Isolated corticotropin deficiency in adults. Report of 10 cases and review of literature.

The clinical and laboratory findings in 76 patients with isolated corticotropin deficiency (10 of our own and 66 from literature) were analyzed with the following observations. With the exceptions of hyperpigmentation and hyperkalemia, the similarity of symptoms and signs to those of Addison's disease and their reversibility by glucocorticoids indicate that most, but not all, manifestation of isolated corticotropin deficiency is caused by glucocorticoid deficiency. Isolated corticotropin deficiency seems to be of pituitary origin in most patients, as shown by lack of corticotropin response to insulin-induced hypoglycemia, vasopressin, or corticotropin-releasing factor. Secretion of other pituitary hormones is frequently abnormal, which is mostly attributable to glucocorticoid deficiency. Although the pathogenesis of isolated corticotropin deficiency is unknown in most patients, association with other autoimmune endocrinopathies, postpartum onset in women, or serum antipituitary antibodies suggests an autoimmune pathogenesis in some patients. In two of our 10 patients, cancer developed during glucocorticoid treatment. More observations of complications and long-term prognosis following glucocorticoid therapy are needed for optimal clinical decision making.

A pressor formation by trypsin from renin-denatured human plasma protein.

Trypsin, when incubated with human plasma protein either undenatured or denatured by pretreatment with acid or alkali or by heat, produced an angiotensin II-like pressor substance instead of the depressor bradykinin which has been reported to be formed from various plasma fractions and trypsin. This reaction may be due to the activation of prorenin by trypsin, but this is rather unlikely since it appears that angiotensin II rather than I is formed. It seems to be more likely a direct production of the angiotensin hormone from the substrate, and we propose to call tentatively the active product "tryptensin".

Inhibition of PDGF- and TGF-beta 1-induced collagen synthesis, migration and proliferation by tranilast in vascular smooth muscle cells from spontaneously hypertensive rats.

Vascular smooth muscle cells (VSMC) from spontaneously hypertensive rats (SHR) proliferate faster and are more sensitive to transforming growth factor-beta 1 (TGF-beta 1) than those of normotensive Wistar-Kyoto rats. We studied the in vitro effects of tranilast, an anti-allergic drug, on the proliferation, migration and extracellular matrix synthesis in the SHR-VSMC. There were many inhibitory effects of tranilast (30-300 microM) on SHR-VSMC. One is the effect on the proliferation stimulated with fetal bovine serum (FBS), TGF-beta 1 and platelet-derived growth factor-BB (PDGF-BB). Another is the effect on the PDGF-BB-induced migration. Lastly, tranilast exhibited inhibitory effects on spontaneous collagen synthesis and TGF-beta 1-induced collagen and glycosaminoglycan synthesis. On the other hand, collagen induced the VSMC migration concentration-dependently. These results suggest that tranilast may prevent restenosis after percutaneous transluminal coronary angioplasty.

Tranilast antagonizes angiotensin II and inhibits its biological effects in vascular smooth muscle cells.

Recent studies have been reported indicating that angiotensin II may potentiate neointimal formation. In the present study, we examined the antagonistic effect of tranilast on angiotensin II. Losartan was used as the reference compound. First, tranilast inhibited the angiotensin II-induced contraction of rabbit aortic strips in a noncompetitive manner (pD'(2) = 3.7), whereas it had little effect on the contraction induced by noradrenaline or endothelin-l. Second, tranilast inhibited the binding of (125)I-labeled angiotensin II to angiotensin AT1 receptors in rat liver membranes with an IC(50) value of 289 mu M. Finally, functional antagonism of tranilast (100 and 300 mu M) was demonstrated by its blockade of angiotensin II (10(-8)M)-induced (45)Ca(2+) -efflux from human vascular smooth muscle cells (VSMC). However, tranilast (30-300 mu M) exerted no influence on PDGF-induced formation of inositol triphosphates which cause an increase in [Ca(2+)]i in human VSMC. The antagonistic activity of tranilast towards angiotensin II may be involved in part in preventing restenosis after percutaneous transluminal coronary angioplasty (PTCA).

Tranilast suppresses the vascular intimal hyperplasia after balloon injury in rabbits fed on a high-cholesterol diet.

Intimal hyperplasia is a serious problem after percutaneous transluminal coronary angioplasty. In this study, we assessed the effect of tranilast on vascular intimal hyperplasia after balloon injury in rabbits fed on a high-cholesterol diet. In this animal model, intimal hyperplasia more severe than that in rabbits fed on a normal diet was observed. In addition, medial thickening and lipid deposits in both media and intima were also noted. These findings indicate that balloon injury caused intimal and medial hyperplasia and that this hyperplasia was accelerated by the high cholesterol load. Tranilast (300 mg/kg) significantly decreased the intimal area, medial area, and stenosis ratio, and increased the luminal/total area ratio, in the cholesterol-fed rabbits. These results suggest that tranilast may be useful for prevention of restenosis after percutaneous transluminal coronary angioplasty of patients, including those with a clinical risk of hypercholesterolemia.

Effects of low molecular weight heparin on a severely antithrombin III-decreased disseminated intravascular coagulation model in rabbits.

The effect of dalteparin, a low molecular weight heparin, on severely antithrombin III (ATIII)-decreased disseminated intravascular coagulation (DIC) model was compared with that of unfractionated heparin (heparin). The DIC model in rabbits was produced by continuous infusion of thrombin in combination with bolus injection of latex. After a 3 hr infusion of thrombin, plasma ATIII activity was lowered to 30% of normal plasma. Platelet number, fibrinogen content and alpha 2 plasmin inhibitor (alpha 2PI) activity were also decreased. Dalteparin (25-100 IU/kg/hr) and heparin (25-100 U/kg/hr) inhibited the decrease in ATIII activity, platelet number and fibrinogen content, and had no effect on alpha 2PI activity. Activated partial thromboplastin time (APTT) was prolonged by heparin (50 and 100 U/kg/hr), but not by dalteparin (25-100 IU/kg/hr). The ratio of anti-factor Xa (F.Xa) activity to anti-thrombin activity for dalteparin (50 IU/kg/hr) was higher than that for heparin (50 U/kg/hr). With the addition of exogenous ATIII, the ratio of anti-F.Xa to anti-thrombin for heparin increased, but that for dalteparin did not change. However, the increased ratio for heparin was still lower than the unchanged ratio for dalteparin. These results suggest that both dalteparin and heparin have the ability to rectify the abnormal parameters of severely ATIII-decreased DIC, and that the effects of dalteparin are mainly involved with anti-F.Xa activity whereas the effects of heparin are via anti-thrombin activity.

Factors associated with mortality of myxedema coma: report of eight cases and literature survey.

High-dose thyroid hormone replacement has been recommended for treatment of myxedema coma (MC) while questions of safety of the therapy and of efficacy of low-dose thyroid hormone replacement have not been systematically addressed. We treated 8 patients with MC in a period of 18 years, the first 3 with high-dose intravenous injections of levotriiodothyronine (LT3) and the other 5 patients with a smaller amount of either LT3 or levothyroxine (LT4). Two of the first 3 patients died of pneumonia and the other 5 recovered despite pulmonary abnormalities at the outset. To find factors associated with fatal outcome after treatment, the MEDLINE database was searched for MC cases with data of thyroid hormone replacement and outcome within 1 month of therapy. Clinical data for our 5 patients and 82 cases from the MEDLINE search were pooled and factors associated with mortality were sought among age, gender, presence of cardiac or pulmonary complications, and doses of thyroid hormone by multiple logistic regression analysis. It revealed that greater age, cardiac complications, and high-dose thyroid hormone replacement (LT4 > or = 500 microg/d or LT3 > or = 75 microg/d) were significantly associated with a fatal outcome within 1 month of treatment. Elderly MC patients can be treated with low-dose hormone replacement. A bolus of 500 microg LT4, especially by mouth or via nasogastric tube, appears to be tolerated by younger patients (< 55 years) without cardiac complication. The conclusion remains to be confirmed in more patients.

Ozone injection into an activated carbon bed to remove hydrogen sulfide in the presence of concurrent substances.

Adsorption using activated carbon is one of the most reliable techniques for preventing odor by substances such as H2S. Concurrent substances in effluent gas often reduce the removal capacity of activated carbon for H2S. As a means of restoring capacity under such conditions, ozone injection into an activated carbon column was examined. When activated carbon was saturated with substances such as toluene, ethanol, n-butanol, or iso-butanol, its capacity to remove H2S decreased in proportion to the amount of the saturating substance. Under such conditions, ozone injection greatly increased capacity. Toluene, which is not easily decomposed by ozone, was displaced by ozone and by oxidized products of H2S. Ethanol, which is adsorbed in small amounts by activated carbon and easily decomposed by ozone, was removed by ozone injection. Butanols, which are also decomposed by ozone and adsorbed in large quantities by activated carbon, showed intermediate behavior between that of toluene and ethanol.

Cryogenic trapping for determination of odor concentration.

The sensory testing method applied under Japanese law to measure odor concentration has a lower detection limit of 10 in the specified Odor Index. To measure odor below the limit, a condensing procedure using solid sorbents (Tenax-TA, Unicarbon B and Carbosieve SIII) has been developed and used in Japan. This procedure however cannot condense all odorous substances, and is specifically unsuited to hydrogen sulfide, methyl mercaptan, dimethyl sulfide, ammonia, and other typical odorous substances. In the present study, cryogenic trapping was tested to improve recovery rate. As water in sample air causes choking of the trap tube, vacant pre-columns to condense the water were connected to the Tenax-TA-packed column. The columns were chilled with liquid oxygen before passage of 100 L of sample air. The columns were then heated to 200 degrees C under passage of 50 mL/min of nitrogen carrier gas to desorb odors. The desorbed gases were captured in sampling bags made of polyethylene terephthalate film. The total volume of desorbed gases was approximately 1 L. The method showed good recovery rates for hydrogen sulfide, methyl mercaptan, dimethyl sulfide and ammonia, and was useful for determining low-level odor concentrations during measurement of odor in ambient air at various sites in Osaka City.

[Defect of taste in a patient with hypothyroidism].

A 74-year-old male presented with a total loss of taste of ten weeks' duration. He could not recognize both saturated sugar and salt solutions but his acuity for smell was normal. He also had a slight hoarseness, mild dysarthria and hyporeflexia of all extremities. Laboratory data revealed marked hypothyroidism and positive tests for antithyroglobulin and antimicrosomal antibodies. Shortly after the institution of thyroxine replacement, subjective response in taste acuity was seen. Almost complete recovery of taste followed after a month of incremental dose of thyroxine. The case indicates that thyroid hormones play a significant role in taste acuity. Hypothyroidism should be considered as one of the possible causes in taste defect.

[Treatment of Guillain-Barré syndrome with high-dose intravenous immunoglobulins--a comparison with plasma exchange].

We used high-dose intravenous immunoglobulin (IVIG) in the treatment of Guillain-Barré syndrome (GBS) and compared its therapeutic effects with those who were treated by plasma exchange (PE). For this study, we selected patients who had been within seven days from the onset and unable to walk without support at that time. Four patients (3 male, 1 female, mean age 41.8) were treated by plasma exchange with 3,000-4,000 ml exchange of plasma/day for 4-6 days. Other four patients (2 male, 2 female, mean age 45.7) were treated with intravenous high-dose immunoglobulin: 400 mg/kg/day for 3-5 days. The functional scale was measured at study entry and after the treatment daily. The mean times to the recovery of independent walk (a functional grade 2) were 23.8 and 10.0 days for PE and IVIG respectively. Although there was a difference of disease severity between these two groups, IVIG was at least as effective as PE in the treatment of GBS.

[Different characteristics of 123I-IMP SPECT images of cerebral embolism and cerebral thrombosis].

We performed 123I-IMP SPECT in patients with cerebral infarction within 48 hours after onset, to investigate its usefulness in differentiating cerebral embolism from thrombosis. Clearcut wedge-shaped defect was seen on the SPECT image in all six cases of clinically suspected cerebral embolism in our series, while this pattern was not observed among the five cases of cerebral thrombosis.

N2O emissions at solid waste disposal sites in Osaka City.

Nitrous oxide (N2O) is a trace gas contributing to stratospheric ozone depletion and global warming. Although a large quantity of information exists about N2O emissions from various ecosystems, this study was initiated to demonstrate the features of N2O emissions from sea-based waste disposal sites in Osaka City in relation to CH4 emissions. Average N2O emissions at an active landfill (S-Site) were several times higher than those at a closed landfill (N-Site). Average CH4 emissions were also much greater at the S-Site. Regarding the nature of N2O emissions, remarkable emissions often were observed with aerobic waste layers at the N-Site, suggesting almost inversely related N2O emissions with CH4 production at the N-Site. However, at the S-Site a few exceptionally high N2O emissions were noted in cases of high CH4 emissions.

Pathogenesis of extracellular fluid abnormalities of hypothalamic hypodipsia-hypernatremia syndrome.

A 26-year-old man with hypothalamic hypodipsia-hypernatremia syndrome is reported, who presented with adipsia, hypernatremia, and impaired osmolality-mediated arginine vassopressin (AVP) secretion. A chorionic gonadotropin-secreting tumor was detected in the anterior hypothalamus and treated with external irradiation. After the treatment, hypernatremia persisted and was not corrected by fluid loading, osmolality-mediated AVP secretion remained impaired. Despite the absence of signs of hydropenia, hypovolemia was suggested by low blood pressure and elevated plasma indices of the renin-angiotensin system, and supported by blood volume determination. The plasma aldosterone concentrations were inappropriately low for the renin-angiotensin status. The plasma atrial natriuretic polypeptide (ANP) level was normal in spite of hypovolemia and increased more than double after fluid loading. Hypernatremia, primarily caused by hypodipsia and impaired osmolality-mediated AVP secretion, secondarily sustained ANP secretion and suppressed aldosterone release, which conceivably contributed to the development and perpetuation of hypovolemia in this patient.

Inhibitory effects of tranilast on proliferation, migration, and collagen synthesis of human vascular smooth muscle cells.

The aim of this study was to examine the effects of tranilast (anti-allergic drug) on proliferation, migration, and collagen synthesis in cultures of human vascular smooth muscle cells. Tranilast at 100 and 300 microM had several inhibitory effects. One is the effect on vascular smooth muscle cell proliferation induced by fetal bovine serum and platelet-derived growth factor (PDGF)-BB. Second is the effect on PDGF-BB-induced migration. Third is the effect on c-myc expression after PDGF-BB stimulation. Lastly, tranilast reduced the spontaneous collagen synthesis without reducing total protein synthesis. These results suggest that tranilast may prevent restenosis after percutaneous transluminal coronary angioplasty via the inhibitory effects on proliferation, migration, c-myc gene expression, and collagen synthesis of vascular smooth muscle cells.

Dual facets of hyponatraemia and arginine vasopressin in patients with ACTH deficiency.

OBJECTIVE: Hyponatraemia is often observed in patients with ACTH deficiency who are thought not to suffer from volume depletion. Their high plasma AVP levels relative to plasma osmolality are presumed to be maintained by non-osmotic mechanisms. We attempted to assess volume status from changes in selected clinical measurements related to body fluid balance in the course of i.v. fluid supplementation and following glucocorticoid (GC) replacement in ACTH-deficient patients, and to interpret plasma AVP levels in the context of the estimated volume status. PATIENTS AND DESIGN: This report consists of three parts. First, an ACTH-deficient patient with hyponatraemia and volume depletion who was followed through volume replacement to recovery after GC replacement is described (case report). Secondly, medical records of five ACTH-deficient patients with hypovolaemia and hyponatraemia were surveyed retrospectively to observe changes in serum levels of sodium, uric acid (UA) and haematocrit (Hct) following i.v. fluid supplementation of low sodium content (retrospective study). Thirdly, five ACTH-deficient patients with or without overt dehydration were studied with regard to body weight, blood pressure, serum sodium, total proteins, Hct and blood urea nitrogen before and after GC replacement (prospective study). Plasma AVP levels were measured after i.v. fluid supplementation without GC replacement in the patients of the retrospective study, and before and after GC replacement in the patients of the prospective study. RESULTS: The first patient became more hyponatraemic after i.v. fluid supplementation and recovered ultimately from hyponatraemia after GC replacement. In five patients studied retrospectively, the serum sodium levels fell progressively following i.v. fluid supplementation, concurrent with reduction in UA levels and Hct, which indicated the dilutional nature of the hyponatraemia. In the patients observed prospectively, the accumulation of fluid and sodium was indicated by a rise in body weight, blood pressure and serum sodium levels and a decline in Hct and total proteins after GC replacement. Plasma AVP levels rose similarly in patients with dilutional hyponatraemia and in patients with borderline hyponatraemia before GC replacement. CONCLUSION: Patients with untreated ACTH deficiency may have either of two kinds of hyponatraemia--i.e. borderline hyponatraemia associated with subclinical hypovolaemia, or dilutional hyponatraemia. Similarity of plasma AVP levels in two hyponatraemic states suggests their AVP secretion is regulated by non-osmotic, non-volume mechanisms, possibly released from GC suppression at low plasma osmolality.