bluuebunny/crossref_metadata_2025 huggingface dataset:
Oxidative Stress and Life Span Determination in the Nematode Caenorhabditis elegans
Authors: HONDA YOKO , HONDA SHUJI
Published: July 2010

The free radical theory of aging proposes that oxidative stress is one of the determinants of an organism's life span. In Caenorhabditis elegans, genetic or environmental changes have been shown to modulate life span. Here we discuss whether changes in the generation and destruction of free radicals are implicated in these life span modulations. Changes in culture oxygen concentrations that are considered to reflect free radical generation perturb the life span. The life spans under high and low oxygen concentrations were shorter and longer, respectively, than those under normoxic conditions. Short‐term exposure to high oxygen concentration lengthens the life span. This is considered to be the result of an increase in antioxidant defense induced by short‐term oxidative stress. Mutations in genes such as age‐1 and daf‐2 that compose the insulin‐like signaling network conferred oxidative stress resistance and an increase in Mn‐SOD gene expression as well as life span extension.
Mitochondrial Decay in the Aging Rat Heart
Authors: HAGEN TORY M. , MOREAU RÉGIS , SUH JUNG H. , VISIOLI FRANCESCO
Published: July 2010

Mitochondrial decay has been postulated to be a significant underlying part of the aging process. Decline in mitochondrial function may lead to cellular energy deficits, especially in times of greater energy demand, and compromise vital ATP‐dependent cellular operations, including detoxification, repair systems, DNA replication, and osmotic balance. Mitochondrial decay may also lead to enhanced oxidant production and thus render the cell more prone to oxidative insult. In particular, the heart may be especially susceptible to mitochondrial dysfunction due to myocardial dependency on β‐oxidation of fatty acids for energy and the postmitotic nature of cardiac myocytes, which would allow for greater accumulation of mitochondrial mutations and deletions. Thus, maintenance of mitochondrial function may be important to maintain overall myocardial function. Herein, we review the major age‐related changes that occur to mitochondria in the aging heart and the evidence that two such supplements, acetyl‐l‐carnitine (ALCAR) and (R)‐α‐lipoic acid, may improve myocardial bioenergetics and lower the increased oxidative stress associated with aging. We and others have shown that feeding old rats ALCAR reverses the age‐related decline in carnitine levels and improves mitochondrial β‐oxidation in a number of tissues studied. However, ALCAR supplementation does not appear to reverse the age‐related decline in cardiac antioxidant status and thus may not substantially alter indices of oxidative stress. Lipoic acid, a potent thiol antioxidant and mitochondrial metabolite, appears to increase low molecular weight antioxidant status and thereby decreases age‐associated oxidative insult. Thus, ALCAR along with lipoic acid may be effective supplemental regimens to maintain myocardial function.
Use of In Vitro‐Generated, Stem Cell‐Derived Islets to Cure Type 1 Diabetes
Authors: PECK A. B. , CORNELIUS J. G. , CHAUDHARI M. , SHATZ D. , RAMIYA V. K.
Published: July 2010

Abstract: Recent successes in treating type 1 diabetic patients with islet transplantation portends a future need for an increase in available islets. Ductal structures of the adult pancreas contain multipotent stem cells that, under the proper in vitro conditions, can both self‐renew and differentiate into functional islets of Langerhans. In vitro‐generated islets exhibit temporal changes in mRNA transcripts for islet‐associated markers as well as regulated insulin responses following glucose challenge. When implanted into diabetic mice, in vitro‐generated islets induce neovascularization and reverse insulin‐dependent diabetes. The possibility of growing functional endocrine pancreas from stem cells provides new opportunities to produce large numbers of islets, even autologous islets, for use as implants.
Regulatory Natural Killer T Cells Protect against Spontaneous and Recurrent Type 1 Diabetes
Authors: SHARIF SHAYAN , ARREAZA GUILLERMO A. , ZUCKER PETER , DELOVITCH TERRY L.
Published: July 2010

Abstract: Autoimmune diseases, especially type 1 diabetes (T1D), may be caused by dysregulation of the immune system, which leads to hyporesponsiveness of regulatory T helper 2 (Th2) cells and promotion of autoimmune Th1 cells. Natural killer T (NKT) cells, which comprise a minor subpopulation of T cells, play a critical role in immunoregulation as a result of a rapid burst of IL‐4 and IFN‐γ secretion. These cells are functionally and numerically deficient in individuals at risk of T1D, as well as in nonobese diabetic (NOD) mice. It is conceivable that protection from T1D may be achieved by correction of this deficiency. Alpha‐galactosylceramide (α‐GalCer) specifically binds to NKT cells in a CD1‐dependent manner and stimulates these cells to proliferate and to produce various cytokines, including IFN‐γ, IL‐4, and IL‐10. In this review, we present evidence that a multiple‐dose α‐GalCer treatment regimen, which is known to promote a dominant Th2 environment, can prevent the onset of spontaneous and cyclophosphamide (CY)‐accelerated T1D. This protection is associated with elevated IL‐4 and IL‐10 in the spleen and pancreas of protected female NOD mice. Concomitantly, IFN‐γ levels are reduced in both tissues. More importantly, the protective effect of γ‐GalCer in CY‐accelerated T1D is abrogated by the in vivo blockade of IL‐10 activity. We also show that α‐GalCer treatment significantly prolongs syngeneic islet graft survival in recipient diabetic NOD mice. These findings raise the possibility that α‐GalCer treatment may be used therapeutically to prevent the onset and recurrence of human T1D.
Latent Autoimmune Diabetes in Adults
Authors: LANDIN‐OLSSON MONA
Published: July 2010

Abstract: Latent autoimmune diabetes in adults (LADA) is a special form of diabetes that is clinically similar to type 2 diabetes but with positivity for pancreatic autoantibodies. The frequency of LADA patients among all patients diagnosed as type 2 varies between 6‐50% in various populations. The frequency is higher in younger age groups. It is clear, however, that the frequency of autoimmune diabetes among adults is underestimated. Clinical features such as age and severity of symptoms are of no help in identifying these patients. Body mass index and C peptide levels in the general population increase with age, and these parameters are of limited use in identifying LADA patients. Determination of autoantibodies is necessary in order to correctly classify the type of diabetes. Among antibodies, GADA is the most frequently occurring autoantibody, followed by ICA. The natural course of these patients shows that C peptide will decrease with time in parallel with the curve for C peptide in classical type 1 diabetic patients. Most of the LADA patients will require insulin within three years. Our recommendation is that all patients be tested for pancreatic islet autoantibodies at diagnosis of diabetes to enable correct diagnosis and to avoid future failure of hypoglycemic agents and risk of complications due to hyperglycemia. It is still unclear whether early treatment with insulin is beneficial for the remaining beta cells.
Corticosteroid‐Responsive Diabetes Mellitus Associated with Autoimmune Pancreatitis
Authors: TANAKA SHOICHIRO , KOBAYASHI TETSURO , NAKANISHI KOJI , OKUBO MINORU , ODAWARA MASATO , MURASE TOSHIO , HASHIMOTO MASAJI , WATANABE GORO , MATSUSHITA HIROSHI , INOKO HIDETOSHI , TAKEUCHI KAZUO
Published: July 2010

Abstract: Histopathological changes of biopsied pancreata were examined in three diabetic patients with autoimmune chronic pancreatitis (ACP). We found intra‐ and periinsular mononuclear cell (MNC)—mainly CD8+ T cell—infiltration as well as MNC infiltration around the ductal cells. Islet β cell volume decreased significantly. Some ductal cells expressed insulin and insulin promoter factor‐1 concomitantly in the affected pancreas. These findings provide new insight toward understanding the pathological mechanisms of corticosteroid treatment‐responsive diabetes associated with ACP.
The Role of Fas Ligand in Beta Cell Destruction in Autoimmune Diabetes of NOD Mice
Authors: PETROVSKY N. , SILVA D. , SOCHA L. , SLATTERY R. , CHARLTON B.
Published: July 2010

Abstract: Fas ligand (FasL), a type 2 membrane protein belonging to the TNF family, plays an important role in the induction of cell death. Ligation of Fas receptors by FasL results in apoptosis of the Fas‐expressing cell. Autoimmune diabetes results from β cell destruction by islet‐reactive T cells, a process that involves β cell apoptosis. This raises the question of whether the FasL‐Fas pathway plays a major role in β cell death. To address this issue it is important to know whether β cells express Fas and/or FasL and, if so, whether induction of these molecules leads to β cell death. In fact, both Fas and FasL have been demonstrated to be expressed by β cells in response to cytokine stimulation, although there remains an argument in the literature as to whether β cells truly express FasL. This is largely because FasL expression has only been demonstrable by immunohistochemistry and not by flow cytometry. Transgenic NOD mice with β cells expressing a FasL transgene develop an accelerated form of diabetes. We show here that β cells from FasL transgenic NOD mice are more susceptible to cytokine‐induced apoptosis than wild‐type β cells, consistent with the hypothesis that if β cells express FasL then Fas‐FasL interaction on the β cell surface is able to mediate β cell self‐death in the absence of T cells. Interventions that block the Fas‐FasL pathway may be useful, therefore, in the prevention or treatment of type 1 diabetes.
Autoantibodies and HLA Susceptibility Markers in Canadian First‐Degree Relatives of Patients with Type 1 Diabetes
Authors: BEHME M. T. , MAHON J. L. , DUPRÉ J.
Published: July 2010

Abstract: We examined the frequencies of autoantibodies to glutamate decarboxylase, GAD65, protein tyrosine phosphatase, IA‐2/ICA512, and insulin, and of HLA class II markers in ICA‐positive first‐degree relatives of patients with type 1 diabetes. Our results indicate that while the presence of HLA susceptibility markers is associated with anti‐islet autoantibodies, protective DQB1 markers do not absolutely prevent development of autoantibodies or progression to autoimmune diabetes.
GAD65 and ICA512 Antibodies in Undernourished and Normally Nourished South Indian Patients with Diabetes
Authors: DAS A. K. , SHTAUVERE‐BRAMEUS A. , SANJEEVI C. B.
Published: July 2010

Abstract: The frequency of GAD65 and ICA512 antibodies in Indian IDDM patients is similar to that in Caucasians. The aim of the study was to test whether undernutrition is associated with autoimmunity as evidenced by increased or decreased autoantibody formation in both clinically diagnosed IDDM and NIDDM patients from south India. The prevalence of GAD65 and ICA512 autoantibodies in controls from south India was 4% and 2%, respectively. One hundred thirty‐one diabetic patients (undernourished [UNDM], n= 67; and normal nourished [NNDM], n= 64) were assayed for GAD65 and ICA512 autoantibodies. None were obese. All patients were new onset or with duration <5 years. GAD65 autoantibodies were present in 73/131 (55%), and ICA512 antibodies were present in 43/131 (33%) of patients. The results suggest that GAD65 and ICA512 antibody frequencies are neither significantly increased nor decreased in UNDM patients compared to NNDM patients. In addition, the increased frequency of autoantibodies among NIDDM compared to IDDM in both nutrition groups suggests high prevalence of slow‐onset IDDM. In conclusion, undernutrition does not predispose to autoimmunity in south Indian diabetic patients.
Antibodies to New Beta Cell Antigen ICA12 in Latvian Diabetes Patients
Authors: SHTAUVERE‐BRAMEUS A. , HAGOPIAN W. , RUMBA I. , SANJEEVI C. B.
Published: July 2010

Abstract: In Latvia diabetes mellitus is diagnosed using the WHO's clinical criteria, and assays for the detection of autoantibodies are not available. In consequence, slowly progressive autoimmune diabetes or LADA is likely to be missed. Antibodies to GAD65 and IA‐2 are the major immunological markers in autoimmune diabetes. Recently, a new β cell antigen, called ICA12, has been identified, which has a homology to the SOX family of transcription factors. The aim of the study was to analyze the prevalence of ICA12 antibodies in diabetes mellitus patients and controls from Latvia and to see whether this antigen is important in revealing autoimmunity when antibodies against major antigens are not present. We studied 88 IDDM patients and 100 NIDDM patients as well as controls for the prevalence of GAD65, IA‐2, and ICA12 antibodies by radioligand binding assay (RIA) using 35S‐labeled islet antigens. We found ICA12Abs in 26 of 88 IDDM patients (30%) vs. 4% in healthy controls (4/100) and in 9 of 100 NIDDM patients (9%) vs. 2% controls (2/100). ICA12Abs alone are present in only 3% (3/88) of the patients with IDDM and 1% (1/100) of the NIDDM patients. We conclude that ICA12 represents the minor antigens in autoimmune diabetes and that, as a minor antigen, ICA12 alone does not contribute significantly in revealing new cases of autoimmunity.
Immunogenetics of Autoimmune Diseases in Asian Indians
Authors: MEHRA N. K. , KAUR GURVINDER , KANGA UMA , TANDON NIKHIL
Published: July 2010

Abstract: The HLA class II molecules play a critical role in the processing and presentation of specific peptides derived from autoantigens of pancreatic beta cells or gluten for T cell scrutiny in IDDM and CD. In the present study, extended DR3‐positive haplotypes associated with autoimmunity in northern Indian patients have been reported. The haplotype A26‐B8‐DR3 was the most common autoimmunity‐favoring haplotype encountered among these patients. This association is, indeed, unique to Indian autoimmune patients, as it replaces the otherwise most commonly associated Caucasian haplotype A1‐B8‐DR3 (AH8.1) in this population. Further, CD patients revealed 100% association with DQB1*0201 along with DQA*0501 (97%) either in cis or trans configuration.
Microsatellite Allele 5 of MHC Class I Chain‐Related Gene A Increases the Risk for Insulin‐Dependent Diabetes Mellitus in Latvians
Authors: SHTAUVERE‐BRAMEUS A. , GHADERI M. , RUMBA I. , SANJEEVI C. B.
Published: July 2010

Abstract: Insulin‐dependent diabetes mellitus (IDDM) is one of the most common chronic diseases. It is an autoimmune, polygenic disease, associated with several genes on different chromosomes. The most important gene is human leukocyte antigen (HLA), also known as major histocompatibility complex (MHC), which is located on chromosome 6p21.3. HLA‐DQ8/DR4 and DQ2/DR3 are positively associated with IDDM and DQ6 is negatively associated with IDDM in most Caucasian populations. The MICA gene is located in the MHC class I region and is expressed by monocytes, keratinocytes, and endothelial cells. Sequence determination of the MICA gene identifies 5 alleles with 4, 5, 6, and 9 repetitions of GCT or 5 repetitions of GCT with 1 additional insertion (GGCT), and the alleles are referred to as A4, A5, A5.1, A6, and A9. Analysis of allele distribution among 93 Latvian IDDM patients and 108 healthy controls showed that allele A5 of MICA is significantly increased in IDDM patients [33/93 (35%)] compared to healthy controls [22/108 (20%)] (OR = 2.15; P= 0.016). In conclusion, we believe that MICA may play an important role in the etiopathogenesis of IDDM.
Tumor Necrosis Factor‐α Allele 2 Shows an Association with Insulin‐Dependent Diabetes Mellitus in Latvians
Authors: SHTAUVERE‐BRAMEUS A. , DABADGHAO P. , RUMBA I. , SANJEEVI C. B.
Published: July 2010

Abstract: Insulin‐dependent diabetes mellitus (IDDM) is one of the most common chronic diseases. It is an autoimmune disease. Genes contributing the most for development of IDDM are located on chromosome 6p21.3 in the region called the major histocompatibility complex (MHC). HLA‐DQ8/DR4 and DQ2/DR3 have shown positive association with IDDM, while DQ6 has negative association with IDDM in most Caucasian populations. The location of the tumor necrosis factor alpha (TNF‐α) gene in the MHC suggests the role of TNF in the etiology of IDDM as an autoimmune disease. The TNF region contains several polymorphisms that are associated with different levels of TNF‐α production and susceptibility to autoimmune and infectious diseases. Ninety‐two Latvian IDDM patients corresponding to WHO diagnostic criteria and 107 unrelated age‐ and sex‐matched healthy controls were analyzed for the frequency of TNF‐α alleles to test the hypothesis that TNF‐α is associated with IDDM. We found that TNF‐α microsatellite allele 2 is associated with IDDM, 29/92 (32%), versus 14/107 (13%) in healthy controls. The test of the strongest association of the MICA A5 allele and TNF‐α allele 2 with IDDM showed that both are independently associated with the disease.
Metallosupramolecular Coordination Polyelectrolytes
Authors: KURTH DIRK G.
Published: July 2010

Abstract: Metal‐ion‐induced self‐assembly of ditopic ligands, based on bis‐terpyridines, and transition metal ions result in formation of metallosupramolecular coordination polyelectrolytes (MEPE). The positive charge of MEPE can be utilized in several ways to process highly ordered architectures. Alternating adsorption of MEPE and oppositely charged polyelectrolytes on solid substrates results in multilayers. The sequential nature of this process allows combining MEPEs with other functional components. This process permits nanometer thickness control, is readily adapted for automated processing, and is applicable to two‐dimensional substrates as well as to colloidal templates. The surface chemical properties of MEPE are readily controlled by complexing MEPE with negatively charged amphiphiles. The resulting polyelectrolyte‐amphiphile complexes (PAC) are soluble in organic solvents and form liquid crystalline phases. The PAC also spreads at the air‐water interface as Langmuir monolayer, which can be transferred onto solid substrates. The resulting Langmuir‐Blodgett multilayers are highly ordered and anisotropic. Materials with transition metal ions possess many interesting properties, including spin transitions, magnetism, as well as photochemical assets that are relevant for the construction of functional devices and materials. The presented approach combines principles of supramolecular and colloidal chemistry as well as surface science, is highly modular in nature, and provides extensive control of structure and function from molecular to macroscopic levels.
Tunneling Through a Tilted Tight‐Binding Band
Authors: ONIPKO ALEXANDER , MALYSHEVA LYUBA
Published: July 2010

Abstract: In the single‐band approximation, an explicit expression of the exponential factor, that governs tunneling through a thin crystal subjected to a constant electric field, is derived. The basic features of Wannier‐Stark, Airy, and intermediate type of quantization, as they are displayed in the transmission spectrum and hence in tunneling current, are thus described analytically.
Modeling the Electrostatic Potential Spatial Profile of Molecular Junctions
Authors: GONZALEZ CARLOS , MUJICA VLADIMIRO , RATNER MARK A.
Published: July 2010

Abstract: The spatial profile of the electrostatic potential across a molecular junction is one of the single most influential factors in determining the form of intensity‐voltage characteristics. We have modeled the influence of bridge electronic defects (site substitutions) and weak links (local weak bonds) on the potential profile. The potential is determined self‐consistently by solving Poisson and Schrödinger equations simultaneously. We have considered the simplest model of a one‐dimensional molecular wire. This system already exhibits some of the most relevant features observed in I‐V curves of real chemically modified junctions, where strong asymmetries and rectification effects have been reported.
Biomolecular Electronic Devices Based on Self‐Organized Deoxyguanosine Nanocrystals
Authors: RINALDI ROSS , BRANCA EMANUELA , CINGOLANI ROBERTO , DI FELICE ROSA , CALZOLARI ARRIGO , MOLINARI ELISA , MASIERO SALVATORE , SPADA GIANPIERO , GOTTARELLI GIOVANNI , GARBESI ANNA
Published: July 2010

Abstract: We report on a new class of hybrid electronic devices based on a DNA nucleoside (deoxyguanosine lipophilic derivative) whose assembled polymeric ribbons interconnect a submicron metallic gate. The device exhibits large conductivity at room temperature, rectifying behavior and strong curent‐voltage hysteresis. The transport mechanism through the molecules is investigated by comparing films with different self‐assembling morphology. We found that the main transport mechanism is connected to π‐π interactions between guanosine molecules and to the formation of a strong dipole along ribbons, consistently with the results of our first‐principles calculations.
Quantum‐Dot Cellular Automata at a Molecular Scale
Authors: LIEBERMAN MARYA , CHELLAMMA SUDHA , VARUGHESE BINDHU , WANG YULIANG , LENT CRAIG , BERNSTEIN GARY H. , SNIDER GREGORY , PEIRIS FRANK C.
Published: July 2010

Abstract:Quantum‐dot cellular automata (QCA) is a scheme for molecular electronics in which information is transmitted and processed through electrostatic interactions between charges in an array of quantum dots. QCA wires, majority gates, clocked cell operation, and (recently) true power gain between QCA cells has been demonstrated in a metal‐dot prototype system at cryogenic temperatures. Molecular QCA offers very high device densities, low power dissipation, and ways to directly integrate sensors with QCA logic and memory elements. A group of faculty at Notre Dame has been working to implement QCA at the size scale of molecules, where room‐temperature operation is theoretically predicted. This paper reviews QCA theory and the experimental measurements in metal‐dot QCA systems, and describes progress toward making QCA molecules and working out surface attachment chemistry compatible with QCA operation.
Gene Therapy of Hepatocellular Carcinoma and Gastrointestinal Tumors
Authors: SANGRO BRUNO , QIAN CHENG , SCHMITZ VOLKER , PRIETO JESUS
Published: July 2010

Abstract: Primary liver cancer and liver metastases from gastrointestinal tumors lack effective therapy. Gene therapy is a promising therapeutic approach and is based on the introduction of genetic material into cells to generate a curative biological effect. Adenoviral vectors can very efficiently transduce a wide variety of malignant epithelial cells both in vitro and in vivo. A variety of gene therapy‐based anticancer strategies have been effective in animal tumor models, including replacement of tumor suppressor genes, selective activation of prodrugs, genetic immunotherapy, and antiangiogenic actions. Enzymes used for genetic activation include viral thymidine kinase (tk), which may activate nucleoside analogs such as ganciclovir. We and others have demonstrated the efficacy of the tk/ganciclovir system in the treatment of hepatocellular carcinoma and metastatic colorectal cancer in experimental models. Also, this strategy can be safely applied to patients with liver tumors. Interleukin‐12 (IL‐12) is among the most potent cytokines in stimulating antitumor immunity. In models of primary and metastatic liver cancer we showed that intratumoral administration of recombinant adenovirus encoding IL‐12 activates natural killer cells, induces specific antitumor immunity, and displays a powerful antiangiogenic effect, resulting in tumor regression. There is a synergistic effect with the gene transfer of the chemokine IP‐10. Also, intratumoral injection of either dendritic cells transfected ex vivo with recombinant adenovirus encoding IL‐12 (Ad.IL‐12) or an adenovirus coding for the CD40 ligand have shown an intense antitumor effect against experimental colorectal cancer. In summary, a variety of gene therapy strategies have been effective against animal models of gastrointestinal tumors. Clinical trials should determine whether human patients can be treated safely and effectively by such strategies.
Proteomic Patterns of Cultured Breast Cancer Cells and Epithelial Mammary Cells
Authors: PUCCI‐MINAFRA IDA , FONTANA SIMONA , CANCEMI PATRIZIA , ALAIMO GIUSEPPINA , MINAFRA SALVATORE
Published: July 2010

Abstract: Breast cancer is one of the leading causes of death from cancer among women in western countries. The different types of breast cancer are grouped into invasive and noninvasive forms. Among the invasive types, ductal infiltrating carcinoma (DIC) is the most common and aggressive form. Using an in vitro model consisting of a DIC‐derived cell line (8701‐BC) and a nontumoral mammary epithelial cell line (HB2), we used the proteomics approach to search for homology and differences in protein expression patterns between tumoral and nontumoral phenotypes. Within an analysis window comprising 1,750 discernible spots we have currently catalogued 140 protein spots of potential interest. Fifty‐eight of them were identified by gel matching with reference maps, immunodetection, or N‐terminal microsequencing and classified into four functional groups. Twelve proteins were found differentially expressed in two cell lines: four were uniquely present in the neoplastic cell proteome and eight in epithelial cells. In addition, 53 proteins displayed different relative expression levels between the two cell lines, that is, 44 were more elevated in cancer cells and 9 in HB2 cells. Among proteins with greater relative abundance in cancer cells we identified glycolytic enzymes (or their isoforms), which may indicate that the known metabolic dysregulation in cancer can reflect oncogenic‐related defects of glycolytic gene expression.
Current Understanding of Gastrointestinal Immunoregulation and Its Relation to Food Allergy
Authors: BRANDTZAEG PER
Published: July 2010

Abstract: Tolerance to food antigens induced via the gut (“oral tolerance”) appears to be a rather robust adaptive immune mechanism. However, the neonatal period is particularly critical in terms of mucosal defense, with regard to infections and priming for allergic disease. This is so because the intestinal barrier function provided by secretory antibodies, as well as the immunoregulatory network, is poorly developed for a variable period after birth. Notably, the postnatal development of mucosal immune homeostasis depends on the establishment of a normal commensal microbial flora and also on adequate timing and dose of dietary antigens when first introduced. In this context, breastfeeding apears to exert both shielding and positive regulatory effects. Altogether, the intestinal immune system normally seems rather fit for tolerance induction against innocuous antigens because most children with food allergy “outgrow” their problems, whereas airway allergy tends to persist.
Current Understanding of Food Allergens
Authors: LEHRER SAMUEL B. , AYUSO ROSALIA , REESE GERALD
Published: July 2010

Abstract: Food allergies are IgE‐mediated immunological reactions; this distinguishes them from other adverse reactions to foods. Most (>90%) of the recognized food allergies are generally thought to be caused by eight foods or food groups. A number of factors can affect food allergy development, including diet and culture, route of exposure, processing, cooking, and digestion. In addition, it is thought that the properties of certain food proteins render them more likely to be allergenic than other proteins. Most food allergens are major proteins, polyvalent molecules with at least two or more IgE‐binding sites, and are recognized as foreign molecules (hence immunogenic). A number of major food allergens have been recently characterized, and amino acid sequences determined. Tropomyosin is the only major allergen of shrimp. A number of IgE‐binding epitopes have been identified in this molecule, though they may vary from one shrimp‐allergic individual to another. Single amino acid substitutions within epitopes based on that of homologous, nonreactive tropomyosins can substantially enhance or abolish IgE antibody binding. Using the accumulated knowledge of food allergen protein structure, the allergenicity of novel proteins to which there has been no prior human exposure has been assessed. This has been based primarily on the lability or resistance of a protein to enzymatic degradation. Clearly, further criteria must be developed to refine this process. In this regard, the development of animal models that have been sufficiently validated as surrogates of human IgE antibody responses is needed for more precise assessment of the allergenic potential of proteins.
Gene Expression Profiles in the Brain from Phencyclidine‐Treated Mouse by Using DNA Microarray
Authors: TOYOOKA K. , USUI M. , WASHIYAMA K. , KUMANISHI T. , TAKAHASHI Y.
Published: July 2010

Abstract: Recently DNA microarray technology has been introduced into analyses of comprehensive biological functions. This DNA microarray is a new technology for simultaneous analysis to examine expression patterns of thousands of genes. It was thought that this technique should be very useful for examination of cellular and molecular mechanisms of drugs of abuse: cocaine, amphetamine, and others. This technology was therefore applied for the rapid analysis of gene expression in the brain from phencyclidine‐treated mice. Mainly mouse DNA microarray was examined by using labeled cDNAs produced from a control mouse brain mRNA and from brain mRNA of mouse exposed to drugs as probes. Some changes in a probe from brain mRNA of drug‐treated mouse could be observed, but it was necessary to examine another DNA microarray, including more samples from the brain.
Appetite Suppressants as Agonist Substitution Therapies for Stimulant Dependence
Authors: ROTHMAN RICHARD B. , BLOUGH BRUCE E. , BAUMANN MICHAEL H.
Published: July 2010

Abstract:Several lines of evidence support a dual‐deficit model of stimulant withdrawal in which decreases in synaptic dopamine (DA) and serotonin (5‐HT) contribute to withdrawal symptoms, drug craving, and relapse. According to the dual‐deficit model, DA dysfunction during withdrawal underlies anhedonia and psychomotor disturbances, whereas 5‐HT dysfunction gives rise to depressed mood, obsessive thoughts, and lack of impulse control. The model suggests that medications capable of normalizing stimulant‐induced DA and 5‐HT deficits should be effective treatment adjuncts. Furthermore, the model may explain why medications targeting only one neurotransmitter system (i.e., DA) have failed to treat cocaine dependence. Amphetamine‐type appetite suppressants are logical choices for neurochemical normalization therapy of stimulant dependence, yet few clinical studies have tested anorectics in this regard. The chief purpose of the present work is to profile the activity of various anorectic agents at DA, 5‐HT, and NE transporters, in order to identify possible medications for stimulant dependence. Compounds were testedin vitrofor their ability to stimulate release and inhibit uptake of [3H]DA, [3H]NE, and [3H]5‐HT. Selected compounds were testedin vivofor their ability to elevate extracellular levels of DA and 5‐HT in rat nucleus accumbens. The results show that clinically available appetite suppressants display a wide range of activities at monoamine transporters. However, no single medication possesses equal potency at DA and 5‐HT transporters, suggesting that none of the anorectics is ideally suited for treatment of stimulant addictions. Future efforts should focus on developing new medications that possess the desired therapeutic activity but lack the adverse effects associated with older amphetamine‐type anorectics.
A Single Exposure to Restraint Stress Induces Behavioral and Neurochemical Sensitization to Stimulating Effects of Amphetamine
Authors: PACCHIONI A. M. , GIOINO G. , ASSIS A. , CANCELA L. M.
Published: July 2010

Abstract: Evidence indicates that repeated exposure to stressful events sensitizes the motor and addictive effects of drugs of abuse in rats. Regarding a single exposure to one restraint stress, previous findings have shown that it is sufficient to induce behavioral sensitization to stimulating and reinforcing properties of abuse drugs (e.g., amphetamine and morphine), as measured by locomotor activity and conditioned place preference, respectively. It is well known that enhanced dopaminergic neurotransmission in the nucleus accumbens and striatum plays a critical role in the development and/or expression of repeated stress‐induced or drug‐induced sensitization. In addition, involvement of NMDA receptors has been implicated in its development. However, whether sensitization induced by a single restraint stress exposure represents the same neurobiologic phenomenon is unknown. We studied the following issues: (a) influence of a single restraint exposure on the stimulating effects of amphetamine on dopamine release by microdialysis from striatum and (b) involvement of glutamatergic pathways, specifically those innervating striatum, on stress‐induced sensitization to amphetamine, by administering MK‐801 ip (0.1 mg/kg) or intrastriatally (1 μg/0.5 μL) previous to an acute restraint stress. For microdialysis studies (a) or intrastriatal administration of MK‐801 (b), Wistar rats (250‐330 g) were implanted stereotactically under anesthesia with a guide cannula in the striatum. After 2 days, animals were immobilized for 2 hours in a Plexiglas device. Control animals remained in their home cages. The following day we evaluated the stimulating effect of amphetamine on (a) dopamine release from striatum or (b) locomotor activity. In studies (a), dialysis probes were inserted into the guide cannula, and baseline dopamine levels were collected for 2 hours before a challenge of amphetamine (1.5 mg/kg ip). Dialysates were then collected by 3 hours. Amphetamine challenge induced a significantly higher increase in dopamine release and locomotor activity in animals previously subjected to one restraint stress exposure, relative to that observed in the no‐restraint stress group. MK‐801 administered ip or intrastriatally blocked the restraint stress‐induced sensitization to amphetamine. First, our results point out that a single restraint stress exposure is a pertinent stimulus to induce sensitization of amphetamine's stimulating effects on dopaminergic neurotransmission in the striatum. Secondly, NMDA‐glutamatergic receptors, specifically those placed in the striatum, are implicated in the development of stress restraint‐induced sensitization.
Factors for Susceptibility to Episode Recurrence in Spontaneous Recurrence of Methamphetamine Psychosis
Authors: YUI KUNIO , IKEMOTO SHIGENORI , GOTO KIMIHIKO
Published: July 2010

Abstract:The relation between increased sensitivity to stress associated with noradrenergic hyperactivity and dopaminergic changes, and susceptibility to subsequent spontaneous recurrences of methamphetamine (MAP) psychosis (flashbacks) was examined. Plasma monoamine metabolite levels were assayed in 19 flashbackers, of whom 10 experienced a single flashback and 9 exhibited subsequent flashbacks, 18 nonflashbackers with a history of MAP psychosis, 9 subjects with persistent MAP psychosis, and 22 MAP user and 10 nonuser controls. All flashbackers had undergone frightening stressful experiences during previous MAP use. They exhibited flashbacks in response to mild psychosocial stressors. There was no significant difference in the number of stressful experiences and having mild psychosocial stressors between the two flashbacker subgroups. Plasma norepinephrine (NE) levels increased with a small increase in plasma levels of 3‐methoxytyramine (3‐MT), an index of dopamine release, during flashbacks in the 19 flashbackers. Of the 19 flashbackers, the 9 with subsequent episodes had markedly increased NE levels and slightly increased 3‐MT levels during flashbacks, while the 10 with a single episode displayed small increases in NE and 3‐MT levels during flashbacks. The 9 flashbackers with subsequent episodes had a longer duration of imprisonment than the 10 flashbackers with a single episode. Thus, robust noradrenergic hyperactivity with slightly increased DA release in response to mild stress may predict subsequent flashbacks. Long‐term exposure to distressing situations appears to contribute to susceptibility to subsequent flashbacks.
Developmental Expression of the β‐Amyloid Precursor Protein and Heat‐Shock Protein 70 in the Cerebral Hemisphere Region of the Rat Brain
Authors: LAHIRI D. K. , NALL C. , CHEN D. , ZAPHIRIOU M. , MORGAN C. , NURNBERGER J. I.
Published: July 2010

Abstract: Alzheimer's disease (AD) is characterized by depositions of the amyloid β protein (Aβ) in the brain in the form of extracellular plaques and cerebrovascular amyloid. Aβ (∼4 kDa) is derived from a family of large (∼110 kDa) β‐amyloid precursor proteins (APP), which are integral membrane glycoproteins. Although a connection between AD and alcoholism has recently been suggested, this relationship has not been explored at the molecular level. Our hypothesis is that APP has a role in brain development and that abnormal APP levels may be involved in dementia associated with AD and alcoholism. We compared the profile of total APP levels between ethanol naïve alcohol‐preferring (P) and alcohol‐nonpreferring (NP) rats. We also investigated the possibility that APP levels can be regulated in an age‐dependent manner in young rats. We studied the distribution of two proteins in the cerebral hemisphere region of the rat brain at various developmental periods. Six groups composed of the following different ages of rats were used: 7, 14, 21, 36, 43, and 78 (postnatal) days. Cell extracts from different regions of the brain were subjected to Western immunoblotting using mAb22C11. Our results suggest that levels of high‐molecular‐weight APP bands were greater in brain extracts from 7‐day‐old P rats than in other samples tested, and that the distribution of APP levels was more uneven in brain extracts from different ages of P than from NP rats. These initial results suggest that APP may play an important role in the early development of the rat brain and the alcohol‐preferring trait may influence APP processing in the developing brain.
Action of MDMA (Ecstasy) and Its Metabolites on Arginine Vasopressin Release
Authors: FALLON J. K. , SHAH D. , KICMAN A. T. , HUTT A. J. , HENRY J. A. , COWAN D. A. , FORSLING M.
Published: July 2010

Abstract: 3,4‐Methylenedioxymethamphetamine (MDMA) has been reported to cause hyponatraemia, which appears to result from inappropriate secretion of the antidiuretic hormone arginine vasopressin (AVP). After administration of a low dose of (R,S)‐MDMA (40 mg) to eight healthy drug‐free male volunteers, concentrations of AVP in plasma increased significantly at 1, 2, and 4 hours. Although no relation between plasma MDMA and AVP was found on an examination of the entire data set over the 24‐hour study period, a statistically significant negative correlation was observed at 1 hour. As this occurred at a time when both AVP and MDMA concentrations were rising, it was postulated that a metabolite, or metabolites, could primarily be responsible for the increase in AVP. To test this hypothesis we examined the effect of MDMA and five of its metabolites, in the dose range 0.1‐1,000 nM, on AVP release from the isolated rat hypothalamus. All compounds tested were found to increase AVP release (using 10 nM and 1,000 nM concentrations), with 4‐hydroxy‐3‐methoxymethamphetamine (HMMA), the major metabolite of MDMA, being the most potent, and 3,4‐dihydroxymethamphetamine (DHMA) the least potent. Each compound (1,000 nM), with the exception of DHMA, also enhanced the response to 40‐mM potassium stimulation. Our findings confirm that metabolites of MDMA, in addition to the parent drug, contribute to AVP secretion in vitro. Further work will demonstrate whether this is also true in vivo.
Comparative Effects of Substituted Amphetamines (PMA, MDMA, and METH) on Monoamines in Rat Caudate
Authors: GOUGH BOBBY , IMAM SYED Z. , BLOUGH BRUCE , SLIKKER WILLIAM , ALI SYED F.
Published: July 2010

Abstract:Paramethoxyamphetamine (PMA) is a methoxylated phenethylamine derivative that has been used illicitly in Australia since 1994. PMA is also becoming popular at rave parties in the United States. PMA raised concern when a series of fatalities resulted after its use in South Australia, where it was marketed as “ecstasy,” which is the colloquial name for MDMA. In the present study, we evaluated the comparative neurotoxicity of substituted amphetamines in rats. Extracellular levels of dopamine (DA), 3,4‐dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), serotonin (5‐HT), and 5‐hydroxyindoleacetic acid (5‐HIAA) were assayed in the caudate of freely moving rats using microdialysis and HPLC‐EC. Dialysates were assayed every 20 minutes for 4 hours after an intraperitoneal (i.p.) injection of PMA (2.5, 5, 10, 20 mg/kg), MDMA (10 and 20 mg/kg), or METH (2.5 mg/kg). METH produced a significant increase in extracellular DA (700%), and significant decreases in extracellular DOPAC and HVA (30% and 50%), with no detectable changes in either 5‐HT or 5‐HIAA. MDMA produced significant increases in DA (700% at 10 mg/kg and 950% at 20 mg/kg) and decreases in DOPAC (15% for both 10 and 20 mg/kg), and HVA (50% at 10 mg/kg and 35% at 20 mg/kg). MDMA also increased 5‐HT (350% at 10, and 575% at 20 mg/kg), and decreased 5‐HIAA to 60% for both dose levels. PMA produced no detectable increases in DA at dose levels of 2.5, 5, or 10 mg/kg, but significantly increased DA (975%) at a dose of 20 mg/kg. However, PMA significantly decreased DOPAC at all dose levels (75% at 2.5; 40% at 5; 30% at 10; 10% at 20 mg/kg), with comparable decreases in HVA at all dose levels. PMA also produced significant increases in 5‐HT at 10 and 20 mg/kg (350% for both dose levels), with no detectable changes in 5‐HT at 2.5 or 5 mg/kg. All dose levels of PMA significantly decreased 5‐HIAA (50 to 70%). These data suggest that PMA, like MDMA and METH, is capable of producing dopaminergic and serotonergic neurotoxicity.
The Competition Between Endogenous Dopamine and Radioligands for Specific Binding to Dopamine Receptors
Authors: CUMMING PAUL , WONG DEAN F. , DANNALS ROBERT F. , GILLINGS NIC , HILTON JOHN , SCHEFFEL URSULA , GJEDDE ALBERT
Published: July 2010

Abstract:The ternary complex model of G‐protein‐linkage to receptors holds that agonists increase the affinity of the receptors for the G protein. Consequently, an agonist can exert the greatest inhibition of the binding of radioligands which are also agonists. We hypothesized that competition from endogenous dopamine in striatum of living mice should thus have a greater effect on the binding of the D2,3agonistN‐[3H]propylnorapomorphine ([3H]NPA), than on the binding of the D2,3antagonist [11C]raclopride in living brain. The binding potential (pB(0)), defined as the ratio of bound‐to‐unbound ligand after reserpine treatment, was measured in mouse striatum for [11C]raclopride,image

and for [3H]NPA.image

Relative to these baseline values after dopamine depletion, saline‐treatment decreased thepBof [3H]NPA by one‐half, while thepBof [11C]raclopride declined by only one‐third. Amphetamine decreased thepBof [3H]NPA to a greater extent than that of [11C]raclopride. The apparent inhibition constant of endogenous dopamine depended on the dopamine occupancy and declined to a value 1.66 times greater for [3H]NPA than for [11C]raclopride at its highest occupancies. Thus, the agonist binding was more sensitive than antagonist binding to competition from endogenous dopamine. Dopamine agonist ligands may be especially useful for PET studies of dopamine receptor occupancy by endogenous synaptic dopamine. Analysis of the effect of dopamine occupancy on the inhibition of agonist indicated a limited supply of G protein, with a maximum ternary complex fraction of 40% of maximum antagonist binding capacity.
Enzyme and Receptor Antagonists for Preventing Toxicity from the Gamma‐Hydroxybutyric Acid Precursor 1,4‐Butanediol in CD‐1 Mice
Authors: QUANG LAWRENCE S. , DESAI MALHAR C. , KRANER JAMES C. , SHANNON MICHAEL W. , WOOLF ALAN D. , MAHER TIMOTHY J.
Published: July 2010

Abstract:1,4‐Butanediol (1,4‐BD), the diol alcohol precursor of gamma‐hydroxybutyric acid (GHB), undergoesin vivoenzymatic biotransformation to GHB by alcohol dehydrogenase (ADH) and aldehyde dehydrogenase. The subsequent metabolite, GHB, is pharmacologically active at GABABand GHB receptors. GHB can be metabolizedin vivoto gamma‐aminobutyric acid (GABA) andtrans‐4‐hydroxycrotonic acid (T‐HCA), which are also pharmacologically active at GABABreceptors and GHB receptors, respectively. Therefore, we speculate that 1,4‐BD overdose toxicity can be prevented or attenuated with the ADH enzyme inhibitor 4‐methylpyrazole (4‐MP) as well as with CGP‐35348 and NCS‐382, novel high‐affinity receptor antagonists of GABABreceptors and GHB receptors, respectively. In our murine model of acute 1,4‐BD overdose, pretreatment of CD‐1 mice with 4‐MP significantly attenuated increases in blood GHB concentrations and prevented loss of the righting reflex and failure of the rotarod test. Also, pretreatment with CGP‐35348 and its combination with NCS‐382 significantly decreased the duration of failure for the rotarod test and the percentage of animals failing the rotarod test, respectively. However, pretreatment of CD‐1 mice with NCS‐382 alone produced prolonged failure of the rotarod test, an unexpected synergistic effect with 1,4‐BD and presumably GHB, which has not previously been demonstrated.
Toxic Effects of Opioid and Stimulant Drugs on Undifferentiated PC12 Cells
Authors: OLIVEIRA M. T. , REGO A. C. , MORGADINHO M. T. , MACEDO T.R. A. , OLIVEIRA C. R.
Published: July 2010

Abstract:Cell death and reactive oxygen species production have been suggested to be involved in neurodegeneration induced by the drugs of abuse. In this study we analyze the toxicity of the following drugs of abuse: heroin, morphine,d‐amphetamine, and cocaine in undifferentiated PC12 cells, used as dopaminergic neuronal models. Our data show that opioid drugs (heroin and morphine) are more toxic than stimulant drugs (d‐amphetamine and cocaine). Toxic effects induced by heroin are associated with a decrease in intracellular dopamine, an increase in DOPAC levels, and the formation of ROS, whereas toxic effects induced by amphetamine are associated with a decrease in intracellular dopamine and in ATP/ADP levels. In contrast with cocaine, both amphetamine and heroin induced features of apoptosis. The data suggest that the death of cultured PC12 cells induced by the drugs of abuse is correlated with a decrease in intracellular dopamine levels, which can be associated with an increased dopamine turnover and oxidative cell injury.