Antineural antibodies in Guillain-Barré syndrome and lymphocytic meningoradiculitis (Bannwarth's syndrome).

Antineural antibodies occur in Guillain-Barré syndrome (GBS), but have not been studied in lymphocytic meningoradiculitis (Bannwarth's syndrome), which has clinical features in common with GBS. Employing a sensitive complement-fixation assay with homogenates of nerve root and brain as antigens, we recorded positive serum reactions to either tissue in 14 of 18 samples from patients with GBS during the first three weeks of the disease. Five of nine samples were positive during the fourth to eighth weeks, whereas all seven patients sampled thereafter had negative reactions. Four GBS serum samples reacted only with nerve root, seven reacted only with brain, and eight reacted with both antigen preparations. One of 12 patients with meningoradiculitis and one of 50 supposedly healthy blood donors had serum antibodies to brain. Our results support the concept of an autoimmune mechanism in GBS, while in Bannwarth's syndrome an infectious cause related to that of Lyme disease may be suspected.

Extra- and intrathecal production of antinerve and antibrain antibodies in Guillain-Barré syndrome: evaluation by an antibody index.

In serum and CSF samples from 19 patients with the Guillain-Barré syndrome (GBS), we assayed complement-fixing autoantibodies that react with peripheral and central nervous tissue. About two thirds of the serum and CSF samples reacted with preparations of one or both tissues. The distribution of antibodies, evaluated by the antibody index (CSF/serum titer divided by CSF/serum albumin), suggested predominantly extrathecal production in most patients, but an intrathecal contribution was also seen. Thus, the possible pathogenic effects of antineural antibodies in GBS may be exerted on both sides of the blood-brain barrier.

The ontogenetic mouse brain model employed in the characterization of antibrain antibodies in multiple sclerosis.

The complement-fixing antibrain antibodies which may be found in patients with multiple sclerosis (MS) belong to several specificities, of which only two are as yet identified. In order to study three of the incompletely characterized specificities, the ontogenetic evolution of the corresponding antigens in mouse brain was followed. MS serum containing antibodies to sulfatide, a relatively myelin-specific glycolipid, served as a control. The studied antigens were virtually absent at birth and accumulated at different rates during the postnatal period. The results give valuable clues for the further study of the antibrain antibodies in MS.

Repeated in vivo determinations of bone mineral density during parathyroid hormone treatment in ovariectomized mice.

The recent development of different genetically modified mice with potentially interesting bone phenotypes has increased the demand for effective non-invasive methods to evaluate effects on bone of mice during growth and development, and for drug evaluation. In the present study, the skeleton was analyzed by repeated in vivo scans using dual energy X-ray absorptiometry (DXA) and peripheral quantitative computed tomography (pQCT). Ovariectomized (ovx) mice treated with parathyroid hormone (PTH) were used as an animal model to evaluate these two techniques at different times after the onset of treatment. Female mice (6 weeks of age) were allocated randomly to four groups: (1) sham-operated+vehicle; (2) ovx+vehicle; (3) sham-operated+PTH(1-84) 150 microg/kg per day; (4) ovx+PTH. Six weeks after ovariectomy the drug treatment began and was continued for 8 weeks. The total body bone mineral content (BMC) and total body areal bone mineral density (BMD) were measured by DXA. Ovariectomy reduced total body BMC and total body areal BMD by 6.2+/-1.7% and 2.6+/-0.9% respectively. No effect of PTH on total body BMC was seen during the treatment period. The trabecular volumetric BMD was measured by pQCT. Ovariectomy reduced the trabecular volumetric BMD by 52+/-6.7%. The pQCT technique detected a clear effect on trabecular volumetric BMD after 2 weeks of PTH treatment (ovx 94+/-29% and sham-operated 46+/-10% more than vehicle-treated). The cortical bone was measured in a mid-diaphyseal pQCT scan of the tibia. Ovariectomy reduced the cortical BMC by 9+/-2%. PTH treatment for 8 weeks increased cortical BMC in ovx mice. In conclusion, the pQCT technique is more sensitive than the DXA technique in the detection of bone loss after ovariectomy and increased bone mass after PTH treatment in mice. Notably, the pQCT, but not the DXA, technique detected a dramatic effect as early as after 2 weeks of PTH treatment. Dynamic pQCT measurements will be useful for monitoring skeletal changes during growth and development, and for drug evaluation in mice.

Drug-induced prevention of gastrectomy- and ovariectomy-induced osteopaenia in the young female rat.

Both ovariectomy (Ovx) and gastrectomy (Gx) induce osteopaenia in rats and humans. While the effect of Ovx has been ascribed to oestrogen deficiency, the underlying mechanism behind Gx is poorly understood. Alendronate, oestrogen and parathyroid hormone (PTH) are known to prevent the osteopaenia induced by Ovx in rats. The purpose of the present study was to determine whether alendronate, oestrogen or PTH could also prevent Gx-evoked osteopaenia. Rats were Ovx-, Gx-, or were sham-operated (Sham) and were then treated with alendronate (50 micro g/kg/day), oestrogen (10 micro g/kg/day) or PTH(1-84) (75 micro g/kg/day) for eight weeks. At sacrifice, serum PTH was unaffected by surgery (Ovx, 64+/-8 pg/ml; Gx, 75+/-13 pg/ml; Sham, 58+/-11 pg/ml). The bone mineral density (BMD) of the fifth lumbar vertebra (L5) was analysed. Ovx and Gx reduced the BMD (ash weight/Volume) of the L5 by 15+/-4% and 22+/-3% respectively. Trabecular BMD and the cortical bone mineral content (BMC) of the femur were assessed using peripheral computed tomography. Both Ovx and Gx markedly reduced trabecular BMD in the metaphyseal area of the distal femur (Ovx, -37+/-7%; Gx, -49+/-7%). The cortical BMC of the femur was only slightly reduced. Alendronate prevented trabecular bone loss after both Ovx and Gx, while oestrogen and PTH prevented trabecular bone loss after Ovx but not after Gx. In conclusion, the bisphosphonate alendronate prevented both Ovx- and Gx-induced trabecular bone loss. In contrast, PTH and oestrogen prevented Ovx-induced but not Gx-induced trabecular bone loss, suggesting that the mechanism behind the trabecular bone loss in Ovx rats differs from that in Gx rats. The results support the notion that the mechanism of action for the bone-sparing effect of these drugs differs. The ability of alendronate, and probably also other bisphosphonates, to prevent Gx-evoked osteopaenia in the rat might be of potential clinical interest when dealing with post-Gx osteopaenia in humans.

Hypergastrinaemia produces trophic effects in stomach but not in pancreas and intestines.

Hypo- or anacidity, caused by antisecretagogues, stimulates gastrin release and leads to hypergastrinaemia. If drug treatment is maintained over a period of time, the hypergastrinaemia can be expected to give rise to trophic effects. We examined the trophic consequences of the very marked hypergastrinaemia produced by long-term treatment (16-20 weeks) of rats with large doses of the substituted benzimidazole, omeprazole, a potent and long-acting blocker of acid secretion. The weight of the stomach and the oxyntic mucosal thickness were increased, whereas the weight of the pancreas and the intestines and the thickness of the mucosa of the antrum and small and large intestine were unaffected. The number of exocrine cells (parietal, zymogen and mucous cells) were uniformly increased by 25-30%. The density of parietal and zymogen cells, expressed as number of cell nuclei per mm2 epithelium, was unchanged. The volume density of parietal cells, expressed as % of epithelial volume, was also unchanged, implying that the volume of the individual parietal cell had not increased. The density of endocrine ECL cells in the stomach increased 5-fold. Thus, the findings demonstrate a growth-promoting effect of the hypergastrinaemia on the oxyntic mucosa, the ECL cells in particular, and the lack of such an effect on the antrum, pancreas and intestines.

Intraocular transplants of a human gastrinoma in immuno-suppressed rats: morphological, chromatographic and functional studies.

Tissue pieces of a metastatic human gastrinoma (ultrastructural Type II) were successfully transplanted to the anterior eye-chamber of rats immunosuppressed with Cyclosporin A. Immunocytochemical investigation of the transplants showed evidence for preserved endocrine activity of tumour cells with immunoreactivity towards the C-terminal of the gastrin/cholecystokinin molecule. Studies of gastric acid secretion in tumour-bearing rats and sham-operated controls with chronic gastric fistulas showed that the basal acid output did not differ between the groups during 3 weeks of study. However, the stimulated gastric acid secretion decreased after 5 days in both groups to remain significantly depressed throughout the study, an effect probably due to Cyclosporin A treatment of the groups. The concentration of immunoreactive gastrin in plasma from rats with tumours in oculo was 5 times higher than in sham-operated rats. Gastrin-34 was the major immunoreactive component in both patient serum and rat plasma. An immunoreactive fraction corresponding to component I was found in the patient serum, but not in the rat plasma, although present in the chamber fluid. Components corresponding to gastrin-17 were found both in the patient serum and in the rat plasma. The chromatographic pattern of the tumour was similar to that in rat chamber fluid. The dominating component corresponded to gastrin-17, while gastrin-34 represented the quantitatively smaller component. Gastrin-34 was, however, relatively more abundant in the tumour extract than in the chamber fluid. The study also indicates that a gastrin-producing tumour transplanted in oculo in immunosuppressed rats may increase the rat plasma concentration of the same molecular forms of gastrin as seen in the clinical situation.

Gastrin and somatostatin in the rat antrum. The effect of removal of acid-secreting mucosa.

Female rats were subjected to operations aimed at reducing the amount of oxyntic gland mucosa draining its acid secretion to the antrum. The rats were provided either with Heidenhain or Pavlov pouches reducing the oxyntic mucosa draining its secretion to the antrum by about 50% or subjected to various degrees (75, 90 and 100%) of fundectomy. Ten weeks following surgery, plasma levels of gastrin and somatostatin were assayed. At the same time, antral mucosal content of gastrin and somatostatin was determined as well as the mucosal density of these hormone-producing cells. There was a relationship between the amount of acid-secreting mucosa removed and the ensuring plasma concentration of gastrin. Thus, a stepwise increase in plasma gastrin was found with the highest levels obtained in rats subjected to 90 or 100% fundectomy. The somatostatin concentration in plasma was reduced only in rats subjected to fundectomy with the most sustained decrease in animals in which all oxyntic gland mucosa had been removed. There was also a relationship between the amount of acid-secreting mucosa removed and the gastrin content of the antral mucosa. An inverse relationship seemed to exist between antral gastrin and somatostatin concentrations. However, a significant decrease in somatostatin concentration of the antral mucosa was seen only in rats subjected to a fundectomy. The number of gastrin cells in the antral mucosa was increased in fundectomized rats only, with the largest density seen in rats deprived of all oxyntic mucosa. A corresponding decrease in the number of somatostatin cells was noticed. Our results would suggest an apparent functional relationship between antral gastrin and somatostatin cells, where the antral acid load (or pH) appears to be the major factor of physiological significance.

Omeprazole and ranitidine, antisecretagogues with different modes of action, are equally effective in causing hyperplasia of enterochromaffin-like cells in rat stomach.

Female rats were treated for 28 days with high doses of the gastric acid secretion inhibitors omeprazole and ranitidine. Omeprazole, which is long-acting, was given orally once daily. Ranitidine, which is short-acting, was given by continuous infusion (via osmotic minipumps, implanted subcutaneously). The aim was to produce a similar degree of acid inhibition with the two drugs. The inhibition of acid secretion over the day and night was more pronounced in the omeprazole-treated rats (maximal inhibition 100%, minimum 85%) than in those receiving ranitidine (mean 70%). In both groups, there was a great increase in plasma gastrin, somewhat greater after omeprazole than after ranitidine. The gastrin concentration in the antrum was almost doubled by both treatments and there was a moderate increase in the number of antral gastrin cells in the omeprazole-treated rats. The number of enterochromaffin-like (ECL) cells (per visual field) increased in the oxyntic mucosa to the same extent (greater than 100%) in the ranitidine- and omeprazole-treated rats. Apart from the gastrin cells in the antrum and the ECL cells in the corpus no other gastric endocrine cell type seemed to respond to treatments with antisecretagogues. We conclude that, regardless of the type of antisecretagogue used, effective and long-term suppression of gastric acid secretion results in sustained hypergastrinemia and increased number of ECL cells. Conceivably therefore, the ECL cell hyperplasia reflects the trophic effect of gastrin.

Serum antibodies to peripheral nerve tissue in acute Guillain-Barré syndrome in relation to outcome of plasma exchange.

Mixed haemagglutination and complement fixation tests were used to detect serum antibodies to peripheral nerve in 36 patients with acute Guillain-Barré syndrome. Twenty patients were treated with plasma exchange, 16 served as controls. A significant antibody titre was found in 19 patients with the haemagglutination test; 30 had complement-fixing antibodies. Patients lacking complement-fixing antibodies were less disabled at entry (P less than 0.01). However, there was no correlation between the course of the disease and any of the antibodies in the two patient groups. The two tests were therefore not able to select patients for treatment by plasma exchange.

Anticomplementary activity in multiple sclerosis.

Anticomplementary activity (ACA) is a common problem in serological work. Often it is regarded as an indicator of circulating immune complexes and has been clinically used as such. In a longitudinal study (Ryberg 1982b) ACA was determined in heated (56 degrees C for 30 min) sera from 35 MS patients followed for up to 5 years; in 18 of them ACA in heated CSF was also assayed. Persistent or transitory ACA of low titre was found in some sequences, usually without evident correlation with clinical events. Marked ACA in unheated sera was found more often in MS patients than in controls and showed dramatic changes in most of 15 sequences studied for this property, sometimes in a way suggesting a correlation with clinical exacerbations. This activity was heat labile and was not bound by an immunosorbent with affinity to human IgG and, therefore, is not likely to represent IgG containing aggregates or immune complexes.

Intrathecal and extrathecal production of antibrain antibodies in multiple sclerosis.

Complement-fixing antibrain antibodies of several specificities were titrated in paired serum and CSF samples from 27 MS patients. The results indicated that the antibodies were synthesized on both sides of the blood-brain barrier in proportions that showed a great interindividual variation. It is suggested that this variation applies also to other MS-associated immunoglobulins.

Antibrain antibodies in multiple sclerosis. Relation to clinical variables.

IgG antibrain antibodies (ABA) of several specificities can be demonstrated in multiple sclerosis (MS) with the complement fixation technique. This technique seems to discriminate between IgG specifically and non-specifically bound to CNS preparations. Complement-fixing ABA were titrated in paired serum and CSF samples from 87 patients with clinically definite MS, 15 patients with probable MS, 29 patients with other neurological diseases, and 13 "healthy" controls. In addition, sera from 55 non-MS patients were tested. In 40% of the sera and 88% of the CSF samples from patients with clinically definite MS, ABA reacting with human brain homogenate were demonstrated. The corresponding figures for probable MS were 21% and 73%, and for the controls 11% and 6%. Two of 9 sera from patients with the Guillain-Barré syndrome were strongly positive. There was a tendency for higher CSF ABA titres in younger MS patients and in those with an earlier onset of disease. ABA titres in serum and CSF were both correlated with a more malignant course. Irrespective of the mechanism of induction of ABA in MS--an excessive immunogenic stimulation and/or a defective immunoregulation--they are potentially pathogenic in several ways, e.g. (1) by direct antibody action. (2) by interaction with complement, (3) by antibody-dependent K-cell-mediated cytotoxicity, and (4) by interaction with phagocytic cells. Of several correlations among the routine CSF variables in MS, the finding of more pronounced abnormalities in male patients was notable.

A longitudinal study of antibrain antibodies in multiple sclerosis.

The presence of complement-fixing antibrain antibodies is a distinctive feature of multiple sclerosis (MS). In a longitudinal study of 35 MS patients antibrain antibody titres in serum were followed for up to 5 years; in 18 of them also CSF titres were determined. No consistent correlations between antibrain antibody titres and clinical events were found. Thus, MS relapses are not caused by a general increase in antibrain antibody titres, and conversely the relapses did not cause a boosting of antibrain antibodies. Significant variations in the local plaque environment are, however, not ruled out by the present results.

Multiple specificities of antibrain antibodies in multiple sclerosis and chronic myelopathy.

The presence of complement-fixing antibodies against brain antigens was tested in paired serum and cerebrospinal fluid (CSF) samples from 60 multiple sclerosis (MS) patients, 15 patients with chronic myelopathy of undetermined cause (CM) and 60 control patients. Six MS sera, 34 MS CSF, 4 CM sera, 3 CM CSF, 4 control sera and 1 control CSF gave positive reactions either with a lipid extract or a saline extract of normal human brain. The proportion of anticomplementary CSF was significantly higher in the MS group than in the control group (15% vs 0%, P less than 0.01). The reactivity of a large number of individual positive samples was further investigated. Seven antibody specificities were discerned in the MS samples. Most samples reacted with non-lipid antigens, the dominating being a heat-labile, nonlipid component associated with CNS myelin. Antibodies to cerebroside and sulfatide were detected in a few patients. A number of samples reacted with cholesterol in combination with a variety of lipids. Positive samples from the CM patients exhibited a similar heterogeneity. In the control group positive reactions were seen in one patient with systemic lupus erythematosus (SLE), two patients with rheumatoid arthritis (RA), and one with a spinal meningioma. The reaction patterns of these patients were different from those commonly seen in MS patients. The complement-fixing antibrain antibodies in MS CSF are usually of IgG class (Ryberg 1976). This applies also to the positive MS sera in this study. The distribution of the antibodies between serum and CSF indicated, in several cases, an intrathecal synthesis. All of a number of human brains, including one MS brain, contained all 6 antigens (haptens) reactive in saline extracts. Antibodies to tissues outside the CNS were rarely detected in MS patients. The varied humoral autoimmune response in MS might reflect a heterogeneity in the MS patients, the disease itself or its causative agent.

Analysis of the actions of cimetidine and metiamide on gastric acid secretion in the isolated guinea pig gastric mucosa.

Cumulative dose-response curves for histamine were determined on acid secretion from the isolated guinea pig gastric mucosa. Two H2-receptor antagonists-metiamide and cimetidine-behaved like competitive antagonists to histamine on gastric acid secretion in vitro. The isolated guinea pig gastric mucosa seems to be a suitable in vitro model for analysing the action of compounds on receptors involved in acid secretion.

Pharmacology and toxicology of omeprazole--with special reference to the effects on the gastric mucosa.

Omeprazole is a long acting inhibitor of gastric acid secretion in different species including rat and dog. Due to the long duration of action, steady state inhibition at repeated once daily administration is reaches within 4-5 days in dogs and in about 3 days in rats. Daily dosing at high dose levels results in virtually complete 24-hour inhibition of acid secretion in experimental animals. The elimination of the inhibitory feedback effect of acid on gastrin secretion leads to hypergastrinaemia. Because gastrin has a trophic effect on the oxyntic mucosa, the hypergastrinaemia results in a reversible hypertrophy of the oxyntic mucosa and an increased capacity to produce acid following maximal stimulation with exogenous secretagogues after discontinuing treatment. Despite the increased capacity to produce acid, basal acid secretion seems to be unchanged. The pronounced hypergastrinaemia which occurs during long-term treatment with high doses rapidly normalizes after discontinuing treatment. The hyperplasia of the oxyntic endocrine ECL cells, and the eventual development of gastric ECL cell carcinoids after lifelong treatment of rats with high doses, can also be attributed to the hypergastrinaemia developing after almost complete elimination of gastric acid secretion in these animals.