bluuebunny/crossref_metadata_2025 huggingface dataset:
Intracerebral Evoked Potentials in Pitch Perception Reveal a Functional Asymmetry of the Human Auditory Cortex
Authors: LIÉGEOIS‐CHAUVEL CATHERINE , GIRAUD KIMBERLY , BADIER JEAN‐MICHEL , MARQUIS PATRICK , CHAUVEL PATRICK
Published: July 2010

Abstract: One acoustic feature that plays an important role in pitch perception is frequency. Studies on the processing of frequency in the human and animal brain have shown that the auditory cortex is tonotopically organized: low frequencies are represented laterally whereas high frequencies are represented medially. To date, the study of the functional organization of the human auditory cortex in the processing of frequency has been limited to the use of either scalp‐recorded auditory evoked potentials (AEPs), which have relatively poor spatial resolving power, or functional imagery techniques, which have poor temporal resolving power. The present study uses intracerebrally recorded AEPs to explore this topic in the primary and secondary auditory cortices of both hemispheres of the human brain. Recordings were carried out in 45 adult patients with drug‐resistant partial seizures. In the right hemisphere, clear spectrally organized tonotopic maps were observed with distinct separations between different frequency‐processing regions. AEPs for high frequencies were recorded medially, whereas AEPs for low frequencies were recorded laterally. In the left hemisphere, however, this tonotopic organization was less evident, with different regions involved in the processing of a range of frequencies. The hemisphere‐related difference in the processing of tonal frequency is discussed in relation to pitch perception.
The Neural Processing of Complex Sounds
Authors: GRIFFITHS TIMOTHY D.
Published: July 2010

Abstract: This paper considers the temporal processing of complex sounds relevant to musical analysis. Functional imaging studies, using positron emission tomography (PET), functional magnetic resonance imaging (fMRI), and magnetoencephalography (MEG), and the psychophysical assessment of patients with lesions allow two different approaches to this. Functional imaging allows the determination of structures normally involved in temporal analysis, while patient studies allow inference about the necessary structures for temporal analysis. Both approaches suggest a hierarchal organization in the brain corresponding to the processing of music. The features of individual notes are analyzed in the pathway up to and including the auditory cortices, while higher‐order patterns formed by those features are analyzed by distributed networks in the temporal lobe and frontal lobes distinct from the auditory cortices.
Exploring the Functional Neuroanatomy of Music Performance, Perception, and Comprehension
Authors: PARSONS LAWRENCE M.
Published: July 2010

Abstract:This chapter highlights findings by my colleagues and me in four neuroimaging and neurological studies of music performance, perception, and comprehension. These investigations elucidate the neural subsystems supporting musical pitch, melody, harmony, rhythm, tempo, meter, and duration. In a positron emission tomography (PET) study of pianists, a memorized performance of a musical piece was contrasted with that of scales to localize brain areas specifically supporting music. A second PET study assayed brain areas subserving selectively the comprehension of harmony, melody, and rhythm. Musicians sight‐read a score while detecting specific melodic, harmonic, or rhythmic errors in its heard performance. In a third PET study, musicians and nonmusicians discriminated pairs of rhythms with respect to pattern, tempo, meter, or duration. Data in these studies implicated the cerebellum in nonmotor, nonsomatic, sensory, or cognitive processing. In a fourth study, neurological patients with degeneration of the cerebellum were found to be impaired in fine discrimination of pitch. Overall, these data suggest that the neural systems underlying music are distributed throughout the left and right cerebral and cerebellar hemispheres, with different aspects of music processed by distinct neural circuits. Also discussed are key issues for interpreting the role in music of brain areas implicated in neuroimaging studies.
Musical Sound Processing in the Human Brain
Authors: TERVANIEMI MARI
Published: July 2010

Abstract: Recently, our knowledge regarding the brain's ability to represent invariant features of musical information even during the performance of a simultaneous task (unrelated to the sounds) has accumulated rapidly. Recordings of the change‐specific mismatch negativity component of event‐related brain potentials have shown that temporally and spectrally complex sounds as well as their relations are automatically processed by human auditory cortex. Furthermore, recent magnetoencephalographic and positron emission topographic investigations indicate that this processing differs between phonetic and musical sounds within and between the cerebral hemispheres. These data thus suggest that despite the focus of listeners' conscious attention, relatively complex sound phenomena can be encoded by neural mechanisms that are specialized for musical sounds.
The Sounds of Poetry Viewed as Music
Authors: LERDAHL FRED
Published: July 2010

Abstract: An extended parallel is developed between musical and prosodic structures, using the author's cognitively oriented music theory and recent work in generative phonology. For illustration, the sounds of a short poem by Robert Frost are treated entirely in musical terms. The poem is assigned a phonological stress grid and then musical grouping and meter. These structures enable a durational realization. Phonological stress also helps assign the poem's normative melodic contour. Finally, the similarities and differences in sound repetition are given hierarchical structure by means of musical prolongational theory. These formal parallels suggest a corresponding realization in brain localization and function. Evidence from the neuropsychological literature is cited in support of this view. The picture emerges that grouping, meter, duration, contour, and timbral similarity are mind/brain systems shared by music and language, whereas linguistic syntax and semantics and musical pitch relations are systems not shared by the two domains.
Clinical and Molecular Genetics of ADHD and Tourette Syndrome
Authors: COMINGS DAVID E.
Published: July 2010

Abstract:ADHD is a polygenic disorder due to the additive effect of genes affecting dopamine, norepinephrine, serotonin, GABA, and other neurotransmitters. Some of the specific loci involved are dopamine genes—DRD2, DRD4, DRD5, and thedopamine transporter; norepinephrine (NE) and epinephrine (EPI) genes—dopamineb‐hydroxylase, ADRA2A, ADRA2C, PNMT, norepinephrine transporter, MAOA, COMT; serotonin genes—TDO2, HTR1A, HTR1DA, serotonin transporter; GABA genes—GABRB3; androgen receptor and other genes. This model is consistent with all of the present knowledge about ADHD including (a) the increased frequency of ADHD in the relatives of ADHD probands, (b) the presence of a wide spectrum of comorbid behaviors (depression, anxiety, learning, conduct, oppositional‐defiant, conduct and substance abuse disorders) in ADHD probands and their relatives on both parental sides, (c) the close relationship to Tourette syndrome (TS), (d) the failure to find the genes for TS using linkage analysis, (e) the brain imaging studies showing hypometabolism of the frontal lobes, (f) the relationship between dopamine D2receptor density and regional blood flow, (g) the correlation between tics and dopamine D2receptor density in TS, (h) the motor hyperactivity of dopamine transporter and dopamine D3receptor gene knockout mice, (i) the LeMoal and Shaywitz dopamine deficiency animal models of ADHD, (j) the NE models of ADHD, (k) the failure to explain ADHD on the basis of any single neurotransmitter defect, (l) the response of ADHD to dopamine and a2‐adrenergic agonists, (m) the small percentage of the variance of specific behaviors accounted for by each gene, and numerous other aspects of ADHD. The implications of the polygenic model for the understanding, diagnosis and treatment of ADHD and TS, as well as other psychiatric disorders, are reviewed.
Adult ADHD
Authors: De QUIROS GUILLERMO B. , KINSBOURNE MARCEL
Published: July 2010

Abstract: It is customary to acquire behavior ratings of children with ADHD from parents and teachers, but comparable informants are typically not available for adults. Self‐rating is substituted. The present study presents self‐ratings of ADHD and control adults on a 43‐item scale. The groups differed significantly on all but 4 descriptors, and 3 sufficed to account for more than 50% of the variance, reflecting distractibility, impulsivity and lack of control of behavior, respectively. Discriminant analysis revealed 83% and 90% correct classification of ADHD and controls, respectively. The results support the usefulness of self‐rating in adults with ADHD and corroborate the resemblance and continuity between childhood and adult ADHD.
Attention Deficit/Hyperactivity Disorder as a Right Hemisphere Syndrome
Authors: STEFANATOS GERRY A. , WASSERSTEIN JEANETTE
Published: July 2010

Abstract:Recent studies of ADHD implicate well‐defined neuroanatomical networks and neurochemical pathways in its pathophysiological basis. Considerable attention has focused on the role of anterior and superior frontal regions and portions of the basal ganglia, including the caudate nucleus and globus pallidus. This paper reviews a growing literature suggesting differential involvement of right hemisphere mechanisms specialized for behavioral regulation and attention. Supportive data are drawn from neuropsychology, neuroanatomy, and neurochemistry. In addition, three cases are presented that illustrate the complex role of right hemisphere dysfunction in adult manifestations of ADHD. We suggest that the pleomorphic presentations of ADHD can be understood in terms of a spectrum of disturbances in overlapping neural regions, especially involving frontal and parietal areas of the right hemisphere and their connections to subcortical structures (including the striatum, limbic system and diencephalic nuclei).
Comorbidity in Adults with Attention‐Deficit/Hyperactivity Disorder
Authors: MARKS DAVID J. , NEWCORN JEFFREY H. , HALPERIN JEFFREY M.
Published: July 2010

Abstract: This paper describes the clinical manifestations of attention‐deficit/hyperactivity disorder (ADHD) in adulthood, with particular emphasis placed on issues relating to comorbidity. Prospective and retrospective studies are reviewed to evaluate the degree to which adults with ADHD exhibit clinical features that mirror their childhood counterparts with analogous comorbid psychiatric (e.g., antisocial, mood, and anxiety) and/or cognitive (i.e., learning) disorders. We also address the question of whether comorbid disorders in adults represent independent diagnostic entities and whether the presence of psychiatric comorbidity varies as a function of ADHD subtype (i.e., inattentive, hyperactive‐impulsive, combined, and residual). As is the case for ADHD in childhood, comorbidity is not uncommon among adults with ADHD. However, the reported prevalence of comorbid conditions among adults with ADHD varies considerably depending upon whether the research used a prospective or retrospective design.
Attention Deficit/Hyperactivity Disorder and Substance Abuse
Authors: SULLIVAN MARIA A. , RUDNIK‐LEVIN FRANCES
Published: July 2010

Abstract:Patterns of association between attention deficit hyperactivity disorder (ADHD) and substance‐use disorders are considered. Recent investigations have found that up to 50% of individuals with continuing ADHD symptoms have a substance‐use disorder. ADHD appears to represent an independent risk factor for substance abuse. We review clinical challenges posed by the diagnosis of ADHD in substance‐abusing populations. Nicotine dependence is also substantially more common among adults with ADHD (40%) than in the general population (26%). While several classes of substances of abuse may ameliorate various symptoms of ADHD, individuals with ADHD may also be vulnerable to substance use because of poor judgment or impulsive behavior in social settings. Evidence is reviewed from genetic studies examining the role of the dopamine D2 (DRD2) gene in the etiology of ADHD. The presence of ADHD may affect the course of adolescent substance abuse in several ways: predicting earlier age of onset, longer duration of substance‐use disorder, and progression of alcohol abuse to another drug‐use disorder. Individuals with ADHD have been noted to have a shorter interval between the onsets of drug abuse and drug dependence. Such individuals are also at greater risk for treatment failure, as their disruptive behaviors interfere with treatment access and response. Lastly, we review advances in pharmacotherapeutic agents used for treating ADHD and consider the impact of these interventions on comorbid substance‐use disorders. We suggest promising areas of focus for clinical research trials targeting the subpopulation of substance abusers with concurrent ADHD.
EEG Biofeedback Treatment of ADD
Authors: RAMIREZ PAUL MICHAEL , DESANTIS DEBORAH , OPLER LEWIS A.
Published: July 2010

Abstract: Literature searches dating back to 1968 were conducted through Psychlit and Medline services to review the scientific literature on EEG biofeedback treatment of ADD. While anecdotal and case reports cite promising evidence, methodological problems coupled with a paucity of research precludes any definitive conclusions as to the efficacy of enhanced alpha and hemisphere‐specific EEG biofeedback training. One of the more promising EEG biofeedback treatment paradigms involves theta/beta training. Studies have reported that academic, intellectual, and behavioral gains have been attained with this approach. Significant behavioral and cognitive changes have also been reported following SMR training. However, research into these treatment approaches has also been marred by methodological inadequacies and lack of sufficient follow‐up studies. A number of recommendations for future research into this treatment approach are made.
Metacognitive Remediation in Adult ADHD
Authors: WASSERSTEIN JEANETTE , LYNN ANTOINETTE
Published: July 2010

Abstract: The neuropathology underlying ADHD most consistently points to dysfunction in corticostriatal pathways—leading to inactivation, or insufficient engagement, of frontal and prefrontal lobes. By implication there may be functional disconnection between the anterior and posterior higher cortical regions, instead of a fixed dysfunction in either one. Given this premise, reconnection of these systems via cognitive interventions constitutes a logical remedial approach in the treatment of ADHD, which this paper introduces. In particular, a hybrid model is developed which proposes integration of existing psychodynamic, cognitive, and neuropsychological interventions. An organizing theme is expansion of metacognitive understanding through these procedures, powerfully exemplified via use of metaphor in clinical vignettes.
Treatment of Suicidality in Schizophrenia
Authors: Meltzer Herbert Y.
Published: July 2010

Abstract: Between 4 and 13% of people with schizophrenia commit suicide and between 25 and 50% make a suicide attempt, a reflection of the devastating toll this syndrome takes on the quality of life, that is, the subjective and objective sense of well‐being. Many risk factors for suicide in schizophrenia have been identified, the most important of which are previous suicide attempts, depression, hopelessness, substance abuse, and male gender. Insight into having a serious mental illness and less severe cognitive impairment are also associated with increased risk for suicide in schizophrenia, most likely when accompanied by feelings of hopelessness. Typical neuroleptic drugs have not been shown to reduce the risk of suicide. However, several types of evidence suggest that clozapine, an atypical antipsychotic drug, appreciably reduces the suicide attempt and completion rates in schizophrenia and schizoaffective disorder, perhaps by as much as 75‐85%. Other atypical antipsychotic drugs may have a similar effect, but direct evidence is lacking. Improvement in positive and negative symptoms, reduced extrapyramidal side effects (EPS), a direct antidepressant action, improved cognitive function, and improved compliance may contribute to reduced suicidality. The International Suicide Prevention Trial (InterSePT) is a large prospective, randomized study intended to compare the effectiveness of clozapine with that of olanzapine in reducing suicide and suicide‐related events in schizophrenic and schizoaffective patients. Some information about suicidality in the patient sample is reported here.
Assessment and Treatment of the Youthful Suicidal Patient
Authors: Brent David A.
Published: July 2010

Abstract:In this review, a framework for the assessment of suicidal risk in the adolescent is described, based on existing epidemiological and clinical studies. The assessment of risk can then be used to determine the immediate disposition, intensity of treatment, and level of care. Furthermore, the assessment of psychiatric and psychological characteristics of the individual and family, as well as the motivation and precipitants for the suicidal episode, can be used to target areas of vulnerability and thereby help the patient reduce the risk of recurrent suicidal behavior. The approach to treatment, guided by the assessment, uses a model of suicidal behavior that is based on our clinical experience and the few extant clinical trials of the treatment of suicidal behavior. Recommended interventions involve treatment of psychopathology; amelioration of cognitive distortion and difficulties with social skills, problem‐solving, and affect regulation; and family psychoeducation and intervention. Given the chronic and recurrent nature of the conditions associated with adolescent suicide attempts, a long‐term care plan involving both continuation and maintenance treatment is advocated. Further research is necessary to identify the most effective approaches to the treatment of adolescent suicide attempters.
Role of Neurotransmitters in Sensitization of Pain Responses
Authors: Willis William D.
Published: July 2010

Abstract:Injection of capsaicin into the skin results in pain, primary heat and mechanical hyperalgesia, and secondary mechanical allodynia and hyperalgesia. Sensory receptors in the area of secondary mechanical allodynia and hyperalgesia are unaffected, and so the sensory changes must be due to central actions of the initial intense nociceptive discharge that follows the capsaicin injection. Central sensitization of the responses of spinothalamic tract neurons lasts several hours, but can be prevented by spinal cord administration of non‐NMDA and NMDA glutamate receptor antagonists or NK1 substance P receptor antagonists. The long‐lasting increase in excitability of spinothalamic tract cells depends on the activation of several second messenger cascades (PKC, PKA, and NO/PKG signal transduction pathways). The excitability change also depends on activation of calcium/calmodulin‐dependent kinase II, which is consistent with the proposal that this central sensitization response is a form of long‐term potentiation.
Mediators of Inflammation and Their Interaction with Sleep
Authors: Mullington Janet M. , Hinze‐Selch Dunja , Pollmächer Thomas
Published: July 2010

Abstract: In humans, activation of the primary host defense system leads to increased or decreased NREM sleep quality, depending on the degree of early immune activation. Modest elevations of certain inflammatory cytokines are found during experimental sleep loss in humans and, in addition, relatively small elevations of cytokines are seen following commencement of pharmacological treatments with clozapine, a CNS active antipsychotic agent, known to have immunomodulatory properties. Cytokines such as TNF‐α, its soluble receptors, and IL‐6, present in the periphery and the CNS, comprise a link between peripheral immune stimulation and CNS‐mediated behaviors and experiences such as sleep, sleepiness, and fatigue. The debilitating fatigue experienced in chronic fatigue syndrome and related diseases may also be related to altered cytokine profiles.
Secondary Flows in Axial Turbines—A Review
Authors: LANGSTON L.S.
Published: July 2010

Abstract: An important problem that arises in the design and the performance of axial flow turbines is the understanding, analysis, prediction and control of secondary flows. Sieverding1 has given a review of secondary flow literature, covering up to 1985. In this paper a brief review of pre‐1985 work is given, and then a survey of open literature secondary flow investigations since the Sieverding review is presented. Most of the studies reviewed deal with plane or annular cascade flows. Tip clearance effects are not covered. The basic secondary flow picture for a turbine cascade, as measured and verified by a number of investigators is described. Recent work that shows refined secondary flow vortex structures is examined. A flow parameter based on inlet boundary layer properties used to predict horseshoe vortex swirl is presented. Work on secondary flow loss reduction, involving airfoil geometry, endwall fences and endwall contouring is briefly reviewed. A new leading edge bulb geometry that has demonstrated impressive loss reduction is considered. It is concluded that accurate routine prediction of secondary flow losses has not yet been achieved, and must await either a better turbulence model or more experiments to reveal new endwall loss production mechanisms. Lastly, loss is examined from the standpoint of entropy generation.
The Detailed Structure and Behavior of Discrete Cooling Jets in a Turbine
Authors: LEBOEUF FRANCIS , SGARZI OLIVIER
Published: July 2010

Abstract: Three‐dimensional jets are an efficient way of cooling the walls of modern high‐pressure turbines. Introduced in the external flow that develops around the turbine blade, they are associated with a set of vortex structures. The purpose of this paper is to underline the respective origin and importance of these structures, with reference to both experimental and numerical results. Steady and unsteady vortices will be analyzed. Recommendations for numerical simulations will be proposed from these observations.
Some Current Research in Rotating‐Disc Systems
Authors: OWEN J MICHAEL , WILSON MICHAEL
Published: July 2010

Abstract: Rotating‐disc systems are used to model the flow and heat transfer that occurs inside the cooling‐air systems of gas‐turbine engines. In this paper, recent computational and experimental research in three systems is discussed: rotor‐stator systems, rotating cavities with superposed flow and buoyancy‐induced flow in a rotating cavity. Discussion of the first two systems concentrates respectively on pre‐swirl systems and rotating cavities with a peripheral inflow and outflow of cooling air. Buoyancy‐induced flow in a rotating cavity is one of the most difficult problems facing computationalists and experimentalists, and there are similarities between the circulation in the Earth's atmosphere and the flow inside gas‐turbine rotors. For this case, results are presented for heat transfer in sealed annuli and in rotating cavities with an axial throughflow of cooling air.
Mass/Heat Transfer in Dimpled Two‐Pass Coolant Passages with Rotation
Authors: ZHOU FUGUO , ACHARYA SUMANTA
Published: July 2010

Abstract:Mass/heat transfer measurements are made in dimpled (hemispherical depressions) inlet and outlet coolant flow passages using the naphthalene sublimation method. The leading and trailing surfaces are dimpled, while the side walls are kept smooth. Measurements are made at a Reynolds number of 21,000 and for Rotation numbers of 0 and 0.2. The measurements indicate that dimples enhance surface mass/heat transfer. This enhancement is stronger in the inlet passage than in the outlet passage. Peak mass/heat transfer occurs immediately downstream of the dimples, while the minimum mass/heat transfer occurs in the dimple region itself. Higher mass/heat transfer is also observed along the lateral edges of the dimple. The location of the Sherwood number peaks suggest the existence of streamwise vortical structures generated from the leading and lateral edges of the dimples.
Numerical Simulation of Local Heat Transfer in Rotating Two‐Pass Square Channels
Authors: KIRILLOV A.I. , RIS V.V. , SMIRNOV E.M. , ZAITSEV D.K.
Published: July 2010

Abstract:3D turbulent air flow and heat transfer developing in a two‐pass square channel rotating in the orthogonal mode are simulated using the high‐Rek‐ε turbulence model and a recently developed modification of wall functions. Auxiliary problem for accurate definition of inlet boundary conditions formed by a long unheated upstream section is considered. Details of flow structure are presented. Local heat transfer results are compared with experimental data.
Are Changes of the Cell Membrane Structure Causally Involved in the Aging Process?
Authors: SPITELLER GERHARD
Published: July 2010

Lipid peroxidation is recognized by proliferation, wounding, and aging. The connecting link between these different events is a change in cell wall structure, which activates membrane bound phospholipases. These cleave phospholipids. Thus liberated polyunsaturated fatty acids (PUFAs) are substrates for lipoxygenases, which accept equally well linoleic acid and arachidonic acid and generate lipid hydroperoxides (LOOHs). If the amount of free PUFAs exceeds a certain amount, lipoxygenases commit suicide. The consequence is liberation of free iron ions that react with LOOHs by formation of radicals. These start a chain reaction. LOO• radicals produced in the course of this process attack proteins, nucleic acids, and also double bonds of all unsaturated compounds by epoxidation. Morever LOOHs are decomposed to toxic epoxy acids and αβγδ‐unsaturated aldehydes. Both species react with glutathione. The resulting products seem to induce apoptosis. Since the products generated by wounding or aging are formed by decomposition of LOOHs the investigation of the aging processes can be simplified by studying the physiological action of artificially generated lipid peroxidation products derived from pure PUFAs. Degradation products of LOOHs are generated by thermal decompositon of fat‐containing PUFAs. These products are induced into the body by adsorption in the intestine. They are at least partly incorporated in low density lipoproteins (LDLs). Primarily investigations seem to indicate that an overload of a diet rich in PUFAs induces only after two days an increase in oxidized LDL/PUFAs for a factor up to two in young people and for a factor of more than two in old individuals.
Dietary Restriction Initiated in Late Adulthood Can Reverse Age‐related Alterations of Protein and Protein Metabolism
Authors: GOTO SATARO , TAKAHASHI RYOYA , ARAKI SACHIKO , NAKAMOTO HIDEKO
Published: July 2010

Many reports have been published on the effects of lifelong dietary restriction (DR) on a variety of parameters such as life span, carcinogenesis, immunosenescence, memory function, and oxidative stress. There is, however, limited available information on the effect of late onset DR that might have potential application to intervene in human aging. We have investigated the effect of DR initiated late in life on protein and protein degradation. Two months of DR in 23.5‐month‐old mice significantly reduced heat‐labile altered proteins in the liver, kidney, and brain. DR reversed the age‐associated increase in the half‐life of proteins, suggesting that the dwelling time of the proteins is reduced in DR animals. In accordance with this observation, the activity of proteasome, which is suggested to be responsible for degradation of altered proteins, was found increased in the liver of rats 30 months of age subjected to 3.5 months of DR. Thus, DR can increase turnover of proteins, thereby possibly attenuating potentially harmful consequences by altered proteins. Likewise, DR in old rats reduced carbonylated proteins in liver mitochondria, although the effect was not observed in cytosolic proteins. Fasting induced apoA‐IV synthesis in the liver of young mice for efficient mobilization of stored tissue fats, while it occurred only marginally in the old. DR for 2 months from 23 months of age partially restored inducibility of this protein, suggesting the beneficial effect of DR. Taking all these findings together, it is conceivable that DR conducted in old age can be beneficial not only to retard age‐related functional decline but also to restore functional activity in young rodents. Interestingly, recent evidence that involves DNA array gene expression analysis supports the findings on the age‐related decrease in protein turnover and its reversion by late‐onset DR.
Role of Mitochondria in Oxidative Stress and Aging
Authors: LENAZ GIORGIO , BOVINA CARLA , D'AURELIO MARILENA , FATO ROMANA , FORMIGGINI GABRIELLA , GENOVA MARIA LUISA , GIULIANO GIOVANNI , PICH MILENA MERLO , PAOLUCCI UGO , CASTELLI GIOVANNA PARENTI , VENTURA BARBARA
Published: July 2010

The mitochondrial respiratory chain is a powerful source of reactive oxygen species (ROS), considered as the pathogenic agent of many diseases and of aging. We have investigated the role of Complex I in superoxide radical production and found by combined use of specific inhibitors of Complex I that the one‐electron donor in the Complex to oxygen is a redox center located prior to the sites where three different types of coenzyme Q (CoQ) competitors bind, to be identified with an Fe‐S cluster, most probably N2, or possibly an ubisemiquinone intermediate insensitive to all the above inhibitors. Short‐chain coenzyme Q analogues enhance superoxide formation, presumably by mediating electron transfer from N2 to oxygen. The clinically used CoQ analogue idebenone is particularly effective, raising doubts about its safety as a drug. The mitochondrial theory of aging considers somatic mutations of mitochondrial DNA induced by ROS as the primary cause of energy decline; in rat liver mitochondria, Complex I appears to be most affected by aging and to become strongly rate limiting for electron transfer. Mitochondrial energetics is also deranged in human platelets upon aging, as demonstrated by the decreased Pasteur effect (enhancement of lactate production by respiratory inhibitors). Cells counteract oxidative stress by antioxidants: CoQ is the only lipophilic antioxidant to be biosynthesized. Exogenous CoQ, however, protects cells from oxidative stress by conversion into its reduced antioxidant form by cellular reductases. The plasma membrane oxidoreductase and DT‐diaphorase are two such systems: likewise, they are overexpressed under oxidative stress conditions.
Can Antioxidant Diet Supplementation Protect against Age‐related Mitochondrial Damage?
Authors: MIQUEL JAIME
Published: July 2010

Harman's free radical theory of aging and our electron‐microscopic finding of an age‐related mitochondrial degeneration in the somatic tissues of the insect Drosophila melanogaster as well as in the fixed postmitotic Leydig and Sertoli cells of the mouse testis led us to propose a mitochondrial theory of aging, according to which metazoan senescence may be linked to oxygen stress‐injury to the genome and membranes of the mitochondria of somatic differentiated cells. These concepts attract a great deal of attention, since, according to recent work, the mitochondrial damage caused by reactive oxygen species (ROS) and concomitant decline in ATP synthesis seem to play a key role not only in aging, but also in the fundamental cellular process of apoptosis. Although diet supplementation with antioxidants has not been able to increase consistently the species‐characteristic maximum life span, it results in significant extension of the mean life span of laboratory animals. Moreover, diets containing high levels of antioxidants such as vitamins C and E seem able to reduce the risk of suffering age‐related immune dysfunctions and arteriosclerosis. Presently, the focus of age‐related antioxidant research is on compounds, such as deprenyl, coenzyme Q10, alpha‐lipoic acid, and the glutathione‐precursors thioproline and N‐acetylcysteine, which may be able to neutralize the ROS at their sites of production in the mitochondria. Diet supplementation with these antioxidants may protect the mitochondria against respiration‐linked oxygen stress, with preservation of the genomic and structural integrity of these energy‐producing organelles and concomitant increase in functional life span.
Oral Tolerance, Systemic Immunoregulation, and Autoimmunity
Authors: STROBEL STEPHAN
Published: July 2010

Abstract: Convincing clinical and experimental evidence suggests that the disturbance of important immunoregulatory and suppressive immunological events induced after oral (mucosal) antigen exposure (oral tolerance) may lead to allergic and autoimmune diseases. Within a variety of factors, age of the host and timing of antigen (food) administration are important characteristics in the development of food allergic disease. Induction of tolerance is seen as a Th2 skewed response, which on one side may prevent harmful mucosal immune reactions but on the other side may contribute to adverse responses in the susceptible individual. The primary mechanisms by which tolerance may be mediated include deletion, anergy, suppression, “ignorance,” and apoptosis. Cell‐mediated delayed hypersensitivity reactions (Th1), which are implicated in the development of autoimmune and gastrointestinal diseases, are particularly well suppressed. Regulatory events after mucosal exposure of antigen are not well characterized and remain controversial. The balance between tolerance (suppression) and sensitization (priming) is dependent on several factors, such as: (a) genetic background, (b) nature and dose of antigen, (c) frequency of administration, (d) age at first antigen exposure, (e) immunological status of the host, (f) antigen transmission via breast milk, and others. Overall there is evidence in rodents that multiple low‐dose feeds are more likely to induce regulatory cytokines (e.g., TGF‐β, IL‐10, IL‐4) in part secreted by CD4+CD25+ T regulatory cells. Despite the powerful suppressive effects of oral autoantigen exposure observed in experimental models of autoimmune diseases (including bystander suppression), their translation into clinical trials of autoimmune diseases has not yet yielded the expected beneficial results.
Antidiabetogenic Effect of Mycophenolate Mofetil Is Associated with Down‐Regulation of Adhesive Interactions and Autoreactive Cell Activation
Authors: MAKSIMOVIC D. , STOJKOVIC M. MOSTARICA , STOSIC‐GRUJICIC S.
Published: July 2010

Abstract: We have investigated the immunomodulatory potential of mycophenolate mofetil (MMF) on the development of autoimmune diabetes induced by multiple low doses of streptozotocin (MLD‐SZ) in genetically susceptible DA rats. Administration of 25 mg/kg MMF continuously during the 7 weeks of MLD‐SZ treatment, or as a 10‐day treatment starting together with MLD‐SZ (early treatment), or 5 days after the last dose of SZ (late treatment) significantly suppressed the development of hyperglycemia. Ex vivo analyses performed on day 10 after diabetes induction showed that MMF treatment down‐regulates adhesive interactions and proliferation of autoreactive spleen cells. Similar effects were observed in vitro when MLD‐SZ‐derived splenocytes were cultured with an active metabolite of MMF, mycophenolic acid (MPA). These results suggest that the antidiabetogenic effect of MMF involves inhibition of the expansion and migration of autoreactive cells.
Autoantibodies to Tissue Transglutaminase in Patients from Eastern India with Malnutrition‐Modulated Diabetes Mellitus, Insulin‐Dependent Diabetes Mellitus, and Non‐Insulin‐Dependent Diabetes Mellitus
Authors: KANUNGO A. , SHTAUVERE‐BRAMEUS A. , SAMAL K. C. , SANJEEVI C. B.
Published: July 2010

Abstract: Antibodies to tyrosine phosphatase (IA2‐Ab) and glutamate decarboxylase 65 (GAD65‐Ab) are major markers for IDDM in Caucasians. TTG‐Ab is specific for celiac disease. Celiac disease is caused by ingestion of the protein gliadin, a component of wheat gluten, and usually resolves on its withdrawal. Ten to twenty percent of celiac disease patients also have IDDM. The aim of the study was to estimate the prevalence of TTG‐Ab in MMDM (n= 71), IDDM (n= 74), and NIDDM (n= 216) and 122 controls from Cuttack in eastern India. MMDM patients are typically young at onset with low body mass index, require insulin for glycemic control, have insulin resistance, and do not develop ketosis on withdrawal of insulin. TTG‐Ab was evaluated by radioimmunoassay using in vitro translated recombinant human 35S‐TTG. In controls, TTG‐Ab was present in 3/122 (2%); in MMDM, TTG‐Ab was present in 14/71 (20%); 11/74 (15%) IDDM (P < 0.05 vs. controls) and 23/216 (11%) NIDDM (P < 0.05 vs. controls) were also positive for TTG‐Ab. We conclude that MMDM, IDDM, and NIDDM patients from Cuttack have a significantly high proportion of TTG‐Ab compared to healthy controls. The highest significance is seen with MMDM patients. It is important to note that subclinical celiac disease must be considered in the differential diagnosis of MMDM.
Newborn Screening for High‐Risk Human Leukocyte Antigen Markers Associated with Insulin‐Dependent Diabetes Mellitus
Authors: BERZINA L. , SHTAUVERE‐BRAMEUS A. , LUDVIGSSON J. , SANJEEVI C. B.
Published: July 2010

Abstract: Type 1 (insulin‐dependent) diabetes mellitus is associated with specific high‐risk HLA DQ and DR haplotypes and islet cell antibodies. IDDM susceptibility in Caucasians is more strongly associated with DQ2/DQ8 (DQA1*0501‐DQB1*0201/DQA1*0301‐DQB1*0302) and DQ6 (B1*0604) than with DRB1*03/DRB1*04, while a single copy of DQ6 (B1*0602) gives sufficient protection against type 1 diabetes. As a part of the ABIS (All Babies in Southeast Sweden) study we have done typing of DQA1, DQB1, and DRB1 by polymerase chain reaction (PCR) amplification of the second exon of the genes, manually dot‐blotting onto nylon membranes synthetic sequence‐specific oligonucleotide (SSO) probes, 3′ end‐labeling with 32P‐dCTP, and hybridization followed by stringency washes and autoradiography using the SSO probe. Among 3756 newborns born in southeast Sweden we have found the high‐risk genotype DQ2/DR3‐DO8/DR4 to be present in 1%, haplotype DQ8/DR4 in 7.8%, and haplotype DQ2/DR3 in 9.6%. DQ2/DR3 or DQ8/DR4 was carried by 16.4% of newborns; the low‐risk DQ6 molecule was carried by newborns as follows: DQ2/DR3‐DQ6/DR15, 1.3%; DQ8/DR4‐DQ6/DR15, 1.3%; and DQ6/DR15, 9.4%. We conclude from our results that the high incidence of IDDM in Sweden is at least in part due to increased prevalence of high‐risk HLA haplotypes compared to protective haplotypes (20% vs. 13%) in the general population.
Contribution of MIC‐A Polymorphism to Type 1 Diabetes Mellitus in Basques
Authors: BILBAO J. RAMÓN , MARTÍN‐PAGOLA AINHOA , CALVO BEGOÑA , PEREZ DE NANCLARES GUIOMAR , GEPV‐N  , CASTAÑO LUIS
Published: July 2010

Abstract: The maximum genetic susceptibility to type 1 diabetes (T1DM) in Basques is conferred by extended HLA haplotype F1C30‐DR3‐DQ2‐DPB1*0202. Due to the strong linkage disequilibrium within the haplotype, it is difficult to determine which individual allele shows the strongest association with T1DM. Recent studies of the MIC‐A gene have shown an HLA‐independent association of allele A5 with T1DM and A5.1 with Addison's disease. In order to test for association of the MIC‐A exon 5 polymorphism with T1DM and to further characterize risk and protection haplotypes in Basques, we typed 70 Basque families with T1DM for MIC‐A exon 5 polymorphism using fluorescent PCR and electrophoresis on an ABI sequencing machine. When analyzed individually, allele A4 was associated with disease [OR = 2.93 (1.58‐5.5)], while the presence of A9 conferred protection from T1DM [OR = 0.27 (0.08‐0.74)]. In the context of HLA haplotypes, allele A4 was found to be associated to the F1C30‐DR3‐DQ2‐DPB*0202 risk haplotype, both for T1DM and AFBAC alleles (Pc= 0.0003). Allele A5.1 was strongly associated with protective haplotype SC31‐DRB1*1501‐DQB1*0602, present only in AFBAC alleles, but also with risk haplotype SC01‐DR3‐DQ2. In conclusion, polymorphisms in exon 5 of the MIC‐A gene are associated with genetic susceptibility/protection to T1DM, but in the context of susceptibility HLA haplotypes. Nevertheless, the protective effect of A9 allele seems independent from HLA, since it does not appear to be associated with any particular extended haplotype.
IgM, IgG, and IgA Response to Enterobacteria in Patients with Ankylosing Spondylitis in Southern India
Authors: MADHAVAN RADHA , PORKODI R. , RAJENDRAN C. PANCHAPAKESA , CHANDRASEKARAN A. N. , UMADEVI K. R. , ALAMELU RAJA
Published: July 2010

Abstract: IgM, IgA, and IgG response to three different antigenic preparations—lipopolysaccharide (LPS), culture supernatant proteins, and outer membrane protein (OMP) of Klebsiella pneumoniae, Escherichia coli and Salmonella typhi—were measured in the sera of 20 patients with primary ankylosing spondylitis (AS), 10 with enterogenic reactive arthritis (ReA) (disease controls), and 15 voluntary blood donors (healthy controls) by ELISA using biotinylated anti‐human immunoglobulins M, G, and A. Serum immunoglobulin levels were measured by immunoturbidimetric assay in 20 AS patients, 20 patients with enterogenic reactive arthritis (ReA), 20 with ulcerative colitis (UC), and 20 voluntary blood donors. Student's t‐test was applied for comparison. Compared to healthy controls, AS patients showed significantly elevated IgG response against culture supernatant proteins of all the three organisms (P <0.05), LPS of E. coli (P < 0.05) and Klebsiella (P < 0.005), as well as OMP only of Klebsiella pneumoniae. This was reflected as significantly elevated IgG level in AS compared to controls (P < 0.05 vs. ReA and 0.005 vs. UC and healthy controls). This suggests the involvement of outer membrane proteins of Klebsiella pneumoniae in the pathogenic mechanism of ankylosing spondylitis.
Cardiovascular Function in Patients with Insulin‐Dependent Diabetes Mellitus
Authors: RAJAN S. K. , GOKHALE SHEFALI M.
Published: July 2010

Abstract: This study used noninvasive methods to assess disturbance in cardiovascular function in insulin‐dependent diabetes mellitus (IDDM) patients. Cardiovascular function and the autonomic nervous system of 38 IDDM patients were assessed, and the presence or absence of left ventricular dysfunction was determined. Fifty‐six percent of the patients were found to have autonomic neuropathy. Twelve percent had left ventricular diastolic dysfunction; none had left ventricular systolic dysfunction. Heart disease in IDDM patients was found to constitute a separate entity, termed diabetic cardiomyopathy. All IDDM patients with left ventricular diastolic dysfunction had evidence of autonomic neuropathy. However, there was no correlation with left ventricular systolic dysfunction. Also, there was no correlation between left ventricular dysfunction and microvascular complications of diabetes mellitus.
Geometrical Factors in Conductance Through Molecular Films
Authors: KORNILOVITCH P. E. , BRATKOVSKY A. M.
Published: July 2010

Abstract: We have studied the conductance of molecular films as a function of orientation of the molecules in the film with respect to electrodes. Depending on the angle between the axis of the molecules and the normal to the electrode, the conductance may change by more than an order of magnitude. This is a consequence of the strong directional character of p orbitals that determine the conductance through the conjugated molecules. We illustrate this general result on an exactly solvable model and also present the calculations for two different experimentally studied molecular films sandwiched between gold electrodes.
Breast Cancer Registry in Palermo and Its Province
Authors: TRAINA A. , CUSIMANO R. , LIQUORI M. , FERRIGNO V. , GUTTADAURO A. , RAVAZZOLO B. , GIAMMANCO A. M. , CASTAGNETTA L.
Published: July 2010

Abstract: The incidence of breast cancer in the city of Palermo and its Province was investigated. The cancer rate was higher in the city of Palermo (100.8/100,000/year), a great southern urban area, than in the 81 municipalities of the Province (79.2/100,000/year). Rates were also compared with those in other geographic areas of Italy, showing a smaller than expected negative north‐south gradient in incidence, especially in the young age group, as shown by the cumulative risk observed in the 0‐54‐year‐old group. These findings confirm the role of recent life style changes in the cancer risk distribution.
Ligand Binding and Cytochemical Analysis of Estrogen and Progesterone Receptors in Relation to Follow‐Up in Patients with Breast Cancer
Authors: CASTAGNETTA L. , TRAINA A. , AGOSTARA B. , MIELE M. , CAMPISI I. , CALABRÒ M. , MARASÀ L. , CARRUBA G.
Published: July 2010

Abstract: Soluble and nuclear estrogen receptor (ER) content was measured by ligand binding assay, and estrogen and progesterone receptors by immunohistochemical assays (ER‐ICA and PR‐ICA) in 214 patients with breast cancer recruited at the “M. Ascoli” Cancer Hospital Centre in Palermo, Sicily, to assess the discriminant and predictive value of these parameters. On follow‐up, data from both ER‐ICA and PR‐ICA showed a statistically significant difference, PR‐positive patients having longer disease‐free (DSF) and overall (OS) survival than PR‐negative ones. Conversely, ER status did not correlate significantly with both DFS (P = 0.6) and OS (P = 0.2). In particular, PR‐positive patients had 59 ± 18 months DFS and 67 ± 12 months OS, compared to 51 ± 22 months DFS and 57 ± 17 months OS of PR‐negative cases. The present evidence implies that a PR‐negative status identifies breast cancer patients with early relapse, as also suggested by previous studies. It also agrees with the results of ligand binding assay of ER, where ER status is a good discriminant and predictor of response to endocrine treatment, but is unable to anticipate early relapse in breast cancer patients. Evidence that PR status is a statistically significant prognostic indicator deserves further study to ascertain whether or not PR should be regarded as an ER‐dependent parameter or be related to other biological variables such as growth factor (e.g., EGF), oncogene (e.g., Her2/Neu), or tumor suppressor gene (e.g., p53) products.