Invited Review Articles
Physiology and Pathophysiology of Bicarbonate Secretion by Pancreatic Duct Epithelium
HIROSHI ISHIGURO, AKIKO YAMAMOTO, MIYUKI NAKAKUKI, LANJUAN YI, MARIKO ISHIGURO, MAKOTO YAMAGUCHI, SHIHO KONDO and YUKA MOCHIMARU
pg(s) 1-18
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HCO3–-rich fluid in the pancreatic juice (2~3 L/day) is secreted by epithelial cells lining the pancreatic
duct tree, while digestive enzymes are secreted by acinar cells with a small amount of Cl–-rich fluid.
Ductal HCO3– secretion is not only regulated by gastrointestinal hormones and cholinergic nerves but
is also influenced by luminal factors: intraductal pressure, Ca2+ concentration, pathological activation
of protease and bile reflux. The maximum HCO3– concentration of the juice under secretin stimulation
reaches 140–150 mM. Thus pancreatic duct cells secrete HCO3– against a ~7-fold concentration gradient.
HCO3– secretion critically depends on the activity of CFTR, a cAMP-dependent anion channel localized
in the apical membrane of various epithelia. In the proximal part of pancreatic ducts close to acinar cells
HCO3– secretion across the apical membrane is largely mediated by SLC26A6 Cl–-HCO3– exchanger. In
distal ducts where the luminal HCO3– concentration is already high, most of the HCO3– secretion is mediated
by HCO3– conductance of CFTR. CFTR is the causative gene for cystic fibrosis. Loss of function due
to severe mutations in both alleles causes typical cystic fibrosis characterized by dehydrated, thick, and
viscous luminal fluid/mucus in the respiratory and gastrointestinal tract, pancreatic duct, and vas deferens.
A compound heterozygote of mutations/polymorphisms (causing a mild dysfunction of CFTR) involves a
risk of developing CFTR-related diseases such as chronic pancreatitis. In cystic fibrosis and certain cases
of chronic pancreatitis, the pancreatic duct epithelium secretes a small amount of fluid with neutral~acidic
pH, which causes an obstruction of the duct lumen by a protein plug or viscous mucus.
Adipocytokines and Obesity-linked Disorders
NORIYUKI OUCHI, KOJI OHASHI, REI SHIBATA and TOYOAKI MUROHARA
pg(s) 19-30
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Obesity is closely associated with an increased risk for metabolic and cardiovascular diseases. Adipose tissue produces a number of secretory bioactive substances, also known as adipocytokines or adipokines, which directly affect adjacent or distant organs. Most adipocytokines are pro-inflammatory, thereby promoting the obesity-linked disorders. In contrast, there are a small number of adipocytokines that exhibit antiinflammatory properties. It is now recognized that dysregulated production or secretion of adipocytokines caused by adipocyte dysfunction leads to the development of obesity-linked complications. In this review, we focus on the functional role of several adipocytokines in metabolic and cardiovascular diseases.
Process of Physical Disability among Older Adults - Contribution of Frailty in the Super-aged Society
MASAFUMI KUZUYA
pg(s) 31-37
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One of the critical issues that Japan, well known for the world’s highest proportion of older adults, a super-aged society, is currently confronting is how to prevent physical disability in old age. This issue is particularly important not only from a medical perspective such as functional prognoses but also from a socio-economic angle in view of reducing the rapid rise in the cost of medical and long-term care insurance services. Functional decline in old age results not only from acute diseases but also from frailty. Such a common and important syndrome that is increasingly prevalent with advancing age can be the cause. The present article intends to review what is known about frailty, including its definition, epidemiology, and pathophysiology, and to examine potential areas of future research.
Original Papers
Determination of Ferritin and Hemosiderin Iron in Patients with Normal Iron Stores and Iron Overload by Serum Ferritin Kinetics
HIROSHI SAITO, AKIHIRO TOMITA, HARUHIKO OHASHI, HIDEAKI MAEDA, HISAO HAYASHI and TOMOKI NAOE
pg(s) 39-49
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We attempted to clarify the storage iron metabolism from the change in the serum ferritin level. We
assumed that the nonlinear decrease in serum ferritin was caused by serum ferritin increase in iron mobilization. Under this assumption, we determined both ferritin and hemosiderin iron levels by computer-assisted simulation of the row of decreasing assay-dots of serum ferritin in 11 patients with normal iron stores free of both iron deficiency and iron overload; chronic hepatitis C (CHC) and iron deficiency anemia after treatment, and 11 patients with iron overload; hereditary hemochromatosis (HH) and transfusion-dependent anemias (TD). We determined the iron removal rates of 20 and 17 mg/day by administering mean doses of deferasirox at 631 and 616 mg/day in 2 TD during the period of balance of iron addition and removal as indicated by the serum ferritin returned to the previous level. The ferritin-per-hemosiderin ratio was almost the same in both HH and CHC. This matched the localized hepatic hemosiderin deposition in CHC with normal iron stores. We detected the ferritin increased by utilizing the hemosiderin iron in iron removal and the ferritin reduced by transforming ferritin into hemosiderin in iron additions. The iron storing capacity of hemosiderin was limitless, while that of ferritin was suppressed when ferritin iron exceeded around 5 grams. We confirmed the pathway of iron from hemosiderin to ferritin in iron mobilization, and that from ferritin to hemosiderin in iron deposition. Thus, serum ferritin kinetics enabled us to be the first to clinically clarify storage iron metabolism.
Cardiovascular Disease Risk Factors among Rural Kazakh Population
GULNARA KULKAYEVA, MD. HARUN-OR-RASHID, YOSHITOKU YOSHIDA, KAZBEK TULEBAYEV and JUNICHI SAKAMOTO
pg(s) 51-61
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Cardiovascular diseases (CVDs) have remained a leading cause of mortality in Kazakhstan. The objectives of the present study were to estimate the prevalence of CVD risk factors (RFs) among the Kazakh
population, and their ability to identify those CVD RFs. We interviewed 611 subjects aged 25–65 years
using a structured self-administered questionnaire from April to July, 2008. Odds ratios (ORs) and 95%
confidence intervals (CIs) were estimated to determine associations between CVD RFs and its correlations,
such as socioeconomic status and level of knowledge of CVD RFs through a logistic regression model.
Mean age of the respondents was 43.2 years, and 49.8% were male. Tobacco smoking, overweight (body
mass index ≥ 25.0), hypertension (systolic blood pressure ≥ 140 mm Hg and diastolic blood pressure ≥ 90
mm Hg), and alcohol drinking were identified as important CVD RFs. Risk of overweight was greatest
among the population aged 45–54 years, with an OR of 5.3 (95% CI=3.1–9.2). The overweight population
was significantly associated with higher income (OR=1.6, 95% CI=1.1–2.4) and knowledge of RF
(OR=1.7, 95% CI=1.2–2.4), with p<0.05. Only 25.0% of respondents had good knowledge about CVD
RFs. Alcohol drinking was inversely related to the level of knowledge about CVD RFs (OR=0.7, 95%
CI=0.5–0.9). We concluded that CVD RFs were very high among the Kazakh population, although their
level of knowledge to identify those RFs was very low. Increasing knowledge about CVD RFs through
awareness campaign activities can reduce CVD-related morbidity and mortality and ensure a better quality
of life for the Kazakh population.
Prevalence of Helicobacter Pylori Infection Measured with Urinary Antibody in an Urban Area of Japan, 2008–2010
TAKASHI TAMURA, EMI MORITA, TAKAAKI KONDO, JUN UEYAMA, TETSUYA TANAKA, YUTO KIDA, YOKO HORI, SHIGERU INOUE, KOUTARO TOMITA, RIEKO OKADA, SAYO KAWAI, ASAHI HISHIDA, MARIKO NAITO, KENJI WAKAI and NOBUYUKI HAMAJIMA
pg(s) 63-70
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Helicobacter pylori (H. pylori) has expanded to infect about half the world’s population. Although there
were many studies on the prevalence of H. pylori infection for defined areas in the 1990s throughout
the world, there were only limited sources tracking its latest prevalence among large populations. In the
present study, we estimated the prevalence of H. pylori among the inhabitants of Nagoya, an urban area
of Japan. Study subjects were 5,167 participants (1,467 males and 3,700 females) aged 35 to 69 years
from the Daiko Study, a part of the Japan Multi-Institutional Collaborative Cohort Study (J-MICC Study).
A urinary anti-H. pylori antibody was used to detect H. pylori infection. The history of eradication
treatments for H. pylori infection was obtained using self-administered questionnaires. The prevalence
detected by the urinary test included 19.6% (95% confidence interval; 16.8–22.6%) for those aged 35–39
years, 25.8% (23.5–28.2%) for 40–49 years, 39.4% (36.8–42.1%) for 50–59 years, 50.3% (47.8–52.7%)
for 60–69 years, and 36.4% (35.1–37.7%). Among 5,167 participants, 266 (5.1%) stated that they had
received an eradication treatment. Since 167 subjects with negative urinary tests replied that they had
been seropositive for H. pylori in the past, they were included among the ever-infected inhabitant group.
Consequently, the overall rate of those with a history of persistent infection was 39.6% (38.3–40.9%).
The prevalence of H. pylori infection observed in Nagoya seemed to be lower than the corresponding
prevalence reported in other studies of Japan. That lower rate might be due to the reduced exposure from
improved urban sanitary conditions.
Elderly Health and its Correlations among Uzbek Population
GOOLBAHOR PULATOVA, MD. HARUN-OR-RASHID, YOSHITOKU YOSHIDA and JUNICHI SAKAMOTO
pg(s) 71-82
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This study was conducted from November, 2007 to May, 2008 to evaluate the health status of the
elderly and correlated factors affecting their health. We collected data from 682 individuals 65 years or older
(214 male) from greater Tashkent City in Uzbekistan. The study revealed that 75.4% of the respondents
were aged <75 years and that 16.8% of them were not educated. About three-quarters of the respondents
rated themselves as ‘healthy.’ The odds ratios (ORs) and 95% confidence intervals (CIs) were estimated
through a logistic regression model to determine correlations of elderly health, and adjusted for age and
sex. The elderly who had additional income were 2.6 times (95% CI=1.8–4.0) more likely to be healthy.
Similarly, those <75 years old (OR=1.5, 95% CI=1.0–2.2), were able to do everyday duties (OR=6.0, 95%
CI=3.8–9.3), and those who were married (OR=4.1, 95% CI=1.7–9.7) were also healthy. Conversely, males
(OR=0.6, 95% CI=0.4–0.9) and the elderly who were supported by sources other than their own income
from work were not healthy. We concluded that having a strong family relationship and adhering to a
traditional lifestyle are important for protecting elderly health in Uzbekistan. Substantial financial support
and personal care are necessary for the elderly. Creating a healthy atmosphere for them at an individual
and family level could ensure a better quality life for the elderly in Uzbekistan.
The Impact of Maternal Obesity on Mother and Neonatal Health: Study in a Tertiary Hospital of Astana, Kazakhstan
GULZHAN AIMUKHAMETOVA, TALSHYN UKYBASOVA, ZAITUNA HAMIDULLINA, KARLYGASH ZHUBANYSHEVA, MD. HARUN-OR-RASHID, YOSHITOKU YOSHIDA, HIDEKI KASUYA and JUNICHI SAKAMOTO
pg(s) 83-92
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This study was aimed to investigate the impact of maternal obesity on mothers and their neonatal
health. Our study population consisted of 157 women with completed singleton pregnancies, which included
both obese (Body mass index, BMI≥30) and non-obese women (BMI<30). Data were collected from case
histories, and ante- and postnatal records at the tertiary hospital in Astana, Kazakhstan between January
and February of 2008. Associations between pregnancy and delivery-related complications, outcomes,
and maternal obesity were estimated as odds ratios (ORs) and 95% confidence intervals (CIs) using a
logistic regression model. Women aged 30 years or more were at higher risk of obesity (OR=3.1, 95%
CI=0.8–11.6) than women less than 30 years old. Multiparous women were also at higher risk of obesity
(OR=4.1, 95% CI=0.9–19.6) than primiparous ones. Obese women were also more likely to have longer
hospital stays of more than 10 days (OR=2.2, 95% CI=0.8–6.2), and were more prone to eclampsia/preeclampsia
(OR=24.7, 95% CI=2.2–44.8), cesarean sections (OR=2.1, 95% CI=0.7–6.2), and abnormal labor
(OR=8.1, 95% CI=1.0–63.8) compared to non-obese women. Neonatal complications such as pneumonia
(OR=3.4, 95% CI=0.6–20.2) and fetal macrosomia (OR=2.2, 95% CI=0.6–8.0) were also more common
among babies born to obese mothers. Congenital baby birth defects were strongly associated with maternal
obesity (P=0.016). We concluded that maternal obesity is associated with increased risks of both maternal
and neonatal complications, and that such risks increase with advanced age and parity of the mother.
Hence, medical practices must take these complications into account by ensuring an adaptable and early
management in order to improve mothers and their neonatal health.
A Permission System for Carbapenem Use Reduced Incidence of Drug-resistant Bacteria and Cost of Antimicrobials at a General Hospital in Japan
YOSHIAKI IKEDA, TAKAYOSHI MAMIYA HIDEKI NISHIYAMA, SHIHO NARUSAWA, TAKENAO KOSEKI, AKIHIRO MOURI and TOSHITAKA NABESHIMA
pg(s) 93-104
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Some drug management systems have been established in Japanese hospitals to reduce medical costs
and regulate drug usage. Among the many available prescription drugs, antimicrobials should be given
special attention because their inappropriate use often leads to sudden outbreaks of resistant bacteria. As
drug specialists, pharmacists should monitor the use of all drugs, particularly antimicrobials. Carbapenems
are a class of broad-spectrum antimicrobials that are widely used to treat infections worldwide. However,
their inappropriate use has led to an increase in the incidence of drug-resistant bacteria and consequently,
medical costs, at hospitals. To reduce inappropriate use and drug resistance, we have established a permission
system to control the use of carbapenems at the Japanese Red Cross Nagoya Daiichi Hospital. In this
study, we retrospectively evaluated the applicability of the new permission system compared to that of the
notification system and the non control system for 14 months each. The two management systems were able
to maintain total antibiotic use density and control the outbreak of drug-resistant bacteria (P. aeruginosa,
E. coli, and K. pneumoniae). The number of carbapenem prescriptions was decreased dramatically when
this permission system was enforced. Compared to the non control system, the cost of antimicrobials was
reduced by $757,470 for the 14-month study period using the permission system. These results suggest
that our system to control the use of antimicrobials can efficiently suppress the incidence of drug-resistant
bacteria and medical costs at hospitals.
Risk Factors for Extended-spectrum β-Lactamaseproducing Escherichia Coli Infection in Hospitalized Patients
YOSHIAKI IKEDA, TAKAYOSHI MAMIYA, HIDEKI NISHIYAMA, TAKENAO KOSEKI, AKIHIRO MOURI and TOSHITAKA NABESHIMA
pg(s) 105-114
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The incidence of nosocomial infection caused by extended-spectrum b-lactamase (ESBL)-producing
bacteria is increasing worldwide. Infections caused by ESBL producers have been associated with severe
adverse clinical outcomes that have led to increased mortality, prolonged hospitalization, and rising medical
costs. To avoid such adverse events and ineffective treatment, an appropriate use of drugs for infectious
diseases is needed. To suppress the emergence and spread of drug-resistant bacteria in hospitals, it is
important to be vigilant about ESBL-producing Escherichia coli (E. coli). In this study, we examined
and compared seven items in a blood test between patients with ESBL-producing E. coli and non-
ESBL-producing E. coli among febrile patients. We examined the levels of serum albumin, hemoglobin,
and C-reactive protein (CRP), and the numbers of leucocytes, neutrophils, lymphocytes, and platelets in
blood on the day of admission, the screening day during hospitalization, and the day immediately before
discharge from the hospital. There were no significant differences in clinical background characteristics
between the two groups of patients. In patients with invasive infections caused by ESBL-producing E.
coli, serum albumin levels and the number of lymphocytes were significantly lower than those in patients
not infected with ESBL producers. These values recovered to their baseline levels on the day of hospital
discharge. This retrospective study suggests that serum albumin levels and the number of lymphocytes may
serve as risk factors for infection by ESBL-producing E. coli, thereby supporting the appropriate use of
antimicrobials in hospitals.
Preventive Medical Services Not Covered by Public Health Insurance at Daiko Medical Center in Japan, 2004–2011
TAKASHI TAMURA, MIO KURATA, TAKAAKI KONDO, YASUYUKI GOTO, YOSHIKAZU KAMIYA, SAYO KAWAI, YOKO MITSUDA and NOBUYUKI HAMAJIMA
pg(s) 115-121
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Preventive medical services not covered by public health insurance started in the Daiko Medical Center
of Nagoya University in June, 2004. Those services included: 1) Helicobacter pylori (H. pylori) diagnosis
and eradication treatments, for which CYP2C19 genotyping was introduced in November 2005; 2) smoking
cessation support with genotype tests of CYP1A1 Ile462Val, GSTM1 present/null, GSTT1 present/null, and
NQO1 Pro187Ser; 3) advice on alcohol consumption with genotype tests of ADH Arg47His and ALDH2
Glu487Lys; 4) advice on folate-associated diseases with a genotype test of MTHFR C677T; 5) advice on
a tumor marker CA19-9 with genotype tests of Lewis and Secretor genes; and 6) raloxifene prescription
aimed to prevent breast cancer for high-risk postmenopausal women. A total of 683 patients visited the
Center until it closed in March 2011. Those given diagnoses and eradication treatments for H. pylori
numbered 567, followed by 44 for smoking cessation support, 35 for advice on folate-associated diseases,
26 for advice on alcohol consumption, 8 for CA19-9, and 3 for raloxifene prescription. Around 2004,
public interest in H. pylori was relatively high, but thereafter patient numbers dropped markedly. The Center
closed in March 2011 due to the reduction in patient visits. Our unique trial showed that continuing to
provide uninsured preventive services at a clinic was difficult in Japan without the affiliation of hospitals/
clinics providing medical services covered by public health insurance.
Geranylgeranylacetone Attenuates Cisplatin-induced Reductions in Cell Viability by Suppressing the Elevation of Intracellular P53 Content Without Heat Shock Protein Induction
MOTOFUSA HASEGAWA, KAZUHIRO ISHIGURO, TAKAFUMI ANDO and HIDEMI GOTO
pg(s) 123-131
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Geranylgeranylacetone (GGA) was originally used as an anti-ulcer drug to protect gastric mucosa
from various stresses, and it is also known to induce heat shock proteins (HSPs), especially HSP70.
However, it remains unclear how GGA affects cellular functions in the presence of anti-cancer drugs.
We investigated the effects of GGA on cellular viability, caspase-3 activation, HSP induction and p53
content in the presence of cisplatin (CDDP). Rat intestinal epithelium-derived IEC-18 cells and human
colon cancer-derived CW-2 cells were incubated with GGA in the presence of CDDP, and we observed
that GGA attenuated CDDP-induced viability reductions. GGA also suppressed CDDP-induced caspase-3
activation. However, GGA induced neither HSP70 nor GRP78 expression in the presence of CDDP. We
found that GGA suppressed the CDDP-induced elevation of intracellular p53 content. In conclusion, GGA
attenuates viability reductions and caspase-3 activation in CDDP-treated cells by suppressing the elevation
of intracellular p53 content without HSP induction.
Genetic Polymorphisms of the Adenosine Triphosphate-binding Cassette Transporters (ABCG2, ABCB1) and Gefitinib Toxicity
MARIKO TAMURA, MASASHI KONDO, MIHOKO HORIO, MAKI ANDO, HIROSHI SAITO, MASASHI YAMAMOTO, YOSHITSUGU HORIO and YOSHINORI HASEGAWA
pg(s) 133-140
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The purpose of this study is to investigate associations between allelic variations of ABCG2 and ABCB1
with skin toxicity, diarrhea, liver injury and interstitial lung disease (ILD) in gefitinib-treated patients.
A prospective clinical study of 83 Japanese patients with non–small–cell lung cancer was performed.
Polymorphic loci in ABCG2 and ABCB1 were genotyped, and their effects on gefitinib toxicities were
evaluated. ABCG2 34G>A was statistically associated with occurrence of skin rash; 13 (42%) of the 32
patients with at least one variant ABCG2 34G>A allele (G/A and A/A) developed grade 2 or worse skin
rash, whereas only 10 (19%) of 51 patients homozygous for the reference allele (G/G) for the wild-type
sequence for both alleles did so (P = 0.046). There was no significant association between severe toxicities
and polymorphisms of ABCG2 421C>A nor ABCB1 3435C>T. The results suggested that ABCG2 34G>A
would be useful for predicting grade 2 or worse skin rash.
Prognostic Factors for Tumor Recurrence after Gamma Knife Radiosurgery of Partially Resected and Recurrent Craniopharyngiomas
TATSUYA KOBAYASHI, YOSHIMASA MORI, TAKAHIKO TSUGAWA, CHISA HASHIZUME and HIROSHI TAKAHASHI
pg(s) 141-147
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A study was conducted to clarify the prognostic factors related to recurrence of craniopharyngioma
and to improve the quality of life of patients by the treatment with intentional partial removal and gamma
knife radiosurgery. One hundred cases of craniopharyngioma have been treated at Komaki City Hospital
since 1991. In a mean follow-up period of 65.5 months, the tumor control rate was 79.5%. The 5- and
10-year actuarial survival rates were 94.1% and 91%, respectively. However, the recurrence-free survival
rates were 73.6% at 5 years and 60.2% at 10 years. Nine factors thought to be related to the recurrence
were selected from past references and previous studies, including gender, age, pediatric (≤17 years) or
adult patient, partial removal or recurrence, mean tumor diameter, tumor type (solid or cyst), pathological
types (squamous cell or adamantinoma), number of previous treatments, and radiation dose. Statistical
analysis was performed to determine which factors had a significant prognostic impact. Multivariate analysis
showed that mean tumor diameter and radiation dose were independent predictors of outcome. To maximize
the prognostic power of these factors, cut-off levels were determined using ROC analysis. These levels
were 19 mm for tumor diameter and 13.2 Gy for marginal dose. Significant prognostic factors related to
recurrence of craniopharyngioma are tumor diameter and radiation dose. A tumor diameter of <19 mm and
a marginal dose of ≥13.2 Gy are favorable prognostic factors for gamma knife radiosurgery.
Incidence of Young Onset Insulin-requiring Diabetes Mellitus among 18- to 30-year-olds in Dhaka, Bangladesh (1994−2003) Saika
SAIKA NIZAM, MD. KHALEQUZZAMAN, HIROSHI YATSUYA, PARVIN AKTER KHANAM, M. ABU SAYEED, HISAO NAITO and TAMIE NAKAJIMA
pg(s) 149-156
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Little information is available regarding the epidemiology of young onset insulin-requiring diabetes
mellitus (IRDM). We described the incidence of young onset IRDM and its trend in males and females
of Dhaka, Bangladesh. Subsequently, factors related to possible sex difference were investigated. Young
onset IRDM was defined as diabetic patients aged 18–30 years who required three months or more insulin
treatment but presented no ketonuria. Between 1994 to 2003, 1,804 cases were registered. Incidence rates
were calculated with denominators based on the population census 2001. The overall annual incidence of
young onset IRDM for the period 1994–2003 was 8.5 per 100,000 persons (95% CI: 7.2–7.9), and the
corresponding value for females (10.9 per 100,000 persons, 95% CI: 9.2–12.1) was higher than that in
males (6.7 per 100,000 persons, 95% CI 5.6–7.9). The incidence rate significantly increased in females
during the investigated period, but not in males (p for sex interaction < 0.01). There was a significantly
higher increment of female cases with a body mass index ≥ 25.0 kg/m2 (overweight/obesity) (19 percentage
point) compared to that of males (3 percentage point) between 1994–1998 and 1999–2003 (p for sex
interaction < 0.01). The incidence of young onset IRDM is increasing in the Dhaka City population among
females, which is attributed to the increase in overweight/obese female cases.
Establishment and Optimal Culture Conditions of MicroRNA-induced Pluripotent Stem Cells Generated from HEK293 Cells via Transfection of Microrna-302S Expression Vector
NAOSHI KOIDE, KAORI YASUDA, KENJI KADOMATSU and YOSHIFUMI TAKEI
pg(s) 157-165
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Induced pluripotent stem cells (iPSCs) have been directly generated from fibroblast cultures though
retrovirus- or lentivirus-mediated ectopic overexpression of only a few defined transcriptional factors. This
remarkable achievement has greatly enhanced our ability to explore the causes of, and potential cures for,
many genetic diseases, and strengthened the promise of regenerative medicine. In fact, to date, many kinds
of somatic cells from different tissues have exhibited a capacity for reprogramming toward an embryonic
stem cell-like state, but major bottlenecks in iPSC derivation and therapeutic use remain, including low
reprogramming efficiencies and the tumorigenesis of the generated iPSC. Here, we successfully generated
miR-302s-induced pluripotent stem cells (mirPS cells) from human embryonic kidney (HEK) 293 cells
via transfection of the miR-302s expression vector. We also determined the optimal culture conditions to
generate mirPS on feeder cells, which included the use of serum-free N2B27 medium. The mirPS cells
generated by our improved conditions showed the expression of pluripotent marker genes such as OCT3/4,
NANOG, and SOX2 under growth conditions via reverse transcription-PCR, whereas no expression of these
genes was observed in HEK293 cells. On the other hand, under differentiation conditions, mirPS cells
formed ball-shaped structures (embryoid bodies), and showed the ability to differentiate into three germ
layers (ectoderm, mesoderm, and endoderm) in vitro. The results suggested that our generated mirPS cells
are actually functional as a cell resource to apply to regenerative medicine, and mirPS cells are suitable
materials to clarify the mechanism underlying the reprogramming from somatic cells.
Tilt of the Radius from Forearm Rotational Axis Reliably Predicts Rotational Improvement after Corrective Osteotomy for Malunited Forearm Fractures
MASAHIRO TATEBE, TAKAAKI SHINOHARA, NOBUYUKI OKUI, MICHIRO YAMAMOTO, SHIGERU KURIMOTO and HITOSHI HIRATA
pg(s) 167-171
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Forearm rotation occurs around an axis connecting the center of the radial head and the fovea of the
distal ulna. The purpose of the present study was to demonstrate the usefulness of the difference between
forearm and proximal radial axis in the treatment of malunited forearm fractures. We reviewed the results
of eight corrective osteotomies for malunited fractures of the forearm without dislocations of the wrist
or elbow. Subjects were 6 men and 2 women (mean age, 15 years; range, 10−21 years). Corrective
osteotomy was performed at the fracture site. Preoperatively and at final follow-up, the arc of forearm
rotation was recorded and anteroposterior and lateral X-rays were taken. Proximal radius tilt was defined
as the angle between the rotational axis of the forearm and the axis of the proximal radius. Corrective
osteotomy improved proximal radius tilt in all cases. Three patients were considered to have malrotation.
Postoperative rotational arc correlated with proximal radial tilt (r = −0.83). No significant difference in
rotational arc was evident between malunited cases and the remaining cases. To improve forearm rotation,
corrective osteotomy should be planned to minimize proximal radius tilt.
Case Reports
Simultaneous Surgical Resections of Two Distant Metastatic Malignant Melanoma Lesions — Case Report —
TAKAFUMI TANEI, NORIMOTO NAKAHARA, SHIGENORI TAKEBAYASHI and TOSHIHIKO WAKABAYASHI
pg(s) 173-179
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A 41-year-old woman presented with disturbance of consciousness, right hemiparesis, and symptoms
of Gerstmann syndrome. She had a history of malignant melanoma resections of an ear mole and her
right neck lymph nodes and parotid gland, with subsequent chemotherapy and radiotherapy. Computed
tomography showed two large lesions in the right frontal and left parietal lobes surrounded by severe brain
edema. Magnetic resonance images revealed that the two lesions were strongly enhanced with cystic change,
and a small round lesion was located in the left head of the caudate nucleus. (18F) fluoro-2-deoxyglucose
positron emission tomography showed high accumulation in both lesions, and no sign of metastatic lesions
except within the brain. The two lesions were large, causing increased intracranial pressure. Simultaneous
surgical resections were performed using two approaches. The patient’s neurological symptoms were greatly
improved after surgery, and her Karnofsky Performance Status improved from 20% to 90%. She was
discharged to her home almost completely free of neurological deficits. Although, simultaneous one-stage
tumor resections for multiple metastatic brain tumors do not extend the survival period, they improve the
quality of the patient’s limited remaining life, and may be a treatment choice for young patients with
well-controlled systemic disease.
Postoperative Recovery from Unilateral Blindness Caused by Tuberculum Sellae Meningioma
HIROFUMI OYAMA, AKIRA KITO, HIDEKI MAKI, KENICHI HATTORI, TOMOYUKI NODA and KENTARO WADA
pg(s) 181-187
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A 47-year-old female had noticed diminished visual acuity in both eyes 2 months previously. The patient
had vision loss (no light perception) in her right eye on admission. Her left visual acuity was 1.2 (naked
vision) and an upper temporal quadrant hemianopsia was revealed in her left eye. Optic disc atrophy was
also found bilaterally during a fundus examination. The tumor was located at the tuberculum sella.
The first operation was performed using a right pterional approach. The right optic nerve was thin
and atrophic and was severely encased by the tumor. Considering the deterioration of her visual evoked
potential, the operation was terminated in the remaining major part of the tumor. Postoperatively, the patient
suffered visual loss in her right eye (no light perception), decreased visual acuity (naked: 0.6 (corrected:
1.0)), and deteriorated visual field defects (upper temporal quadrant hemianopsia) in her left eye.
The tumor remnant was resected again 2 weeks later using the right frontobasal and pterional approaches.
The tumor around the bilateral internal carotid arteries and optic nerves was not resected. Light
perception in the right eye appeared 2 weeks after the operation. Although an opthalmological examination
revealed right optic atrophy, finger counting was possible in the upper nasal visual field of the right eye
three months after the second operation. Her visual acuity was 0.7 (1.0), and the upper temporal quadrant
hemianopia of the left eye improved in comparison with the preoperative one. Our case demonstrated the
possibility of a recovery from blindness.
Extravasation of Pegylated-liposomal Doxorubicin: Favorable Outcome after Immediate Subcutaneous Administration of Corticosteroids
AYAKO MITSUMA, MASATAKA SAWAKI, TAKASHI SHIBATA, SACHI MORITA, MEGUMI INADA, TOMOYA SHIMOKATA, MIHOKO SUGISHITA, KOICHI KITAGAWA, MASAKI SAWADA, AKIHIRO NAWA and YUICHI ANDO
pg(s) 189-192
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A massive extravasation of pegylated-liposomal doxorubicin (Doxil&rights;) accidentally occurred, affecting the
right forearm of a 54-year-old woman with metastatic ovarian cancer who was receiving an intravenous
infusion of the drug. In accordance with the institutional guidelines for vesicant drugs, a corticosteroid
preparation was immediately injected subcutaneously into the surrounding tissues. Clobetasol propionate
and an ice pack were then topically applied to the affected region. There were no serious complications
at the extravasation site, such as tissue necrosis or severe pain, and only a transient erythema of the skin
and desquamation remained after 2 months.
Repair of Carotid Blow-out Using a Carotid Sheath in a Patient with Recurrent Thyroid Cancer
HIROFUMI OYAMA, AKIRA KITO, HIDEKI MAKI, KENICHI HATTORI, TOMOYUKI NODA and KENTARO WADA
pg(s) 193-198
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The patient had thyroid cancer and underwent subtotal thyroidectomy. Local recurrence occurred on
both sides 5 years and 6 months later. The sterno-hyoid muscle and sterno-thyroid muscle were severed
and the tumor around the cricoid cartilage was removed. The tumor extended into the space between the
right common carotid artery and internal jugular vein and was located under the right common carotid
artery and vagus nerve on the lateral side. The carotid sheath was peeled off of the carotid artery quite
easily. The right common carotid artery ruptured abruptly at the distal side during this procedure.
The right common carotid artery had two layers, which were very fragile, so the direct suture or repair
with a graft was impossible. The carotid artery could not be trapped with ligation because the cerebral
vascular supply was not examined preoperatively. This portion was repaired using the remaining carotid
sheath. However, re-bleeding occurred at the proximal portion of the previous laceration spontaneously.
Fibrin glue with oxidized cellulose was initially used to seal the second small hole in this lesion. The
second ruptured section was repaired using the remaining sterno-thyroid and sterno-hyoid muscles. The
proximal portion of the right common carotid artery was reinforced with the harvested external jugular
vein.
These procedures resulted in hemostasis. Three-dimensional CT angiography showed irregular stenosis
just after the operation, but it recovered 11 days later. No cerebral infarction occurred after the operation
and the patient’s general condition was good.
Schwannoma Originating from Lower Cranial Nerves: Report of 4 Cases
HIROFUMI OYAMA, AKIRA KITO, HIDEKI MAKI, KENICHI HATTORI, TOMOYUKI NODA and KENTARO WADA
pg(s) 199-206
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Four cases of schwannoma originating from the lower cranial nerves are presented. Case 1 is a schwannoma
of the vagus nerve in the parapharyngeal space. The operation was performed by the transcervical
approach. Although the tumor capsule was not dissected from the vagus nerve, hoarseness and dysphagia
happened transiently after the operation. Case 2 is a schwannoma in the jugular foramen. The operation
was performed by the infralabyrinthine approach. Although only the intracapsular tumor was enucleated,
facial palsy, hoarseness, dysphagia and paresis of the deltoid muscle occurred transiently after the
operation. The patient’s hearing had also slightly deteriorated. Case 3 is a dumbbell-typed schwannoma
originating from the hypoglossal nerve. The hypoglossal canal was markedly enlarged by the tumor. As
the hypoglossal nerves were embedded in the tumor, the tumor around the hypoglossal nerves was not
resected. The tumor was significantly enlarged for a while after stereotactic irradiation. Case 4 is an
intracranial cystic schwannoma originating from the IXth or Xth cranial nerves. The tumor was resected
through the cerebello-medullary fissure. The tumor capsule attached to the brain stem was not removed.
Hoarseness and dysphagia happened transiently after the operation. Cranial nerve palsy readily occurs after
the removal of the schwannoma originating from the lower cranial nerves. Mechanical injury caused by
retraction, extension and compression of the nerve and heat injury during the drilling of the petrous bone
should be cautiously avoided.
A Spinal Epidural Hematoma with Symptoms Mimicking Cerebral Stroke
HIROSHI SHIMA, MUNEYOSHI YASUDA, MOTOHIRO NOMURA, KENTARO MORI, KATSUYOSHI MIYASHITA, AKIRA TAMASE, YOSHIHISA KITAMURA, KOJI OSUKA and MASAKAZU TAKAYASU
pg(s) 207-210
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A spontaneous cervical epidural hematoma (SCEH) is a rare condition, which usually requires urgent
treatment. However, unusual manifestations, such as hemiparesis, may lead to a misdiagnosis. We herein
report a case of SCEH that presented with pure motor hemiparesis to discuss the appropriate and prompt
diagnosis and treatment of such cases. An 84-year-old female was brought to our emergency department
complaining of nuchal pain, followed by right hemiparesis. A contrast-enhanced computed tomography (CT)
scan of the neck demonstrated a spinal epidural hematoma right posterolateral to the spinal cord, extending
from C2 to C3. She was managed conservatively and her symptoms improved significantly. The authors
emphasize that cervical spinal lesions should be considered in the differential diagnosis for patients with
acute onset of hemiparesis, when they are associated with neck pain. Even though magnetic resonance
imaging is the gold standard, a CT scan is also useful for quick screening for SCEH.
Surgical Results of Parasagittal and Falx Meningioma
HIROFUMI OYAMA, AKIRA KITO, HIDEKI MAKI, KENICHI HATTORI, TOMOYUKI NODA and KENTARO WADA
pg(s) 211-216
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Sixteen operative cases of parasagittal and falx meningioma were analyzed retrospectively. Parasagittal
meningioma totaled 12 cases and falx meningioma numbered 4 cases. Preoperative symptoms were paresis
of a lower extremity in 7 cases and disturbed consciousness or mentality in 6 cases. Paresis and/or
consciousness deteriorated just after the operation in 11 cases. The deterioration was identified in paresis
(6 cases), consciousness (3 cases), paresis and consciousness (2 cases). Motor function further deteriorated
postoperatively when the patients had shown preoperative paresis. The cause of postoperative deterioration
of motor function and/or consciousness level was intracerebral hematoma in 1 case, and newly-developed
brain edema in 1 case. There was no obvious explanation for the symptomatic exacerbation in the other
9 cases. At discharge, 5 cases showed deterioration of motor function in comparison to their preoperative
condition, and 3 cases showed an improvement. Eleven cases showed no change of consciousness in
comparison to the preoperative condition, and 5 cases showed improvement at discharge. Surgical result
was good for consciousness or mentality, but was relatively poor for motor function. It was considered
that surgery should be performed carefully in patients with preoperative paresis.