Invited Review Articles
CD40/CD40 Ligand Interactions in Immune Responses and Pulmonary Immunity
TSUTOMU KAWABE, MIYOKO MATSUSHIMA, NAOZUMI HASHIMOTO, KAZUYOSHI IMAIZUMI and YOSHINORI HASEGAWA
pg(s) 69-78
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The CD40 ligand/CD40 pathway is widely recognized for its prominent role in immune regulation
and homeostasis. CD40, a member of the tumor necrosis factor receptor family, is expressed by antigenpresenting
cells, as well as non-immune cells and tumors. The engagement of the CD40 and CD40 ligands,
which are transiently expressed on T cells and other non-immune cells under inflammatory conditions,
regulates a wide spectrum of molecular and cellular processes, including the initiation and progression of
cellular and humoral adaptive immunity. Based on recent research findings, the engagement of the CD40
with a deregulated amount of CD40 ligand has been implicated in a number of inflammatory diseases. We
will discuss the involvement of the CD40 ligand/CD40 interaction in the pathophysiology of inflammatory
diseases, including autoimmune diseases, atherothrombosis, cancer, and respiratory diseases.
Updated Molecular Genetics and Pathogenesis of Ichthyoses
MASASHI AKIYAMA
pg(s) 79-90
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Research into the molecular genetics and pathomechanisms of ichthyoses have advanced considerably,
resulting in the identification of several causative genes and molecules underlying the disease. In 2009,
the First Ichthyosis Consensus Conference was held to establish a consensus for the nomenclature and
classification of inherited ichthyoses, by which an international consensus for the classification of inherited
ichthyosis was achieved. In this review, the pathogeneses of various ichthyoses are summarized based
on their revised classification and terminology. Skin barrier defects are involved in the pathogenesis
of various types of ichthyosis. The known causative molecules underlying ichthyosis include ABCA12,
lipoxygenase-3, 12R-lipoxygenase, CYP4F22, ichthyin and steroid sulfatase, all of which are thought to be
related to the intercellular lipid layers. ABCA12 is a known keratinocyte lipid transporter associated with
lipid transport in lamellar granules and a loss of ABCA12 function leads to defective lipid transport in the
keratinocytes, resulting in the most severe, harlequin ichthyosis phenotype. Other causative molecules for
ichthyoses are transglutaminase 1, keratins and filaggrin. Transglutaminase 1 plays a role in cornified cell
envelope formation. Keratins 1, 10 and 2 are involved in the keratin network of suprabasal keratinocytes
and filaggrin is essential for the formation of keratohyalin granules. It is important to obtain information
concerning genetic defects and to elucidate ichthyotic disease pathomechanisms for the establishment of
an effective therapy and beneficial genetic counseling, including a prenatal diagnosis for families affected
by ichthyotic disease.
Cardioprotective Mechanisms of Lifestyle Modifications and Pharmacotherapies on Cardiac Remodeling and Dysfunction in Hypertensive Heart Disease: An Overview
KOHZO NAGATA and TAKUYA HATTORI
pg(s) 91-105
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The incidence of cardiovascular events in hypertensive patients is clearly related to a left ventricular
mass during treatment, and a regression of left ventricular hypertrophy is associated with a better prognosis.
This is the case even independently of changes in other risk factors, including blood pressure. Evidence
indicates that lifestyle modifications such as dietary salt restriction and weight loss are effective means
in preventing the development of hypertension and reducing blood pressure and left ventricular mass
in hypertensive patients. Salt restriction may also reduce the long-term risk of cardiovascular events. It
has been recognized that the primary targets of current antihypertensive drugs are the renin-angiotensinaldosterone
system, calcium homeostasis, the ionic transport mechanisms in the kidneys, and the sympathetic
nervous system. Clinical as well as experimental studies have demonstrated the cardioprotective effects
of antihypertensive drugs independently of their blood pressure lowering effects. Hypertension is often
complicated by other disease states including diabetes, dyslipidemia, and ischemic heart disease. Some of
the drugs used for the treatment of such complications are also shown to produce cardioprotective effects
in addition to their original effects. We ought to better understand these pleiotropic effects for the most
effective treatments of hypertension and its complications.
Physical and Psychological Health Problems among Japanese Family Caregivers
YOKO HORI, JUNKO HOSHINO and KISHIKO SUZUKI
pg(s) 107-115
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The authors commenced research in 2005 with the goal of on constructing a health support system for
primary caregivers. This ongoing study aims to develop a health support program and construct a system
of regional assistance based on examining the health situation of family caregivers. Furthermore, it aims
to present proposals that will put the minds of citizens at ease in respect to their ability to live in a
super aging society. A survey was conducted with 213 male and female caregivers and a control group of
477 community residents not engaged in care. This paper collates the various research findings reported
in journals and conference presentations by the authors. Among both male and female caregivers, blood
pressure levels required regulation. Among female caregivers, grip strength and musculoskeletal symptoms
were worse than those in the control group, even when participants were matched for age. We attempted
to determine the characteristics of caregivers who have strong feelings of responsibility and obligation
toward their provision of care. Age was a significantly higher factor in the group with stronger feelings in
that regard. The group with weaker feelings of responsibility and obligation was younger. The percentage
of participants who were caring for a spouse, living with a spouse, had no secondary caregivers, or were
providing all-day care, was significantly higher in the group with stronger feelings of responsibility and
obligation. There was no significant difference between the groups in the mean total score on the J-ZBI-8
that measures burden of care. As the aging population of Japan grows larger, support for caregivers with
physical and psychological health problems, and at the very least, concern of government administrators
and the general public, will assume greater importance.
Original Papers
Spatial and Temporal Distribution of Growth Factors Receptors in the Callus: Implications for Improvement of Distraction Osteogenesis
KAROLINA A SIWICKA, HIROSHI KITOH, MOTOAKI KAWASUMI and NAOKI ISHIGURO
pg(s) 117-127
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Management of bone deficits by distraction osteogenesis is an appreciated but lengthy procedure. To
accelerate the consolidation of newly formed distraction callus, an administration of growth factors into
the distraction gap has been suggested. Changes in expression of growth factors receptors in the distracted
callus during consolidation were studied in order to improve our understanding of the underlying molecular
mechanisms and to provide a scientific basis for clinical application of growth factors. In a model of rat
bone lengthening the expression of receptors for: vascular endothelial growth factor, transforming growth
factor β1, insulin like growth factor and platelet derived growth factor were evaluated semiquantitatively
with immunohistochemistry and quantitatively with real time PCR in various callus zones at zero, one and
two weeks of consolidation. Overall growth factors receptors’ expression was highest at the beginning of
consolidation. It was strongest in the trabecular bone and weakest in the fibrous zone. Transforming growth
factor β receptor 1 was most abundant and vascular endothelial growth factor receptor 1, although scarce,
showed the most consistent expression. In contrast to the osteogenic zones, the fibrous zone demonstrated
a dramatic loss of the growth factors receptors over time. High growth factors receptors expression shortly
after termination of the distraction may warrant the maximal callus’ response to injected growth factors.
Rapid decline of growth factors receptors in the fibrous zone may imply its decreasing sensitivity to growth
factors and, as a consequence, a declining osteogenic potential.
Fragment Size Analysis of Free Fetal DNA in Maternal Plasma Using Y-STR Loci and SRY Gene Amplification
MACHIKO KIMURA, MASAAKI HARA, ATSUO ITAKURA, CHIAKI SATO, KENJI IKEBUCHI and OSAMU ISHIHARA
pg(s) 129-135
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Free fetal DNA (ffDNA) in maternal plasma has now become a valuable source for noninvasive
prenatal diagnosis. Being able to accurately identify the size of ffDNA in maternal plasma is essential for
a noninvasive prenatal diagnosis. Furthermore, it is important to investigate the molecular characteristics
related to apoptosis which gives rise to ffDNA. We investigated the fragment size of ffDNA in each
sample more precisely, using both Y-STR and SRY primers, in 20 maternal plasma samples from the
17th to 39th weeks of gestation. PCR was conducted with Y-STR and SRY primers which can be used to
amplify 100–524 bp fragments. In samples from 10 pregnant women carrying male fetuses, the maximum
fragment size detected by Y-STR and SRY primers ranged from 219 to 313 bp. As a result, the mean
average maximum fragment size of free fetal DNA detected by Y-STR and SRY primers was 286±28 bp.
The Y-STR alleles detected in each maternal plasma DNA sample were all in agreement with the results
of their cord blood samples. We concluded that the fragment size of ffDNA comprises 2 nucleosomal
complexes or less, but not exceeding 3.
Strong Antibody Reaction against Glycosphingolipids Injected in Liposome-Embedded Forms in β3Gn-T5 Knockout
Mice
XIAOYAN FAN, YUJI KONDO, NORIYO TOKUDA, YUHSUKE OHMI, REIKO ANDO,
TOMOKAZU UMEZU, QING ZHANG, KEIKO FURUKAWA, KIYOSUMI SHIBATA,
AKIRA TOGAYACHI, HISASHI NARIMATSU, TETSUYA OKAJIMA, KOJI KIKKAWA and KOICHI FURUKAWA
pg(s) 137-146
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It is known that mutant mice of the β-1,3-N-acetylglucosaminyltransferase gene (β3Gn-T5) respond
well to T-cell dependent and independent antigens. Here, we examined the effectiveness of anti-ganglioside
antibody generation by immunization of β3Gn-T5 mutant mice with liposome-embedded glycosphingolipids
such as GD1a and GT1b. Consequently, the mutant mice showed a more efficient generation of anti-GD1a
or anti-GT1b antibodies than wild-type mice in an enzyme-linked immunosorbent assay using sera during
immunization. Thus, the β3Gn-T5 deficient mutant mice proved more responsive than wild-type mice to
not only protein antigens, but also to carbohydrates in glycolipids. Furthermore, about 50% of monoclonal
antibodies generated using splenocytes of the immunized mutant mice were of the IgG class. Besides general
high responsiveness to proteins and glycolipids, it could be expected that the mutant mice of β3Gn-T5
would be useful in the generation of monoclonal antibodies towards lacto-/neolacto-series glycolipids,
since these mutants lack lacto-/neolacto-series glycolipids. In fact, they showed a good serum response
in immuno-fluorescence assay with cultured living cells when immunized by glycolipids extracted from
ovarian cancer cell lines. These results suggested that β3Gn-T5 mutant mice are useful for the generation
of anti-glycolipid antigens with lacto-/neolacto-core structures expressed in cancer cells.
Early Prediction of Response to Neoadjuvant Chemotherapy for Locally Advanced Breast Cancer Using MRI
MARIKO KAWAMURA, HIROKO SATAKE, SATOKO ISHIGAKI,
AKIKO NISHIO, MASATAKA SAWAKI and SHINJI NAGANAWA
pg(s) 147-156
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Neoadjuvant chemotherapy (NAC) is the favored treatment of choice among locally advanced breast
cancer patients because it significantly increases the possibility of breast-conserving surgery. However, for
non-responders, an early prediction of response to NAC is essential. The purpose of this study was to
determine whether an early prediction of response to NAC is possible using MRI. Eleven breast cancer
patients (12 lesions) scheduled to receive NAC were recruited for this study. The patients were examined
by MRI prior to and after the first and fourth courses of anthracycline-containing chemotherapy and after
subsequent taxane-containing chemotherapy. Lesions were divided into 2 types (mass type and non-mass
type) based on contrast MRI prior to chemotherapy. Among 8 mass types, 6 were responders (R) and 2
were non-responders (NR). R cases showed either an increased apparent diffusion coefficient (ADC) or
volume reduction after the first course of NAC, whereas NR cases showed neither (p<0.005). Of the 4
non-mass types, 2 were R and 2 were NR. Changes in ADC or volume after the first course of NAC
may indicate chemo-sensitivity for mass-type breast cancer. However, the same method cannot be used to
predict the response to NAC for non-mass types.
An Assessment of Antibiotics Prescribed at the Secondary Health-Care Level in the Kyrgyz Republic
KAMBARALIEVA BAKTYGUL, BOZGUNCHIEV MARAT, ZURDINOV ASHIRALI,
MD. HARUN-OR-RASHID and JUNICHI SAKAMOTO
pg(s) 157-168
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This study was undertaken to evaluate the pattern of antibiotic prescriptions in a secondary health care
setting in Kyrgyzstan. A retrospective analysis was performed of antibiotic prescriptions in 251 inpatient
records of patients admitted to the Sokuluk Territorial Hospital. A total of 19 different antibiotics were
prescribed. Penicillin G (24.9%), gentamicin (16.1%), metronidazole (15.6%) and cefazolin (14.5%) were
those most frequently prescribed. The major indications for antibiotics were diseases of the respiratory
system (28.0%), injury, poisoning and certain other consequences from external causes (25.5%), and diseases
of the digestive system (14.3%). Almost three-quarters of the antibiotics were used parenterally, 252 of
which (58.9%) were administered intramuscularly and 70 (16.4%) intravenously. Forty-five percent of the
patients received two antibiotics, and 12.0% received three antibiotics during their stay at the hospital.
Antibiotic therapy proved inappropriate for 184 patients (73.3%). The most common reason given for
inappropriateness was the unjustified (not indicated) use of antibiotics in 143 (48.6%) cases. There was a
significantly higher inappropriate choice of antibiotics in gynecology (OR=2.70, 95% CI=1.02–7.69) when
compared with that in other wards. Although antibiotics were prescribed in all cases post-operatively, none
of those patients were given pre-operative prophylactic antibiotics when indicated. We concluded that
antibiotic prescriptions were seriously inappropriate in the Kyrgyz Republic with prescribing patterns failing
to strictly adhere to the national guidelines. Adoption of an international standard and locally conformable
guidelines of antibiotic use can help correct such problems.
No Association between Angiotensin I converting Enzyme (ACE) I/D Polymorphism and Gastric Cancer Risk among
Japanese
SATOSHI HIBI, YASUYUKI GOTO, TAKAFUMI ANDO, KEITARO MATSUO,
KENJI WAKAI, KAZUO TAJIMA, HIDEMI GOTO and NOBUYUKI HAMAJIMA
pg(s) 169-175
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The angiotensin I-converting enzyme (ACE) is involved in cell proliferation, angiogenesis, inflammation,
and tissue remodeling, all of which could play a role in carcinogenesis. The DD genotype of ACE I/D polymorphism with a higher ACE level than either ID or II genotypes was reported to increase the risk
of several cancers. This is a case-control study examining the association between the polymorphism and
gastric cancer risks among Japanese. Cases numbered 583 patients aged 27 to 80 years with gastric cancer
diagnosed at the Aichi Cancer Center Hospital from 2001 to 2005. Controls were 1,742 sex and age
frequency-matched cancer-free patients, who visited the same hospital during that same period. The ACE
I/D polymorphism was genotyped using a polymerase chain reaction with confronting two-pair primers. The
results showed that the age- and sex- adjusted ORs of gastric cancer were 0.95 (95% CI, 0.78-1.16) for
ID, and 1.08 (95% CI, 0.80-1.46) for DD relative to II. Among the controls with H. pylori sero-positive or
gastric atrophy (GA), the ORs of ID and DD relative to II were 1.20 (95% CI, 0.88-1.63) and 1.16 (95%
CI, 0.73-1.84) for mild GA, and 1.22 (95% CI, 0.84-1.78) and 1.08 (95% CI, 0.61-1.89) for severe GA,
respectively. In conclusion, there was no significant association of the ACE I/D polymorphism with the risk
of gastric cancer. Among the controls, the polymorphism was not associated with the severity of GA.
Healthcare Workers’ Knowledge and Practices Regarding Expanded Program on Immunization in Kalasin, Thailand
ONPRASONK WIDSANUGORN, ONPRASONK SUWATTANA, MD. HARUN-OR-RASHID and JUNICHI SAKAMOTO
pg(s) 177-185
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Primary vaccine failures can occur after high immunization coverage has been achieved. Healthcare
workers’ knowledge and practices are influential factors in preventing vaccine failures. Adequate knowledge
and practices in the cold chain system are important to keep potency of vaccines and effectiveness of
immunization. This cross-sectional study was performed to assess healthcare workers’ knowledge and
practices regarding an expanded program on immunization and the cold chain system in Kalasin, Thailand.
Data collection methods included interviews, observations and document audit. Ninety primary care units
and 117 respondents were selected. Only 55.6% of respondents provided correct answers for questions
regarding the immunization schedule of school children and 59.0% of respondents answered correctly for
questions about Measles-Mumps-Rubella Vaccine. Healthcare workers in hospitals had better knowledge
than healthcare workers in health centers (P<0.001). Healthcare workers who had sufficient training had
better knowledge than healthcare workers who had no training (P<0.001). Only 61.1% of primary care units
recorded the temperature in the vaccine refrigerator twice a day and 63.3% of primary care units had a
flowchart regarding what to do when there is an electric power failure. About 13% of vaccine refrigerators
had temperatures outside the recommended range of 2 to 8°C. Practices in hospitals were also better than
those in health centers (P=0.001). Knowledge and practices were significantly different between healthcare
workers in hospitals and in health centers. Coverage training and regular supervision on vaccine handling
and the cold chain system are recommended, especially for health centers in remote areas.
Note
Study Profile on Baseline Survey of Daiko Study in the Japan Multi-Institutional Collaborative Cohort Study (J-MICC
Study)
EMI MORITA, NOBUYUKI HAMAJIMA, ASAHI HISHIDA, KYOKO AOYAMA,
RIEKO OKADA, SAYO KAWAI, KOUTARO TOMITA, SAYAKA KURIKI, TAKASHI TAMURA,
MARIKO NAITO, TAKAAKI KONDO, JUN UEYAMA, AKIKO KIMATA, KANAMI YAMAMOTO,
YOKO HORI, JUNKO HOSHINO, RITSUKO HAMAMOTO, SANAE TSUKAMOTO, JOJI ONISHI,
SHOICHI HAGIKURA, HISAO NAITO, SATOSHI HIBI, YOSHINORI ITO and KENJI WAKAI
pg(s) 187-195
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The Japan Multi-Institutional Collaborative Cohort Study (J-MIC Study) is a long-term cohort study
to investigate the interactions among genotypes, lifestyles, and lifestyle-related diseases, especially cancer.
This article reports the outline of the baseline survey of the Daiko Study, one site of the J-MIC Study.
That survey was conducted between June 9, 2008 and May 31, 2010 at the Daiko Medical Center of
Nagoya University in Nagoya, Japan. Subjects were registered residents of Nagoya City aged 35 to 69
years who had not participated in other J-MIC sites. Recruitment was mainly announced through leaflets
distributed in mailboxes citywide, personal communications, and regional information, such as posters in
public or commercial facilities. Participants provided blood plasma, serum, buffy coat, urine, and data on
health check-ups. They also completed a self-reported questionnaire on lifestyle, disease history, family
history, and for women, reproductive history. As of the end of September 2010, 4 out of 5,172 registered
participants had withdrawn from the study, leaving data from 5,168 participants (1,467 males and 3,701
females) available for analysis. Mean age ± standard deviation (SD) was 52.5 ± 10.3 years. Current
smokers accounted for 24.1% (n=354) of males and 6.9% (n=256) of females. Current drinkers included
74.9% (n=1,099) of males and 45.9% (n=1,699) of females. Lifestyle data and specimens were successfully
collected to examine any associations among disease biomarkers, lifestyles, and genotypes.
Case Reports
Total En Bloc Spondylectomy for L2 Chordoma: A Case Report
NORIMITSU WAKAO, SHIRO IMAGAMA,
ZENYA ITO, KEI ANDO, KENICHI HIRANO, RYOJI TAUCHI, AKIO MURAMOTO,
HIROKI MATSUI, TOMOHIRO MATSUMOTO, YUKIHIRO MATSUYAMA and NAOKI ISHIGURO
pg(s) 197-203
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Chordoma is a rare vertebral tumor that develops from the chorda. The high malignant potential of
this tumor, which is associated with a poor life prognosis, has been recognized particularly in the case of
tumors originating at the mobile spine. In recent years, en bloc resections of such tumors and an increasing
emphasis on a complete local cure have resulted in a certain degree of improvement in the prognosis.
This case concerns a 61-year-old male with an L2 chordoma on whom en bloc spondylectomy was
performed using a combined anterolateral retroperitoneal, and posterior approach. During the follow-up
period, since the transplanted bone was fractured and the rod was broken, a reoperation was performed.
Although the surgical margin became intralesional, a favorable course without any metastasis or recurrence
during a 10-year postoperative follow-up has been observed. The presenting symptoms, imaging studies, and
related literature are reviewed in this report. Thus, the method used in this case may also be considered
potentially effective in achieving a radical cure in advanced cases with a local recurrence.
A Case of Autoimmune Hepatitis with Graves’ Disease Treated by Propylthiouracil
IKUKO SATO, TAKU TSUNEKAWA, YURI SHINOHARA, YUICHIRO NISHIO,
YUKO SHIMIZU, YASUHIKO SUZUKI and SHUKO YOSHIOKA
pg(s) 205-209
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A 58-year-old woman was referred to our hospital because of liver dysfunction. Her serum levels of
AST (619 IU/l) and ALT (603 IU/l) had increased. Histological findings in the liver biopsy were compatible
to autoimmune hepatitis (AIH), and the diagnosis of AIH was confirmed by the diagnostic criteria.
She was admitted to a nearby hospital 3 years ago, and diagnosed with Graves’ disease. She received
methimazole (MMI) at first, which was discontinued due to liver injury in one month, then propylthiouracil
(PTU) was administered. One year later, transaminase increased and was decreased by stopping PTU
administration. PTU was restarted after her transaminase decreased, but a recurrence of hepatotoxicity was
observed, and she was referred to our hospital. Oral prednisolone decreased liver function immediately.
In this case, PTU-induced liver injury was suspected as a possible trigger of AIH. While PTU remains a
commonly used drug in the treatment of hyperthyroidism, severe liver injury is reported in some cases. If
liver injury is observed in patients treated with PTU, rechallenge is not recommended in order to avoid
severe hepatotoxicity.
Subtrochanteric Fracture in a Patient Receiving Zoledronic Acid Therapy for Metastatic Breast Cancer
YASUZUMI KISHIMOTO, TOSHIKI IWASE, ATSUSHI KOYAMA,
TETSUO MASUI, GO YOSHIDA, HIDEO MATSUO and NAOKI ISHIGURO
pg(s) 211-215
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A 61-year-old woman presented with acute pain of the right thigh after falling on a public street. She
had been diagnosed with metastatic breast cancer and bisphosphonate therapy along with zoledronic acid.
Radiographs demonstrated transverse subtrochanteric femoral fracture with thickening of the lateral cortex
and spike of the medial cortex at the site of fracture. The contralateral femur showed thickening of the
lateral cortex at the same site. This type of stress fracture is related to severe suppression of bone turnover
(SSBT) under bisphosphonate therapy. Our patient had been receiving zoledronic acid therapy for 3.6 years,
and the radiographic findings were typical of stress fracture associated with bisphosphonate. Therefore,
the facture in our patient was considered related to SSBT under zoledronic acid therapy. Zoledronic acid
is administered to patients with osteoporosis or complications due to cancer such as hypercalcemia of
malignancy. Recently stress fractures associated with zoledronic acid therapy for osteoporosis have attracted
attention. However, there are few reports of fracture associated with zoledronic acid therapy for cancer.
Doses of zoledronic acid recommended for cancer patients are much greater than those for patients with
osteoporosis. Clinicians treating such cancer patients need to cautiously manage stress fractures as a
complication of zoledronic acid therapy.
