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A case of plasma cell leukaemia of non-producer type is described. The patient presented with typical clinical features of plasma cell myeloma, including multiple osteolytic lesions, hypercalcaemia, renal failure and reduced polyclonal immunoglobulins, except that M-component was not detected in either the serum or urine. Morphological examinations showed a plasmacytoid appearance of the neoplastic cells, while immunological studies failed to detect cytoplasmic immunoglobulin or secretory capacity. The surface phenotype of CD38+, PCA-1+, DR-, CD20-, CD24-, CD9-, CD10- and surface immunoglobulin- was compatible with mature plasma cells. Chromosomal analysis showed the 14q+ marker due to translocation (6;14) and deletion of the short arm of chromosome 1. Analysis of immunoglobulin genes revealed the presence of heavy chain gene rearrangement, but the light chain genes, both kappa and lambda, remained in germline configuration. Such defective immunoglobulin gene rearrangement may be responsible for the failure of immunoglobulin biosynthesis and secretion by the neoplastic plasma cells. Furthermore, it is suggested that the morphological and phenotypic development of B cells may not necessarily depend on immunoglobulin light chain gene rearrangement, and that the oncogenic event in myeloma may occur at an earlier stage of B cell differentiation.

The effect of islet-activating protein (IAP) purified from culture medium of Bordetella pertussis was examined in dogs. This was assessed by the levels of pancreatic polypeptide (PP) as well as the responses of plasma insulin and glucagon to a parasympathomimetic agent, bethanechol. Plasma responses of these pancreatic hormones were measured before and 5 days after IAP injection. Although IAP had no significant effect on the bethanechol-stimulated increase in plasma glucose, insulin and glucagon, the PP response to bethanechol was significantly reduced after IAP treatment compared with that before IAP (p less than 0.05). In conclusion, IAP significantly and selectively reduced bethanechol-stimulated PP release in the dog although the mechanism remained to be elucidated.

To test the hypothesis that diabetes is a form of accelerated aging, the following observations were made. 1) The incidence rate of diabetes mellitus had its peak at around 50 years of age with a gradually decreasing rate thereafter. This was clearly different from the manner of incidence of such disease as arteriosclerosis which increased with advancing age. 2) 100g of the oral glucose tolerance test performed on elderly subjects aged 60 to 89 years revealed high incidence of abnormal tolerance, 21% diabetic and 53% borderline types. 3) The insulin secretory capacity to glucose load of subjects was not different from that of young and middle-aged subjects from 20 to 49 years old. Therefore, decreased tolerance to glucose load could not ba ascribed to deficient insulin secretion. 4) No abnormality of glucagon response to glucose load was found in the old. 5) Serum beta-N-acetylhexosaminidase activity was not increased in elderly subjects, again contrasting with the increased activity found in diabetics. 6) Both glycolytic and gluconeogenic enzyme activities were decreased in the liver of aged rats. 7) No specific abnromality in insulin secretory response was observed in Werner's syndrome which might be considered to be a model for aging. All the above observations do not support the aforementioned hypothesis. Abnormality of glucose tolerance frequently observed in elderly subjects appears to be caused by other pathogenesis than diabetes mellitus.

Ultrastructures of normal T-cell subpopulations, Tγ and Tμ cells, were studied. Tγ cells were isolated and identified by repeating the rosetting method; firstly, by E rosette formation with neuraminidase-treated sheep red blood cells (SRBC), and next by EAy-rosette formation with ox red blood cells coated with IgG antibody (EAox). Before EAox rosetting, SRBC on isolated T cells were lysed by autologous plasma instead of ammonium chloride solution. Normal Tγ cells were heterogeneous with regard to their granules; the majority of Tγ cells had parallel tubular arrays (PTA) and a few had electron-dense granules. When ammonium chloride solution was employed to lyse SRBC, PTA were never observed; PTA in normal Tγ cells and in chronic lympho-cytic leukemia cells with Tγ character both seemed to change into electron-dense granules after ammonium chloride treatment. In contrast to Tγ cells, Tμ cells were characterized by clustered dense bodies, i.e. focal aggregates of electron-dense granules.

This experiment was undertaken to explore a novel method of therapy for insulin-dependent diabetes mellitus (IDDM), using nonobese diabetic (NOD) mice that had symptoms and histologic changes similar to those of human IDDM patients. We examined preventive and therapeutic effects of large-dose nicotinamide administration on diabetes in NOD mice. Eighteen young female NOD mice without glycosuria were randomly divided into two groups; nine received subcutaneous nicotinamide (0.5 mg/g body wt) injections every day and the other nine were maintained as a control group and not injected. After 40 days, all of the mice given nicotinamide showed almost normal glucose tolerance and only mild insulitis on histologic study. On the other hand, marked glycosuria and severe insulitis were observed in six of the nine mice not injected. Four of six NOD mice given nicotinamide from the day of the first occurrence of marked glycosuria displayed a disappearance of glycosuria and an improvement in glucose tolerance during the therapy; however, urine sugar became negative in only one of six mice that received nicotinamide from 1 to 2 wk after the onset of marked glycosuria. These results indicate that nicotinamide has preventive and therapeutic effects on diabetes in NOD mice, and suggest the reversibility of B-cell damage, at least at a very early Stage of IDDM.

Purified virions of HVJ (Sendai virus) were found to contain a guanylate cyclase activity that converts GTP to cyclic GMP. Activities of adenylate cyclase and 5'-nucleotidase which are frequently used as marker enzymes of cell membranes were not detected in the virus. Guanylate cyclase and virion-associated activities, neuraminidase and hemagglutinin, were co-purified during a purification of virions. Guanylate cyclase activity was not detected without disruption of the virions with a detergent, Triton X-100 or Nonident P-40. Treatment of intact HVJ with a proteolytic enzyme, trypsin or chymotrypsin, destroyed both neuraminidase and hemagglutinin; however, most of the guanylate cyclase ws retained. Guanylate cyclase activity was found in fractions containing nucleocapsids after sucrose density gradient centrifugation of disrupted virions. These results indicated that the enzyme was tightly bound to cores of HVJ and, therefore, its presence could not be explained by binding of host cell enzyme to the surface of virions. Properties of the virus-derived enzyme and particulate fractions of host cell homogenates were similar. Antiserum against nucleocapsids of HVJ inhibited guanylate cyclase activity of HVJ and particulate fractions of cells such as chorioallantoic membrane and rat liver, while soluble guanylate cyclase was not inhibited by antiserum. The biological significance and origin of guanylate cyclase found in HVJ are obscure and await further study.

Thyroglobulin (Tg) concentrations in the aspirates of various types of cystic neck masses were measured by RIA to assess the usefulness of this determination in differential diagnosis. The subjects consisted of 16 patients, whose final diagnoses were all established on the basis of operative results; three patients had follicular thyroid adenomas (F-Ad), 11 had papillary thyroid carcinomas (P-Ca), one had a thyroglossal duct cyst (TDC) and one had a lateral cervical cyst (LCC). Tg concentrations in the cyst fluids of F-Ad and P-Ca were very high (0.042-2.83 mg/ml) compared with serum Tg concentrations. There was no difference in Tg concentrations in the fluids of P-Ca between primary lesions (n = 5) and metastatic lesions (n = 6). On the other hand, Tg concentrations of TDC and LCC were very low (less than 100 ng/ml). Difficulty was experienced in diagnosing three patients, even though they had been examined by all nonsurgical diagnostic techniques. However, an occult thyroid carcinoma with lymph node metastasis was diagnosed by demonstrating a high Tg concentration in the aspirate of the cystic lymph node. T3 concentrations in cyst fluids of F-Ad were higher than those of P-Ca. T3 concentrations in the fluids of P-Ca, TDC and LCC did not differ, and were similar to serum T3 levels. Cytology of cyst fluids was positive in four of 10 patients examined with P-Ca. In conclusion, we can clearly confirm the thyroid origin of a cystic neck mass by demonstrating a high Tg concentration in the aspirate. This is especially useful for diagnosis in patients with thyroid carcinoma, including occult thyroid carcinomas with cystic lymph node metastasis.

We determined the insulin response to an oral glucose ingestion and levels of serum lipoproteins in 25 untreated patients with type 2 diabetes mellitus, in 26 subjects with impaired glucose tolerance (IGT), and in 35 non-diabetic control subjects. The three groups had similar compositions with respect to age and sex distribution. The levels of VLDL triglyceride in the subjects with type 2 diabetes or IGT were higher than those in controls. Serum HDL- and HDL2 cholesterol were significantly decreased in type 2 diabetics, and the subjects with IGT showed a similar tendency. Serum apolipoprotein A-II levels were lower in the male subjects with type 2 diabetes or IGT than in controls. Insulin response, i.e., sum of immunoreactive insulin (IRI) levels at basal, 30, 60, 90 and 120 min after a 75-g oral glucose load, negatively correlated to HDL- and HDL2 cholesterol levels (r = -0.396, P less than 0.05; r = -0.482, P less than 0.001, respectively), and positively correlated to VLDL triglyceride values (r = 0.485, P less than 0.001) in the male subjects with type 2 diabetes or IGT. In the female subjects, fasting plasma IRI values significantly correlated to HDL cholesterol (r = -0.496, P less than 0.05). There was a significant negative correlation between the concentrations of HDL2 cholesterol and VLDL triglyceride. These data show that lipoprotein metabolism, not only in type 2 diabetics, but also in IGT tends to show changes such as decreased HDL2 cholesterol and increased VLDL triglyceride levels, and which might be related to the hypersecretion of endogenous insulin.

Effects of prostaglandin D 2 on pancreatic islet function in perfused rat pancreas were examined in comparison with those of prostaglandin E 2 , which has hitherto been suggested to be a modifier of pancreatic hormone release. In the presence of 2.8 mM glucose, only glucagon release was strongly stimulated by 14μM of prostaglandin D 2 , while release of both glucagon and insulin was augmented by 14μM of prostaglandin E 2 . When the glucose concentration was elevated to 11.2 mM, insulin release was accelerated by 14μM of prostaglandin D 2 but there was no effect upon glucagon release. Again, release of both glucagon and insulin was augmented by 14μM of prostaglandin E 2 in the presence of 11.2 mM of glucose. The regulation of glucagon and insulin release through prostaglandin D 2 is apparently adapted to glycemic changes, and may be a physiological modulator of pancreatic islet function.

Antibody to acetylcholine receptor from Narke electroplax japonica was isolated from serum of rabbits with experimental autoimmune myasthenia gravis by affinity chromatography on a column of torpedo AChR-agarose conjugates. Sixty-three to eight hundred and ninety-six micrograms of antibody protein were obtained per milliliter myasthenic serum. Serum concentrations of antibody protein correlated with the intensity of the disease and were in exact proportion to the antibody titers of the same samples measured by double immunoprecipitant method. This study showed that anti-AChR antibody played a major role in experimental autoimmune myasthenia gravis and provided the first direct, quantitative evidence that the titers measured by Lindstrom's method could be quite a reliable index of antibody protein concentration in the serum of experimental myasthenia gravis subjects.

A 50-year-old male with unresectable hepatocellular carcinoma (HCC) had a hypercalcemic crisis with a serum calcium concentration of 7.8 mEq/zeta, without any evidence for bone metastases or parathyroid lesions. The hypercalcemia was thought to be due to increased renal reabsorption of calcium and increased bone resorption, which was probably caused by humoral factors derived from the HCC, some being parathyroid hormone-like factors. Since conservative therapy for hypercalcemia was not sufficiently effective and was accompanied by progressive exacerbation of ascites and leg edema, transcatheter arterial chemo-embolization (TACE) was performed. On the following day, serum calcium concentration decreased from 6.3 mEq/zeta to the normal range, although serum alpha-fetoprotein levels decreased only slightly. Thereafter hypercalcemia did not develop for about 4 weeks. The results demonstrated that TACE can be effective for humoral hypercalcemia of HCC.

The thyroid glands of the rats treated with 100 mg/kg/day of minocycline for 35 days showed black discoloration. In these thyroids, brown pigment granules were seen in the follicle epithelial cells, and they histochemically stained in the same manner as melanin. By electron microscopy, the deposition of the electron-dense material first occurred in lysosome-like granules and, with further administration, was observed also in the rough endoplasmic reticulum in some cells. Thin-layer chromatography showed that the R f value of the extract from minocycline-treated rat thyroid was the same as that of the black substance obtained by mixing minocycline and 3% hydrogen peroxide but different from that of melanin. In minocycline-treated rats, the release of thyroxine (T 4 ) from perifused thyroids was significantly less than that from control, and the analysis of iodoamino acids showed an increased monoiodotyrosine fraction. Thus, (1) the pigment of thyroid in minocycline-treated rats was demonstrated to be a metabolic derivative of minocycline itself and (2) minocycline may interfere with thyroid function in high-dose, long-term treatment.

To investigate altered fructose-2,6-bisphosphate (fructose-2,6-P2) metabolism, we measured fructose-2,6-P2 levels and fructose-6-phosphate,2-kinase (fructose-6-P,2-kinase) activities in various tissues, including liver, kidney, heart, and skeletal muscle, of ventromedial hypothalamus (VMH)-lesioned rats during feeding and starvation. The plasma insulin level was 6 times or more higher in these rats than in the controls. The fructose-2,6-P2 level in liver was much greater in VMH-lesioned rats than in the controls: 15.1 +/- 2.2 nmol/g tissue versus 7.7 +/- 0.7 in the fed state, 5.3 +/- 1.1 versus 1.6 +/- 0.4 in the starved state. In kidney, heart, and skeletal muscle, fructose-2,6-P2 levels were not different between the two animal groups. The activity of hepatic fructose-6-P,2-kinase remained high after 20 h of starvation in VMH-lesioned rats, whereas it was decreased markedly in the controls. The hepatic concentration of fructose-6-phosphate was also high in VMH-lesioned rats. Both fructose-6-P,2-kinase activity and fructose-6-phosphate concentration in the liver of starved VMH-lesioned rats were comparable to those of control rats in fed conditions. These results indicate that the alteration of fructose-2,6-P2 metabolism is characteristic of liver in VMH-lesioned rats, and that the increase in hepatic fructose-2,6-P2 may activate hepatic glycolysis not only during feeding but also during starvation, leading to the enhanced lipogenesis in these obese rats.

Clinical features including changes in the peripheral nerve conduction were analyzed in 10 cases with ethambutol neuropathy. There were abnormalities in the visual field in seven and optic atrophy in five of 10 cases. Seven of 10 cases complained of numbness in the lower limbs. The age of onset and dose of ethambutol the patients continue to take after the occurrence of visual impairment were found to be important in determining the severity of neurological symptoms. A functional disturbance was more conspicuous in ethambutol neuropathy, particularly in the sensory system than in the motor system so far as the peripheral nerve conduction was serially examined. Some cases still had serious optic disturbances even about seven years after the onset of the disease and the presence of irreversible lesions was suspected.

The effects of intraileal administration of bile on gastric acid secretion stimulated by a submaximal dose of intravenous pentagastrin infusion and on plasma concentrations of gut glucagon-like immunoreactivity (gut GLI) were studied in anesthetized dogs. Gastric acid secretion was measured for a 2-h period at 15-min intervals before and after intraluminal instillation of test solutions. 100 ml of canine bladder bile diluted to 10% in saline evoked a significant inhibition (20%) of gastric acid secretion. The inhibition of gastric acid secretion was accompanied by an elevation of plasma concentration of gut GLI, whereas saline instillation (in controls) caused no responses. Although the inhibition of gastric acid secretion and the elevation of plasma gut GLI are parallel phenomena, gut GLI can be reasonably postulated as one of the candidate mediators of bile-induced inhibition of gastric acid secretion, since its structurally related peptides, pancreatic glucagon, glicentin and oxyntomodulin have been reported as inhibitors of gastric acid secretion.

Tumor-induced osteomalacia is recognized as vitamin D-resistant hypophosphatemic osteomalacia that heals after resection of a coexisting mesenchymal tumor in either bone or soft tissue. We have investigated the underlying causal mechanism for osteomalacia in a 27-yr-old woman who presented witha several-year history of progressive muscle weakness and pain. Bone roentgenograms showed Looser's zones, and blood chemistry revealed severe hypophosphatemia (1.3 mg/dl) and a high alkaline phosphatase level (31 King-Armstrong units). Bone biopsy confirmed the diagnosis of osteomalacia. Increased urinary phosphorus excretion was shown by decreased tubular resorption of phosphate (75.8%) and a low (0.9 mg/dl) calculated renal phosphorus threshold. Renal glucosuria (271 ± 60 mg/day) and generalized aminoaciduria (2,063 mg/day) also were discovered, indicating impaired proximal renal tubular reabsorptive function. Chronic renal insufficiency, systemic acidosis, malabsorption, and hypophosphatasia were excluded as cau...

The clinical significance of serum aspartate aminotransferase (GOT) isozymes was studied in 18 patients with polymyositis. Abnormally high levels of mitochondrial GOT (mGOT) (6.2 +/- 1.2 IU/L, mean +/- SEM; normal, less than 2.0 IU/L) and cytosol GOT (sGOT) (95 +/- 21.6 IU/L; normal, less than 25 IU/L) were observed in sera. In polymyositic muscles, the sGOT level was significantly decreased but mGOT was not. The levels of serum sGOT and mGOT and the ratio of mGOT/tGOT before corticosteroid therapy correlated well with the severity of muscle weakness. Serial determination of CPK, sGOT, and mGOT during corticosteroid therapy revealed that mGOT most rapidly returned to normal. Exercise did not increase serum mGOT in polymyositis.

メチルコラントレン誘導性ラット肝チトクロームP-450(チトクロームP-450MC)に対する抗体を作製し,蛍光抗体間接法を用いてメチルコラントレン投与をうけたラットにおけるチトクロームP-450MCの経時的な肝小葉内誘導状態を観察した.またあわせて長期エタノール投与がチトクロームP-450MCにおよぼす影響についても同様に検討した.蛍光抗体間接法におけるチトクロームP-450MCに対する特異蛍光は非誘導ラット肝において肝細胞細胞質内に弱く認められ,その小葉内分布は小葉周辺域に比し中心域および中間帯でわずかに強い傾向を示した.メチルコラントレン20mg/kg体重の1回腹腔内投与後6, 12, 24, 48時間における特異蛍光の強さおよび小葉内分布の変化を検討した.特異蛍光の強さは時間が経るにつれ増強し,その分布はすべて均一であった.長期エタノール投与ラット肝と対照ラット肝の間に特異蛍光の強さおよび分布に差を認めなかった.

Serum lipids, lipoproteins and Achilles tendon thickness in 52 patients with heterozygous familial hypercholesterolemia (FH) were investigated in order to clarify what are the important factors for the development of coronary artery disease (CAD) in heterozygous FH patients. There were no significant differences in the average concentration of total cholesterol and triglyceride between the patients with and those without CAD. The HDL cholesterol (HDL-C) level was significantly lower in patients with CAD than in those without, and the HDL-C value was within the normal range in most of the patients with heterozygous FH, if not associated with CAD. Although most of the males aged over 50 years had CAD and a decreased level of HDL-C, many of the aged females were without signs of CAD. The HDL-C value of heterozygous FH patients with CAD was significantly lower compared with the age-matched group without CAD. The Achilles tendon was thicker in patients with CAD than in those without CAD, both for males and females, although it was less closely correlated with the incidence of CAD than HDL-C or the atherogenic index. A forecast concerning the development of CAD in heterozygous FH may be possible if we consider multiple parameters, such as HDL-C, atherogenic index, Achilles tendon thickness, etc.

We found severe hypercalcemia in the course of hydrocortisone withdrawal in a patient who had undergone unilateral adrenalectomy to resect a cortisolhypersecreting adenoma. Serum calcium gradually but progressively increased after unilateral adrenalectomy. Severe hypercalcemia developed on the 77th postoperative day (the 15th day after discontinuing hydrocortisone replacement). The serum concentration of calcium, PTH, 25 (OH) D, and 1, 25 (OH) 2D were 8.0mEq/1, less than 100pg/ml, 10.1ng/ml and 29.6pg/ml, respectively. This hypercalcemia was accompanied by marked urinary hydroxyproline excretion and less calcium excretion in the urine than the prevailing level of serum calcium. Serum concentrations of 25 (OH) D, 1, 25 (OH) 2D and PTH were not elevated during the severe hypercalcemia. We concluded that the hypercalcemia in this patient was due in part to enhanced bone resorption and increased renal tubular reabsorption of calcium as a result of glucocorticoid withdrawal, but not to the elevation of serum PTH or serum 25 (OH) D and serum 1, 25 (OH) 2D.

An extract of porcine thyroid gland in 0.1 N acetic acid exerted dose-dependent potentiation of ACTH-induced corticosterone production in isolated rat adrenal cells. The extract by itself manifested no steroidogenic activity. Upon gel-filtration of the extract, potentiating activities were demonstrated in three main peaks with molecular weights of about 10,000, 5,000 and 2,000. These findings indicate the presence of heterogeneous forms of ACTH-potentiating factors in the thyroid. Significant enhancement of ACTH-induced steroidogenesis was readily apparent with three gel-filtration fractions at a lower concentration of ACTH (4.75 pM). At this concentration, dose-dependent potentiation was observed with these three fractions. Enhanced corticosterone production responses by cells preincubated with the thyroid extract were observed and the results indicated the existence of potentiating mechanisms other than inhibition of ACTH proteolysis. The lack of T4, T3 and thyroglobulin in this activity suggests that the activity resides in other constituents of the thyroid.

The present data describe the mechanism of the inhibitory effects of human plasma apolipoproteins A-I and A-II on hydrolysis of triglyceride catalyzed by hepatic triglyceride lipase using a substrate of triolein particles stabilized with gum arabic in vitro. The experimental data could well be described by a model in which apolipoproteins bound to the surface of lipid substrate particles inhibited the enzyme reaction. The values of Km obtained were similar with or without inhibitors and the calculated saturation levels of apolipoprotein binding to the lipid were in good agreement with those obtained in independent binding experiments.

Plasma insulin clearnce was studied in a patient with autoantibodies to the insulin receptor, manifesting persistent hyperinsulinemia associated with alternating hyper- and hypoglycemia. In the postabsorptive period, the plasma glucose level gradually decreased. To prevent the development of hypoglycemia, glucose was infused and the glycemic level was clamped at 50 mg/dl without insulin infusion. The plasma C-peptide level was below the detectable range during the clamp, indicating no appreciable secretion of insulin. The plasma insulin level declined exponentially with a markedly prolonged disappearance rate (half-time: 3.0 h) during the study. These results indicate that hyperinsulinemia in the postabsorptive period in this patient is attributable to the impairment of plasma insulin clearance through receptor-mediated mechanisms, and also confirm that the receptor plays the principal role in plasma insulin removal.

In order to clarify morphological changes of the liver in the uremic state, 16 uremic patients treated with chronic hemodialysis were studied. Biopsy was performed in 14 cases under laparoscopic observation and in two on the occasion of renal transplantation. One uremic patients not being treated with dialysis was also studied for comparison. All biopsy specimens were examined by light and electron microscopy. The liver usually appeared mildly or moderately swollen under laparoscopic observations, which was considered at least partially due to the enlargement of the hepatocytes. All patients had hepatocytes with an Orcein-negative "ground glass" appearance, in which marked proliferation of smooth endoplasmic reticulum (SER) was found by electron microscopy. Since the patient not being on dialysis also had such hepatocytes, this finding may be characteristic of uremia. With electron microscopy, in addition to proliferation of SER, alteration of mitochondria and rough endoplasmic reticulum (RER) and an increase in cytoplasmic lipid droplets were observed. Hypertrophy of the Golgi apparatus containing electron-dense particles (VLDL) was often found in patients associated with hypertriglyceridemia. Amorphous electron-dense inclusions in microbodies were occasionally observed. Siderosis was observed in nine patients including three having parenchymal siderosis. With electron microscopy, various siderosomes were seen in the cytoplasm of hepatocytes in patients with parencymal siderosis. Conclusively, these histological and ultrastructral features of hepatocytes are rather associated with several metabolic abnormalities in uremia.

To test the possibility that insulitis might play an etiological role in the pathogenesis of insulin dependent diabetes, functions of 3 kinds of islet constituting cells (A, B and PP cells) were estimated by quantifying secretory responses of glucagon-, C-peptide-and pancreatic polypeptide-producing cells to hyperglycemia and hypoglycemia. In insulin dependent diabetes, all 3 hormonal responses were severely impaired to the same extent. On the other hand, 3 islet cell functions were uniformly but less severely impaired in insulin independent diabetics without a diabetic family history. These results suggest that A, B, and PP cells of islet of Langerhans are evenly destroyed in parallel fashion at least in insulin dependent diabetes and in some insulin independent diabetes, suggesting insulitis as a possible cause of these types of diabetes.

Nine non-insulin dependent type diabetic patients were hospitalized and place on the standard diabetic diet throughout this study period. (25 cal/kg ideal weight/day). After three days of diet therapy alone, 5 mg of glibenclamide was given orally for three days, followed by an interval of four days without medication. 16 units of lente insulin was then administered subcutaneously for three days. The diurnal levels of plasma glucose (PG) and serum immunoreactive insulin (IRI) were determined on the third day of each treatment, and the integrated areas below the curves of the diurnal profile of PG and IRI were compared. The mean fasting PG level before treatment was 200 +/- 21 mg% (mean +/- SE). The initial PG area during diet therapy alone, (4,245 +/- 669 mg . h/dl) decreased significantly to similar levels both by glibenclamide (3, 317 +/- 384 mg . h/dl, P less than 0.05) and by lente insulin (3,177 +/- 552 mg . h/dl, P less than 0.01). The IRI area increased from 187 +/- 24 micromicron . h/ml during diet therapy alone to 296 +/- 65 micromicron . h/ml by glibenclamide (P less than 0.01), and to 267 +/- 43 micromicron . h/ml by lente insulin (P less than 0.05). There was no significant difference between glibenclamide and lente insulin treatments either in PG area or IRI area. These finding suggest that the hypoglycemic effect of glibenclamide treatment in the short term is mainly, if not entirely, due to augmented endogenous insulin secretion.

We report a case of subacute thyroiditis complicated by thyrotoxic myopathy. Previously thyrotoxic myopathy has been described as being associated with Graves' disease. The patient in this study was a 35-year-old man who developed proximal dominant muscular weakness and atrophy during the course of subacute thyroiditis. His myopathic symptoms regressed as his serum thyroxine and triiodothyronine levels returned to normal, however it took a relatively long period of time for them to do so. This suggests that marked myopathy may develop even in cases of subacute thyroiditis if the thyrotoxic state persists for a long period of time.

Various preparations of glucagontreated with chloramine-T under different conditionshave been studied with respect to theirimmunoreactivity toward two different glucagonantisera; one specific for pancreatic glucagon andthe other capable of reacting with enteroglucagon aswell. The glucagon preparations exposed to chloramine-T for different periods reacted almost identicallywith the nonspecific antibody whetherthey were used as tracer or standard. On thecontrary, treatment with chloramine-T under severeconditions led to reduced immunoreactivity towardthe specific antibody. Inclusion of dimethyl sulfoxide(DMSO) in the chloramine-T reaction resultedin preservation of the immunoreactivity ofthe treated preparations. The cyanogen bromidecleaved-glucagon, (1-26) homoserine lactone,showed little cross-reactivity with the specific antibodywhereas it reacted to a similar extent with thenonspecific antibody as natural glucagon did. Ami noacid analysis of the hormone exposed tochloramine-T demonstrated that the methi...

Clinical and electrophysiological studies were carried out on 39 patients with the Guillain-Barré syndrome to evaluate which elements were of prognostic value during the acute phase. Residual clinical signs such as motor weakness and absent patellar tendon reflexes were found in 16 (52%) of those patients who had had a preceding illness. Persistence of deficit was significantly correlated to age at onset, the degree of quadriparesis and loss of deep sensation in the acute phase. Of the 10 patients who showed a reduction in motor nerve conduction velocity (MCV) in the early stage, 8 (80%) revealed significantly residual clinical symptoms at follow-up. There was a tendency for the incidence of residual signs to be more common in the patients with slowing of mixed nerve conduction velocity, and prolonged latency of H-wave and the residual latency. Nerve conduction studies, especially measurement of MCV, were of value as a reliable prognostic indicator in this syndrome.

The mechanism of the hypoglycemic action of sulfonylureas during long-term treatment was investigated in twenty-four patients with noninsulin-dependent diabetes mellitus treated for 1.5 to 19 yr in the out-patient clinic. The subjects received the first oral glucose tolerance test (OGTT) while on sulfonylureas and the second OGTT one month after their withdrawal. As the degree of elevation of the fasting plasma glucose level after withdrawal varied, the subjects were classified into two groups. Fourteen subjects showing an increase of more than 15 mg/dl were arbitrarily designated as group I, and the rest as group II. The mean fasting plasma glucose of group I was 134 +/- 4 mg/dl (mean +/- SE) and 194 +/- 14 mg/dl with and without sulfonylureas, respectively. Group II did no exhibit any significant change in fasting plasma glucose. A mean fasting serum IRI of either group was not changed. In group I, a mean glucose area of 807 +/- 31 mg . h/dl on OGTT increased significantly to 1121 +/- 72 mg . h/dl (p less than 0.001) and, the same time, a mean IRI area decreased significantly from 102 +/- 10 microU . h/ml to 73 +/- 7 microU . h/ml (p less than 0.001). The ratio of IRI area to glucose area, which might indicate the responsiveness of pancreatic B cells to hyperglycemia, was reduced on an average by 48% in group I. However, group II showed no significant change in the mean value of the glucose area, IRI area or the ratio one month after the discontinuation of sulfonylurea treatment. These findings suggest that the insulinotropic action of sulfonylureas is maintained even after long-term treatment and contributes to their antidiabetic effect.

Ingestion of lunch is known to be associated with acute release of prolactin (PRL). The neuroendocrine mechanism of this release was examined by measuring changes in serum vasoactive intestinal peptides (VIP) and cholecystokinin (CCK) after the noon meal in six normal men. The serum PRL concentration was significantly increased (40% above the level before lunch) from 30 min to 1 h 45 min after beginning to eat. However, the ingestion of lunch had no remarkable effects on the plasma immunoreactive concentration of VIP and CCK. Thus the changes in the plasma concentration of these two gut-brain peptides did not coincided with acute PRL release after ingestion of lunch, suggesting either that these two gut-brain peptides are probably not involved in PRL release after lunch, or that the level of these two gut-brain peptides in the general circulation may not represent that in the hypophyseal portal plasma.

Debromination of 1,2-dibromoethane (DBE) by a rabbit liver microsomal preparation and a reconstituted cytochrome P-450 enzyme system was investigated. The reaction was performed in our newly constructed reaction vessel, in which a bromide electrode was installed. During the reaction, the liberated bromide ion was continuously measured by the bromide electrode, and the amount was recorded. In the microsomal preparation, the DBE-debromination rate per nmol cytochrome P-450 was enhanced by phenobarbital-pretreatment of rabbits compared with the untreated microsomes, whereas it was diminished by 3-methylcholanthrene-pretreatment. The debromination reaction was reconstituted in a purified enzyme system containing phenobarbital-inducible rabbit liver microsomal cytochrome P-450 (P-450PB), NADPH-cytochrome P-450 reductase, and NADPH. The optimum conditions required the presence of dilauroylphosphatidylcholine and cytochrome b5. Cytochrome b5 was found not to be an obligatory component for the DBE-debromination in the reconstituted system, but it stimulated the activity about 3.4-fold. Preincubation of the reconstituted mixture with guinea pig anti-cytochrome P-450PB antiserum markedly inhibited the debromination reaction.

A case of "nonsecretory" myeloma is described. The patient had typical osteolytic lesions and marked infiltration of myeloma cells in the bone marrow, and plasma cell leukemia. A good partial remission was obtained with Melphalan, but the patient relapsed and died one year later. Immunofluorescent and immunoelectroscopic studies on the myeloma cells demonstrated the presence of cytoplasmic gamma-and kappa-chains at the initial stage and of only kappa-chains at a relapse. The electron microscopic method for polysome analysis indicated that both L-and H-chains were synthesized on membrane-bound polysomes initially, but the ability to produce H-chain was missing at the relapse.

還元的ハロセン代謝におけるcytochrome b5の関与について検討した.マロチレート投与にてcytochrome b5を誘導したラット(マロチレート群)を用いてin vivo及びin vitroにおいて産生された還元的ハロセン代謝産物2-chloro-1,1,1-trifluoroethane (CTE)及び2-chloro-1,1-difluoroethylene(CDE)を測定した.14%O2下1%ハロセン麻酔2時間目の動脈血中CDE/CTEはマロチレート群において対照群に比し有意に高値であった.マロチレート投与により肝ミクロソームにおけるin vitroでのCDE産生及びCDE/CTEの有意な上昇を認めた.精製したcytochrome P-450PBを含む再構成系での検討においてcytochrome b5添加でCTE産生が減少しCDE産生が促進された.以上よりcytochrome b5がCTE産生からCDE産生の方向に代謝を変化させることが明らかになった.CTEは有害な遊離ラジカル中間体から,一方CDEはラジカル反応を伴わず産生されるとされており,cytochrome b5がラジカル中間体の遊離を抑制しうることが示された.

In an in vitro bioassay system for adrenocorticotropic hormone using isolated rat adrenal cells, kaurenol, a diterpene alcohol, stimulated corticosterone production and augmented the steroidogenic effect of adrenocorticotropin or forskolin, dose-dependently. Kaurenol had no effect on cyclic AMP production by the cells. The diterpene also had no stimulatory effect on the adrenal adenylate cyclase activity in a cell free system. The results suggest that this particular diterpene exerts a steroidogenic effect through a mechanism independent of cyclic AMP generation.

Employing an immunoblotting procedure, we have identified and characterized an autoantigen carried on glycoprotein (GP) IIb in a patient with chronic idiopathic thrombocytopenic purpura (ITP), and have compared the location of the autoantigen with that of the platelet-specific alloantigen Baka. Immunoblots, using the partially purified GP IIb/IIIa complex as the target antigen, indicated that GP IIb alpha carried both the ITP autoantigen and the Baka alloantigen. The ITP plasma contained another antibody against a 100 kD protein (P100), a trace contaminant in the GP IIb/IIIa sample, which is probably a proteolytic fragment of an internal 124 kD protein. After chymotrypsin treatment, the auto- and alloantigen were found to be located on 65 kD fragments detectable under reducing conditions. In addition, immunoblots made after two-dimensional nonreduced-reduced SDS-polyacrylamide gel electrophoresis (SDS-PAGE) directly demonstrated that both 65 kD fragments had a molecular weight of 80 kD under nonreducing conditions; this provides evidence that these fragments were one and the same, and were derived from GP IIb alpha. Immunoblots of platelets digested in situ with chymotrypsin indicated that the 65 kD fragment of GP IIb alpha was retained by the platelet membrane. We conclude, therefore, that a 65 kD fragment, which represents the membrane side of the chymotrypsin cleavage site on GP IIb alpha, carries a clinically important determinant(s) recognized not only by the anti-Baka alloantibody, but also by the ITP autoantibody.

正常値の2～5倍の血清コリンエステラーゼ(acylcholine-acyl-hydrolase, EC3.1. 1.8,以下Ch-E)値を示す遺伝性変異Ch-Eの2家系を経験したので報告する.2家系中Ch-E高値を示した4例には,二次的に高Ch-E血症を来たすネフローゼ,脂肪肝,糖尿病,高脂血症,甲状腺機能亢進症などの基礎疾患を認めず,血清のポリアクリルアミド電気泳動にて通常のCh-E活性帯よりも泳動度の遅いextra band (Additional Band)が認められた.またdibucaine, sodium fluorideによるその活性阻害率は両家系共に正常であった.家系調査の結果,この変異Ch-Eは常染色体優性遺伝をすると考えられた.以上の成績よりここに報告したCh-EはNeitlichの言うE Cynthiana変異Ch-Eと同じであると考えられた.

We examined the activities of intestinal acyl-CoA:cholesterol acyltransferase (ACAT) and cholesterol esterase, enzymes regulating cholesterol absorption, in rats with streptozocin-induced diabetes (STZ-D) to clarify the effect of diabetes on cholesterol absorption. Three weeks after the induction of diabetes, plasma cholesterol levels were slightly but significantly increased in diabetic rats compared with control animals, whereas a far more remarkable increase in plasma cholesterol was observed in diabetic rats when fed an atherogenic diet containing 1% cholesterol, 0.5% cholic acid, and 5% lard. Microsomal ACAT activity in intestinal mucosa was three times higher in diabetic than in control rats. However, no significant difference in the enzyme activity could be detected between diabetic animals fed control chow and those fed the atherogenic diet. Furthermore, insulin supplementation given to diabetic rats caused a reduction of enzyme activity to the levels found in control animals. In contrast, cholesterol esterase activity in rat intestinal mucosa was unaffected by either the induction of diabetes or the atherogenic diet feeding. In conclusion, we disclosed that apparent ACAT activity in intestinal mucosa is elevated in STZ-D rats. Therefore, we postulate that enhancement of CoA-dependent cholesterol esterification in the intestine might be one of the major factors responsible for hypercholesterolemia in diabetes.