric, 127 duodenal) were studied for periods of up to 3 years; 261 patients (152 gastric ulcer, 109 duodenal ulcer) completed the 3-year follow-up. Cimetidine (400 mg at night) was compared with placebo in a double-blind, randomized prospective study. Intention-to-treat analysis was used. In the placebo group, the major costs of ulcer disease in gastric ulcer patients were attributable to endoscopic procedures and absenteeism; in duodenal ulcer patients, the major costs were endoscopic procedures, absenteeism, and surgery. Cimetidine was cost-effective in both gastric ulcer and duodenal ulcer patients in the first 2 years after healing. Over the 3-year period it was also cost-effective, but no benefit was seen in the third year.

Lack of association between gastric emptying of solids and symptoms in nonulcer dyspepsia.

Gastric motor dysfunction and concomitant gastric stasis have been implicated in the pathogenesis of nonulcer dyspepsia, but a cause-and-effect relationship is not established. Essential dyspepsia refers to a subgroup of nonulcer dyspepsia patients who have no evidence of irritable bowel syndrome, gastroesophageal reflux, or pancreaticobiliary disease. In 32 patients with essential dyspepsia, and 32 randomly selected dyspepsia-free community controls of similar age and sex, we measured gastric emptying of solids using Tc99m-Sulphur Colloid in a fried egg sandwich. Subjects with neuromuscular or other diseases that may alter gastric emptying were excluded. Symptoms were assessed by a standard questionnaire. Data processing was carried out "blinded" to the subjects' clinical status. Female patients took significantly longer to empty half the initial stomach activity (mean 90 min) than female controls (mean, 73 min; p = 0.02). The rate of emptying at 25 min was also significantly less in female patients than in controls. Female and male controls, and male patients, had similar emptying times. Delayed emptying was not associated with the occurrence of postprandial pain, belching, or nausea; there was a trend for the half-time rate of emptying to be greater in patients with abdominal distention. While gastric emptying of solids is slightly delayed in females with essential dyspepsia as a group, this may not explain their symptoms.