Adriamycin-Lipiodol suspension for i. a. chemotherapy of hepatocellular carcinoma

Summary Physicochemical properties of two types of adriamycin preparation, suspensions and emulsions prepared for i.a. chemotherapy of hepatocellular cacinoma, were investigated. A suspension was prepared by dispersing adriamycin directly into the lipid contrast medium, Lipiodol, whereas an emulsion was obtained by emulsifying an aqueous solution of adriamycin into Lipiodol. The dispersibility of the drug in each preparation was examined microscopically. The chemical stability of and drug release from the preparation were determined by high-performance liquid chromatography and spectrophotometry, respectively. The suspension was then given to ten patients with primary hepatocellular carcinoma. The suspension maintained good dispersibility without coagulation of drug particles, whereas coalescence of aqueous droplets and the resultant phase separation occurred 4 h after preparation of the emulsion. Both preparations maintained the initial drug content for at least 1 week at room temperature. The release of adriamycin was more prolonged in the suspension than in the emulsion. After i.a. administration of the suspension, a selective accumulation of Lipiodol in the tumor and decrease in serum -fetoprotein (AFP) levels were found in most patients. A significant amount of adriamycin was still detected in hepatic speciments resected from two patients 1 and 2 months after treatment. These findings suggest that the adriamycin-Lipiodol suspension may be a useful preparation for targeting chemotherapy to hepatocellular carcinoma.     

Antiphospholipid antibodies

The concept of antiphospholipid syndrome(APS) has been widely accepted. Antiphospholipid antibodies originally included anticardiolipin antibodies and lupus anticoagulants as serological marker of APS. However, recent advances have shown that most pathogenic antiphospholipid antibodies are directed to phospholipid binding proteins such as beta 2-glycoprotein I and prothrombin as well as phospholipids. The preliminary classification criteria for definite APS have been advocated as the "Sapporo criteria". Further prospective investigations are required to re-evaluate the clinical significance of so-called antiphospholipid antibodies.     

Respiratory responses to occlusion or hypercapnic blood injection of the anterior inferior cerebellar artery in cats

To examine whether the central chemoreceptors of respiration are located in the perfused area of the anterior inferior cerebellar artery (AICA), we occluded arteries or injected hypercapnic blood into arteries in the ventral surface of the medulla in anesthetized, paralyzed, and peripherally chemodenervated cats. Phrenic nerve activity, as an index of respiratory output, was augmented by an injection of hypercapnic blood into the vertebral artery. This vertebral-injection response decreased during bilateral occlusion of AICA. However, responses of phrenic nerve activity to the occlusion of AICA were complicated; activity increased in 19 cats, did not change in 10, and decreased in 9 during occlusion. In experiments with blood of various PCO2 levels being bilaterally injected into AICA, phrenic discharges increased with increases of PCO2. During the injection of constant PCO2 blood into AICA, phrenic response to alveolar PCO2 decreased by 80% compared with the original response. From these results, the blood flow and blood PCO2 level of AICA seemed to be related to the central chemosensitivity for respiration. To examine the perfused area, the ventral surface pH of the medulla was measured with a micro-combination pH electrode (2 mm diameter). During the injection into AICA, pH in the rostral medulla depended on the PCO2 of injected blood, and pH in other areas depended on the PCO2 of systemic blood. Also, histological study of India ink injection into AICA showed that ink-filled vessels were exclusively observed in the rostral medulla. Thus, we conclude that at least part of the central chemoreceptors of respiration are located in the perfused area of AICA, that is, in the rostral medulla.     

Prevention of endotoxin shock by an antibody against leukocyte integrin {beta}2 through inhibiting production and action of TNF

Septic shock remains a serious disorder associated with highmortality. Accumulating evidence indicates that TNF is a majorand essential mediator of endotoxin shock. We report here thatadministration of an antibody against CD18 dramatically reducedendotoxin-induced shock inrabbits as revealed by preventionof severe hypotension, metabolic acidosis and a pathologicalchange suggestive of disseminated intravascular coagulationwith concomitant inhibition of elevation of plasma TNF activity.The anti-CD18 antibody also inhibited the hypotension inducedby administering recombinant TNF. Furthermore, an antibody againsta ligand for CD18 complexes, intercellular adhesion molecule-1,also prevented TNF-induced shock as well as endotoxin shockinrabbits. These observations suggest that adhesion of leukocytesto endothelium may be of primary importance in the action ofTNF as well as in the production of TNF in vivo and that theantibody against adhesion molecules could be of therapeuticbenefit in life-threatening septic shock in humans.     

Diagnosis and management for antiphospholipid syndrome

It has been reported that antiphospholipid antibodies have the diversity against epitopes and the clinical significance, while the concept of antiphospholipid syndrome has been established. Dr. Harris and Dr. Hughes proposed the diagnostic criteria for antiphospholipid syndrome, and their criteria were widely used. Thrombosis, recurrent fetal loss (intrauterine fetal death), thrombocytopenia, IgG anticardiolipin antibodies and lupus anticoagulants were adopted in their criteria. However, recent studies have revealed the evaluation of the standardization of the methods to detect antiphospholipid antibodies and the clinical significance of both anti-cardiolipin-beta 2-GPI complex antibodies and other isotypes of antiphospholipid antibodies. Thus, the preliminary classification criteria for antiphospholipid syndrome have been discussed. It has been reported that anticoagulation therapy is effective in the management of antiphospholipid syndrome by the recent retrospective studies. It is necessary to confirm these points by the prospective study in the near future.     

Epidemiologic survey and genetic analysis of endemic hepatitis C virus infection in a Japanese town with a high prevalence of hepatitis B virus carriers

Mass screening for hepatitis C virus antibody was carried out in 875 inhabitants (313 men and 562 women) of a town in Japan with a high rate of hepatitis B virus infection. The overall rate of positivity for anti-HCV was 8.8% (6.4% in men and 10,1% in women). The rate of positivity for hepatitis B virus surface antigen was 11.2%. Five subjects (0.6%) were positive for both markers. HCV-RNA was detected in 65 (88.4%) of 77 individuals who were positive for anti-HCV and in 1 (1.5%) of 60 individuals negative for anti-HCV. The genotype of the HCV genome was determined by PCR analysis using type-specific primers in 60 individuals. HCV type 1b was detected in 51 subjects (85%), type 2a in 3 subjects (5%), and type 2b in 6 subjects (10%). None of the individuals was infected with more than one genotype. The nucleotide sequences of the partial nonstructural 5 region of HCV type 1b genotype obtained from 6 individuals showed at least 92.0% homology in the nucleotide sequence, and 94.8% homology in the amino acid sequence. Homology among these clones was greater than their homology with previously described type 1 b sequences. The findings suggest that there was a specific local origin of HCV infection, although it was not possible to identify any single source of HCV infection. The results also indicate the presence of asymptomatic HCV carriers. © 1995 Wiley-Liss, Inc.     

Preclinical evaluation of a hollow fiber silicone membrane oxygenator for extracorporeal membrane oxygenator application

A silicone membrane hollow fiber oxygenator applicable for use as an extracorporeal membrane oxygenator (ECMO) has been developed in our laboratory. This silicone hollow fiber displays astonishing mechanical stability, is barely compressible or stretchable, and assembles easily while maintaining good gas permeability. The priming volume is 140 cc with a surface area of 0.8 m2. This study evaluated the gas transfer performances and biocompatibility of the oxygenator under ECMO and CPB conditions. In vitro studies that were performed at a blood flow rate of 2 L/min, and revealed O2 and CO2 gas transfer rates of 82.35 +/- 0.56 ml/m2/L/min and 38.72 +/- 2.88 ml/m2/L/min, respectively. The commercially available Kolobow (Avecor 1500) oxygenator was used as the control, and had O2 and CO2 gas transfer rates of 53.8 +/- 0.5 ml/m2/L/min and 24.7 +/- 2.0 ml/m2/L/min. To evaluate blood trauma, Normalized Index of Hemolysis (NIH) was measured according to American Society of Testing and Materials (ASTM) standards. The NIH findings were 0.0112 g/100L at a blood flow of 1 L/min, and 0.0152 g/100L at 5 L/min. Three ex vivo experiments, using a blood flow rate of 1 L/min, were performed with venoarterial bypass, and O2 transfer rate and CO2 transfer rate of the oxygenators were well maintained. This indicates that this preclinical silicone membrane hollow fiber oxygenator has superior efficiency, less blood trauma, and is smaller when compared with the only clinically available Kolobow oxygenator.     

Prediction of effectiveness of shunting in patients with normal pressure hydrocephalus by cerebral blood flow measurement and computed tomography cisternography

Measurement of cerebral blood flow (CBF) and computed tomography (CT) cisternography were performed in 37 patients with a tentative diagnosis of normal pressure hydrocephalus (NPH) to predict their surgical outcome. The mean CBF of the whole brain was measured quantitatively by single photon emission computed tomography with technetium-99m-hexamethylpropylene amine oxime before surgery. The results of CT cisternography were classified into four patterns: type I, no ventricular stasis at 24 hours; type II, no ventricular stasis with delayed clearance of cerebral blush; type III, persistent ventricular stasis with prominent cerebral blush; type IV, persistent ventricular stasis with diminished cerebral blush and/or asymmetrical filling of the sylvian fissures. The mean CBF was significantly lower than that of age-matched controls (p < 0.005). Patients with a favorable outcome had a significantly higher mean CBF than patients with an unfavorable outcome (p < 0.005). Patients with the type I pattern did not respond to shunting. Some patients with type II and III patterns responded to shunting but improvement was unsatisfactory. Patients with type IV pattern responded well to shunting, and those with a mean CBF of 35 ml/100 g/min or over achieved a favorable outcome. The combination of CBF measurement and CT cisternography can improve the prediction of surgical outcome in patients with suspected NPH.     

Predictive Factors for the Development or Regression of Fatty Liver in Japanese Adults

Fatty liver is commonly associated with alcohol or metabolic syndrome. We aimed to examine the longitudinal aspects of fatty liver, and clarify the independent predictors for the development or regression of fatty liver. In the present study, the clinical features of 1578 Japanese adults (1208 men and 370 women; 35 to 69 years of age) who visited our center both in 2000 and 2007–2008 were recorded and compared, including liver status diagnosed by ultrasonography. Of the 1578 participants, 217 (13.8%) showed fatty liver development, and 74 (4.7%) showed fatty liver regression. Logistic regression analysis revealed that body mass index and percentage body fat were strongly associated with the development or regression of fatty liver. Metabolic syndrome-related disorders such as serum levels of total cholesterol, triglyceride, uric acid, and fasting blood glucose were also associated with clinical course to some degree. However, the history of alcohol intake, the presence of metabolic syndrome, blood pressure, and habitual physical exercise were not independent predictors for the development or regression of fatty liver. Our present data suggest that control of body weight in men and the percentage body fat in women are particularly important for the prevention or treatment of fatty liver.     

Clinical significance of lipoprotein(a) in carotid plaque types and ischemic stroke in the elderly

Background:   The relationship between lipoprotein(a) (Lp(a)) and ischemic stroke is still controversial in the elderly. The purpose of the present paper was to evaluate the significance of Lp(a) in the development of extracranial carotid lesions and ischemic stroke.
Methods:   A total of 371 elderly subjects, studied with carotid ultrasonography (US) and brain computed tomography (CT), was stratified into two groups according to serum Lp(a) levels: the normal Lp(a) and high Lp(a) (>40 mg/dL) groups. Carotid plaques were divided into three types based on the US echogenicity: hypoechoic, hyperechoic, and heterogeneous plaques. Low-density areas (LDA) on brain CT images were classified into three groups depending on their distribution: basal ganglionic, cortical and only leuko-araiosis types.
Results:   The incidence of bilateral carotid lesions and the ratios of hypoechoic and heterogeneous plaques were significantly higher in the high Lp(a) group than in the normal Lp(a) group. Both the mean height and length of plaque were also greater in the high Lp(a) group. Mean Lp(a) levels were significantly elevated in cases with hypoechoic and heterogeneous types, compared to the cases without lesions. Higher mean Lp(a) levels were seen in cases with any kind of LDA than in normal subjects on CT, but there was no significant difference in the incidence of each LDA between the two groups.
Conclusions   These findings indicate that serum Lp(a) is strongly related to carotid lesions, especially hypoechoic and heterogeneous plaque types, in Japanese elderly patients. This suggests that Lp(a) could promote the formation of lipid-rich atheromatous plaque with intraplaque hemorrhage or superimposed thrombi. Serum Lp(a) also seemed to be a risk for all types of LDA.