bluuebunny/crossref_metadata_2025 huggingface dataset:
Association between psychosocial factors and periodontitis: a case–control study
Authors: Castro G. D. C. , Oppermann R. V. , HAAS A. N. , Winter R. , Alchieri J. C.
Published: January 2006

Objective: This case‐control study investigated the association between life events, anxiety, and depression with periodontitis.

Methodology: The study counted with 165 individuals, both sexes, 35–60 years of age. Case group included 96 individuals suffering from periodontal disease; and in control group 69 subjects with no history of periodontitis. Clinical examinations were performed by a single examiner. Psychological assessment included four inventories: Life Events Scale, Beck Anxiety Inventory, State‐Trait Anxiety Inventory and Beck Depression Inventory. Bivariate and multivariate logistic regression analyses were performed to compare cases and controls.

Results: Mean probing depth and clinical attachment level were 3.44±0.80 and 4.01±1.61 in the case group and 1.96±0.19 and 0.95±0.50 in the control group, respectively (p<0.05). Positive association of periodontitis with age (odds ratio (OR)=1.15 95% confidence interval (CI): 1.06–1.24), male gender (OR=2.71, CI: 1.13–6.49), smoking (OR=6.05, CI: 1.67–21.94) and educational level (OR=6.49, CI: 1.14–36.95) was confirmed. Bivariate analysis did not demonstrate significant mean differences in life events, anxiety symptoms, trait or state of anxiety, or depression symptoms between cases and controls. Multivariate logistic regression, controlling for confounding factors, demonstrated no significant association between psychosocial factors and periodontal disease.

Conclusions: Within the limits of this study it is possible to conclude that there was no significant association between periodontitis and the psychosocial factors analysed.
CROSS‐MODAL ADDITIVITY OF TASTE AND SMELL
Authors: DELWICHE JEANNINE F. , HEFFELFINGER AMANDA L.
Published: January 2006

Subjects were simultaneously given subthreshold levels of taste and odor stimuli, delivered orally, for both a commonly paired and an uncommonly paired taste–odor combination. Results indicate cross‐modal summation of subthreshold concentrations of both taste–odor pairs when the olfactory stimulus is delivered orally. Results of control studies suggest that the summation was indeed across modalities, and not due to the taste of the odor compound or the smell of the taste compounds. Furthermore, results indicate that regardless of taste–odor pair commonness, taste and smell can combine in a completely additive fashion (i.e., at threshold detectability when both stimuli are presented simultaneously at 50% threshold level) if the taste–odor pair is presented orally. In several instances, but not all, measured probabilities exceeded those predicted by probability summation, indicating that hyperadditive mixing often occurs, but there do seem to be individual differences. Cross‐modal summation, regardless of taste–odor pair commonness, has broader implications for the development of foods, beverages and pharmaceuticals, especially in masking undesirable tastes and smells.
Disorders in Timing and Force of Finger Opening in Overarm Throws Made by Cerebellar Subjects
Authors: HORE J. , TIMMANN D. , WATTS S.
Published: January 2006

Abstract: Although there is agreement that an important sign of cerebellar dysfunction is disorder in timing of movement, it appears that authors who study different behaviors mean different things when they use the term “timing,” and that the underlying mechanisms are likely to be different. For overarm throwing, skilled throwers can time ball release with a precision of less than 7 ms, whereas cerebellar subjects show a large variability of 50 ms or more in this timing. Furthermore, cerebellar patients show a larger variability in the amplitude of finger opening which could either reflect a disorder in force, or result indirectly from the increased variability in timing. To determine whether timing and force of finger opening were dependent variables, the time of ball release was plotted against the amplitude of finger opening. In control subjects these two parameters were related, with early (mistimed) throws having smaller finger amplitudes. However, in cerebellar subjects the increased variability in finger amplitude could not be accounted for by the increased variability in timing. Similarly, the increased timing windows could not be explained by disorder in force at the fingers. It is concluded that the abnormal finger opening that occurs in cerebellar patients when making overarm throws results from increased variability in both the timing and force of finger extension. Whether the increased variability in timing is a disorder in triggering finger opening at the right moment, or is due to a failure to combine finger opening appropriately with the hand trajectory, remains to be determined.
The Nodulus and Uvula: Source of Cerebellar Control of Spatial Orientation of the Angular Vestibulo‐Ocular Reflex
Authors: COHEN BERNARD , JOHN PADMORE , YAKUSHIN SERGEI B. , BUETTNER‐ENNEVER JEAN , RAPHAN THEODORE
Published: January 2006

Abstract: The nodulus and rostral‐ventral uvula of the vestibulo‐cerebellum play a critical role in orienting eye velocity of the slow component of the angular vestibulo‐ocular reflex (aVOR) to gravito‐inertial acceleration (GIA). This is done by altering the time constants of “velocity storage” in the vestibular system and by generating “cross‐coupled” eye velocities that shift the eye velocity vector from along the body yaw axis to the yaw axis in a spatial frame. In this report, we show that eye velocity generated through the aVOR by constant velocity centrifugation in the monkey orients to the GIA in space, regardless of the position of the head with respect to the axis of rotation. We also show that, after removal of the nodulus and rostral‐ventral uvula, the spatial orientation of eye velocity to the GIA is lost and that eye velocity is then purely driven by the semicircular canals in a body frame of reference. These findings are further confirmation that these regions of the vestibulo‐cerebellum control spatial orientation of the aVOR.
Cerebellar Mechanisms in Eyeblink Conditioning
Authors: ATTWELL PHILIP J.E. , IVARSSON MAGNUS , MILLAR LAURIE , YEO CHRISTOPHER H.
Published: January 2006

Abstract: A recent model of cerebellar learning in eyeblink conditioning predicts two sites of plasticity, the cerebellar cortex and cerebellar nuclei, which store information relating to timing and driving the movement, respectively. Consistent with this idea, lesions of the cortex or reversible “disconnections” of Purkinje cell output to the nuclei have been shown to disrupt response timing to produce short‐latency conditioned eyeblinks. To better characterize potential cortical and nuclear plasticities, we analyzed the effects upon nictitating membrane (NM) and eyeblink conditioned responses (CRs) of different drugs administered to the cortex and to the nuclei. When either excitatory or inhibitory inputs to the cerebellar cortical lobule HVI were blocked by infusions of the AMPA receptor antagonist CNQX or the GABA‐A receptor antagonists picrotoxin or SR95531, CRs were abolished. Similarly GABA‐A receptor antagonists in the cerebellar nuclei abolished CRs. CR latencies were never shortened. However, blockade of AMPA/kainate receptor‐mediated excitatory transmission to the nuclei had no effect upon CR frequencies or latencies. These results suggest that normal cortical and nuclear function is required for performance of NM and eyeblink CRs. We saw no evidence that CRs can be driven by AMPA/kainate receptor‐mediated transmission from mossy fiber afferents to the cerebellar nuclei. So, although plasticity in the cerebellar nuclei is not ruled out, it is unlikely that a long‐term change in AMPA receptor‐mediated transmission from mossy fiber inputs to the nuclei is an essential mechanism in eyeblink conditioning. Our findings indicate that a fully functional olivo‐cortico‐nuclear loop is required to express all characteristics of associatively conditioned responses.
Dynamic Correlation of Neuronal Activity in Rat Cerebellar Cortex Modulated by Behavior
Authors: HECK DETLEF , KÜMMELL FELIX , THACH WILLIAM T. , AERTSENA AD
Published: January 2006

Abstract: Sprague‐Dawley rats (2–4 months old) were trained to perform a reaching‐grasping task while their head was fixated and multielectrode recordings were performed in the ipsilateral cerebellar hemisphere. Multiunit (MU) activity was recorded with 2–3 electrodes in the Purkinje cell layer at various depths (1.5–4.5 mm) from the pial surface while the animal either performed the reaching‐grasping task or was at rest. Recording sites were visually aligned along the transverse or the sagittal axis of Crus IIa. Excess correlations of MU spike activity were calculated at 10‐ms time resolution using the joint peristimulus time histogram (JPSTH), to reveal the dynamics of cross‐correlations corrected for nonstationarities in spike rates. Peak correlation amplitudes and areas were calculated separately for a time period preceding the movement and for a succeeding period during which the movement occurred. Correlations were compared across different paradigms: transversal versus sagittal alignment of recordings sites and behavior versus rest. No significant differences were found between transversally and sagittally aligned recording sites. Significant differences in peak correlation amplitude and/or peak area, however, were found both between premovement and movement time, as well as between both these time periods and periods while the animal was at rest.
Temporal Organization of Activity in the Cerebellar Cortex: A Manifesto for Synchrony
Authors: ISOPE PHILIPPE , DIEUDONNÉ STÉPHANE , BARBOUR BORIS
Published: January 2006

Abstract: The issues of temporal coding and the temporal organization of activity have aroused a great deal of interest in sensory systems, cortex, thalamus, and hippocampus. Strangely, despite the important timing roles attributed to the cerebellum, little consideration has been given to the organization of activity within the cerebellar circuitry. In fact, there is evidence of a remarkable temporal patterning of activity in even the earliest cerebellar recordings. The evidence for the existence of high‐frequency oscillations in the cerebellar cortex is reviewed and possible mechanisms are discussed; one involves the synchrony of parallel fiber inputs to Purkinje cells. It is shown how synchronous and oscillatory activity can enable extremely precise timing and also how they can maximize the information storage capacity of the cerebellar cortex.
Functional Significance of Climbing‐Fiber Synchrony
Authors: WELSH JOHN P.
Published: January 2006

Abstract: Population coding and behavioral approaches were taken toward analyzing the functional significance of the climbing‐fiber system. Analyses of neuronal interaction using the joint peristimulus time histogram showed that given a low rate of firing, the climbing‐fiber system organizes itself to fire synchronously during movement—a feature that bears little or no relationship to the modulation in firing rate during movement or whether olivary neurons respond to a sensory stimulus. Moreover, the climbing‐fiber system avoids synchrony during a passive sensory response but actively makes a transition into synchrony as a movement is initiated. Thus, from a functional viewpoint, the active feature of the climbing‐fiber system to organize into synchronously firing cell ensembles is uniquely motor. Analyses of behaving rats without an inferior olive revealed that the climbing‐fiber system optimizes the timing of skilled movement by reducing reaction time and the interval between repetitive movements by 100 milliseconds. Finally, using classical delay eyeblink conditioning, it was found that the inferior olive is essential for learning about rapid sequences of events but not the same event sequence when given more slowly. It was concluded that the climbing‐fiber system exerts its function through synchrony, which provides a 100 ms advantage in movement speed and the ability to learn about events that are rapidly presented in time.
Inhibitory Control of Olivary Discharge
Authors: GIBSON ALAN R. , HORN KRIS M. , PONG MILTON
Published: January 2006

Abstract: The inferior olivary nucleus is the sole source of an entire afferent system to the cerebellum, the climbing‐fiber system. Inferior olivary neurons are very sensitive to the appropriate sensory stimuli, such as light contact to the paw. Yet, when animals move about, olivary cells show little change in discharge rate. Apparently some mechanism prevents the cells from discharging to stimuli generated by the animal's own movement. The inferior olive receives a massive inhibitory input from small cells in the cerebellar and vestibular nuclei. This article reviews the results from several experiments that suggest that the inferior olive is specifically targeted by inhibitory inputs that prevent responses to stimuli resulting from self‐produced movement. Oscarsson proposed that the inferior olive provides the cerebellum with information about errors of motor performance and about spinal reflexes. We argue that it is unlikely that the inferior olive provides information about movement errors, although the olive may signal the occurrence of sensory events that are likely to elicit reflex movements. Another popular theory of climbing‐fiber action argues that the climbing fibers play a role in altering the strength of the parallel fiber‐Purkinje cell synapse. The cerebellum is important for the formation of classically conditioned responses, and input generated by the unconditioned stimulus does provide effective stimulation of olivary neurons. Although the olive does not generate the unconditioned response, it may provide the cerebellum with information necessary for the formation of conditioned responses.
Complex Spike Activity in the Flocculus Signals More than the Eye Can See
Authors: SIMPSON J. I. , BELTON T. , SUH M. , WINKELMAN B.
Published: January 2006

Abstract: Modulation of the complex spike activity of Purkinje cells in the cerebellar flocculus can convey not only visual signals but also nonvisual signals. The nonvisual complex spike modulation, which is readily observed with vestibular stimulation of the awake rabbit in darkness, is approximately in‐phase with the concomitant simple spike modulation. This nonreciprocal relationship contrasts to the reciprocal relationship found when the rabbit is afforded vision.
Historical Review of the Significance of the Cerebellum and the Role of Purkinje Cells in Motor Learning
Authors: ITO MASAO
Published: January 2006

Abstract:Classic studies of the cerebellum before the middle of the twentieth century established the structural entity of the cerebellum and characterized its function as enabling animals and humans to carry out smooth and accurate movements, even at a high speed and without visual feedback. In the 1960s, neuronal circuit structures of the cerebellum were analyzed in detail, which promoted computational approaches toward the study of neuronal network principles of the cerebellum. In the 1970s and 1980s, vestibulo‐ocular reflex adaptation, adaptive locomotion, eye blink conditioning, and learning in hand/arm movement were established as effective experimental paradigms for investigating neural mechanisms of cerebellar functions. In the 1980s, long‐term depression (LTD) was discovered and considered as a memory process in the cerebellum; in the 1990s, complex signal transduction processes underlying LTD were revealed. It was also in the 1980s that computational approaches were advanced for modeling control system functions of the cerebellum. Currently, there are two alternative models proposed for VOR adaptation. In this decade, we envisage new developments toward the fusion of knowledge of the cerebellum at molecular and cellular levels and those in systems and computation. Studies of LTD will play a key role in pursuing this direction.
Role of the Posterolateral Cerebellum in Language
Authors: GEBHART ANDREA L. , PETERSEN STEVEN E. , THACH W. T.
Published: January 2006

Abstract: Historically, scientists have believed that the cerebellum controls only movement. However, recent evidence from neuroimaging and human lesion studies suggests that the right posterolateral cerebellar hemisphere is involved, independently of movement, in helping an individual to generate verbs for given nouns. We sought to elucidate the key factors contributing to the verb generation deficits of subjects with right posterolateral cerebellar damage and thus to better understand the specific contributions of the postero‐lateral cerebellum to language. We compared the performance of subjects with focal left‐sided posterolateral cerebellar lesions, those with focal right‐sided posterolateral cerebellar lesions, and neurologically normal pilot control subjects on an antonym generation task, noun (category member) generation task, verb selection task, and lexical decision task. Preliminary results show that subjects with right cerebellar lesions are impaired relative to other subjects only on the antonym generation task. The results provide evidence that the right cerebellar language deficit is not due solely to deficits in “mental movement” coupled to a verb and that internal generation of a word seems to be a key factor in eliciting a deficit. In addition, a semantic processing demand may be necessary but insufficient to elicit a right cerebellar language deficit. The results support the theory that the right posterolateral cerebellar hemisphere assists the left cerebral hemisphere in helping an individual learn to generate specific types of spoken, two‐word associations. The full nature of this process awaits further investigation.
The Making of a Complex Spike: Ionic Composition and Plasticity
Authors: SCHMOLESKY MATTHEW T. , WEBER JOHN T. , de ZEEUW CHRIS I. , HANSEL CHRISTIAN
Published: January 2006

Abstract: Climbing fiber (CF) activation evokes a large all‐or‐nothing electrical response in Purkinje cells (PCs), the complex spike. It has been suggested that the role of CFs (and thus complex spikes) is that of a “teacher” in simple learning paradigms such as associative eyeblink conditioning. An alternative hypothesis describes the olivocerebellar system as part of a timing device and denies a role of the CF input in learning. To date, neither of these hypotheses nor others can definitively be verified or discounted. Similarly, the complex spike evades a clear understanding when it comes to the cellular events underlying complex spike generation. What is known, however, is that complex spikes are associated with large dendritic calcium signals that are required for the induction of long‐term depression (LTD) at the parallel fiber (PF)‐PC synapse. PF‐LTD is a form of long‐term synaptic plasticity that has been suggested to underlie certain forms of cerebellar motor learning. In contrast to the PF input, the CF input has been considered invariant. Our recent discovery of LTD at the CF input shows that complex spikes are less static than previously assumed. In addition to depression of CF‐evoked excitatory postsynaptic currents, long‐lasting, selective reduction of slow complex spike components could be observed after brief CF tetanization. To understand the functional implications of CF‐LTD, it is crucial to know the types of currents constituting the specific complex spike components. Here we review the “anatomy” of the complex spike as well as our observations of activity‐dependent complex spike waveform modifications. In addition, we discuss which properties CF‐LTD might add to the circuitry of the cerebellar cortex.
Motor Performance and Motor Learning in Lurcher Mice
Authors: Van ALPHEN A. M. , SCHEPERS T. , LUO C. , de ZEEUW C. I.
Published: January 2006

Abstract: In adult Lurcher mice virtually all cerebellar Purkinje cells have degenerated as a direct consequence of mutant gene action, providing a natural model for studying the effect of cerebellar cortical lesions on the generation of compensatory eye movements. Lurcher mice possess both optokinetic (OKR) and vestibular (VOR) compensatory reflexes. However, clear differences were observed in control of the OKR consisting of a large reduction in gain and a moderate increase in phase lag. Minor differences were also observed in the VOR in that gain and phase lead of the reflex were both increased in Lurcher animals. Subjecting Lurcher animals to eight days of visuovestibular training tested the assumption that increased VOR gain reflected an adaptive mechanism within remaining brainstem oculomotor pathways to compensate for the reduced OKR. Contrary to control animals, Lurcher animals were unable to modify either VOR or OKR in the course of training and therefore confirmed that an intact cerebellum is indispensable for the implementation of adaptive modifications to the oculomotor system.
Cerebellar Plasticity and the Ocular Following Response
Authors: YAMAMOTO KENJI , KOBAYASHI YASUSHI , TAKEMURA AYA , KAWANO KENJI , KAWATO MITSUO
Published: January 2006

Abstract: We constructed a realistic simulation model to elucidate whether the characteristics of the cerebellar synaptic plasticity reported in vitro guide the acquisition and adaptation of the ocular following response (OFR). The model reconstructed the firing frequency of the inputs of granule cell axons (GCA), inhibitory cells (IC), and climbing fibers (CF) to cerebellar Purkinje cells for the OFR, to simulate the reported cerebellar plasticity, including long‐term depression, long‐term potentiation, and rebound potentiation. When the model used the same visual inputs as reported for monkeys, it successfully simulated the real characteristics of simple spikes in Purkinje cells of adult monkeys and adaptation of gain and direction. The success of our simulation relied on the temporal relationship of the synaptic weight changes when CF inputs preceded GCA and IC inputs, corresponding to the relationship reported by Chen and Thompson and reanalysis of the data of Karachot et al. The success of our simulation strongly suggests that acquisition and adaptation of the OFR arise from cerebellar plasticity.
Modeling Cerebellar Flocculus and Paraflocculus Involvement in Complex Predictive Smooth Eye Pursuit in Monkeys
Authors: KETTNER RONALD E. , SUH MINAH , DAVIS DITA , LEUNG HOI‐CHUNG
Published: January 2006

Abstract: The role of flocculus and paraflocculus neurons in the cerebellar control of predictive eye movements was examined using two modeling techniques. The first study characterized the dependence of individual Purkinje‐cell firing patterns on oculomotor output, visual input, and response timing using multilinear regression techniques. Interestingly, no dependence on visual input was detected. Purkinje cell firing was explained by sensitivities to eye position and eye velocity alone. However, complex responses occurred when sensitivity vectors pointed in different directions. For example, some neurons showed a preference for circular pursuit in a particular rotation direction. Responses also tended to lead the eye during predictable pursuit and to lag during unpredictable, visually driven pursuit. This suggests that flocculus and paraflocculus neurons played a stronger role during predictive pursuit than visually driven pursuit. A second modeling study demonstrated how the flocculus/paraflocculus system might generate predictive pursuit. A biologically realistic neural network was simulated based on the known anatomy and physiology of this cerebellar system. It included mossy and climbing fibers with realistic responses, Purkinje cells acting on well‐characterized brain‐stem circuits, and granule, Golgi, basket, and stellate cells with appropriate connections. The network was able to learn new pursuit trajectories based on long‐term alterations in synaptic connectivity at parallel‐to‐Purkinje synapses. Interestingly, this model was able to generate predictive pursuit without visual input based only on eye‐motion input. Thus, both models provide complementary evidence for the generation of nonvisual predictive control by flocculus and paraflocculus neurons.
Erythrocytes and the regulation of human skeletal muscle blood flow and oxygen delivery: role of erythrocyte count and oxygenation state of haemoglobin
Authors: González‐Alonso José , Mortensen Stefan P. , Dawson Ellen A. , Secher Niels H. , Damsgaard Rasmus
Published: January 2006

Blood flow to dynamically contracting myocytes is regulated to match O2 delivery to metabolic demand. The red blood cell (RBC) itself functions as an O2 sensor, contributing to the control of O2 delivery by releasing the vasodilators ATP and S‐nitrosohaemoglobin with the offloading of O2 from the haemoglobin molecule. Whether RBC number is sensed remains unknown. To investigate the role of RBC number, in isolation and in combination with alterations in blood oxygenation, on muscle and systemic perfusion, we measured local and central haemodynamics during one‐legged knee‐extensor exercise (∼50% peak power) in 10 healthy males under conditions of normocythaemia (control), anaemia, anaemia + plasma volume expansion (PVX), anaemia + PVX + hypoxia, polycythaemia, polycythaemia + hyperoxia and polycythaemia + hypoxia, which changed either RBC count alone or both RBC count and oxyhaemoglobin. Leg blood flow (LBF), cardiac output (Q) and vascular conductance did not change with either anaemia or polycythaemia alone. However, LBF increased with anaemia + PVX (28 ± 4%) and anaemia + PVX + hypoxia (46 ± 6%) and decreased with polycythaemia + hyperoxia (18 ± 5%). LBF and Q with anaemia + PVX + hypoxia (8.0 ± 0.5 and 15.8 ± 0.7 l min−1, respectively) equalled those during maximal knee‐extensor exercise. Collectively, LBF and vascular conductance were intimately related to leg arterial–venous (a–v) O2 difference (r2= 0.89–0.93; P < 0.001), suggesting a pivotal role of blood O2 gradients in muscle microcirculatory control. The systemic circulation accommodated to the changes in muscle perfusion. Our results indicate that, when coping with severe haematological challenges, local regulation of skeletal muscle blood flow and O2 delivery primarily senses alterations in the oxygenation state of haemoglobin and, to a lesser extent, alterations in the number of RBCs and haemoglobin molecules.
Xanthine oxidase does not contribute to impaired peripheral conduit artery endothelium‐dependent dilatation with ageing
Authors: Eskurza Iratxe , Kahn Zachary D. , Seals Douglas R.
Published: January 2006

Vascular oxidative stress is the key mechanism involved in the age‐related decline in endothelium‐dependent dilatation (EDD). We tested the hypothesis that xanthine oxidase (XO), a major vascular source of reactive oxygen species, contributes to the impairment in EDD with ageing. At baseline, brachial artery flow‐mediated dilatation (FMD) was 55% lower in older (n= 9, 64 ± 2 years, 8M/1F, mean ±s.e.m.) versus young (n= 9, 26 ± 1 years, 8M/1F) healthy adults (3.41 ± 0.44 versus 7.53 ± 0.67%, P < 0.001), whereas endothelium‐independent dilatation (EID; sublingual nitroglycerin) did not differ between groups. Plasma oxidized low‐density lipoprotein (oxi‐LDL), a measure of systemic oxidative stress, was greater at baseline in the older subjects (58.3 ± 5.9 versus 46.8 ± 2.4 U l−1, P < 0.05) and inversely correlated with baseline FMD (r=− 0.54; P < 0.05). Acute administration of allopurinol, a competitive inhibitor of XO, reduced plasma uric acid concentrations similarly in both groups (P < 0.001), but did not affect FMD, EID, or oxi‐LDL in either group. Vascular endothelial protein expression of XO (immunofluorescence) was not different in antecubital venous cells from the young and older subjects (0.56 ± 0.12 versus 0.68 ± 0.19 XO intensity/human umbilical vein endothelial cell intensity, P= 0.49). We conclude that XO does not contribute to oxidative stress‐associated reductions in peripheral conduit artery EDD with ageing in humans, possibly due to an absence of age‐associated up‐regulation of endothelial XO.
Motor commands contribute to human position sense
Authors: Gandevia Simon C. , Smith Janette L. , Crawford Matthew , Proske Uwe , Taylor Janet L.
Published: January 2006

The role of afferent inflow and efferent outflow (or command) signals in judgements of limb position has been debated for over a century. One way to assess this is to check for changes during complete paralysis, with the current view being that perceived movements or position changes do not usually accompany attempts to contract paralysed muscles. To re‐examine this, we asked six naïve subjects to carry out a simple position‐matching task at the wrist. In the absence of vision, subjects accurately perceived the position to which their right wrist had been moved by the experimenter by matching it with their left hand. There was no significant change in perception when position was matched during sustained flexion or extension efforts. Then we paralysed and anaesthetized the right arm with ischaemia in order to produce a ‘phantom’ hand. The perceived position of the wrist changed by more than 20 deg when subjects attempted to flex or extend their hand when it was paralysed and anaesthetized. Further studies showed that this illusion was not dependent on the way in which the paralysis was produced and that the size of the position illusion increased when the level of effort during paralysis increased. These results establish for the first time a definitive role for ‘outflow’ signals in position sense.
Muscarinic receptor activation tunes mouse stratum oriens interneurones to amplify spike reliability
Authors: Lawrence J. Josh , Grinspan Zachary M. , Statland Jeffrey M. , McBain Chris J.
Published: January 2006

Cholinergic activation of hippocampal targets can initiate and sustain network oscillations in vivo and in vitro, yet the impact of cholinergic modulation on the oscillatory properties of interneurones remains virtually unexplored. Using whole cell current clamp recordings in acute hippocampal slices, we investigated the influence of muscarinic receptor (mAChR) activation on the oscillatory properties of CA1 stratum oriens (SO) interneurones in vitro. In response to suprathreshold oscillatory input, mAChR activation increased spike reliability and precision, and extended the bandwidth that interneurone firing phase‐locked. These suprathreshold effects were largest at theta frequencies, indicating that mAChR activation tunes active conductances to enhance firing reliability and precision to theta frequency input. Muscarinic tuning of the intrinsic oscillatory properties of interneurones is a novel mechanism that may be crucial for the genesis of the theta rhythm.
GABAA, GABAC and glycine receptor‐mediated inhibition differentially affects light‐evoked signalling from mouse retinal rod bipolar cells
Authors: Eggers Erika D. , Lukasiewicz Peter D.
Published: January 2006

Rod bipolar cells relay visual signals evoked by dim illumination from the outer to the inner retina. GABAergic and glycinergic amacrine cells contact rod bipolar cell terminals, where they modulate transmitter release and contribute to the receptive field properties of third order neurones. However, it is not known how these distinct inhibitory inputs affect rod bipolar cell output and subsequent retinal processing. To determine whether GABAA, GABAC and glycine receptors made different contributions to light‐evoked inhibition, we recorded light‐evoked inhibitory postsynaptic currents (L‐IPSCs) from rod bipolar cells mediated by each pharmacologically isolated receptor. All three receptors contributed to L‐IPSCs, but their relative roles differed; GABAC receptors transferred significantly more charge than GABAA and glycine receptors. We determined how these distinct inhibitory inputs affected rod bipolar cell output by recording light‐evoked excitatory postsynaptic currents (L‐EPSCs) from postsynaptic AII and A17 amacrine cells. Consistent with their relative contributions to L‐IPSCs, GABAC receptor activation most effectively reduced the L‐EPSCs, while glycine and GABAA receptor activation reduced the L‐EPSCs to a lesser extent. We also found that GABAergic L‐IPSCs in rod bipolar cells were limited by GABAA receptor‐mediated inhibition between amacrine cells. We show that GABAA, GABAC and glycine receptors mediate functionally distinct inhibition to rod bipolar cells, which differentially modulated light‐evoked rod bipolar cell output. Our findings suggest that modulating the relative proportions of these inhibitory inputs could change the characteristics of rod bipolar cell output.
Programming placental nutrient transport capacity
Authors: Fowden A. L. , Ward J. W. , Wooding F. P. B. , Forhead A. J. , Constancia M.
Published: January 2006

Many animal studies and human epidemiological findings have shown that impaired growthin uterois associated with physiological abnormalities in later life and have linked this to tissue programming during suboptimal intrauterine conditions at critical periods of development. However, few of these studies have considered the contribution of the placenta to the ensuing adult phenotype. In mammals, the major determinant of intrauterine growth is the placental nutrient supply, which, in turn, depends on the size, morphology, blood supply and transporter abundance of the placenta and on synthesis and metabolism of nutrients and hormones by the uteroplacental tissues. This review examines the regulation of placental nutrient transfer capacity and the potential programming effects of nutrition and glucocorticoid over‐exposure on placental phenotype with particular emphasis on the role of theIgf2gene in these processes.
Large-Scale Sequence Analysis of Avian Influenza Isolates
Authors: Obenauer John C. , Denson Jackie , Mehta Perdeep K. , Su Xiaoping , Mukatira Suraj , Finkelstein David B. , Xu Xiequn , Wang Jinhua , Ma Jing , Fan Yiping , Rakestraw Karen M. , Webster Robert G. , Hoffmann Erich , Krauss Scott , Zheng Jie , Zhang Ziwei , Naeve Clayton W.
Published: January 2006

The spread of H5N1 avian influenza viruses (AIVs) from China to Europe has raised global concern about their potential to infect humans and cause a pandemic. In spite of their substantial threat to human health, remarkably little AIV whole-genome information is available. We report here a preliminary analysis of the first large-scale sequencing of AIVs, including 2196 AIV genes and 169 complete genomes. We combine this new information with public AIV data to identify new gene alleles, persistent genotypes, compensatory mutations, and a potential virulence determinant.
A Molecular Jump Mechanism of Water Reorientation
Authors: Laage Damien , Hynes James T.
Published: January 2006

Despite long study, a molecular picture of the mechanism of water reorientation is still lacking. Using numerical simulations, we find support for a pathway in which the rotating water molecule breaks a hydrogen bond (H-bond) with an overcoordinated first-shell neighbor to form an H-bond with an undercoordinated second-shell neighbor. The H-bond cleavage and the molecular reorientation occur concertedly and not successively as usually considered. This water reorientation mechanism involves large-amplitude angular jumps, rather than the commonly accepted sequence of small diffusive steps, and therefore calls for reinterpretation of many experimental data wherein water rotational relaxation is assumed to be diffusive.
Synthesis of Aminopropyl Phosphonate Nucleosides with Purine and Pyrimidine Bases
Authors: Zhou Ding , Lagoja Irene M. , Van Aerschot Arthur , Herdewijn Piet
Published: January 2006

The synthesis and antiviral evaluation of new acyclic phosphonate nucleosides related to HPMPC (Cidofovir) has been described. These aminopropyl phosphonate nucleosides 1-3 have an amino function within either the acyclic chain (series 2 and 3) or as substituent (series 1). Both purine and pyrimidine nucleotide analogues have been synthesized. In contrast to HPMPC the oxygen analogue of 2c, only a weak antiherpes virus activity could be demonstrated for 2b and 2c.
Interferon γ accelerates NF-κB activation of biliary epithelial cells induced by Toll-like receptor and ligand interaction
Authors: Harada K , Isse K , Nakanuma Y
Published: January 2006

Background:The Toll-like receptor (TLR) family recognises pathogen associated molecular patterns (PAMPs) and plays a pivotal role in the innate immune response. Biliary epithelial cells (BECs) lining the intrahepatic bile ducts are potentially exposed to bacterial components in bile, and murine BECs possess TLRs that recognise PAMPs, resulting in nuclear factor κB (NF-κB) activation.

Aims:To examine the presence of TLRs in human BECs and the influence of cytokines and PAMPs on TLR expression and NF-κB activation.

Methods:The expression of TLR2–5, MD-2, MyD88, and IRAK1 was examined in human liver tissue and cultured BECs by immunohistochemistry or reverse transcription polymerase chain reaction. The influence of PAMPs (peptidoglycan and lipopolysaccharide) in cultured cells preincubated with interferon γ (IFNγ) was evaluated by NF-κB activation.

Results:TLR2–5, MyD88, and IRAK-1 proteins were detectable in BECs of the intrahepatic biliary tree in human liver tissue. TLR2–5, MD-2, MyD88, and IRAK-1 mRNA was demonstrated in human cultured BECs. The expression of these TLRs was upregulated by IFNγ, and TLR2 was upregulated by tumour necrosis factor α. Interleukins 4 and 6 failed to induce TLR upregulation. Interestingly, preincubation with IFNγ synergistically increased the upregulation of NF-κB induced by PAMPs in cultured BECs.

Conclusion:These results suggest that the TLR family is present in human biliary cells and participates in the innate immunity of the intrahepatic biliary tree. Disordered regulation of TLRs after intracellular signalling by cytokines and PAMPs may be involved in immune mediated biliary diseases.
Prognostic value of stage IV neuroblastoma metastatic immunophenotype in the bone marrow: preliminary report: Table 1
Authors: Nowicki M , Ostalska-Nowicka D , Miskowiak B
Published: January 2006

Aim:To correlate the immunophenotype of metastatic cells in the bone marrow of patients with neuroblastoma with early treatment failure.

Methods:The studies were performed on bone marrow material obtained from children treated in the department of paediatric oncology, haematology, and transplantology, Poznan University of Medical Sciences, Poland from 1996 to 2003. Immunocytochemical analysis of nervous tissue markers (using the immunomax technique) was performed on 108 bone marrow preparations obtained from 36 children diagnosed with neuroblastoma (stage IV with bone marrow metastases). The analysis included expression of PGP 9.5 protein, substance P, chromogranin A, bombesin, galanin, neuropeptide Y (NPY), and vasoactive intestinal peptide in neuroblastoma metastatic cells defined by the expression of neurone specific enolase.

Results:Nineteen relapses occurred within 12 months of the end of treatment. Correlation between the various markers studied and early treatment failure, using Fisher’s exact test, revealed that chromogranin A and NPY are strong indicators of an unfavourable prognosis in patients with stage IV neuroblastoma (p < 0.001 and p < 0.0002, respectively).

Conclusion:Determination of metastatic cell immunophenotypes in bone marrow (particularly chromogranin A and NPY) may help establish the short term prognosis in children with neuroblastoma.
Usefulness of the MicroSeq 500 16S rDNA bacterial identification system for identification of anaerobic Gram positive bacilli isolated from blood cultures
Authors: Lau S K P , Ng K H L , Woo P C Y , Yip K-t , Fung A M Y , Woo G K S , Chan K-m , Que T-l , Yuen K-y
Published: January 2006

Using full 16S ribosomal RNA (rRNA) gene sequencing as the gold standard, 20 non-duplicating anaerobic Gram positive bacilli isolated from blood cultures were analysed by the MicroSeq 500 16S rDNA bacterial identification system. The MicroSeq system successfully identified 13 of the 20 isolates. Four and three isolates were misidentified at the genus and species level, respectively. Although the MicroSeq 500 16S rDNA bacterial identification system is better than three commercially available identification systems also evaluated, its database needs to be expanded for accurate identification of anaerobic Gram positive bacilli.
Platelet volume indices in patients with coronary artery disease and acute myocardial infarction: an Indian scenario
Authors: Khandekar M M , Khurana A S , Deshmukh S D , Kakrani A L , Katdare A D , Inamdar A K
Published: January 2006

Aims:To study platelet volume indices (PVI) in the spectrum of ischaemic heart diseases.

Methods:A total of 210 cases were studied; 94 patients had unstable angina (UA) or acute myocardial infarction (AMI) diagnosed on the basis of history, characteristic electrocardiographic changes, and increased cardiac enzyme activities. Seventy patients had stable coronary artery disease (stable CAD) or were admitted for a coronary angiography or coronary artery bypass graft procedure. The third group comprised 30 age and sex matched healthy controls with no history of heart disease and a normal electrocardiogram.

Results:All PVI—mean platelet volume (MPV), platelet distribution width (PDW), and platelet large cell ratio (P-LCR)—were significantly raised in patients with AMI and UA (mean MPV, 10.43 (SD, 1.03) fL; mean PDW, 13.19 (SD, 2.34) fL; mean P-LCR, 29.4% (SD, 7.38%)) compared with those with stable CAD (mean MPV, 9.37 (SD, 0.99) fL; mean PDW, 11.35 (SD, 1.95) fL; mean P-LCR, 22.55% (SD, 6.65%)) and the control group (mean MPV, 9.2 (SD, 0.91) fL; mean PDW, 10.75 (SD, l.42) fL; mean P-LCR, 20.65% (SD, 6.14%)).

Conclusions:Larger platelets are haemostatically more active and are a risk factor for developing coronary thrombosis, leading to myocardial infarction. Patients with larger platelets can easily be identified during routine haematological analysis and could possibly benefit from preventive treatment. Thus, PVI are an important, simple, effortless, and cost effective tool that should be used and explored extensively, especially in countries such as India, for predicting the possibility of impending acute events.
Impact of a national external quality assessment scheme for breast pathology in the UK
Authors: Ellis I O , Coleman D , Wells C , Kodikara S , Paish E M , Moss S , Al-sam S , Anderson N , Bobrow L , Buley I , Connolly C E , Dallimore N S , Hales S , Hanby A , Humphreys S , Knox F , Lowe J , Macartney J , Nash R , Parham D , Patnick J , Pinder S E , Quinn C M , Robertson A J , Shrimankar J , Walker R A , Winder R
Published: January 2006

Background:This article presents the results and observed effects of the UK National Health Service Breast Screening Programme (NHSBSP) external quality assurance scheme in breast histopathology.

Aims/Methods:The major objectives were to monitor and improve the consistency of diagnoses made by pathologists and the quality of prognostic information in pathology reports. The scheme is based on a twice yearly circulation of 12 cases to over 600 registered participants. The level of agreement was generally measured using κ statistics.

Results:Four main situations were encountered with respect to diagnostic consistency, namely: (1) where consistency is naturally very high—this included diagnosing in situ and invasive carcinomas (and certain distinctive subtypes) and uncomplicated benign lesions; (2) where the level of consistency was low but could be improved by making guidelines more detailed and explicit—this included histological grading; (3) where consistency could be improved but only by changing the system of classification—this included classification of ductal carcinoma in situ; and (4) where no improvement in consistency could be achieved—this included diagnosing atypical hyperplasia and reporting vascular invasion. Size measurements were more consistent for invasive than in situ carcinomas. Even in cases where there is a high level of agreement on tumour size, a few widely outlying measurements were encountered, for which no explanation is readily forthcoming.

Conclusions:These results broadly confirm the robustness of the systems of breast disease diagnosis and classification adopted by the NHSBSP, and also identify areas where improvement or new approaches are required.
Caspase activity is downregulated in choriocarcinoma: a cDNA array differential expression study
Authors: Fong P-Y , Xue W-C , Ngan H Y S , Chiu P-M , Chan K Y K , Tsao S W , Cheung A N Y
Published: January 2006

Background:Placental trophoblast can be considered to be pseudomalignant tissue and the pathogenesis of gestational trophoblastic diseases remains to be clarified.

Aims:To examine the role of caspases 8 and 10, identified by differential expression, on trophoblast tumorigenesis.

Methods:cDNA array hybridisation was used to compare gene expression profiles in choriocarcinoma cell lines (JAR, JEG, and BeWo) and normal first trimester human placentas, followed by confirmation with quantitative real time polymerase chain reaction and immunohistochemistry. Caspase 10 and its closely related family member caspase 8 were analysed.

Results:Downregulation of caspase 10 in choriocarcinoma was detected by both Atlas™ human cDNA expression array and Atlas™ human 1.2 array. Caspase 10 mRNA expression was significantly lower in hydatidiform mole (p  =  0.035) and chorioarcinoma (p  =  0.002) compared with normal placenta. The caspase 8 and 10 proteins were expressed predominantly in the cytotrophoblast and syncytiotrophoblast, respectively, with significantly lower expression in choriocarcinomas than other trophoblastic tissues (p < 0.05). Immunoreactivity for both caspase 8 and 10 correlated with the apoptotic index previously assessed by terminal deoxynucleotidyl transferase mediated dUTP nick end labelling (p  =  0.02 and p  =  0.04, respectively) and M30 (p < 0.001 and p  =  0.003, respectively) approaches.

Conclusions:These results suggest that the downregulation of capases 8 and 10 might contribute to the pathogenesis of choriocarcinoma.
Immunohistochemical assessment of hepatitis C virus antigen in cholestatic hepatitis after liver transplantation
Authors: Fenwick F , Bassendine M F , Agarwal K , Bevitt D , Pumeechockchai W , Burt A D , Toms G L
Published: January 2006

Background:Patients with common variable immunodeficiency may exhibit rapidly progressive hepatitis when infected with hepatitis C virus (HCV), leading to cirrhosis and liver failure. Liver transplantation in these patients may result in a cholestatic form of HCV reinfection with exceptionally high virus loads.

Aims:To report an immunohistochemical investigation of the pretransplant and post-transplant liver of one such patient.

Methods/Results:On immunohistochemical staining of frozen sections with anti-HCV core monoclonal antibody or fluorescein labelled human polyclonal anti-HCV IgG, no HCV antigens were demonstrated in the native cirrhotic liver removed at transplant, despite a viral load of 106.4genomes/g. The transplanted liver, collected six weeks post-transplant, exhibited cholestatic recurrent hepatitis, had an HCV virus load of 1010genomes/g of liver, and revealed HCV antigen in the cytoplasm of most hepatocytes, with a pronounced periportal distribution. No virus antigen was demonstrable in other cell types. The core antigen was also detected in paraffin wax embedded, formaldehyde fixed tissue of this liver after high temperature antigen retrieval, but not in the native cirrhotic liver or a selection of HCV positive livers collected pretransplant from immunocompetent patients. Attempts to delineate the distribution of E1, NS3, and NS4 antigens were unsuccessful because monoclonal antibodies to these antigens produced “false positive” staining of foci of hepatocytes in the post-transplant livers of HCV seronegative patients with cholestasis.

Conclusion:This case provided an opportunity to study the natural development of HCV during acute infection in the absence of an immune response, and may help to elucidate the pathogenesis of HCV recurrence in liver allografts.