Invited Review Article
Immunoregulation of Hepatitis B Virus Infection –Rationale and Clinical Application–
TETSUYA ISHIKAWA
pg(s) 217-232
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Hepatitis B virus (HBV) is susceptible to the cellular immune responses, especially to the signal of interferon (IFN)-γ. The action of IFN-γ is pleiotropic, and causes downregulation of HBV in protein, RNA, and possibly DNA levels. Therefore, therapeutic vaccination to induce cellular immune responses to HBV is a promising approach for controlling chronic HBV infection. A number of clinical trials with this approach have been conducted to date, however, they have not been as successful as initially expected.T-cell exhaustion induced by the excessive HBV antigens caused by persistent infection is thought to be one of the main causes of poor responses to therapeutic vaccination. In this review, the mechanisms behind immunoregulation of HBV replication and immunodysfunction during chronic HBV infection are summarized, and novel approaches to improve the efficacy of therapeutic vaccination, from basic research to clinical trials, are introduced.
Original Papers
Improvements in the Status of Women and Increased Use of Maternal Health Services in Rural Egypt
CHIFA CHIANG, INASS HELMY HASSAN ELSHAIR, LEO KAWAGUCHI, NAWAL ABDEL MONEIM FOUAD, NAGAH MAHMOUD ABDOU, MICHIYO HIGUCHI, SANEYA RIZK EL BANNA and ATSUKO AOYAMA
pg(s) 233-240
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This research investigated the association between the household status of women and their use of
maternal health services in rural Egypt. Face-to-face interviews with a structured questionnaire to 201
married women were carried out in a village, posing questions about their health service utilization and
their household socio-economic status. The association between service utilization and other variables was
statistically analysed. Older ages at first marriage and higher education levels showed significant positive
associations with the three outcome variables—regular antenatal care (ANC), deliveries attended by skilled
health professionals, and deliveries at heath facilities—of the use of maternal health services. Women who
had not experienced physical assaults by husbands and had knowledge of community activities were more
likely to receive ANC regularly; however, there were no significant association with the other two outcome
variables. Participation in household decision-making and availability of assistance with household chores
had no significant linkage to the use of maternal health services. Marriages to husbands with secondary
or higher levels of education and residence in extended families were significantly associated with greater
maternal health service usage. Our results suggest that the improved status of women in the household
and moral support from family members contributes to an increase in the use of maternal health services.
Postoperative Function Following Radical Surgery in Gastric and Colorectal Cancer Patients over
80 Years of Age – An Objection to "Ageism"
SHINJI FUKATA, MASAHIKO ANDO,
TAKESHI AMEMIYA, KOJIRO KUROIWA and KOJI ODA
pg(s) 241-252
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PURPOSE: With rapid growth in the elderly population, the number of elderly cancer patients who
should be offered life-prolonging radical surgery has been increasing. The aim of this report is to demonstrate
the outcome of elective radical surgery for gastric or colorectal cancer patients 80 years of age or
older, including the natural course of recovery of functional independence, in order to avoid the negative
attitude held toward surgery that is due only to patients’ high chronological age.
METHODS: Physical condition, ADL, and QOL of 108 patients 80 years of age or older with gastric or
colorectal cancer were evaluated preoperatively and at the 1st, 3rd, and 6th postoperative months.
RESULTS: There were no operative deaths, and the morbidity rate was 27.9%. Only 6% of the patients
showed a decrease in ADL at the 6th postoperative month. This decrease typically occurred following
discharge from the hospital. Patient QOL showed recovery to an extent equal to or better than average
preoperative scores.
CONCLUSIONS: Of the patients who underwent elective surgery for gastric or colorectal cancer, only a
few showed a protracted decline in ADL, and most exhibited better QOL after surgery. Surgical treatment
should therefore be considered, whenever needed, for elderly patients 80 years of age or older with gastric
or colorectal cancer.
Morphologic Characterization and Quantification of Superficial Calcifications of the Coronary Artery
—In Vivo Assessment Using Optical Coherence Tomography—
MASAYA MATSUMOTO,
DAIJI YOSHIKAWA, HIDEKI ISHII, SEIICHI HAYAKAWA, MIHO TANAKA,
SOICHIRO KUMAGAI, MUTSUHARU HAYASHI and TOYOAKI MUROHARA
pg(s) 253-260
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Coronary calcification is proportional to the extent and severity of atherosclerotic disease, and is a
predictor of cardiac events. Furthermore, coronary calcification protruding into the lumen is considered as
one type of vulnerable plaque. Optical coherence tomography (OCT) can provide in vivo imaging of the
detailed vessel wall structure of the coronary artery with high resolution, as in the histological approach.
We analyzed coronary calcification in that fashion using OCT in vivo. This study consisted of 70 superficial
coronary calcifications of 39 consecutive patients who underwent percutaneous coronary intervention. After
revascularization, OCT was performed in the treated vessel. We analyzed morphologic characteristics and the
quantification of OCT-determined coronary calcification. Superficial coronary calcifications were classified
into two groups depending on whether they did not intrude the lumen (type I) or did (type II). The distance
from the lumen and the volume of each calcification were then measured. Superficial coronary calcifications
were classified into two groups; type I, n = 39 (56%) and type II, n = 31 (44%). Type II calcifications
were located significantly closer to the lumen [80 μm (60–130) vs.130 μm (90–260), p = 0.015], and
tended to be smaller, but did not show a significant difference [0.65 (0.26–1.3) mm3 vs. 1.2 (0.47–1.9)
mm3, p = 0.153] compared to those of type I. In conclusion, OCT could visualize superficial coronary
calcifications in detail and enable us to evaluate in vivo morphologic characterizations and quantify them.
Involvement of KRAS G12A Mutation in the IL-2-Independent Growth of a Human T-LGL Leukemia
Cell Line, PLT-2
NAOKI MIZUTANI, HIROMI ITO,
KAZUMI HAGIWARA, MISA KOBAYASHI, ASUKA HOSHIKAWA,
YAYOI NISHIDA, AKIRA TAKAGI, TETSUHITO KOJIMA, MOTOSHI SUZUKI,
YOSUKE OSAWA, KAZUNORI OHNISHI, MASANORI DAIBATA and TAKASHI MURATE
pg(s) 261-272
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Cytokine-dependent cell lines have been used to analyze the cytokine-induced cellular signaling and the
mechanism of oncogenesis. In the current study, we analyzed MOTN-1 and PLT-2 cell lines established
from different stages of a T-cell large granular lymphocyte leukemia patient (Daibata et al. 2004).
MOTN-1 is IL-2-dependent derived from the chronic phase, whereas IL-2-independent PLT-2 is from the
aggressive and terminal stage. They shared considerable chromosome abnormalities and the pattern of
T-cell receptor rearrangement, presuming that the cytokine independence of PLT-2 was due to the additive
genetic abnormality. Besides IL-2, IL-15 supported MOTN-1 cell growth, because these receptors share
β- and γ-subunits. IL-2 activated ERK, AKT and STAT pathway of MOTN-1. STAT3 pathway of PLT-2
was also activated by IL-2, suggesting intact IL-2 induces signal transduction of PLT-2. However, ERK1/2
but not AKT, was continuously activated in PLT-2, consistent with the increased Ras-activity of PLT-2.
Sequence analysis revealed KRAS G12A mutation but not NRAS and HRAS mutation of PLT-2 but not
MOTN-1. Another signaling molecule affecting Ras-signaling pathway, SHP2, which has been frequently
mutated in juvenile myelomonocytic leukemia (JMML), did not show mutation. Moreover, MEK inhibitor,
PD98059, as well as farnesylation inhibitor inhibited PLT-2 cell growth. Using NIH3T3 and MOTN-1, ERK
activation, increased cell proliferation and survival by KRAS G12A were shown, suggesting the important
role of KRAS G12A in IL-2-independent growth of PLT-2. Taken together, KRAS G12A is important for
IL-2-independent growth of PLT-2 cells and suggests the possibility of involvement of KRAS mutation
with disease progression.
Social Correlates of Female Infertility in Uzbekistan
IZATULLA JUMAYEV,
MD. HARUN-OR-RASHID, OYBEK RUSTAMOV,
NODIRA ZAKIROVA, HIDEKI KASUYA and JUNICHI SAKAMOTO
pg(s) 273-284
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The purpose of this matched case-control study was to investigate the social correlates of primary
infertility among females aged 35 years or less. The study was conducted in the Clinics of Samarkand
Medical Institute, Uzbekistan, among 120 infertile and 120 healthy women matched by age, residential
area, and occupation from January to June 2009. Data were collected by face-to-face interviews using a
structured questionnaire. Median duration of infertility was 10.0 months (interquartile range = 6.0–13.0).
The rate of remarriage was 3.5 times higher among infertile women compared with healthy subjects.
Insufficient family income, poor quality of life, life stress, and discontentment with daily routines as well
as ‘bad’ relationships with family members (husband, mother- and father-in-law) were significant correlates
of female infertility. Infertile women were more likely to underestimate the importance of sexual intimacy,
and a negative attitude to sex. Female infertility is associated with various social correlates leading to
higher remarriage rates and to further complicating the problem of infertility. Thus, a correction of women’s
basic attitudes and their relationships to their surrounding social habitat should be an essential component
of any program of infertility management.
Association of Obesity and Diabetes with Serum Prostate-Specific Antigen Levels in Japanese
Males
MARIKO NAITO, YATAMI ASAI, ATSUYOSHI MORI, YUKO FUKADA,
MAYUMI KUWABARA, SHIRO KATASE, ASAHI HISHIDA, EMI MORITA,
SAYO KAWAI, RIEKO OKADA, KAZUKO NISHIO, AKIKO TAMAKOSHI,
KENJI WAKAI and NOBUYUKI HAMAJIMA
pg(s) 285-292
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Patients with diabetes have been reported to be at an increased risk for cancers of the pancreas, liver,
and colon; however, recent studies have suggested that men with diabetes are at a decreased risk for
prostate cancer. Previous studies have found that obese men have lower serum prostate-specific antigen
(PSA) concentrations than do non-obese men. Further understanding of how obesity and diabetes affect
the PSA concentration may improve our ability to detect clinically relevant prostate tumors. This study
examined the relationships among serum PSA level, obesity, and diabetes in apparently healthy Japanese
males. We analyzed the baseline data from 2,172 Japanese males (age, 56.8 ± 6.1 years [mean ± SD])
who participated in the Japan Multi-Institutional Collaborative Cohort Study. Diabetes was defined as the
presence of both a hemoglobin A1c (JDS) of ≥6.1% and a fasting plasma glucose level of ≥126 mg/dL,
or a positive medical history. After adjusting for age, the PSA levels were elevated among males with a
higher normal BMI (ranging from 23.0 to 24.9) and lowered among men with a BMI of ≥25.0. In the
stratified analysis, these significant differences in BMI categories were absent among diabetics. The mean
PSA levels were significantly lower in diabetics than in non-diabetics among subjects aged 60 and over.
Our findings suggest that the pre-overweight men had increased PSA levels, and the diabetes was associated
with a reduction of PSA levels in elderly.
CFTR Polymorphisms of Healthy Individuals in Two Chinese Cities—Changchun and Nanjing
CHUN XIANG JIN, KOTOYO FUJIKI, YING SONG,
ZHANG PING, MIYUKI NAKAKUKI, MU XIN WEI,
SU MIN ZHANG, HIROSHI ISHIGURO and SATORU NARUSE
pg(s) 293-302
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Background and Aim Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR)
gene, which encodes a chloride channel, cause cystic fibrosis. In order to investigate the polymorphic
backgrounds of CFTR genes of healthy populations in different Chinese cities (Changchun and Nanjing),
we analyzed 119 blood samples (Changchun 64, Nanjing 55) of randomly selected healthy individuals
for poly T, TG-repeats and M470V polymorphisms. We analyzed the differences of CFTR polymorphic
distributions between the two Chinese cities from the south and the north. Methods Genomic DNA was
extracted from whole blood. DNA fragments of CFTR gene were amplified by polymerase chain reaction
(PCR). Poly-T and TG repeats were directly sequenced by auto sequencer (ABI 310). M470V was detected
by a HphI restriction enzyme. Results The T7 allele was the most common haplotype in Changchun (0.938)
and Nanjing (0.927) populations. The T5 allele was present in only 7 Changchun and 3 Nanjing subjects.
The TG11 and TG12 alleles were dominant haplotypes in Changchun (TG11 0.500, TG12 0.453) and
Nanjing (TG11 0.345, TG12 0.609). The frequency of the V470 allele was 0.633 in Changchun, which
was higher than that in Nanjing (0.500) (p<0.05). There were three major haplotypes: T7-TG11-V470,
T7-TG12-M470 and T7-TG12-V470. The T7-TG11-V470 was the most common haplotype in Changchun
(0.514), while T7-TG12-M470 was the most common haplotype in Nanjing (0.500). Conclusion Though
Changchun and Nanjing are in the same country, their polymorphic backgrounds of CFTR gene are very
different. Most of the two populations have genotypes that cause lower CFTR function.
Restricted Expression of New Guanine Nucleotide Exchange Factor Zizimin2 in Aged Acquired
Immune System
YANJUN JIA, ISAMU SAKABE, TAKENORI MATSUDA,
TOMOKO HAYAKAWA and MITSUO MARUYAMA
pg(s) 303-311
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The activity of various biological functions, such as nervous, endocrine and immune systems including
acquired immunity, is known to decline along with aging. To elucidate the molecular mechanism of this
phenomenon, we here compared the number of thymocytes, splenocytes, and bone marrow lymphocytes
in young and aged mice and found the age-related functional fragility of the immune system. However,
the molecular mechanisms or even the key molecules remain elusive. Therefore, we further focused on a
candidate for immunosenesence-related molecules, Zizimin2, which we have recently isolated and identified
as a novel guanine nucleotide exchange factor that is highly expressed in murine splenic germinal center
B cells after immunization with a T cell-dependent antigen. Here, we showed that endogenous Zizimin2
protein as well as mRNA expression levels in immune organs are strictly suppressed in aged mice. We
further observed that the serum antigen specific antibody response is hampered in aged mice compared to
that in young animals. Moreover, the Zizimin2 mRNA expression level was not activated after immunization
in aged mice. Taken together, these data suggested that Zizimin2 is associated with the reduction of
immune response in acquired immunity along with aging.
Case Reports
Inflammatory Index and Treatment of Brain Abscess
HIROFUMI OYAMA, AKIRA KITO,
HIDEKI MAKI, KENICHI HATTORI, TOMOYUKI NODA and KENTARO WADA
pg(s) 313-324
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This study retrospectively analyzed 12 patients with brain abscesses. Half of the patients were diagnosed
inaccurately in the initial stage, and 7.2 days were required to achieve the final diagnosis of brain
abscess. The patients presented only with a moderately elevated leukocyte count, serum CRP levels, or
body temperatures during the initial stage. These markers changed, first with an increase in the leukocyte
count, followed by the CRP and body temperature. The degree of elevation tended to be less prominent,
and the time for each inflammatory index to reach its maximum value tended to be longer in the patients
without ventriculitis than in those with it.
The causative organisms of a brain abscess were detected in 10 cases. The primary causative organisms
from dental caries were Streptococcus viridians or milleri, and Fusobacterium nucleatum. Nocardia sp. or
farcinica were common when the abscess was found in other regions. The primary causative organisms
of unrecognized sources of infection were Streptococcus milleri and Prolionibacterium sp. Nocardia is
resistant to many antibiotics. However, carbapenem, tetracycline and quinolone were effective for Nocardia
as well as many other kinds of bacteria.
In summary, the brain abscesses presented with only mildly elevated inflammatory markers of body
temperature, leukocyte and CRP. These inflammatory markers were less obvious in the patients without
ventriculitis and/or meningitis. The source of infection tended to suggest some specific primary causative
organism. It was reasonable to initiate therapy with carbapenem.
Treatment of a Cerebral Dissecting Aneurysm in Anterior Circulation: Report of 11 Subarachnoid
Hemorrhage Cases
HIROFUMI OYAMA, AKIRA KITO, HIDEKI MAKI,
KENICHI HATTORI, TOMOYUKI NODA and KENTARO WADA
pg(s) 325-338
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This report presents 8 cases of internal carotid artery aneurysms, 1 case of a middle cerebral artery
aneurysm, and 2 cases of anterior cerebral artery aneurysms, together with a discussion of the treatment
of aneurysms in anterior circulation. All cases showed subarachnoid hemorrhage. Two of the 8 internal
carotid artery aneurysms were trapped with a low-flow bypass; however, both patients died of an immediate
hemodynamic infarction or vasospasm-induced infarction. Five of the 8 internal carotid artery aneurysms
were trapped after revascularization with high flow bypass. Four of those patients were self-supporting at
discharge, but one patient was discharged in a vegetative state due to the sacrifice of arterial branches
which were included in the dissecting portion. One case of the dissecting aneurysm in the M2 portion of
the middle cerebral artery was trapped after low-flow bypass. This patient was self-supporting at discharge.
In 2 cases of anterior cerebral artery aneurysms, the lesions were first wrapped with Bemsheets, and then
the aneurysmal clip was applied on the wrapped dome. Trapping following high-flow bypass is the best
method for treating a dissecting aneurysm in the internal carotid artery. Trapping also can be used to
treat a dissecting aneurysm of the middle cerebral artery, after low-flow bypass. Clipping on the wrapped
aneurysm can also be performed successfully in the anterior cerebral artery aneurysm.
Air Vent of Vein Graft in Extracranial-Intracranial Bypass Surgery
HIROFUMI OYAMA,
AKIRA KITO, HIDEKI MAKI, KENICHI HATTORI, TOMOYUKI NODA and KENTARO WADA
pg(s) 339-345
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Revascularization with a vein graft is a mandatory method for treatment of dissecting or pseudoaneurysms
of the internal carotid artery. We report the necessity for an air vent from the vein graft and explain
its use in our two cases. In Case 1, we searched for a great saphenous vein around its junction with a
femoral vein during the harvest of vein graft. An accessory branch of that great saphenous vein was also
found around the junctional region with a femoral vein, and was temporarily ligated. At first, anastomosis
was completed on both the distal and proximal sides. After the proximal side of a vein graft was opened
and the ligation of the branch was loosened, an air vent could be made through the branch of the vein
graft. Multiple air bubbles and a large quantity of white microemboli were discharged through this branch.
The postoperative course was uneventful. In Case 2, the air vent was omitted to shorten ischemia. During
the opening of the vein graft, the migrated air was observed to move to the middle cerebral artery. A
computed tomography scan demonstrated that brain infarction and dysarthria occurred postoperatively. The
air vent of the vein graft is essential in extracranial-intracranial bypass surgery, because the air bubbles or
microthrombi are easily trapped around the valve and cause cerebral infarction. An air vent can be easily
made if the branch of a vein graft exists in the outflow pathway, because intraluminal air or thrombus
can be washed out through the branch at the final stage of surgery.
Metastatic Breast Cancer to the Uterine Cervix Mimicking a Giant Cervical Leiomyoma
MAI HORIKAWA, YUKIKO MORI, SACHI NAGAI, SHIHO TANAKA,
SHIGEKO SAITO and TOMOMITSU OKAMOTO
pg(s) 347-352
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Metastasis to the uterine cervix is a complication of breast cancer that is not commonly known.
Detection of cervical metastasis before the diagnosis of the primary tumor is even rarer. The present report
describes a case of a 52-year-old woman who had a large cervical tumor appearing as a leiomyoma.
She underwent a total abdominal hysterectomy with bilateral salpingo-oophorectomy. Histopathological
examination of the cervical tumor showed patterns characteristic of invasive lobular carcinoma of the
breast, leading to the discovery of the primary in the left breast. She subsequently underwent mastectomy,
hormone therapy and chemotherapy, and is alive at 7-year follow-up.
Intravascular Lymphoma of the Central Nervous System Presenting as Multiple Cerebral
Infarctions
HIROYUKI MOMOTA, YOSHITAKA NARITA,
YASUJI MIYAKITA and SOICHIRO SHIBUI
pg(s) 353-358
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A 67-year-old woman presented with an acute onset of left-sided weakness. Magnetic resonance
(MR) imaging revealed multiple cerebral infarctions and gadolinium-enhanced lesions in both cerebral
hemispheres. Her symptoms once improved after starting steroid treatment; however, soon developed
consciousness disturbance and hemiparesis on the left side. She was referred to our hospital where she
underwent stereotactic needle biopsy, that revealed an intravascular large B-cell lymphoma in the cerebrum.
She received high-dose methotrexate chemotherapy followed by whole-brain radiation therapy, and the MR
findings improved. However, her medical condition gradually worsened, and she died 6 months after disease
onset. Intravascular lymphoma (IVL) limited to the central nervous system (CNS) is very rare, and the
optimal treatment for this medical condition has not been established yet. IVLs showing only neurologic
manifestations might be overlooked or misdiagnosed as cerebral infarctions. Here, we present a case of CNS
IVL, with its radiographic and pathologic features and treatment with high-dose methotrexate chemotherapy
Short Communication
Pilot Study on the Effects of a 1-Day Sleep Education Program: Influence on Sleep of Stopping
Alcohol Intake at Bedtime
EMI MORITA, SOICHIRO MIYAZAKI
and MASAKO OKAWA
pg(s) 359-365
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The aim of this pilot study was to evaluate whether sleep was improved by a 1-day sleep education
program in an occupational setting and whether stopping alcohol intake at bedtime might influence sleep.
Subjects were 40 high school employees. The sleep education program lasted 4.5 hours and consisted
of sleep science information, and sleep hygiene education including the risk of sleep related breathing
disorder resulting from alcohol intake. Sleep conditions were evaluated by self-administered questionnaires
at baseline and approximately 1 month later. The mean the Epworth Sleepiness Scale (ESS) score was
significantly decreased by 1.2 points (P = 0.04), while the mean sleep duration was significantly decreased
by 10 minutes (P = 0.02). Shortened sleep duration coincided with a decrease in sleepiness. This may
indicate an improvement in sleep quality. The percentage of habitual alcohol intake at bedtime was
significantly decreased (from 38.5% (15/39) to 20.5% (8/39), P = 0.04). Subjects who stopped alcohol
intake at bedtime (n = 8) received the most benefit, with decreased scores of ESS and Insomnia Severity
Index (ISI), although the reductions were not significant. This education program offers the possibility of
improving sleep conditions among the general population, especially in those who cease habitual alcohol
intake at bedtime. Further larger, randomized, controlled studies are warranted.
