Invited Review Articles
Vitamin B6 and Arteriosclerosis
FUMIO KUZUYA
pg(s) 1- 9
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In 1949, Rinehart and Greenberg reported that marked arteriosclerosis occurs in vitamin-B6-deficient
monkeys. The present study investigates the relationship between vitamin B6 and arteriosclerosis and summarizes
the results. I found that thrombogenesis, disorder of collagen metabolism and production of free
radicals may be the processes that cause arteriosclerosis in human and experimental animals with vitamin B6
deficiency.
Cerebellar Hypoplasia in the Hyperbilirubinemic Gunn Rat: Morphological Aspects
HIDEKI YAMAMURA and YOSHIKO TAKAGISHI
pg(s) 11- 21
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Gunn rats, a mutant strain of rats, suffer from autosomal recessive hyperbilirubinemia. The homozygotes
(j/j) develop jaundice soon after birth and often exhibit kernicterus and cerebellar hypoplasia that are due to
bilirubin. Therefore, j/j Gunn rats have been used as an animal model of bilirubin encephalopathy, as well as
of neonatal hyperbilirubinemia. In this review, we discuss morphological aspects of the cerebellar hypoplasia
that is due to bilirubin and describe the relationship between plasma bilirubin levels and cerebellar hypoplasia,
as well as the pathogenesis of cerebellar hypoplasia, including abnormal histogenesis of the cerebellar
cortex, abnormalities associated with Purkinje cells and abnormal synaptogenesis in j/j Gunn rats.
Measles and Measles Vaccine in Japan
SHIN ISOMURA
pg(s) 23 - 32
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Before the introduction of measles vaccine in 1971, measles was a common and well-recognized disease
in Japanese children. Seroepidemiological studies conducted before the general use of the vaccine disclosed
that measles epidemics differed from community to community; in rural areas, epidemics appeared at intervals
of several years with the accumulation of susceptibles, and in urban areas, measles was endemic affecting
younger children.
The measles vaccines developed in Japan showed excellent safety and efficacy in the clinical trials for
general use. Since 1978 measles vaccines have been routinely given to children aged 12 months or older, and
incidence of measles decreased dramatically. However, the vaccine acceptance rate has been only as high as
85% to 90% and small-scale outbreaks of measles have been observed periodically among unimmunized
children: Measles is far from being eradicated in Japan. This is primarily due to the insufficient vaccine acceptance
rate, and more efforts towards mobilization of parents to have their children vaccinated are now in
progress.
Original Papers
Considerations for Standard Chest Radiography: the Long Film-Focus Distance Technique
MITSUHIKO HIROSE, MITSURU IKEDA, KENGO ITO, TAKEO ISHIGAKI and SADAYUKI SAKUMA
pg(s) 33 - 39
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The possibility of using long film-focus distance radiography as a new screening method for lung cancer
diagnosis was investigated. Long-film focus distance radiogyaphy produced exceptionally superior image
sharpness suitable for use as clinical photographs, at a distance of about FFD (Film-Focus Distance) 20 m.
The effective energy was increased by narrowing the radiation spectrum via an air-filter effect, which may
prove useful in reducing radiation exposure dosage. Questionnaire results indicate good visualization of cardiac
posterior and trachea shadow regions in the diaphragm.
Further study is required regarding methods for stabilizing patient position and synchronization with
heart beat and respiration to improve reproducibility.
Cisplatin, Etoposide, and Vincristine Combination Chemotherapy in the Treatment of Non-Small Cell Lung Cancer
ATSUSHI WATANABE, SATOSHI ICHIYAMA, KAORU SHIMOKATA, EIICHI NAGURA, HIROSHI SAITO, HIDEO SAKA, FUMIO NOMURA, SHUZO SAKAI and HIDEHIKO SAITO
pg(s) 41 - 46
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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 l000/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.
Ultrastructural and Morphometrical Studies on the Reticular Framework and Reticular Fibers in the Reticuloendothelial System of Rats
ABU ABED Y. MOHAMMAD and JUNPEI ASAI
pg(s) 47 - 56
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The reticular framework and reticular fibers in the thymus, cervical lymph node, spleen and bone marrow
of Wistar rats were studied by transmission electron microscopy and morphometrical method. The reticular
framework was usually observed in these organs as a common structure that consisted mainly of the slender
cytoplasmic processes of the fibroblastic reticular cells interconnected with tihgt junction. Ultrastructurally,
the reticular fibers were a mixture of collagen fibrils and amorphous materials, and were almost completely
ensheathed by the cytoplasm of fibroblastic reticular cells. Such characteristic structure of the reticular fibers
was found not only in the thymus, lymph node and spleen, but also in the bone marrow where it has not
been clearly demonstrated previously. Morphometrical analysis revealed that the content of collagen fibrils in
the reticular fiber in the lymphoid tissues (the thymus, lymph node and splenic white pulp) was much greater
than that in the hematopoietic tissues (the bone marrow and splenic red pulp). Based on these evidences, it
was reasonably considered that the reticular framework and reticular fiber ensheathed by the cytoplasm of
the fibroblastic reticular cells were the most representative common structure in the reticuloendothelial system
(RES) and played some important roles in the functions of RES.
Quantitative Analysis of Species Identification Tests of Bloodstains Using Anti-Human Serum
HIROSHI OKAJIMA and YOSHINAO KATSUMATA
pg(s) 57 - 63
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Immunological reactions of bloodstains of human and animals to anti-human serum were analysed quantitatively
to determine which technique is the most effective to differentiate human bloodstains from those of
animals. The lower threshold of counter-electrophoresis was 10-25 μg protein/ml and increased only
slightly with increasing age of the bloodstains, while that of the ring test and immunodiffusion decreased
greatly. In counter-electrophoresis, absorption of anti-human serum by Japanese monkey serum resulted in a
marked decrease in the cross reaction with animals, and still showed no change in the lower threshold for
human samples. The present results show that counter-electrophoresis is especially useful for the identification
of human bloodstains.
The Relationship of High-Density Lipoprotein Cholesterol to Obesity, drinking and Smoking Habits
MASARU MIYAO, MASASHI FURUTA, TAKA-AKI KONDO, HISATAKA SAKAKIBARA,
SHIN'YA ISHIHARA, KATSUMI YAMANAKA and SHIN'YA YAMADA
pg(s) 65 - 70
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Subjects were a total of 726 Japanese male transport service workers between the ages of 35 and 50.
They were analyzed for obesity and drinking or smoking habits in relation to their HDL-cholesterollevel and
total cholesterol concentration. The cases were 100 low HDL-cholesterol (less than 40 mg/dl) and 121 high
total cholesterol (greater than 230 mg/dl) subjects. We used a multiple logistic regression analysis. As for
abnormally high total cholesterol, it was determined that the odds ratios at 40, 45, and 50 years of age were
1.95, 2.23, and 2.65, respectively, when 35-year-olds were considered the baseline. Abnormally high total
cholesterol showed an odds ratio of 0.27 among thin subjects with a Body Mass Index (BMI) less than 21.0,
when subjects with a standard BMI were calculated as the baseline. With reference to low HDL-cholesterol,
the odds ratio for lean subjects was 0.30 against those who had standard habitus, while subjects with a BMI
of more than 25.1 had an odds ratio of more than double. Compared with nondrinkers, low HDL-cholester01
exhibited odds ratios of 0.16 and 0.23, respectively, for moderate and heavy drinkers. In cases of low
HDL-cholesterol, the odds ratios for mild and heavy smokers were 1.91 and 2.27, respectively, versus nonsmokers.
Microassay of Sperm Concentration in the Rat Epididymis by Micropuncture Technique
MASANORI YAMAMOTO, YOSHIKAZU TSUJI and KOJI MIYAKE
pg(s) 71 - 75
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Micropuncture samples taken from the rete testis, caput, corpus and cauda epididymidis of adult rats
were assayed for intraluminal sperm concentrations. The amount of fluid resorbed from the efferent duct
and epididymal lumen was calculated based on the sperm concentration. Epididymal sperm concentrations
increased from the rete fluid to the cauda fluid through the caput fluid. Eighty-nine percent of the fluid leaving
the rete testis is resorbed by the efferent ducts and proximal epididymal tubule, and 96% of the fluid
leaving the rete testis is resorbed in the distal cauda epididymidis. Resorption is important for the control of
intraluminal fluid by the epididymis.
Prosthodontic Closure of Palatal Fistula with Osseointegrated Implants and Onlay Bone Grafts - Case Report -
MINORD UEDA, YOSHIHIRO SAWAKI and TOSHIO KANEDA
pg(s) 77 - 82
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A case treated with onlay bone grafting and simultaneous osseointegrated implant insertion is reported.
The patient had an oronasal fistula in the center of the premaxillary region due to failed repair of a bilateral
cleft palate. Four fixtures were inserted with onlay bone grafting of the maxillary alveolar ridge. Twelve
months postsurgery, one fixture was lost as a result of severe bone resorption around the fixture, but three
fixtures integrated strongly.
We constructed an overdenture stabilized with ball attachments connected to the implants 13 months
after the first operation. Speech and masticatory function improved remarkably with closure of the fistula
and good fixation of the denture.
Cervicofacial Actinomycosis: Report of Two Cases
MICHIO KAWAI, HIDEKI MIZUTANI, MINORU UEDA, TAKESHI HOSHINO and TOSHIO KANEDA
pg(s) 83 - 88
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This article presents two cases of actinomycosis. Case 1 was a 39-year-old man who was first seen with
the chief complaint of swelling around the left submandibular region. Case 2 was a 40-year-old woman who
was first seen with the chief complaint of mass formation around the left buccal area. Both cases were initially
diagnosed as malignant tumors and were later histopathologically interpreted as actinomycosis because
of the presence of sulfur granules.
Cuproproteins of Hepatocyte Lysosomes in Normal and Fatty Liver
NAOKI HISHIDA, AKIRA YAGI, TOMOYUKI HIGUCHI, HISAO HAYASHI,
and NOBUO SAKAMOTO
pg(s) 89 - 96
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The pathophysiological significance of cuproproteins in hepatocyte lysosomes was studied in 7 patients
with structurally normal livers and 13 patients with fatty livers by energy-dispersion X-ray microanalysis. In
most patients, in both groups, copper and sulfur coexisted in hepatocyte lysosomes. The correlation between
copper and sulfur indicated that copper transfer between the cytosol and lysosomes was mediated by a cuproprotein.
The copper indices of the lysosomal proteins and transfer proteins were high in some fatty livers.
These observations suggest that cuproproteins in hepatocytes are not necessarily pathological, but are present
in greater amounts in some fatty livers, probably because of impaired bile drainage.
Solitary Intraosseous Neurofibroma of the Mandible: Report of a Case
MINORU UEDA, HIDEHARU SUZUKI and TOSHIO KANEDA
pg(s) 97 - 101
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A case of solitary intraosseous neurofibroma of the mandible is reported. The tumor was located in the
body of the right mandible. Segmental mandibulectomy including the surrounding tissue was performed and
the mandibule was reconstructed with the free scapular osteocutaneous flap. From histological examination
of the resected mandible, typical findings of a tumor invading the adjacent bone along the mandibular nerve
were observed. Immunohistochemical examination of the tumor showed positive staining of the tumor cells
for anti-S100 protein antibodies. Numerous nerve-like fibers were also noted by Bodian stain.
Remission of Myasthenia Gravis: Clinical, Electrophysiological and Immunological Studies
KAZUO MANOI, TOSHIHIKO TAKEGAMI, SUSUMU OKAMOTOI
and AKlRA TAKAHASHI
pg(s) 103 - 113
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The prognosis of 142 palients with myasthenia gravis (MG) was clinically investigated. Forty-nine (35%)
had clinical remission (CR) and 23 (16%) good improvement (GI), while 70 (49%) remained in poor condition.
Favorable clinical factors for CR were the onset of MG before the age of 20 years, a pre-thymectomy
period of less than one year, and a post-thymectomy period of six years or more. Single-fiber electromyography
(SFEMG) showed abnormal jitter in nine (47%) of the 19 CR patients, while abnormal jitter
was shown in 13 (81%) of the 16 GJ patients. Abnormal jitter in CR patients was correlated with the following
clinical factors: complication with the thymoma, a period of three or more years from thymectomy to remission,
and a remission period of less than six years. An anti-acetylcholine receptor (anti-AChR) antibody
was positive in 12 CR patients (63%) as well as in 13 GI patients (81%). Based upon these facts, we point
out that true remission seldom occurs in MG patients, and that there exist clinical features that may favorably
induce clinical remission. We would like to postulate that electrophysiological and immunological follow-
up is indispensable even in CR patients to predict recurrence.
Hepatic Copper Accumulation in Patients
with Primary Biliary Cirrhosis
HIROTOMO TAKESHIMA, AKIRA YAGI, MOTOYOSHI YANO, NOBUO SAKAMOTO,
SHOSHI KATO, JUNSUKE KURIKI, MOTOHIRO ARAO,
TOSHIKUNI TAKIKAWA and HISAO HAYASHI
pg(s) 115 - 123
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Liver biopsy specimens from 18 patients with primary biliary cirrhosis were examined histochemically
and by energy-dispersive x-ray microanalysis. Using two indices, we classified hepatic copper accumulation
into three stages based on the Cu x-ray intensity of cuproproteins that had accumulated in hepatocyte lysosomes
and on the binding ratio of postulated copper transfer proteins between the cytosol and Iysosomes.
Eight patients were in stage 1 with an initial accumulation of lysosomal cuproproteins, mediated by transfer
proteins not saturated with copper. Two patients were in stage 2, in which transfer proteins were saturated
with copper. The first two stages gave negative results for histochemical copper. The remaining eight patients
were in stage 3, in which copper accumulation detected by histochemical included transfer proteins saturated
with copper and large amounts of lysosomal cuproproteins. Five patients (one each in stages 1 and 2, and
three in stage 3) underwent a second liver biopsy after treatment with 600 mg of ursodeoxycholic acid daily
for 14 to 39 months. Results of blood chemistry tests improved, but liver histologic findings and copper accumulation
were unchanged in all five patients. It seems likely that ursodeoxycholic acid does not affect the
copper accumulation in hepatocyte lysosomes that reflects the state of cholestasis in patients with primary
biliary cirrhosis.
Expression of Proto-Oncogenes and Tumor
Suppressor Genes in in vitro Cell Lines
Derived from a Thymus, Thymoma,
and Malignant Thymoma of Rats
YOSHIHISA SAKAI, WORAWIDH WAJJWALKUI, MASAHIDE TAKAHASHI, AKIRA
MASUDA, KAZUHIKO R. UTSUMI and MUTSUSHI MATSUYAMA
pg(s) 125 - 130
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To analyze the processes of the development of thymoma and malignant thymoma from normal thymic
epithelial cells, we have examined the expression of 15 proto-oncogenes and tumor suppressor genes in
seven in vitro epithelial cell lines established from a normal thymus (TuD1-1, TuD1-3, and TuD1-5), thymoma
(TaD1-3 and TaD1-8), and malignant thymoma (MTHC-1 and MTHC-3) of rats. Northern blot analysis
indicated that most of these genes examined were transcribed at similar levels. However, higher levels of
transcription of epidermal growth factor receptor (EGFR) were observed in TuD1-1, TuD1-3, TuD1-5,
TaD1-3, and TaD1-8 cells than in MTHC-1 and MTHC-3 cells. Conversely, four of the former five cell
lines showed no TGF-β transcription while the latter two cell lines had high levels of its expression. In addition,
c-fos proto-oncogene was highly expressed in TuD1-5 cells, which showed the fastest growth rate
among the seven cell lines. These results denote that some molecular changes in the regulation of gene expression
occurred in the processes of malignant transformation of thymic epithelial cells.
Intrahepatocellular Localization
of Copper in Wilson's Disease
MOTOYOSHI YANO, NOBUO SAKAMOTO, TOSHIKUNI TAKIKAWA,
and HISAO HAYASHI
pg(s) 131 - 137
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It is well known that excess copper plays a role in the pathogenesis of Wilson's disease; however, the hepatic
copper contents, determined either histochemically or biochemically, are not always correlated with the
activity of Wilson's disease. To better understand copper-induced cytotoxicity, intrahepatocellular localization
of copper was studied in five patients with Wilson's disease. The liver specimens were obtained by biopsy
to confirm the clinical diagnosis of Wilson's disease before treatment. Neither hepatic copper content
nor histochemical copper deposits were correlated with any of the biochemical indices studied. Energy-dispersion
X-ray microanalysis was done on the nuclei, lysosomes and lysosome-free cytoplasm of hepatocytes.
Lysosomes had the highest Cu X-ray intensity but no correlation was shown between the lysosomal copper
content and biochemical indices. The nucleus/lysosome-free cytoplasm ratio of the copper content was
correlated with the serum levels of aminotransferases. These results suggest that the copper increasing gradient
from the lysosome-free cytoplasm to the nucleus is associated with hepatocyte necrosis, and probably
causes irreversible nuclear damage.