Ehime University Institutional Repository

Ehime University (愛媛大学)博士(学術)thesi

SANDY, EDITH BENITEZ GARCIA

（様式５）(Style5) 
学位論文全文に代わる要約 
Extended Summary in Lieu of Dissertation 
 
氏名： 
Name 
SANDY EDITH BENITEZ GARCIA 
 
学位論文題目： 
Title of Dissertation 
A STUDY ON AIR-POLLUTION CHARACTERISTICS AND THREE-DIMENSIONAL 
BEHAVIOR OF PHOTOCHEMICAL OZONE IN MEXICO 
(メキシコにおける大気汚染の特徴と光化学オゾンの立体的挙
動に関する研究) 
 
学位論文要約： 
Dissertation Summary 
 
Since the beginning of the industrial revolution until current times, air pollution problems have risen in 
urban areas with large population density, often called megacities. In megacities, industrial development, 
anthropogenic activities, fast and uncontrolled growth of population and severe weather conditions are 
considered as contributors to deteriorated air quality. If urbanization proceeds in an uncontrolled way, negative 
impacts on the ecosystem are expected and the health risks trend to increase. 
 In the atmosphere, various meteorological phenomena occur as results of or causes of energy and 
material transfer, with influences on chemical and physical processes among trace constituents of the 
atmosphere. Among other pollutants, ozone needs special attention because it plays a central role in the 
atmospheric chemistry, is itself a product of photochemical reactions, and interacts with meteorological 
conditions in a complex manner.  
 A comparison of seasonal and diurnal trends of air pollutants between selected Mexican and Japanese 
areas is presented to gain insights into the emission characteristics and atmospheric processes in both countries. 
Further analysis of the air monitoring data was carried out for the three largest Mexican metropolitan areas: 
Mexico City (MCMA), Guadalajara (GMA), and Monterrey (MMA), from January 2000 to December 2011. 
Among other features, causes of concentration variations were identified.  
 With the aim of understanding how ozone (O3) is produced and distributed in the atmospheric boundary 
layer of the MCMA, vertical profiles of meteorological parameters and ozone concentrations were measured by 
ozonesonde, in two field campaigns in the change from wet to dry-cold (November 2011) and dry-warm (March 
2012) seasons in MCMA. Unlike previous similar field campaigns, ozonesonde was launched twice daily to 
reveal production and distribution of ozone in the convective boundary layer. Besides, numerical simulations 
using an atmospheric chemical transport model, Weather Research and Forecasting model (WRF) coupled with a 
chemistry module (WRF-Chem), were carried out to reveal the three-dimensional behavior of O3.  
Analysis of air monitoring data between Mexican and Japanese cities  
Comparison of the air monitoring data between Mexican (MCMA, GMA, and MMA) and Japanese 
(Tokyo metropolitan area and Ehime Prefecture) areas (Fig. 1) is expected to produce valuable information, 
useful for the development of air-pollution control strategies. 
In order to compare air quality levels, seasonal variation and diurnal behavior among the selected areas, 
data from air monitoring stations were collected for the Japanese fiscal year 2009 (from April 2009 to March 
2010). Pollutants analyzed were criteria pollutants for which environmental standards are set in both Japan and 
Mexico: carbon monoxide (CO), nitrogen dioxide (NO2), sulfur dioxide (SO2), O3 and particulate matter with 
aerodynamic diameter less than 2.5 micrometers (PM2.5). 
Concentrations of CO and NO2 were high in winter in Mexican and Japanese areas. Seasonal 
variations of CO and NO2 were similar, indicating contribution of combustion processes during winter in both 
countries. CO levels in Mexican areas were more than twice higher than those in Japanese areas. On the other 
hand, NO2 concentrations in Tokyo and Mexico City were at the same level, which was about 70% higher than 
concentrations in MMA and Ehime prefecture. The major contribution to NO2 is considered to be vehicular 
traffic which emits NO that is oxidized to NO2.  
From this analysis, the effect of anthropogenic activities (mainly vehicular traffic) on 
concentration of pollutants such as CO, NO2, and PM2.5 in urban areas was noted. Further the strong 
influence of stationary sources on SO2 concentration was found in areas with high population density 
(Tokyo) as well as in areas with lower population density (Ehime). O3 concentrations could be posing a 
（様式５）(Style5) 
serious threat in both countries. Further analysis of O3 precursors and meteorological variables are 
necessary to enhance the knowledge about O3 production, and to be assertive in the action plans to 
improve the air quality, control emission sources and prevent future episodes of high pollution in urban 
areas with high and low population density. 
Analysis of criteria air pollutant trends in Mexican metropolitan areas  
(Benitez-Garcia, et. al., 2014) 
Hourly data of air pollutants designated as criteria species according to the Mexican legislation were 
collected: CO, NO2, SO2, O3 and PM10, from air monitoring networks located in MCMA, GMA and MMA. A 
threshold of 75% validity of the hourly data was adopted in calculating the daily, monthly and annual averages 
for each station. In order to evaluate against the Mexican Air Quality Guidelines, various statistical measures 
according to the Mexican legislation, such as 8-h moving average or annual maximum were calculated. 
By regression analysis clear long-term decreasing trends were observed for CO, SO2, and O3 in the 
MCMA; CO, SO2 and PM10 in the GMA; and SO2 in the MMA. No clear trend could be discerned for NO2 and 
PM10 in the MCMA; CO and NO2 in the GMA; and CO, NO2, and PM10 in the MMA. An increasing trend was 
observed for O3 in the GMA and MMA. Particularly large reductions in annual mean concentrations were 
observed for SO2: 67% in the MCMA (from 2000 to 2011), 68% in the GMA (from 2005 to 2011), and 36% in 
the MMA (from 2004 to 2011). In the MCMA, episodes of high SO2 concentration occurred due to stationary 
sources northwest of the area, and in the MMA, a considerable amount of SO2 likely came from the northeastern 
part of the area. 
The annual mean concentration of O3 in the MCMA decreased 13% from 2005 to 2010. In contrast, the 
annual mean concentrations of O3 in the GMA and MMA increased 47% and 42%, respectively, from 2000 to 
2011. Linear regression analysis between daily maximum O3 concentrations and temperatures suggested that 
additional factors other than temperature are relevant to the long-term trend of O3 concentration. 
The annual mean concentration of PM10 in the MMA was around 37% higher than that in the MCMA 
and around 42% higher than that in the GMA from 2001 to 2009. Although a number of action plans have been 
implemented, additional recommendations for improving air quality in these areas are needed, especially with 
respect to O3 and PM10. 
This analysis revealed that substantially different characteristics of air pollution can exist in different 
large cities even in the same country due to differences in geography, meteorology, emission regulations, and 
economic structure. Therefore, area-specific mitigation measures will have to be implemented to improve the air 
quality efficiently. This part of the study could identify the area-specific causes for high concentration of primary 
pollutants such as CO and SO2, but could not clearly determine the causes for high or increasing concentration of 
secondary pollutants such as O3 and the fine fraction of PM10. For a better understanding of such secondary 
 
Fig. 1. (a) Japanese territory and location of Ehime Prefecture and Tokyo metropolitan area; (b) Mexican territory and location 
of three Mexican metropolitan areas (Mexico City, Monterrey and Guadalajara). Urban areas are indicated by grey shade).  
（様式５）(Style5) 
pollutants, it would be necessary to monitor more precursor substances such as volatic organic compounds 
(VOCs), analyze components of particulate matter, and apply chemical transport models. The results obtained in 
this analysis will be an important basis for further discussion when more measurements and model results are 
produced in the future. 
Three-dimensional observations of meteorological parameters and ozone in Mexico City 
(Kanda, et.al., 2014) 
 Based on the past researches, various countermeasures against the air pollution have been implemented 
in the MCMA (SMA-GDF, 2012), resulting in rapid decrease of the annual mean O3 concentration until around 
2000 and almost constant gradual decrease in recent years although large fluctuations occurred in some years. 
However, with the emissions inventories of O3 precursors such as NOx and VOCs still having many problems in 
accuracy and considering the nonlinear nature of O3 production where reduction of a precursor substance does 
not necessarily lead to decrease of O3, continued observation of O3 is necessary.  
 Vertical profile measurement is important because O3 is produced in the atmosphere by photochemical 
reaction, transported by horizontal and vertical air flows, and destroyed by chemical reaction in the atmosphere 
and decomposition on solid surfaces. Various aspects of the vertical structure of air pollution has been clarified by 
the previous studies, but a critical question still remains unanswered on how O3 is produced and distributed in the 
atmospheric boundary layer.  
The ozonesonde measurements analyzed in this section were part of a more comprehensive field study 
including measurements of VOCs and PM2.5. Intensive field campaigns were conducted in the change from wet 
to dry-cold (November 2011) and dry-warm (March 2012) seasons in Mexico City. This research describes how 
meteorological condition affects the development of the vertical profile of O3 in the MCMA.  
Ozonesonde measurements were carried out twice daily, one in the morning and the other in the 
afternoon, to clarify the production and vertical redistribution of O3 in the mixing layer. For three days in 
November 2011 (17, 22 and 23) and six days in March 2012 (7, 8, 9, 12, 13, 14), radiosonde (at 8:30 and 17:30 
local standard time, LST) and ozonesonde (at 11:30 and 14:30 LST) were launched in MCMA. The balloon 
launch site was the rooftop of the Mexican National Weather Service (SMN) building (2313 m above sea level, 
ASL; 19°24’13”N, 99°11’ 46”W) where routine atmospheric sounding is conducted twice daily at 06:00 and 
18:00 LST.  
The observation days in November 2011 were characterized by cloudy weather and wind patterns 
favorable for the dispersion of pollutants. Under the warmer weather condition during the observation days in 
March 2012, the following diurnal pattern was clearly observed: thermal inversions at surface level occurred in 
the morning, rapid heating of the ground followed, and the mixing layer (ML) height grew relatively fast after the 
MCMA rush hours (8-9 LST).  
In the first week of the March-2012 campaign, relatively high temperature was recorded as well as high 
O3 concentration. During the weekend of 10-11 March 2012, a cold surge arrived from the north of the MCMA 
producing a decrease in the temperature. The next weekdays were relatively cool and occasional rain was 
observed in the evening, with decreasing O3 concentrations. The ML height and ventilation coefficient (VC) were 
estimated from the meteorological data. O3 produced and stored (∆QO3) in ML between 11:30 and 14:30 LST 
was estimated from the vertical profiles obtained by ozonesonde. The magnitude of ∆QO3 was confirmed to be 
positively correlated with the daily maximum temperature for most of the observation days.  
Application of a numerical simulation model for estimation of ozone production in Mexico City  
       Diurnal variations of meteorological parameters and concentrations of chemical species obtained during 
2 field campaigns in November-2011 and March-2012, were compared in the horizontal and vertical between 
observation and model simulation using the WRF-Chem model. As a result, a good agreement was found with 
respect to the meteorological parameters in the temporal and vertical variations (Fig.2). O3 vertical distributions in 
the November-2011 period were overestimated by the model probably because of excessively high emission 
setting of O3 precursors, which suppressed titration by NO. From the O3 profiles obtained by the observation and 
model simulation, the amount of O3 produced between 11:30 and 14:30 LST was estimated. The model 
underestimates the amount of O3 measured by experimental observations by 15-29% in the morning and 
overestimate by 21-29% in the afternoon. A positive correlation was found between daily maximum temperature 
at surface and O3 production estimated by the simulation, similar to that found for observational data. Special 
attention may have to be paid to the heat island effect in the MCMA because the resulting increase in temperature 
might increase the rate of O3 production.   
（様式５）(Style5) 
General conclusions 
Through this research, large 
differences in the behaviors of air 
pollutants were found among Mexican 
and Japanese areas. Because of higher 
concentrations observed in Mexican 
than in Japanese areas, more detailed 
analysis of the Mexican areas was 
conducted for a longer time frame 
from 2000 to 2011. High ozone levels 
in Mexican areas were observed. In 
order to reveal temporal variation of 
the vertical profiles of O3 
concentration, ozonesonde 
observations were conducted in the 
MCMA in November 2011 and March 
2012.   
  From the results obtained by 
field campaigns, it was possible to 
confirm the importance of vertical 
sounding of the atmosphere. Especially, 
the significance of frequent and deep 
soundings should be emphasized; the 
twice-daily ozondesonde observations 
through and beyond the mixing layer 
enabled estimation of the amount of 
photochemically produced ozone, and 
the four-times-daily radiosonde 
observations helped identify the causes 
for the behaviors where the ΔQO3 - 
daily maximum temperature relation 
was exceptional. In the past studies, 
similar analysis could not be 
conducted because the vertical 
soundings were either frequent but 
shallow, or deep but infrequent.   
In describing the diurnal and 
three-dimensional behavior of O3, 
combination of ozonesonde measurements and model simulation was found to provide valuable information. 
Using VC obtained by field measurements and model simulation, production of O3 in the ML of the MCMA 
could be related quantitatively to meteorological conditions. However, for the model simulation to be used as a 
tool of environmental assessment, more accurate data of emission inventories in Mexico are required. 
Publications 
Benítez-García S.-E., Kanda I., Wakamatsu, S., Okazaki, Y.,  Kawano, M.: Analysis of criteria air pollutant 
trends in three Mexican metropolitan areas. Atmosphere, 5, 806-829 (2014). 
Kanda, I., Basaldud, R., Horikoshi, N., Okazaki, Y., Benítez-Garcia, S.E., Ortínez, A., Ramos-Benítez, V., 
Cárdenas, B., Wakamatsu, S.: Interference of sulphur dioxide on balloon-borne electrochemical 
concentration cell ozone sensors over the Mexico City Metropolitan Area. Asian Journal of Atmospheric 
Environment, 8(3), 162-174 (2014). 
 
 
Fig. 2. Comparison of vertical distribution of potential temperature (θ), 
specific humidity (SH), wind speed (WS), wind direction (WD) and O3 for 
March 08, 2012. Symbols represent values calculate by the model and lines 
values from ozonesonde observations. 


English

A STUDY ON AIR-POLLUTION CHARACTERISTICS AND THREE-DIMENSIONAL BEHAVIOR OF PHOTOCHEMICAL OZONE IN MEXICO

愛媛大学Ehime University博士(理学)thesi

和田, 光平

WADA, Kohei

 
近年、超高圧発生装置で用いられるアンビル材は、使用目的に応じて様々な種類の超硬
合金が用いられており、それぞれの目的に合った超硬合金の開発が必要であった。そこで
本研究では、特に高圧条件下での中性子回折・磁性測定実験、30GPa 以上の超高圧発生実
験、超高圧条件下における物質合成実験に着目し、それぞれの目的に応じた超硬合金の開
発を行い、一軸圧縮実験と実際の超高圧発生装置で使用する事により、開発した材料の評
価を行った。 
第 2 章では、圧縮特性値を正確に測定する為の一軸圧縮実験装置の開発を行った。3 枚
の軸歪ゲージを用いた加圧精度の評価と、既存超硬合金とセラミックスの圧縮特性値を測
定し、一軸圧縮実験以外で測定できる機械的特性値と比較する事により、加圧精度の評価
を行った。その結果、高い実験精度で一軸圧縮実験が行える事がわかり、この開発した装
置を用いて新材料の評価を行った。 
第 3 章では、超高圧条件下での磁性測定実験や中性子回折実験を行う場合に使用する、
超微粒低結合相量の WC-Ni 系超硬合金を開発した。低結合相量の WC-Ni 系超硬合金は、従
来 WC 相よりも粗大な Ni プールが生じる為に、高強度の合金が得られなかった。また焼結
温度も WC-Co 超硬合金よりも高い為に、WC 平均粒度が 0.5μm よりも小さな超微粒 WC-Ni
系超硬合金も得られなかった。そこで、粉末の調製条件を新たに開発し、更に添加する炭
化物の量を最適化する事により、Ni プールのない高強度の超微粒低結合相量の WC-Ni 系超
硬合金を開発する事に成功した。開発した超硬合金は、既存 WC-Ni 系超硬合金 MF10 より
も圧縮強度が 1.4GPa 以上優れていた。更に、パリ・エジンバラ超高圧発生装置を用いて
圧力発生実験を行った結果、MF10 をアンビル材として用いた場合、12.5GPa が圧力発生限
界であったが、開発した超硬合金をアンビル材として用いた場合、16GPa を発生する事が
出来た。以上の事から、開発した超微粒低結合相量の WC-Ni 系超硬合金は大容量のプレス
を用いた超高圧条件下での中性子回折実験や磁性測定実験において、圧力発生限界を上昇
させる為に有用な材料であると考えられる。 
 第 4 章では、既存超硬合金よりも高圧力が発生可能な超微粒バインダレス超硬合金の開
発を行った。既存バインダレス超硬合金は、通常パルス通電焼結法やホットプレスを用い
て焼結している為に焼結性が悪い、もしくは予備焼結と HIP 処理を組み合わせた一般焼結
法で焼結した場合、WC 粒度が 0.8μm より大きい為に、圧縮強度が低かった。本研究では、
Cr3C2と VC の添加量を最適化する事により、一般焼結法で WC-M2C または WC-M2C-Ni の相か
ら構成される、WC 平均粒度が 0.5μm 以下の超微粒バインダレス超硬合金の開発に成功し
た。これらの開発した超硬合金の圧縮強度は、7GPa 以上の高い値を示した。そこでアンビ
ル材としての性能を、6-8 型超高圧発生装置を用い、既存超硬合金材種の中で最も高い圧
力発生が可能である TF05 と比較する事で評価した。アンビル先端サイズ 3mm で評価した
結果、TF05 を用いた場合、31.5GPa が圧力発生限界であった。一方、開発したバインダレ
ス超硬合金を用いた場合、36.5GPa を発生させる事が出来た。以上の事から、開発した超
微粒バインダレス超硬合金は、超高圧力を発生させるアンビル材として優れた性能を持ち、
6-8 型超高圧発生装置で 30GPa 以上の高圧力条件下での実験を行う為に、有用な材料であ
ると考えられる。 
 第 5 章では、超高圧条件下における物質合成で用いた場合に、長寿命となると考えられ
る結合相の圧力誘起変態が起こらない超硬合金の開発を行った。焼結、HIP 処理後の WC-Co
系超硬合金の結合相である Co 相は、WC 相の拘束などの為に、主として高温安定相の fcc
相で存在しており、非平衡状態にある。この為、超硬合金を変形させると、fcc 相で存在
している結合相は、常温安定相である hcp 相に圧力誘起変態を起こす。この圧力誘起変態
が、クラックの発生や遅れ破壊の発生の要因の一つとなっていると考えられる。本研究で
は、超微粒 WC-Co-Ni 系超硬合金の Co と Ni の混合比率と結合相量の最適化を行う事によ
り、現在超高圧条件下における物質合成で、アンビル材として使用されている超微粒 WC-Co
系超硬合金 TF06 と同等の機械的特性値を持ち、結合相の変態の起こらない超硬合金を開
発する事に成功した。そこで、この超硬合金を 6-8 型超高圧発生装置で用いて評価した結
果、TF06 と同等の圧力発生効率を示した。以上のことから、開発した WC-Co-Ni 系超硬合
金は従来材と同じように使用する事が可能であり、結合相の変態がない為に、既存材種よ
りも長寿命となる可能性があると考えられる。 
 


Japanese

新しい超硬合金の開発と超高圧発生装置への応用

Eduardo, A. Gomez Landires

（様式５）(Style5) 
学位論文全文に代わる要約 
Extended Summary in Lieu of Dissertation 
 
 
氏名： 
Name 
 
Eduardo A. Gomez Landires 
学位論文題目： 
Title of Dissertation 
Ecological and Epidemiological Studies on Sandfly Vectors of 
Leishmaniasis in Ecuador, with Special Reference to the Transmission  
in the Andes Regions 
 (エクアドル国におけるリーシュマニア症媒介昆虫サシチョウバエに関す
る生態学的・疫学的研究 －とくにアンデス地域における伝播を中心に－） 
 
学位論文要約： 
Dissertation Summary 
 
Ecuador is one of the smallest countries in South America, with an area of about 284,000 km
2
. 
However, the country is highly varied in all aspects; geographic, climatic, ecological, ethnical, and 
socio-economical and patho-epidemiological differences are found between each natural region.  At 
first, in order to present a clear picture of the relationship between the wide distribution of 
leishmaniasis and its vector sandflies and the ecological aspects of each area, a brief review was given 
on the most important points of interest for each region of continental Ecuador, excluding Galapagos 
Islands since these are so far free of the disease and the vector sandflies. The Andes, a range of 
mountains which traverses Ecuador from north to south, divides the country into three natural regions: 
the Littoral or Pacific coast region, the Sierra or Andean region, and the Oriente or Amazonian region. 
In Ecuador there are 24 provinces including Galapagos Islands. Among them, 21 provinces are 
positive for Lutzomyia sandflies and Leishmania parasites. 
Leishmaniasis is one of the most important emerging and re-emerging infectious parasitic 
diseases, second to malaria in terms of affected people. The disease is also one of the most neglected 
diseases worldwide, having strong and complex associations with poverty. It is prevalent in tropical 
and subtropical countries in the World, affecting at least 12 million people in 98 countries and regions. 
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Leishmaniasis is a vector/insect-borne parasitic disease caused by an obligate intracellular protozoan of 
the genus Leishmania. In human the disease is caused by infection with about 20 Leishmania species, 
and transmitted from infected reservoir mammals to humans or from human to human, by the bite of 
female sandflies of the genera Phlebotomus and Lutzomyia in the Old World and the New World, 
respectively. At present, approximately 800 sandfly species are recorded; however, less than 10% of 
them have capacity to transmit each particular Leishmania species. Investigations on the prevalent 
parasite and vector sandfly species are therefore important for risk assessment and appropriate 
treatment against the specific species of the genus Leishmania at given leishmaniasis-endemic areas. 
Clinically, the disease is divided into three principal manifestations, cutaneous (CL), mucocutaneous 
(MCL) and visceral forms (VL); the last one is most severe and fatal, if not treated appropriately. The 
first and second ones are caused by at least 14 species of the subgenera Leishmania and Viannia of the 
genus Leishmania, while the last one is caused by two species, L. (L.) donovani and L. (L.) infantum.  
Since 1982, the author has been conducting epidemiological studies in the New World, 
especially in Ecuador. In the country, transmission of CL and MCL occurs in rural populations living 
in bilateral regions of the Andes Mountains from the lowlands to highlands up to the elevation of 2,500 
m. The disease is widely spread in most provinces and is a considerable public health problem in 
Ecuador. In the endemic areas, however, epidemiological studies have still been done insufficiently on 
the community base, and no control measure has been applied to reduce or interrupt the transmission 
of the disease.  
During our research activities, we have discovered a form of the disease in persons living on 
the Andean plateau/valleys, where ecological conditions are very similar to that of ‘Peruvian uta’ 
endemic areas, but that the clinical picture, causative agent and vector are completely different. These 
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findings have added a new insight with the distribution of Andean leishmaniasis in the South 
America. Before our study, the form of leishmaniasis in the Andes was thought to be only ‘Peruvian 
uta’ caused by L. (Viannia) peruviana. Thus, in Peru the causative agent of the disease is L. (V.) 
peruviana and the suspected vectors are Lu. (Lutzomyia) verrucarum, Lu. (Lu.) peruensis, and Lu. 
(Lu.) ayacuchensis. In contrast, two species of the genus Leishmania, L. (Leishmania) mexicana and L. 
(L.) major-like seemed to be involved in Andean highland leishmaniasis in Ecuador; the latter infection 
however almost negligible at public health level. The only incriminated vector species is Lu. (Lu.) 
ayacuchensis, and the infection rate of L. (L.) mexicana is high (1-8%) in highland areas, which is 
uncommon in most endemic areas of Ecuador. 
The present study deals with the results obtained from long-term studies, during the period 
from 1982 to date, carried out in different leishmaniasis-endemic areas of Ecuador, from the various 
points of view of the investigations, including vector/medical entomology, parasitology, epidemiology 
and molecular biology, etc. Special emphasis was given to the understanding of the transmission 
mode(s) of the disease, especially of the Andean type leishmaniasis, analyzing the different factors at 
given endemic areas of Ecuador. Furthermore, countrywide distribution of man-biting (anthropophilic) 
sandfly species and their role as vectors of the disease were also discussed, based on the accumulated 
data of sandfly collection and dissection. All the principal information given in the present study is 
summarized as follows. 
1) Performing a brief review of the literatures and our own data obtained, ecological features 
of each area of Ecuador which relate to the mammalian (reservoir host of the parasite Leishmania) and 
sandfly (vector of the parasite) fauna were taken into special consideration on the factors related to the 
distribution of sandflies Lutzomyia spp. and parasites Leishmania spp. Leishmaniasis is the most 
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widespread tropical zoonosis in Ecuador. In this study Ecuadorian leishmaniasis-endemic areas were 
detected on the basis of the occurrence of clinical cases reported to date. The distribution of the parasite, 
Leishmania, depends on the biological divergence at given endemic area, and the rate of endemicity 
and/or infection intensity would be estimated by measurement of the incidence of natural infections of 
both sandflies and reservoir host mammals. Tropical rain forest gives the preferred habitat for many 
New World human Leishmania spp. Human cases are always the result of accidental transmission in 
South and Central American countries including Ecuador. Thus the author concluded that the 
Amazonian region is an important endemic area of leishmaniasis as a zoonosis with relatively few 
human cases, while the Pacific Coast （littoral）region is an ecologically less diverse endemic area of 
the disease with many human cases. 
2) In total, 29 man-biting species of the genus Lutzomyia were identified at different 
provinces of Ecuador. Among them, from the view point of transmission of leishmaniasis, most 
prevalent and/or important 10 species in the country were listed as follows: Lutzomyia gomezi, Lu. 
robusta, Lu. hartmanni, Lu. shannoni, Lu. trapidoi, Lu. panamensis, Lu. maranonensis, Lu. 
ayacuchensis, Lu. tortura and Lu. yuilli yuilli. In the present study a total of 18,119 man-biting 
sandflies were collected and dissected. Only 197 (1.09%) of the total samples dissected, of four 
Lutzomyia species, were positive for Leishmania promastigotes. Lutzomyia ayacuchensis showed a 
relatively high infection rate (2.69% to 3.42%) against Leishmania (Leishmania) mexicana in the 
Andean regions, followed by Lu. tortura positive for L. (Viannia) naiffi with 2.20% (3/148 flies tested) 
in the Amazonian regions. Only two (0.09%) of the 2,055 Lu. gomezi and one (0.04%) of the 2,542 Lu. 
trapidoi showed positive for Leishmania. However, other predominant man-biting species, i.e., Lu. 
hartmanni (4,525 flies tested) and Lu. robusta (1,164 flies tested), were negative for Leishmania 
（様式５）(Style5) 
parasites. On the other hand, Endotrypanum was recognized in five Lutzomyia species, Lu. robusta, Lu. 
hartmanni, Lu. trapidoi, Lu. panamensis and Lu. yuilli yuilli, suggesting its wide vector-ranges. 
Interestingly, however, none of 2,055 Lu. gomezi, a species with wide range of distribution at 
provincial level, was positive for Endotrypanum parasites at any areas. These data on the man-biting 
species of the genus Lutzomyia and their natural infections with Leishmania and Endotrypanum would 
be useful for the transmission study and surveillance of leishmaniasis. The differential identification 
between the two flagellate species would be critical for the estimation of the natural infection rates of 
sandflies at given areas.  
3) In our preliminary study during 1986 and 1988 at Paute, an Andean small town in 
Department of Azuay, 25 human cases were positive for Leishmania parasites, demonstrating 
abundant amastigotes in smears taken from cutaneous lesions. At the beginning, the disease symptoms 
were clinically suspected to be similar to those exhibited by diseases of ‘Peruvian uta’, caused by 
Leishmania (Viannia) peruviana which had been reported from Peru. Fifteen Leishmania isolates, 
including 11 from human skin lesions, two from dog livers and two from phlebotomine sandfly guts, 
were obtained from the area. All of the isolates obtained from humans and one from a dog were 
identified as Leishmania (L.) pifanoi (now L. (L.) mexicana) by serodeme, zymodeme and schizodeme 
analysis. Later, the isolates from the mid-gut of sandflies, Lutzomyia ayacuchensis, were also identified 
as L. (L.) mexicana. 
4) In order to clarify the role of Lutzomyia ayacuchensis in the transmission of leishmaniasis 
in a newly found Andean endemic focus mentioned above, a sequential field study was performed 
over 13 months. Dissections were performed on a minimum of 200 anthropophilic sandflies collected 
at nights every month. A total of 2,600 sandflies were separated from a low number of Lu. osornoi 
（様式５）(Style5) 
（another anthropophilic species in the area）and dissected. Ninety-five （3.65%） of Lu. ayacuchensis 
were found naturally infected with Leishmania promastigotes． The parasites were always located in 
the sandfly foregut and midgut, suggesting that they belong to the L. (L.) mexicana rather than the L. 
(V.) braziliensis complex. The results revealed a marked monthly variation in both natural infections 
with Leishmania and biting activity of sandflies in the Paute endemic area, suggesting that high 
transmission intensity occurred during the rainy season. 
5) The transmission cycle of Andean type leishmaniasis seems to be regulated by a set of factors 
that are influenced by climatic conditions. The first consists of three habitat categories; open field
（rural）, suburban and urban. Each of these habitats is occupied at the same time by humans, domestic 
and wild mammals (reservoirs)． The second consists of the relationships between sandflies （Lu. 
ayacuchensis）and the principal reservoir hosts of Leishmania, presumed to be rats （Rattus rattus）. 
Sequential changes in the incidence and frequency of human cases of Andean type of leishmaniasis in 
this endemic area are considered to be the result of migrations of sandflies and rodents among the three 
habitat categories. 
6) A vertical distribution of Lu. ayacuchensis, the vector of L. (L.) mexicana was surveyed at 
different altitudes (300-2,500 m above sea level) in Ecuadorian Andes. The vector species Lu. 
ayacuchensis was identified at altitude of 650 m and higher areas, and higher distribution ratio of the 
species was observed at higher altitudes. In addition, high infection rates of L. (L.) mexicana were 
detected in higher areas, but none in lower populations of the sandflies.  Since an association between 
a sandfly population and the vector competence has been suggested in Lu. ayacuchensis, a haplotype 
analysis was performed on the species from different altitudes of the study areas; however, no apparent 
difference was observed among populations. These results suggested that Lu. ayacuchensis in Andean 
（様式５）(Style5) 
slope areas of Ecuador have a potential to transmit L. (L.) mexicana and have a risk to spread 
leishmaniasis in these areas.  
7) As mentioned above, the form of leishmaniasis in the Andes had been considered to be 
only ‘Peruvian uta’ caused by L. (V.) peruviana until 1986. However, our research group discovered 
another type of leishmaniasis in the Ecuadorian Andes. It had ecologically and epidemiologically very 
similar to the ‘Peruvian uta’, but the features of causative agents, vectors and clinical forms of the 
patients are completely different from those of ‘Peruvian uta’.  In the study, therefore, a review and/or 
an analysis of the differences of Andean type of leishmaniasis between the two countries, Ecuador and 
Peru was also given briefly. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(注) 要約の文量は，学位論文の文量の約１０分の１として下さい。図表や写真を含めても構いません。
(Note)  The Summary should be about 10％ of the entire dissertation and may include illustrations 


Ecological and Epidemiological Studies on Sandfly Vectors of Leishmaniasis in Ecuador, with Special Reference to the Transmission in the Andes Regions

Ehime University (愛媛大学)博士(医学)thesi

武, 洲英

BU, Shuei

（第３号様式）     
 
 
学 位 論 文 要 旨 
 
 
          氏   名  武 洲英 
 
 
 
            論 文 名 HMGA2 は MLL-AF4 融合遺伝子を有する乳児急性リンパ性
白血病での分子標的になりうる 
 
 
 
 
 
学位論文要旨 
【Background and aims】 
Acute lymphoblastic leukemia (ALL) of infants is one of the intractable cancers in childhood and efficient, 
less toxic molecular targeting therapies have been anticipated. Leukemic cells of infant ALL frequently 
carry the mixed-lineage leukemia (MLL) rearrangement resulting in a generation of fusion genes such as 
MLL-AF4, which is a hallmark of poor prognosis. 
 In infant ALL cells with MLL fusion, the microRNA let-7b is significantly downregulated by DNA 
hypermethylation of its promoter region. HMGA2 oncogene, which is frequently truncated or 
overexpressioned in cancer cell, is negatively regulated by let-7b. One of the targets of HMGA2 is the 
CDKN2A gene, which encodes the two cell cycle regulators p16INK4A and p14ARF. This 
let-7b-HMGA2-CDKN2A axis regulates stem cell ageing in both normal and pathological states such as 
cancer. Therefore, demethylating agents such as 5-azacytidine could be applied to recover the expression 
of suppressed let-7b in leukemic cells, representing a possible candidate drug for molecular therapy of 
infant ALL with the MLL fusion gene. In addition, HMGA proteins could be suitable candidates for 
molecular therapy against HMGA-overexpressing cancer. In this study, we aim to investigate whether the 
let-7b-HMGA2-CDKN2A pathway can be a possible target for molecular targeting therapy of infant ALL 
with MLL-AF4. 
【Materials and methods】 
The expression of HMGA2 was examined by quantitative RT-PCR using leukemic cells collected from the 
infants with ALL. Written informed consent was obtained from the parents of all patients participating in 
this study, and all research was approved by the institutional review board. 
Leukemic cell lines established from ALL patients were used to assess the effects of drugs targeting  
氏名 武 洲英     
the let-7b-HMGA2-CDKN2A axis. SiRNA against HMGA2 was used to evaluate the effects of HMGA2 
inhibition over leukemic cell growth. Demethylating agent 5-Azacytidine and HMGA2 inhibitor netropsin 
dihydrochloride were also used as possible therapeutic agents which target the let-7b-HMGA2-CDKN2A 
axis. Methylation analysis with bisulfite modification was performed to assess methylation status of the 
promoter region of the let-7b host gene to evaluate the effects of demethylating agent 5-Azacytidine. MTT 
assay was performed after leukemic cell lines were treated with 5-azacytidine and/or netropsin to assess 
their effects on leukemic cell growth and western blotting was used to assess the amount of HMGA2 and 
p16 protein. 
【Results】 
HMGA2 was highly expressed in most patients with an MLL gene rearrangement, particularly in MLL-AF4 
positive cases indicating HMGA2 as a possible target for molecular therapy. 
 After 5-azacytidine treatment, expression of let-7b, as well as p16INK4A, was recovered in 
MLL-AF4-harboring leukemic cells with concomitant demethylation of its promoter region. In accordance 
with the negative regulation by let-7b, 5-azacytidine gradually suppressed the amount of HMGA2 protein 
and also suppressed the growth of MLL-AF4-harboring leukemic cells. Inhibition of HMGA2 by siRNA or 
its inhibitor netropsin could also suppress the growth of MLL-AF4-harboring leukemic cells. 
 Although netropsin itself showed no ability to recover the expression of let-7b by removing DNA 
methylation, co-presence of 5-azacytidine and netropsin elevated the expression levels of let-7b and 
p16INK4A in leukemic cells more effectively, compared to 5-azacytidine alone. Synergic effects of 
5-azacytidine and netropsin were also observed on growth inhibition of leukemic cells. Growth of 
MLL-AF4-harboring leukemic cells was significantly suppressed in the presence of both 5-azacytidine and 
netropsin, compared to single-drug treatment, and the inhibitory effect was accompanied by re-expression 
of p16INK4A. 
【Discussion】 
Because expression of HMGA2 was elevated in MLL-AF4-positive ALL, HMGA2 is a suitable target for 
molecular targeting therapy against MLL-AF4-positive leukemia. Our results indicated some usefulness of 
demethylating agents such as 5-azacytidine and HMGA2 inhibitor such as netropsin in growth suppression 
of leukemic cells with MLL-AF4 fusion gene. While recovery of let-7b by demethylating agents is useful 
ways to suppress the action of HMGA2, demethylating agents alone was not sufficient to upregulate and 
sustain the expression level of let-7b in the presence of active MLL-AF4 fusion protein, which is a 
powerful inhibitor of let-7b. In this regard, combination of both agents could be more useful as the effects 
of netropsin became more prominent in combination with the demethylating agent 5-azacytidine. 
【Conclusion】 
Although the complete mechanism underlying the induction of leukemogenesis in MLL-rearranged infant 
ALL remains obscure, downregulation of the miRNA let-7b and upregulation of oncogenic HMGA2 
protein by an MLL fusion protein may play a key role in this process. HMGA2 inhibitors such as netropsin 
could be a new therapeutic agents for MLL-AF4-positive infant ALL, particularly in combination with 
demethylating agents such as 5-azacytidine. 
キーワード（３～５） infant, acute lymphoblastic leukemia, MLL-AF4, HMGA2 


HMGA2 as a potential molecular target in KMTA-AFF1-positive infant acute lymphoblastic leukaemia"

横山, らみ

YOKOYAMA, Rami

（第 12 号様式） 
 
 
学 位 論 文 の 要 約 
（ 研 究 成 果 の ま と め ） 
 
 
 
            氏   名 横山 らみ 
 
 
            学位論文名 心臓サルコイドーシスにおける 18F-FDG PET/CT を用いた心筋集積
             の定量的評価 
 
 
    学位論文の要約 
【緒言】 
 サルコイドーシスは、諸臓器に乾酪壊死のない類上皮細胞肉芽腫が形成される全身性の肉芽
腫疾患である。一般には自然寛解する予後良好な疾患と考えられるが、心病変の合併は極め
て予後不良とされている。心病変の合併は本症の死亡原因の第一位を占めるため、早期発見
と治療は本症において重要な課題である。心臓サルコイドーシス（心サル）の診断ガイトド
ラインは、1992 年平賀らによってはじめて作成され、2006 年に日本サルコイドーシス学会
と日本心臓病学会との合同委員会によって修正が行われた。心サルの診断には造影 MRI 検査
における心筋の遅延造影所見も有用とされているが、多くの症例でペースメーカーや ICD が
挿入されており、MRI は心サルの診断や経過観察には限界があると考えられる。心サルと診
断された場合、重症度評価、予後予測、ステロイド療法などの治療の点から、疾患活動性の
判定が重要となる。この判定に、核医学による炎症イメージングとして 67Ga イメージングが
活用されてきたが、診断感度が低く検出力が劣ることが指摘されている。 
 
【目的】 
 18F‒fluorodeoxyglucose（FDG）positron emission tomography（PET）は、悪性腫瘍の診
断のみならず、炎症性疾患の診断にも応用されつつある。2012 年には、心サルの炎症部位
の診断に対して FDG PET の保険償還が認められた。現在、心サルの診断ガイドラインを改訂
する動きがあり、主徴候の一つに FDG PET の陽性所見を加えることが検討されている。今回
我々は心サルが疑われ、FDG PET/CT が施行された症例において、心筋の FDG 集積を定量化し,
心サルの心病変の評価を行った。 
 
【方法】 
 PET CT の撮影では、生理的心筋集積を最小限に抑制する目的で、検査前日の夕食を 5g 以
下の低炭水化物食とし、その後 18 時間以上の絶食、FDG 投与前のヘパリン投与を行った。20
09 年 3 月から 2014 年 12 月までの期間に心サルが疑われ、サルコイドーシスの既往歴、心室
中隔基部の菲薄化、心電図異常（高度房室ブロック、心室頻拍、多源性あるいは頻発する心
室期外収縮）のいずれかを満たし、PET を施行された 125 症例の患者が、十分な説明と同意
を得て登録された。すでに心サルと診断されステロイド治療導入後の 12 症例、冠動脈疾患
の既往歴のある 3 症例を除外した。また、PET 施行前の絶食時間が 18 時間未満であった 12
症例と、FDG 投与前の血糖値が 126mg/dl 以上の 6 症例も除外し、92 症例を検討対象とした。
心サルの診断には 2006 年に改訂された診断基準を用いた。92 症例のうち 32 症例が心サルと
診断された。肝臓と心筋の FDG 集積の程度を視覚的に 1〜4 段階にスコア化して、3 以上の症
例を集積陽性とした。定量的評価では、心筋の maximum standardized uptake value: SUVm
ax、Heart/Blood Pool（H/BP）SUV ratio: 心大動脈比、Heart/Liver（H/L）SUV ratio: 心
肝比を用いて診断能を評価した。そして、定量的評価と視覚的評価の診断能に差があるかを
検討した。 
 
【結果】 
 視覚的評価における心サルの診断能は、感度 97.3%,特異度 70.9%であった。心サル群にお
ける心筋 SUVmax は 9.5 ± 4.8 であり、陰性群の 3.0 ± 1.7 と比較し、有意に FDG 高集積で
あった（p < 0.0001）。心サル群における ROC 解析の AUC は、心筋 SUVmax: 0.960、H/BP S
UV ratio: 0.949、H/L SUV ratio: 0.946 であり、心筋 SUVmax における AUC が最大であっ
た。心筋 SUVmax = 4.0 をカットオフとすると、感度 97.3%,特異度 83.6%と良好な診断能を
得た。SUVmax による定量的評価を用いることで、視覚的評価と比べて有意に特異度の上昇を
認めた（p = 0.039）。また、臨床所見等の 10 項目による多変量ロジスティック解析におい
て、心筋 SUVmax は、心サルの独立した診断予測因子であった（OR, 4.29; 95% CI, 1.39–13.
21; p = 0.011）。ステロイド治療後に経過観察の PET が施行された 18 例の検討では、心筋
SUVmax は、9.8 ± 4.2 から 5.5 ± 3.5 とステロイド治療後において有意に低下した（p = 0.
003）。 
 
【結語】 
 生理的心筋集積を抑制する前処置を施行した FDG PET の心筋 SUVmax は、心サルの診断能
向上、ステロイド治療後の経過観察に有用であると考えられた。なお、この学位論文の内容
は、以下の原著論文に既に公表済である。 
 
主論文：Yokoyama R, Miyagawa M, Okayama H, Inoue T, Miki H, Ogimoto A, Higaki J, M
ochizuki T. Quantitative analysis of myocardial 18F-fluorodeoxyglucose uptake by P
ET/CT for detection of cardiac sarcoidosis. Int J Cardiol. 2015 Sep 15;195:180-7. 
DOI: 10.1016/j.ijcard.2015.05.075. 


Quantitative analysis of myocardial ^18F-fluorodeeoxyglucose uptake by PET/CT for detection of cardiac sarcoidosis

黒田, 太良

KURODA, Taira

（第 12 号様式） 
 
 
学 位 論 文 の 要 約 
（ 研 究 成 果 の ま と め ） 
 
 
 
    氏   名  黒 田  太 良 
 
 
 学位論文名 門脈圧亢進を伴う肝硬変患者における膵うっ血およびインスリン分泌能低下 
 
学位論文の要約 
[背景と目的] 
 門脈圧亢進を有する肝硬変（LC）患者はしばしば糖尿病を合併するが，LC 患者特有の代謝障
害や栄養障害のためその治療に難渋することが多い．糖尿病に膵は重要な臓器である．LC 患者
では門脈圧亢進により膵から門脈への排血障害が想定され，膵血流異常が膵の内分泌機能に影響
することが推測される．しかし門脈圧亢進による膵血流異常と内分泌機能の関連を検討した報告
はこれまでにない． 
申請者は，門脈圧亢進症を有する LC 症例において，膵の血流動態および内分泌機能を評価し，
さらに膵組織を評価することで，1) 生体内における膵血流異常が内分泌機能に関連するか，2) 
LC 患者の膵組織において門脈圧亢進に伴う膵組織学的変化がみられるか，について明らかにす
ることを目的とし研究を行った．  
 
[対象と方法] 
1. 造影超音波による検討 
LC 患者と非 LC 患者の膵血流動態の違いを評価するために以下の検討を行った．膵血流を直
接評価するためには，膵への流入血管や膵からの流出血管の血流圧を測定する必要がある．しか
し生体内でそれらを評価するためには，動脈や門脈穿刺を用いた血管造影が必要になり高度な侵
襲を伴う．そこで，非侵襲的かつリアルタイムで血流評価が可能な造影超音波を用いて膵血流評
価を行った．対象は 2012 年 4 月から 2013 年 7 月までに当科で肝生検により診断した LC 群 20
例と非 LC 群 21 例．両群に造影超音波を行い，膵における血流変化を Time Intensity Curve に
変換し前向きに比較検討した．  
次に評価した血流と内分泌機能の間に相関関係があるかどうかを確認するため，膵内分泌機能
評価としてグルカゴン負荷試験を行い，膵からの排血時間と delta C-peptide immunoreactivity
（ΔCPR）の関連性を評価した． 
 
2. 病理組織学的検討 
 LC による門脈圧亢進症とそれによる膵病理組織学的変化について評価することを目的に，LC
患者と非 LC 患者における膵組織の比較検討を行った．対象は 2000 年 4 月から 2012 年 10 月ま
でに当科を含めた 2 施設で病理解剖を行った LC 群 20 例と非 LC 群 23 例．膵血管は 
Elastic-Masson 染色，Picrosirius Red 染色を用いて血管形態を評価し，膵島はインスリン免疫
染色を用いて膵島径，およびインスリン陽性細胞比率を評価した． 
 
[結果と考察] 
1. 造影超音波による検討 
LC 群では門脈圧亢進を示唆するパラメーター（腹水，静脈瘤，脾重量，門脈本幹径）が有意
に高値で，血小板数は有意に低かった．LC 群では排血時間が有意に遅延しており（LC 群 5.6
秒；非 LC 群 3.0 秒，P < 0.0001），ΔCPRも低下していた（LC 群 2.3ng/mL；非 LC 群 3.7n
g/mL，P = 0.005）．排血時間と ΔCPRとの間には有意な負の相関がみられた（R = 0.42，P 
= 0.0069）．以上より門脈圧亢進症を伴う LC 症例では膵血流の排血遅延に伴い膵うっ血がみら
れ，膵うっ血に相関して膵内分泌機能低下がみられることが明らかになった． 
 
2. 病理組織学的検討 
 LC 群の膵組織では静脈壁が有意に肥厚していた（LC 群 40.2μm；非 LC 群 22.3μm，P = 0.
0014）．Picrosirius-red 染色において肥厚した静脈壁（主に内膜）には 3 型コラーゲンの沈着が
みられ，圧損傷に伴う代償性変化が推測された．非 LC 患者群にはこの変化はみられなかった．
さらに LC 群では膵島の過形成がみられ（LC 群 320.8μm；非 LC 群 141.5μm，P < 0.0001），
インスリン陽性細胞比率は有意に低下していた（LC 群 45.8%；非 LC 群 75.5%，P < 0.000
1）．静脈壁の厚さとインスリン陽性細胞比率との間には有意な負の相関がみられた（R = 0.63，
P < 0.0001）．門脈亢進症を有する LC 患者では膵うっ血に伴う 3 型コラーゲンを主体とした
静脈壁肥厚がみられ，肥厚の程度が強いほど内分泌機能が低下していることが示唆された． 
  
[結論] 
 門脈圧亢進症を有する LC 症例において，膵うっ血が存在し，膵うっ血に関連して膵の静脈
壁肥厚，膵島過形成，インスリン陽性細胞比率の低下，インスリン分泌機能低下がみられた．L
C 患者における膵内分泌機能障害のメカニズムの１つとして，門脈圧亢進に伴う膵血流変化が関
与している可能性が考えられる．肝性糖尿病の治療として，門脈圧亢進症に対する積極的な治療
が有効となりうると考えられた．今後前向きな臨床研究で，門脈圧亢進症と膵内分泌機能低下の
直接的な関係についてさらに明らかにしていきたい． 
なお，この学位論文の内容は以下の原著論文に既に公表済である． 
 
主論文： Taira Kuroda, Masashi Hirooka, Yoichi Hiasa, et al. Pancreatic congestion in liver cirrh
osis correlates with impaired insulin secretion. Journal of Gastroenterology. [Epub ahead of print] 
DOI: 10.1007/s00535-014-1001-8 


Pancreatic congestion in liver cirrhosis correlates with impaired insulin secretion

松田, 卓也

MATSUDA, Takuya

（第７号様式） 
 
学位論文審査結果の要旨 
 
   氏     名  松田 卓也 
 
 
 
 
 
   審 査 委 員 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
      
 論  文  名 心筋梗塞に対する心臓遅延造影の CT 評価の試み 
 審査結果の要旨 
【背景】虚血性心疾患の患者では治療方針の決定において心筋のバイアビリティ評価が重要であ
る。核磁気共鳴画像法（Magnetic resonance imaging: MRI）を用いた遅延造影と病理学的心筋
梗塞巣とは良好に相関し、現在、遅延造影 MRI は心筋梗塞巣の同定と心筋バイアビリティ評価の
第一選択である。 
 一方、computed tomography（CT）でも遅延造影の描出が可能であるが、CT は放射線被曝に加
え、MRI 遅延造影に較べて正常心筋と病変部とのコントラストが小さく、画像ノイズが高いため、
診断感度が低いことが問題である。本論文は被爆量を抑え且つ特殊フィルタを用いて画像処理す
ることによりノイズを低減することで、遅延造影 CT が MRI に代わる心筋バイアビリティ検査法
になり得るか検討したものである。 
【方法】対象は 19 例の緊急経皮的冠動脈インターベンション（PCI）を行った急性心筋梗塞患者
である。PCI から退院までの各々異なる日に、遅延造影 MRI ならびに冠動脈 CT に引き続いて行
う Dual Energy CT を用いた遅延造影 CT を撮像した。4 種の遅延造影 CT 画像 100kVp+140kVp の m
ix 画像（mixed）および 140kVp 画像(140kVp)、100kVp 画像(100kVp)、ノイズ低減処理した 100k
Vp 画像（denoised-100kVp）について、contrast-to-noise ratio(CNR)および心臓各セグメント
の遅延造影の有無による診断能、心筋全体に対する遅延造影の割合を検討した。診断能の評価は
遅延 MRI による結果を基準とした感度、特異度、陽性適中率、陰性的中率、正診率で行った。 
【結果】CNR の中央値はそれぞれ 3.49（mixed）、1.21（140kVp）、3.57(100kVp)、6.08（deno
ised-100kVp）と、ノイズ低減処理した 100kVp 画像で有意に高かった。MRI では 304 セグメント
中 53 セグメントで遅延造影が認められた。ノイズ低減処理した 100kVp 画像では感度 81.1%、特
異度 96.0%、陽性的中率 81.1%、陰性的中率 96.0%、正診率 93.4%であり、感度および陰性的中率、
正診率は他の 3 種の画像より高かった。遅延造影領域の割合の中央値は MRI が 5.54%、CT がそれ
ぞれ 5.72%（mixed）、3.31%（140kVp）、5.09%(100kVp)、5.59%（denoised-100kVp）であった。
MRI と CT の Spearman 相関係数は 0.937（mixed）、0.907（140kVp）、0.775(100kVp)、0.846（d
enoised-100kVp）であり、4 種の何れの遅延造影 CT 画像も遅延造影 MRI 画像と良い相関が得ら
れた。 
【考察】一般に CT 画像は MRI に比べて正常心筋と病変部のコントラストが小さく、ノイズが高
いため、画像評価の指標である CNR が低く、診断感度が低いことが短所である。しかし、本研究
の結果から低電圧画像にノイズ低減処理を併用することで、良好な CNR が得られることが示され
た。CNR の向上はノイズ低減に加えて低電圧撮像によるコントラスの上昇の結果である。また、
高 CNR が高い診断能につながった。さらに遅延造影領域の割合は CT と MRI で良好な相関を示し、
低電圧画像にノイズ低減処理を併用した場合には MRI に匹敵するものであった。CT は MRI に完
全に置き換わる検査とはならないものの、MRI 禁忌症例への代替法となることが示唆され、心筋
バイアビリティ評価の補助的検査法となることが期待できる。 
【結論】遅延造影 CT において低電圧撮像にノイズ低減処理を併用することで、心筋虚血部と正
常心筋との高い CNR を達成できることを示した。これにより、急性心筋梗塞 PCI 後の心筋バイ
アビリティ評価に遅延造影 CT が極めて有用であることが明らかとなった。 
 
 本論文の公開審査会は 2015 年 1 月 28 日に開催された。申請者は研究内容を明確に発表し、
以下の内容を含む多くの質疑に対し的確に応答した。 
１）研究対象を PCI 後の急性期に設定した意義、２）遅延造影 MRI が CT よりコントラストが
良い理由、３）CT 画像での遅延造影部位と組織学的所見の相関、４）遅延造影 CT と梗塞巣の
大きさを反映する血液検査値の関係、５）遅延造影 CT が再潅流されない心筋を過小評価する
可能性、６）CT と MRI の撮像日が異なることが結果に与える影響、７）冠動脈 CT 血管造影と
遅延造影 CT を同時撮像の可能性、８）ノイズ低減フィルタの短所、９）遅延造影 CT が MRI に
勝る利点。 
 
 申請者は、低電圧画像にノイズ低減処理を併用した遅延造影 CT が、急性心筋梗塞における病
巣の同定と心筋バイアビリティの評価法として従来おこなわれている MRI 遅延造影と同様に極め
て有用であることを明らかにした。本研究で得られた知見は今後、臨床応用が期待できるものと
して高く評価される。審査会は全員一致して本論文が学位論文に値すると判定した。 
 
 


Diagnostic accuracy of late iodine enhancement on cardiac computed tomography with a denoise filter for the evaluation of myocardial infarction

東, 晴彦

HIGASHI, Haruhiko

 （第３号様式）     
 
 
学 位 論 文 要 旨 
 
 
 
          氏   名  東 晴彦 
 
 
 
          論 文 名  冠動脈 CT で左冠動脈近位部の評価不能症例における経胸壁ドプラ 
                        心エコーの有用性 
 
 
 
 
 
 
学位論文要旨 
【背景】心臓病は本邦における死因の第 2 位である。高齢化や生活習慣の欧米化に伴い,今も
尚急性心筋梗塞や狭心症などの冠動脈疾患は増加の一途をたどっており,その早期発見と治療
が重要である。冠動脈疾患が疑われる症例に対する検査として冠動脈 CT 検査が広く行われお
り,ガイドラインでも重要な位置を占めている。しかしながら,高齢化に伴い冠動脈に高度な石
灰化を有する症例は多く,このような症例においては blooming アーチファクトや beam-harden
ing アーチファクトにより冠動脈 CT での狭窄評価は困難である。近年,経胸壁ドプラ心エコー
（TTDE）を用いて冠動脈狭窄を検出することが可能となり,その有用性が報告されている。
【仮説】TTDE は冠動脈 CT で評価不能な冠動脈狭窄の検出に貢献する。【目的】冠動脈 CT で
左冠動脈近位部の評価が不能であった狭心症患者において,TTDE の有用性を検討すること。
【方法】狭心症疑いで冠動脈 CT を施行した連続 574 症例の中で冠動脈の石灰化またはステン
ト留置のため左冠動脈近位部の評価が不能であった 58 症例を対象とした。冠動脈血流速度に
影響を与えると考えられる心筋梗塞,うっ血性心不全,肥大型心筋症,左室肥大,冠動脈バイパス
術の既往,左室駆出率 60%未満,心房細動,有意な弁膜症,左前下行枝の慢性完全閉塞症例は除外
した。冠動脈 CT は Siemens 社製の dual source CT を使用した。冠動脈エコーは GE 社製の Vi
vid 7 dimension,M4S プローブを使用した。左冠動脈近位部血流速度はカラードプラ法とパル
スドプラ法により測定した。カラードプラ法に関しては,傍胸骨短軸像の大動脈基部から左冠
動脈近位部の血流をカラードプラガイド下で描出し,冠動脈カラードプラ画像の速度レンジを
19 cm/s に設定し,エリアシング血流が検出された場合には速度レンジをエリアシング血流が
消失するまで徐々に上昇させた。エリアシング血流が消失した速度レンジを“isovelocity”
氏名  東 晴彦     
と定義した。パルスドプラ法に関しては,左冠動脈近位部の冠動脈血流が検出された部位にサ
ンプルボリュームを設定し,平均拡張期最大血流速度（ADPV）を測定した。全症例で冠動脈造
影検査を施行し,70%狭窄以上を高度狭窄,40%狭窄以上 70%狭窄未満を中等度狭窄と定義した。
高度狭窄と中等度狭窄を合わせて有意狭窄とした。【結果】左冠動脈近位部の血流は 58 例の
うち 45 例（78%）で検出可能であった。高度狭窄群は中等度狭窄群や非有意狭窄群に比較しカ
ラードプラ法で測定した isovelocity（148±42 cm/s, 89±40 cm/s, 41±22 cm/s, p <0.0
5）,パルスドプラ法で測定した ADPV(143±61 cm/s, 82±33 cm/s, 39±17 cm/s, p <0.05)と
も有意に高値であった。また,ROC 解析の結果,左冠動脈近位部の高度狭窄を予測する isoveloc
ity の至適 cut-off 値は 92 cm/s(感度 100%,特異度 90%,陽性的中率 56%,陰性的中率 100%),ADP
V の至適 cut-off 値は 81 cm/s(感度 100%,特異度 85%,陽性的中率 45%,陰性的中率 100%)であっ
た。同様に,有意狭窄を予測する isovelocity の至適 cut-off 値は 57 cm/s(感度 90%,特異度 7
7%,陽性的中率 74%,陰性的中率 91%),ADPV の至適 cut-off 値は 61 cm/s(感度 84%,特異度 88%,
陽性的中率 84%,陰性的中率 88%)であった。【考察】冠動脈疾患は治療が遅れると予後も悪く
なるため迅速で的確な診断が求められる。中でも左冠動脈近位部病変はその灌流域も広く,予
後に与える影響も大きいため重要視されるべき病変である。本研究では冠動脈 CT で左冠動脈
近位部の評価が困難であった症例における TTDE の有用性を評価した。結果,8 割近くの症例で
評価が可能であり,非常に高い感度,特異度で冠動脈狭窄を検出可能であった。カラードプラ法
で測定した isovelocity,パルスドプラ法で測定した ADPV とも有用性は同等であったが,心周
期に合わせて移動する冠動脈血流にサンプルボリュームを合わせる必要がなく,角度補正も不
要な isovelocity の方が簡便である。また,冠動脈血流速度は狭窄の程度のみで決定されるも
のではなく,心肥大や心不全などにより心筋酸素需要が増大しているときは血流速度も速くな
っているため狭窄を過大評価する可能性がある。【結論】冠動脈 CT で左冠動脈近位部の評価
が不能な症例において,TTDE は左冠動脈近位部狭窄を良好な感度,特異度で検出可能であり冠
動脈疾患の診断に有用である。 
 
 
 
 
 
 
 
 
 
 
 
キーワード（３～５） 
 
 
 
狭心症 
虚血性心疾患 
経胸壁ドプラ心エコー 
冠動脈CT 
 


Role of Transthoracic Doppler Echocardiography in Patients With a Proximal Left Cornary Artery Lesion That Cannot be Diagnosed by Computed Tomography Angiography

Ehime University (愛媛大学)博士(医学)doctoral thesi

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Pancreatic congestion in liver cirrhosis correlates with impaired insulin secretion

Diagnostic accuracy of late iodine enhancement on cardiac computed tomography with a denoise filter for the evaluation of myocardial infarction

Role of Transthoracic Doppler Echocardiography in Patients With a Proximal Left Cornary Artery Lesion That Cannot be Diagnosed by Computed Tomography Angiography

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