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The effects of acute hyper- and hypotension on the stria vascularis and spiral ligament of the rat were studied electron microscopically with the horseradish peroxidase (HRP) tracer method. Acute hypertension was induced by i.v. infusion of methoxamine chloride (Mexan), and acute hypotension by i.v. infusion of a ganglion-blocker (Arfonad) and by venesection. In both acute hyper- and hypotensive experiments, a large amount of leaked HRP spread into the intercellular spaces until it was stopped by tight junctions bordering the stria vascularis. The stria capillary endothelium displayed a dense distribution of labelled vesicles, which suggests increased vesicular transport. There was no extravasation of HRP from capillaries in the spiral ligament, despite the presence of some labelled pinocytotic vesicles. The present paper deals with the discovery of enhanced capillary permeability of the stria vascularis under acute hyper- and hypotension, and makes comparison between acute hyper- and hypotension in order to define the function of the stria vascularis.

Neonatal thyrotoxicosis induced by transferred TSH receptor antibody (TRAb) is the ideal human in-vivo experimental system for the evaluation of TRAb. The clinical significance of circulating TRAb in Graves' disease was evaluated by this 'natural in-vivo human assay'. TRAb activity in vitro was measured by radioreceptor assay (thyrotrophin-binding inhibitor immunoglobulin, TBII) and sensitive cAMP accumulation assay using FRTL-5 cells (thyroid-stimulating antibody, TSAb). Further, the binding-stimulation index (B-S index) was newly introduced, which was the most useful indicator for prediction of neonatal thyrotoxicosis, calculated as the product of TBII and TSAb (Tamaki et al., 1988a). Maternal serum TRAb indices showed highly significant correlations with the serum free T4 index (FT4I) and free T3 index (FT3I) in neonates (5-10 days after birth) born to 20 mothers with Graves' disease who had positive TBII and/or TSAb (FT4I: r = 0.825 for TBII, r = 0.908 for TSAb, r = 0.944 for the B-S index, P less than 0.001; FT3I: r = 0.622 for TBII, P less than 0.01, r = 0.812 for TSAb, r = 0.791 for the B-S index, P less than 0.001; n = 20). In contrast, in 57 untreated adult patients with hyperthyroid Graves' disease, the FT4I and FT3I levels were not correlated with any of the TRAb indices. The linear regression relationship between the B-S index and FT4I found in neonates was applied to values in adult patients with Graves' disease, and the patients were divided into three groups on the basis of the 95% confidence limit: high, normal, and low responders of thyroid hormone (FT4I) secretion to the B-S index. FT4I and the ratio of FT4I to the B-S index were highest and the TRAb indices were lowest in the high responders, while FT4I and the FT4I/B-S index ratio were lowest and the TRAb indices were highest in the low responders. The FT4I/B-S index ratio was inversely correlated with the titres of antithyroid microsomal antibody in all the adult patients with untreated Graves' disease (r = -0.288, P less than 0.05). The results suggest that in-vitro assays using animal thyroid cells and cAMP as an index of response are suitable for detecting circulating thyroid stimulating activity in vivo. Secretion of thyroid hormones in Graves' disease may be regulated not only by circulating thyroid-stimulating antibodies but also by intrathyroidal stimulatory factors or by inhibitory or destructive factors.

Studies were performed on 42 unselected clinically euthyroid patients with Graves' disease under maintenance doses of antithyroid drugs for various clinical parameters to determine the remission rate and to investigate which parameters carry weight in determining the outcome of the disease and could be good predictive factors. T3 suppression test was performed in all patients, after which antithyroid drugs were discontinued and outcome of drug therapy was evaluated for 18-24 months. Patients were divided into two groups; group A, 12 patients, who stayed in remission and group B, 30, who had recurrence during the first year (0.5-9 months) after discontinuation of therapy. Duration of clinical history was not different between group A (mean 62.3 months) and group B (59.6 months), nor euthyroid periods before the test (15.5 months for group A and 17.6 months for group B). For thyroid specific parameters T4, T3, RT3U, TSH, thyroglobulin (Tg), thyroid suppressibility after T3 administration and goiter size; and anti-thyroglobulin antibody (TGHA), anti-thyroid microsomal antibody (MCHA), TSH-binding inhibitor immunoglobulins (TBII), thyroid-stimulating antibodies (TSAb), peripheral lymphocytes count and lymphocyte subsets [CD3, CD4, CD8, Leu7 and CD20 (B1)], as immunological parameters were analysed by linear discriminant analysis method to observe the significance in discriminating patients with or without remission and to evaluate the validity for predictive factors. (ABSTRACT TRUNCATED AT 250 WORDS)

The effects of bovine thyrotropin (TSH) on DNA synthesis and cyclic AMP production were studied in porcine thyroid follicles using suspension culture. During the early 72 hours incubation, the time-dependent uptake of [3H]thymidine by the follicles was observed. In the presence of 10 mU/ml TSH, the uptake of [3H] thymidine was significantly depressed at 72 hours incubation. TSH inhibition of [3H] thymidine incorporation was related to its concentration and the 50% inhibition was observed by using 1.0 mU/ml TSH. Under the same conditions, cyclic AMP production was stimulated by TSH and the stimulation was observed to be related to TSH concentration. In these experiments, the incubation time was 30 min. Dibutyryl cyclic AMP, an analogue of cyclic AMP, inhibited the [3H] thymidine uptake at 72 hours incubation. From these results, it is suggested that TSH inhibits DNA synthesis, and that the inhibition may be mediated by cyclic AMP that is produced by TSH stimulation.

Peripheral large granular lymphocytes (LGL) were enumerated in normal subjects and patients with autoimmune thyroid diseases. In normal subjects, the percentage of LGL was significantly lower in women (mean +/- s.d., 17.0 +/- 3.6%; n = 35; P less than 0.05) than in men (19.5 +/- 5.3%; n = 20). In untreated patients with thyrotoxic Graves' disease (GD), both the percentage (11.5 +/- 2.7%; n = 12; P less than 0.001) and the absolute count (244 +/- 102/mm3; P less than 0.01) of LGL were significantly lower than those in normal women (17.0 +/- 3.6% and 334 +/- 122/mm3; n = 35). No significant differences from normal controls were observed in the percentages or absolute counts of LGL in patients with euthyroid GD under treatment or in euthyroid or hypothyroid patients with Hashimoto's disease (HD). The percentage of LGL was inversely correlated with the serum levels of T4 and T3 and the free T4 index, but not with the titre of anti-thyroid antibodies, the size of goitre or the degree of proptosis in the group of untreated patients with GD and HD. The decreased levels of LGL in thyrotoxic patients with GD may be related to the self-perpetuation of thyrotoxicosis in patients with this disease.

A simple method was established for separating lymphocytes infiltrating the thyroid from thyroid epithelial cells. Namely, suspensions of minced thyroid from patients with Graves' disease were layered on a Percoll two-step density gradient (p = 1.050 and 1.077 g/ml) and centrifuged (400g, 30 min, 4 degrees C). In this way 0.1-18 X 10(5) lymphocytes/g of thyroid tissue with a purity of 65-95% were obtained. Thyroid lymphocytes were analyzed quantitatively with monoclonal antibodies by laser flow cytometry and compared with peripheral lymphocytes. The proportion of OKT3+ cells was decreased with increase in OKIa+ cells. The percentage of OKIa+ cells was significantly correlated with that of Leu12+ cells. The percentages of OKT4+ cells and OKIa+ cells were higher when analyzed with an extended gate window, which was arranged for detection of activated, large-sized lymphocytes. The percentages of OKT8+ and Leu7+ cells were not significantly different from those in peripheral blood. From these results it was concluded that the proportion of B lymphocytes is increased and that of T lymphocytes is decreased, the proportion of activated B lymphocytes is increased, some helper/inducer T cells are activated in the thyroid gland in Graves' disease, and these activated lymphocytes may be important in local production of antithyroid autoantibodies.

Effects of trimebutine maleate (TM-906) on the spontaneous contraction of isolated duodenum and ileum were studied in both guinea pigs and rabbits. In the duodenum and ileum of both guinea pigs and rabbits, TM-906 (10(-6) g/ml, 10(-5) g/ml) produced a potentiation of the spontaneous contraction in preparations with low contractile activity (low tone or small contraction), while it caused an inhibition of the spontaneous contraction in preparations with high contractile activity (high tone or large contraction). The potentiation of spontaneous contraction by TM-906 was more pronounced in the ileum than in the duodenum of both guinea pigs and rabbits. When the spontaneous contraction of duodenum and ileum was decreased by atropine, the potentiation of spontaneous contraction by TM-906 was further augmented and was more pronounced in the ileum than in the duodenum. When the spontaneous contraction was remarkably potentiated by physostigmine or acetylcholine, TM-906 markedly inhibited the potentiated spontaneous contraction, and the potentiation by TM-906 seen in preparations with low contractile activity disappeared. From these results, it is concluded that TM-906 produces, depending on the contractile activity of the preparations, a potentiation or an inhibition of the spontaneous contraction of duodenum and ileum in both guinea pigs and rabbits and that the potentiation by TM-906 is more pronounced in the ileum than in the duodenum. It is suggested that the endogenous acetylcholine partly modifies the effects of TM-906, but that it does not relate to the more pronounced potentiation by TM-906 in the ileum than in the duodenum.

The relationship of structural polarity to functional activities was examined in cultured human thyroid follicles, which were isolated from the thyroid gland of patients with Graves' disease by collagenase treatment. Structural polarity was examined morphologically by electron microscopy, while the functional response to bovine TSH was examined by measuring intracellular cAMP accumulation and T3 release. In freshly isolated thyroid follicles, structural polarity was normal and TSH induced significant cAMP accumulation but no significant release of T3. After culture for 5 days the structural polarity of thyroid follicles became inverted in the absence of thyroid stimulators, but normal polarity was retained in the presence of TSH or dibutyryl cAMP [Bu)2 cAMP). The response to TSH of cAMP accumulation increased markedly after culture in either the presence or absence of TSH, suggesting that cAMP accumulation in response to TSH is not related to structural polarity. In contrast, thyroid follicles cultured without thyroid stimulators showed no significant T3 release in response to TSH, whereas those cultured with TSH or (Bu)2 cAMP showed significant T3 release in response to TSH. These data indicate that in cultured human thyroid follicles, the responses to TSH of cAMP accumulation and T3 release are not always correlated. Among many other explanations, the results were at least compatible with the idea that normal structural polarity is necessary for thyroid hormone release in response to TSH.

An effective method of prediction of neonatal transient hypothyroidism was examined in 105 neonates (including a pair of twins) born to mothers with chronic thyroiditis (92 mothers with goitrous Hashimoto's disease and 12 with primary atrophic hypothyroidism). Antithyroid microsomal antibody was measured by a hemagglutination technique (MCHA), and antithyroid-stimulating hormone (TSH) receptor antibody by both radioreceptor assay (TBII) and biologic thyroid-stimulation blocking assay (TSBAb). For generalization of predictive criteria, the expression of TBII activity was standardized using standard serum made taking units of MRC-LATS-standard B as a reference, and that of TSBAb activity was standardized as the degree of dilution with normal pooled serum to attain 50% inhibition of TSH (100 microU/ml)-induced cyclic adenosine monophosphate increase (TSBAb50). The MCHA titer in maternal serum at delivery correlated well with that of the corresponding cord serum, but not with the free thyroxine (T4) index or the TSH level in cord serum. TBII activity was positive in only 4 of 12 mothers with primary atrophic hypothyroidism, TSBAb activity was also positive only in these four mothers, and neonatal thyroid dysfunction was observed in three of their neonates. Two of these neonates developed transient hypothyroidism requiring T4 treatment, and the t third developed mild transient hyperthyrotropinemia with normal T4 and triidothyronine levels. The mothers whose neonates showed transient hypothyroidism had TBII activities of more than 300 U/ml and TSBAb50 activities of more than 300. Ninety-two mothers with goitrous Hashimoto's disease had neither TBII nor TSBAb activity, irrespective of their thyroid function, and delivered euthyroid babies.(ABSTRACT TRUNCATED AT 250 WORDS)

The long term clinical outcome of postpartum hypothyroidism was investigated by follow-up studies of 44 patients (59 postpartum episodes; mean age of mothers at delivery, 28.2 yr) 5 or more yr later (mean interval after delivery, 8.7 yr; range, 5-16 yr). Forty-nine episodes (83%) in 34 women were followed by recovery within 1 yr postpartum, and those women remained euthyroid thereafter (group A); 10 women [10 episodes (17%)] developed permanent hypothyroidism during the follow-up period (group B). Five women in group B recovered during the first year, but became hypothyroid again later, the other 5 women in Group B remained persistently hypothyroid. HLA typing revealed significantly higher frequencies of HLA-DR3, -DRW8, -DRW9, -A26, -BW46, and -BW67, and significantly lower frequencies of HLA-DR2, -BW52, -BW62, and -CW7 in women with postpartum hypothyroidism than in normal women. Of 9 women with postpartum hypothyroidism who had HLA-DRW9 and/or -B51 associated with antithyroglobulin-antibody titers of 2(3) X 10 or higher, 6 developed permanent hypothyroidism. We conclude that long term follow-up is essential for women of postpartum hypothyroidism because of the risk of permanent hypothyroidism. The results suggest that some immunogenetic factors may be related to the etiology of postpartum hypothyroidism and that women with HLA-DRW9 and/or -B51 and higher titers of antithyroglobulin antibody are likely to develop permanent hypothyroidism.

An unusual case of a coexistence of pancreas divisum and intestinal malrotation in a patient with cholecystolithiasis is described herein. The diagnosis of pancreas divisum was established by endoscopic retrograde pancreatography, and the intestinal malrotation was diagnosed by duodenography and barium enema. An operation was performed for the cholecystolithiasis. The pancreas was soft, and its shape was almost normal. Cholecystectomy and prophylactic appendectomy were performed, however nothing was done to the pancreas.

Effects of timepidium bromide (TB) on the motility of various smooth muscles and the secretion of digestive juice were examined and the activity was compared with those of hyoscine-N-butylbromide (HB) and atropine sulfate (Atr). In dogs, TB inhibited the spontaneous and bethanechol-induced motility of various regions of the gastrointestinal tract, the activity being almost the same as that of Atr but stronger than that of HB. All these drugs exhibited a similar inhibitory effect on the motility of the gallbladder. On the contrary, the inhbitory effect of TB on the spontaneous motion of urinary bladder was somewhat weaker than those of HB and Atr, while this effect on the bethanechol-induced motility was nearly equal the effects of HB and Atr. It was also evident that TB inhibited the gastric acid secretion induced by bethanechol: the activity was stronger than that of HB, while it was weaker than that of Atr. Similar effects on the gastric acid secretion were also found in rats. In the case of salivary secretion, however, TB and HB produced much weaker inhibitory actions than Atr. TB even at a higher dose produced little significant effect on the pancreatic and biliary secretion of rats. The uterine contraction induced by methacholine was inhibited by all these drugs. The mydriatic activity of TB in mice was found to be the weakest among the drugs tested.

Immunological effect of pregnancy on the level of anti-TSH receptor antibody (TRAb) and antithyroid microsomal antibody (MCAb) was examined serially in twelve patients; ten with active Graves' disease treated with antithyroid drugs for some time during pregnancy, one with previous Graves' disease with stimulating type TRAb, and one with primary atrophic hypothyroidism with blocking type TRAb. TRAb was measured by radioreceptor assay (TSH-binding inhibitor immunoglobulin, TBII) and MCAb was determined by radioimmunoassay. Among the ten patients with active Graves' disease, TBII level decreased as pregnancy progressed in seven but increased during pregnancy in three, whereas MCAb level decreased uniformly during pregnancy in all ten patients. However, possible immunosuppressive effect of antithyroid drugs on these antibody levels could not be completely excluded in these patients. On the other hand, in the two consecutive pregnancies of the patient with previous Graves' disease, TBII level increased "spontaneously" to 10-fold the initial value at 30 weeks during the first pregnancy, while it did not show consistent increase or decrease during the second one. Another patient with primary hypothyroidism showed increase in TBII level during pregnancy to 5-fold the initial value at week 28. In contrast to these TBII changes, MCAb levels and immunoglobulin concentrations decreased consistently during pregnancy in these two patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Polar mutations in trpA, the first structural gene of the tryptophan operon of Salmonella typhimurium, have an uncoordinate effect on the expression of the distal genes, with trpB, the second gene, being more drastically affected than the last three. A number of these polar mutant strains grow very poorly on anthranilic acid-supplemented minimal medium. By selecting for more rapid growth in the presence of anthranilic acid, secondary mutant clones showing a correction of the polar effect were isolated. A few of these were analyzed and shown to contain deletions of various segments of the trpA gene. Ten randomly isolated deletion mutants missing various segments of the trp operon were analyzed for possible pleiotropic effects. Five of them showed a pleiotropic effect of some sort and five did not. Of those showing pleiotropic effects, one had lost the promotor-like elements necessary to initiate expression of the operon, three showed possible antipolar effects, and one showed both polar and antipolar effects simultaneously.