Antagonism by riluzole of entry of calcium evoked by NMDA and veratridine in rat cultured granule cells: evidence for a dual mechanism of action.

1. Intracellular calcium levels were measured in cultured cerebellar granule cells of the rat by use of the fluorescent dye, indo-1/AM. 2. Intracellular calcium levels were increased by depolarizing stimuli such as N-methyl-D-aspartate (NMDA) (100 microM), glutamic acid (20 microM), and veratridine (10 microM). This increase was essentially due to entry of external calcium. 3. Riluzole (10 microM) blocked responses to all the depolarizing agents. 4. Riluzole could still block the increase in intracellular calcium evoked by NMDA or glutamic acid when sodium channels were blocked by tetrodotoxin, suggesting that this effect is not mediated by a direct action of riluzole on the voltage-dependent sodium channel. 5. Pretreatment of the cells with pertussis toxin (0.1 micrograms ml-1) did not modify the increases in intracellular calcium evoked by NMDA, glutamic acid or veratridine. 6. In pertussis toxin-treated cells, riluzole could no longer block responses to excitatory amino acids, but still blocked responses to veratridine. 7. It is concluded that riluzole has a dual action on cerebellar granule cells, both blocking voltage-dependent sodium channels and interfering with NMDA receptor-mediated responses via a pertussis toxin-sensitive mechanism. Furthermore, these two processes have been shown to be independent.

Effects of depolarizing stimuli on calcium homeostasis in cultured rat motoneurones.

Intracellular calcium concentrations in individual rat motoneurones in enriched primary cultures were measured by Indo-1 fluorimetry. Motoneurones in the cultures were characterized morphometrically and by cholineacetyltransferase immunocytochemistry. Depolarization of the cells with glutamic acid or veratridine increased intracellular calcium levels, which returned to baseline only slowly after removal of the depolarizing agent. The use of selective agonists (N-methyl-D-aspartic acid, AMPA, kainic acid, quisqualic acid and 1R-3S-ACPD) and antagonists (MK 801 and CNQX) showed that the excitatory amino acid-evoked responses were mediated by AMPA/kainate receptors rather than by NMDA receptors. Depolarization-evoked calcium transients in motoneurones are blocked by the neuroprotective drug riluzole Calcium transients reflected entry of calcium from without the cell, and their blockade by nitrendipine and lanthanum chloride suggested that this entry took place primarily through voltage-dependent calcium channels. These findings may be relevant for understanding the selective vulnerability of motoneurones to excitotoxicity in amyotrophic lateral sclerosis, and the therapeutic activity of riluzole in the treatment of this disease.

Aortic graft-enteric fistula.

Fifteen years' experience with 20 patients undergoing 24 operations for intestinal bleeding from aortic graft-enteric fistula at the Mayo Clinic has been reviewed. A review of the English language literature permits analysis of an additional 127 patients who underwent surgical intervention for this condition. Associated operative mortality in our experience and in that of others has been high--55% and 46%, respectively. Long-term survival in both groups remains low--approximately 15%. Consideration has therefore been given to aspects of prophylaxis, diagnosis, and intervention which may minimize future morbidity and mortality.

Truncal vagotomy and resection in the treatment of duodenal ulcer.

A retrospective analysis was conducted of 466 patients who underwent elective truncal vagotomy with antrectomy or hemigastrectomy for chronic duodenal ulcer. The postoperative (30-day) mortality was 1.1%. In 412 of 466 patients (88.4%), follow-up was obtained, and in 290 patients alive at the writing of this paper, the mean follow-up was 17.1 years; the remaining 54 patients (11.6%) were lost to follow-up. The overall ulcer recurrence rate was 0.7%. Severe postoperative sequelae--postvagotomy diarrhea and postgastrectomy dumping--were uncommon--0.7% and 1.0% of patients, respectively. The combination of truncal vagotomy and gastric resection is a viable alternative in the surgical treatment of chronic duodenal ulcer disease and is the authors' operation of choice for most such patients.

Action of colchicine on axonal flow and pituicytes in the hypothalamopituitary system of the rat.

Changes in the hypothalamo-pituitary tract and the pituicytes of the rat were studied after intrathecal and intraperitoneal injections of colchicine. Radioautography with 35S-cysteine demonstrates that intrathecal colchicine prevents the migration of neurosecretory granules from the supraoptic and paraventricular nuclei to the posterior lobe of the pituitary. This results in accumulations of neurosecretory granules and in the formation in the axons of elongated structures resembling neurosecretory products, although they sometimes have a fibrillary content. Neurotubules appear to remain intact in these conditions. The stimulation of the posterior pituitary by dehydration, in particular after injection of the diuretic furosemide, leads to an increased activity of pituicytes. When colchicine is injected at the same time as furosemide, a considerable new formation of centrioles is observed in the pituicytes. These become associated with ciliary vesicles, and form numerous cilia of the 9 + 0 type. An increased number of centrioles is also seen in the endothelial cells of the posterior lobe of the pituitary. These apparently paradoxical results were briefly discussed in relation to the action of colchicine on neurotubules and axonal flow and to the limited data from the literature indicating a stimulation of cilia formation under the action of colchicine and other drugs.

Solitary renal artery aneurysm.

The records of all patients with solitary renal artery aneurysms seen between January 1968 and December 1978 were reviewed. Patients with fibromuscular dysplasia were excluded from analysis. Of the 67 patients seen, 34 had the diagnosis made on the basis of arteriography, 31 on the basis of abdominal roentgenography, and 2 at surgery. The ages of the 67 patients (34 men and 33 women) ranged from 21 to 90 years, with a mean of 61 years. Only five patients (8%) were symptomatic; all five presented with abdominal pain. Forty-six patients (69%) had associated hypertension. Five patients underwent surgical repair when initially seen. Only one patient had preoperative abdominal pain that was considered to be related to the aneurysm. The aneurysm sizes ranged from 0.3 to 4.0 cm, with a mean of 1.5 cm. In 45 patients (67%) the aneurysm was calcified. Follow-up ranged from 1 to 17 years, with a mean 5.7 and a median of 8.0 years. During follow-up, all aneurysms remained clinically silent. No aneurysms were subsequently repaired, no new cases of hypertension developed, no nephrectomies had to be performed, and no ruptures occurred. Eight patients (12%) died; no death was related to a complication of the aneurysm. This study supports the view that patients with asymptomatic solitary saccular renal artery aneurysm may be safely observed without surgical intervention.

Occult papillary carcinoma of the thyroid.

Retrospective review was undertaken of 137 patients with occult papillary carcinoma of the thyroid (lesions less than or equal to 1.5 cm in diameter) who were operated on at the Mayo Clinic, Rochester, Minn, between 1926 and 1955. Mean follow-up period was 25.3 years. Operations were conservative. No patient underwent bilateral total lobectomy. For 55 patients with lymph node involvement, lymphadenectomy generally involved selective node excision or modified neck dissection. Subsequent surgery was required in 12 patients; modified radical neck dissection was necessary in only four. No operative deaths occurred. Long-term follow-up showed that all patients were alive and without disease or were dead without proof of thyroid-related disease. Thus, occult papillary thyroid carcinoma with or without nodal metastasis is a nonlethal and curable disease when treated by conservative surgical means. Radical surgical or medical extirpation of all thyroid tissue is unnecessary in the treatment of this disease.

Ibotenic acid stimulates D-[3H]aspartate release from cultured cerebellar granule cells.

The release of D-[3H]aspartate from cultured cerebellar granule cells can be evoked by potassium depolarization or by superfusion with the excitatory amino acids glutamic and aspartic acids. The latter phenomenon is not mediated by N-methyl-D-aspartate (NMDA)-, kainate- or quisqualate-preferring receptors, but is stimulated by ibotenic acid. Excitatory amino acid-stimulated D-[3H]aspartate release is antagonised by L-serine-O-phosphate and riluzole. These compounds did not block potassium-stimulated D-[3H]aspartate release. This pharmacology resembles an excitatory amino acid receptor coupled to inositol phosphate (PI) turnover.

Pertussis toxin pretreatment abolishes the inhibitory effect of riluzole and carbachol on D-[3H]aspartate release from cultured cerebellar granule cells.

The release of D-[3H]aspartate from cultured cerebellar granule cells evoked by glutamic acid can be inhibited by riluzole and the muscarinic agonist carbachol. The combined application of maximally efficacious concentrations of riluzole and carbachol produces no greater inhibition than that seen with either agent alone, indicating that a common mechanism is involved. The effects of both agents are abolished when the cells have been pretreated with pertussis toxin, which suggests that this mechanism may involve a GTP-binding protein. The effect of pertussis toxin pretreatment is not mimicked by cholera toxin, nor does pertussis toxin pretreatment interfere with the inhibitory effect of the competitive excitatory amino acid receptor antagonist D-alpha-aminoadipic acid.

Patient acceptance of mastectomy for cancer.

Of 300 women who had mastectomy for breast carcinoma, 278 (93 percent) responded to a questionnaire about how well they accepted loss of a breast. Of those responding, 73 percent stated that they had no appreciable adverse reaction to the extent of the operation. Twenty patients (7 percent) cited major work, social or sexual problems resulting from mastectomy. Among the 20, sexual problems--cited by 85 percent--predominated. Four (1 percent) of the 278 patients expressed major dissatisfaction with the cosmetic result of an external prosthesis. Two of these patients and four others had surgical reconstruction of the breast, which was satisfactory in five.

[Pituitary modifications in a case of Schilder disease (author's transl)]. / Modifications hypophysaires dans un cas de maladie de Schilder

In a case of Schilder disease with a heavy atrophy of adrenal cortex the immunocytological analysis of anterior pituitary shows a generalized hypertrophy and a severe last of granulations of the beta cells which reacted very weakly to au anti-serum anti-ACTH 17-39. These modifications agree with biological titration proving an hypersecretion of ACTH and beta MSH.

Papillary carcinoma of the thyroid.

Cancer of the thyroid gland occurs infrequently, and, although the majority of lesions are papillary and well differentiated, some patients do die of the disease. Since mortality and morbidity for thyroidectomy are low, surgical treatment is advised for patients who have nodular goiters that might be cancerous and for those who have goiters that are suspected of being cancerous. Thyroidectomy is the treatment of choice for patients with known papillary thyroid cancer. Only when lymphatic metastases are present should a complimentary modified neck dissection be performed in addition to thyroid resection. Prognosis is related to extent of the primary lesion rather than to presence or absence of regional nodal metastases. Patients with intrathyroidal lesions fare better than those with extrathyroidal extension. Thyroid surgery in the hands of experienced surgeons should carry an exceedingly low risk and be capable of providing excellent long-term cure and palliation of thyroid cancer.

[Grawitz tumour in children (author's transl)]. / La tumeur de Grawitz chez l'enfant

A Grawitz tumour was discovered in a five year old boy. Nephrectomy was performed. The child died four years later in the course of a metastatic generalization. The clinical diagnosis was oriented by haematuria and radiographs which disclosed a calcified tumour at the lower pole of the right kidney. The diagnosis was substantiated by biopsy and morbid anatomy.

Multiple tuberculomas of the brain. Report of a case.

A case of multiple tuberculomas of the brain in a pregnant patient is reported. The symptoms and signs suggested a lesion of the cerebellum which was found to be only congested and oedematous at craniotomy. The correct diagnosis was made at autopsy.

Substance P-evoked calcium mobilization and ionic current activation in the human astrocytoma cell line U 373 MG: pharmacological characterization.

In the human astrocytoma cell line U 373 MG, application of substance P (SP) leads to a transient increase in cytosolic calcium concentration and to a biphasic current response in voltage-clamped cells. Using these two functional assays we have characterized pharmacologically the SP response in U 373 MG cells. SP and [L-Pro9]SP displayed high potencies in both assays with EC50 values of 2.5 x 10(-9) M and 1 x 10(-9) M on calcium responses and 1 x 10(-9) M and 5 x 10(-9) M on ion current responses, respectively. The high potency of SP and [L-Pro9]SP as well as the low potency of [Lys5,MeLeu9,N-Leu10]neurokinin A(4-10) and the inactivity of senktide demonstrate the NK1-type pharmacology of these responses. Furthermore, the NK1 antagonists (+/-)-CP 96,345, its chloro analogue, (+/-)-cis-3-(2-chlorobenzylamino)-2-benzhydrylquinuclidine, and RP 67580 were potent antagonists of both SP responses. For the calcium mobilization induced by SP (10(-7) M), the IC50 values for the three antagonists were 4 x 10(-10) M, 4 x 10(-9) M, and 9 x 10(-9) M, respectively, whereas on the current response evoked by SP (10(-8) M), the IC50 values were 8 x 10(-9) M, 2.4 x 10(-8) M, and 1.2 x 10(-7) M, respectively. Despite differences in the absolute IC50 values obtained with both techniques, the relative potencies of the three antagonists correlate fairly well.(ABSTRACT TRUNCATED AT 250 WORDS)

The surgical management of bleeding stress ulcers.

The series included 52 patients with acute bleeding stress ulcers of the stomach and duodenum seen at the Mayo Clinic during a 25-year period. All patients underwent operation for control of massive bleeding that was unresponsive to intensive medical therapy. All ulcers were superficial and occurred during clinically stressful circumstances. No patient had a history or findings suggestive of pre-existing peptic ulcer disease or imbibation of ulcerogenic substances. Overall operative mortality was 54%, and this rate seemed to be related to multiple factors acting together; patients with multiple predisposing stress factors and those requiring large transfusion volumes (greater than 17 total units) were at greatest risk of death. Fifty-two patients underwent 60 operative procedures for control of hemorrhage. Of the 60 procedures, 23 (38%) failed to prevent rebleeding. Of the 28 patients who died, six (21%) died of hemorrhage and five (18%) died of hemorrhage as one of many contributing factors. Of eight different procedures performed, near-total to total gastrectomy was the single procedure that was most effective in controlling hemorrhage. The authors support the selection of rapid intervention and generous extirpative surgery once intensive medical measures fail to control hemorrhage.