bluuebunny/crossref_metadata_2025 huggingface dataset:
Schizophrenia and Attention Deficit Disorder
Authors: BARR WILLIAM B.
Published: July 2010

Abstract: Attentional dysfunction can be found in nearly every form of psychopathology, not just in attention deficit disorder (ADD). Being able to distinguish ADD from other psychiatric conditions is crucial for clinicians working with adolescents and young adults, particularly in the case of psychoses where making the correct diagnosis and beginning treatment promptly is extremely important. In this paper we review the literature on the attentional dysfunction found in schizophrenia and compare it to that found in ADD in an effort to increase our knowledge of etiology and underlying mechanisms. Investigators studying ADD may learn from the study of schizophrenia by realizing that ADD is also a complex disorder of attention that occurs across the developmental spectrum and is characterized by various predispositional, environmental, and maturational factors.
Attention Deficit Disorders and Sleep/Arousal Disturbance
Authors: BROWN THOMAS E. , McMULLEN WILLIAM J.
Published: July 2010

Abstract: Many children, adolescents, and adults with Attention Deficit Disorders report chronic difficulties with falling asleep, awakening and/or maintaining adequate daytime alertness. These problems may be due to a variety of factors, including environment, lifestyle, and psychiatric comorbidities. Impairments in sleep/arousal may also be related more directly to the underlying pathophysiology of ADD. This chapter describes clinical manifestations of sleep/arousal problems often associated with ADD and reviews behavioral and medication options for treatment.
Psychostimulants in the Treatment of Adults with Psychosis and Attention Deficit Disorder
Authors: OPLER LEWIS A. , FRANK DENISE M. , RAMIREZ PAUL M.
Published: July 2010

Abstract: Whether conceptualized as comorbid ADD with psychosis or as a distinct diagnostic entity—ADD psychosis—patients with features of both ADD and psychosis benefit from treatment with psychostimulants. It is hypothesized that psychostimulants have their therapeutic effect via amelioration of frontal lobe dysfunction.
Alternative Treatments for Adults with Attention‐Deficit Hyperactivity Disorder (ADHD)
Authors: ARNOLD L. EUGENE
Published: July 2010

Abstract:A previous review of alternative treatments (Tx) of ADHD—those other than psychoactive medication and behavioral/psychosocial Tx—was supplemented with an additional literature search focused on adults with ADHD. Twenty‐four alternative Tx were identified, ranging in scientific documentation from discrediting controlled studies through mere hypotheses to positive controlled double‐blind clinical trials. Many of them are applicable only to a specific subgroup. Although oligoantigenic (few‐foods) diets have convincing double‐blind evidence of efficacy for a properly selected subgroup of children, they do not appear promising for adults. Enzyme‐potentiated desensitization, relaxation/EMG biofeedback, and deleading also have controlled evidence of efficacy. Iron supplementation, magnesium supplementation, Chinese herbals, EEG biofeedback, massage, meditation, mirror feedback, channel‐specific perceptual training, and vestibular stimulation all have promising prospective pilot data, many of these tests reasonably controlled. Single‐vitamin megadosage has some intriguing pilot trial data. Zinc supplementation is hypothetically supported by systematic case‐control data, but no systematic clinical trial. Laser acupuncture has promising unpublished pilot data and may be more applicable to adults than children. Essential fatty acid supplementation has promising systematic case‐control data, but clinical trials are equivocal. RDA vitamin supplementation, non‐Chinese herbals, homeopathic remedies, and antifungal therapy have no systematic data in ADHD. Megadose multivitamin combinations are probably ineffective for most patients and are possibly dangerous. Simple sugar restriction seems ineffective. Amino acid supplementation is mildly effective in the short term, but not beyond 2‐3 months. Thyroid treatment is effective in the presence of documented thyroid abnormality. Some alternative Tx of ADHD are effective or probably effective, but mainly for certain patients. In some cases, they are the Tx of choice, and initial evaluation should consider the relevant etiologies. A few have failed to prove effective in controlled trials. Most need research to determine whether they are effective and/or to define the applicable subgroup. Some of them, although not safer than standard Tx, may be preferable for an etiologic subgroup.
Treating Impulsivity and Anxiety in the Suicidal Patient
Authors: Fawcett Jan
Published: July 2010

Abstract: It has been found that while over 90% of people who commit suicide have a psychiatric illness at the time, over 50% are under active psychiatric or mental health care. How can suicide risk be detected and preventive treatment provided? Both communication of suicidal ideation or intent and prior suicide attempts have been shown to be risk factors, which should be assessed in patients with psychiatric illness. Research shows that suicidal ideation is often not communicated to professionals or is denied by patients just prior to suicide and, when present, is often useful not as an immediate risk factor, but as a chronic risk factor. Suicide attempts predict a 10‐30% occurrence of suicide over 10 years, but often do not indicate immediate risk. Recent research has shown that impulsiveness and severe anxiety, panic attacks, and agitation comorbid with depression are often immediate suicide risk factors that are potentially modifiable if recognized and treated urgently with effective medications and watchful support.
Treating the Suicidal Patient
Authors: Maltsberger John T.
Published: July 2010

Abstract: Successful psychotherapy with suicidal patients requires an emotionally full, active engagement from the therapist with his patient. Emphasis is on the real relationship, not the transference, and the therapist must be available to the patient as a sturdy, reliable object with whom to identify. The therapist's attitude must be loving, not neutral; the alliance is built upon the therapist's devotion to the patient's growth and the development of the attributes necessary for successful autonomous adult functioning. Patients require emotional containment and support, assistance in modulating painful affect, validation, education, help with reality testing, and kindly limit setting. Countertransference reactions must be expected and kept in check, so that the therapist does not get in the patient's way as he tries to build up the faulty mental structures that got him into trouble in the first place.
Central Neuroplasticity and Pathological Pain
Authors: Melzack Ronald , Coderre Terence J. , Katz Joel , Vaccarino Anthony L.
Published: July 2010

Abstract: The traditional specificity theory of pain perception holds that pain involves a direct transmission system from somatic receptors to the brain. The amount of pain perceived, moreover, is assumed to be directly proportional to the extent of injury. Recent research, however, indicates far more complex mechanisms. Clinical and experimental evidence shows that noxious stimuli may sensitize central neural structures involved in pain perception. Salient clinical examples of these effects include amputees with pains in a phantom limb that are similar or identical to those felt in the limb before it was amputated, and patients after surgery who have benefited from preemptive analgesia which blocks the surgery‐induced afferent barrage and/or its central consequences. Experimental evidence of these changes is illustrated by the development of sensitization, wind‐up, or expansion of receptive fields of CNS neurons, as well as by the enhancement of flexion reflexes and the persistence of pain or hyperalgesia after inputs from injured tissues are blocked. It is clear from the material presented that the perception of pain does not simply involve a moment‐to‐moment analysis of afferent noxious input, but rather involves a dynamic process that is influenced by the effects of past experiences. Sensory stimuli act on neural systems that have been modified by past inputs, and the behavioral output is significantly influenced by the “memory” of these prior events. An increased understanding of the central changes induced by peripheral injury or noxious stimulation should lead to new and improved clinical treatment for the relief and prevention of pathological pain.
Potential Mechanisms in Chemical Intolerance and Related Conditions
Authors: Clauw Daniel J.
Published: July 2010

Abstract: The symptom of chemical intolerance may occur in isolation, but often occurs in conjunction with other chronic symptoms such as pain, fatigue, memory disturbances, etc. This frequent clustering of symptoms in individuals has led to the definition of several chronic multisymptom syndromes, such as multiple chemical sensitivity, fibromyalgia, chronic fatigue syndrome, and Gulf War illnesses. The aggregate research into these syndromes has suggested some unifying mechanisms that contribute to symptomatology. Multiple lines of evidence suggest that there is aberrant function of numerous efferent neural pathways, such as the autonomic nervous system and hypothalamic‐pituitary axes, in subsets of individuals with these conditions. There is perhaps the greatest evidence for abnormal sensory processing in these syndromes, with a low “unpleasantness threshold” for multiple types of sensory stimuli. Psychological and behavioral factors are known to play a significant role in initiating or perpetuating symptoms in some persons with these illnesses. In the field of pain research, the interrelationship between physiologic and psychologic factors in symptom expression has been well studied. Using both established and novel methodologies, studies have suggested that psychologic factors such as hypervigilance and expectancy are playing a relatively minor role in most individuals with fibromyalgia and that clear evidence exists of physiologic amplification of sensory stimuli. These studies need to be extended to more sensory tasks and to larger numbers of subjects with related conditions. It is of note, though, that existing data on this spectrum of illnesses would suggest that there may be greater psychologic contributions to symptomatology if an illness is defined in part by behavior (e.g., avoidance of chemical exposures) rather than on the basis of symptoms alone.
Plasticity of the Hippocampus: Adaptation to Chronic Stress and Allostatic Load
Authors: McEwen Bruce S.
Published: July 2010

Abstract: The hippocampus is an important structure for declarative, spatial, and contextual memory and is implicated in the perception of chronic pain. The hippocampal formation is vulnerable to damage from seizures, ischemia, and head trauma and is particularly sensitive to the effects of adrenal glucocorticoids secreted during the diurnal rhythm and chronic stress. Adrenal steroids typically have adaptive effects in the short run, but promote pathophysiology when there is either repeated stress or dysregulation of the HPA axis. The damaging actions of glucocorticoids under such conditions have been termed “allostatic load”, referring to the cost to the body of adaptation to adverse conditions. Adrenal steroids display both protective and damaging effects in the hippocampus. They biphasically modulate excitability of hippocampal neurons, and high glucocorticoid levels and severe acute stress impair declarative memory in a reversible manner. The hippocampus also displays structural plasticity, involving ongoing neurogenesis of the dentate gyrus, synaptogenesis under control of estrogens in the CA1 region, and dendritic remodeling caused by repeated stress or elevated levels of exogenous glucocorticoids in the CA3 region. In all three forms of structural plasticity, excitatory amino acids participate along with circulating steroid hormones. Glucocorticoids and stressors suppress neurogenesis in the dentate gyrus. They also potentiate the damage produced by ischemia and seizures. Moreover, the aging rat hippocampus displays elevated and prolonged levels of excitatory amino acids released during acute stress. Our working hypothesis is that structural plasticity in response to repeated stress starts out as an adaptive and protective response, but ends up as damage if the imbalance in the regulation of the key mediators is not resolved. It is likely that morphological rearrangements in the hippocampus brought on by various types of allostatic load alter the manner in which the hippocampus participates in memory functions and it is conceivable that these may also have a role in chronic pain perception.
Unsteady Flow Modelling in Turbine Stage
Authors: MARTELLI FRANCESCO
Published: July 2010

Abstract: The paper deals with the problems of unsteady flow modelling in turbine stage. The impact of unsteadiness in the design procedure as well as in the real flow phenomena are briefly addressed. After a discussion of the physical aspects of the real flow in turbine stage which differ from the unsteady flow in a single row environment, the paper reports a survey of the actual and more recent approaches to the numerical modelling on the unsteady flow in multiple rows environment. The classical steady models, used for long time in the design procedure, are addressed and their limits are focused. The more complex procedures ranging from quasi‐unsteady methods to the fully unsteady methods are reported and investigated in details. The discussion on the specific features of the different approaches is pointed to assess the accuracy, the feasibility, the robustness and the usability (i.e. the computer time and storage requirements). Sample results from the author research activity are reported and presented. Discussion of crucial and open questions to improve the prediction capability of the methods are finally reported as well as some comments on the possibility to joint classical (steady methods) and advanced approaches (fully unsteady methods) to improve the actual design procedure are addressed.
Flow and Heat Transfer Predictions for Film Cooling
Authors: ACHARYA SUMANTA , TYAGI MAYANK , HODA ASIF
Published: July 2010

Abstract: Film cooling flows are characterized by a row of jets injected at an angle from the blade surface or endwalls into the heated crossflow. The resulting flowfield is quite complex, and accurate predictions of the flow and heat transfer have been difficult to obtain, particularly in the near field of the injected jet. The flowfield is characterized by a spectrum of vortical structures including the dominant kidney vortex, the horse‐shoe vortex, the wake vortices and the shear layer vortices. These anisotropic and unsteady structures are not well represented by empirical or ad‐hoc turbulence models, and lead to inaccurate predictions in the near field of the jet. In this paper, a variety of modeling approaches have been reviewed, and the limitations of these approaches are identified. Recent emergence of Direct Numerical Simulation (DNS) and Large Eddy Simulation (LES) tools allow the resolution of the coherent structure dynamics, and it is shown in this paper, that such approaches provide improved predictions over that obtained with turbulence models.
Heat/Mass Transfer Characteristics on Turbine Shroud with Blade Tip Clearance
Authors: CHO H. H. , RHEE D. H. , CHOI J. H.
Published: July 2010

Abstract: The present study is conducted to investigate the local heat/mass transfer characteristics on the shroud with blade tip clearances. The relative motion between blade and shroud is neglected, and four‐bladed linear cascade is used in this study. naphthalene sublimation method is employed to determine the detailed local heat/mass transfer coefficients on the surface of shroud. The tip clearance is changed from 0.66%t to 2.85%t of the blade chord length. The flow enters the gap between the blade tip and shroud at the pressure side due to the high pressure side due to the high pressure difference. Therefore, the heat/mass transfer characteristics of the shroud are changed significantly from those with endwall. A first, high heat/mass transfer occurs along the profile of blade a the pressure side due to the entrance effect and acceleration of the gap flow. Then, the heat/mass transfer coefficients on the shroud increase along the suction side of the blade because tip leakage vortices are generated and interact with the main flow. The results show that the heat/mass transfer characteristics are changed largely with the gap distance between the tip of turbine blade and the shroud.
The Variation of Heat Transfer Coefficient, Adiabatic Effectiveness and Aerodynamic Loss with Film Cooling Hole Shape
Authors: SARGISON J.E. , GUO S.M. , OLDFIELD M.L.G. , RAWLINSON A.J.
Published: July 2010

Abstract: The heat transfer coefficient and adiabatic effectiveness of cylindrical, fan shaped holes and a slot are presented for the region zero to 50 diameters downstream of the holes. Narrow‐band liquid crystals were used on a heated flat plate with heated air coolant. These parameters have been measured in a steady state, low speed facility at engine representative Reynolds number based on hole diameter and pressure difference ratio (ideal momentum flux ratio). The aerodynamic loss due to each of the film cooling geometries has been measured using a traverse of the boundary layer far downstream of the film cooling holes.

Compared to the cylindrical holes, the fan shaped hole case showed an improvement in the uniformity of cooling downstream of the holes and in the level of laterally averaged film cooling effectiveness. The fan effectiveness approached the slot level and both the fan and cylindrical hole cases show lower heat transfer coefficients than the slot and non film cooled cases based on the laterally averaged results. The drawback to the fan shaped hole was that the aerodynamic loss was significantly higher than both the slot and cylindrical hole values due to inefficient diffusion in the hole exit expansion.
Numerical Investigation of Film Cooling Flow Induced by Cylindrical and Shaped Holes
Authors: BARTHET Sylvain , KULISA Pascale
Published: July 2010

Abstract: The present study is the second half of a two part work carried out in collaboration with SNECMA which tends to investigate a shaped hole film cooling experimentally and numerically. The aim of this paper is the numerical study of 3D phenomena induced by cylindrical and shaped hole film cooling on a flat wall.

The two calculations show up classical structures such as horseshoe or kidney vortices and their differences according to the shape configuration. A detailed study demonstrates their influence on the jet behaviour. Comparing both cases reveals the impact of shaping on the velocity field and vortex motions.

The calculations were performed by resolving the 3D Navier‐Stokes equations associated with a k‐ε turbulence model. The solver is the CANARI code developed by ONERA.
Prediction of pressure loss and heat transfer in internal cooling passages
Authors: HERMANSON K. , PARNEIX S. , Von WOLFERSDORF J. , SEMMLER K.
Published: July 2010

Abstract: This paper reports CFD‐simulations of the turbulent flow, pressure loss and heat transfer occurring in ribbed passages. The channel section is rectangular, with an aspect ratio of 2.04. Ribs are square cross‐section, their height is 10% of the channel height, and their inclination is varied from 90° to 33°. Reynolds number is 30,000. Three turbulence models (k‐ε wall functions and 2‐layer, V2F) are used and compared to the experimental data of Cho et al.1. All three models accurately predict the pressure losses due to the ribs and the qualitative heat transfer distribution on the ribbed wall. However, only the V2F model can accurately reproduce the absolute heat transfer levels, this at all inclination angles. The correlation developed by Han and co‐workers for smaller rib‐heights under‐predicts the friction factor and wall heat transfer level on the current configuration. This shows the danger of using a correlation outside of its application range.
EXPERIMENTAL DETERMINATION OF AVERAGE TURBULENT HEAT TRANSFER AND FRICTION FACTOR IN STATOR INTERNAL RIB‐ ROUGHENED COOLING CHANNELS
Authors: BATTISTI L. , BAGGIO P.
Published: July 2010

Abstract: In gas turbine cooling design, techniques for heat extraction from the surfaces exposed to the hot stream are based on the increase of the inner heat transfer areas and on the promotion of the turbulence of the cooling flow. This is currently obtained by casting periodic ribs on one or more sides of the serpentine passages into the core of the blade. Fluid dynamic and thermal behaviour of the cooling flow have been extensively investigated by means of experimental facilities and many papers dealing with this subject have appeared in the latest years. The evaluation of the average value of the heat transfer coefficient most of the time is inferred from local measurements obtained by various experimental techniques. Moreover the great majority of these studies are not concerned with the overall average heat transfer coefficient for the combined ribs and region between them, but do focus just on one of them.

This paper presents an attempt to collect information about the average Nusselt number inside a straight ribbed duct. Series of measurements have been performed in steady state eliminating the error sources inherently connected with transient methods. A low speed wind tunnel, operating in steady state flow, has been built to simulate the actual flow condition occurring in a rectilinear blade cooling channel. A straight square channel with 20 transverse ribs on two sides has been tested for Re of about 3·104, 4.5·1O4 and 6·104. The ribbed wall test section is electrically heated and the heat removed by a stationary flow of known thermal and fluid dynamic characteristics.
Replicative Aging, Telomeres, and Oxidative Stress
Authors: SARETZKI GABRIELE , VON ZGLINICKI THOMAS
Published: July 2010

Aging is a very complex phenomenon, both in vivo and in vitro. Free radicals and oxidative stress have been suggested for a long time to be involved in or even to be causal for the aging process. Telomeres are special structures at the end of chromosomes. They shorten during each round of replication and this has been characterized as a mitotic counting mechanism. Our experiments show that the rate of telomere shortening in vitro is modulated by oxidative stress as well as by differences in antioxidative defence capacity between cell strains. In vivo we found a strong correlation between short telomeres in blood lymphocytes and the incidence of vascular dementia. These data suggest that parameters that characterise replicative senescence in vitro offer potential for understanding of, and intervention into, the aging process in vivo.
Exercise‐induced Modulation of Antioxidant Defense
Authors: JI LI LI
Published: July 2010

Maintaining mobility is a critical element for the quality of life. Skeletal muscle, the primary organ for locomotion, undergoes age‐associated deterioration in size, structure, and function. Recent research suggests that oxidative stress is an important etiology for sarcopenia. The level of oxidative stress imposed on aging muscle is influenced by two fundamental biological processes: the increased generation of reactive oxygen species (ROS) and age‐associated changes in antioxidant defense. It appears that despite increased ROS production, aging muscle has a decreased gene expression of antioxidant enzymes possibly due to a diminished ability for cell signaling. A major benefit of nonexhaustive exercise is to induce a mild oxidative stress that stimulates the expression of certain antioxidant enzymes. This is mediated by the activation of redox‐sensitive signaling pathways. For example, gene expression of muscle mitochondrial (Mn) superoxide dismutase is enhanced after an acute bout of exercise preceded by an elevated level of NF‐κB and AP‐1 binding. An increase in de novo protein synthesis of an antioxidant enzyme usually requires repeated bouts of exercise. Aging does not abolish but seems to attenuate training adaptations of antioxidant enzymes. Thus, for senescent muscle, training should be assisted with supplementation of exogenous antioxidants to research the optimal level of defense.
Generation of Reactive Oxygen and Nitrogen Species in Contracting Skeletal Muscle
Authors: REID MICHAEL B. , DURHAM WILLIAM J.
Published: July 2010

Since the early 1980s biologists have recognized that skeletal muscle generates free radicals. Of particular interest are two closely related redox cascades—reactive oxygen species (ROS) and nitric oxide (NO) derivatives. The ROS cascade is initiated by superoxide anion radicals derived from the mitochondrial electron transport chain, the membrane‐associated NAD(P)H oxidase complex, or other sources. NO is produced by two NO synthase isoforms constitutively expressed by muscle fibers. ROS and NO derivatives are produced continually and are detectable in both the cytosolic and extracellular compartments. Production increases during strenuous exercise. Both ROS and NO modulate contractile function. Under basal conditions, low levels of ROS enhance force production. Excessive ROS accumulation inhibits force, for example, during fatiguing exercise. NO inhibits skeletal muscle contraction, an effect that is partially mediated by cyclic GMP as a second messenger. With aging, redox modulation of muscle contraction may be altered by changes in the rates of ROS and NO production, the levels of endogenous antioxidants that buffer ROS and NO, and the sensitivities of regulatory proteins to ROS and NO action. The impact of aging on contractile regulation depends on the relative magnitude of these changes and their net effects on ROS and NO activities at the cellular level.
Enhancing Cognitive Function across the Life Span
Authors: KOROL DONNA L.
Published: July 2010

Glucose administration regulates many neural and behavioral processes in rodents, including learning and memory. Given the important role of glucose in brain function and the safety of glucose as a treatment, we have investigated the effects of glucose administration in humans of different ages. In previous work, we examined the effects of early‐morning glucose consumption on cognitive functions in elderly individuals. In this population, glucose enhanced performance on specific measures, particularly on those tasks where mild age‐related deficits appear (e.g., verbal declarative memory). Interestingly, glucose failed to enhance cognitive functions in young adults. Our recent work has examined three issues related to glucose enhancement of cognition: First, is glucose effective only in reversing impairments or can it also facilitate performance in highly functioning individuals? Second, are glucose effects dependent either on time of day or on interactions with other meals? Third, are typical breakfast foods as effective as glucose in enhancing cognitive performance? Our findings suggest that glucose can improve memory in highly functioning populations as it does in populations with deficits. However, enhancement by glucose may require sufficient levels of task difficulty and of blood glucose. In addition, like glucose, early morning consumption of cereal can improve performance on some cognitive tests. These results have important implications for the nature of glucose facilitation of memory and for the role of dietary factors in performance of many daily activities.
Nitrones as Neuroprotectants and Antiaging Drugs
Authors: FLOYD ROBERT A. , HENSLEY KENNETH , FORSTER MICHAEL J. , KELLEHER‐ANDERSON JUDITH A. , WOOD PAUL L.
Published: July 2010

Specific nitrones have been used for more than 30 years in analytical chemistry and biochemistry to trap and stabilize free radicals for the purpose of their identification and characterization. PBN (α‐phenyl‐tert‐butyl nitrone), one of the more widely used nitrones for this purpose, has been shown to have potent pharmacologic activities in models of a number of aging‐related diseases, most notably the neurodegenerative diseases of stroke and Alzheimer's disease. Studies in cell and animal models strongly suggest that PBN has potent antiaging activity. A novel nitrone, CPI‐1429, has been shown to extend the life span of mice when administration was started in older animals. It has also shown efficacy in the prevention of memory dysfunction associated with normal aging in a mouse model. Mechanistic studies have shown that the neuroprotective activity of nitrones is not due to mass‐action free radical‐trapping activity, but due to cessation of enhanced signal transduction processes associated with neuroinflammatory processes known to be enhanced in several neurodegenerative conditions. Enhanced neuroinflammatory processes produce higher levels of neurotoxins, which cause death or dysfunction of neurons. Therefore, quelling of these processes is considered to have a beneficial effect allowing proper neuronal functioning. The possible antiaging activity of nitrones may reside in their ability to quell enhanced production of reactive oxygen species associated with age‐related conditions. On the basis of novel ideas about the action of secretory products formed by senescent cells on bystander cells, it is postulated that nitrones will mitigate these processes and that this may be the mechanism of their antiaging activity.
Involvement of Mitochondria and Other Free Radical Sources in Normal and Abnormal Fetal Development
Authors: FANTEL ALAN G. , PERSON RICHARD E.
Published: July 2010

Shepard and Mackler have documented quantitative increases in mitochondrial cristae between gestational days 10 and 14 in rats accompanied by decreased glucose utilization and increased NADH oxidase activity. Findings show a shift from glycolytic to oxidative metabolism starting at around the time of implantation. Exposure to many substances that cause transient uteroplacental hypoperfusion, including cocaine, phenytoin, calcium channel blockers, and nitric oxide synthase (NOS) inhibitors, induce limb and central nervous system (CNS) malformations while sparing the heart. We have reported that isolated electron transport particles prepared from sensitive tissues show reduced NADH oxidase activities compared with insensitive heart. They also have significantly greater superoxide formation in association with significantly reduced superoxide dismutase activities. NOS inhibitors induce severe limb reductions in late gestation. Exposure is associated with hemorrhage and nitrotyrosine (NT) formation shortly after treatment. Hemorrhage, malformations, and NT formation can be significantly reduced by coadministration of PBN, allopurinol, or aminoguanidine. On the basis of these findings, we have proposed a role for the formation of reactive oxygen species (ROS) and reactive nitrogen species (RNS) in the genesis of limb reduction defects. It is important to note that limb reduction defects occur in humans (∼0.22/1000) and have been associated with the agents listed above.
Frequent Intracellular Clonal Expansions of Somatic mtDNA Mutations
Authors: COLLER HILARY A. , BODYAK NATALYA D. , KHRAPKO KONSTANTIN
Published: July 2010

It has been proposed that age‐dependent accumulation of somatic mutations in mtDNA is responsible for some aspects of the aging process. However, most cells contain hundreds to thousands of mtDNA molecules. Any nascent somatic mutant therefore appears as a single copy among a majority of wild‐type species. A single mutant molecule is unlikely to influence the physiology of the cell and thus cannot play a role in the aging process. To affect cellular physiology, the nascent somatic mutants must somehow accumulate clonally in the cell to significant levels. The evidence supporting the view that, indeed, clonal expansion of mtDNA mutations is a widespread process in various human tissues, and the mechanisms by which clonal expansions may affect the aging process, are reviewed. Originally, clonal expansion was demonstrated for mtDNA with large deletions in muscle. Cell‐by‐cell analysis of human cardiomyocytes and buccal epithelial cells revealed that clonal expansion affects point mtDNA mutations as well as deletions. Expansions are not limited to muscle, but likely are present in most tissues, and almost every cell of an aged tissue is likely to be affected by an expansion. While the very existence of clonal expansion is beyond doubt, the mechanisms driving this process are largely controversial. The hypotheses explaining expansion includes random or various selective mechanisms, or both. We show that the spectra of expanded point mutations are drastically different in cardiomyocytes and epithelial cells. This suggests that the mechanisms of expansion in these tissues are different. In particular, we propose random segregation and positive selection models for epithelial and muscle cells, respectively.
International Workshop on Lessons from Animal Models for Human Type 1 Diabetes
Authors: BONIFACIO EZIO , ATKINSON MARK , EISENBARTH GEORGE , SERREZE DAVID , KAY THOMAS W. H. , LEE‐CHAN EDWIN , SINGH BHAGIRATH
Published: July 2010

Abstract: The aim of this workshop was to identify autoantibody assays that could provide useful markers of autoimmunity in the NOD mouse model for type 1 diabetes. It was demonstrated that insulin autoantibodies measured by sensitive radiobinding assay are a marker of autoimmunity in NOD mice and draw into question the true nature of GADA and IA‐2A in this animal model.
Autoantibody Profile and Epitope Mapping in Latent Autoimmune Diabetes in Adults
Authors: FALORNI ALBERTO , CALCINARO FILIPPO
Published: July 2010

Abstract: The presence of islet cell autoantibodies in adult diabetic subjects who do not require insulin treatment for at least six months after the initial clinical diagnosis identifies the so‐called latent autoimmune diabetes in the adult (LADA). Glutamic acid decarboxylase autoantibodies (GAD65Ab) are the best immune marker to identify LADA patients, while other islet autoantibodies, such as IA‐2 autoantibodies, have a very low diagnostic sensitivity. Islet cell antibodies, as detected by indirect immunofluorescence, may improve the diagnostic specificity of the immune analysis when detected in GAD65Ab‐positive patients. Although the majority of LADA patients progresses towards insulin dependency within a few years after the diagnosis, this form of diabetes is heterogeneous. The presence of high titers of GAD65Ab and/or GAD65Ab directed towards COOH‐terminal epitopes of the autoantigen (GAD65‐CAb) identifies a subgroup of LADA patients with clinical characteristics similar to those of typical type 1 diabetes and at very high risk of progression toward insulin dependency. On the other hand, low titers of GAD65Ab, or the exclusive presence of GAD65Ab directed to middle epitopes of the autoantigen, characterizes LADA patients with clinical characteristics almost indistinguishable from those of GAD65Ab‐negative type 2 diabetic patients. LADA subjects, especially in the presence of high titers of GAD65Ab and/or GAD65‐CAb, have an increased risk for other organ‐specific autoimmune diseases such as thyroid autoimmune diseases or autoimmune Addison's. LADA should be considered a major component of the autoimmune polyendocrine syndromes, and screening for other autoimmune diseases should be performed in all LADA patients.
Dendritic Cell‐Based Proliferative Assays of Peripheral T Cell Responses to Tetanus Toxoid
Authors: NARENDRAN PARTH , ELSEGOOD KATHRYN , LEECH NICOLA J. , DAYAN COLIN M.
Published: July 2010

Abstract: Antigen‐specific proliferative responses of peripheral blood T cells are widely used in humans to study the T cell compartment. However, responses to autoantigens are often weak and poorly reproducible. Here we show, using a test recall antigen (tetanus toxoid), that absolute levels of proliferation, minimally detectable antigen doses, and/or ability to detect statistically significant responses can be enhanced using in vitro‐generated autologous dendritic cells as antigen presenting cells.
A New Model for Analyzing Immunomodulation of T Cell Responses Induced by Oral Administration of Islet Cell Antigens
Authors: BREGENHOLT SØREN , WANG MIKALA , ZDRAVKOVIC MAJA , DYRBERG THOMAS , PETERSEN JACOB S.
Published: July 2010

Abstract: Based on the coimmunization of BALB/c mice with insulin and ovalbumin, we here describe a feasible efficacy model for analyzing the tolerogenic effect of the oral administration of sequestered antigens—for example, islet‐specific proteins such as insulin and GAD65.
IL‐1β Expression in Islet Cells of the NOD Mouse and Its Spatial Relationship to Beta Cells and Inducible Nitric Oxide Synthase
Authors: REDDY SHIVA , YOUNG MAY
Published: July 2010

Abstract: The expression of IL‐1β in the NOD mouse pancreas was examined following disease acceleration with cyclophosphamide (Cy). Female NOD mice were injected with Cy at day 95 and the pancreas examined immunohistochemically at days 0, 4, 7, 11, and 14 (Cy group). Cyclophosphamide was also administered to NOD mice that were given oral nicotinamide from day 21. At day 0 (Cy group), IL‐1β was expressed in selective intraislet macrophages but showed an increase from day 7 onwards in macrophages, a few beta cells, and somatostatin cells. Peak expression was seen at day 11, when it was significantly higher than in day‐11 mice given nicotinamide. In the Cy group a proportion of macrophages coexpressed IL‐1β and inducible nitric oxide synthase (iNOS). IL‐1β expressed within the islet macrophages may act in concert with other cytokines, promote free radical generation including NO, and promote beta cell death during IDDM.
Induction of Donor‐Specific Tolerance to Islet Allografts in Nonhuman Primates
Authors: GAUR LAKSHMI K. , KENNEDY E. , NITTA Y. , NEPOM G. T. , NELSON K. A. , ALLEN M. , LERNMARK Å.
Published: July 2010

Abstract: Pancreatic tissue grafting is by far the most physiological therapeutic solution to the insulin deficiency of diabetes. Recent clinical trials have indicated somewhat successful use of nonsteroidal immunosuppressive regimens and a successful nonhuman primate trial using CD154 for costimulation blockade was reported. However, these protocols need to be replaced with safe and efficacious ones in which long‐term allotolerance would make these treatments routine in a clinical setting. With the specific objective of testing whether peripheral infusions of stem cells or stem cell fractions in conjunction with islet allografting would induce allograft tolerance, we have established a macaque diabetic model. The macaques were rendered diabetic by streptozotocin and required daily doses of insulin to maintain lower blood glucose levels. The diabetic macaques then received islets and stem cells from unrelated and MHC‐mismatched donors without any immunosuppression. In our initial analysis, 5 of 7 macaques that received stem cell infusions at the time of islet allografting have shown allograft survival longer than the group of macaques that received islets without the stem cell infusion. One of these five macaques has been normoglycemic for 10 months, with no exogenous insulin. This macaque received stem cell population enriched for CD34+ cells with depletion of CD18 cells, which have shown low or no allostimulatory potential in mixed lymphocyte cultures. Increased levels in insulin and C‐peptide levels were shown in the macaques after islet transplantation.
Distinct IA‐2 Autoantibody Epitope Recognition between Childhood‐Onset and Adult‐Onset Type 1 Diabetes
Authors: KAWASAKI EIJI , SERA YASUNORI , ABIRU NORIO , YAMAUCHI MIKAKO , OZAKI MASAKO , YAMAKAWA KENICHI , ABE TAKAHIRO , UOTANI SHIGEO , YAMASAKI HIRONORI , YAMAGUCHI YOSHIHIKO , EGUCHI KATSUMI
Published: July 2010

Abstract: Different autoimmune mechanisms may be involved in childhood‐ and adult‐onset type 1 diabetes. Our aim was to explore the differences in IA‐2 autoantibody epitope recognition between childhood‐ and adult‐onset type 1 diabetes. Therefore, in vitro synthesized radiolabeled IA‐2ic (amino acid 601‐979), IA‐2JM (amino acid 557‐629), and IA‐2PTP (amino acid 630‐979) were used to analyze the IA‐2 autoantibody epitope specificities in 93 patients with new‐onset type 1 diabetes. Among 93 patients with type 1 diabetes the prevalences of autoantibodies to GAD, IA‐2ic, and insulin were 69.9%, 58.1%, and 45.2%, respectively. The prevalence of IA‐2ic autoantibodies in patients with childhood‐onset type 1 diabetes (aged ≤18 years, n= 60) was significantly higher than that in patients with adult‐onset diabetes (68.3 vs. 36.4%, P < 0.002). Ninety‐two percent of type 1 diabetic patients positive for IA‐2ic autoantibodies recognized the PTP domain of IA‐2, whereas 8% reacted with the JM region only. Among 60 patients with childhood‐onset type 1 diabetes, 2% recognized the JM region only, 48% bound the PTP domain of IA‐2 only, and 18% recognized both JM and PTP epitopes. Among 33 patients with adult‐onset diabetes, 9% recognized the IA‐2JM only, 18% bound the IA‐2PTP only, and 9% recognized both the IA‐2JM and the IA‐2PTP. IA‐2PTP autoantibodies were prevalent in patients with childhood‐onset type 1 diabetes. By contrast, the proportion of patients with the IA‐2JM autoantibody only in type 1 diabetes who were positive for IA‐2ic autoantibodies was significantly higher in adult‐onset than in childhood‐onset diabetes (P < 0.05). These results demonstrate that autoantibody recognition of the IA‐2 epitope is distinct in childhood‐onset and adult‐onset type 1 diabetes.
Women Diagnosed with Gestational Diabetes Mellitus Do Not Carry Antibodies against Minor Islet Cell Antigens
Authors: BALAJI MADHURI , SHTAUVERE‐BRAMEUS A. , BALAJI V. , SESHIAH V. , SANJEEVI C. B.
Published: July 2010

Abstract: Women with gestational diabetes mellitus (GDM) have considerable risk for developing both type 1 and type 2 diabetes in life. Autoantibodies against glutamic acid decarboxylase (GAD65) and tyrosine phosphatase (IA‐2) are strongly associated with autoimmune diabetes and can be useful in early identification of the development of type 1 diabetes in women with GDM. On the other hand antibodies against minor islet antigens in adults can be predictors for autoimmune polyendocrine syndrome. The aim of our study was to estimate the prevalence of autoantibodies against minor antigens—tissue transglutaminase (TTG), ICA12, and 21‐hydroxylase (21‐0H)—in GDM patients from southern India. Eighty‐six serum samples from GDM subjects and 114 samples from healthy controls were tested for the presence of GAD65 and IA‐2Ab as well as for the presence of 21‐OH, TTG, and ICA12Ab by radiobinding assay with in vitro translated recombinant human 35S‐GAD65, IA‐2, TTG, ICA12, and 21‐OH antigens. We observed the presence of GAD65 or IA‐2 autoantibodies in 41% (35/86) of GDM patients, while none of the patients tested positive for any of the minor autoantibodies. Our results demonstrate that there is a high prevalence of autoantibodies in GDM subjects that are at higher risk of developing autoimmune diabetes later, but none of the patients carries antibodies against minor antigens, which could predict autoimmune polyendocrine syndrome in adults.
MHC Class I Chain‐Related Gene A Alleles Distinguish Malnutrition‐Modulated Diabetes, Insulin‐Dependent Diabetes, and Non‐Insulin‐ Dependent Diabetes Mellitus Patients from Eastern India
Authors: SANJEEVI C. B. , KANUNGO A. , BERZINA L. , SHTAUVERE‐BRAMEUS A. , GHADERI M. , SAMAL K. C.
Published: July 2010

Abstract: Insulin‐dependent diabetes mellitus (IDDM) is a polygenic disorder with an autoimmune basis for disease development. In addition to HLA, a second susceptibility locus for IDDM has been identified to lie in the major histocompatibility class III region. MIC‐A is located in the MHC class III region and is expressed by monocytes, keratinocytes, and endothelial cells. Sequence determination of the MIC‐A gene identifies trinucleotide repeat (GCT) microsatellite polymorphism in exon 5. Five alleles with 4, 5, 6, and 9 repetitions of GCT or 5 repetitions of GCT with 1 additional nucleotide insertion (GGCT) are identified. The alleles are A4, A5, A5.1, A6, and A9. The aim of our study was to find the association of MIC‐A alleles with IDDM, malnutrition‐modulated diabetes mellitus (MMDM), and non‐insulin‐dependent diabetes mellitus (NIDDM) patients. IDDM (n= 52), MMDM (n= 41), NIDDM (n= 212), and healthy controls (n= 73) from Cuttack, in eastern India, were studied. Of the 212 NIDDM patients analyzed, 96 of them were found to be positive for either GAD65 or IA‐2 antibodies. Autoantibodies to GAD65 and IA‐2 were measured by radioligand binding assay using 35S‐labeled recombinant human GAD65 and IA‐2 in an in vitro transcription/translation system. Autoantibody‐positive NIDDM patients (n= 96) and adult healthy controls for NIDDM (n= 113) were also compared. These autoantibody‐positive NIDDM patients are considered as slow‐onset IDDM or latent autoimmune diabetes in adults (LADA) patients. The samples were analyzed for MIC‐A by PCR amplification, and fragment sizes were determined in an ABI prism DNA sequencer. The results of the MIC‐A typing are: allele 9 of MIC‐A is positively associated (OR 3.62; P < 0.001), and allele 4 is negatively associated (OR 0.31; P < 0.05) with MMDM patients compared to controls. Allele 5 is positively associated with IDDM (OR 2.64; P < 0.05) when compared to controls. Allele 5.1 is positively associated in the autoantibody‐positive NIDDM patients compared to adult controls. Our findings of a significant increase of allele A9 in MMDM patients compared to healthy controls suggest that MMDM is immunogenetically different from IDDM in eastern India. MIC‐A is important in the pathogenesis of MMDM patients from Cuttack. MIC‐A alleles distinguish acute‐onset IDDM from slow‐onset IDDM, indicating that this molecule may be important for delaying the onset of IDDM with the result that these patients are diagnosed clinically as NIDDM.
The Combination of Several Polymorphic Amino Acid Residues in the DQα and DQβ Chains Forms a Domain Structure Pattern and Is Associated with Insulin‐Dependent Diabetes Mellitus
Authors: SANJEEVI C. B. , LANDIN‐OLSSON M. , KOCKUM I. , DAHLQUIST G. , LERNMARK Å.
Published: July 2010

Abstract: IDDM is positively associated with HLA‐DQA1*0301‐DQB1*0302 (DQ8) and DQA1*0501‐DQB1*0201 (DQ2) and negatively associated with DQA1*0102‐DQB1*0602 (DQ6). The aim of the present study was to analyze the importance of several polymorphic residues and domains of DQα and DQβ, in addition to residue 52 DQα and residue 57 DQβ, with regard to susceptibility or resistance in new‐onset 0‐ to 15‐year‐old Swedish children with IDDM (n= 425) and matched controls (n= 367). HLA genotyping identified several polymorphic residues of the DQα and DQβ to be either positively or negatively associated with IDDM, including Arg 52 DQα and Asp 57 DQβ. Leu 69 DQα was positively (OR 7.02, P < 0.0001), Ala 69 DQα was negatively (OR 0.22, P < 0.0001), Gln 47 DQα was positively (OR 5.8, P < 0.0001), Cys 47 DQα was positively (OR 2.2, P < 0.0001), Lys 47 DQα was negatively (OR 0.47, P < 0.005), and Arg 47 DQα was negatively (OR 0.22, P < 0.005) associated with IDDM. Similarly, residues at 11, 18, 45, 48, 50, 53, 55, 61, 64, 66, 76, and 80 were either positively or negatively associated with IDDM. Likewise, for DQβ, Leu 53 DQβ was positively (OR 11.01, P < 0.0001), Gln 53 DQβ was negatively (OR 0.22, P < 0.0005), Arg 70 DQβ was positively (OR 11.01, P < 0.0001), and Gly 70 DQβ was negatively (OR 0.19, P < 0.0001) associated like other residues at 71, 74, 84, 85, 86, 89, and 90 DQβ with IDDM. Certain domains in the DQα, RFTIL (at DQα positions 52, 61, 64, 66, and 69), were present in 95% of patients compared to 69% of controls (OR 9.01, Pc < 0.0001), and DQβ domain GR (at DQβ positions 45 and 70) was present in 95% of patients and 68% of controls (OR 8.68, P < 0.0001), which correlated better than the individual amino acid residues with IDDM. A combination of the DQα and DQβ chain domains was present in 94% of patients compared to 60% of controls (OR 10.6, P < 0.001). In conclusion, domains in the DQα, DQβ, or both in the DQ molecule explain susceptibility or resistance to IDDM better than individual amino acid residues of DQA1 and DQB1.