Macroglobulinemia and membranoproliferative glomerulonephritis in a hepatitis C virus-positive patient.

A 72-year-old female was admitted to our hospital for massive proteinuria. She had previously been diagnosed with hepatitis C virus (HCV) infection and macroglobulinemia. Renal histological examination demonstrated membranoproliferative glomerulonephritis (MPGN), and type 2 cryoglobulinemia was positive in her serum. It is generally recognized that MPGN is the most common nephritis associated with HCV infection and cryoglobulinemia, but this is the first report of an HCV-infected patient with macroglobulinemia associated with MPGN. After treatment with prednisolone and melphalan, proteinuria disappeared, but macroglobulinemia and cryoglobulinemia were not improved.

Preferential pharmacological inhibition of macrophage ACAT increases plaque formation in mouse and rabbit models of atherogenesis.

The cholesteryl ester, foam cell-enriched vulnerable plaque is a principle pharmacological target for reducing athero-thrombosis. Acyl CoA:cholesterol Acyl Transferase (ACAT) catalyzes the esterification of free cholesterol in intestine, liver, adrenal and macrophages, leading in the latter cells to intracellular cholesteryl ester accumulation and foam cell formation in the arterial intima. Previous studies suggested the existence of several isoforms of ACAT with different tissue distribution and this has largely been confirmed by molecular cloning of ACAT-1 and ACAT-2. We developed a series of ACAT inhibitors that preferentially inhibited macrophage ACAT relative to hepatic or intestinal ACAT based on in vitro assays and ex vivo bioavailability studies. Four of these compounds were tested in three models of atherosclerosis at oral doses shown to give sufficient bioavailable monocyte/macrophage ACAT inhibitory activity. In fat-fed C57BL/6 mice, chow fed apo E-/- mice and KHC rabbits, the various ACAT inhibitors had either no effect or increased indices of atherosclerotic foam cell formation. Direct and indirect measurements suggest that the increase in plaque formation may have been related to inhibition of macrophage ACAT possibly leading to cytotoxic effects due to augmented free cholesterol. These results suggest that pharmacological inhibition of macrophage ACAT may not reduce, but actually aggravate, foam cell formation and progression.

Amelioration of neurovascular deficits in diabetic rats by a novel aldose reductase inhibitor, GP-1447: minor contribution of nitric oxide.

The effects of a novel potent aldose reductase inhibitor, GP-1447 [3-[(4,5,7-trifluorobenzothiazol-2-yl)methyl]-5-methylphenylace tic acid] on the sciatic nerve blood flow in streptozotocin-induced diabetic rats were examined. Blood flow was analyzed in terms of mass, i.e. the volume of blood in tissue, and of velocity, i.e. the velocity of the blood flow. In diabetic rats, a 63% decrease in blood flow due to a decrease in velocity was observed. The blood mass in the same animals fluctuated, thereby increasing its range of values. Treatment with GP-1447 at a dose of 30 mg/kg per day for 4 consecutive weeks following a 3-week period without treatment ameliorated the reduced blood flow by 51%, and was accompanied by a recovery of velocity. The increase in the range of blood mass values was reversed by treatment with GP-1447. The restoration of the range of blood mass values, but not that of the blood flow, by GP-1447 was blocked by treatment with the nitric oxide (NO) synthase inhibitor, NG-nitro-L-arginine. Motor nerve conduction velocity (MCV) changes in parallel with blood flow values, while it is inversely proportionate to alterations in the range of blood mass values. It is suggested that the observed beneficial effect of GP-1447 on blood flow is involved in the restoration of decreased MCV in diabetes. It would appear that GP-1447-induced amelioration of neurovascular defects is not mediated solely by the improvement of the NO system.

Effects of a novel potent aldose reductase inhibitor, GP-1447, on aldose reductase activity in vitro and on diabetic neuropathy and cataract formation in rats.

GP-1447 {3-[(4,5,7-trifluorobenzothiazol-2-yl) methyl]-5-methylphenylacetic acid}, a novel aldose reductase (AR) inhibitor, exhibited highly potent and specific inhibition of AR activity from human placenta, human muscle, porcine and rat lens with IC50 values ranging from 3 to 10 nM. Lineweaver-Burk plots revealed non-competitive inhibition between DL-glyceraldehyde or beta-NADPH and inhibition of AR by GP-1447. In contrast to epalrestat, AR activity inhibited by GP-1447 did not recover after dialysis for 24 hr. Administration of GP-1447 to streptozotocin (STZ)-induced diabetic rats for 5 days beginning 1 week after STZ injection effectively inhibited the accumulation of sorbitol in the sciatic nerve, lens and retina with ED50 values of 0.25, 1.6 and 2.9 mg/kg/day, respectively. The motor nerve conduction velocity (MCV) in STZ-induced diabetic rats was significantly decreased 4 weeks after the induction of diabetes. Treatment with GP-1447 for the following 2 weeks dose-dependently restored the decreased MCV with an ED50 value of 0.28 mg/kg/day. Administration of GP-1447 (3 and 15 mg/kg/day for 12 weeks beginning 3 days after STZ injection) completely prevented cataract formation and was accompanied by marked inhibition of sorbitol accumulation in the lens. Furthermore, partial reversibility of cataract formation and morphological changes of the lens was observed in diabetic rats treated with 15 mg/kg/day of GP-1447 for 5 weeks beginning 8 weeks after the induction of diabetes. From these results, GP-1447 would be expected to exert potent ameliorating effects on some diabetic complications. Potent inhibition of cataract formation will be one of the characteristics of this compound.

[Anti-atheromatous effects of fenofibrate, a hypolipidemic drug. I: Anti-atheromatous effects are independent of its hypolipidemic effect in cholesterol-fed rabbits].

Anti-atheromatous effects of fenofibrate were studied in cholesterol-fed rabbits. Rabbits in the control group (HCD) and fenofibrate group (F-HCD) were fed the 0.5% cholesterol diet and the 0.5% cholesterol plus 0.11% fenofibrate diet (corresponding to ca. 30 mg/kg/day), respectively, for 2, 4 or 10 weeks. Fenofibrate did not change serum levels of total cholesterol, HDL-cholesterol and triglyceride during the feeding period. The percentage of plaque area (PPA) formation in the thoracic aorta was time-dependently increased. PPA values were reduced in the rabbits treated with fenofibrate for 2 and 4 weeks, but not in those treated for 10 weeks. Fenofibrate had no effect on the plaque thickness. The percentage of circulating free platelets in the HCD group was reduced at the 4th week of feeding, but that in the F-HCD group was not. The anti-platelet effect of fenofibrate might cause the anti-atheromatous effect. Fenofibric acid, an active metabolite of fenofibrate, had no inhibitory effect on LDL peroxidation in vitro. From these results, we conclude that fenofibrate manifests an anti-atheromatous effect independent of the hypolipidemic effect in cholesterol-fed rabbits and that it may inhibit an early event in the atherogenesis.

[Anti-atheromatous effects of fenofibrate, a hypolipidemic drug. II: Anti-atheromatous effects are independent of its hypolipidemic effect in hereditary hyperlipidemic rabbits].

Anti-atheromatous effects of fenofibrate were studied in KHC rabbits with a hereditary deletion in LDL receptors, a defect similar to that in Watanabe heritable hyperlipidemic rabbits. KHC rabbits (10-weeks-old) were given a dietary admixture of fenofibrate (ca. 30 or ca. 100 mg/kg/day) for 20 weeks. Fenofibrate did not change serum total cholesterol, high density lipoprotein and triglyceride levels. Fenofibrate decreased the percent of plaque area formation in the thoracic aorta, but not the degree of foam cell formation, fibrosis and edematous change, and thickness of the intima. Furthermore, fenofibrate markedly inhibited the medial damage with foam cell formation in the aorta at week 20. From these results, we conclude that fenofibrate manifested the anti-atheromatous effect in KHC rabbit and also the previous model of cholesterol-fed rabbits, particularly against the medial damage in KHC rabbits, independent of the hypolipidemic effect.

[Therapeutic effect of IGN-2098, a new antiulcer drug (H2-antagonist), in the ulcer diminishing period against acetic acid-induced gastric ulcer in rats].

The effects of IGN-2098 on the healing process of acetic acid-induced gastric ulcer was investigated in comparison with the other histamine H2-receptor antagonists, famotidine and roxatidine acetate HCl, in rats. Ulcer was induced by the injection of acetic acid solution (20%, 0.05 ml). From the 4th day to 17th day after the ulcer induction, drugs were orally administered twice a day. On the 18th day after the ulcer induction, rats were sacrificed to measure the ulcer index macroscopically and to take pictures of the stomachs. Judging from the photographs, the prominence of ulcer the edge was graded into 4 classes, which showed a significant correlation with the histological amount of connective tissue at the ulcer edge. All drugs accelerated the healing of the ulcer, and the effect of IGN-2098 was the most remarkable. In addition, IGN-2098-treatment exhibited more marked inhibition against the prominence of the ulcer edge as compared with the control group. Based on these results, it is concluded that IGN-2098 may be a useful drug for the clinical treatment of ulcer and that the healing acceleration by IGN-2098 without prominence of the ulcer edge may induce no relapse of the ulcer after healing.

Astronaut psychiatric selection procedures: a Japanese experience.

This paper presents the results of the first application of a structured NASA psychiatric interview for Japanese astronaut selection. We undertook a semi-structured, diagnostic, clinical psychiatric interview with 45 Japanese astronaut applicants for the position of mission specialist-astronaut, and performed "select-out" psychiatric evaluations according to DSM-III-R psychiatric diagnostic criteria. Two applicants (4.4%) who met Axis I or Axis II disorder criteria in DSM-III-R were evaluated as "Disqualified." There were 13 applicants "Qualified with Reservation"; the majority of their diagnoses were "hypomania." Those applicants "Qualified with Reservation" and "Disqualified" were not finally selected to be astronauts. This structured interview was not only useful for "select-out" psychiatric screening of Japanese astronauts, but also made clear the Japanese characteristics of this selection procedure.

Recovery of the vestibular function after vestibular neuronitis.

We performed steroid therapy on 34 cases with vestibular neuronitis and compared them with 77 patients not subjected to this therapy to examine the role of recovery of their vestibular function. Since no relation was noted between use of steroid and changes in subjective symptom of dizziness, the use of steroid is likely to facilitate the disappearance of spontaneous nystagmus in the early recovery stage. Canal paralysis recovered significantly by steroid and in cases of slight and moderate paralysis at the onset, recovery was more significant. Steroid therapy is argued to be effective for the recovery of vestibular function in cases of vestibular neuronitis.

A clinical observation of benign paroxysmal positional vertigo (BPPV) after vestibular neuronitis (VN).

We observed 9 cases of BPPV developed after vestibular neuronitis. The interval between the onset of BPPV and vestibular neuronitis ranged from 2 weeks to 20 years. All cases were examined for critical head position which provoked vertigo, non-gaze nystagmus, positional and positioning nystagmus and caloric nystagmus. No characteristic signs and symptoms could be observed. The function of the posterior canal is thought to be necessary to provoke positional vertigo. Thus in BPPV after vestibular neuronitis the function of the posterior canal would presumably have been preserved to some degree. The first possibility is that the function of the posterior canal was not impaired in spite of the damage of the lateral canal. The fact that each canal differs in involvement in vestibular neuronitis may be explained by the difference in the blood supply or the innervation between lateral and posterior canals. If only the artery or nerve which is related to the lateral canal is damaged and the artery or nerve to the posterior canal is not involved, then the function of the posterior canal is preserved. So BPPV may occur soon after the disappearance of severe vertigo. The second possibility is that if the posterior canal had been damaged together with the lateral canal and the functions are recovering, BPPV may occur some time after the onset of vestibular neuronitis. The locus of vestibular neuronitis is in the peripheral vestibular system and the extent and degree of the lesion vary, which may explain why there can be time difference of the recovery between the two canals.

Exploratory eye movements in schizophrenic patients and patients with frontal lobe lesions.

Exploratory eye movements in 20 schizophrenics, 18 patients with frontal lobe lesions (9 right-sided and 9 left-sided) and 20 normal controls were examined with an eye mark recorder while they viewed stationary S-shaped figures. The eye movements made during the subject's first 15-s viewing of an original figure were analyzed. Patients with right frontal lobe lesions (RF) and schizophrenics (S) had lower scores than normal controls (NC) for the number of eye fixations, total eye scanning length and mean eye scanning length. Each subject was then shown two other figures slightly different from the original and was requested to compare them with the original. After comparing them, the subject was asked the question, "Are there any other differences?" The eye movements made over the ensuing 5 s in response to this question were scored using the responsive search score (RSS). The RSS was low only in the S group. The subject was also asked to reproduce the original figure before and after making comparisons between the figures. The RF and S groups were poorer at reproduction than the NC group. These findings suggest that there is disordered function of the right frontal lobe in schizophrenia, and that schizophrenia is due not only to localized damage to one part of the brain but to more widespread damage.

[The effect of aldioxa on the formation of gastritis induced with sodium hydroxide].

The effects of aldioxa and cetraxate hydrochloride on the formative process of gastritis induced with intragastric application of 2% sodium hydroxide were studied. Rats were given food including either aldioxa or cetraxate hydrochloride for 6 weeks after the sodium hydroxide application. After sacrifice, the stomachs were removed, and the gastric mucosa were observed macroscopically and histologically. Gastric mucosal injury was widely induced with sodium hydroxide, being histologically characterized by mucosal hypertrophy, cell infiltration and intestinal metaplasia. These lesions seem to be the early stage of chronic gastritis. The aldioxa group showed a decrease of mucosal hypertrophy and cell infiltration as compared with the control group. In the cetraxate hydrochloride group, the mucosal surface of white gray color and the mucosal bosselation were observed macroscopically. Histologically, these were found to be cell infiltration and cyst formation. Moreover, intestinal metaplasia occurred at high incidence in this group. These findings in the cetraxate hydrochloride group are recognized to be an aggravation of chronic gastritis. From the above results, it is suggested that aldioxa promotes good regeneration of mucosa and should be useful for the clinical therapy of chronic gastritis.

[A quantitative measurement of the cerebral infarct focus induced by arachidonate infusion and the relationship between measured values and stroke signs].

A method for measuring the organic infarct focus induced by arachidonate infusion into rat brain was devised, and the statistical relationship between the measured values and stroke signs in the rat was studied. By the infusion of arachidonate, a high incidence of cerebral infarction was found in the live rats with uniformly necrotized foci. The size of these foci (infarction rate) were measured by transcripting them to a graduated brain sheet. The relationship between the independent parameter of the infarction rate and the dependent parameter of stroke signs was fully analyzed by multidimensional quantification. Many animals showed no stroke signs despite having lesions (false negative). By contract, no animal without any lesion showed stroke signs (false positive). When each parameter of these signs were quantified and normalized, the stumbling and abnormal posture signs showed a wide range of values, relatively accurately reflecting the infarction degree. Moreover, the highest partial correlation ratio between the various parameters was found to be that between the stumbling and abnormal posture stroke signs. Thus, it may be said that the stumbling and the abnormal posture stroke signs can be considered relatively good parameters for evaluating the degree of an infarction. These parameters should be useful for the testing of anti-infarction drugs.