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Volume 34 , Issue Special_
Issue II
Showing 1-22 articles out of 22 articles from the selected issue
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  • Jun Kanno
    Volume 34 (2009) Issue Special_ Pages SP199-SP200
    Released: July 01, 2009
    JOURNALS FREE ACCESS
    “Children are not small adults”. This is a well-known phrase, especially in the clinics for diagnosis, efficacy of treatment, side effect, and prognosis. However, in the field of toxicology, this issue has long been a challenge. The knowledge has been limited to the differences in metabolism and other physiological factors. Currently available test guidelines for fetuses and immature animals are teratogenicity and reproductive toxicity studies. These tests look for straight-forward (essentially macroscopic) outcomes established within a rather short period of exposure to the test substances. However, recent advances in molecular toxicology allow combination of in vitro and in vivo studies at molecular levels. The target molecules and receptors can be identified in quantitative fashion and at the fine structure levels around and below the resolution of normal light microscopy. Such expansion of the knowledge lead us to consider a rather new category of “receptor mediated toxicity” or “signal toxicity”. Such non-organic insults would merely induce transient effects on adults. However, there are growing evidences that such slight insults on the developing and maturating organisms can leave irreversible effects that become overt in adulthood. As an overview, toxicology has entered a new phase where children’s toxicology becomes a renovating study field of the irreversible “early exposure-delayed effects”.
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  • Yuzo Hayashi
    Volume 34 (2009) Issue Special_ Pages SP201-SP207
    Released: July 01, 2009
    JOURNALS FREE ACCESS
    Based on the advance of toxicology and related sciences, a regulatory regime for the safety of chemicals related to daily life has been rapidly established. Especially for the food-related substances, the process of risk analysis has facilitated the collaboration by all the players including consumers toward the security of their safety. On the other hand, except for pharmaceuticals, science-based decisions and governmental actions on safety issues have not always gained confidence of the public. One of the reasons was the inadequacy in the way of use of scientific knowledge, or in other words, inappropriateness of decision making by “the regulatory science”. Regulatory science is a science to warrant the decision making processes for governmental acts (Mitsuru Uchiyama). In the case of chemical safety, it can be redefined as a theoretical concept to complements the uncertainty of scientific knowledge for the decision of governmental acts that is adequate in both scientific and social ways. Therefore, the regulatory science is an indispensable discipline to effectively apply risk analysis. Here, the significance of the regulatory science for the hazard assessment of the chemicals, especially for children is described. In the past, the hazard effects of chemicals have been assessed for adults. Recently, however, the importance of the assessment for children has gained international emphases. Not only for pharmaceuticals, but for food-related substances, the acceptable daily intake (ADI) and tolerable daily intake (TDI) are often set differently for adults and children. The child-specific responses against chemicals are related not only to the physiological factors such as body weight, basal metabolism, but also rapid growth of the body with developmental status of various organs. General knowledge on these issues will be discussed mainly referring the World Health Organization (WHO) documents. Although the cutting edge technology backs up the development of toxicology, it would appear that it is reaching a turning point from technology-centrism to look toward the direction for contribution to society from the stand point of regulatory science.
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  • Tim Anderson, Nasir K. Khan, Melissa S. Tassinari, Mark E. Hurtt
    Volume 34 (2009) Issue Special_ Pages SP209-SP215
    Released: July 01, 2009
    JOURNALS FREE ACCESS
    Differences in drug response in patients of various ages including children and the elderly are common, often leading to challenges in optimizing dosages and duration of use. For example, developmental changes in renal function can dramatically alter the plasma clearance of compounds with extensive renal elimination and thus can enhance renal and systemic toxicity of these drugs. Preclinical and clinical research of new therapeutics is initially focused on adults, and provides little relevant information for children especially those who are still going through skeletal and organ development. The organ systems in the pediatric population that can be most susceptible are lungs, brain, kidneys, immune, skeletal, and reproductive systems. Considering that significant differences can exist between adult and juvenile populations that may affect drug safety, major regulatory agencies around the world are encouraging and sometimes requiring companies to generate preclinical juvenile animal data to predict for potential drug toxicity in children. However, data generated from such studies are useful only if obtained using the most appropriate species at the most relevant age considering comparability of specific organ system development in question. Other factors in the design of juvenile safety studies should include the indication, existing toxicological data and likely route of human exposure. This report will discuss these factors with a focus on reviewing species-specific developmental schedules for specific target organs and relevance of preclinical data in the design and conduct of clinical pediatric studies. Specific examples will be used to discuss the relationship of preclinical juvenile toxicity observations to risk assessment in humans.
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  • Tetsuya Ito
    Volume 34 (2009) Issue Special_ Pages SP217-SP222
    Released: July 01, 2009
    JOURNALS FREE ACCESS
    Congenital disorders of metabolism show a wide spectrum of symptoms as a consequence of impairment of a certain metabolic pathway by mutated enzymes resulting in abnormal accumulation of enzyme substrates, deficiency of expected products, and abnormal burden to collateral metabolic pathways, etc. However, in some occasions, depending on which pathway up to what degree of disturbance, it can be asymptomatic until a certain kind of burden is placed on to the patient. Enzyme deficiency involved in pyrimidine degradation, such as Dihydropyrimidine dehydrogenase (DPD) and Dihydropyrimidinase (DHP), has been reported with convulsion or autism as symptoms, but many asymptomatic cases are also reported. However, when the patients are treated with 5-fluorouracil, a pyrimidine analogue anticancer drug, lethal side-effects can be seen even in asymptomatic patients. Some oral cephem antibiotics have pivalic acid side chain to increase absorption rate at intestine. These antibiotics degrade into active antibiotics and pivalic acid at the intestinal wall. This pivalic acid is carnitine-conjugated and excreted into urine. Carnitine acts as a carrier of long chain fatty acid to mitochondria and to beta-oxidation, thus an important molecule for energy production by beta-oxidation and maintenance of mitochondrial function. Because of this, long term administration of such antibiotics could induce depletion of carnitine from the body and lead to low ketotic hypoglycemia, convulsion and consciousness disturbance. This paper reports some possible serious side effects closely linked to drug metabolism.
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  • Kimitaka Takitani, Hiroshi Miyazaki, Atsushi Yoden, Hiroshi Tamai
    Volume 34 (2009) Issue Special_ Pages SP223-SP228
    Released: July 01, 2009
    JOURNALS FREE ACCESS
    Nonalcoholic fatty liver disease (NAFLD) is a state of excessive accumulation of fat in the liver of persons whose alcohol intake is lower than the classical level for causing liver damage. When inflammation and fibrosis occur in addition to fatty liver, followed by the development of chronic hepatic dysfunction, the condition is called non-alcoholic steatohepatitis (NASH). Vitamin E possesses antioxidant activity and is effective for NASH, but the mechanism of action is not known. We utilized a methionine-choline deficiency rat model (MCD rats) to investigate the mechanism by which vitamin E improves NASH. In MCD rats, high-dose vitamin E therapy reduced the hepatic content of thiobarbituric acid-reactive substances, but failed to improve liver histopathology. The hepatic content of α-tocopherol was also elevated and this might be related to the expression of α-tocopherol transfer protein.
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  • Hironori Nagasaka, Masaki Takayanagi, Hirokazu Tsukahara
    Volume 34 (2009) Issue Special_ Pages SP229-SP236
    Released: July 01, 2009
    JOURNALS FREE ACCESS
    The role of oxidative stress in the pathogenesis of liver disease in Wilson disease (WD), a genetic disorder characterized by excess hepatic deposition of copper, which generates free radicals, remains unclear. This study investigates oxidative stress on the liver and hepatic anti-oxidant responses in WD using liver specimens from affected patients showing mild liver damage (group I, n = 3), moderate or greater liver damage (group II, n = 5) and fulminant hepatic failure (group III, n = 5), and from asymptomatic carriers (n = 2). Decreased ratios of reduced glutathione (GSH) to oxidized glutathione (GSSG) and increased thiobarbituric acid reactive substance (TBARS), a lipid peroxidation product, were found in every affected patient, especially in groups II and III patients. Activities and protein expressions of Mn-dependent superoxide dismutase (Mn-SOD), CuZn-SOD, and catalase were decreased in all patients, especially in group III patients. Glutathione peroxidase activity was decreased only in group III patients. Asymptomatic carriers without any clinical manifestations showed normal TBARS level and GSH/GSSG ratio with increases in both GSH and GSSG levels. Their CuZn-SOD, Mn-SOD and catalase activities were increased. These results suggest that excessive copper-derived oxidants contribute to development and progression of liver disease in WD.
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  • Kei Murayama, Akira Ohtake
    Volume 34 (2009) Issue Special_ Pages SP237-SP243
    Released: July 01, 2009
    JOURNALS FREE ACCESS
    Objectives: The present study was aimed to ascertain the contributions of mitochondrial respiratory chain (MRC) enzymes to the development of liver failure and to the liver pathophysiology of metabolic liver diseases. Methods: We investigated liver samples obtained from 8 patients with liver failure due to unknown etiology and from 15 patients with metabolic disease: ornithine transcarbamylase deficiency, 6 cases; Wilson disease, 3 cases; metylmalonic aciduria (MMA); 3 cases, neonatal hemochromatosis, 2 cases. The estimation of MRC enzymes was carried out by the following independent methods; i) blue native polyacrylamide gel electrophoresis (BN-PAGE) in gel enzyme staining, ii) BN-PAGE western blotting, iii) in vitro MRC enzyme assay. Furthermore, we estimated the quantities of mtDNA and nDNA using qPCR. Result: 4 cases with liver failure showed low activities and protein levels of complex I, III and IV. We also performed qPCR and estimated the ratio mtDNA/nDNA using these samples. They all exhibited extremely low ratio. They were diagnosed as mtDNA depletion syndrome. All cases except MMA cases exhibited mildly or moderately suppressed activities of complex I-IV. However, the respective protein levels remained almost normal. MMA cases exhibited low activities and protein levels of complex I, III and IV. In particular, their low activities and protein levels of complex I were noticeable. They all exhibited normal ratios of mtDNA to nDNA. Conclusion: MRC defect might be an etiology of liver failure in a considerable number of patients in Japan. The present study suggested that considerable disturbance of MRC occurs in children with metabolic diseases and possibly modifies the pathophysiology.
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  • Takashi Sekine, Ken-ichiro Miura, Kazuhiro Takahashi, Takashi Igarashi
    Volume 34 (2009) Issue Special_ Pages SP245-SP250
    Released: July 01, 2009
    JOURNALS FREE ACCESS
    Development of fetal kidney is a finely programmed sequence, and is regulated by many important molecules. The perturbation of normal kidney development leads to congenital anomalies of kidney and urinary tract (CAKUT). CAKUT includes hypoplastic/dysplastic kidney, obstructive nephropathy and several other anomalies. CAKUT is of clinically importance, since it could lead to end stage renal failure when its anomaly grade is severe. So far, several causative genes responsible for development of CAKUT have been identified, including genes encoding molecules related to the renin-angiotensin-aldosterone system, RAS system. In humans, maternal administration of agents with inhibitory effects on the RAS system, such as angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin type 1 receptor blockers (ARBs), have been reported to cause severe renal malformation, designated as ACEI/ARB fetopathy. In this paper, we overview the development of fetal kidney and address the effects of ACEIs/ARBs on fetal kidney.
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  • Mikiya Fujieda, Akira Matsunaga, Atsushi Hayashi, Hiromichi Tauchi, Ko ...
    Volume 34 (2009) Issue Special_ Pages SP251-SP257
    Released: July 01, 2009
    JOURNALS FREE ACCESS
    Cisplatin and carboplatin cause dose-dependent renal dysfunction. Electrolyte abnormalities such as hypomagnesaemia and hypokalemia are commonly reported adverse effects, in addition to increased serum creatinine and uremia. Cumulative dose, dehydration, hypoalbuminemia, and concurrent use of nephrotoxic drugs have been suggested as risk factors for cisplatin nephrotoxicity. The adverse effects of ifosfamide include proximal tubular damage, and renal wasting of electrolytes, glucose and amino acids, Fanconi syndrome, rickets and osteomalacia have also been reported with ifosfamide treatment. Risk factors for ifosfamide nephrotoxicity include the cumulative dose, young age, previous or concurrent cisplatin treatment, and unilateral nephrectomy. Ifosfamide/Carboplatin/Etoposide (ICE) combination therapy induces hypouricemia, which frequently includes renal wasting of electrolytes, and persistent hypouricemia has been observed in recurrent or chemotherapy-resistant patients. We retrospectively examined the incidence of hypouricemia and clinical findings in pediatric patients treated with an ICE regimen. Twenty of 28 (71.4%) pediatric patients had hypouricemia. The duration of hypouricemia was longer in the non-remission subgroup of patients, which suggests that hypouricemia may be a predictive marker for prognosis of malignant disease and efficacy of drugs such as ifosfamide, carboplatin and cisplatin. Nephrotoxicity induced by these drugs may also be more common in pediatric patients than in adults, but it is unclear why a young age is a risk factor and further research is required regarding the mechanism of antineoplastic drug induced-nephrotoxicity in children.
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  • Takashi Sekine, Hitoshi Endou
    Volume 34 (2009) Issue Special_ Pages SP259-SP265
    Released: July 01, 2009
    JOURNALS FREE ACCESS
    The kidney is susceptible to drugs and environmental substances because of its anatomical and functional reasons, one of which is the existence of drug transport systems in proximal tubular cells. Among those, Organic anion transporter family (OAT family) plays the central role in elimination of drugs from the kidney and development of nephrotoxicity. Regarding drug nephrotoxicity in children, development of the child and the kidney should also be taken into account. This review focuses on the mechanisms of toxic nephropathy in children with special attention to the OAT family.
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  • Masami Suzuki
    Volume 34 (2009) Issue Special_ Pages SP267-SP271
    Released: July 01, 2009
    JOURNALS FREE ACCESS
    The kidney is a major target of toxic compounds. Susceptibility of the kidney to toxic effects of compounds is attributed to the unique morphologic and physiologic features of this organ. Renal development and maturation begins in the fetal period and continuous throughout the postnatal period. The effects of noxious compounds on the kidney are influenced by the state of renal development and maturation. Therefore, to asses the renal toxic potential of a compound in fetuses and infants, the development and maturation of the kidney should be taken into account. Renal development and maturation involves both morphological and functional aspects. Renal development begins in the fetus and proceeds to partial functional capacity before birth. After birth, the kidney continues morphologic and functional maturation during the postnatal period of infancy. The fetal or infant kidney is vulnerable to the renal toxicity of certain compounds due to its morphological and functional characteristics. On the other hand, the infant kidney is sometimes more tolerant to nephrotoxic compounds compared to the adult kidney because of its immature glomerular filtration, concentrating capability and active transportation. Design and interpretation of studies in fetuses and infants regarding renal toxicity should include careful consideration of the state of renal development and maturation and of the mechanisms of renal injury.
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  • Yoshihiro Fukui, Hiromi Sakata-Haga
    Volume 34 (2009) Issue Special_ Pages SP273-SP278
    Released: July 01, 2009
    JOURNALS FREE ACCESS
    Exposure to ethanol during prenatal development can have devastating consequences on developing fetuses, the so-called fetal alcohol spectrum disordres (FASD). Among FASD, cases that exhibit all of three criterion; 1) central nervous system dysfunction, 2) prenatal and postnatal growth deficiency, and 3) characteristic cranial/facial abnormalities, referred as fetal alcohol syndrome (FAS). Children born to drinking mothers may suffer from severe brain damage that is expressed by a variety of behavioral alterations. We examined the effects of ethanol exposure during brain development on brain morphogenesis and circadian rhythm using a rat model. Pregnant Sprague-Dawley (SD) rats were fed a liquid diet containing 2.5-5.0% (w/v) ethanol during gestational days 10 to 21. Mean daily ethanol consumption by these dams was 11.53 ± 2.54 g/kg/day. In rats prenatally exposed to ethanol, ectopias on the cerebral cortex, aberrant distribution of hippocampal mossy fibers, and fusion of cerebellar folia were found. Rats exposed to ethanol during the prenatal or postnatal period suffered from a fragile synchronizing system of circadian rhythms in adulthood. Although the prevalence of FAS in Japan is lower than in the United States, the increasing number of Japanese women with the drinking habit are cause for great concern. However, the preventive action of FAS/FASD has been advanced recently, and now alcoholic beverages carry labels warning of the risk of drinking during pregnancy and breastfeeding of babies. Although little is still known about how ethanol affects brain development, the only and most certain way to prevent FAS/FASD is total abstinence from alcohol during pregnancy and breastfeeding.
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  • Kentaro Tanemura, Katsuhide Igarashi, Toshiko-R Matsugami, Ken-ichi Ai ...
    Volume 34 (2009) Issue Special_ Pages SP279-SP286
    Released: July 01, 2009
    JOURNALS FREE ACCESS
    To demonstrate induction of delayed central nervous toxicity by disturbing neuronal activities in the developing brain, we administered a single intraperitoneal dose of domoic acid (DA; 1 mg/kg), a potent glutamate receptor agonist, to pregnant female mice at the gestational day of 11.5, 14.5 or 17.5. The dams had recovered from acute symptoms within 24 hr, followed by normal delivery, feeding and weaning. All male offspring mice after weaning were apparently normal in response to handlers during cage maintenance, body weight measurement and to mate mice in group housing conditions. At the age of 11 weeks, our neurobehavior testing battery revealed severe impairment of learning and memory with serious deviances of anxiety-related behaviors. The developed brain of prenatally exposed mice showed myelination failure and the overgrowth of neuronal processes of the limbic cortex neurons. This study indicates that the temporal disturbance of neurotransmission of the developing brain induces irreversible structural and functional damage to offspring which becomes monitorable in their adulthood by a proper battery of neurobehavioral tests.
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  • Kohei Shiota, Shigehito Yamada
    Volume 34 (2009) Issue Special_ Pages SP287-SP291
    Released: July 01, 2009
    JOURNALS FREE ACCESS
    In vitro fertilization (IVF) and other assisted reproductive technologies (ART) are widely used clinically as infertility treatments. Although ART procedures are generally considered safe, some studies have suggested an increase in the occurrence of major malformations and some other complications in babies conceived by ART. Further, it has recently been suggested that ART are associated with imprinting disorders in the offspring such as Beckwith-Wiedemann syndrome and Angelman syndrome. We review the human and animal studies investigating the outcome of ART pregnancies and discuss the potential risk of ART to pre- and perinatal development.
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  • Keizo Takao, Tsuyoshi Miyakawa
    Volume 34 (2009) Issue Special_ Pages SP293-SP305
    Released: July 01, 2009
    JOURNALS FREE ACCESS
    Despite massive research efforts, the exact pathogenesis and pathophysiology of psychiatric disorders, such as schizophrenia and bipolar disorder, remain largely unknown. Animal models can serve as essential tools for investigating the etiology and treatment of such disorders. Some mutant mouse strains were found to exhibit behavioral abnormalities reminiscent of human psychiatric disorders. Here we outline our unique approach of extrapolating findings in mice to humans, and present studies on alpha-CaMKII heterozygous knockout (alpha-CaMKII+/-) mice as examples. Alpha-CaMKII+/- mice have profoundly dysregulated behaviorbehaviours and impaired neuronal development in the dentate gyrus (DG). The behavioral abnormalities include a severe working memory deficit and an exaggerated infradian rhythm, which are similar to symptoms seen in schizophrenia, bipolar mood disorder and other psychiatric disorders. By conducting a series of experiments, we discovered that almost all the neurons in the mutant DG were very similar to the immature DG neurons of normal rodents. In other words, alpha-CaMKII+/- mice have an “immature DG”. We proposed that an “immature DG” in adulthood might induce alterations in behavior and serve as a promising candidate endophenotype* of schizophrenia and other human psychiatric disorders. The impact of a large-scale mouse phenotyping on studies of psychiatric disorders and the potential utility of an "animal-model-array" of psychiatric disorders for the development of suitable therapeutic agents is also discussed.
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  • Tsuyoshi Yokoi
    Volume 34 (2009) Issue Special_ Pages SP307-SP312
    Released: July 01, 2009
    JOURNALS FREE ACCESS
    During childhood, as the body weight and its function changes drastically by age, drug therapy should be arranged according to the age-related changes in pharmacokinetics of its age. The gastric absorption of oral drugs is affected by the high pH of gastric juice in newborns and slow gastric emptying up to six months of age, resulting generally in poor absorption except for lipophilic drugs. Intestinal absorption is also poor in newborns. Due to the low serum protein level, the protein binding ratio is low in newborns, though the serum protein level increases to the adult level at one to three years after birth. Drug metabolism capability generally develops quickly after birth and reaches the adult level in two to three years, though there are many exceptions. The CYP3A7 activity is relatively high just after birth, which affects the clearance of its substrate drugs. In terms of conjugation enzyme activities, sulfate conjugation develops fast and glucuronate conjugation develops slowly. Among the glucuronosyltransferase (UGT) enzymes, UGT1A1 and UGT2B7 reach the adult level by 3 months of age, whereas UGT1A6, UGT1A9 and UGT2B7 take a few years to ten years. Although there is no definitive report on enzyme induction ability, both CYP and UGT are suggested to be more inducible in children than in adults. The hepatic drug metabolism of children is characterized by the fact that the relative liver weight and hepatic blood flow rate per unit liver weight is larger in children than in adults. Drug excretion from the kidney is undeveloped in newborns, below 50% of the adult level up to the age of two to three months. Therefore, the effective dose range and toxic dose range of drugs is closer in such young subjects, but reaches adult level by the age of one year. The glomerular filteration rate is low in newborns, and rapidly increases up to 200% of that in adults in one year, and then gradually decreases to the adult level. As mentioned above, newborns, infants and children show different pharmacokinetics for different drugs and therefore cannot always be discussed in the same way. For the safe use of drugs, the pharmacokinetics data of each drug should be considered.
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  • Hirohisa Saito
    Volume 34 (2009) Issue Special_ Pages SP313-SP319
    Released: July 01, 2009
    JOURNALS FREE ACCESS
    Regulatory T- (TREG) cells are considered to inhibit the development of both type 1 and type 2 helper T (TH1 and TH2) cells. However, the number of TREG cells in patients with allergic diseases who have high levels of serum IgE and blood eosinophils is reduced as compared to individuals who have similarly high levels of IgE and eosinophils but are asymptomatic. Therefore, TREG cells may suppress the onset of allergic disease by downregulating other types of immune cells besides TH1 and TH2 cells. The newly discovered interleukin (IL-)17-producing helper T- (TH17) cells responsible for autoimmune inflammatory diseases may counteract with TREG cells even in allergic diseases. TH2 cells capable of producing of high levels of tumor necrosis factor (TNF)-a may also be involved in the inflammation in allergic diseases. In this review, the role of TH1, TH2, TH17 and TREG cells in allergic diseases is further discussed by using the balancing square model and the factors differentiating between patients with clinical manifestations of allergic symptomatic versus atopic individuals who are sensitized but asymptomatic.
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  • Keiji Terao
    Volume 34 (2009) Issue Special_ Pages SP321-SP325
    Released: July 01, 2009
    JOURNALS FREE ACCESS
    Macaque monkeys are essential laboratory animals in preclinical safety assessment for human-specific biological products including humanized antibody drug. In most case, investigators are leaving their ages out of consideration, and young individuals aged around 3 years are mainly used because of their small individual differences in biological responses to various stimulations. Since the immune system starts to develop just after birth and remarkable phenotypic and functional changes occur in various kinds of immunocompetent cells during the first few years of life in macaque monkeys, their actual immunological condition must be carefully considered in case of safety assessment of novel drugs which modulate human immune function. The early development of major immune functions of macaque monkeys is summarized as follows. These findings suggest that immunocompetent cells drastically differentiate into activated ones during early development. 1) The serum immunoglobulin contents gradually rise with increasing age up to sexual maturity. 2) The blood group-associated antibodies, anti-A and anti-B antibody, are detected around 40-days of age and antibody levels rapidly increase after one year old. 3) Infant cynomolgus monkeys obviously produce the significant levels of IgG antibody against Campylobactor jejuni within 4 weeks after infection when maternal antibody becomes undetectable (8 weeks of age). 4) The frequency of lymphocyte subpopulations expressing the resting surface phenotypes is much higher than that having activated phenotypes in neonates, and the relative population of lymphocyte subsets with resting phenotype decrease with increasing age, while the subpopulation associated with activation gradually increase with age.
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  • Neha Sheth
    Volume 34 (2009) Issue Special_ Pages SP327-SP329
    Released: July 01, 2009
    JOURNALS FREE ACCESS
    Juvenile toxicology studies in animals provide useful information to guide monitoring of potential adverse effects in children especially on growth and development. In order to continue to gain knowledge and build upon these preclinical studies, recent experience has suggested that additional approaches for monitoring of safety concerns in the pediatric population may be required. Recently, pediatric guidance has become available from the health authorities which provide pharmacovigilance concepts as they specifically relate to drugs being developed for pediatric indications. Clinical trials are typically not robust enough to detect rare or delayed safety effects as the pediatric trials are relatively short-term. Furthermore, such long term or rare effects may not be detected via standard voluntary postmarketing surveillance. Safety monitoring of children with Juvenile Inflammatory Arthritis (JIA) taking nonsteroid anti-inflammatory drug (NSAID)s will be used as an example to describe a post-marketing risk management and pharmacovigilance program that serves to better evaluate safety data from various sources. The intent of this program is to identify adverse events (AE), including events with longer latency, which may be associated with NSAID use in a pediatric population. In this presentation, the 4 major components of the program are to be addressed. Such a program may serve as a model to proactively generate and monitor safety data in order to identify AEs that may be associated with new therapeutics for a pediatric population.
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  • Orie Nakamura
    Volume 34 (2009) Issue Special_ Pages SP331-SP339
    Released: July 01, 2009
    JOURNALS FREE ACCESS
    In mammals, pregnancy has very interesting interaction between the maternal uterus and the fetus. For maternal immune system, fetus is recognized as semiallograft. However the maternal immune cells do not attack and reject a fetus during a pregnant period. The reason why that immune tolerance is established in the maternal decidua is the specific area defined as the feto-maternal interface. While, if maternal immune cells recognize fetus as the not-self, the maternal immune cells will try to reject fetus, and then abortion will occur. For example, in a human, one of the reasons why the habitual abortion is understood as the failure of the maternal immune system. The extravillous cytotrophoblast are not attacked by the maternal immune cells, although that trophoblasts might reach even the myometrium. Exceeding the maternal myometrium doesn’t decide the invasion of extravillous cytotrophoblast on the other hand. This suggests that proliferation in decidua be strictly adjusted. In human and mice, the maternal immune cells recognize the fetus trophoblasts. To escape from attack of lymphocytes, villous trophoblasts do not express classical major histocompatibility complex (MHC) class I molecules. But, in a human, extravillous trophoblasts express MHC-class I molecules such as human leukocyte antigen (HLA)-C, HLA-E and HLA-G, which are specific ligands for uterine NK (uNK) cells. In the decidua, various lymphocytes including T-cells, Tregs, macrophages, and uNK cells exist. Each immunocytes are not identified on their function, compose network with the decidual cells under progesterone existence, and interact with the success of pregnancy.
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  • Shoji Yamamoto, Tin-Tin-Win Shwe, Yasuhiro Yoshida, Naoki Kunugita, Ke ...
    Volume 34 (2009) Issue Special_ Pages SP341-SP348
    Released: July 01, 2009
    JOURNALS FREE ACCESS
    It has been reported that the newborn immune system differs quantitatively and functionally from that of adults. Development of the immune system has important implications for childhood diseases. The immaturity of the immune system in the prenatal or suckling stage may contribute to susceptibility to environmental toxic chemical exposure. In the present study, to clarify the effect of low-level toluene exposure on immune functions during developmental stage, pregnant mice were exposed to 0, 5, and 50 ppm toluene from gestational day 14 to day 19 with or without stimulation by peptidoglycan (PGN) of a Gram-positive bacterial cell wall component, a toll-like receptor (TLR) 2 ligand. We examined Th1/Th2 balance in the offspring’s at 3 weeks old using ELISA and real-time RT-PCR methods. Exposure of mice to 50 ppm toluene enhanced total immunoglobulin (Ig) G2a (Th1-dependent) level in plasma. On the other hand, splenic expression of transcription factor T-bet (Th1-specific), GATA-3 (Th2-specific) and Foxp3 (gene marker for regulatory CD4+CD25+ T-cells) mRNAs was suppressed in these mice, but not in the combination of 5 or 50 ppm toluene with PGN. In addition, total IgG1 (Th2 dependent) level was suppressed in the combination of 5 or 50 ppm toluene with PGN. Our findings indicate that modulation of Th1- and Th2-responses may occur in low-level toluene exposure and/or combination with PGN stimulation in infant mice.
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  • Sho Ishikawa
    Volume 34 (2009) Issue Special_ Pages SP349-SP361
    Released: July 01, 2009
    JOURNALS FREE ACCESS
    We have recently reported breakdown of mucosal immunity in the gut by tetraclorodibenzo-p-dioxin (TCDD). That is, single oral administration of low dose 2,3,7,8-TCDD resulted in a marked decrease in IgA secretion in AhR-dependent manner and impaired oral tolerance in the gut. In the present study, we found TCDD exposure by breast feeding also resulted in decreased level of IgA in the gut. Ig production by B cells by LPS stimulation was not affected by TCDD administration. Instead, particular chemokine receptor expression on B1 cells, a major cell source for intestinal IgA antibody, was decreased in mice treated with TCDD. In consistence with this observation, B1, but not B2 cells from TCDD treated mice showed impaired chemotaxis towards B lymphocyte chemokine (BLC)/CXCL13. In contrast, chemotaxis of intestinal dendritic cells (DCs) towards secondary lymphoid-tissue chemokine (SLC)/CXCL19 was not impaired in mice treated with TCDD. Furthermore, there was no change in the number and profile of intesitinal microflora in TCDD-treated mice. These results indicate that TCDD exposure by breast feeding results in breakdown of intestinal mucosal immunity of pups and that it may be attributed in part to impaired B1 cell migration from the peritoneal cavity to intestinal mucosa.
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