Cardiovascular and Adrenal Proliferative Lesions in Fischer 344 Rats Induced by Long-term Treatment with Type III Phosphodiesterase Inhibitors (Positive Inotropic Agents), Isomazole and Indolidan

Male and female Fischer 344 rats were treated with the positiveinotropic agents, isomazole or indolidan, in the diet for 104weeks. The doses were 0.0, 11.5, 23.5, or 48.0 mg\kg and 0.0,0.12, 0.40, or 1.3 mg\kg, respectively. Only 17% of the malestreated with 48.0 mg\kg isomazole survived the duration of thestudy. The male component of the indolidan study was terminatedat 22 months, with only 18% of the high-dose males surviving.Sixty-five percent of the males treated with 48.0 mg\kg isomazoleand 70% of the males treated with 1.3 mg\kg indolidan were foundto have severe periarteritis, often with thrombi located mainlyin the mesenteric arteries. Fifty-four percent of the male ratstreated with 48.0 mg\kg isomazole and 55% of the male rats treatedwith 1.3 mg\kg indolidan died from cardiovascular disease comparedto 1–2% among the control males. Animals in the low- andmiddle-dose groups of both studies had a lower incidence ofcardiovascular disease than did those in the high-dose group.Additional lesions associated with the long-term administrationof both drugs were markedly increased incidence of adrenal medullaryproliferative lesions (both hyperplasia and pheochromocytomas)and increased incidence of chronic progressive glomerulonephrosis.These lesions, like those in the cardiovascular system, occurredin a dose-dependent manner and were more frequent in males thanin females. Treatment-related effects in these studies werejudged to be related to the pharmacologic action of these compounds.     

Indications and Techniques for Endoscopic Mucosal Resection in the Lesions of A Colorectal Tumor

We evaluated the possibility of an extended application of endoscopic treatment for submucosal‐invading colorectal cancers, and describe the method of endoscopic mucosal resection (EMR) using a one channel colonoscope. A total of 328 submucosal‐invading cancers were examined from July 1985 to September 2002. The patterns of infiltrating growth into the submucosal layer were further divided into two groups: expanding growth, and infiltrating growth. Lymph node metastasis occurred in sm2 and extension cancer in more advanced stages. The lowest measurement of submucosal invading cancer with lymph node metastasis was 1250 µm. As for patterns of invasion, the frequencies of lymph node metastasis in the groups of expanding growth and infiltrating growth were 0% (0/87) and 14.5% (16/110), respectively, (P = 0.0002, Fisher's direct method). Results showed that endoscopic treatment is suitable for sm1 extension without vessel invasion, but there is a possibility that some sm2 extension cancers can be cured radically when the pattern of submucosal invasion shows expanding growth with a distinct border.     

Dissolution of bupivacaine 3-hydroxy-2-naphthoate into phosphate buffers

Dissolution behaviour of bupivacaine 3-hydroxy-2-naphthoate (BUPNH) into phosphate buffers, pH 7·4 was investigated at 25° and 37°C. Although the dissolution pattern of the salt at 25°C was normal, i.e. the concentrations of the acid and base component agreed, during the entire dissolution period, that at 37°C was anomalous. The dissolution consisted of two phases, i.e. an initial normal phase was followed by a second slower phase in which the concentration of the acid became, at equilibrium, markedly higher than that of the base. This unusual dissolution behaviour at 37°C was shown to be due to the precipitation of the base, which, in turn, is attributed to the unusual temperature dependency of the solubility of the base in phosphate buffers, i.e. decrease in solubility with increasing temperature.     

The behaviour of red cells in narrow tubes in vitro as a model of the microcirculation

To investigate the behaviour of red cells in the microcirculation, we established a new capillary method using narrow fluorinated ethylenepropylene copolymer tubes with internal diameters of 12.5 and 25.0 μm. Red cell flow in the tubes under a given range of pressure was analysed through a video system connected to a microscope. The experimental condition was adjusted so that the velocity of the control normocytes would be compatible with that in corresponding vessels in vivo , 0.5–1.5 mm/s. In the 12.5 μm tube, normocytes obtained from 12 young normal volunteers ran in an axisymmetric edge-on orientation with a folded shape at higher pressures, but rolled along freely without deformation at lower pressures. Deformation during the passage of the microcytes obtained from four patients with polycythaemia vera complicated with iron-deficient microcytosis and 10 patients with iron deficiency anaemia was relatively mild, whereas that of the macrocytes obtained from eight patients with refractory anaemia was marked. Even after the screening effect at the tube entrance was taken into consideration, the velocities of both microcytes and macrocytes were found to be significantly lower than the control normocytes. Therefore this method may be a new way to investigate the flow properties of red cells in the microcirculation.     

Evolutionary aspects of positioning and identification of vertebrate limbs

Emerging developmental studies contribute to our understanding of vertebrate evolution because changes in the developmental process and the genes responsible for such changes provide a unique way for evaluating the evolution of morphology. Endoskeletal limbs, the locomotor organs that are unique to vertebrates, are a popular model system in the fields of palaeontology and phylogeny because their structure is highly visible and their bony pattern is easily preserved in the fossil records. Similarly, limb development has long served as an excellent model system for studying vertebrate pattern formation. In this review, the evolution of vertebrate limb development is examined in the light of the latest knowledge, viewpoints and hypotheses.     

Psoriasis vulgaris coexistent with epidermolysis bullosa acquisita

Summary Autoimmune bullous diseases, such as bullous pemphigoid or pemphigus vulgaris. occasionally develop in psoriatic patients. In addition, a novel subepidermal bullous disease with autoantibodies against a lower lamina lucida antigen of 200kDa has recently been reported in association with psoriasis. We describe here a patient with psoriasis vulgaris who developed epidermolysis bullosa acquisita (EBA). Direct immunofluorescence revealed linear deposition of IgCl and C3 at the basement membrane zone. The patient's serum bound to the dermal side of salt-split normal human skin. However, immnumohlol analysis demonstrated that the patient's serum reacted with an EBA antigen of 290 kDa. EBA should be included in the list of autoimmune diseases associated with psoriasis vulgaris.     

Successful induction of immune tolerance by continuous infusion of recombinant factor VIII in a haemophilia A patient with high-inhibitor titres

The successful and persistent abolition of the inhibitor is of significant clinical benefit, as it allows for the restoration of the usual treatment with clotting factor concentrate. We describe a successful induction of immune tolerance by continuous infusion of recombinant factor VIII (rFVIII) in a 5-year-old boy with severe haemophilia A and high-responding inhibitor. He had previously been subjected to immune tolerance induction (ITI) with rFVIII at 100 units (U) kg(-1) three times weekly. One year after the beginning of therapy tolerance was not achieved and a high titer of inhibitor was detected (15 Bethesda Units). The patient had a sudden onset of severe neck pain. The diagnosis of spinal epidural haematoma was revealed by magnetic resonance imaging, and emergency laminectomy with evacuation of the haematoma was required. The patient received sequential therapy for surgery first as bolus rFVIII injection of 500 U kg(-1) in order to overwhelm the inhibitor and then as continuous infusion at 6 to 12 U kg(-1) hour(-1) to avoid bleeding episodes in the postoperative period. After the 3 weeks of continuous infusion, the inhibitor became undetectable. Thereafter, prophylactic treatment with rFVIII was started three times weekly, and the inhibitor has remained undetectable for 6 months. The, present case suggests that continuous infusion of rFVIII may be an effective therapy to induce immune tolerance.     

Relationships (I) of International Classification of High-resolution Computed Tomography for Occupational and Environmental Respiratory Diseases with the ILO International Classification of Radiographs of Pneumoconioses for parenchymal abnormalities

The International Classification of High-resolution Computed Tomography (HRCT) for Occupational and Environmental Respiratory Diseases (ICOERD) has been developed for the screening, diagnosis, and epidemiological reporting of respiratory diseases caused by occupational hazards. This study aimed to establish a correlation between readings of HRCT (according to the ICOERD) and those of chest radiography (CXR) pneumoconiotic parenchymal opacities (according to the International Labor Organization Classification/International Classification of Radiographs of Pneumoconioses [ILO/ICRP]). Forty-six patients with and 28 controls without mineral dust exposure underwent posterior-anterior CXR and HRCT. We recorded all subjects’ exposure and smoking history. Experts independently read CXRs (using ILO/ICRP). Experts independently assessed HRCT using the ICOERD parenchymal abnormalities grades for well-defined rounded opacities (RO), linear and/or irregular opacities (IR), and emphysema (EM). The correlation between the ICOERD summed grades and ILO/ICRP profusions was evaluated using Spearman’s rank-order correlation. Twenty-three patients had small opacities on CXR. HRCT showed that 21 patients had RO; 20 patients, IR opacities; and 23 patients, EM. The correlation between ILO/ICRP profusions and the ICOERD grades was 0.844 for rounded opacities (p<0.01). ICOERD readings from HRCT scans correlated well with previously validated ILO/ICRP criteria. The ICOERD adequately detects pneumoconiotic micronodules and can be used for the interpretation of pneumoconiosis.