Postural dysfunction in a transgenic mouse model of spinocerebellar ataxia type 3.

During voluntary limb movements, humans exert anticipatory postural adjustments (APAs) to prevent any upcoming equilibrium disturbance that might be provoked by limb movements. Dysfunction in generation or control of APAs is associated with postural deficits in some human patients with cerebellar damage. To examine the role of the cerebellum in APAs, we investigated a conditional transgenic mouse of spinocerebellar ataxia type 3 (SCA3Tg) that has defective cerebellar Purkinje cells. Kinematic analyses and monitoring of electromyographic activities during quadrupedal standing showed that SCA3Tg mice exhibited greater hindlimb instability than wild-type (WT) mice. This instability increased during a reaching task that required postural adjustments associated with voluntary neck movements. Normally, the activities of the hindlimb muscles are synchronized with those in the neck that are the agonists for movement of the head in this reaching task; however, in SCA3Tg mice, activities in the hindlimbs were markedly delayed compared to the neck. These observations cannot simply be explained as a secondary outcome of the muscle atrophy that occurs in SCA3Tg mice. In WT mice with muscle atrophy induced by immobilization of the hindlimbs, we did not find impairment of APAs. These findings suggest that the deficits in APAs during the reaching task in SCA3Tg mice were not due to muscle atrophy in the hindlimbs, but were mainly caused by cerebellar degeneration. Therefore, we conclude that the cerebellum is critically involved in APAs.

[A recurrent case of amebic liver abscess seventeen years after the first occurrence].

A 49-year-old male who had been diagnosed as having amebic liver abscess when he was 32-year-old was admitted to our hospital with fever and watery diarrhea. Ultrasonography and CT examination demonstrated a solitary abscess in the right lobe of the liver. Cysts of Entamoeba histolytica were detected in the stool and an aspiration of the liver abscess looked like anchovy paste. Serum amebic antibody by the IFA method was positive and the case was diagnosed as amebic liver abscess. The patient was treated with metronidazole, and percutaneous transhepatic abscess drainage was performed. The liver abscess decreased remarkably in size and serum amebic antibody was negative after the treatment. Recurrence of amebic liver abscess is rare and we report this case with some literature.

Massive intrathoracic haemorrhage after CT-guided lung biopsy.

CT-guided lung biopsy is now widely performed for tumorous lesions in the lung, and both its usefulness in this context and the associated complications have been well described in the literature. Although severe complications are rare, we describe a case in which massive intrathoracic haemorrhage developed after lung biopsy and necessitated emergency operation for control. Intraoperative findings suggested that the source of the haemorrhage was a fibrous, cord-like substance present at the site of adhesion associated with old tuberculosis. We attributed this haemorrhage to a pneumothorax, which developed after lung biopsy and caused the new vessels penetrating the centre of the fibrous, cord-like substance to stretch and rupture. Numerous cases have been reported of spontaneous haemopneumothorax precipitated by spontaneous pneumothorax and resulting from the rupture of such vessels.

Stimulative effects of saponin from kikyo-to, a Japanese herbal medicine, on pancreatic exocrine secretion of conscious rats.

Our previous report stated that kikyo-to, a Japanese herbal medicine, consisting of the roots of Platycodon grandiflorum and Glycyrrhiza sp., stimulates the pancreatic exocrine secretion of conscious rats. The present study focused on the effective components of kikyo-to and the mechanism of stimuli to pancreatic secretion of rats. When 10 to 100 mg of platycodin D, a saponin from the root of Platycodon grandiflorum, was intragastrically administered, the pancreatic secretion of rats was stimulated. At the same time, the plasma CCK concentration increased. On the other hand, the stimulative effects of glycyrrhizin, a saponin from the root of Glycyrrhiza sp. were weak compared to platycodin D. The effects of 10 mg/kg of platycodin D on pancreatic secretion were inhibited by loxiglumide (50 mg/kg, i.g.), a CCK receptor antagonist. In contrast, the suppressive effect of atropine (300 micrograms/kg/h, i.v.) on pancreatic secretion was reduced by administering 10 mg/kg of platycodin D. In addition, up to 1 mM of platycodin D did not inhibit the trypsin activities in vitro. In conclusion, kikyo-to serves to stimulate pancreatic exocrine secretion mainly because platycodin D causes gastrointestinal hormones, particularly, CCK to be released from the duodenum.

Decreased contractile effect of endothelin-1 on hyperplastic prostate.

1. The contractile activity, binding activity and localization of endothelin (ET)-1 were evaluated in human nonhyperplastic (control) and hyperplastic prostates. 2. ET-1 caused contraction of both prostates in a dose-dependent manner. However, this contraction was markedly decreased in hyperplastic prostates. 3. Bmax and Kd values of hyperplastic prostates were greater than those of the control. 4. The muscle and proliferative epithelium of hyperplastic prostates showed strong staining for the anti-ET-1 antibody. However, the glandular epithelium of control prostates was weakly stained. 5. These findings indicate that responsiveness to ET-1 is decreased, though the ET-1 and ET-1 receptors increase in the hyperplastic prostate. Namely, the increase in ET-1 receptors is not effective in regulating the contractile response of the prostate, because its expression is rather dominant in proliferated gland. 6. These suggest that ET-1 may not have an important role in the release of the obstructive symptoms of benign prostatic hypertrophy.

Multidirectional contraction of human hypertrophied prostate.

1. The purpose of the present investigation is to evaluate muscle contraction in two directions (longitudinal and circumferential to urethra) physiologically and morphologically for alpha-adrenoceptor agonists. 2. Norepinephrine (10(-7)-10(-4) M), phenylephrine (10(-7)-10(-4) M) and clonidine (10(-7)-10(-4) M) induced contractions in a dose-dependent manner on human prostate from patients with benign prostatic hypertrophy (BPH). 3. No significant differences were observed between longitudinal and circumferential directions of human prostate in 50% of the maximal muscle contraction (EC50 values) and the maximal muscle contractions caused by any agents used. 4. Morphometric analysis for muscle in prostates was performed using formalin-fixed, paraffin-embedded sections stained by the Mallory-Azan method. 5. There was no significant difference in the density of the muscle area between longitudinal and circumferential directions of prostatic strips. 6. These results suggest that there are no significant differences in responsiveness of alpha-adrenoceptor agonists and the smooth muscle contents in longitudinal and circumferential directions to urethra, for human hypertrophied prostate.

Effects of CD-832, a dihydropyridine derivative with a nitrate ester moiety on rabbit femoral artery and vein.

We investigated the effects of CD-832 ((4R)-(-)-2-(nicotinoyl-amino)ethyl 3-nitroxypropyl 1,4-dihydro-2,6-dimethyl-4,3-nitrophenyl, 3,5-pyridine dicarboxylate), a dihydropyridine derivative with a nitrate ester moiety, on contractile responses in rabbit femoral arteries and veins. CD-832 (10(-8) to 10(-6) M and nifedipine inhibited the 64 mM KCl-induced and 10(-6) M norepinephrine-induced contractions of rabbit femoral arteries, while nitro compounds had no effect on the contractions. CD-832 (10(-8) to 10(-6) M) and nitro compounds inhibited the 10(-6) M norepinephrine-induced contractions in rabbit femoral veins, while other Ca2+ channel antagonists had little effect. The inhibitory effects of CD-832 (10(-7) M) on norepinephrine-induced contractions were antagonized by treatment with methylene blue (10(-5) M). These results indicate that CD-832 potently relaxes venous smooth muscle, and that it may be a useful agent for the treatment of angina pectoris.

Role of cyclic GMP in inhibitory effects of CD-349 in isolated blood vessels.

1. We investigated the effects of CD-349, a dihydropyridine derivative with nitrate ester, on contractile responses induced by high K+, norepinephrine (NE) and Ca2+ in isolated rabbit aorta. 2. CD-349 (10(-9)-10(-5) M) and nifedipine (10(-9)-10(-5) M) equally inhibited the 64 mM KCl-induced contraction of the aortic strips in a concentration-dependent manner. 8-Br-cyclic GMP (10(-3) M) did not inhibit the KCl-induced contraction of the aortic strips. 3. CD-349 (10(-8)-10(-5) M) and 8-Br-cyclic GMP (10(-6)-10(-3) M) inhibited the 10(-6) M NE-induced contraction of the aortic strips in a concentration-dependent manner. However, nifedipine had no effect on the NE-induced contraction in rabbit aorta. 4. The inhibitory effects of CD-349 on NE-induced contraction were antagonized by treatment with methylene blue and oxyhemoglobin, while they were augmented by treatment with zaprinast. 5. CD-349 (10(-8)-10(-5) M) and 8-Br-cyclic GMP (10(-5)-10(-4) M) inhibited the NE-induced phasic contraction and Ca(2+)-induced contraction of the aortic strips preincubated with NE in Ca(2+)-free medium. However, nifedipine (10(-5) M) had little or no effect on both NE-induced phasic contraction and Ca(2+)-induced contraction of the aortic strips preincubated with NE in Ca(2+)-free medium. 6. CD-349 (10(-7)-10(-5) M) increased the levels of cyclic GMP in rabbit aorta. 7. These results indicate that CD-349 has a hybrid property deriving from Ca(2+)-antagonist and cyclic GMP increasing agents.

CD-832, a new dihydropyridine derivative with both nitrate-like and Ca2+ channel antagonist vasodilator activities.

We investigated the effects of CD-832 ((4R)-(-)-2-(nicotinoylamino)ethyl 3-nitroxypropyl 1,4-dihydro-2,6-dimethyl-4,3-nitrophenyl, 3,5-pyridine dicarboxylate), a new dihydropyridine derivative with nitrate ester, on contraction and relaxation responses induced by various vasoactive agents in rabbit aorta. CD-832 potently inhibited the specific binding of [3H](+)-PN200-110 to rat brain membranes. The IC50 values for [3](+)-PN200-110 binding were 2.8 nM and 4.9 nM in CD-832 and nifedipine, respectively. CD-832 (10(-8) to 10(-5) M), diltiazem (10(-8) to 10(-5) M) and benidipine (10(-8) to 10(-5) M) inhibited the 64 mM KCl-induced contraction of the aortic strips in a concentration-dependent manner. Neither nitroglycerin (10(-8) to 10(-5) M) nor nicorandil (10(-8) to 10(-5) M) affected the 64 mM KCl-induced contraction in rabbit aorta. CD-832 (10(-8) to 10(-5) M), nitroglycerin (10(-8) to 10(-5) M) and nicorandil (10(-5) M) had no effect on norepinephrine-induced contraction in rabbit aorta. Nitroglycerin (10(-5) M), atrial natriuretic peptide (10(-8) M), nicorandil (10(-5) M) and CD-832 (10(-7) to 10(-5) M) augmented the isoproterenol-induced relaxation responses of rabbit aorta precontracted with endothelin-1 (1 x 10(-7) to 2 x 10(-7) M). The effects of nitroglycerin (10(-5) M), nicorandil (10(-5) M) and CD-832 (10(-5) M) on isoproterenol-induced relaxation responses were antagonized by treatment with methylene blue (10(-5) M) and oxyhemoglobin (10(-5) M).(ABSTRACT TRUNCATED AT 250 WORDS)

[Two cases of early Acanthamoeba keratitis].

Early Acanthamoeba keratitis was diagnosed in two soft contact lens wearers. Both patients had initially been diagnosed as having herpes simplex keratitis and treated with antiherpes drugs. In one patient, slit-lamp examination disclosed dendritiform epithelial keratitis, subepithelial opacities, linear stromal infiltrate along the corneal nerve (radial keratoneuritis), and marked swelling and hyperemia of the limbal conjunctiva. Acanthamoeba castellanii was cultured from the corneal scrapings and contact lens case. The second patient also showed dendritiform keratitis and subepithelial opacities, with swelling of the limbal conjunctiva. Cultures were positive for A. polyphaga from the contact lens case, but negative from the corneal scrapings. The patients were cured of Acanthamoeba keratitis with medical therapy consisting of topical fluconazole and miconazole, systemic fluconazole, and topical corticosteroids. Recognition of distinctive characteristics of the clinical findings in early Acanthamoeba keratitis can lead to the early diagnosis of the disease.

Impairment of endothelium-dependent relaxation of superior mesenteric artery in genetically diabetic WBN/Kob rats.

The endothelium-dependent relaxation of superior mesenteric arteries of Wistar and genetically diabetic WBN/Kob rats was compared. Endothelium-dependent relaxation induced by acetylcholine (ACh) and A23187 was depressed in WBN/Kob rats. Relaxation induced by sodium nitroprusside, an endothelium-independent agent, in strips from WBN/Kob rats was similar to that in strips from Wistar rats. Indomethacin (5 x 10(-6) M) enhanced the relaxation responses to ACh in strips from both WBN/Kob and Wistar rats; however, endothelium-dependent relaxation induced by ACh remained attenuated in WBN/Kob rats. These results show that endothelium-dependent relaxation is impaired not only in thoracic aorta but also in superior mesenteric arteries in genetically diabetic rats.

Effects of VA-045, a novel apovincaminic acid derivative, on isolated blood vessels: cerebroarterial selectivity.

We investigated the effects of VA-045, an apovincaminic acid derivative, on isolated blood vessels. VA-045 (10(-7)-10(-5) M) and vinpocetine (10(-7)-10(-5) M) inhibited the 64 mM KCl-induced and 10(-6)M norepinephrine (NE)-induced contraction of rat aortic strips. VA-045 (10(-7)-10(-4) M) and vinpocetine (10(-7)-10(-4) M) inhibited the activity of cyclic AMP and cyclic GMP phosphodiesterase in porcine coronary artery. VA-045 (3 x 10(-9-3 x 10(-6) M) relaxed the 64 mM KCl-induced contraction of the canine basilar artery without affecting the peripheral arteries. These results indicate that VA-045 selectively dilates canine cerebral artery, and that it may be a useful agent for the treatment of cerebrovascular diseases such as stroke.

Effects of CD-349 and 8-BrcGMP on isoproterenol-induced relaxation in rabbit aorta precontracted with endothelin-1.

We investigated the effects of CD-349, a dihydropyridine derivative, on isoproterenol (Iso)-induced relaxation in rabbit aorta precontracted with endothelin-1 (ET-1). The Iso (10(-8)-10(-5) M)-induced relaxation responses in rabbit aorta precontracted with 1-2 x 10(-7) M ET-1 were augmented by pretreatment with CD-349 (10(-9)-10(-5) M) in a concentration-dependent manner. The effects of CD-349 on Iso-induced relaxation of the aortic strips precontracted with ET-1 were inhibited by treatment with methylene blue (10(-5) M) and oxyhemoglobin (10(-5) M), whereas they were augmented by treatment with N omega-nitro-L-arginine (10(-4) M). The Iso-induced relaxation responses were also augmented by pretreatment with 8-Br-guanosine 3',5'-cyclic monophosphate (cGMP) (3 x 10(-6)-3 x 10(-4) M) in a concentration-dependent manner. However, nifedipine (10(-5) M) and nicardipine (10(-5) M) had no effect on Iso-induced relaxation responses of the aortic strips precontracted with 10(-7) M ET-1. CD-349 also augmented forskolin (10(-8)-10(-5) M)-induced relaxation responses of rabbit aorta in a concentration-dependent manner. CD-349 (10(-7)-10(-5) M) increased the levels of cGMP but not of adenosine 3',5'-cyclic monophosphate (cAMP) in a concentration-dependent manner in rabbit aorta without endothelium. Both CD-349 (10(-5) M) and 8-BrcGMP (3 x 10(-5) M) augmented the Iso-induced elevations of cAMP in rabbit aorta without endothelium. These results indicate that CD-349 and 8-BrcGMP can augment Iso-induced relaxation responses by enhancing the accumulation of cAMP.

Changes in responsiveness of the aorta to vasorelaxant agents in genetically diabetic rats: a study in WBN/Kob rats.

The effects of various vasorelaxant agents on aortas from control and genetically diabetic rats were examined. The concentration-response curves for the isoproterenol (ISO)-induced relaxation of both aortic strips with and without endothelium are shifted to the right in diabetic rats. The relaxation responses of diabetic aorta to forskolin and vasoactive intestinal peptide did not differ from those of controls. The relaxation responses of diabetic aorta to cromakalim and nicorandil did not differ from those of controls. These results indirectly indicate that ISO-induced relaxation responses of the aortic strips from genetically diabetic rats decreased, and that this decreased relaxation response of the strips to ISO may be due to decreased density or affinity of beta adrenoceptors on the endothelium and vascular smooth muscle.

Biological nature of Cryptosporidium sp. isolated from a cat.

A small type of Cryptosporidium oocysts was isolated from a naturally infected cat and its biological nature was investigated. In cats experimentally inoculated with Cryptosporidium oocysts, long-lasting shedding of the oocysts occurred after a prepatent period of 8-10 days, and a number of peaks of oocyst count appeared at intervals of several days to a few weeks, earlier in the infection course. Cryptosporidium infection in cats is likely to pass from an acute to a chronic stage. During the chronic stage, prednisolone injection into the cats gave rise to a recurrence of proliferation of the parasite along with a marked increase in the number of oocysts shed. None of the infected cats showed clinical symptoms. Infection experiments using Cryptosporidium oocysts were unsuccessful in several species of animals such as mice, rats, guinea pigs, dogs, suckling mice and mice previously injected with prednisolone or hydrocortisone.

Stage-specific response of preimplantation mouse embryos to W-7, a calmodulin antagonist.

Involvement of calmodulin-dependent processes in preimplantation development of mouse embryos was studied with the use of N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7), a specific antagonist of calmodulin. At 25 microM, W-7 interfered with compaction of eight-cell embryos, caused decompaction of compacted eight-cell embryos, inhibited cavitation of late morulae, and caused collapse and degeneration of blastocysts. These effects of W-7 appear to be due to specific inhibition of calmodulin-dependent processes, because W-5, a less active analogue of W-7, was less effective in interfering with development; at 25 microM, W-5 had only a slight effect on compaction and had no effect on blastocyst formation, maintenance of blastocoels, or post-blastocyst development. In addition to the developmental effects just described, W-7 inhibited cell proliferation in four-cell embryos and reduced cell numbers of morulae after treatment at the two- to eight-cell stages. There was a marked increase in embryos' sensitivity to W-7 at the late morula stage, and the sensitivity increased further as embryos developed into blastocysts; the effects of W-7 were largely reversible after treatment at the two-cell through the compacted eight-cell stages, but not after treatment at the late morula or blastocyst stage. At the blastocyst stage, inner cell mass cells appeared to be slightly more resistant to W-7 than trophectoderm cells. This differential sensitivity became more pronounced at the late blastocyst stage: after 3.5-4-h exposure of late blastocysts to 25 microM W-7, all trophectoderm cells degenerated but most of the inner cell masses survived. From these results it appears that calmodulin-dependent processes are involved in development of mouse embryos at all of the preimplantation stages examined.

Brain atrophy and cerebral infarction.

The subjects of the study (109 males, 48 females) were all diagnosed to have cerebral infarction by computerized tomography (CT). The cerebrospinal fluid (CSF) space volume and cranial cavity volume in the normal hemisphere of the patients were estimated using CT at the time from 1 to 3 weeks after the attack of cerebral infarction. The percentage of the CSF space volume to the cranial cavity volume was calculated as an indicator for brain atrophy and called brain atrophy index (BAI): BAI (%) = 100(%) X (CSF space volume/cranial cavity volume). The BAI immediately after the attack of infarction (6.6 +/- 2.2, n = 15), during which no detectable change occurred on CT examination, was the same as the BAI at the time from 1 to 332 days after the attack (6.6 +/- 2.4, n = 20). Therefore we compared the BAI in patients without infarction with the BAI in patients with infarction irrespective of secondary atrophy of the brain after the attack. The BAIs in males with infarction were significantly greater than the BAIs in males without infarction in the age of fifties, sixties and seventies. The BAIs in females with infarction were significantly greater than in females without infarction in the age of fifties, sixties and eighties.