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Effect of indole-3-acetic acid derivatives on neuroepithelium in rat embryos.

Indole-3-acetic acid (IAA), a natural auxin, induces microencephaly in rats exposed to IAA during gestation days (Days) 12-14, corresponding to the early stage of cerebral cortex development. The purpose of this study was to examine the effects of 5 IAA derivatives administration in pregnant rats on neuroepithelial cells in the embryos. N-Methylindole-3-acetic acid (1Me-IAA), 2-Methylindole-3-acetic acid (2Me-IAA), 2-Methyl-5-methoxyindole-3-acetic acid (2Me-5MeO-IAA), 5-Methoxyindole-3-acetic acid (5MeO-IAA), Indole butyric acid (IBA), and IAA were administered at 1,000 mg/kg except for 2Me-IAA at 500 mg/kg on Days 12, 13 and 14, and then embryos/fetuses were harvested on Day 14.5 or 21. The dams in the 1Me-IAA and 2Me-IAA groups exhibited rigidity and a decrease in locomotor activity. Although a decrease in the absolute brain weight was observed in the 1Me-IAA, 5MeO-IAA, IBA and IAA groups, a decrease in the relative brain weight was observed in only the IAA group. Histopathologically, apoptotic cells were observed mainly in the medial and dorsal layer of the neuroepithelium in the 5MeO-IAA and IAA groups on Day 14.5. The degree of induced neuroepithelial cell apoptosis was less in the 5MeO-IAA group than in the IAA group. However, it was confirmed that the histopathological changes induced by 5MeO-IAA were quite similar to the lesions induced by IAA and may have resulted from the same mechanisms.

Administration, Oral↗

Isolation and characterization of anaerobic indole- and skatole-degrading bacteria from composting animal wastes.

Four species of indole-degrading Clostridium and 3 species of skatole-degrading Clostridium were isolated from piggery or chicken manure composting processes. Since type strains of respective isolates did not degrade these compounds, the degradability of the compounds was a novel characteristic. All isolates were mesophilic. The maximum growth allowance concentrations of these isolates were 300 to 800 mg/l in indole and 100 to 300 mg/l in skatole. All isolates showed better growth and utilization of indolic compounds in nutrient-rich medium than in minimal medium. Skatole-degrading isolates degraded some substituted indoles tested, 3-indoleacetic acid, indole and oxindole, but did not degrade 1-methylindole, 2-methylindole, isatin or anthranilic acid. On the other hand, indole-degrading isolates degraded only oxindole. The growth of Clostridium malenominatum A-3 was inhibited by a low concentration (0.005%) of indole or skatole, even when 200-fold excess glucose was present in the medium. When 0.03% indole or skatole was added to the medium, C. malenominatum A-3 showed a lag phase for about 10 and 70 h, respectively. When 0.01% of these compounds was added to the medium, the uptake of glucose was inhibited. C. malenominatum A-3 degraded these compounds under nutrient-rich and minimal conditions.

Journal Article↗

Inhibition of ruminal degradation of L-tryptophan to 3-methylindole, in vitro.

Available evidence supports the view that acute bovine pulmonary edema and emphysema (ABPE) is related to ruminal production of 3-methylindole (3MI) from L-tryptophan (TRP). Ruminal production of 3MI is a two-step process involving the conversion of TRP to indoleacetic acid (IAA) followed by decarboxylation of IAA and 3MI. Reduction in ruminal 2MI production by the inhibition of either of these processes may prevent the onset of ABPE. A closed-system, in vitro ruminal fermentation technique was used to screen 27 compounds for their ability to reduce the conversion of TRP to 3MI. Several compounds tended to reduce 3MI production at both 25 and 5 micrograms/ml. Desoxysalinomycin, X-206, chloral hydrate, nigericin, lasalocid, monensin, narasin and salinomycin all reduced 3MI production by more than 80% at 5 micrograms/ml without reducing total VFA production. All of these compounds, except chloral hydrate, are polyether antibiotics. At least part of the inhibition due to monensin and narasin occurs at the level of TRP conversion to IAA.

Animals↗

Ketanserin versus placebo in carcinoid syndrome. A clinical controlled trial.

Seven patients, four women and three men, with a median age of 64 years (range, 53-74 years) were randomized to treatment with either ketanserin, 40-160 mg daily, or placebo. The study included 13 treatment periods with ketanserin and 13 with placebo. All patients had typical symptoms, with flushing as their main complaint. The diagnosis had been verified histologically. All had elevated excretion of 5-hydroxy-3-indoleacetic acid in urine. During the trial ketanserin reduced the number of flushing attacks in five patients (p less than 0.05). Diarrhoea was reduced in two patients. No side effects were observed. Ketanserin seems valuable for the symptomatic relief in the carcinoid syndrome.

Aged↗

Treatment of malignant metastatic midgut carcinoid tumours with recombinant human alpha2b interferon with or without prior hepatic artery embolization.

Nineteen patients with histologically verified midgut carcinoid tumours and liver metastases were included in a prospective study with daily recombinant human alpha 2b interferon injections of 5 million IU subcutaneously for 1 year. All had as much as possible of the primary tumour removed at laparotomy. Whenever technically possible (in seven cases), an embolization of the hepatic arteries was performed before interferon start. The response rate of the combined embolization and interferon treatment (n = 7) was 86% after 1 year, as judged from either a 50% reduction in excretion of 5-hydroxy-3-indoleacetic acid in the urine or a 50% reduction in the area of the largest liver metastasis as evaluated by computed tomography. All patients experienced an improvement in diarrhoea and/or flushing. When interferon was given alone (n = 12), 40% responded on the basis of objective criteria (50% after 6 months), whereas an improvement in either diarrhoea or flushing was experienced by 70% (75% after 6 months). In this group one patient had died and one had decided to withdraw after 6 months, at which time both were responders. We conclude that interferon seems to be an effective treatment of malignant metastatic midgut carcinoid tumours and that embolization of the liver arteries seems to increase the response rate, as judged after 1 year.

Adult↗

Recombinant alpha-2 interferon with or without hepatic artery embolization in the treatment of midgut carcinoid tumours. A preliminary report.

Nineteen patients with histologically verified midgut carcinoid tumours and liver metastases were included in a prospective study with daily interferon therapy 3 mill IU x m-2 subcutaneously for one year. All had the primary tumour removed at laparotomy, and whenever technically possible, an embolization of the hepatic arteries was performed prior to interferon start. Recombinant human alpha-2b interferon from Schering was employed. When interferon was given alone for one year 40% responded, judged from either a 50% reduction in excretion of 5-hydroxy-indoleacetic acid in the urine or a 50% reduction in the area of the largest liver metastasis, as evaluated by computer tomography. One patient died later on and one withdrew from therapy of her own will; both were responders at the evaluation at 6 months. When prior embolization of the liver arteries had been performed, the response rate was 85% after one year. When diarrhoea and/or flushing was evaluated, 70% had response on interferon alone, while all patients experienced improvement after the combined procedure. We conclude that interferon is an effective treatment of malignant metastatic midgut carcinoid and that embolization of the liver arteries seems to increase the response rate.

Carcinoid Tumor↗

Circadian rhythm variations in the adult rat induced by low and high protein diets administered at various stages of development.

Hypothalamic tryptophan (TP), serotonin (5HT) and 5-hydroxy-indoleacetic acid (5HIAA), serum tryptophan (free and total), and circulating corticosterone and aldosterone were measured over 24 hr in 60-day-old male rats fed high (60%) and low (6%) protein diets. The diets were administered during specific stages of rat growth: fetal phase and suckling (when the process of mitosis is most rapid), post-lactation, and from the fetal phase through to the adult stage. In all groups, there was a direct correlation between protein intake and hypothalamic and serum TP levels. Remarkable decreases in the amplitude and mesor of the aldosterone rhythm were observed when the hyperprotein diet was administered in the fetal and suckling phases, or from the fetal phase until the adult stages. The rhythm of the serotonin system was significantly altered by a low protein diet: decreased 5-HT amplitude (low protein diet in the fetal stage and suckling), decreased 5-HT amplitude and deranged 5-HIAA rhythm (low protein in the post-lactation period), deranged 5-HIAA rhythm (low protein diet throughout the experiment). Lastly, there was a remarkable increase in the corticosterone mesor in rats administered a low protein diet after weaning and in rats constantly given this diet. Growth was greatly inhibited in these two groups of animals, therefore, it cannot be excluded that the high levels of circulating hormone resulted from their debilitated condition.

Aldosterone↗

Serotonin in early onset, male alcoholics with violent behaviour.

Several lines of evidence suggest that abnormal brain serotonin metabolism may occur in early onset, type 2 alcoholism in men. Low cerebrospinal fluid 5-hydroxy-indoleacetic acid concentration has been found to be associated with a history of paternal alcoholism, and abnormal oral glucose tolerance tests (tendency to low blood glucose nadir) in subjects who are prone to exhibit impulsive, aggressive behaviour under the influence of alcohol. Moreover, a low ratio of the concentrations of tryptophan and other large neutral amino acids in plasma seems to correlate with early onset alcohol abuse and violent tendencies. More knowledge is required about neurochemical changes in homogenous subgroups of alcoholics such as the putative type 2 so as to understand which of the relationships are causative and to provide treatment strategies for alcoholism and its complications.

Alcoholism↗

[Primary carcinoid tumor of the testis with metastasis to the upper vertebrae. Report of a case].

A case of primary carcinoid tumor of the right testis with metastases to the cervical and thoracic vertebrae and epidural is reported. A 53-year-old man was first recognized as being with dysthesia of the left arm and shoulder in April 1986. In June, 1987, he was admitted to the Neurology service, complaining of sudden occurrence of abasia. Myelography and computerized tomography demonstrated an epidural mass and several high density areas in the vertebral bodies of Th1 and Th2. The patient underwent laminectomy from C7 to Th2. At operation, the neurosurgeons noticed a tumor mass in the right scrotum and requested our consultation. Thus right high orchiectomy was performed. Pathological examination including Grimerius' and Fontana-Masson's stain revealed carcinoid tumor of the right testis associated with metastases to the spinal column. Postoperatively, tumor maker studies revealed elevation of blood 5-hydroxytryptophan and marked increase of urinary 5-hydroxy-indoleacetic acid excretion. They showed remarkable decreases after a course of PVB chemotherapy. The patient has been under our observation as an out-patient for the past 27 months with metastases. This is the first case of primary carcinoid tumor of the testis with metastases so far reported in the domestic literature.

Carcinoid Tumor↗

[Relationship between cancer chemotherapeutic drug-induced delayed emesis and plasma levels of substance P in two patients with small cell lung cancer].

We investigated the relationship between delayed emesis caused by cisplatin (CDDP) based chemotherapy and plasma levels of serotonin, 5-hydroxy-indoleacetic acid (5-HIAA), and substance P in two patients with small cell lung cancer. In each of the cases, we used the 5-HT3 receptor antagonist ramosetron every morning on day 1-4 of the chemotherapy. In case 1, plasma levels of serotonin were low, whereas substance P levels increased since 24 hours after the injection of CDDP. The increase in substance P levels paralleled the onset of vomiting. In this case, however, substance P levels decreased and yet vomiting occurred. Similarly, in case 2, plasma levels of serotonin were low, whereas substance P levels increased since 24 hours. The increase in plasma levels of substance P and the onset of vomiting were observed at the same time 2-3 days after cisplatin administration. In this case, however, vomiting was not observed during the 5 days when the substance P was highest. Therefore, we suggested that substance P was closely associated with CDDP-induced delayed emesis, though some chemical mediators other than substance P might also be related to the emesis.

Adult↗

Lesions of midbrain raphe and ethanol narcosis in rats.

Serotonin -- depleting lesions involving nucleus raphe medianus markedly prolonged ethanol-induced sleep in rats. Lesioned animals showed increased general activity and decreased serotonin and 5-hydroxy-indoleacetic acid concentrations in the forebrain.

Animals↗