bluuebunny/crossref_metadata_2025 huggingface dataset:
Multisensory Activation of the Intraparietal Area When Classifying Grating Orientation: A Functional Magnetic Resonance Imaging Study
Authors: Kitada Ryo , Kito Tomonori , Saito Daisuke N. , Kochiyama Takanori , Matsumura Michikazu , Sadato Norihiro , Lederman Susan J.
Published: July 2006

Humans can judge grating orientation by touch. Previous studies indicate that the extrastriate cortex is involved in tactile orientation judgments, suggesting that this area is related to visual imagery. However, it has been unclear which neural mechanisms are crucial for the tactile processing of orientation, because visual imagery is not always required for tactile spatial tasks. We expect that such neural mechanisms involve multisensory areas, because our perception of space is highly integrated across modalities. The current study uses functional magnetic resonance imaging during the classification of grating orientations to evaluate the neural substrates responsible for the multisensory spatial processing of orientation. We hypothesized that a region within the intraparietal sulcus (IPS) would be engaged in orientation processing, regardless of the sensory modality. Sixteen human subjects classified the orientations of passively touched gratings and performed two control tasks with both the right and left hands. Tactile orientation classification activated regions around the right postcentral sulcus and IPS, regardless of the hand used, when contrasted with roughness classification of the same stimuli. Right-lateralized activation was confirmed in these regions by evaluating the hemispheric effects of tactile spatial processing with both hands. In contrast, visual orientation classification activated the left middle occipital gyrus when contrasted with color classification of the same stimuli. Furthermore, visual orientation classification activated a part of the right IPS that was also activated by the tactile orientation task. Thus, we suggest that a part of the right IPS is engaged in the multisensory spatial processing of grating orientation.
FoxP2Regulation during Undirected Singing in Adult Songbirds
Authors: Teramitsu Ikuko , White Stephanie A.
Published: July 2006

Learned vocal communication, including human speech, is a socially influenced behavior limited to certain animals. This ability requires auditory feedback during vocalization, which allows for on-line evaluation, to achieve the desired vocal output. To date, FOXP2 (forkhead box P2), a transcriptional repressor, is the only molecule directly linked to human speech. IdentifiedFOXP2mutations cause orofacial dyspraxia accompanied by abnormalities in corticostriatal circuitry controlling voluntary orofacial movements. These observations implicate FOXP2 in the developmental formation of neural circuits used in speech, but whether FOXP2 additionally plays an active role in mature circuitry was unknown. To address this question, we use a songbird, the zebra finch (Taeniopygia guttata), whose learned song and underlying circuitry are well characterized. We show that, when adult males sing,FoxP2mRNA is acutely downregulated within area X, the specific region of the songbird striatum dedicated to song. Furthermore, we find downregulation in males that sing by themselves (undirected singers) but not in males that sing to females (directed singers). ThisFoxP2downregulation cannot be a simple consequence of the motor act because birds sang in both directed and undirected contexts. Our data suggest thatFoxP2is important not only for the formation but also for the function of vocal control circuitry. Social context-dependent, acute changes inFoxP2within the basal ganglia of adult songbirds also suggest, by analogy, that the core deficits of affected humans extend beyond development and beyond basic central motor control.
Theta and Gamma Oscillations Predict Encoding and Retrieval of Declarative Memory
Authors: Osipova Daria , Takashima Atsuko , Oostenveld Robert , Fernández Guillén , Maris Eric , Jensen Ole
Published: July 2006

Although studies in animals and patients have demonstrated that brain oscillations play a role in declarative memory encoding and retrieval, little has been done to investigate the temporal dynamics and sources of brain activity in healthy human subjects performing such tasks. In a magnetoencephalography study using pictorial stimuli, we have now identified oscillatory activity in the gamma (60–90 Hz) and theta (4.5–8.5 Hz) band during declarative memory operations in healthy participants. Both theta and gamma activity was stronger for the later remembered compared with the later forgotten items (the “subsequent memory effect”). In the retrieval session, theta and gamma activity was stronger for recognized items compared with correctly rejected new items (the “old/new effect”). The gamma activity was also stronger for recognized compared with forgotten old items (the “recognition effect”). The effects in the theta band were observed over right parietotemporal areas, whereas the sources of the effects in the gamma band were identified in Brodmann area 18/19. We propose that the theta activity is directly engaged in mnemonic operations. The increase in neuronal synchronization in the gamma band in occipital areas may result in a stronger drive to subsequent areas, thus facilitating both memory encoding and retrieval. Alternatively, the gamma synchronization might reflect representations being reinforced by top-down activity from higher-level memory areas. Our results provide additional insight on human declarative memory operations and oscillatory brain activity that complements previous electrophysiological and brain imaging studies.
Calcium Spikes in Basal Dendrites of Layer 5 Pyramidal Neurons during Action Potential Bursts
Authors: Kampa Björn M. , Stuart Greg J.
Published: July 2006

Patch-clamp recording from dendrites has lead to a significant increase in our understanding of the mechanisms underlying signal integration and propagation in neurons. The majority of synaptic input to neurons, however, is made onto small-diameter dendrites, currently beyond the scope of patch-clamp recording techniques. Here we use both calcium and voltage imaging to investigate propagation of action potentials (APs) in fine basal dendrites of cortical layer 5 pyramidal neurons. High-frequency (200 Hz) AP bursts caused supralinear increases in dendritic calcium at distal, but not proximal, basal locations. Supralinear increases in dendritic calcium were also observed at distal basal locations during AP trains above a critical frequency (∼100 Hz). Using voltage imaging, we show that single APs undergo significant attenuation as they propagate into basal dendrites, whereas AP bursts lead to generation of dendritic calcium spikes. Focal and bath application of 4-AP increased the amplitude of calcium transients evoked by APs at distal, but not proximal, locations, suggesting that A-type potassium channels regulate AP backpropagation into basal dendrites. Finally, we show that pairing EPSPs with AP bursts is an effective means of activating synaptic NMDA receptors in basal dendrites. The experimental observations on the role of A-type potassium channels in regulation of AP backpropagation in basal dendrites, as well as the generation of dendritic calcium spikes during AP bursts, were reproduced in a morphologically realistic neuronal model with uniform distributions of dendritic sodium, calcium, and potassium channels. Together, these findings have important implications for understanding dendritic integration and synaptic plasticity in cortical basal dendrites.
Intersubunit Interactions in EAAT4 Glutamate Transporters
Authors: Torres-Salazar Delany , Fahlke Christoph
Published: July 2006

Excitatory amino acid transporters (EAATs) play a central role in the termination of synaptic transmission and in extracellular glutamate homeostasis in the mammalian CNS. A functional transporter is assembled as oligomer consisting of three subunits, each of which appears to transport glutamate independently from the neighboring subunits. EAATs do not only sustain a secondary-active glutamate transport but also function as anion channel. We here address the question whether intersubunit interactions play a role in pore-mediated anion conduction. We expressed a neuronal isoform, EAAT4, heterologously inXenopusoocytes and mammalian cells and measured glutamate flux and anion currents under various concentrations of Na+and glutamate. EAAT4 anion channels are active in the absence of both substrates, and increasing concentrations activate EAAT4 anion currents with a sigmoidal concentration dependence. Because only one glutamate molecule is cotransported per uptake cycle, the cooperativity between glutamate binding sites most likely arises from an interaction between different carrier domains. This interaction is modified by two point mutations close to the putative glutamate binding site, G464S and Q467S. Both mutations alter the dissociation constants and Hill coefficient of the substrate dependence of anion currents, leaving the concentration dependence of glutamate uptake unaffected. Our results demonstrate that glutamate carriers cooperatively interact during anion channel activation.
Activity-Dependent Bidirectional Modification of Inhibitory Synaptic Transmission in Rat Subthalamic Neurons
Authors: Wang Lie , Kitai Stephen T. , Xiang Zixiu
Published: July 2006

Rebound burst activity can be generated in neurons in the subthalamic nucleus (STN) by strong GABAergic inhibitory inputs from the globus pallidus externa (GPe) that is reciprocally connected with the STN. It has been proposed that the rebound burst activity in STN neurons is a key event for generating synchronized rhythmic burst activity in the GPe–STN loop, which may be relevant to the resting tremor in Parkinson’s disease. Here we report that rebound burst firing of STN neurons induces long-lasting bidirectional modifications of GABAergic synaptic transmission in STN neurons themselves. Using the gramicidin perforated-patch clamp technique in the brain slice preparation, we recorded IPSPs from STN neurons during electrical stimulation of the internal capsule. Rebound spikes triggered by hyperpolarizing current pulses were used to induce modification of inhibitory synaptic transmission. We found that long-lasting potentiation of IPSPs could be induced in the neurons exhibiting three or more rebound spikes that had interspike intervals shorter than half of those during base spontaneous activity, whereas long-lasting depression or no change of IPSP amplitude was likely to be observed in neurons that had no rebound burst or two rebound spikes within a burst. The potentiation or depression of IPSPs was associated with a negative or positive shift of reversal potential of IPSPs (EIPSP). The modifications of IPSPs were dependent on activation of postsynaptic voltage-gated calcium channels. This study is the first demonstration that activity-dependent bidirectional modifications of inhibitory synaptic transmission are attributable to bidirectional shifts ofEIPSP.
Prefrontal Projections to the Thalamic Reticular Nucleus form a Unique Circuit for Attentional Mechanisms
Authors: Zikopoulos Basilis , Barbas Helen
Published: July 2006

The inhibitory thalamic reticular nucleus (TRN) intercepts and modulates all corticothalamic and thalamocortical communications. Previous studies showed that projections from sensory and motor cortices originate in layer VI and terminate as small boutons in central and caudal TRN. Here we show that prefrontal projections to TRN in rhesus monkeys have a different topographic organization and mode of termination. Prefrontal cortices projected mainly to the anterior TRN, at sites connected with the mediodorsal, ventral anterior, and anterior medial thalamic nuclei. However, projections from areas 46, 13, and 9 terminated widely in TRN and colocalized caudally with projections from temporal auditory, visual, and polymodal association cortices. Population analysis and serial EM reconstruction revealed two distinct classes of corticoreticular terminals synapsing with GABA/parvalbumin-positive dendritic shafts of TRN neurons. Most labeled boutons from prefrontal axons were small, but a second class of large boutons was also prominent. This is in contrast to the homogeneous small TRN terminations from sensory cortices noted previously and in the present study, which are thought to arise exclusively from layer VI. The two bouton types were often observed on the same axon, suggesting that both prefrontal layers V and VI could project to TRN. The dual mode of termination suggests a more complex role of prefrontal input in the functional regulation of TRN and gating of thalamic output back to the cortex. The targeting of sensory tiers of TRN by specific prefrontal areas may underlie attentional regulation for the selection of relevant sensory signals and suppression of distractors.
Oestradiol-17β inhibits tamoxifen-induced LHRH self-priming blocking hormone-dependent and ligand-independent activation of the gonadotrope progesterone receptor in the rat
Authors: Sánchez-Criado José E , Garrido-Gracia José C , Bellido Carmina , Aguilar Rafaela , Guelmes Pedro , Abreu Pedro , Alonso Rafael , Barranco Inmaculada , Millán Yolanda , de las Mulas Juana Martín
Published: July 2006

In the rat, administration of tamoxifen (TX) in the absence of oestrogen (E) induces LHRH self-priming, the progesterone receptor (PR)-dependent property of LHRH that increases gonadotrope responsiveness to itself. The oestrogen-dependent PR can be phosphorylated/activated by progesterone (P4) and, in the absence of the cognate ligand, by intracellular LHRH signals, particularly cAMP/protein kinase A. We have recently found that oestradiol-17β (E2), acting on a putative membrane estrogen receptor-α in the gonadotrope, inhibits this agonist action of TX. This study investigated the mechanism by which E2 inhibits TX-elicited LHRH self-priming using both incubated pituitaries from TX-treated ovariectomized (OVX) rats and anterior pituitary cells from OVX rats cultured with TX. It was found that (1) in addition to the inhibitory effect on TX-elicited LHRH self-priming, E2 blocked P4 and adenylyl cyclase activator forskolin augmentation of LHRH-stimulated LH secretion, and (2) E2 did not affect the increasing action of TX on gonadotrope PR expression or pituitary cAMP content. Furthermore, inhibition of protein phosphatases with okadaic acid suppressed E2 inhibition of TX-elicited LHRH-induced LH secretion, while stimulation of protein phosphatases with ceramide blocked TX-induced LHRH self-priming. Together, these results indicated that membrane ER-mediated E2 inhibition of the TX-stimulated LHRH self-priming pathway involves a blockade of gonadotrope PR phosphorylation/activation, but not a deficient response of PR to phosphorylases. Results also suggested that the inhibitory effect of E2on TX-induced LHRH self-priming is exerted through modulation of cellular protein phosphatase activity in the gonadotrope.
Selenium treatment in autoimmune thyroiditis: 9-month follow-up with variable doses
Authors: Turker Omer , Kumanlioglu Kamil , Karapolat Inanc , Dogan Ismail
Published: July 2006

The aim of this study is to investigate the long-term (9 months) effects of variable doses (200/100 μg/day) of l-selenomethionine on autoimmune thyroiditis (AIT) and the parameters affecting the success rate of this therapy. The present study was designed in three steps: (1) 88 female patients with AIT (mean age = 40.1 ± 13.3 years) were randomized into two groups according to their initial serum TSH, thyroid peroxidase antibody (TPOAb) concentrations, and age. All the patients were receiving l-thyroxine to keep serum TSH ≤2 mIU/l. Group S2 (n = 48, mean TPOAb = 803.9 ± 483.8 IU/ml) received 200 μg l-selenomethionine per day, orally for 3 months, and group C (n = 40, mean TPOAb = 770.3 ± 406.2 IU/ml) received placebo. (2) 40 volunteers of group S2 were randomized into two age- and TPOAb-matched groups. Group S22 (n = 20) went on taking l-selenomethionine 200 μg/day, while others (group S21) lowered the dose to 100 μg/day. (3) 12 patients of group S22 (group S222) went on taking l-selenomethionine 200 μg/day, while 12 patients of group S21 (S212) increased the dose to 200 μg/day. Serum titers of TPOAb decreased significantly in group S2 (26.2%, P < 0.001), group S22 (23.7%, P < 0.01) and group S212 (30.3%, P < 0.01). There were no significant changes in group C and group S222 (P > 0.05). TPOAb titers increased significantly in group S21 (38.1%, P < 0.01). A significant decrease in thyroglobulin antibody titers was only noted in group S2 (5.2%, P < 0.01). l-selenomethionine substitution suppresses serum concentrations of TPOAb in patients with AIT, but suppression requires doses higher than 100 μg/day which is sufficient to maximize glutathione peroxidase activities. The suppression rate decreases with time.
Glial cell-line-derived neurotropic factor and its receptors are expressed by germinal and somatic cells of the rat testis
Authors: Fouchécourt Sophie , Godet Murielle , Sabido Odile , Durand Philippe
Published: July 2006

Glial cell-line-derived neurotropic factor (GDNF) and its receptors glial cell-line-derived neurotropic factor α (GFR1α) and rearranged during transformation (RET) have been localized in the rat testis during postnatal development. The three mRNAs, and GDNF and GFR1α proteins were detected in testis extracts from 1- to 90-day-old rats by reverse transcriptase PCR and Western blotting respectively. The three mRNAs were present in Sertoli cells from 20- and 55-day-old rats, pachytene spermatocytes (PS), and round spermatids (RS). The GDNF and GFR1α proteins were detected in PS, RS, and Sertoli cells. GDNF and GFR1α were also detected using flow cytometry in spermatogonia and preleptotene spermatocytes, and in secondary spermatocytes. The localization of GDNF and GFR1α in germ and Sertoli cells was confirmed by immunocytochemistry. The hypothesis that GDNF may control DNA synthesis of Sertoli cells and/or spermatogonia in the immature rat was addressed using cultures of seminiferous tubules from 7- to 8-day-old rats. Addition of GDNF for 48 h resulted in a twofold decrease in the percentage of spermatogonia able to duplicate DNA, whereas Sertoli cells were not affected. These results are consistent with a role of GDNF in inhibiting the S-phase entrance of a large subset of differentiated type A spermatogonia, together with an enhancing effect of the factor on a small population of undifferentiated (stem cells) spermatogonia. Moreover, the wide temporal and spatial expression of GDNF and its receptors in the rat testis suggest that it might act at several stages of spermatogenesis.
Evolution of glucocorticoid receptors with different glucocorticoid sensitivity
Authors: Stolte Ellen H , van Kemenade B M Lidy Verburg , Savelkoul Huub F J , Flik Gert
Published: July 2006

Glucocorticoids (GCs) are commonly used to treat a variety of immune diseases. However, the efficacy of treatment is greatly influenced by an individual variation in sensitivity to GCs, which is caused by differences in the glucocorticoid receptor (GR). The variable receptor profile results from variations in the GR gene, or alternative splicing of the gene coded. We investigated the evolution of the GR gene by comparing genomic GR sequences of vertebrates. Exon length and amino acid sequence are conserved among all classes of vertebrates studied, which indicates strong evolutionary pressure on conservation of this gene. Interestingly, teleostean fishes have two different GR proteins. One of the duplicate fish GR genes has a nine-amino-acid insert in the DNA binding region that results from alternative splicing. The duplicate GR genes and products of alternative splicing in teleostean fishes are differentially expressed in vivo and show different transactivation capacity in vitro. The presence of two GR genes appears to be a result of divergence of receptors rather than of ligands. Teleostean fishes express different, evolutionarily related, functional GR proteins within a single organism. Hereby, teleostean fishes present a model that facilitates investigation of the molecular basis of cortisol resistance and different regulatory functions of cortisol.
Transforming growth factor-β1 and activin A generate antiproliferative signaling in thyroid cancer cells
Authors: Matsuo Sílvia Emiko , Leoni Suzana Garcia , Colquhoun Alison , Kimura Edna Teruko
Published: July 2006

Transforming growth factor-beta 1 (TGF-β1) and activin A (ActA) induce similar intracellular signaling mediated by the mothers against decapentaplegic homolog (SMAD) proteins. TGF-β1 is a potent antimitogenic factor for thyroid follicular cells, while the role of ActA is not clear. In our study, the proliferation of TPC-1, the papillary thyroid carcinoma cell line, was reduced by both recombinant ActA and TGF-β1. Due to the concomitant expression of TGF-β1 and ActA in thyroid tumors, we investigated the effects of either TGF-β1 or ActA gene silencing by RNA interference in TPC-1 cells in order to distinguish the specific participation of each in proliferation and intracellular signaling. An increased proliferation and reduced SMAD2, SMAD3, and SMAD4 mRNA expression were observed in both TGF-β1 and ActA knockdown cells. Recombinant TGF-β1 and ActA increased the expression of inhibitory SMAD7, whereas they reduced c-MYC. Accordingly, we detected a reduction in SMAD7 expression in knockdown cells while, unexpectedly, c-MYC was reduced. Our data indicate that both TGF-β1 and ActA generate SMADs signaling with each regulating the expression of their target genes, SMAD7 and c-MYC. Furthermore, TGF-β1 and ActA have an antiproliferative effect on thyroid papillary carcinoma cell, exerting an important role in the control of thyroid tumorigenesis.
Gonadectomy in mice of the inbred strain CE/J induces proliferation of sub-capsular adrenal cells expressing gonadal marker genes
Authors: Johnsen Inga K , Slawik Marc , Shapiro Igor , Hartmann Michaela F , Wudy Stefan A , Looyenga Brendan D , Hammer Gary D , Reincke Martin , Beuschlein Felix
Published: July 2006

Mouse models of adrenal tumorigenesis have the potential to give insights in the dysregulation of adrenal growth and differentiation. The inbred mouse strain CE/J has been reported to develop adrenal tumors upon gonadectomy (GDX) similar to mice with targeted deletions of the inhibin alpha subunit (Inh−/−). We performed a detailed morphological and molecular characterization of adrenal glands from CE/J mice 8–50 weeks of age to define the cellular origin of these tumors as well as the spatial and temporal expression of marker genes associated with tumor growth. In contrast to the induction of x-zone growth upon GDX in Inh−/− mice, GDX in CE/J mice induced the appearance of sub-capsular nests of densely packed cells that progress into adrenal tumors. Staining for proliferative cell nuclear antigen confirms a substantial increased in cellular proliferation within this sub-capsular compartment and lack of apoptosis upon GDX. Induction of adrenal tumor growth was accompanied by transcriptional changes that otherwise define gonadal endocrine cells. These regulated genes included transcription factors such as GATA-4, WT-1, FOG-1, and steroidogenic factor-1 (SF-1), peptide hormones such as Mullerian-inhibiting substance (MIS), hormone receptors including luteinizing hormone and MIS receptor, and steroidogenic enzymes such as P450c17 and P450 aromatase. The functional significance of steroid enzyme expression was demonstrated by a gradual increase of adrenal androgens after GDX. Taken together these data suggest that adrenal tumors in gonad-ectomized CE/J mice are direct derivatives from cells of the proposed sub-capsular stem cell zone. The distinct expression pattern of this cell population is consistent with a defect in the differentiation of these cells into a cell population with functional properties that otherwise define a gonadal endocrine phenotype.
Physiological consequences of social descent: studies in Astatotilapia burtoni
Authors: Parikh Victoria N , Clement Tricia , Fernald Russell D
Published: July 2006

In many species, social interactions regulate reproductive capacity, although the exact mechanisms of such regulation are unclear. Since social stress is often related to reproductive regulation, we measured the physiological signatures of change in reproductive state as they relate to short-term stress and the stress hormone cortisol. We used an African cichlid fish, Astatotilapia burtoni, with two distinct, reversible male phenotypes: dominant (territorial, T) males that are larger, more brightly colored, more aggressive, and reproductively competent and non-dominant males (non-territorial, NT) that are smaller, camouflage colored, and have regressed gonads. Male status, and hence reproductive competence, depends on social experience in this system. Specifically, if a T male is placed among larger male fish, it quickly becomes NT in behavior and coloration, but complete regression of its reproductive axis takes ca. 3 weeks (White et al. 2002). Reproduction in all vertebrates is controlled by the hypothalamic–pituitary–gonadal axis in which the key signaling molecule from the brain to the pituitary is GnRH1. Here, we subjected T males to territory loss, a social manipulation which results in status descent. We measured the effects of this status change in levels of circulating cortisol and testosterone as well as mRNA levels of GnRH1 and GnRH receptor-1 (GnRH-R1) in the brain and pituitary, respectively. Following short-term social suppression (4 h), no change was observed in plasma cortisol level, GnRH1 mRNA expression, GnRH-R1 mRNA expression, or plasma testosterone level. However, following a somewhat longer social suppression (24 h), cortisol and GnRH1 mRNA levels were significantly increased, and testosterone levels were significantly decreased. These results suggest that in the short run, deposed T males essentially mount a neural ‘defense’ against loss of status.
Endocrinology: the next 60 years – the helix and the chip
Authors: Waters Michael J
Published: July 2006

In the 60 years since C H Li reported the isolation of bovine growth hormone (GH), endocrinologists have seen the widespread use of human GH for statural disorders, the measurement of plasma GH as a diagnostic test, the full development of the somatomedin hypothesis and the molecular details of the function of the GH receptor responsible for regulating somatic growth and metabolism. In diabetes, we have passed from administration of animal insulin to formulations with different release rates, insulin pumps and inhalers, insulin sensitizers and a greater understanding of insulin signalling and insulin resistance through genetically engineered murine models. What might we expect over the next few decades?
Endocrinology: the next 60 years
Authors: Ho Ken K Y
Published: July 2006

Advances in clinical chemistry, molecular biology and information technology have brought about major changes in the field of endocrinology. The future practice of endocrinology will be influenced by secular health trends, consumer expectations and the globalisation of health. Pharmacotherapy will remain the backbone of endocrine therapy led by developments in drug delivery technology, pharmacogenomics, combinatorial chemistry and paracrinology. The endocrine-related consequences of obesity and ageing will be major health problems, demand for anti-obesity and anti-ageing treatments will escalate. There will be increased blurring between endocrine disease and non-disease. The future clinical endocrinologist must continue to practice evidence-based medicine to improve the treatment of genuine endocrinopathies.
Measuring Social Aspects of Distributed Learning Groups
Authors: Jochems Wim , Kreijns Karel
Published: July 2006

Computer-supported group-based learning requires that interaction has to be structured within the group; otherwise it will not happen. Also, it is important to pay attention to social aspects of a distributed learning group (i.e. group dynamics); otherwise a good working team will not emerge. This article proposes a process-oriented framework that considers five critical elements for enhancing interaction in the cognitive dimension. Enhancing social interaction for achieving a sound social space requires a sociable computer-supported collaborative learning environment (CSCL) in which social presence of the group members exists. Such sound social space is considered by many, if not most, educational researchers to be a necessary prerequisite for epistemic interaction. In order to allow designers and teachers to develop sociable CSCL environments, this article proposes three scales to measure social aspects. Although the validation of these scales is somewhat limited, the scales are a first step for making certain characteristics of distributed interaction visible. To provide a more firm base for the scales, this article also calls for more research on this issue.
Use of Online Assessment to Enhance Teaching and Learning: The PASS-IT Project
Authors: Ashton Helen , Wood Christine
Published: July 2006

This article describes a recent collaborative project (PASS-IT) which investigated the use of online assessment in secondary and further education in Scotland. The aim of PASS-IT was to explore the potential of formative and summative assessment in secondary education, and to build on previous research into the applicability and validity of online assessments. An overview of the project is given. Examples of online questions are provided in section 2 with a discussion of some of the issues and benefits. Section 3 outlines the main research findings of the project, which provide evidence for the validity of online assessments.
Postmodern Research and E-learning: Anatomy and Representation
Authors: Harrison Colin
Published: July 2006

This article attempts to do two things: first, to present some postmodern reflections on the current state of research into the relationship between information technology and learning, and second, to relate those reflections to the concept of representation, in ways that, it is hoped, offer some useful and positive models for extending our understanding. Using representations in anatomy and physics as examples, the article outlines three examples from current research of ways in which visual representations of learning can enhance our understanding of complexity and offer the potential for greater interconnectedness in our thinking. These examples are taken from representations of learning with technology in multiple environments, representations of statistical data on relative gains in learning with ICT, and representations of complex Internet search task behaviour. The article argues that making use of a wider range of representations might be valuable in moving the field beyond bivariate descriptions of e-learning, particularly in complex domains.
A Protocol for the Handling of Tissue Obtained by Operative Lung Biopsy: Recommendations of the chILD Pathology Co-Operative Group
Authors: Langston Claire , Patterson Kathleen , Dishop Megan K. , Baker Peter , Chou Pauline , Cool Carlyne , Coventry Susan , Cutz Ernest , Davis Mary , Deutsch Gail , Galambos Csaba , Pugh Judy , Wert Susan , White Frances ,   for the chILD Pathology Co-operative Group: Fred Askin
Published: July 2006

This is the first of a series on pediatric pulmonary disease that will appear as Perspectives in Pediatric Pathology over the coming months. The series will include practical issues, such as this protocol for handling lung biopsies and another on bronchoalveolar lavage in childhood, as well as reviews of advances in various areas in pediatric pulmonary pathology. It has been 11 years since the last Perspectives on pulmonary disease. Much has happened since then in this area, and this collection will highlight some emerging and rapidly advancing areas in pediatric lung disease. These will include a review of molecular mechanisms of lung development, and another of mechanisms of pulmonary vascular development. The surfactant system and its disorders, as well as recent advances in the biology of the pulmonary neuroendocrine system and mechanisms of respiratory viral disease, will be addressed. Articles on pulmonary hypertension, pulmonary neoplasia, and pediatric lung transplantation, with their implications for the pediatric pathologist, are also planned. The contributors to this series are a diverse group with special interests and expertise in these areas. As Dr. William Thurlbeck noted in his foreword to the previous volume, Pulmonary Disease, volume 18 of Perspectives in Pediatric Pathology, pediatric pathology had been largely concerned with phenomenology, rather than with mechanisms, model systems, and experimental investigation. I think he would have been pleased to see the changes that have occurred over the past 10 years in pediatric lung biology and pathology in particular, because these were particularly favored interests of his later years.
Bilateral Cystic Dysplasia of the Rete Testis with Renal Adysplasia
Authors: Soglio Dorothée Bouron-Dal , Harvey Isabelle , Jovanovic Mubina , Oligny Luc L. , Fournet Jean-Christophe
Published: July 2006

Cystic dyplasia of the rete testis (CDRT) is an uncommon, generally unilateral lesion characterized by anastomosing cystic spaces lined by a flattened simple cuboidal epithelium in the rete testis. In the literature this lesion often is associated with an ipsilateral urogenital lesion such as renal agenesia or multicystic dysplasia of the kidney, in order of frequency. The pathogenesis is explained by some authors by their common embryologic origin. We are reporting the finding of bilateral CDRT associated with ultrasound-diagnosed renal adysplasia in a 20-week gestational age fetus with oligohydramnios. Although CDRT has been referred to as being associated with multicystic renal dysplasia or renal agenesis, the present case appears to be unique in combining all the malformations together.
Sirenomelia of an Intracytoplasmic Sperm Injection Conceptus: A Case Report and Review of Mechanism
Authors: Bakhtar Omid , Benirschke Kurt , Masliah Eliezer
Published: July 2006

Postmortem dissection of the 18-week male conceptus, product of intracytoplasmic sperm injection (ICSI), demonstrated the hallmark findings of sirenomelia. The lower legs were fused and the left knee was rotated medially. Internal organs showed hypoplastic lungs, a multicystic kidney, and unilateral ureteral hypoplasia. The vitelline artery was absorbed, in a classic fashion, into the umbilical artery and communicated with the aorta at a point proximal to the iliac arteries. The tributaries distal to this point were hypoplastic. This finding is consistent with previously documented cases of sirenomelia and is thought to be the pathogenetic mechanism resulting in a vascular steal from the lower extremities. A rare finding was the presence of a penis on the dorsal side just below a perforate anus. In this case report, we discuss the pertinent clinical history and autopsy findings. A brief review of the mechanism thought to give rise to sirenomelia is provided. To our knowledge, this is the first reported case of sirenomelia in an ICSI conceptus.
Portopulmonary Hypertension in Childhood Presenting as Sudden Death
Authors: Weber Martin A. , Ashworth Michael T. , Sebire Neil J.
Published: July 2006

We present the case of a 9-year-old boy with portal hypertension who died suddenly and unexpectedly due to pulmonary hypertensive crisis during a routine endoscopic procedure. He had known portal hypertension with esophageal varices but had no preceding clinical symptoms suggestive of significant pulmonary hypertensive disease despite postmortem histological evidence of advanced pulmonary vascular changes. Portopulmonary hypertension is a well-described and distinct clinical syndrome that is rare in childhood and is associated with a relatively poor prognosis. Occasional patients with histologically advanced disease may remain asymptomatic but present with pulmonary hypertensive crisis. Children with portopulmonary hypertension should be considered at high risk for surgical procedures, and pulmonary hypertensive complications should be excluded as a cause of death in all children dying suddenly in the setting of portal hypertension.
Activation of Wnt/β-Catenin Signaling in Distinct Histologic Subtypes of Human Germ Cell Tumors
Authors: Fritsch Michael K. , Schneider Dominik T. , Schuster Amy E. , Murdoch Fern E. , Perlman Elizabeth J.
Published: July 2006

The molecular signaling pathways mediating human germ cell tumor (GCT) formation and progression are poorly understood despite a large number of studies detailing recurrent cytogenetic abnormalities. Germ cell tumors consist of multiple histologic subtypes and can also be divided into infantile/childhood or adolescent/adult tumors as well as gonadal or nongonadal sites of origin. All of these parameters are important in defining clinical outcome and in understanding the pathogenesis of these tumors. We utilized complementary DNA (cDNA) microarray analysis to identify differences in signal transduction pathways between 2 histologic subtypes of malignant ovarian GCTs (dysgerminomas versus ovarian endodermal sinus tumors). Hierarchical cluster analysis using only the genes involved in Wnt/ β-catenin signaling was able to distinguish these 2 tumor subtypes from each other. Wnt13 and β-catenin showed significant differential expression patterns between the 2 tumor subtypes, and the results were confirmed by semiquantitative reverse transcriptase–polymerase chain reaction. Additional GCTs were studied for the expression of other members of Wnt/ β-catenin signaling, including Wnt13, frizzled, disheveled, low-density lipoprotein receptor-related protein 6, and β-catenin. Differential expression levels were identified for several histologic subtypes of human GCTs. Finally, we prepared tissue microarrays containing GCTs from 83 different patients and demonstrated high levels of β-catenin protein expression in 100% and nuclear accumulation in approximately 50% to 70% of all endodermal sinus tumors and immature teratomas (ITs). This pattern was independent of the patient's age. No nuclear accumulation of β-catenin was observed in germinomas, embryonal carcinomas, or choriocarcinomas. These results indicate that activation of Wnt/ β-catenin signaling plays an important role in the pathogenesis of 2 histologic subtypes of human GCTs.
Giant Inflammatory Polyposis Coli as a Manifestation of Crohn's Disease in Patients with Coexistent Cystic Fibrosis
Authors: Banville Niamh , Broderick Annemarie , Fitzgerald Ray , Drumm Brendan , McDermott Michael
Published: July 2006

Crohn's disease (CD) arising in children with cystic fibrosis (CF) is well recognized. Indeed, reports suggest that CD is significantly more common in patients with CF than in the general population. Giant inflammatory polyposis is a rare manifestation of idiopathic inflammatory bowel disease and may complicate both ulcerative colitis and CD. Giant inflammatory polyposis has not been specifically reported in patients with coexistent CF and CD. Herein, we report the occurrence of giant inflammatory polyposis in 2 boys attending a tertiary care hospital, with an established diagnosis of CF who subsequently developed CD. Both boys required surgical treatment for CD. In addition to classical features of CD, both colonic resection specimens showed giant inflammatory polyposis. The appearances were modified by the presence of a layer of thick mucus. It is suggested that the coexistence of CF in patients with CD may predispose to the development of giant inflammatory polyposis. In addition to contributing to their development, it also appears that there is a propensity for CF to alter the morphological appearance of giant inflammatory polyposis. This may lead to diagnostic confusion when examining endoscopic biopsies.
Effects on virological and immunological parameters during CD34 mobilization in HIV patients with lymphoma
Authors: Bortolin Maria Teresa , Simonelli Cecilia , Zanussi Stefania , Pratesi Chiara , Bidoli Ettore , Rupolo Maurizio , Berretta Massimiliano , Tedeschi Rosamaria , De Paoli Paolo
Published: July 2006

The effects of CD34 mobilization with chemotherapy and G‐CSF administration were evaluated in 13 HIV‐positive patients with relapsed lymphomas and low CD4 counts. After mobilization, CD4+ cells increased significantly while HIV‐RNA and integrated HIV‐DNA showed no increases. G‐CSF led to an increase of CD4+ cells with limited effects on HIV replication. Am. J. Hematol., 2006. © 2006 Wiley‐Liss, Inc.
Transcriptosome and serum cytokine profiling of an atypical case of myelodysplastic syndrome with progression to acute myelogenous leukemia
Authors: Mahadevan Daruka , DiMento Johanna , Croce Kimiko Della , Riley Christopher , George Benjamin , Fuchs Deborah , Mathews Timothy , Wilson Charlton , Lobell Michael
Published: July 2006

A Native American‐Indian female presenting with anemia and thrombocytosis was diagnosed with myelodysplastic syndrome (MDS, refractory anemia). Over the course of 5 years she developed cytopenias and periods of leukocytosis with normal bone marrow (BM) blast counts, features of an unclassifiable MDS/MPS syndrome. The patient ultimately progressed to acute myelogenous leukemia (AML, FAB M2) and had a normal karyotype throughout her course. The episodes of leukocytosis were associated with infectious complications. Transformation to AML was characterized by a BM blast percentage of 49%. Peripheral blood and BM samples were obtained for serum protein analysis and gene expression profiling (GEP) to elucidate her disease process. An ELISA assay of the serum analyzed ∼80 cytokines, which demonstrated that hepatocyte growth factor/scatter factor and insulin‐like growth factor binding protein 1 were markedly elevated compared to normal. GEP demonstrated a unique “tumor molecular profile,” which included overexpression of oncogenes (HOXA9, N‐MYC, KOC1), proliferative genes (PAWR, DLG5, AKR1C3), invasion/metastatic genes (FN1, N‐CAM‐1, ITGB5), pro‐angiogenesis genes (c‐Kit), and down regulation of tumor suppressor genes (SUI1, BARD1) and anti‐apoptotic genes (PGLYRP, SERPINB2, MPO). Hence, a biomics approach has provided insight into elucidating disease mechanisms, molecular prognostic factors, and discovery of novel targets for therapeutic intervention. Am. J. Hematol., 2006. © 2006 Wiley‐Liss, Inc.
Duration of vitamin K antagonist therapy for venous thromboembolism: A systematic review of the literature
Authors: Streiff Michael B. , Segal Jodi B. , Tamariz Leonardo J. , Jenckes Mollie W. , Bolger Dennis T. , Eng John , Krishnan Jerry A. , Bass Eric B.
Published: July 2006

Purpose:

The aim of this study was to evaluate the evidence on the optimal duration of vitamin K antagonist (VKA) therapy for venous thromboembolism (VTE).

Methods:

Randomized controlled trials of VKA for VTE were identified by a computerized database search. Summary event rates for relevant outcomes were calculated using a random effects model with 95% confidence intervals (95% CI).

Results:

Ten studies met inclusion criteria. The incidence of recurrent VTE (3 months, 7.9 VTE per 100 patient‐years [95% CI, 5.2 to 10] versus 4–12 months, 4.9 VTE per 100 patient‐years [95% CI, 3.6 to 6.2] versus continuous therapy, 0.7 VTE per 100 patient‐years [95% CI, 0.3 to 1.1]) and total adverse events (3 months, 11.2 events per 100 patient‐years [95%CI, 7.1 to 15.4] versus 4–12 months, 7.4 events per 100 patient‐years [95%CI, 6.2 to 8.5] versus continuous therapy 3.1 events per 100 patient‐years [95%CI, 2.2 to 4.0] declined as VKA therapy duration increased. Continuous reduced intensity therapy (INR 1.5–2) was associated with more recurrent VTE (2.3 VTE per 100 patient‐years [95%CI, 1.5 to 3.0]). Continuous VKA therapy (INR 2–3) was beneficial for patients with a second VTE and antiphospholipid antibodies. The incidence of recurrent VTE was similar with 6 or 12 weeks of therapy for isolated calf DVT.

Conclusion:

Randomized controlled trials indicate that continuous VKA therapy (INR 2–3) for VTE is associated with better clinical outcomes than shorter durations. Patients with a second VTE or antiphospholipid antibodies also benefit from continuous anticoagulation. Patients with calf DVT should be treated for at least 6 weeks. Am. J. Hematol., 2006. © 2006 Wiley‐Liss, Inc.
Treatment of hepatitis C in hemophiliacs
Authors: Franchini Massimo , Nicolini Nicoletta , Capra Franco
Published: July 2006

Hepatitis C virus (HCV) infection is a major cause of morbidity and mortality in hemophiliacs who received nonvirucidally treated large‐pool clotting factor concentrates before 1986. In fact, although many hemophiliacs infected with HCV have a slow progression of liver disease, in a minority of them hepatitis evolves toward end‐stage liver disease and hepatocarcinoma. Moreover, a significant percentage of HCV‐infected hemophiliacs were also coinfected with human immunodeficiency virus (HIV), which can accelerate the progression of liver disease. Thus, the aim of anti‐HCV therapy is to interrupt the chronic infection in order to prevent the progression of hepatitis to cirrhosis, liver decompensation, cancer and, ultimately, death. In this review we present the literature data on anti‐HCV treatment in hemophiliacs. Combination therapy with interferon (IFN) and ribavirin has improved the poor results obtained with IFN monotherapy and has become the standard treatment of chronic hepatitis C. Given the positive results obtained with pegylated interferon plus ribavirin in nonhemophiliacs, ongoing trials are evaluating this promising therapy in HCV‐chronically infected hemophilic patients; preliminary results show a sustained response rate similar to that in patients without coagulopathy. Finally, based on the encouraging results in coinfected nonhemophiliacs, anti‐HCV treatment should also be considered for those HIV‐positive hemophiliacs in whom anti‐retroviral treatment has stabilized the HIV infection. Am. J. Hematol., 2006. © 2006 Wiley‐Liss, Inc.
Iron overload and prolonged ingestion of iron supplements: Clinical features and mutation analysis of hemochromatosis‐associated genes in four cases
Authors: Barton James C. , Lee Pauline L. , West Carol , Bottomley Sylvia S.
Published: July 2006

We evaluated and treated four white adults (one man, three women) who had iron overload associated with daily ingestion of iron supplements for 7, 15, 35, and 61 years, respectively. We performed HFE mutation analysis to detect C282Y, H63D, and S65C in each patient; in two patients, HFE exons were sequenced. In two patients, direct sequencing was performed to detect coding region mutations of TFR2, HAMP, FPN1, HJV, and ALAS2. Patients 1–4 ingested ˜153, 547, 1,341, and 4,898 g of inorganic iron as supplements. Patient 1 had hemochromatosis, HFE C282Y homozygosity, and β‐thalassemia minor. Patient 2 had spherocytosis and no HFE coding region mutations. Patient 3 had no anemia, a normal HFE genotype, and no coding region mutations in HAMP, FPN1, HJV, or ALAS2; she was heterozygous for the TFR2 coding region mutation V583I (nt 1,747 G→A, exon 15). Patient 4 had no anemia and no coding region mutations in HFE, TFR2, HAMP, FPN1, HJV, or ALAS2. Iron removed by phlebotomy was 32.4, 10.4, 15.2, and 4.0 g, respectively. There was a positive correlation of log10 serum ferritin and the quantity of iron removed by phlebotomy (P = 0.0371). Estimated absorption of iron from supplements in patients 1–4 was 20.9%, 1.9%, 1.1%, and 0.08%. We conclude that the clinical phenotypes and hemochromatosis genotypes of adults who develop iron overload after ingesting iron supplements over long periods are heterogeneous. Therapeutic phlebotomy is feasible and effective, and would prevent complications of iron overload. Am. J. Hematol., 2006. © 2006 Wiley‐Liss, Inc.