Thrombomodulin Attenuates Inflammatory Damage Due to Liver Ischemia and Reperfusion Injury in Mice in Toll-Like Receptor 4-Dependent Manner.

Liver ischemia reperfusion injury (IRI) is an important problem in liver transplantation. Thrombomodulin (TM), an effective drug for disseminated intravascular coagulation, is also known to exhibit an anti-inflammatory effect through binding to the high-mobility group box 1 protein (HMGB-1) known as a proinflammatory mediator. We examined the effect of recombinant human TM (rTM) on a partial warm hepatic IRI model in wild-type (WT) and toll-like receptor 4 (TLR-4) KO mice focusing on the HMGB-1/TLR-4 axis. As in vitro experiments, peritoneal macrophages were stimulated with recombinant HMGB-1 protein. The rTM showed a protective effect on liver IRI. The rTM diminished the downstream signals of TLR-4 and also HMGB-1 expression in liver cells, as well as release of HMGB-1 from the liver. Interestingly, neither rTM treatment in vivo nor HMGB-1 treatment in vitro showed any effect on TLR-4 KO mice. Parallel in vitro studies have confirmed that rTM interfered with the interaction between HMGB-1 and TLR-4. Furthermore, the recombinant N-terminal lectin-like domain 1 (D1) subunit of TM (rTMD1) also ameliorated liver IRI to the same extent as whole rTM. Not only rTM but also rTMD1 might be a novel and useful medicine for liver transplantation. This is the first report clarifying that rTM ameliorates inflammation such as IRI in a TLR-4 pathway-dependent manner.

Both head extension and mouth opening impair the ability to swallow in the supine position.

Head position and mouth opening in the supine position may impair the ability to swallow. If this does occur, it would lead to retention of intra-oral fluids during dental treatment, which would lead to stimulation of the cough reflex. This study was conducted to investigate how head position and mouth opening affect swallowing ability. The water swallowing test was performed in 13 healthy adult subjects in the supine position. The subjects were asked to swallow 10 mL of water that was injected into the mouth in a single attempt. After swallowing, the residual intra-oral water was suctioned and its volume was measured. An electromyogram (EMG) of the suprahyoid (SH) muscles was also recorded during the test. The duration of SH muscle activity and peak amplitude of SH EMG were examined. The water swallowing test was performed under three head positions (neutral, extended and flexed) and four mouth opening patterns (interincisal distances of 0, 20, 30 and 40 mm). The wider the subject opened the mouth, the more the water remained in the mouth after swallowing. The residual volume of water was more in the extended position compared with that in the neutral and flexed positions. Peak amplitude of SH EMG decreased with mouth opening. Duration of SH muscle activity was longer in the extended position than in the neutral and flexed positions. Head extension and mouth opening can induce difficulty in swallowing in the supine position by extending the duration of SH muscle activity while reducing its intensity.

Prominent quasiparticle peak in the photoemission spectrum of the metallic phase of V2O3.

We present the first observation of a prominent quasiparticle peak in the photoemission spectrum of the metallic phase of V2O3 and report new spectral calculations that combine the local-density approximation with the dynamical mean-field theory (using quantum Monte Carlo simulations) to show the development of such a distinct peak with decreasing temperature. The experimental peak width and weight are significantly larger than in the theory.

A silver-containing halogen-free inorganic photochromic glass.

A halogen-free inorganic photochromic soda-lime silicate glass containing silver ions has been developed; reversible change between colorless and yellow color in this glass is achieved through combined 193 nm excimer laser irradiation and heat treatment.

Precise anatomic configuration changes in the first ray of the hallux valgus foot.

To detect precise anatomical configuration of the first ray in feet with hallux valgus, a two-dimensional coordinate system was devised for evaluation of a weight-bearing dorsoplantar radiograph. The radiographs, taken from 229 feet of 114 patients with symptomatic hallux valgus and 94 normal feet, were investigated. A comparative study showed the first metatarsal head of a foot with hallux valgus was located on the medial side of that of the normal foot and the base of the proximal phalanx of the hallux valgus foot was located on the same point of that of the normal foot. Lateral translation of the base of the proximal phalanx occurred only in cases with overlap toes. Our study shows that subluxation of the metatarsophalangeal joint in hallux valgus is primarily caused by metatarsus primus varus. This study indicated that first metatarsal osteotomies should be given the first priority in consideration for bunion surgery, because these procedures could move the first metatarsal heads laterally in a more normal position.

[Alpha 1-antitrypsin deficiency (Siiyama) with pulmonary emphysema].

A 44-year-old man was admitted to the hospital with dyspnea on exertion. Chest radiographs and pulmonary function tests showed evidence of pulmonary emphysema. Serum alpha 1-antitrypsin (alpha 1-AT) could not be detected by nephelometry, immuno-electrophoresis, or iso-electric focusing. However, allele-specific PCR revealed a genotype homozygotic for an alpha 1-AT deficient variant of the Siiyama allele. An elder sister of the proband was also a homozygous carrier of the Siiyama allele. The amino acid sequence for normal alpha 1-AT variants had been substituted by Arg101-Val213-Glu376 in the proband, demonstrating that the alpha 1-antitrypsin-deficient Siiyama variant in this pedigree was derived from M 1 (Val213).

Distribution and excretion of boron after intravenous administration of disodium mercaptoundecahydro-closo-dodecaborate to rats.

Disodium mercaptoundecahydro-closo-dodecaborate (BSH) is an important compound for boron neutron capture therapy. The pharmacokinetics of boron by BSH were studied in normal rats after rapid intravenous injection at three doses (30, 100, 300 mg/kg) or continuous infusion (100 mg/kg/30 min). The boron concentration in biological samples was measured by inductively coupled plasma atomic emission spectroscopy. The blood half-lives of boron in the elimination phase (t1/2 beta) after rapid injection of BSH at doses of 30, 100 and 300 mg/kg were 1.7, 17 and 19 hr, respectively. AUC (32, 219 and 4030 micrograms.hr/ml) increased with the dose, but there was no proportionality among the values. Total clearance decreased drastically from 233 ml/hr/kg (100 mg/kg) to 38 ml/hr/kg (300 mg/kg). As boron was excreted mainly into urine, these results suggest that renal function failure might occur with dosing of 300 mg/kg. In the case of continuous infusion of 100 mg/kg of BSH for 30 min, the pharmacokinetic parameters were similar to those of rapid injection of 100 mg/kg. The highest boron concentration was observed in the kidney and the lowest in the brain. After multiple dosing of BSH at 100 mg/kg/day x 14 days, the boron concentrations in blood, liver, lung and kidney at 24 hr after the last dosing were higher than those after single dosing and were similar to those of simulated values calculated from the single dosing parameters. These results clearly indicated that boron does not accumulate unexpectedly in any tissue with multiple dosing of 100 mg/kg of BSH for two weeks.

Disposition and metabolism of the new hypocholesterolemic compound S-8921 in rats and dogs.

S-8921 (methyl 1-(3,4-dimethoxyphenyl)-3-(3-ethylvaleryl)-4-hydroxy-6,7,8-trimeth oxy-2- naphthoate, CAS 151165-96-7) is a novel hypocholesterolemic agent which was found to inhibit ileal Na+/bile acid cotransporter. In this report, the pharmacokinetic profile of S-8921 was studied in rats and dogs. After dosing of 14C-S-8921 to rats at 1 to 25 mg/kg as 0.5% methylcellulose (MC) suspension, tmax was observed during 5-6 h, and AUCs increased with the dose, but not proportionally. The elimination half-lives were around 38-41 h for the doses examined. The apparent absorption ratio of 5 mg/kg of 14C-S-8921 as MC suspension was about 14%. Most of the radioactivity (98% of dose) was excreted into the feces and only 1-2% into the urine. Biliary excretion of radioactivity after dosing of 1, 5 or 25 mg/kg was 22, 20, 15%, respectively. Saturation of the absorption process was suggested. Even in case of intravenous dosing, about 88% was excreted into the bile. Enterohepatic circulation of biliary metabolites was also observed in rat. Its extent was small (6%), but, it may be contribute to the slow elimination of S-8921 from rat. The highest radioactivity was observed in the liver, with other tissues showing similar radioactivity profiles to that of plasma. The elimination half-lives of radioactivity from tissues were very long, e.g. 68 h for the liver and 58 h for the kidney. After 14 days multiple dosing, most tissues showed about two times higher radioactivity than that after a single dose. The simulation curves of liver and plasma showed a good fit with those of the observed values. These results suggested that there is no serious accumulation of radioactivity in tissues by multiple dosing of 14C-S-8921 in rats. The plasma radioactivity after oral dosing of 5 mg/kg of 14C-S-8921 to dogs as an MC suspension reached maximum concentration (c.a. 33 ng/ml) at 2 h, then decreased very slowly with a half-life of 169 h. The apparent absorption ratio was 4.6% for MC suspension. The excretion of radioactivity into bile, feces and urine after oral dosing of 14C-S-8921 at 5 mg/kg as an MC suspension were 3.0%, 94.6% and 0.3%, respectively. Even in the case of intravenous dosing, urinary excretion was very small (2.2%) and most of the radioactivity was excreted very slowly into the feces. The major metabolite of S-8921 in rat bile was its glucuronide. Other minor metabolites identified were the demethylated forms of 7-methoxy and 4'-methoxy moieties of S-8921. They were also excreted into bile as their glucuronides.

[Clinical evaluation on causes of death in patients with pulmonary tuberculosis who died within one year after diagnosing as TB].

We evaluated the cause of death in patients with pulmonary tuberculosis who died within one year after diagnosing as tuberculosis. Of 325 bacillary patients during the past seven years, 43 (13.2%) died within one year. Twenty-three patients (53.5%) died directly of tuberculosis. In this group, 13 patients died in emaciation state. Most of them were aged and under a poor nutritional condition. Some patients died in spite of improvement of tuberculosis. The fact indicates the need to detect tuberculosis as early as possible in elderly persons, and treatment should be initiated immediately. Eight patients died of respiratory failure and their chest X-ray film showed wade-spread tuberculosis. Seven of the patients died in spite of initiating treatment within one month after the onset of symptoms. This fact suggests the importance of regular check up by chest X-ray to detect tuberculosis early. Two patients died of massive hemoptysis. They had an episode of bloody sputum and the laboratory examination showed anemia. On the other hand, 20 patients died due to coexisting diseases unrelated to tuberculosis. Ten patients died of malignant diseases and most of them were lung cancer. Two patients died of hepatic failure possibly caused by the adverse reaction of TB chemotherapy. The interval between the onset of the treatment and death was less than a month, and the fact suggests the need to observe carefully for adverse reactions especially in the early stage of treatment.

[Conversion of chronic necrotizing pulmonary aspergillosis to invasive pulmonary aspergillosis, and successful treatment with fluconazole].

An 82-year-old man with rheumatoid arthritis was admitted to the hospital because of bloody sputum, appetite loss, and a chest-radiographic abnormality. He had previously been treated with oral steroid therapy. The chest X-ray film showed an infiltrative shadow with airlucency in the right upper lung field. Sputum culture for fungi was negative, but a test for aspergillus antigen in serum was positive. Other clinical findings were also compatible with conversion of chronic necrotizing pulmonary aspergillosis to invasive pulmonary aspergillosis. The patient was successfully treated with a drip infusion of fulconazole. The patients condition was stable for several months, after which he died due to uncontrollable atrial flutter. Mild immunosuppression due to oral steroid therapy probably caused chronic necrotizing pulmonary aspergillosis in this case. The patient's general condition worsened after admission and invasive pulmonary aspergillosis developed. This case taught us that therapy for chronic necrotizing pulmonary aspergillosis should include management of the patient's general condition as well as treatment of the pulmonary lesions.

[A case of acquired immunodeficiency syndrome with disseminated Mycobacterium avium complex infection in which M. avium was isolated from bone marrow].

A 46-year old man was admitted to a hospital because of cough and dyspnea. He was diagnosed as interstitial pneumonia and was treated with prednisolone (PSL) and antibiotics. The symptoms improved temporarily but he soon developed acute respiratory failure and was transferred to our hospital. Chest X-ray and CT revealed ground-glass opacities in both lung fields. He was treated with methyl PSL, antibiotics, and antimycobacterial drugs but he died on the fourth hospital day. Retrospectively, hematologic laboratory examinations revealed that CD4+ cell count was 0/microliter and serological tests for HIV were positive by both EIA and Western blot methods. The culture of the bone marrow specimens was positive for mycobacteria other than M. tuberculosis, and the bacilli were identified as Mycobacterium avium. Thus, his disease was eventually diagnosed as disseminated Mycobacterium avium complex (MAC) infection. In the past reports, the diagnosis of disseminated MAC infection was most often made by blood cultures, however, the isolation of MAC from bone marrow is another sensitive and specific method for the diagnosis of this infection. In some cases, bone marrow examination would be useful to diagnose disseminated MAC infection.

Ocular absorption, distribution, and systemic absorption of a novel antiglaucoma medication, prostaglandin derivative, in male white rabbits.

A prostaglandin derivative, (5Z,9 alpha,11 alpha,13E)-9,11-dihydroxyprosta- 5,13-dienoic acid sodium salt (S-1033), that lowers intraocular pressure with little adverse effect, may have clinical value in the treatment of glaucoma. After [14C]S-1033 (0.2% solution) was instilled into the eye of a white rabbit, radioactivity and S-1033 appeared in systemic plasma so rapidly (tmax, 5 min) and S-1033 was eliminated very rapidly with half-lives of 2.8 and 11.0 min at alpha- and beta-phases, respectively. The metabolite, M-1, [1R-[1 alpha,2 beta-(1E),3 alpha,5 alpha]]-3,5-dihydroxy-2-(1- octenyl)-cyclopentanepropanoic acid (tetranor-S-1033), appeared in plasma very rapidly (tmax, 5 min), suggesting that a fast metabolism was a major factor in the rapid elimination of S-1033 from plasma. The values for the ratios of the area under the curve of ocular instillation to intravenous administration for radioactivity and S-1033 were 1.01 and 0.52, respectively, indicating that more than half of the S-1033 instilled was transported into the systemic circulation. To clarify the contributing pathway of the massive and rapid systemic absorption of S-1033 after topical dosing, plasma levels of S-1033 were investigated after instillation to rabbits in which the nasolacrimal ducts were occluded. Plasma concentrations of S-1033 were slightly higher than those in intact rabbits, suggesting that conjunctiva would be as important as nasal mucosae for the systemic absorption under the physiological condition. As for the intraocular distribution, the highest levels of radioactivity were found in the cornea, conjunctiva, and anterior sclera.(ABSTRACT TRUNCATED AT 250 WORDS)

Stereoselective renal tubular secretion of an organic anion in the isolated perfused rat kidney.

To clarify the stereoselective renal tubular secretion of an organic anion, renal excretion of 5-dimethylsulfamoyl-6,7-dichloro-2,3-dihydrobenzofuran-2-carbox yli c acid (DBCA), a racemic compound, was studied with a single-pass perfused rat kidney preparation under constant perfusion pressure (ca. 120 mm Hg). The steady-state renal extraction ratio of (R)-(+)-DBCA (0.134) was 10 times higher than that of (S)-(-)-DBCA (0.015), indicating high selectivity for (R)-(+)-DBCA. The urinary excretion rate and renal excretory clearance (CLrex) were 4 times larger for (R)-(+)-DBCA, and the unbound fraction in the perfusate also was higher for (R)-(+)-DBCA (R/S = 1.58). Fractional excretion (FE) and intrinsic clearance for tubular secretion (CLrsec,int) were about 3 times larger for (R)-(+)-DBCA than the antipode, showing the stereoselectively predominant secretion of (R)-(+)-DBCA. The N-monodemethylated metabolite, M-1, was found only for the R-(+)-enantiomer in the perfusate and urine, revealing highly stereoselective N-monodemethylation in the kidney. The CLrsec,int value for (R)-(+)-M-1 was 2.5 times larger than that for (R)-(+)-DBCA. The perfusion study using each enantiomer decreased R/S ratios of the extraction ratio (9.9), urinary excretion rate (3.9) and excretory clearance (3.9) in the perfusion of the racemate to 3.9, 2.1 and 2.1, respectively. No significant difference was found between (R)-(+)- and (S)-(-)-DBCA in FE and Clrsec,int. The declined stereoselectivity in renal excretion parameters may be due to competitive inhibition of the tubular secretion of (R)-(+)-DBCA by the (R)-(+)-M-1 formed which possessed greater secretion ability in the (R)-(+)-DBCA perfusion study, whereas (S)-(-)-DBCA was secreted without great inhibition by (S)-(-)-M-1 in the (S)-(-)-DBCA perfusion because of a small amount of generated metabolite. Plotting of FE ratios of DBCA enantiomers to (R)-(+)-M-1 against FE of (R)-(+)-M-1 suggests that the actual FE for (R)-(+)-DBCA was 2 times larger than that for (S)-(-)-DBCA, and that (S)-(-)-DBCA secretion was inhibited more easily by (R)-(+)-M-1.

Early detection of diabetic nephropathy and criteria for the initiation of therapy.

In 86 patients with non-insulin-dependent diabetes mellitus who were negative for proteinuria by a test paper method, the albumin excretion rate was compared to the albumin/creatinine ratio, and a baseline albumin/creatinine ratio value was determined at which therapy to arrest the progression of nephropathy should be initiated. The albumin excretion rate, albumin/creatinine ratio, and urinary creatinine excretion were determined from urine samples obtained at outpatient visits. The reproducibility of time-restricted urine sampling was investigated using the creatinine excretion rate. The mean coefficient of variation was found to be 42%, and inaccurate urine sampling appeared to cause variation in the albumin excretion rate. A significant difference was evident between males and females in creatinine excretion (0.823 +/- 0.152 mg/min for males and 0.577 +/- 0.182 mg/min for females, p < 0.001). The baseline albumin/creatinine ratio value for initiating therapy was established to be 36 mg/g creatinine for males and 51 mg/g creatinine for females. Use of the albumin/creatinine ratio appears to provide a simple and valuable index for determining when to initiate therapy for diabetic nephropathy.

[A diabetic patient with empty sella syndrome accompanied by stimulated guanidinoacetic acid metabolism].

Since urinary guanidinoacetic acid (GAA) derives from the kidneys, its detection is suggested to be associated with renal disease. We have been making a practice of investigating renal GAA production in diabetic patients, using a citrulline/creatine loading test. We noted a marked increase in urinary GAA excretion in 1 patient. Since GAA-synthesis is hormonally regulated, we made a through investigation of endocrine function in this patient. She was a 58-year-old woman with a 15-year history of diabetes mellitus, proliferative diabetic retinopathy, and negative microalbuminuria. There was a high plasma GH level and urinary 17-KS analysis revealed an increase in the adrenal androgen-derived fractions. Based on the X-ray finding of ballooning of the sella turcica and the MRI data, empty sella syndrome was diagnosed. It was suggested that stimulated anabolic hormone release had accelerated renal nitrogen metabolism and induced aggravation of her retinopathy. The findings in this patient implied the involvement of hormones in the development of diabetic complications.

Stereoselective pharmacokinetics of a novel uricosuric antihypertensive diuretic in rats: pharmacokinetic interaction between enantiomers.

5-Dimethylsulfamoyl-6,7-dichloro-2,3-dihydrobenzofuran-2-carboxyli c acid (DBCA), a promising uricosuric, diuretic, and antihypertensive agent, was administered intravenously to rats. The levels of DBCA in plasma and the areas under the curve of concentration versus time (AUC values) of the S(-)-enantiomer were higher than those of the R(+)-enantiomer. Total body clearance was significantly greater for the R(+)-enantiomer. This stereoselective elimination was due to a difference in the nonrenal clearance, which seemed to reflect hepatic metabolism or biliary excretion. Hepatic metabolism seemed more likely because AUC and the amount of urinary excretion of the N-monodemethylated metabolite of DBCA were greater for the R(+)-enantiomer. The plasma had higher free fractions of the S(-)-enantiomer, a result suggesting that this enantiomer is distributed more readily to the tissues, including the liver. This result indicates that protein binding was not responsible for the stereoselective metabolism of (R)-(+)-DBCA. Although there was no difference in the renal clearances of the enantiomers, the renal clearance of free (R)-(+)-DBCA exceeded that of the S(-)-enantiomer, a result indicating the preferential excretion of the R(+)-enantiomer into the urine. Comparison of the pharmacokinetics of individual enantiomers after intravenous administration of each enantiomer or its racemate showed that the enantiomers interact with one another; dosing with racemate delayed the elimination of each enantiomer because of mutual inhibition of hepatic metabolism and renal excretion for (R)-(+)-DBCA and of renal excretion for (S)-(-)-DBCA.

Clinical test of renal guanidinoacetic acid metabolism by oral citrulline and creatine loading.

We devised a clinical test of renal metabolism based on the synthesis of guanidinoacetic acid from citrulline in the proximal convoluted tubule. Intravenous administration of a citrulline/creatine solution to rats with modified levels of renal glycine amidinotransferase activity revealed a strong correlation (r = 0.921) between this activity and urinary guanidinoacetic acid excretion. Citrulline (1.75 g) and creatine (1.50 g) were administered orally to healthy individuals and patients with chronic glomerulonephritis. In the healthy individuals, urinary guanidinoacetic acid excretion increased 5-fold by 2 h after dosing (15.1 +/- 2.2 vs. 2.8 +/- 1.1 mg/h). In the glomerulonephritis patients, blood clearance of citrulline decreased as the creatinine clearance decreased and urinary guanidinoacetic acid excretion also decreased. Of 56 patients with glomerulonephritis or diabetes mellitus, one had increased urinary guanidinoacetic acid excretion associated with an excess of adrenal androgens. This test appears a useful, noninvasive and simple method for examining the metabolic activity of the renal proximal convoluted tubules.

Platelet free Ca2+ concentration in non-insulin-dependent diabetes mellitus.

We made serial measurements of the platelet intracellular free calcium concentration in 167 patients with non-insulin-dependent diabetes mellitus (77 males and 90 females) over a two-year period, and investigated the relationship between this parameter and diabetic angiopathy. We measured both the basal and thrombin-stimulated platelet free calcium concentrations using fura-2/AM as a fluorescent indicator. The patients were grouped according to the severity of nephropathy, retinopathy, and hypertension and their hemoglobin A1c levels. The basal platelet calcium level of the diabetic patients was higher than that of a healthy control group. There were high levels in the patients with mild nephropathy and retinopathy, but low levels in those with severe disease, and the platelet calcium level reflected the degree of progression of diabetic angiopathy. Stimulated platelet calcium varied with the progression of nephropathy, being highest in early nephropathy and lowest after proteinuria developed. Our findings suggested that abnormalities of calcium handling may be related to the onset of diabetic vascular complications, especially diabetic nephropathy.