Argatroban more effectively inhibits the thrombin activity in synovial fluid than naturally occurring thrombin inhibitors.

The purpose of this study was to clarify the precise effect of argatroban on the inhibition of cytokine secretion induced by thrombin on synovial cells. The efficiency of thrombin inactivation by thrombin inhibitors was evaluated in human synovial fluids (SFs). In SFs from 13 osteoarthritis (OA) and 11 rheumatoid arthritis (RA) patients, thrombin, Factor Xa (FXa), plasmin activity, IL-6, MMP-3, VEGF, and D-dimer concentrations were measured. Tissue factor (TF) activity or IL-6, MMP-3, and VEGF secretion of human synovial cells with or without thrombin and argatroban were measured. The efficiency of thrombin inactivation in SFs was compared for thrombin inhibitors: argatroban, antithrombin III (ATIII), or heparin cofactor II (HCII). In SFs, thrombin, FXa, plasmin, D-dimer, IL-6, and MMP-3 were significantly higher in RA than in OA. In synovial cell experiments, TNF-alpha and thrombin enhanced TF activity on the cell surface, and IL-6, MMP-3, and VEGF secretion were enhanced by thrombin. Increased TF activity, and IL-6, MMP-3, and VEGF secretion induced by thrombin were inhibited by argatroban. In SFs, argatroban inactivated thrombin more effectively than ATIII or HCII. Since thrombin plays an important role in the disease activity of OA and RA, it is a potential therapeutic molecular target. Argatroban was the most effective anticoagulant to inhibit thrombin activity in SF. Intra-articular injection is ideal administration because it can deliver high dose of argatroban without high risk of systematic complication.

Study on an antibody against F1F2 fragment of human factor V in a patient with Hashimoto's disease and bullous pemphigoid.

We found a 81-year-old man with Hashimoto's disease and bullous pemphigoid whose activated partial thromboplastin time (APTT) and prothrombin time (PT) were prolonged. Mixing studies with normal plasma failed to correct APTT and PT, suggesting the presence of circulating inhibitor. The patient's factor V activity was 11% of normal control and was not corrected by mixing with normal plasma, indicating the presence of an inhibitor against factor V. This inhibitory activity was observed up to 32 times dilution of the patient's plasma. The inhibitor activity against factor V was not detected in the fraction of the patient's plasma that passed through Protein A Sepharose, but detected in the elution with glycine-HCl buffer. Furthermore, using SDS-PAGE and immunoblotting method, purified IgG from the patient's plasma reacted with a protein with molecular weight (74KD) equivalent to F1F2 of factor Va which was activated by thrombin. The inhibitory activity was associated with IgG4 subclass. These data indicate that the inhibitor was IgG antibody which inhibit F1F2 of factor V. Autoimmune mechanism was strongly suggested for the development of the antibody.

Radiosurgery-induced brain tumor. Case report.

The authors describe a case of glioblastoma multiforme (GBM) associated with previous gamma knife radiosurgery for a cerebral arteriovenous malformation (AVM). A 14-year-old boy had undergone radiosurgery for an AVM, which was performed using a 201-source 60Co gamma knife system at another institution. The maximum and margin radiation doses used in the procedure were 40 and 20 Gy, respectively. One year after radiosurgery, the patient noticed onset of mild left hemiparesis due to radiation necrosis. Six and one-half years after radiosurgery, at the age of 20 years, the patient experienced an attack of generalized tonic-clonic seizure. Magnetic resonance (MR) imaging revealed the existence of a brain tumor in the right parietal lobe. The patient underwent an operation and the histological diagnosis of the lesion was GBM. Ten months following the operation, that is, 99 months postradiosurgery, this patient died. To the best of the authors' knowledge, this is the first reported case of a neoplasm induced by radiosurgery for an AVM and the second case in which it occurred following radiosurgery for intracranial disease.

Spinal intramedullary ependymal cyst: a case report.

BACKGROUND: Spinal intramedullary ependymal cysts are extremely rare. Only seven pathologically proven cases have been reported in the literature. METHOD: We present an 18-month-old female with thoracic spinal intramedullary ependymal cyst that was diagnosed pathologically. RESULTS: Histological diagnosis was made by light microscopy after immunostaining. After partially removing the cyst wall and establishing communication between the cyst and the subarachnoid space, the patient improved neurologically. CONCLUSIONS: For spinal intramedullary ependymal cyst we recommend diagnosis by MR imaging without myelography, then enucleation of the cyst, if possible. Otherwise, we remove the cyst wall as much as possible and create adequate communication between the cyst and the subarachnoid space.

Secretion of tears in patients with hemifacial spasm.

Hemifacial spasm can cause abnormal tear secretion on the affected side. Thirty patients with this disease were examined using the Schirmer's test without topical anesthetic. Twelve of them showed more tear secretion on the affected side than on the unaffected side. The average Schirmer test value was 30.4 +/- 12.3 mm (+/- SD) on the affected side in the patients and 17.4 +/- 10.9 mm (n = 148) in the control subjects (P less than 0.001). Microvascular decompression surgery reduced the hypersecretion of tears. The results suggest that compression of the facial nerve by a blood vessel causes an excitatory stimulus for tear secretion in patients with hemifacial spasm.

[Light and electron microscopic study of orbital cavernous hemangioma].

We examined the specimens of tumors from three patients with orbital cavernous hemangioma by light and electron microscopy. The tumors mostly consisted of many vessels of various sizes. A part of the tumor tissues showed irregular vascular inner spaces like sinusoids. Apart from the sinusoid-like vessels, we divided the other vessels into 10 groups at every 100 microns-interval based on the difference of the inner diameter and measured the maximum and minimum width of the media. The average maximum width increased until the inner diameter reached 300-400 microns, while the average minimum width increased until it reached 200-300 microns. In groups with greater inner diameter, the average maximum and average minimum widths were approximately constant. There were three kinds of vessels: vessels of cuboid endothelia, of flat endothelia, and of both cuboid and flat endothelia. The width of media of the vessels having cuboid and flat endothelia was greater than that of the other types of vessels. The lamina densa of endothelia was broken or stratified. Myofibroblast-like cells proliferated among the vessels and could not be distinguished from tumor cells of hemangiopericytoma. These results indicate that smooth muscle cells proliferate by an unknown mechanism and proliferation is associated with changes of endothelia in cavernous hemangioma, and strongly suggest that this tumor is hamartoma.

[The effect of C 1 esterase inhibitor on ischemia: reperfusion injury in the rat brain].

BACKGROUND: Despite the current interest in thrombolytic therapy for acute stroke, ischemia-reperfusion injury remains a potentially hazardous complication. The complement system is thought to play a major role in initiating some of the inflammatory events occurring in the reperfusion injury. This study was conducted to explore the effect of C 1 esterase inhibitor (C 1 INH) on the reperfusion injury in rat middle cerebral artery (MCA) occlusion-reperfusion model. METHODS: Twenty-nine male Wistar rats were used. Intraluminal MCA occlusion was performed for 60 minutes. Just before the reperfusion, C 1 INH(50 IU/kg, C 1 INH group, n = 15) or saline (control group, n = 14) was administrated. Forty-eight hours after the reperfusion, infarct volume and myeloperoxidase(MPO) activity of the brain were evaluated. RESULT: Infarct volume and MPO activity were significantly smaller in the C 1 INH group(86.5 +/- 76.8 mm3, 0.38 +/- 0.30 U/g) than in control group(179 +/- 92.8 mm3, 1.37 +/- 0.46 U/g) (p < 0.01). CONCLUSION: The results of this study provided the first evidence that C 1 INH reduced polymorphonuclear leukocytes(PMN) accumulation and reperfusion damage in the brain.

[A case report of long-term survival in advanced gastric cancer with multiple liver metastases treated with mitomycin C and tegafur therapy after palliative gastrectomy].

A 64-year-old male with advanced gastric cancer with multiple liver metastasis was treated with intensive chemotherapy including mitomycin C and tegafur after palliative gastrectomy. The patient was medicated with 30 mg iv of mitomycin C after surgery and 1,000 mg ir or 1,200 mg po of tegafur for one year for induction therapy and 400-600 mg po of tegafur for long-term maintenance therapy. All metastatic lesions in liver were completely eliminated three years after the start of treatment. As to acute and chronic toxicity, slight leukopenia was noted in the treatment, but the patient was found to show a good quality of life because of less toxicity. The patient has been healthy with no evidence of malignancy at nine years and nine months after the surgery. The total cumulative dose of tegafur in this treatment was 1,141.0 g, which is probably the largest dose ever reported in Japan, suggesting that the combination of mitomycin C and tegafur is indicated as a modality for advanced gastric cancer with liver metastasis.

[Effect of bisoprolol, a beta 1-selective beta-blocker, on lipid and glucose metabolism and quality of life in elderly patients with essential hypertension].

The present study investigated the effect of bisoprolol, a beta 1-selective beta-blocker without intrinsic sympathomimetic activity (ISA), on lipid and glucose metabolism and quality of life (QOL) in elderly patients with essential hypertention. Bisoprolol at doses of 5-10 mg was administered once daily for 12 weeks to 60 non-elderly and 21 elderly outpatients with mild to moderate essential hypertension. In both groups bisoprolol significantly decreased both systolic and diastolic blood pressures and significantly reduced pulse rates to the same extent. The levels of serum cholesterol, HDL-cholesterol and triglyceride, and the response of plasma glucose and insulin to 75 g oral glucose load, were not changed in either group by the bisoprolol treatment. Bisoprolol significantly improved QOL in both groups. Bradycardia, a side effect attributable to bisoprolol, was noted in only one patient in the elderly group. These results suggest that bisoprolol is a safe and useful antihypertensive drug in elderly and non-elderly patients with essential hypertension.

[Dilator naris activity in relation to obstructive sleep apnea].

We evaluated the activity of dilator nasalis+ EMG (Electro-Myo-Graphy) and submental EMG during sleep in three patients with obstructive sleep apnea syndrome. Both EMG activities involved periodic changes which proved to be correlated with each other (r = 0.85). Apnea and hypopnea episodes always occurred at the nadir of these periodic changes. The activity of dilator nasalis+ EMG, as well as submental EMG, at the nadir of these periodic changes was significantly lower during REM (Rapid Eye Movement) sleep than non-REM sleep and also significantly lower during severe airway obstruction accompanied by paradoxical movements of thorax and abdomen. The correlation of this EMG activity with SaO2 or the duration of obstructive apnea was more remarkable in submental EMG than dilator nasalis+ EMG in the observed patients.

[Tonsillectomy and osteoarthritic disease].

We investigated the clinical outcome of tonsillectomy in 89 cases out of 100 cases of sternocostoclavicular hyperosteosis (SCCH) and 18 cases of rheumatoid arthritis (RA) who went through the operation more than 3 months before in our hospital between April 1984 and May 1993. The effect of tonsillectomy was associated with a decrease in the degree of pain. The symptom improvement was defined as a degree of pain less than 50% of the pre-operative level. The rates of improvement were 80.9% (72/89) in SCCH and 66.7% (12/18) in RA, whole 79% of SCCH patients had pustulosis palmaris et plantaris, a known focal infection of the tonsil. Eight of nine (88.9%) patients and eleven of 13 (84.6%) patients who were positive for the tonsillar provocation test and the annulation test, respectively, showed improved SCCH postoperatively. These results suggest that focal infection of the tonsil may be one of the etiologies of SCCH and RA.

[Effects of uvulopalatopharyngoplasty in adult patients with obstructive sleep apnea syndrome].

We performed uvulopalatopharyngoplasty (UPPP) in 51 adult patients with obstructive sleep apnea syndrome (OSAS). After UPPP, there were statistically significant improvements in apnea-hypopnea index (AHI), the lowest value of oxygen saturation during sleep and total time of apnic episodes. 28 patients (54.9%) were good responders who represented more than 50% improvements in their AHI. Poor responders tended to be more severe and older than good responders. After cephalometric analysis, poor responders were revealed to show significantly poor mandibular prognatism and also lower positioned hyoid bone than good responders.

[A case of right atrial myxoma--the availability of transesophageal echocardiography in the detection of right atrial myxoma].

A 72-year-old woman had experienced palpitation and fatigue during exertion for two months and was referred to our hospital from her nearby hospital. On physical examination, a systolic murmur was heard in the left fourth intercostal space. A chest X-ray film showed cardiac enlargement (CTR 64%). An ECG showed elevated P waves in leads II, III. Transthoracic echocardiography revealed a large oval heterogeneous mass in the right atrium. Transesophageal echocardiography (TEE) revealed the right atrial mass clearly, which was attached to the atrial septum with a short wide stalk. This mass prolapsed from the right atrium into the right ventricle in diastole. And there were some cysts in the homogeneous high-echoic lesion. The chest CT and MRI also showed the mass in the right atrium. However, these images were not clear. Surgical excision of the mass was undertaken. A solid mass measuring 75 x 50 x 45 mm was attached to the fossa ovalis with a wide short stalk. There were several cysts in the mass. Pathological examination showed myxomatous tissue. In this case, TEE was the most valuable means for evaluation of the right atrial mass.

Regulatory mechanisms of C4b-binding protein (C4BP)alpha and beta expression in rat hepatocytes by lipopolysaccharide and interleukin-6.

BACKGROUND: C4b-binding protein (C4BP), a multimeric protein structurally composed of alpha chains (C4BPalpha) and a beta chain (C4BPbeta), regulates the anticoagulant activity of protein S (PS). Patients with sepsis have increased levels of plasma C4BP, which appears to be induced by interleukin (IL)-6. However, it is not fully understood how lipopolysaccharide (LPS) and IL-6 affect the plasma C4BP antigen level and C4BPalpha and C4BPbeta expression in hepatocytes. OBJECTIVES: To assess the effect of LPS and IL-6 on plasma C4BP, PS-C4BP complex levels, PS activity, and C4BP expression by rat liver in vivo and on C4BP expression by isolated rat hepatocytes in vitro. RESULTS: Plasma C4BP antigen level transiently decreased from 2 to 12 h after LPS (2 mg kg(-1)) injection, and then it abruptly increased up to 24 h after LPS injection. Plasma C4BP antigen level increased until 8 h after IL-6 (10 microg kg(-1)) injection, and then gradually decreased up to 24 h after IL-6 injection. LPS significantly decreased the protein and mRNA expression of both C4BPalpha and C4BPbeta in rat hepatocytes, and this effect was inhibited by NFkappaB and MEK/ERK inhibitors. IL-6 mediated increase in C4BPbeta expression in rat hepatocytes, which leads to increased plasma PS-C4BP complex level and to decreased plasma PS activity, was inhibited by inhibition of STAT-3. CONCLUSION: LPS decreases both C4BPalpha and C4BPbeta expression via the NFkappaB and MEK/ERK pathways, whereas IL-6 specifically increases C4BPbeta expression via the STAT-3 pathway, causing an increase in plasma PS-C4BP complex, and thus decreasing the anticoagulant activity of PS.

Hemocytes release phenoloxidase upon contact reaction, an allogeneic interaction, in the ascidian Halocynthia roretzi.

Contact reaction is the morphological expression of allogeneic recognition by hemocytes in the ascidian, Halocynthia roretzi; namely they undergo an exocytotic burst upon contact with non-self (allogeneic) hemocytes in vitro. We have found that contact reaction is accompanied by a burst of cyanide-insensitive oxygen consumption that, unlike exocytotic events of mammalian phagocytes, is Ca(2+)-dependent and does not culminate in the production of superoxide anions or H2O2. Instead, the burst is due to the release of phenoloxidase from hemocytes as known for the self-defense systems in insects and crustaceans. The activity of phenoloxidase released from hemocytes corresponds well to the degree of contact reaction observed under the microscope. Therefore, it is possible to quantify the contact reaction simply by measuring the activity of phenoloxidase released from hemocytes into the medium.

A gating 31P NMR method triggered by pulses for cardiac pacing.

A new gating NMR technique triggered by pulses for the cardiac pacing of isolated, perfused rat heart is described. This technique is suitable for obtaining spectra at the same positions over the cardiac cycle with the same RF pulse repetition time and with constant heart rate. Accordingly, each recovered magnetization level at these positions during the cycle can be kept constant. It also allows a qualitative analysis of the myocardial energy level during the cycle under the condition of the same or different cardiac workload (rate pressure product, HR x LVP). This method was used to observe cyclical changes in the concentration of adenosine triphosphate (ATP), phosphocreatine (PCr), P(i), and in pH during the cardiac cycle, and confirmed that the levels of ATP and PCr showed reversible decreases, and P(i) showed an antiphasic increase at the peak systole. On the other hand, no significant changes in pH were noted during the cardiac cycle. This pacing-gated technique is an improvement over other gated NMR techniques triggered by the blood pressure or by ECG traces.

[Magnesium deficiency dermatitis--changes in leukotriene levels and effects of azelastine hydrochloride on the dermatitis and leukotriene B4].

To estimate the pathogenesis of magnesium deficiency dermatitis (MDD) in the hairless rats fed with a hypomagnesic diet, plasma concentrations of leukotrienes (LTB4, LTC4, LTD4) were measured. Inhibitory effect of azelastine hydrochloride (AZ), which is known as an inhibitor of 5-lipoxygenase, on MDD was also evaluated. In the hairless rats with magnesium deficiency condition, plasma level of leukotriene B4 was increased, whereas LTC4 and LTD4 showed no changes. In AZ-administered rats, MDD was depressed with the dose-dependent tendency. However, the decrease of LTB4 level did not follow therapeutic effect of AZ for gross appearance of dermatitis. These results indicated that development of MDD associates with increase of LTB4, but its pathogenetic role still remains unknown, and inhibitory effect of AZ against MDD not based on reduction of LTB4 production.

Natural UAG suppressor glutamine tRNA is elevated in mouse cells infected with Moloney murine leukemia virus.

Two species of glutamine tRNA were isolated from mouse liver and their nucleotide sequences were determined. The minor glutamine tRNA(tRNA(UmUGGln)) that possesses UmUG (where Um stands for 2'-O-methyluridine) as the anticodon sequence was found to have suppressor activity for the UAG termination codon of tobacco mosaic virus RNA in a rabbit reticulocyte in vitro translation system. The amount of this suppressor glutamine tRNA in mouse liver was 1-2% of the amount of the major glutamine tRNA(tRNA(CUGGln)) that has the CUG anticodon sequence, but it was markedly increased in NIH 3T3 cells infected with Moloney murine leukemia virus and in Ehrlich ascites cells. These results support the hypothesis that tRNA(UmUGGln) actually functions in vivo as a suppressor tRNA that recognizes the UAG termination codon located at the gag-pol gene junction of Moloney murine leukemia virus and results in the synthesis of the virus-encoded protease.

Metal-inducible activities of metallothionein promoters in fish cells and fry.

Activities of trout metallothionein-A promoter and mouse metallothionein-I promoter in fish cells and fry were examined using the chloramphenicol acetyltransferase (CAT) gene as a reporter. Transfection and transient CAT assays on a trout liver cell line indicated that both promoters were inducible by metals, including zinc. In vivo activities of both promoters were examined using microinjection system into medaka eggs. Some of the hatched fry were exposed to zinc and their CAT activities were assayed. Both promoters revealed considerable activities after exposure to zinc while only weak activities were detected in unexposed fry.