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Liposomes are micro-compartments made of lipid bilayer membranes withcharacteristics quite similar to those of biological membranes. To formartificial cell-like structures, we generated liposomes that containedsubunit proteins of cytoskeletons: tubulin or actin. Spherical liposomeswere transformed into bipolar or cell-like shapes by mechanical forcesgenerated by the polymerization of encapsulated subunits of microtubules.Disk- or dumbbell-shaped liposomes were developed by the polymerizationof encapsulated actin. Dynamic processes of morphological transformationsof liposomes were visualized by high intensity dark-field lightmicroscopy.Topological changes, such as fusion and division of membrane vesicles,play an essential role in cellular activities. To investigate themechanism of these processes, we visualized in real time the liposomesundergoing topological transformation. A variety of novel topologicaltransformations were found, including the opening-up of liposomes and thedirect expulsion of inner vesicles.

To assess the efficacy of ultrasound (US)-guided percutaneous acetic acid (in concentrations of 15%, 20%, 30%, 40%, and 50%) injection for small hepatocellular carcinomas (HCCs) for long-term prognosis, percutaneous acetic acid injection using 15% to 50% acetic acid was performed in 91 patients with one to four HCCs smaller than 3 cm during the past 6.5 years. During the series of treatment sessions for each patient, the same concentration of acetic acid was used. All tumors could be treated successfully with percutaneous acetic acid injection despite the differences in acetic acid concentration used. The number of treatment sessions to treat similar size of tumor was less when the higher concentration of acetic acid was used. No serious complications occurred as a direct sequela to percutaneous acetic acid injection. None of the tumor treated regrew. The 1-, 2-, 3-, 4-, and 5-year survival rates for 91 patients were 95%, 87%, 80%, 63%, and 49%, respectively. The 1-, 2-, 3-, 4-, and 5-year cancer-free survival rates of these patients were 83%, 54%, 50%, 37%, and 29%, respectively. Both liver function and size of tumor affected both survival rate and cancer-free survival rate significantly, but the number of tumors did not. The concentration of acetic acid did not affect the survival rate. Percutaneous acetic acid using 15% to 50% acetic acid will be effective therapy for small HCCs for long-term prognosis.

The continuous ECAP process which can provide three-dimensional strain was developed in this study. A die with tri-axis crossed channels having channel angle φ of 90° and curvature ψ of 0° was created. As a result, continuous ECAP process via route Bc for AC4CH aluminium semi-solid alloy could be performed at 573K at pressing speed of 0.5mm/sec using the developed die. The continuous method cut the processing time in half compared to the non-continuously conventional method. The grains became fine from 100μm to approximately 2μm. Workpiece processed 8 passes exhibited four times higher toughness than as-cast alloy.

It is usually difficult to distinguish between idiopathic Parkinson's disease (PD) and parkinsonian-type multiple system atrophy (MSA-P) in the early stage. However, it is important to make a careful early-stage diagnosis. Therefore, we determined whether an examination of pelvic organ dysfunction would be helpful to distinguish between PD and MSA-P.We recruited 61 patients with PD and 54 patients with MSA-P who were examined at our neurology clinic. The mean ages of the patients with PD and MSA-P were 67 and 64 years, respectively. The mean disease duration of both groups was 3.2 years. We administered a questionnaire on pelvic organ dysfunction to the PD and MSA-P groups. The questionnaire had sections focusing on bladder, bowel, and sexual function. Dysfunction, as described in the responses, was evaluated as normal, mild (once a month), moderate (once a week), or severe (once a day). The Mann-Whitney U-test was used for statistical analysis.Compared with the PD group, the prevalence and severity of pelvic dysfunction in the MSA-P group was significantly higher for urinary urgency (MSA-P 76%, PD 58%, P0.05), retardation in initiating urination (79%, 48%, P0.05), prolongation in urination (79%, 72%, P0.05), and constipation (58%, 31%, P0.05). The quality-of-life index among pelvic organ dysfunctions indicated that urinary and bowel function was significantly more impaired in the MSA-P group than in the PD group.Urinary urgency, retardation in initiating urination, prolongation in urination, and constipation are more prevalent and severe in MSA-P compared to PD.

Chromosomal instability (CIN) has been recognized as a hallmark of human cancer and is caused by continuous chromosome missegregation during mitosis. Proper chromosome segregation requires a physical connection between spindle microtubules and centromeric DNA and this attachment occurs at proteinaceous structures called kinetochore. Thus, defect in kinetochore function is a candidate source for CIN and the generation of aneuploidy. Recently, a number of kinetochore components have been shown to be mutated and/or aberrantly expressed in human cancers, which suggests an important role of kinetochore for CIN and carcinogenesis. In this article, we will discuss about how kinetochore dysfunction causes CIN and might lead to the development of cancer.

It is important to clarify the molecular mechanisms of physiological responses of the human body to changes in gravity. Previous reports demonstrated that gravity-changing stress increases the human urinary concentration of 8-hydroxy-2'-deoxyguanosine (8-OHdG). However, it has yet to be clarified whether repetitive parabolic flight modulates the urinary concentration of 8-OHdG after exposure to gravity-changing stress. In the present study, the effects of the number of previous experiences with parabolic flight on urinary excretion of 8-OHdG and concentration of serum ACTH were examined in 12 healthy volunteers.

A retrospective case-control study was performed with TB patients who were admitted to our hospital over the two years from Jan. 1997 to Dec. 1998 and healthy men who underwent a health screening in April 2000 in the same hospital. Thirty-two non-homeless TB patients (the first control group) and 32 healthy men (the second control group) were matched with 32 homeless TB patients according to age. All 3 groups were male. Total protein, albumin, cholesterol, cholinesterase, hemoglobin level and lymphocyte count on admission were significantly lower in the homeless patients than in the non-homeless patients and healthy men. Albumin, cholesterol, cholinesterase, hemoglobin level, white blood cell count and lymphocyte count on admission were significantly lower in non-homeless patients than healthy men. Height, weight and body mass index were significantly lower in the homeless patients than in the healthy men. However, there were no significant differences in these body characteristics between the homeless and non-homeless patients. Twenty-five percent of homeless patients died during hospitalization, compared with 6.3 percent of non-homeless patients. Lymphocyte counts among homeless patients who died during hospitalization were significantly lower than among those who survived during hospitalization. Total protein, albumin, cholesterol, cholinesterase, hemoglobin level and weight were lower in patients who died than in those who survived, although the differences were statistically not significant.

Terminal warm blood cardioplegia, "Hot shot", is the method for providing an energy replenishment and/or early recovery of aerobic metabolism without electromechanical activity at initial reperfusion. The mechanism of beneficial effects of this Hot Shot is multifactorial. This study was designed to assess the effects of terminal warm blood cardioplegia by comparing with oxygenated terminal warm crystalloid cardioplegia.In Group HS-B, n=8 (oxygenated blood; 37 degrees C, Ht: 20%, K+ 20 mEq/l, pH 7.237, PO2 219 mmHg) and in Group HS-C, n=8 (bloodless oxygenated (5% CO2+95%O2) crystalloid, 37 degrees C, K+ 20 mEq/l, pH 7.435, PO2 624 mmHg), terminal warm cardioplegia (20 ml/kg for 5 minutes) was studied in the isolated blood perfused neonatal lamb heart following 2 hr of cardioplegic ischemia. Another eight hearts served as control without any kind of terminal cardioplegia. After 60 min of reperfusion, LV function was measured. Coronary blood flow (CBF), oxygen content, and oxygen consumption (MVO2) were measured and the oxygen extraction ratio was calculated in Group HS-B and HS-C during terminal cardioplegia and/or reperfusion. Results are given as % recovery of preischemic values.HS-B as well as HS-C groups showed better functional recovery in maximum developed pressure (DP: 78.0+/-8.3 in HS-B vs 65.2+/-9.2%; p=0.018), maximum dp/dt (67.3+/-6.2 in HS-B, 65.3+/-7.4 in HS-C vs 55.8+/-5.0%; p=0.003, p=0.02), DP V10 (87.1+/-8.5 in HS-B vs 67.2+/-9.9%; p=0.0001), and peak dp/dt V10 (76.4+/-7.6 in HS-B, 69.8+/-8.1 in HS-C vs 58.6+/-6.9 %; p=0.0001) than the control group. Between the HS-B and HS-C groups, HS-B showed better functional recovery in terms of DP V10 (p=0.01). Oxygen delivery of terminal cardioplegia was almost four times higher in HS-B group (90.4+/-17.7 vs 18.7+/-1.1 mcl/ml), contrarily, HS-C group showed four times higher oxygen extraction ratio compared to HS-B group (0.78+/-0.06 vs 0.18+/-0.11), thus oxygen consumption during hot shot was maintained at the same level in both groups. CBF in the control group was lower than that in the other groups at 60 min of reperfusion.Reperfusion with both terminal warm cardioplegia including blood and oxygenated crystalloid cardioplegia resulted in better recovery of function and higher levels of CBF with slightly better function in terminal warm blood cardioplegia.

IkappaB kinase (IKK) alpha and beta phosphorylate IkappaB proteins and activate the transcription factor, nuclear factor (NF)-kappaB. Although both are highly homologous kinases, gene targeting experiments revealed their differential roles in vivo. IKKalpha is involved in skin and limb morphogenesis, whereas IKKbeta is essential for cytokine signaling. To elucidate in vivo roles of IKKalpha in hematopoietic cells, we have generated bone marrow chimeras by transferring control and IKKalpha-deficient fetal liver cells. The mature B cell population was decreased in IKKalpha(-/-) chimeras. IKKalpha(-/-) chimeras also exhibited a decrease of serum immunoglobulin basal level and impaired antigen-specific immune responses. Histologically, they also manifested marked disruption of germinal center formation and splenic microarchitectures that depend on mature B cells. IKKalpha(-/-) B cells not only showed impairment of survival and mitogenic responses in vitro, accompanied by decreased, although inducible, NF-kappaB activity, but also increased turnover rate in vivo. In addition, transgene expression of bcl-2 could only partially rescue impaired B cell development in IKKalpha(-/-) chimeras. Taken together, these results demonstrate that IKKalpha is critically involved in the prevention of cell death and functional development of mature B cells.

Although the mutant low-Km acetaldehyde dehydrogenase (ALDH2) allele (ALDH2(2)) with reduced capacity to metabolize acetaldehyde offers biological protection against alcoholism and subsequent alcohol-induced organ damage in many individuals, a significant proportion of individuals with heterozygote of the normal and mutant ALDH2 gene (ALDH2(1)/2(2)) consume excessive amounts of alcohol. Indeed, it has been postulated that habitual drinkers with ALDH2(1)/2(2) may be at a higher risk for alcoholic liver disease than those with ALDH2(1)/2(1). In this study, we determined how representative biological markers of alcoholism (gamma-glutamyltransferase [GGT], carbohydrate-deficient transferrin [CDT], and the mean corpuscular volume of erythrocytes [MCV]) differ with respect to the ALDH2 genotypes in Japanese habitual drinkers.We obtained genomic DNA samples from 227 Japanese men with various drinking habits. ALDH2 genotypes were determined by allele-specific polymerase chain reaction. GGT, CDT, and MCV were determined and compared between ALDH2(1)/2(1) and ALDH2(1)/2(2) habitual drinkers who consumed more than 66 g of alcohol per day for more than 5 years. We measured CDT by anion-exchange chromatography followed by turbidity immunoassay by using a commercially available assay kit (Axis %CDT TIA).CDT levels were comparable between the two groups. GGT activities were significantly greater in ALDH2(1)/2(1) than in ALDH2(1)/2(2) habitual drinkers (81 +/- 85 vs. 53 +/- 40 IU/liters, p0.02). MCV values, on the other hand, were significantly larger in ALDH2(1)/2(2) than in ALDH2(1)/2(1) subjects (98.2 +/- 5.8 vs. 95.8 +/- 4.2 fl, p = 0.02). When we used elevation of either CDT or GGT to detect habitual drinking in ALDH2(1)/2(1) and 2(1)/2(2) subjects, the sensitivities were 57% and 46%, respectively. CDT levels were similar between habitual drinkers with normal aspartate aminotransferase levels and those with elevated levels.GGT and MCV, but not CDT, differ with respect to the ALDH2 genotypes in Japanese male habitual drinkers. ALDH2 genotypes should be considered when interpreting data on biological markers of alcoholism.

NF-kappaB is an ubiquitously expressed transcription factor that plays an important role in the immune, anti-apoptotic and inflammatory responses. NF-kappaB is normally sequestered in the cytoplasm by interacting with inhibitory IkappaB molecules. Upon stimulation, IkappaB is phosphorylated and subsequently degraded by the proteasome, allowing NF-kappaB to translocate into the nucleus where they regulate target gene expression. Two kinases, IKK-alpha and IKK-beta, which are responsible for IkappaB phosphorylation were recently identified. We have recently identified a cytokine inducible IKK-i, a kinase related to IKK-alpha and -beta. IKK-i significantly induced NF-kappaB activation upon over-expression, as did IKK-alpha and IKK-beta. Unlike IKK-alpha and IKK-beta, IKK-i phosphorylated Ser36 but not Ser32 in vitro, suggesting that IKK-i activates NF-kappaB by distinct mechanisms from the conventional IKKs.I-TRAF/TANK was isolated as a molecule that interacts specifically with inducible IkappaB kinase (IKK-i) by the yeast two-hybrid screening procedure. The association of IKK-i and I-TRAF is mediated via the interaction between the N-terminal domain of I-TRAF and the C-terminal portion of IKK-i. In vitro kinase assays demonstrate that IKK-i phosphorylates I-TRAF in the middle portion that associates with TRAF2. Interestingly, TRAF2 is freed from the I-TRAF/TRAF2 complex after I-TRAF phosphorylation. NF-kappaB activation by IKK-i is significantly blocked by coexpression of the N-terminal domain of I-TRAF, dominant negative TRAF2, and dominant negative NIK and IKK-beta. IKK-i over-expression also induced c-Jun N-terminal kinase. These results show that I-TRAF is a substrate of IKK-i. NF-kappaB activation by IKK-i may be mediated through phosphorylation of I-TRAF by IKK-i and subsequent liberation of TRAF2.These results indicate that NF-kappaB activation by IKK-i is mediated through phosphorylation of I-TRAF/TANK by IKK-i and subsequent liberation of TRAF2.

Cytochrome P450-2E1 (CYP2E1) is a major component of the microsomal ethanol-oxidizing system (MEOS) and is also involved in the metabolism of a variety of foreign compounds including carcinogens. It has been shown that there is an interindividual variation in the expression of human hepatic CYP2E1. Gene-environmental interactions have been suggested to account for the difference. In this study, we screened nine exons of the human CYP2E1 gene for detecting allelic variants in genomic DNA samples obtained from 115 Japanese controls, 96 Japanese alcoholics and 124 American control subjects. A novel missense mutation in exon 2 (V72L) was found in Japanese controls, and another missense mutation in exon 8 (D394G) was detected in American Caucasians. In addition, two novel silent mutations in exon 6 (T303T) and exon 8 (F420F) were found in Japanese controls and alcoholics. Especially the silent mutation in exon 8 was highly polymorphic among three population groups. The mutation in exon 2 (V72L) was detected only in Japanese controls, but not in alcoholics although it shows no significant difference. Gene frequency of the silent mutation in exon 8 was significantly higher in Japanese than American Caucasians (34.8% vs 21.0%, p0.02). Our data indicated that nucleotide replacement in the open reading frame is no major factor responsible for alcoholism. However, functional significance of the two novel missense mutations remains to be detailed.

Previous experiments have shown that infusion of either adenosine (ADO) or an adenosine receptor agonist during reperfusion after hypothermic ischemia improved the recovery of ventricular function in neonatal lamb hearts. Adenosine has multiple actions that might be beneficial during postischemic reperfusion, and the A2 effects include both coronary vasodilator and leukocyte inhibitory effects. In the current experiment we investigated the relationship between the coronary blood flow (CBF) effects of A2 stimulation and the recovery of postischemic ventricular function.Two hours of 10 degrees C cardioplegic ischemia was induced in 40 isolated, blood-perfused, neonatal lamb hearts (n=8 in each group). Group I had ischemia followed by unmodified reperfusion for 90 minutes. During the first 20 minutes of reperfusion, Group II received 350 micromol/L ADO, Group III received ADO and 100 nmol/L DPCPX (A1 antagonist) to achieve an A2 effect, Group IV received 0.25 micromol/L CPCA (A2 agonist), and Group V received ADO and DPCPX but CBF was limited to that of Group I levels. At 30 and 90 minutes of reperfusion, LV maximum developed pressure (DP), dP/dt, CBF, and oxygen consumption (MVO2) were measured. At 30 minutes of reperfusion Groups II, III, and IV showed better functional recovery than Group I or Group V (DP: G-I=75.7+/-7.3%, G-II=97.6+/-9.5%, G-III=88.1+/-4.8%, G-IV=86.7+/-9.0%, G-V=75.5+/-6.9%, P.05; dP/dt: G-I=69.1+/-9.6%, G-II=94.2+/-10.7%, G-III=95.7+/-13.1%, G-IV=80.1+/-11.1%, G-V=75.2+/-8.2%, P.05). Coronary blood flow was higher in Groups II, III, and IV compared with Group I or V (G-1=129+/-32%, G-II=183+/-36%, G-III=266+/-72%, G-IV=259+/-70%, G-V=132+/-5%, P.05). MVO2/beat was higher in Group II than in Groups I and IV (G-I=98.3+/-21.3%, G-II=135.5+/-28.0%, G-III=126.2+/-21.9%, G-IV=102.5+/-16.7%, G-V=107.5+/-29.3%, P.05). At 90 minutes of reperfusion, Groups II, III, and IV, as well as V, showed better recovery of DP and dP/dt compared with Group I (DP: G-I=50.6+/-11.4%, G-II=63.0+/-8.7%, G-III=69.0+/-10.8%, G-IV=72.5+/-12.7%, G-V=66.2+/-10.0%, P.05; dP/dt: G-I=38.9+/-7.1%, G-II=53.5 +/-3.8%, G-III=61.5+/-10.8%, G-IV=59.8+/-16.3%, G-V=58.2+/-9.8%, P.05) although only in Groups III and IV was CBF higher than in Group I (G-1=116+/-54%, G-II=116+/-27%, G-III=210+/-67%, G-IV=239+/-85%, G-V=130+/-8%, P.05).Reperfusion under conditions of A2 stimulation by ADO, by an A2 agonist, or by ADO plus A1 blockade was associated with improved recovery of LV function. The early A2 effect seems to be related to coronary vasodilation because reduced CBF (equal to Group I) in Group V reduced early recovery of LV function. However, there seems to be a second effect observed at 90 minutes that is not related to CBF inasmuch as Groups II and V had CBF equal to Group I but had significantly higher DP and dP/dt. These findings suggest that mechanisms in addition to vasodilation are involved in the beneficial effects of A2 stimulation during postischemic reperfusion.

Three assays for measuring hepatitis C virus(HCV) were compared with regard to sensitivity and correlations. The methods included were the Roche Amplicor HCV Monitor test(PCR), the branched DNA signal amplification assay(b-probe), and the serum concentration of HCV core protein measured by the sandwich FEIA (Core-Ag). Also, HCV serotypes were determined by the enzyme-linked immunosorbent assay. Testing 105 consecutive HCV-RNA positive samples showed that the PCR was the most sensitive assay(100% quantifiable), followed by the Core-Ag(82.4%) and the b-probe(75.3%). The values obtained by each method correlated well in serotype 1, whereas some discordance was noted in serotype 2 cases. Also, serotype 2 samples were less quantifiable particularly by b-probe assay than serotype 1 samples. These points have to be considered in quantification of serum HCV levels by currently available these three methods.

Currently available enzyme immunoassays for des-gamma-carboxy prothrombin (DCP) are not sensitive enough to detect hepatocellular carcinoma (HCC) at an early stage. Therefore, the objectives of this study were to enhance the sensitivity of the currently available enzyme immunoassay (EIA) for DCP and to assess the diagnostic values of the new methods compared with those of alpha-fetoprotein (AFP) in patients with small-sized HCC.Coded serum samples obtained from a total of 128 patients with chronic liver diseases, including 27 patients with small-sized HCC, were analyzed. DCP levels were determined in three different ways: 1) conventional EIA, 2) the overnight method, similar to the conventional EIA but the first reaction (immunoreaction of DCP with the monoclonal antibody) was proceeded overnight, and 3) the avidin-biotin complex (ABC) method.In 27 patients with HCC (or = 3 cm in diameter), the rates of abnormal values obtained by the conventional, the overnight, and the ABC methods were 14.8, 25.9, and 29.6%, respectively. The overnight and the ABC methods comparably increased the sensitivity, whereas the ABC method gave the highest false-positive value in patients with chronic liver diseases (cirrhosis and chronic hepatitis) without HCC. The negative predictive value was 84.9% when AFP and the overnight DCP assays were combined, whereas the true positive rate by the combination assay of the ABC method for DCP and AFP (cut-off level at 200 ng/ml) was 33.3%.Two modifications of the conventional EIA for DCP comparably increased the sensitivity, but the overnight method may be of more practical value in terms of specificity and ease. The rate of detection of small-sized HCC by tumor markers alone, however, is not satisfactory even when the modified DCP and AFP measurements are combined.

Current EIA for PIVKA-II is not sensitive enough to detect small Hepatocellular Carcinoma (HCC). In an attempt to increase the diagnostic threshold, the current EIA was modified in two different ways: 1) immunoreaction of PIVKA-II in the sample with its monoclonal antibody was carried out overnight at 5 degrees C instead of for two hours at room temperature (the overnight method), 2) Avidin-Biotin technique was used for the second reaction(the ABC method);and their diagnostic values were determined as compared with the current EIA(2hr method) in a total of 138 patients including 36 patients with HCC. In 27 patients with HCC(3 cm in diameter), the rates of abnormal values obtained by the 2hr-, the overnight- and the ABC method were 14.8, 25.9 and 29.6% respectively. False positive rates of these three methods in 69 patients with liver cirrhosis were 1.4, 8.6 and 22.9% respectively. Thus, these two modifications improved the sensitivity of the current EIA and the overnight method appears to be superior to the ABC method in terms of specificity and simplicity. This conclusion was confirmed by ROC analysis.

Pheochromocytomas synthesize and release catecholamines, which subsequently are related to various clinical manifestations of the disease. However, pheochromocytomas are not innervated and the catecholamine release and synthesis are not initiated by neural impulses. It is still unknown how catecholamine synthesis is regulated in pheochromocytomas. As a first step toward understanding the molecular mechanisms by which catecholamine synthesis is controlled in the tumor, we measured the levels of mRNA coding for the catecholamine synthesizing enzyme, tyrosine hydroxylase (TH) and catecholamines in 6 pheochromocytomas and 2 normal adrenal glands. The TH mRNA level was overexpressed and the catecholamine contents were high in 4 out of 6 pheochromocytomas. There was a close correlation between the TH mRNA level and the catecholamines content in the tumors. We also examined the gene expression of the messengers of other catecholamine synthesizing enzymes, dopamine beta-hydroxylase (DBH) and aromatic 1-amino acid decarboxylase (AADC) in pheochromocytomas. The expression of these genes was in parallel with that of TH mRNA in the tumors. These findings indicate that catecholamine overproduction in pheochromocytomas is mediated by the overexpression of genes coding for catecholamines synthesizing enzymes, TH, DBH, and AADC.

SRPX2 (Sushi repeat-containing protein, X-linked 2) has recently emerged as a multifunctional protein that is involved in seizure disorders, angiogenesis and cellular adhesion. Here, we analyzed this protein biochemically. SRPX2 protein was secreted with a highly post-translational modification. Chondroitinase ABC treatment completely decreased the molecular mass of purified SRPX2 protein to its predicted size, whereas heparitinase, keratanase and hyaluroinidase did not. Secreted SRPX2 protein was also detected using an anti-chondroitin sulfate antibody. These results indicate that SRPX2 is a novel chondroitin sulfate proteoglycan (CSPG). Furthermore, a binding assay revealed that hepatocyte growth factor dose-dependently binds to SRPX2 protein, and a ligand–glycosaminoglycans interaction was speculated to be likely in proteoglycans. Regarding its molecular architecture, SRPX2 has sushi repeat modules similar to four other CSPGs/lecticans; however, the molecular architecture of SRPX2 seems to be quite different from that of the lecticans. Taken together, we found that SRPX2 is a novel CSPG that is overexpressed in gastrointestinal cancer cells. Our findings provide key glycobiological insight into SRPX2 in cancer cells and demonstrate that SRPX2 is a new member of the cancer-related proteoglycan family.

The liver plays an important role in the metabolism of trace minerals. Hypozincemia has been well documented in cirrhotic patients and multiple mechanisms, including poor intake and depressed absorption, appear to be responsible for it. Of particular interest is a role of zinc deficiency in hepatic encephalopathy and the therapeutic potential of zinc supplementation in patients with liver cirrhosis. Although some reports indicate beneficial effects of oral zinc supplementation in cirrhotic patients with hepatic encephalopathy, not all studies have been positive. Serum selenium concentration depends on the amount of selenium ingested and the decreased levels found in cirrhotic patients should be interpreted with caution.

Postischemic infusion of adenosine (Ado) has been postulated to reduce reperfusion injury after normothermic ischemia, but the effect of Ado after hypothermic ischemia is unknown.We infused Ado (350 mumol/L), Ado + Ado antagonist theophylline (Ado + T, 7 mmol/L), A1 agonist cyclohexyl-Ado (0.25 mumol/L), A2 agonist cyclopropyl carboxamide Ado (0.25 mumol/L), or blood alone (group C) during the first 20 minutes of reperfusion after 2 hours of cold cardioplegic ischemia using an isolated, blood-perfused neonatal lamb heart model (n = 8 in each group). At 30 minutes of reperfusion, left ventricular (LV) maximum developed pressure (DP), dP/dt, -dP/dt, maximum DP at V10 (volume that gives LVEDP of 10 mm Hg at baseline measurement), dP/dt at V10, and LV stiffness constant (KA) at V10 were measured. Coronary blood flow and oxygen consumption (MVO2) were also measured to evaluate the metabolic recovery. Groups Ado, A1, and A2 showed better functional recovery than group C (DP for group C, 74.6 +/- 5.60%; group Ado, 94.2 +/- 10.7%; group A1, 89.3 +/- 4.40%; group A2, 86.7 +/- 9.00%; P.01), but theophylline offset the Ado effect (Ado + T, 74.6 +/- 6.4%). Coronary blood flow was higher in groups Ado + T and A2 than group C (group C, 156.7 +/- 45.7%; group Ado + T, 238.0 +/- 41.0%; group A2, 258.6 +/- 70.3%; P.05). MVO2 was higher in groups Ado, Ado + T, A1, and A2 than group C (group C, 57.7 +/- 11.0%; group Ado, 91.5 +/- 20.1%; group Ado + T, 210.7 +/- 60.0%; group A1, 82.8 +/- 31.9%; group A2, 83.5 +/- 12.8%; P.05).Ado infusion improved recovery of mechanical function after hypothermic ischemia, and its beneficial effect appears to involve both A1 and A2 receptors. Since group Ado + T had high coronary blood flow but not improved systolic function and group A1 had low coronary blood flow and improved systolic function, coronary vasodilation alone is not responsible for this beneficial effect. Ado may be a useful agent after hypothermic ischemia in the immature heart, although the precise mechanisms remain unclear.

Hormones produced by the anterior pituitary have conventionally been measured in the serum by radioimmunoassays (RIA), whereas more sensitive immunoradiometric assays (IRMA) have now been developed and are replacing RIA. Dynamic tests (stimulatory tests and suppression tests) rather than single and random determinations are often important tools in the study of pituitary functions. Stimulatory tests (such as glucagon plus propranolol test for growth hormone and water deprivation test for arginine-vasopressin) are used to evaluate hypofunction and suppression tests (such as dexamethasone suppression test for adrenocorticotrophic hormone) are used to investigate hyperfunction. This chapter, mainly dealing with representative dynamic tests, describes test protocols and how to interpret test results.

Thirty patients with previously untreated, inoperable non-small cell lung cancer (NSCLC) were treated with cisplatin, etoposide and vincristine. Among twenty-nine evaluable patients, eight patients achieved partial response and the overall response rate was 28%. No patient achieved a complete response. The median survival time was 51 weeks. Myelosuppression was the dose-limiting toxicity. Four patients had a leukocyte nadir of less than 1000/mm3, and one died from severe myelosuppression and sepsis. The other toxicities were nausea/vomiting, peripheral neuropathy, and alopecia. We conclude that cisplatin, etoposide, and vincristine combination chemotherapy offers moderate activity for inoperable non-small cell lung cancer.

Two patients with postoperative sternal wound infection were successfully treated by a pectral musculocutaneous flap. A single-stage procedure of debridement and immediate closure with a pectral musculocutaneous flap can eliminate irrigation, open wound management, or reoperation for closure. Therefore, this method is very safe, simple, and effective for the management of sternal wound infections.

A 79-year-old woman with a previous history of myocardial infarction, suffered acute myocardial infarction again. A coronary angiogram revealed triple vessel disease, and a left ventriculogram showed severe mitral regurgitation. The patient fell into cardiogenic shock after cardiac catheterization, and IABP was started. She underwent MAP and saphenous vein bypass grafting to the left anterior descending coronary artery and left circumflex coronary artery. Although the postoperative course was complicated by acute renal failure and respiratory dysfunction, the patient recovered from the operation and was discharged on the 137th postoperative day. Since the operative mortality of conventional valve replacement combined with CABG in ischemic mitral regurgitation has been high, we preferred MAP for this case.

We report here two cases in which patients fell into pulmonary edema due to ischemic mitral regurgitation (ischemic MR) after cardiac catheterization and underwent emergency coronary artery bypass grafting (CABG) using an intra-aortic balloon pumping. The patient were a 65-year-old man and a 80-year-old woman, and both had a chief complaint of angina after myocardiac infarction. In both cases, coronary angiography revealed triple vessel disease, and left ventriculography showed severe MR. However echocardiography, when they were hospitalized, did not show significant MR. Therefore we thought that they had gone into congestive heart failure because cardiac ischemia and volume load following cardiac catheterization provoked MR. In fact, postoperative left ventriculography and echocardiography showed decreased MR. We now think that it is important to keep in mind the cases of severe ischemic MR for which CABG alone is adequate treatment and to evaluate ischemic MR not only by left ventriculography but also by echocardiography.

Pharmacokinetics of theophylline were determined in patients with liver cirrhosis and idiopathic portal hypertension with reference to estimated hepatic blood flow assessed by indocyanine green (ICG). Decreased plasma clearance of theophylline was noted in patients with liver cirrhosis and the clearance was significantly lower in Child C group than in Child A, B groups (17.5 +/- 3.4 ml/Kg/hr vs 27.6 +/- 8.7, p less than 0.05). Theophylline has been classified as a drug with a low hepatic extraction ratio and it has been believed that changes in hepatic blood flow have little effect on its clearance. The results of present study indicate that theophylline clearance is basically not related to ICG clearance but to theophylline extraction ratio, supporting the common belief. However, it is noteworthy that the clearance was related to decreased hepatic blood flow rather than extraction ratio in a cirrhotic patient with huge extrahepatic shunt, suggesting that hepatic clearance of this drug could be affected by hepatic blood flow under some circumstances.

A 43-year-old male, who had undergone coronary artery bypass grafting 11 years ago, developed exertional chest pain. Selective coronary angiograms revealed severe stenosis and a large aneurysm in the obtuse marginal branch of the circumflex coronary artery. Previous grafts to the left anterior descending coronary artery and diagonal branch were patent. Ligation of the aneurysm and internal mammary artery grafting were performed through a left anterolateral thoracotomy. This approach made it easy to reach the aneurysm and to minimize bleeding during dissecting the adhesions. The patient had an uncomplicated postoperative course, and postoperative coronary angiograms revealed an obstructed aneurysm and a patient internal mammary artery graft. He has done well without recurrence of symptoms.

To assess the effect of interferon therapy on posttransfusion non-A, non-B acute hepatitis, we examined the appearance of serum hepatitis C virus antibody (anti-HCV) and abnormal serum aminotransferase levels after the onset of hepatitis in 12 patients treated with interferon and in 46 patients treated conservatively. Eleven patients were given 3 million units of human fibroblast beta-interferon three times weekly for 4 wk and 1 was given one million units of human lymphoblastoid alpha-interferon daily for 3 months. In the interferon-treated patients, the effect of therapy on hepatic histology was also assessed. Detection of anti-HCV within 6 and 12 months after the onset of hepatitis was less common in interferon-treated patients than in control patients (6/12 vs 35/46 and 5/12 vs 35/46, both p = NS). At 24 months after the onset of hepatitis, anti-HCV levels were significantly lower in interferon-treated patients (0/10, p less than 0.05), but had not changed significantly in control patients (34/46). Abnormal serum aminotransferase levels at 6, 12, and 24 months after the onset of hepatitis were significantly less common in interferon-treated patients than in controls (25% vs 78.3%, p less than 0.005; 25% vs 71.7%, p less than 0.01; and 0% vs 67.4%, p less than 0.001). The percentage of abnormal serum aminotransferase levels at 6, 12, and 24 months after onset of hepatitis was also less in interferon-treated patients than in control patients, both among anti-HCV-positive patients (50% vs 85.7%, p = NS; 50% vs 80%, p = NS; and 0% vs 77.1%, p less than 0.01) and among anti-HCV-negative patients (0% vs 54.5%, p = NS; 0% vs 45.5%, p = NS; and 0% vs 27.3%, p = NS). Immediately after interferon therapy, the histological activity index dropped from 6.0 +/- 4.2 to 4.8 +/- 2.5 in anti-HCV-positive patients (p = NS) and from 4.2 +/- 4.3 to 2.6 +/- 1.7 in anti-HCV-negative patients (p = NS). Biopsy specimens obtained from four patients 12-23 months after interferon therapy revealed normal histology in one anti-HCV-positive patient and two anti-HCV-negative patients, and marked improvement in the other anti-HCV-positive patient. These results indicate that short-term, low-dose interferon therapy may be effective for posttransfusion non-A, non-B acute hepatitis (both anti-HCV-positive and anti-HCV-negative).

To evaluate the development of an anomalous muscle bandle of the right ventricle (RV) and results of surgical intervention, responses of the RV to atrial pacing and the isoproterenol tests were examined in both the pre- and postoperative periods. Although cardiac output did not increase in proportion to the rate of atrial pacing or the dose of isoproterenol, the pressure gradient through the RV increased abnormally from 38 mmHg to 59 mmHg (atrial pacing) and 116 mmHg (isoproterenol). On the other hand, postoperative evaluation showed normal RV responses in these tests. Since the response of the right ventricle to these tolerance tests in patients with DCRV in pre- and postoperative periods has not been well elucidated, a precise evaluation is reported in this paper.

Extrahepatic lymph node metastases are not uncommon in advanced cases of hepatocellular carcinoma (HCC). This is the account of a HCC case in which intrahepatic lymphatics running toward the hepatic hilus were clearly opacified during hepatic arteriography. The patient was treated by hepatic artery embolization followed by selective embolization of the portal branches, but lymph node metastases at the hepatic hilus were later found during follow-up. The clinical course of this case suggests that the communication between the tumor and the lymphatics was responsible for the lymph node metastasis.

The effect of diltiazem as an adjunct to cardioplegia was examined for cardiac eicosanoid release in 12 patients who received aorto-coronary bypass. The patients were divided into two groups: diltiazem group (No. = 6) (10 mg/L of diltiazem in crystalloid potassium cardioplegia) and control group (No. = 6) (same cardioplegia without diltiazem). The plasma levels of thromboxane B2 and 6 keto PGF1 alpha (metabolites of thromboxane A2 and prostacyclin) in systemic artery and coronary sinus blood were measured during early reperfusion. A significantly larger arterio-venous difference in 6 keto PGF1 alpha concentration was found immediately after aortic clamp release in the diltiazem group (124 +/- 77 vs 12 +/- 47 pg/ml, p less than 0.05). The plasma thromboxane B2/6 keto PGF1 alpha ratio in coronary sinus blood was lower in the diltiazem group immediately after aortic clamp release (0.47 +/- 0.16 vs 0.74 +/- 0.18, p less than 0.05). There was no significant difference in arterio-venous TxB2 concentration between the two groups. In terms of myocardial protective effect evaluated by CPK-MB release, there was no significant difference between the two groups. The results indicated that diltiazem used as an adjunct to cardioplegia enhanced the production of endogenous PGI2 during early reperfusion, although its beneficial effect on myocardial protection was not shown in terms of enzyme leakage.

This paper reports CABG which was successfully performed on a male patient of 70-year-old with severe chronic obstructive pulmonary disease (FEV1.0% 43%) and diabetes mellitus. The patient necessitated reintubation because of hypercapnea on 18 POD in spite of bronchodilator and physical therapies. Long respiratory care was continued after tracheotomy, and finally he could wean from the mechanical respiratory care utilizing acetazolamide (carbonic anhydrase inhibitor) on 59 POD.

An in vitro assessment of susceptibility to malotilate was made with peripheral blood mononuclear cells (PBMCs) as targets. PBMCs were incubated with malotilate in the presence or absence of the NADPH generating system and hepatic microsomes. Malotilate cytotoxicity to PBMCs, assessed by trypan blue dye exclusion and lactate dehydrogenase (LDH) release into the culture media, was found to be markedly increased by the addition of the NADPH generating system, indicating that metabolites play a significant role in toxicity. Once the significant role of malotilate metabolites in cytotoxicity was established, we applied this system to patients with suspected malotilate-induced liver injury. It was demonstrated that cytotoxicity was greater in PBMCs which were obtained from patients with chronic active hepatitis with a parallel malotilate-induced liver injury than in those from two different control groups; normal volunteers and patients with chronic active hepatitis who had had long-term malotilate treatment without any adverse reactions. This in vitro system seems to be of value in predicting potential malotilate toxicity in subjects who might be susceptible to this drug.

Three patients with proven Budd-Chiari syndrome were examined with a duplex sonograph consisting of a real-time ultrasonograph and a pulsed Doppler flowmeter. In these cases, the pulsed Doppler analysis associated with the real-time imaging showed abnormalities in the direction of flow in the hepatic vein, communicating vessel between hepatic veins, and/or retrohepatic inferior vena cava, which were consistent with obstruction of hepatic venous outflow. With these findings, duplex sonography can be used to diagnose Budd-Chiari syndrome.

To assess the importance of non-ADH ethanol metabolism, ADH-negative (ADH − ) and ADH-positive (ADH + ) deermice were fed for 2–4 weeks liquid diets containing ethanol or isocaloric carbohydrate. They consumed progressively increasing amounts of ethanol. Blood ethanol clearance (BEC) increased significantly in both strains. It remained almost unchanged at low ethanol concentrations (5–10 mM), but at high levels (40–70 mM) BEC was strinkingly increased with significant differences between ethanol-fed and control animals. Kinetics were consistent with the activity of a non-ADH high K m system such as the microsomal ethanol-oxidizing system (MEOS). Naive ADH − had a more active MEOS and more abundant SER than naive ADH + . After ethanol feeding, MEOS was increased 3–4 times in both strains. There was striking proliferation of SER and cytochrome P-450 was enhanced significantly. Expressed per P-450, MEOS activity was higher in ADH − than ADH + . Thus despite absence of ADH, ADH − deermice can consume large amounts of ethanol: this is associated with increased BEC, SER proliferation, enhanced MEOS activity and quantitative and qualitative changes of cytochrome P-450.

The acute effects of histamine H2 receptor antagonist, famotidine, on hepatic hemodynamics were studied in six normal volunteers and eight patients with chronic liver disease, and its chronic effects on peptic ulcer, portal hemodynamics, and hepatic function were studied in 20 patients with chronic liver disease and peptic ulcer (16 with gastric ulcer, four with duodenal ulcer). Infusion of 20 mg famotidine did not reduce hepatic blood flow and portal blood flow in normal subjects, nor did it reduce cardiac output, the gradient between wedged hepatic vein pressure and free hepatic vein pressure, hepatic blood flow, and portal blood flow in patients with chronic liver disease. An oral dose of 20 mg famotidine twice daily for 2 months healed peptic ulcer in 19 of 20 patients (95%) with chronic liver disease and peptic ulcer, without any change in portal blood flow and hepatic function. Thus famotidine does not appear to alter hepatic hemodynamics and hepatic function in normal subjects and patients with chronic liver disease.

Subjects in a cefotaxime (CTX) single administration group and in a CTX + fosfomycin (FOM) administration group were randomly selected for a comparative study on the utility of each product against respiratory tract infections. Overall improvement rates were 81.3% in 32 cases of the CTX single administration group, and 75.6% in 41 cases of the CTX + FOM concomitant administration group. No statistical difference was observed. As for adverse reactions and abnormal laboratory test results, pyrexia, thrombocytopenia, increases in GOT and GPT, and increase in GPT were observed in 4 cases of the CTX single administration group, while angialgia, increases in GOT and GPT (3 cases), and increases in BUN, (totalling 5), were observed in the CTX + FOM group. However, all the symptoms were transient, and none was serious in nature.

Twelve patients (pts) with coronary and/or valvular heart disease and preoperative creatinine clearance (Ccr) below 30 ml/min underwent cardiac surgery using cardiopulmonary bypass (CPB) with pulsatile (P:n = 7) and nonpulsatile (NP:n = 5) perfusion. Preoperative Ccr was 15.8 +/- 4.4 ml/min in the P group and 26.5 +/- 4.7 ml/min in the NP group. After surgery, the NP group showed significant increases in BUN and serum creatinine within a week, but the P group showed significant increase in BUN only. The NP group had a significant decrease in Ccr on the 7th postoperative day, but there was no significant change in the P group. Three patients, 2 from the NP group and one from the P group, died from complications (operative mortality: 14 vs 40%). These data suggested that P-CPB appeared to be advantageous in patients with preoperatively impaired renal function with low Ccr although many other factors might influence the outcome.