bluuebunny/crossref_metadata_2025 huggingface dataset:
Regulation of monocyte chemokine and MMP-9 secretion by proinflammatory cytokines in tuberculous osteomyelitis
Authors: Wright Kathleen M , Friedland Jon S
Published: March 2004

Tuberculous osteomyelitis causes bony destruction as a result of interactions among the pathogen, resident bone cells, and influxing leukocytes. Recruitment of monocytes and T cells is critical for antimycobacterial granuloma formation, but little is known about mechanisms regulating this in bone. We investigated the role of tumor necrosis factor α (TNF-α) and interleukin (IL)-1, key cytokines in granuloma formation, in networks involving human osteoblasts and monocytes. Experiments focused on CXC ligand (CXCL)8, CCL2, and matrix metalloproteinase (MMP)-9, human monocyte-derived mediators involved in control of leukocyte influx. TNF-α but not IL-1 has a key role stimulating CXCL8 secretion in Mycobacterium tuberculosis-infected human osteoblast MG-63 cells. Conditioned medium from M. tuberculosis-infected osteoblasts (COBTB) drives CXCL8 and some CCL2 gene expression and secretion from primary human monocytes. IL-1 receptor antagonist and to a lesser extent anti-TNF-α inhibited COBTB-induced CXCL8 secretion (P<0.01) but did not affect gene expression. IL-1 blockade had a comparatively lesser effect on CCL2 secretion, whereas anti-TNF decreased CCL2 concentrations from 7840 ± 140 to 360 ± 80 pg/ml/4 × 105 cells. Neither proinflammatory mediator affects MMP-9 secretion from COBTB-stimulated human monocytes. In summary, in a paracrine network, M. tuberculosis-infected osteoblasts drive high-level CXCL8, comparatively less CCL2, but do not alter MMP-9 secretion from uninfected human monocytes. This network is, in part, regulated by IL-1 and TNF-α.
Endothelial monocyte-activating polypeptide-II (EMAP-II): a novel inducer of lymphocyte apoptosis
Authors: Murray J C , Heng Y M , Symonds P , Rice K , Ward W , Huggins M , Todd I , Robins R A
Published: March 2004

The novel, proinflammatory cytokine endothelial monocyte-activating polypeptide-II (EMAP-II) was first found in tumor cell supernatants. EMAP-II is closely related or identical to the p43 auxiliary protein of the multisynthase complex, which is involved in protein synthesis. In vitro, EMAP-II induces procoagulant activity, increased expression of E- and P-selectins and tumor necrosis factor receptor-1, and ultimately, programmed cell death (apoptosis) in cultured endothelial cells. EMAP-II is also chemotactic for monocytes and neutrophils. However, the role of the p43/EMAP-II cytokine form in tumors is not understood. We hypothesized an immune-regulatory role within neoplastic tissues and investigated its effects on lymphocytes. EMAP-II causes a dose-dependent inhibition of proliferation and apoptosis in Jurkat T cells and mitogen-activated peripheral blood mononuclear cells. Coculture with DLD-1 colorectal cancer cells or media conditioned by these cells induces apoptosis in Jurkat cells, which is partially reversed by antibodies against EMAP-II. Our data suggest that EMAP-II constitutes a component of a novel, immunosuppressive pathway in solid tumors, which is not normally expressed outside the cell but in tumors, may be subject to abnormal processing and released from tumor cells.
The roles of transcription factors in B lymphocyte commitment, development, and transformation
Authors: Smith Emma , Sigvardsson Mikael
Published: March 2004

Studies of normal blood cell development and malignant transformation of hematopoietic cells have shown that the correctly regulated expression of stage- and lineage-specific genes is a key issue in hematopoiesis. Experiments in transgenic mice have defined a number of transcription factors such as SCL/Tal, core-binding factor/acute myeloid leukemia, and c-myb, all crucial for the establishment of definitive hematopoiesis and development of all blood cell lineages. Other regulators such as IKAROS, E47/E2A, early B cell factor, Sox-4, and B cell-specific activator protein (Pax-5) appear crucial, more or less selectively, for B lymphopoiesis, allowing for detailed analysis of the development of this lineage. In addition, several of these transcription factors are found translocated in human tumors, often resulting in aberrant gene expression or production of modified proteins. This article concerns the role of transcription factors in B lymphoid development with special focus on lineage initiation and commitment events but also to some extent on the roles of transcription factors in human B lymphoid malignancies.
Interleukin-15 delays human neutrophil apoptosis by intracellular events and not via extracellular factors: role of Mcl-1 and decreased activity of caspase-3 and caspase-8
Authors: Bouchard Amélie , Ratthé Claude , Girard Denis
Published: March 2004

Interleukin-15 (IL-15) induces the de novo protein synthesis of intracellular polypeptides and delays neutrophil apoptosis by a mechanism that is still unclear. Herein, we investigated the potential antiapoptotic role of newly synthesized proteins released into the external milieu in IL-15-induced neutrophils. We found that IL-15 induces the de novo synthesis of an ∼23-kDa protein, representing the predominant protein detected in the milieu, and identified it as IL-1 receptor antagonist (IL-1Ra) by Western blot and immunoprecipitation. We quantified IL-1Ra, IL-1α, and IL-1β concentrations by enzyme-linked immunosorbent assay in intracellular and extracellular fractions from IL-15-induced neutrophils and found that IL-15 does not increase IL-1α or IL-1β production but induces IL-1Ra release. Also, we demonstrated that IL-1Ra does not modulate apoptosis, een at a concentration 250 times greater than that measured in the external milieu. In contrast to granulocyte macrophage-colony stimulating factor, the supernatant harvested from IL-15-induced neutrophils was devoid of antiapoptotic activity. Addition of cycloheximide demonstrates that IL-15 delays apoptosis via de novo synthesis of intracellular proteins and that it increases myeloid cell differentiation factor-1 stability. We demonstrated also that IL-15 decreases the activity of caspase-3 and caspase-8, resulting in an inhibition of vimentin cleavage. Our results indicate that IL-15 can activate an anti-inflammatory loop, based on its ability to induce the synthesis of IL-1Ra by neutrophils. We conclude that IL-15 delays human neutrophil apoptosis by intracellular events and not via extracellular factors.
Tryptophan consumption and indoleamines production by peritoneal cavity macrophages
Authors: Martins E , Ferreira A C F , Skorupa A L , Afeche S C , Cipolla-Neto J , Costa Rosa L F B P
Published: March 2004

Melatonin has been shown to regulate several immune functions, and some authors showed that leukocytes are also able to produce the indolamine. In fact, it seems to take part in some immunoregulatory axis, including that related to interferon (IFN) production. So, we evaluated the rate of tryptophan consumption and melatonin and serotonin production in peritoneal cavity-isolated macrophages and the effect of IFN-α and -γ, lipopolysaccharide (LPS), and phorbol myristate acetate (PMA) on such parameters. Our results indicate that macrophages obtained from the peritoneal cavity of normal rats when incubated with tryptophan show an increase in arylalkylamine N-acetyltransferase activity that corresponds to an increased melatonin production, as determined in the incubation medium. This process is regulated by IFN-α and -γ, PMA, LPS, and the serum from tumor-bearing rats, opening the possibility of speculation about different immunoregulatory loops acting through the balance of melatonin/serotonin production by such cells.
Assessment of left ventricular cardiac output by arterial thermodilution technique via a left atrial catheter in a patient on a right ventricular assist device
Authors: Wiesenack Christoph , Prasser Christopher , Liebold Andreas , Schmid Franz X
Published: March 2004

Following heart transplantation (HTx) in a 49-year old male, the patient’s haemodynamic situation deteriorated in the early postoperative period despite increasing doses of catecholamines. When transoesophageal echocardiography (TEE) showed a dilated right ventricle, but adequate left ventricular (LV) function, a right ventricular assist device (RVAD) was implanted to support the right ventricle of the failing graft. Evaluation of the resulting cardiac output (CO) of the left ventricle and, thus, assessment of the remaining right ventricular function in patients supported by a RVAD is of great clinical interest. In this situation, continuous measurement of LV function, enabling assessment of the remaining right ventricular function, can be performed by pulse contour analysis following initial calibration of the system by arterial thermodilution CO measurement via a left atrial catheter.
Changes in metabolism and blood flow in peripheral tissue (skeletal muscle) during cardiac surgery with cardiopulmonary bypass: the biochemical microdialysis study
Authors: Mand’ák J , Živný P , Lonský V , Palička V , Kakrdová D , Maršíková M , Kuneš P , Kubíček J
Published: March 2004

The aim of this study was to monitor the metabolism and blood flow in the interstitium of the skeletal muscle during cardiac surgery with cardiopulmonary bypass (CPB) and in the early postoperative period by means of microdialysis and to compare metabolic changes during CPB at normothermia (NT) and hypothermia (HT).

Surgical revascularization using CPB was performed in 50 patients, 25 patients (group HT) were operated using hypothermic CPB, 25 (group NT) using normothermic CPB. Interstitial microdialysis was performed by two CMA 60 probes (CMA Microdialysis AB, Solna, Sweden) inserted into the patient’s deltoid muscle. Constituents analysed in the obtained dialysates, collected at intervals, were glucose, urea, glycerol and lactate. Tissue blood flow was monitored by dynamic microdialysis with gentamicin as a marker.

In both groups, NT versus HT, similar dynamics of concentrations were found. Low initial concentrations were followed by gradual increases during CPB and in the following phase of the operation. Concentrations were higher in the NT group. Immediately after the operation, the decrease in values continued, with a gradual increase in the succeeding postoperative period in both groups. Similar dynamic changes in the lactate concentration were found in both groups. The gentamicin concentrations were lower in the NT group (versus the HT group).

The results showed dynamic changes in the interstitial concentrations of glucose, urea, glycerol and lactate, which depend on the phase of the surgery in the CPB and early postoperative phase in the both groups of patients. Higher tissue perfusion of the skeletal muscle was noted in those patients operated on in normothermia. The dynamics of the concentration changes of these substances in the interstitium of the skeletal muscle has been proven to be caused by both the metabolic activity of the tissue and by the blood flow through the interstitium of the muscle.
Selection of optimal quantity of hydroxyethyl starch in the cardiopulmonary bypass prime
Authors: Ali Maha A , Saleh Mohamed
Published: March 2004

Ringer’s solution prime reduces colloid osmotic pressure and causes edema during cardiopulmonary bypass, while hydroxyethyl starch (HES) can be used to attenuate this effect. Fifty patients were classified into five equal groups: Group I (preoperative patients) is the control group and the other four groups (II, III, IV, V) received different volume ratios of Ringer’s solution to HES (1:0, 2:1, 1:2, 0:1, respectively). This study was aimed at evaluating the optimal quantity of HES regarding body fluids expansion, ventilation and recovery time, blood rheologic properties, clotting parameters, platelet counts, blood loss and red blood cell membrane properties. The results showed a reduction in interstitial fluid (ISF) expansion, changes in blood rheologic properties with the increase in HES quantity and shorter ventilation and recovery times in Groups IV and V. We concluded that the optimal HES quantity in the prime is two thirds, which insures an 85% reduction of ISF relative to Group II, shorter ventilation and recovery times and avoidance of the hazards of high levels of HES.
Inhibition of neutrophil activity in cardiac surgery with cardiopulmonary bypass: a novel strategy with the leukocyte inhibition module
Authors: Moreno José Bitu , Margraf Stefan , Schuller Alina M , Simon A , Moritz A , Scholz M
Published: March 2004

Recently, we showed that the arterial in-line application of the leukocyte inhibition module (LIM) within the heart-lung machine limits overshooting leukocyte activity and cardiac tissue damage. Moreover, significantly better cardiac function was found in an experimental animal model when LIM was used. In the meantime, the first promising clinical data exist. LIM has to be regarded as an essential tool in extracorporeal circulation, in the future, to improve postoperative clinical outcome and to reduce costs. This review summarizes the biological background of LIM and the current experience obtained in experimental models and clinical studies.
The support taken through walking aids during hemiplegic gait
Authors: Tyson S F
Published: March 2004

Objective: To assess the effect of different aids on the amount of support hemiplegic subjects took from them. The relationship between the amount of support, severity of hemiplegia and walking ability were also assessed.

Design: Hemiplegic subjects' gait and the amount of support they took from the aid were measured as they walked with a normal height stick, a high stick and a tripod.

Subjects: Fifteen subjects with a hemiplegia of more than three months' duration who could walk independently were recruited.

Outcome measures: Velocity, the gross function section of the Rivermead Motor Assessment, percentage bodyweight taken through the aid, the aid contact time, the placement of the aid, and the lateral shift of the pelvis when weight bearing were assessed.

Results: No differences in the amount of support or walking ability were found with the different aids. There was a significant relationship between severity of hemiplegia and the percentage of bodyweight taken through the aid ( r = –0.67), between aid contact time and severity of hemiplegia (–0.53) and between aid contact time and walking ability (–0.53). No relationship between walking ability and other measures of the amount of support was found.

Conclusions: Different types of aid did not influence the amount of support taken by hemiplegic subjects. These results contradict the beliefs of many neurological physiotherapists in Britain and the clinical implications are discussed.
Electrical stimulation of human tibialis anterior: (A) contractile properties are stable over a range of submaximal voltages; (B) high- and low-frequency fatigue are inducible and reliably assessable at submaximal voltages
Authors: Hanchard Nca , Williamson M , Caley R W , Cooper R G
Published: March 2004

Objectives: To investigate the validity and reliability of submaximal voltage stimulation for assessing the ‘fresh’ contractile properties of human tibialis anterior muscle (TA) and the efficacy of such stimulation in inducing and assessing high- and low-frequency fatigue.

Interventions: (A) Contractile properties of fresh TA were assessed in six normal volunteers using multifrequency stimulation trains (comprising 2 seconds at each of 10, 20 and 50 Hz, arranged contiguously) over a range of submaximal voltages. (B) On three separate occasions, fatigue was induced in the TA of 10 normal volunteers by means of a 3-minute unbroken sequence of the described multifrequency stimulation trains, delivered at a ‘standardized’ submaximal voltage. This fatiguing protocol was preceded by discrete multifrequency stimulation trains, at the same standardized voltage, but followed by discrete multifrequency trains delivered over a range of submaximal voltages (which included the standardized voltage).

Outcome measures: In experiment A the 10:50 Hz and 20:50 Hz force ratios were analysed for between-voltages variability using coefficients of variation (CVs), and for trends using Friedman tests and post-hoc Wilcoxon tests. In experiment B low-frequency fatigue was detected using 10:50 Hz and 20:50 Hz force ratios derived from the discrete multifrequency trains. High-frequency fatigue was calculated from the decline in high-frequency force which occurred during the fatiguing protocol itself. Each parameter was assessed for between-days repeatability using CVs.

Results: In experiment A the ‘fresh’ 10:50 Hz force ratio was clearly unreliable at voltages which generated <10% of maximal voluntary contractile force (MVC) (CV ≤29.7%), but was reasonably reliable at voltages which generated 20–30% of MVC (CV ≤11.5%; p = 0.847). The ‘fresh’ 20:50 Hz force ratio was, in contrast, extremely reliable throughout the tested voltage range (CV ≤5.8%; p = 0.636) in fresh muscle. In experiment B paired t-tests indicated that the fatiguing protocol induced significant high-frequency fatigue ( p <0.0037) and low-frequency fatigue ( p <0.0008 for ‘fresh’ versus ‘fatigued’ 10:50 Hz force ratio; p <0.0001 for ‘fresh’ versus ‘fatigued’ 20:50 Hz force ratio). In muscle thus fatigued, the 20:50 Hz force ratio was extremely reliable in the 20–33% of MVC range (CV ≤7.3%; p = 0.847). Between-days repeatability was poor for the 10:50 Hz force ratio in both fresh and fatigued muscle (CV ≤23.8 and 44.4% respectively), but was highly acceptable for both voluntary and stimulated fatigue indices and for the 20:50 Hz force ratio, the latter in both fresh and fatigued muscle.

Conclusions: These results confirm the validity and reliability of submaximal voltages in assessing contractile properties (including low-frequency fatiguability) and inducing fatigue of human TA.
Relationship between impairments, disability and handicap in reflex sympathetic dystrophy patients: a long-term follow-up study
Authors: Geertzen Jan Hb , Dijkstra Pieter U , Sonderen Eric Lp van , Groothoff Johan W , Duis Henk Jan ten , Eisma Willem H
Published: March 2004

Objective: To determine the relationship between impairments, disability and handicap in reflex sympathetic dystrophy (RSD) patients.

Design: A long-term follow-up study of upper extremity RSD patients.

Setting: A university hospital.

Subjects: Sixty-five patients, 3–9 years (mean interval 5.5 years) after RSD of the upper extremity (mean age 50.2 years).

Main outcome measures: Impairments: range of motion, moving two point discrimination, muscle strength of the hand and pain were measured. Disability was assessed with the Groningen Activity Restriction Scale (GARS) and handicap was assessed with three subscales (social functioning, role limitations due to physical problems and role limitations due to emotional problems) of the RAND-36.

Results: After RSD of the upper extremity, 62% of the patients are limited in activities of daily living (ADL) and/or instrumental ADL (IADL). Pain and restrictions in forward flexion of the shoulder, thumb opposition and grip strength are the most important impairments limiting ADL and IADL. Patients with limitations in ADL and IADL are significantly more handicapped than patients without limitations. Pain is the most important factor contributing to handicap.

Conclusion: The relationship between impairments and disability and between disability and handicap in RSD patients is weak to moderate. Pain is the most important factor leading to disability and handicap.
Categories, Dimensions, and the Mental Health of Children and Adolescents
Authors: RUTTER MICHAEL
Published: March 2004

Abstract: Concepts of mental disorder, and of the causal processes leading to disorder, have undergone radical changes over recent decades. Genetic findings, for example, have shown that (1) many conditions develop on the basis of a dimensional genetic liability; (2) the boundaries of some conditions extend much more broadly than indicated by the traditional diagnostic categories; and (3) there is substantial overlap between conditions previously thought to be distinctively different. On the other hand, genetic findings have also provided support for the validity of some diagnostic distinctions. Early molecular genetic research was conceptualized on the basis of the expectation that there would be disease‐specific genes “for” schizophrenia, bipolar disorder, and the like. It has become apparent that, at best, this constitutes a misleading oversimplification. Almost all mental disorders (in childhood and adult life) have a multifactorial origin, and the genes are likely to operate through a range of direct and indirect routes. Gene‐environment correlations and interactions are important, and there is a biological substrate for individual differences in responses to psychosocial stress and adversity, as well as for the effects of such stress and adversity on the organism. The empirical basis for these changes in concepts is reviewed, and the implications for clinical science and practice are considered.
Using an Animal Model to Assess the Long‐Term Behavioral and Biological Consequences of Adolescent Abuse and Exposure to Alcohol
Authors: FERRIS CRAIG F.
Published: March 2004

Abstract: During adolescence or adulthood, male hamster siblings were divided into control and experimental groups and exposed to periods of either mild or traumatic stress outside their individual nests. Mild stress is the simple exposure to a novel environment while the traumatic stressor is repeated daily subjugation by a dominant hamster. Over adolescence and adulthood, animals had free access to alcohol. The behavior and neuroendocrinology were assessed over these developmental periods in response to these environmental conditions. As adults, animals with a history of traumatic stress in adolescence showed inappropriate and excessive aggressive behavior. Their aggression was context dependent. In the presence of equal size hamsters, they showed little aggression; however, they were excessively aggressive toward smaller, younger animals. Testosterone levels and reproductive behavior were normal after adolescent subjugation; however, release of cortisol during agonistic encounters was suppressed. In comparison, hamsters exposed to chronic social subjugation as adults had low plasma testosterone, reduced reproductive behavior, and exaggerated cortisol release during agonistic encounters. Self‐ingestion of alcohol during adolescence enhanced testosterone release around the peripubertal period but reduced plasma testosterone levels in adulthood. Exposure to alcohol as adolescents enhanced aggression in adulthood. These data demonstrate a pronounced difference in behavior and neuroendocrinology between adolescent and adult hamsters in their response to traumatic stress.
The Amygdala and Development of the Social Brain
Authors: SKUSE DAVID , MORRIS JOHN , LAWRENCE KATE
Published: March 2004

Abstract: The amygdala comprises part of an extended network of neural circuits that are critically involved in the processing of socially salient stimuli. Such stimuli may be explicitly social, such as facial expressions, or they may be only tangentially social, such as abstract shapes moving with apparent intention relative to one another. The coordinated interplay between neural activity in the amygdala and other brain regions, especially the medial prefrontal cortex, the occipitofrontal cortex, the fusiform gyrus, and the superior temporal sulcus, allows us to develop social responses and to engage in social behaviors appropriate to our species. The harmonious functioning of this integrated social cognitive network may be disrupted by congenital or acquired lesions, by genetic anomalies, and by exceptional early experiences. Each form of disruption is associated with a slightly different outcome, dependent on the timing of the experience, the location of the lesion, or the nature of the genetic anomaly. Studies in both humans and primates concur; the dysregulation of basic emotions, especially the processing of fear and anger, is an almost invariable consequence of such disruption. These, in turn, have direct or indirect consequences for social behavior.
Impulsivity, Emotion Regulation, and Developmental Psychopathology: Specificity Versus Generality of Linkages
Authors: Hinshaw Stephen P.
Published: March 2004

Abstract: Impulsivity, closely related to the construct of response (dis)inhibition, is central to conceptions of both attention‐deficit/hyperactivity (ADHD) and aggressive‐spectrum or disruptive behavior disorders. The multifaceted nature of inhibitory deficits requires careful specification in any explanatory accounts of psychopathology. A host of brain regions and neural interconnections are involved in response inhibition; neural models are likely to be complex at the levels of neurotransmitter systems and white‐matter tracts. Despite the substantial heritability of ADHD and the substantial continuity of early‐onset forms of aggression, developmental processes (including gene‐environment correlations and interactions) and transactional models are crucial to the unfolding of regulated versus dysregulated behavioral outcomes. Thus, stressful prenatal and childhood environments must be investigated with as much precision as genetic loci and neural pathways. Differentiating executive inhibition (believed to be largely dopaminergic and frontal/frontal‐striatal in nature) from motivational inhibition (believed to be largely noradrenergic/serotonergic and limbic in nature) is necessary to distinguish subtypes of youth with attentional and aggressive problems, and to differentiate key etiologic processes. Indeed, the executive function deficits in children with ADHD appear to independent of their emotion dysregulation, which is specific to an aggressive subgroup. Sex differences in response inhibition and sex differences in its linkages to psychopathology are relatively unexplored. For progress in subsequent research to occur, the following are required: precision in measurement at both biological and behavioral levels; contrasts with clinical comparison samples and comorbid groups (as well as normal control samples); prospective longitudinal investigations; and attention to both developmental processes and contextual variables, including stressful life events, socialization practices, and cultural parameters.
The Development of Affect Regulation: Bringing Together Basic and Clinical Perspectives
Authors: DAHL RONALD E.
Published: March 2004

Abstract:Some discussion of the development of affect regulation in relation to two papers by Drs. Kalin and Leibenluft is provided. The goals are to frame the broader issues, including the conceptualization and definitions of affect regulation, to address questions about the development of affect regulation, and to consider ways to bridge between basic and clinical approaches to understanding disorders of affect regulation emerging in childhood and adolescence. The conceptual framework for affect regulation presented here focuses on interactions between cognitive systems and affective systems. It also appears that this area of research is at a very early point in its development—one rich with opportunities to bridge between basic research in affective neuroscience, developmental psychology, and developmental psychopathology, and holds great promise to advance understanding regarding the earliest roots of these disorders.
Nonhuman Primate Models to Study Anxiety, Emotion Regulation, and Psychopathology
Authors: KALIN NED H. , SHELTONA STEVEN E.
Published: March 2004

Abstract:This paper demonstrates that the rhesus monkey provides an excellent model to study mechanisms underlying human anxiety and fear and emotion regulation. In previous studies with rhesus monkeys, stable, brain, endocrine, and behavioral characteristics related to individual differences in anxiety were found. It was suggested that, when extreme, these features characterize an anxious endophenotype and that these findings in the monkey are particularly relevant to understanding adaptive and maladaptive anxiety responses in humans. The monkey model is also relevant to understanding the development of human psychopathology. For example, children with extremely inhibited temperament are at increased risk to develop anxiety disorders, and these children have behavioral and biological alterations that are similar to those described in the monkey anxious endophenotype. It is likely that different aspects of the anxious endophenotype are mediated by the interactions of limbic, brain stem, and cortical regions. To understand the brain mechanisms underlying adaptive anxiety responses and their physiological concomitants, a series of studies in monkeys lesioning components of the neural circuitry (amygdala, central nucleus of the amygdala and orbitofrontal cortex) hypothesized to play a role are currently being performed. Initial findings suggest that the central nucleus of the amygdala modulates the expression of behavioral inhibition, a key feature of the endophenotype. In preliminary FDG positron emission tomography (PET) studies, functional linkages were established between the amygdala and prefrontal cortical regions that are associated with the activation of anxiety.
Functional Neuroimaging of Social Cognition in Pervasive Developmental Disorders
Authors: DI MARTINO ADRIANA , CASTELLANOS F XAVIER
Published: March 2004

Abstract:An emerging literature on the neuroanatomical correlates of social cognition in pervasive developmental disorders is reviewed. Studies conducted with high‐functioning adults with autism or Asperger's syndrome highlight patterns of decreased activation in ventromedial prefrontal cortex, temporo‐parietal junction, amygdala, and periamygdaloid cortex, along with aberrantly increased activation in primary sensory cortices. Future studies should extend these important initial results to younger and more severely affected subjects.
Obstetric Complications Correlate with Neurobehavioral and Brain Structural Alterations in Young Relatives at Risk for Schizophrenia
Authors: GILBERT ANDREW R. , MONTROSE DEBRA M. , SAHNI SARAH D. , DIWADKAR VAIBHAV A. , KESHAVAN MATCHERI S.
Published: March 2004

Abstract: As complications of pregnancy and birth may be important risk factors for the development of schizophrenia, studying the “roots” of schizophrenia in high‐risk offspring may better elucidate the interface between biology, environment, and susceptibility to illness. Using magnetic resonance imaging (MRI), neurobehavioral assessments and obstetric histories, we found several significant correlations between these multiple factors, suggesting that birth complications may be a nonspecific etiopathogenic risk factor for psychopathology in young relatives at risk for schizophrenia.
Sex Differences and Hormonal Effects in a Model of Preterm Infant Brain Injury
Authors: NUÑEZ JOSEPH L. , McCARTHY MARGARET M.
Published: March 2004

Abstract: Premature infants are at an exceptionally high risk for brain injury, with damage resulting in permanent behavioral deficits. A contributing factor to the severity of brain injury is gender, with males more sensitive to insult than females. The role of gender and early hormonal environment in addressed in our novel model of prenatal brain damage.
Coping Strategies Moderate the Relation of Hypothalamus‐Pituitary‐Adrenal Axis Reactivity to Self‐Injurious Behavior
Authors: POWERS SALLY I. , MCARDLE ELIZA T.
Published: March 2004

Abstract: An alarming proportion of adolescents engage in purposefully self‐injurious behavior (SIB). SIB is a maladaptive strategy for coping with extreme tension generated in response to stress, particularly interpersonal stress. This study investigated the relation of older adolescents' SIB to the reactivity of the body's major physiological system for responding to stress, the hypothalamus‐pituitary‐adrenal (HPA) axis, after interpersonal stress. Adolescents' behavioral, cognitive, and emotional coping strategies were shown to alter the relation between SIB and HPA reactivity after conflict with a romantic partner.
Reorganization of Unresolved Childhood Traumatic Memories Following Exposure Therapy
Authors: STOVALL‐MCCLOUGH K CHASE , CLOITRE MARYLENE
Published: March 2004

Abstract: As part of an ongoing randomized clinical trial for childhood‐abuse‐related PTSD, this study examined the association between PTSD and unresolved attachment as measured by the Adult Attachment Interview in a sample of 52 female childhood‐abuse survivors. Results revealed that 55% of the sample was classified as preoccupied and almsot 75% was classified as unresolved with regard to trauma. In a preliminary sample of 18 women who completed treatment, 13 were unresolved before treatment and 8 lost their unresolved status following treatment. This effect was significantly more pronounced in the exposure condition compared to the skills training condition.
Ineffective Parenting: A Precursor to Psychopathic Traits and Delinquency in Hispanic Females
Authors: VITACCO MICHAEL J. , NEUMANN CRAIG S. , RAMOS VINCENT , ROBERTS MARY K.
Published: March 2004

Abstract: Research studies with antisocial children have posited that multiple etiologies, including ineffective parenting, can produce psychopathic traits. The current study evaluated 136 Hispanic females and found that poor parenting predicted psychopathology and poor behavioral controls. Effective clinical interventions with antisocial children should focus on improving quality of parenting.
Mother Lowers Glucocorticoid Levels of Preweaning Rats After Acute Threat
Authors: WIEDENMAYER CHRISTOPH P. , MAGARINOS ANA M. , MCEWEN BRUCE S. , BARR GORDON A.
Published: March 2004

Abstract: Exposure to a deadly threat, an adult male rat, induced the release of corticosterone in 14‐day‐old rat pups. The endocrine stress response was decreased when the pups were reunited with their mother immediately after exposure. These findings demonstrate that social variables can reduce the consequences of an aversive experience.
Small Nuclear RING Finger Protein Stimulates the Rat Luteinizing Hormone-β Promoter by Interacting with Sp1 and Steroidogenic Factor-1 and Protects from Androgen Suppression
Authors: Curtin Denis , Ferris Heather A. , Häkli Marika , Gibson Matthew , Jänne Olli A. , Palvimo Jorma J. , Shupnik Margaret A.
Published: March 2004

GnRH controls expression of the LH subunit genes, α and LHβ, with the LHβ subunit regulated most dramatically. Two enhancer regions, distal and proximal, on the rat LHβ gene promoter cooperate for full basal expression and GnRH stimulation. It has been hypothesized that the transcription factors binding to these regions, Sp1, Egr-1, and steroidogenic factor 1 (SF-1), may interact directly or indirectly via a coactivator. One such coactivator may be small nuclear RING finger protein (SNURF), which is expressed in pituitary tissue and the LβT2 gonadotrope cell line. In transfection experiments in LβT2 cells, SNURF stimulated basal expression of LHβ and increased overall GnRH stimulation. SNURF specifically stimulated LHβ, with no effect on the α-subunit promoter. SNURF interacts with Sp1 and SF-1, but not Egr-1, in pull-down experiments. Point mutations or deletions of SNURF functional domains demonstrated that Sp1 and SF-1 interactions with SNURF are required for SNURF stimulatory effects on the LHβ promoter. Endogenous SNURF is associated with the LHβ promoter on native chromatin, suggesting that it plays a physiological role in LHβ gene expression. SNURF also binds the androgen receptor, and SNURF overexpression overcomes androgen suppression of GnRH-stimulated LHβ but not αsubunit promoter activity. SNURF mutations that disrupt Sp1 or SF-1 binding eliminate rescue by SNURF. We conclude that SNURF may mediate interactions between the distal and proximal GnRH response regions of the LHβ promoter to stimulate transcription and can also protect the promoter from androgen suppression.
Central activity of hydroalcoholic extracts from Erythrina velutina and Erythrina mulungu in mice
Authors: Vasconcelos Silvânia M M , Macedo Danielle S , de Melo Carla Thiciane V , Monteiro Andreisa Paiva , Cunha Geanne M A , Sousa Francisca Cléa F , Viana Glauce Socorro B , Rodrigues Alexandre César P , Silveira Edilberto R
Published: March 2004

This work studied the central behavioural effects of hydroalcoholic extracts from the stem bark of Erythrina velutina and Erythrina mulungu on the elevated plus maze, open field, and rota rod tests in mice. These medicinal plants belong to the Fabaceae family and are popularly used in Brazil for their effects on the central nervous system. Single doses of the extracts were administered orally (200, 400 or 800 mg kg−1) or intraperitoneally (200 or 400 mg kg−1) to female mice. A reduction of the locomotor activity was observed in the open field test with both hydroalcoholic extracts after intraperitoneal treatment with all doses, but only with the highest dose after oral administration. In addition, oral and intraperitoneal administration of the extracts decreased the incidence of rearing and grooming. Decreases in the number of entries in the open (NEOA)and closed (NECA)arms of the elevated plus maze were observed after the administration of the highest dose (800 mg kg−1, p.o.) of both hydroalcoholic extracts, and this effect may be due to the decrease in locomotor activity. These hydroalcoholic extracts failed to affect the motor coordination in the rota rod test. In conclusion, we showed that the hydroalcoholic extracts of E. velutina and E. mulungu have depressant effects on the central nervous system, which, at least partially, corroborates the popular use of these species as tranquilizers in Brazilian popular medicine.
Effect of P-glycoprotein inhibition on methadone analgesia and brain distribution in the rat
Authors: Rodriguez Monica , Ortega Ignacio , Soengas Itziar , Suarez Elena , Lukas John C , Calvo Rosario
Published: March 2004

Methadone is an opiate drug that has been identified as an in-vitro substrate of the efflux pump P-glycoprotein (P-gp), active in the intestinal epithelium and in the blood–brain barrier (BBB), among other sites. The objective of this study was to test in vivo, in the rat model, the role of P-gp modulation on the analgesic effect and brain uptake of methadone, as well as identify the most relevant site via dual oral and intravenous (i.v.) experiments. The P-gp specific inhibitor (valspodar or PSC833) was preadministered (10 mg kg−1 i.v.) to test groups. Analgesia was measured using the tailflick test. The ED50 for oral methadone (2, 3, 6 and 8 mg kg−1) decreased three-fold in valspodar groups compared with controls (2.23 + 0.002 mg kg−1 and 6.07 + 0.07 mg kg−1; P < 0.0001). The overall analgesic effect (% antinociception) was elevated 3.1 times in pretreated compared with control rats (90.65% + 0.22 vs 29.23% + 14.0; P < 0.01) after 6 mg kg−1 oral methadone and 2.8 times after i.v. (0.35 mg kg−1) administration (91.75% + 4.27 vs 32.45% + 9.0; P < 0.01). The brain:plasma distribution ratio was higher in pretreated animals and AUCbrain (overall brain concentration) was 6 times higher after oral methadone and 4 times higher after i.v. compared with controls, disproportionally increased relative to plasma, implying an active process at the BBB. P-gp, and hence substrate comedication, plays a critical role in the evolution of the methadone analgesic effect and in its brain uptake, independent of the administration route.
Melatonin reverses urinary system and aorta damage in the rat due to chronic nicotine administration
Authors: Sener Göksel , Kapucu Caner , Paskaloglu Kübra , Ayanoglu-Dülger Gül , Arbak Serap , Ersoy Yasemin , Alican Inci
Published: March 2004

We have evaluated the changes in contractile activity and oxidant damage of corpus cavernosum, urinary bladder, kidney and aorta after chronic nicotine administration in rats. The effects of melatonin on these parameters were investigated also. Male Wistar albino rats were injected intraperitoneally with nicotine hydrogen bitartrate (0.6 mg kg−1 daily for 21 days) or saline. Melatonin (10 mg kg−1, i.p.) was administered either alone or with nicotine injections. Corpus cavernosum, bladder and aorta were used for contractility studies, or stored with kidneys for the measurement of malondialdehyde and glutathione levels. Corpus cavernosum, bladder, and aorta samples were examined histologically and the extent of microscopic tissue damage was scored. In the nicotine-treated group, the contraction of corpus cavernosum, bladder and aorta samples and the relaxation of corporeal and aorta tissues decreased significantly compared with controls. However, melatonin treatment restored these responses. In the nicotine-treated group, there was a significant increase in the malondialdehyde levels of the corporeal tissue, bladder, kidney and aorta, with marked reductions in glutathione levels compared with controls. Melatonin treatment reversed these effects also. Melatonin administration to nicotine-treated animals caused a marked reduction in the microscopic damage of the tissues compared with those of the untreated group. In this study, nicotine-induced dysfunction of the corpus cavernosum, bladder and aorta of rats was reversed by melatonin treatment. Moreover, melatonin, as an antioxidant, abolished elevation in lipid peroxidation products, and reduction in the endogenous antioxidant glutathione, and protected the tissues from severe damage due to nicotine exposure.
Effect of lubricant type and concentration on the punch tip adherence of model ibuprofen formulations
Authors: Roberts Matthew , Ford James L , Rowe Philip H , Dyas A Mark , MacLeod Graeme S , Fell John T , Smith George W
Published: March 2004

A model formulation, comprising ibuprofen and direct compression lactose (Tablettose 80) was used to assess the influence of two lubricants, magnesium stearate and stearic acid, on punch tip adherence. Lubricant concentrations were varied from 0.25% to 2% w/w. Formulations in the presence and absence of 0.5% w/w colloidal silica (Aerosil 200) were examined, to assess the influence of the glidant on the anti-adherent effects of the lubricants. Differential scanning calorimetry (DSC) was used to examine the effect of the lubricants on the melting temperature of ibuprofen. Tablets were compacted using a single punch tablet press at 10 kN using hard chrome-plated punches or at 40 kN using uncoated steel punches, tooling was 12.5-mm diameter in each case. The upper punch faces were characterized by obtaining Taylor Hobson Talysurf surface profiles. Following compaction, ibuprofen attached to the face was quantified by spectroscopy. At low concentrations of each lubricant, the levels of sticking observed were similar. Whilst sticking increased at magnesium stearate concentrations above 1%, sticking with stearic acid remained relatively constant at all concentrations. DSC revealed that the melting temperature of ibuprofen was lowered by the formation of eutectic mixtures with both lubricants. However, the onset temperature of melting and melting point were lowered to a greater extent with magnesium stearate compared with stearic acid. When using uncoated tooling at 40 kN, the deleterious effects of magnesium stearate on the tensile strength of the tablets also contributed to sticking. When using chrome-plated punches at 10 kN, the tensile strength reduction by the presence of magnesium stearate was less pronounced, as was the level of sticking.
Pretreatment with Ginkgo biloba extract weakens the hypnosis action of phenobarbital and its plasma concentration in rats
Authors: Kubota Yoko , Kobayashi Kyoko , Tanaka Naoko , Nakamura Kazuki , Kunitomo Masaru , Shinozuka Kazumasa , Kubota Yoko , Kunitomo Masaru , Shinozuka Kazumasa , Umegaki Keizo
Published: March 2004

In a previous study, we found that orally administered Ginkgo biloba extract (GBE) induced hepatic cytochrome P450 (CYP) in rats, especially the CYP2B type. This fact suggested that GBE influenced the availability and safety of drugs that were metabolized via CYP2B type enzymes. To confirm this possibility, in this study we examined the effect of feeding a 0.1, 0.5 and 1.0% GBE diet for 2 weeks on the pharmacokinetics and pharmacological action of phenobarbital, which is known to be metabolized by CYP2B in Wistar rats. The feeding of GBE markedly shortened the sleeping time in rats. Furthermore, the maximal phenobarbital plasma concentration (Cmax) and the 24-h area under the curve (AUC0–24) were decreased in rats fed GBE. These findings indicate that GBE reduces the therapeutic potency of phenobarbital via enhancement of cytochrome P450 expression, and raises the possibility that GBE and drug interactions may occur clinically.
Quantitative structure-pharmacokinetic relationship modelling: apparent volume of distribution
Authors: Ghafourian Taravat , Barzegar-Jalali Mohammad , Hakimiha Nasim , Ghafourian Taravat , Cronin Mark T D
Published: March 2004

The purpose of this study was to develop a quantitative structure-activity relationship (QSAR) for the prediction of the apparent volume of distribution (Vd) in man for a heterogeneous series of drugs. The relationship of many computed, and some experimental, structural descriptors with Vd, and the Vd corrected for protein binding (unbound Vd), was investigated. Models were constructed using stepwise regression analysis for all the 70 drugs in the dataset, as well as for acidic drugs and basic drugs separately. The predictive power of the models was assessed using half the chemicals as a test set, and revealed that the models for Vd yielded lower prediction errors than those constructed for the unbound Vd (mean fold error of 2.01 for Vd compared with 2.28 for unbound Vd). Moreover, the separation of the compounds into acids and bases did not reduce the prediction error significantly.
Systemic and ocular pharmacokinetics of N-4-benzoylaminophenylsulfonylglycine (BAPSG), a novel aldose reductase inhibitor
Authors: Sunkara Gangadhar , Ayalasomayajula Surya P , Rao Cheruku S , Vennerstrom Jonathan L , Kompella Uday B , DeRuiter Jack , Kompella Uday B
Published: March 2004

To better develop N-[4-(benzoylamino)phenylsulfonyl]glycine (BAPSG), a potent and selective aldose reductase inhibitor capable of delaying the progression of ocular diabetic complications, the objective of this study was to assess its pharmacokinetics. The plasma pharmacokinetics of BASPG was assessed in male Sprague-Dawley rats following intravenous, intraperitoneal and oral routes of administration and its distribution to various tissues including those of the eye was studied following intraperitoneal administration. In addition, rat plasma protein binding of BAPSG was studied using ultracentrifugation method and its ocular tissue disposition was assessed following topical administration in rabbits. Plasma and tissue levels of BAPSG were analysed using an HPLC assay. BAPSG exhibited dose-proportionate AUC0→∞ (area under the plasma concentration-time curve) following both intravenous and intraperitoneal administration over the dose range (5–50 mg kg−1) studied and an erratic oral absorption profile with low oral bioavailability. The fraction bioavailability following oral and intraperitoneal administration was 0.06 and 0.7–1, respectively. BAPSG exhibited short plasma elimination half-lives in the range 0.5–1.5 h. BAPSG was bound to rat plasma proteins and the percent protein binding ranged from 83 to 99.8%. BAPSG was better distributed to cornea, lens and retina than to brain, following intraperitoneal administration in rats. However, the distribution was lower compared with kidney and liver. Following topical administration in rabbits, BAPSG delivery to the surface ocular tissues, cornea and conjunctiva was higher compared with intraocular tissues, aqueous humour, iris-ciliary body and lens. Thus, BAPSG was distributed to ocular tissues following systemic and topical modes of administration.