bluuebunny/crossref_metadata_2025 huggingface dataset:
The role of a relative age effect in the first winter Youth Olympic Games in 2012
Authors: Raschner Christian , Müller Lisa , Hildebrandt Carolin
Published: September 2012

Background

Owing to the separation into age groups at the first winter Youth Olympic Games (YOG), athletes differed in age by up to two years, leading to a potential relative age effect (RAE).

Objective

The purpose of this study was to define the role of the RAE in the first winter YOG with regard to sex, type of sport and performance.

Methods

The birth dates and anthropometric data of all 1021 athletes (557 male, 464 female, 14–19 years old) participating in 15 sports were analysed. A χ2test was used to assess the difference between the observed and expected birth distributions. ANOVA (analysis of variance) and Kruskal−Wallis analyses were used to investigate differences in anthropometrics.

Results

The birth date distribution of the overall sample was significantly different from an equal distribution, with an over-representation of athletes born shortly after the cut-off date (χ2=284.7, p<0.001). A significant RAE was found in both male (χ2=245.1, p<0.001) and female competitors (χ2=74.6, p<0.001). An analysis based on the type of sport showed an RAE in all categories (strength—χ2=229.9, p<0.001, endurance—χ2=60.4, p<0.001 and technique-related sports χ2=25.2, p=0.001). Relatively older competitors were also over-represented among medal winners (χ2=47.9, p<0.001). Relatively older male competitors were significantly taller (p=0.005) and heavier (p<0.001) than younger competitors. No differences were found in female competitors.

Conclusions

The results suggest that relative age had a highly significant influence on participation in various sports regardless of sex. A possible strategy to reduce the RAE would be a fixed quota for each birth year within the two-year age group across events.
Performance and palliative care: a drama module for medical students
Authors: Jeffrey Ewan James , Goddard Jen , Jeffrey David
Published: September 2012

This paper describes an innovative 2 weeks module for medical students facilitated by drama educators and a palliative medicine doctor. The module incorporates drama, end-of-life care, teamwork and reflective practice. The module contents, practical aspects of drama teaching and learning outcomes are discussed. Various themes emerged from a study of Harold Pinter's play,The Caretaker, which were relevant to clinical practice: silence, power, communication, uncertainty and unanswered questions. Drama teaching may be one way of enhancing students’ confidence, increasing self- awareness, developing ethical thinking and fostering teamworking.
Paediatric intra-axial posterior fossa tumours: pictorial review
Authors: Rasalkar Darshana D , Chu Winnie Chiu-wing , Paunipagar Bhawan K , Cheng Frankie W T , Li C K
Published: September 2012

Paediatric brain tumours commonly arise in the posterior cranial fossa. Early diagnosis is often challenging due to initial non-specific clinical symptoms, especially in very young children. The typical MR features of tumours in this region including medulloblastoma, ependymoma, juvenile pilocytic subtype of cerebellar astrocytoma, brain stem glioma and atypical teratoid–rhabdoid tumour are illustrated. Diffusion-weighted imaging and apparent diffusion coefficient values combined with signal characteristics on conventional MR sequences can usually differentiate low-grade from high-grade tumours. Prompt diagnosis is crucial as total surgical resection, which is only possible in localised disease, improves prognosis. A practical MR flow chart is introduced for differentiating different types of posterior cranial fossa tumours, which might be useful in clinical practice.
Scleritis: presentations, disease associations and management
Authors: Sims Joanne
Published: September 2012

Scleritis is a serious inflammatory condition that is often painful, and in severe cases can result in permanent loss of vision. Approximately half the patients affected have no identifiable cause, but 30%–40% have an underlying systemic autoimmune condition. Scleritis may be the initial manifestation of Wegener's granulomatosis or rheumatoid arthritis, and all patients with scleritis require a thorough systemic evaluation.

Scleritis has a variable presentation and disease course, and may be an acute monophasic illness, a relapsing remitting process, or take a chronic course. Treatment options include local therapy with subconjunctival steroid injections for non-necrotising scleritis, and systemic anti-inflammatory or immunosuppressive therapy. Biologic agents have been used with success in some refractory cases. Ocular and systemic morbidity is reduced by timely treatment with immunosuppressant medications.
The risk of serious adverse outcomes associated with hypoxaemia and hyperoxaemia in acute exacerbations of COPD
Authors: Cameron Laird , Pilcher Janine , Weatherall Mark , Beasley Richard , Perrin Kyle
Published: September 2012

Background

Prehospital high concentration oxygen therapy leads to worse clinical outcomes in patients presenting with acute exacerbations of chronic obstructive pulmonary disease (AECOPD). Less is known about the risks of hypoxaemia despite oxygen treatment. Current respiratory and ambulance guidelines recommend titration of supplemental oxygen to a target oxygen saturation range of 88%–92%.

Aim

To explore the association between PaO2 and risk of serious adverse clinical outcomes in AECOPD.

Methods

A retrospective review of consecutive patients presenting via ambulance to the Wellington Regional Hospital Emergency Department with AECOPD between June 2005 and January 2008. Patients with an arterial blood gas taken within 4 h of triage were included in the study and were categorised as hypoxaemic (PaO2<60 mm Hg), normoxaemic (PaO2 60–100 mm Hg) or hyperoxaemic (PaO2>100 mm Hg). Serious adverse outcome was defined as a composite of hypercapnic respiratory failure, assisted ventilation or inpatient death. Multivariate logistic regression analysis examined the association between PaO2 category and the composite outcome.

Results

Of the 680 patients presenting with AECOPD in the review period, 254 presentations in 180 patients had data suitable for analysis. Hyperoxaemia occurred in 61/254 (24%) presentations and was strongly associated with serious adverse outcome compared with normoxaemia (OR 9.17, 95% CI 4.08 to 20.6). Hypoxaemia was also associated with an increased risk of serious adverse outcome compared with normoxaemia (OR 2.16, 95% CI 1.11 to 4.20). Compared with the recommended target oxygen saturation range of 88%–92%, the risk of a serious adverse outcome was increased in both the <88% group (OR 2.0, 95% CI 1.03 to 3.80) and the >96% group (OR 2.37, 95% CI 1.34 to 4.20).

Conclusions

In patients presenting via ambulance to the Emergency Department with AECOPD, serious adverse clinical outcomes are associated with both hypoxaemia and hyperoxaemia. These data provide further support for the principle of titrating supplemental oxygen therapy to target oxygen saturations.
WEAK INTERACTIONS: FROM CURRENT–CURRENT TO STANDARD MODEL AND BEYOND
Authors: MOHAPATRA RABINDRA N.
Published: September 2012

This paper provides a brief overview for nonexperts of some of the highlights in the development of the theory of weak interactions during the past century.
SEPARABILITY OF POINT SETS BY k-LEVEL LINEAR CLASSIFICATION TREES
Authors: ARKIN ESTHER M. , GARIJO DELIA , MÁRQUEZ ALBERTO , MITCHELL JOSEPH S. B. , SEARA CARLOS
Published: September 2012

Let R and B be sets of red and blue points in the plane in general position. We study the problem of computing a k-level binary space partition (BSP) tree to classify/separate R and B, such that the tree defines a linear decision at each internal node and each leaf of the tree corresponds to a (convex) cell of the partition that contains only red or only blue points. Specifically, we show that a 2-level tree can be computed, if one exists, in time O(n2). We show that a minimum-level (3 ≤ k ≤ log n) tree can be computed in time nO( log n). In the special case of axis-parallel partitions, we show that 2-level and 3-level trees can be computed in time O(n), while a minimum-level tree can be computed in time O(n5).
Characterizing seismic-scale faults pre- and post-drilling; Lewisian Basement, West of Shetlands, UK
Authors: Slightam Clare
Published: September 2012

Three exploration wells drilled in the West of Shetlands targeted crystalline Lewisian Basement as the primary reservoir. The objective of these wells was to demonstrate the presence of movable oil in basement and the viability of fault zones within the Lewisian Basement as an exploration target. Lewisian Basement reservoir properties were defined pre-drill through a combination of fieldwork, offset well data, global basement analogues and detailed 3D seismic interpretation. Dip, azimuth and similarity attributes were analysed within the 3D seismic volume in order to delineate the fault network, complimenting manual fault interpretation. Once the fault network had been defined, two fault zones were chosen as a reservoir target for an inclined basement well, based on their length and location within the reservoir.

After drilling over a kilometre of basement across three wells, significant understanding has been gained of the basement reservoir. The comprehensive suites of log data obtained from the wells have allowed some leading edge techniques to be used to bridge the gap between wellbore data and seismic data, with fault zones identified from log data tying to fault zones that had been interpreted using seismic data. The well results have been used to feed back into the predicted fault model to increase the number of mapped faults and to constrain rock properties including lithology and fracture frequency. This paper summarizes the above process and provides specific details regarding the seismic characterization of the fault network.
Prolonged exposure to methylglyoxal causes disruption of vascular KATP channel by mRNA instability
Authors: Yang Yang , Li Shanshan , Konduru Anuhya S. , Zhang Shuang , Trower Timothy C. , Shi Weiwei , Cui Ningren , Yu Lei , Wang Yali , Zhu Daling , Jiang Chun
Published: September 2012

Diabetes mellitus is characterized by hyperglycemia and excessive production of intermediary metabolites including methylglyoxal (MGO), a reactive carbonyl species that can lead to cell injuries. Interacting with proteins, lipids, and DNA, excessive MGO can cause dysfunction of various tissues, especially the vascular walls where diabetic complications often take place. However, the potential vascular targets of excessive MGO remain to be fully understood. Here we show that the vascular Kir6.1/SUR2B isoform of ATP-sensitive K+ (KATP) channels is likely to be disrupted with an exposure to submillimolar MGO. Up to 90% of the Kir6.1/SUR2B currents were suppressed by 1 mM MGO with a time constant of ∼2 h. Consistently, MGO treatment caused a vast reduction of both Kir6.1 and SUR2B mRNAs endogenously expressed in the A10 vascular smooth muscle cells. In the presence of the transcriptional inhibitor actinomycin-D, MGO remained to lower the Kir6.1 and SUR2B mRNAs to the same degree as MGO alone, suggesting that the MGO effect is likely to compromise the mRNA stability. Luciferase reporter assays indicated that the 3′-untranslated regions (UTRs) of the Kir6.1 but not SUR2 mRNA were targeted by MGO. In contrast, the SUR2B mRNAs obtained with in vitro transcription were disrupted by MGO directly, while the Kir6.1 transcripts were unaffected. Consistent with these results, the constriction of mesenteric arterial rings was markedly augmented with an exposure to 1 mM MGO for 2 h, and such an MGO effect was totally eliminated in the presence of glibenclamide. These results therefore suggest that acting on the 3′-UTR of Kir6.1 and the coding region of SUR2B, MGO causes instability of Kir6.1 and SUR2B mRNAs, disruption of vascular KATP channels, and impairment of arterial function.
VDAC: old protein with new roles in diabetes
Authors: Sasaki Koh , Donthamsetty Reshma , Heldak Michael , Cho Young-Eun , Scott Brian T. , Makino Ayako
Published: September 2012

A decrease in capillary density due to an increase in endothelial cell apoptosis in the heart is implicated in cardiac ischemia in diabetes. The voltage-dependent anion channel (VDAC) plays a crucial role in the regulation of mitochondrial metabolic function and mitochondria-mediated apoptosis. This study is designed to examine the role of VDAC in coronary endothelial dysfunction in diabetes. Endothelial cells (ECs) were more apoptotic in diabetic left ventricle of diabetic mice and mouse coronary ECs (MCECs) isolated from diabetic mice exhibited significantly higher mitochondrial Ca2+ concentration and VDAC protein levels than control MCECs. The expression of VDAC-short hairpin RNA (shRNA) not only decreased the resting mitochondrial Ca2+ concentration but also attenuated mitochondrial Ca2+ uptake in diabetic MCECs. Furthermore, the downregulation of VDAC in diabetic MCECs significantly decreased mitochondrial superoxide anion (O2−) production and the activity of the mitochondrial permeability transition pore (mPTP) opening (an indirect indicator of cell apoptosis) toward control levels. These data suggest that the increased VDAC level in diabetic MCECs is responsible for increased mitochondrial Ca2+ concentration, mitochondrial O2− production, and mPTP opening activity. Normalizing VDAC protein level may help to decrease endothelial cell apoptosis, increase capillary density in the heart, and subsequently decrease the incidence of cardiac ischemia in diabetes.
Pannexin1 contributes to pathophysiological ATP release in lipoapoptosis induced by saturated free fatty acids in liver cells
Authors: Xiao Feng , Waldrop Shar L. , Khimji Al-karim , Kilic Gordan
Published: September 2012

Hepatocyte lipoapoptosis induced by saturated free fatty acids (FFA) contributes to hepatic inflammation in lipotoxic liver injury, and the cellular mechanisms involved have not been defined. Recent studies have shown that apoptosis in nonhepatic cells stimulates ATP release via activation of pannexin1 (panx1), and extracellular ATP functions as a proinflammatory signal for recruitment and activation of the inflammatory cells. However, it is not known whether lipoapoptosis stimulates ATP release in liver cells. We found that lipoapoptosis induced by saturated FFA stimulated ATP release in liver cells that increased extracellular ATP concentration by more than fivefold above the values observed in healthy cells. This sustained pathophysiological ATP release was not dependent on caspase-3/7 activation. Inhibition of c-Jun NH2-terminal kinase (JNK), a key mediator of lipoapoptosis, with SP600125 blocked pathophysiological ATP release in a dose-dependent manner. RT-PCR analysis indicated that panx1 is expressed in hepatocytes and multiple liver cell lines. Notably, inhibition of panx1 expression with short hairpin (sh)RNA inhibited in part pathophysiological ATP release. Moreover, lipoapoptosis stimulated uptake of a membrane impermeable dye YoPro-1 (indicative of panx1 activation), which was inhibited by panx1 shRNA, probenecid, and mefloquine. These results suggest that panx1 contributes to pathophysiological ATP release in lipoapoptosis induced by saturated FFA. Thus panx1 may play an important role in hepatic inflammation by mediating an increase in extracellular ATP concentration in lipotoxic liver injury.
Model analysis of the relationship between intracellular Po2and energy demand in skeletal muscle
Authors: Spires Jessica , Gladden L. Bruce , Grassi Bruno , Saidel Gerald M. , Lai Nicola
Published: September 2012

On the basis of experimental studies, the intracellular O2(iPo2)-work rate (WR) relationship in skeletal muscle is not unique. One study found that iPo2reached a plateau at 60% of maximal WR, while another found that iPo2decreased linearly at higher WR, inferring capillary permeability-surface area ( PS) and blood-tissue O2gradient, respectively, as alternative dominant factors for determining O2diffusion changes during exercise. This relationship is affected by several factors, including O2delivery and oxidative and glycolytic capacities of the muscle. In this study, these factors are examined using a mechanistic, mathematical model to analyze experimental data from contracting skeletal muscle and predict the effects of muscle contraction on O2transport, glycogenolysis, and iPo2. The model describes convection, O2diffusion, and cellular metabolism, including anaerobic glycogenolysis. Consequently, the model simulates iPo2in response to muscle contraction under a variety of experimental conditions. The model was validated by comparison of simulations of O2uptake with corresponding experimental responses of electrically stimulated canine muscle under different O2content, blood flow, and contraction intensities. The model allows hypothetical variation of PS, glycogenolytic capacity, and blood flow and predictions of the distinctive effects of these factors on the iPo2-contraction intensity relationship in canine muscle. Although PS is the main factor regulating O2diffusion rate, model simulations indicate that PS and O2gradient have essential roles, depending on the specific conditions. Furthermore, the model predicts that different convection and diffusion patterns and metabolic factors may be responsible for different iPo2-WR relationships in humans.
Effect of voluntary hypocapnic hyperventilation on cutaneous circulation in resting heated humans
Authors: Fujii Naoto , Honda Yasushi , Delliaux Stephane , Tsuji Bun , Watanabe Kazuhito , Sugihara Akira , Kondo Narihiko , Nishiyasu Takeshi
Published: September 2012

Hypocapnia attenuates the sweat response normally seen in hyperthermic resting subjects, but its effect on the blood flow response in their nonglabrous skin under the same hyperthermic conditions remains unclear. In the present study, we investigated whether hypocapnia induced by voluntary hyperventilation affects the blood flow response to heat stress in the nonglabrous skin of resting humans. Nine healthy male subjects were passively heated using legs-only hot water immersion and a water-perfused suit, which caused esophageal temperature (Tes) to increase by as much as 1.0°C. During normothermia and at +0.6°C Tes and +1.0°C Tes, the subjects performed two voluntary 7-min hyperventilation (minute ventilation = 40 l/min) trials (hypocapnic and eucapnic) in random order. End-tidal CO2 pressure was reduced by 23–25 torr during hypocapnic hyperventilation, but it was maintained at the spontaneous breathing level during eucapnic hyperventilation. Cutaneous blood flow was evaluated as the cutaneous red blood cell flux in the forearm (CBFforearm) or forehead (CBFforehead) and was normalized to the normothermic spontaneous breathing value. Hypocapnic hyperventilation at +0.6°C Tes was associated with significantly reduced CBFforearm, compared with eucapnic hyperventilation, after 5–7 min of hyperventilation (395 to 429 vs. 487 to 525% baseline, P < 0.05). No significant difference in CBFforehead was seen during hypocapnic hyperventilation compared with eucapnic hyperventilation at +0.6°C Tes or +1.0°C Tes. These results suggest that in resting humans, hypocapnia achieved through voluntary hyperventilation attenuates the increase in cutaneous blood flow elicited by moderate heat stress in the nonglabrous skin of the forearm, but not the forehead.
Multinephron dynamics on the renal vascular network
Authors: Marsh Donald J. , Wexler Anthony S. , Brazhe Alexey , Postnov Dmitri E. , Sosnovtseva Olga V. , Holstein-Rathlou Niels-Henrik
Published: September 2012

Tubuloglomerular feedback (TGF) and the myogenic mechanism combine in each nephron to regulate blood flow and glomerular filtration rate. Both mechanisms are nonlinear, generate self-sustained oscillations, and interact as their signals converge on arteriolar smooth muscle, forming a regulatory ensemble. Ensembles may synchronize. Smooth muscle cells in the ensemble depolarize periodically, generating electrical signals that propagate along the vascular network. We developed a mathematical model of a nephron-vascular network, with 16 versions of a single nephron model containing representations of both mechanisms in the regulatory ensemble, to examine the effects of network structure on nephron synchronization. Symmetry, as a property of a network, facilitates synchronization. Nephrons received blood from a symmetric electrically conductive vascular tree. Symmetry was created by using identical nephron models at each of the 16 sites and symmetry breaking by varying nephron length. The symmetric model achieved synchronization of all elements in the network. As little as 1% variation in nephron length caused extensive desynchronization, although synchronization was maintained in small nephron clusters. In-phase synchronization predominated among nephrons separated by one or three vascular nodes and antiphase synchronization for five or seven nodes of separation. Nephron dynamics were irregular and contained low-frequency fluctuations. Results are consistent with simultaneous blood flow measurements in multiple nephrons. An interaction between electrical signals propagated through the network to cause synchronization; variation in vascular pressure at vessel bifurcations was a principal cause of desynchronization. The results suggest that the vasculature supplies blood to nephrons but also engages in robust information transfer.
Sensitivity of cochlear nucleus neurons to spatio-temporal changes in auditory nerve activity
Authors: Wang Grace I. , Delgutte Bertrand
Published: September 2012

The spatio-temporal pattern of auditory nerve (AN) activity, representing the relative timing of spikes across the tonotopic axis, contains cues to perceptual features of sounds such as pitch, loudness, timbre, and spatial location. These spatio-temporal cues may be extracted by neurons in the cochlear nucleus (CN) that are sensitive to relative timing of inputs from AN fibers innervating different cochlear regions. One possible mechanism for this extraction is “cross-frequency” coincidence detection (CD), in which a central neuron converts the degree of coincidence across the tonotopic axis into a rate code by preferentially firing when its AN inputs discharge in synchrony. We used Huffman stimuli (Carney LH. J Neurophysiol 64: 437–456, 1990), which have a flat power spectrum but differ in their phase spectra, to systematically manipulate relative timing of spikes across tonotopically neighboring AN fibers without changing overall firing rates. We compared responses of CN units to Huffman stimuli with responses of model CD cells operating on spatio-temporal patterns of AN activity derived from measured responses of AN fibers with the principle of cochlear scaling invariance. We used the maximum likelihood method to determine the CD model cell parameters most likely to produce the measured CN unit responses, and thereby could distinguish units behaving like cross-frequency CD cells from those consistent with same-frequency CD (in which all inputs would originate from the same tonotopic location). We find that certain CN unit types, especially those associated with globular bushy cells, have responses consistent with cross-frequency CD cells. A possible functional role of a cross-frequency CD mechanism in these CN units is to increase the dynamic range of binaural neurons that process cues for sound localization.
Learning selective top-down control enhances performance in a visual categorization task
Authors: Pannunzi Mario , Gigante Guido , Mattia Maurizio , Deco Gustavo , Fusi Stefano , Del Giudice Paolo
Published: September 2012

We model the putative neuronal and synaptic mechanisms involved in learning a visual categorization task, taking inspiration from single-cell recordings in inferior temporal cortex (ITC). Our working hypothesis is that learning the categorization task involves both bottom-up, ITC to prefrontal cortex (PFC), and top-down (PFC to ITC) synaptic plasticity and that the latter enhances the selectivity of the ITC neurons encoding the task-relevant features of the stimuli, thereby improving the signal-to-noise ratio. We test this hypothesis by modeling both areas and their connections with spiking neurons and plastic synapses, ITC acting as a feature-selective layer and PFC as a category coding layer. This minimal model gives interesting clues as to properties and function of the selective feedback signal from PFC to ITC that help solving a categorization task. In particular, we show that, when the stimuli are very noisy because of a large number of nonrelevant features, the feedback structure helps getting better categorization performance and decreasing the reaction time. It also affects the speed and stability of the learning process and sharpens tuning curves of ITC neurons. Furthermore, the model predicts a modulation of neural activities during error trials, by which the differential selectivity of ITC neurons to task-relevant and task-irrelevant features diminishes or is even reversed, and modulations in the time course of neural activities that appear when, after learning, corrupted versions of the stimuli are input to the network.
Regulation of presynaptic calcium in a mammalian synaptic terminal
Authors: Wan Qun-Fang , Nixon Everett , Heidelberger Ruth
Published: September 2012

Ca2+signaling in synaptic terminals plays a critical role in neurotransmitter release and short-term synaptic plasticity. In the present study, we examined the role of synaptic Ca2+handling mechanisms in the synaptic terminals of mammalian rod bipolar cells, neurons that play a pivotal role in the high-sensitivity vision pathway. We found that mitochondria sequester Ca2+under conditions of high Ca2+load, maintaining intraterminal Ca2+near resting levels. Indeed, the effect of the mitochondria was so powerful that the ability to clamp intraterminal Ca2+with a somatically positioned whole cell patch pipette was compromised. The plasma membrane Ca2+-ATPase (PMCA), but not the Na+/Ca2+exchanger (NCX) or the sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA), was an important regulator of resting Ca2+. Furthermore, PMCA activity, but not NCX or SERCA activity, was essential for the recovery of Ca2+levels following depolarization-evoked Ca2+entry. Loss of PMCA function was also associated with impaired restoration of membrane surface area following depolarization-evoked exocytosis. Given its roles in the regulation of intraterminal Ca2+at rest and after a stimulus-evoked Ca2+rise, the PMCA is poised to modulate luminance coding and adaptation to background illumination in the mammalian rod bipolar cell.
Hippocampal neuron firing and local field potentials in the in vitro 4-aminopyridine epilepsy model
Authors: Gonzalez-Sulser Alfredo , Wang Jing , Queenan Bridget N. , Avoli Massimo , Vicini Stefano , Dzakpasu Rhonda
Published: September 2012

Excessive synchronous neuronal activity is a defining feature of epileptic activity. We previously characterized the properties of distinct glutamatergic and GABAergic transmission-dependent synchronous epileptiform discharges in mouse hippocampal slices using the 4-aminopyridine model of epilepsy. In the present study, we sought to identify the specific hippocampal neuronal populations that initiate and underlie these local field potentials (LFPs). A perforated multielectrode array was used to simultaneously record multiunit action potential firing and LFPs during spontaneous epileptiform activity. LFPs had distinct components based on the initiation site, extent of propagation, and pharmacological sensitivity. Individual units, located in different hippocampal subregions, fired action potentials during these LFPs. A specific neuron subgroup generated sustained action potential firing throughout the various components of the LFPs. The activity of this subgroup preceded the LFPs observed in the presence of antagonists of ionotropic glutamatergic synaptic transmission. In the absence of ionotropic glutamatergic and GABAergic transmission, LFPs disappeared, but units with shorter spike duration and high basal firing rates were still active. These spontaneously active units had an increased level of activity during LFPs and consistently preceded all LFPs recorded before blockade of synaptic transmission. Our findings reveal that neuronal subpopulations with interneuron properties are likely responsible for initiating synchronous activity in an in vitro model of epileptiform discharges.
Morphology, PKCδ expression, and synaptic responsiveness of different types of rat central lateral amygdala neurons
Authors: Amano Taiju , Amir Alon , Goswami Sonal , Paré Denis
Published: September 2012

Recent findings implicate the central lateral amygdala (CeL) in conditioned fear. Indeed, CeL contains neurons exhibiting positive (CeL-On) or negative (CeL-Off) responses to fear-inducing conditioned stimuli (CSs). In mice, these cells differ in their expression of protein kinase Cδ (PKCδ) and physiological properties. CeL-Off cells are PKCδ+ and late firing (LF), whereas CeL-On cells are PKCδ− and express a regular-spiking (RS) or low-threshold bursting (LTB) phenotype. However, the scarcity of LF cells in rats raises questions about the correspondence between the organization of CeL in mice and rats. Therefore, we studied the PKCδ expression, morphological properties, synaptic responsiveness, and fear conditioning-induced plasticity of rat CeL neurons. No PKCδ+ LF cells were encountered, but ≈20–25% of RS and LTB neurons were PKCδ+. Compared with RS neurons, a higher proportion of LTB cells projected to central medial amygdala (CeM) and they had fewer primary dendritic branches, yet the amplitude of excitatory postsynaptic potentials (EPSPs) evoked by lateral amygdala (LA) stimulation was similar in RS and LTB cells. In contrast, LA-evoked inhibitory postsynaptic potentials (IPSPs) had a higher amplitude in LTB than RS neurons. Finally, fear conditioning did not induce plasticity at LA inputs to RS or LTB neurons. These findings point to major species differences in the organization of CeL. Since rat LTB cells are subjected to stronger feedforward inhibition, they are more likely to exhibit inhibitory CS responses than RS cells. This is expected to cause a disinhibition of CeM fear output neurons and therefore an increase in fear expression.
An in vivo investigation of inferior colliculus single neuron responses to cochlear nucleus pulse train stimulation
Authors: Mauger Stefan J. , Shivdasani Mohit N. , Rathbone Graeme D. , Paolini Antonio G.
Published: September 2012

The auditory brain stem implant (ABI) is being used clinically to restore hearing to patients unable to benefit from a cochlear implant (CI). Speech perception outcomes for ABI users are typically poor compared with most CI users. The ABI is implanted either on the surface of or penetrating through the cochlear nucleus in the auditory brain stem and uses stimulation strategies developed for auditory nerve stimulation with a CI. Although the stimulus rate may affect speech perception outcomes with current stimulation strategies, no studies have systematically investigated the effect of stimulus rate electrophysiologically or clinically. We therefore investigated rate response properties and temporal response properties of single inferior colliculus (IC) neurons from penetrating ABI stimulation using stimulus rates ranging from 100 to 1,600 pulses/s in the rat. We found that the stimulus rate affected the proportion of response types, thresholds, and dynamic ranges of IC activation. The stimulus rate was also found to affect the temporal properties of IC responses, with higher rates providing more temporally similar responses to acoustic stimulation. Suppression of neural firing and inhibition in IC neurons was also found, with response properties varying with the stimulus rate. This study demonstrated that changes in the ABI stimulus rate results in significant differences in IC neuron response properties. Due to electrophysiological differences, the stimulus rate may also change perceptual properties. We suggest that clinical evaluation of the ABI stimulus rate should be performed.
Startle induces early initiation of classically conditioned postural responses
Authors: Campbell A. D. , Chua R. , Inglis J. T. , Carpenter M. G.
Published: September 2012

Startling acoustic stimuli (SAS) induce the early release of prepared motor responses. The current study used SAS, in conjunction with a classical conditioning paradigm, to examine advanced motor preparation of conditioned postural responses (PRs). After generalized startle responses were induced, standing posture was perturbed in 2 blocks of 15 Conditioning trials, where in each trial the onset of a nonstartling auditory cue [i.e., a conditioned stimulus (CS)] preceded a leftward support-surface translation. Upon completion of each block, a single trial was conducted. After block 1, a CS-Only trial was used to induce conditioned PRs in the absence of balance perturbations. After block 2, a post-Conditioning Startle trial that involved a CS subsequently followed by a SAS was used to examine motor preparation of conditioned PRs. PRs were quantified in terms of center of pressure displacements, ankle and hip kinematics, as well as surface electromyography of proximal and distal bilateral muscle pairs. Results indicated that repeated experience with cued balance perturbations led to PR conditioning and, more importantly, motor preparation of PRs. Conditioning was evidenced in biomechanical and electromyographic responses observed in CS-Only trials, as well as the progressive changes to evoked response parameters during repeated Conditioning trials. SAS presented in post-Conditioning Startle trials evoked early onsets of biomechanical and electromyographic responses, while preserving relative response parameters that were each distinct from generalized startle responses. These results provide important insight into both the consequences of using cues in dynamic postural control studies and the neural mechanisms governing PRs.
MiR-351 transiently increases during muscle regeneration and promotes progenitor cell proliferation and survival upon differentiation
Authors: Chen Yongxin , Melton David W. , Gelfond Jonathan A. L. , McManus Linda M. , Shireman Paula K.
Published: September 2012

MicroRNAs (miRNAs) regulate many biological processes including muscle development. However, little is known regarding miRNA regulation of muscle regeneration. Murine tibialis anterior muscle was evaluated after cardiotoxin-induced injury and used for global miRNA expression analysis. From day 1 through day 21 following injury, 298 miRNAs were significantly changed at least at one time point, including 86 miRNAs that were altered >10-fold compared with uninjured skeletal muscle. Temporal miRNA expression patterns included inflammation-related miRNAs (miR-223 and -147) that increased immediately after injury; this pattern contrasted to that of mature muscle-specific miRNAs (miR-1, -133a, and -499) that abruptly decreased following injury followed by upregulation in later regenerative events. Another cluster of miRNAs were transiently increased in the early days of muscle regeneration including miR-351, a miRNA that was also transiently expressed during myogenic progenitor cell (MPC) differentiation in vitro. Based on computational predictions, further studies demonstrated that E2f3 was a target of miR-351 in myoblasts. Moreover, knockdown of miR-351 expression inhibited MPC proliferation and promoted apoptosis during MPC differentiation, whereas miR-351 overexpression protected MPC from apoptosis during differentiation. Collectively, these observations suggest that miR-351 is involved in both the maintenance of MPC proliferation and the transition into differentiated myotubes. Thus, a novel, time-dependent sequence of molecular events during muscle regeneration has been identified; miR-351 inhibits E2f3 expression, a key regulator of cell cycle progression and proliferation, and promotes MPC proliferation and protects early differentiating MPC from apoptosis, important events in the hostile tissue environment after acute muscle injury.
Endoneurial Macrophages Induce Perineural Invasion of Pancreatic Cancer Cells by Secretion of GDNF and Activation of RET Tyrosine Kinase Receptor
Authors: Cavel Oren , Shomron Olga , Shabtay Ayelet , Vital Joseph , Trejo-Leider Leonor , Weizman Noam , Krelin Yakov , Fong Yuman , Wong Richard J. , Amit Moran , Gil Ziv
Published: September 2012

Perineural invasion of cancer cells (CPNI) is found in most patients with pancreatic adenocarcinomas (PDA), prostate, or head and neck cancers. These patients undergo palliative rather than curative treatment due to dissemination of cancer along nerves, well beyond the extent of any local invasion. Although CPNI is a common source of distant tumor spread and a cause of significant morbidity, its exact mechanism is undefined. Immunohistochemical analysis of specimens excised from patients with PDAs showed a significant increase in the number of endoneurial macrophages (EMΦ) that lie around nerves invaded by cancer compared with normal nerves. Video microscopy and time-lapse analysis revealed that EMΦs are recruited by the tumor cells in response to colony-stimulated factor-1 secreted by invading cancer cells. Conditioned medium (CM) of tumor-activated EMΦs (tEMΦ) induced a 5-fold increase in migration of PDA cells compared with controls. Compared with resting EMΦs, tEMΦs secreted higher levels of glial-derived neurotrophic factor (GDNF), inducing phosphorylation of RET and downstream activation of extracellular signal–regulated kinases (ERK) in PDA cells. Genetic and pharmacologic inhibition of the GDNF receptors GFRA1 and RET abrogated the migratory effect of EMΦ-CM and reduced ERK phosphorylation. In an in vivo CPNI model, CCR2-deficient mice that have reduced macrophage recruitment and activation showed minimal nerve invasion, whereas wild-type mice developed complete sciatic nerve paralysis due to massive CPNI. Taken together, our results identify a paracrine response between EMΦs and PDA cells that orchestrates the formation of cancer nerve invasion. Cancer Res; 72(22); 5733–43. ©2012 AACR.
RhoJ Regulates Melanoma Chemoresistance by Suppressing Pathways That Sense DNA Damage
Authors: Ho Hsiang , Aruri Jayavani , Kapadia Rubina , Mehr Hootan , White Michael A. , Ganesan Anand K.
Published: September 2012

Melanomas resist conventional chemotherapeutics, in part, through intrinsic disrespect of apoptotic checkpoint activation. In this study, using an unbiased genome-wide RNA interference screen, we identified RhoJ and its effector PAK1, as key modulators of melanoma cell sensitivity to DNA damage. We find that RhoJ activates PAK1 in response to drug-induced DNA damage, which then uncouples ATR from its downstream effectors, ultimately resulting in a blunted DNA damage response (DDR). In addition, ATR suppression leads to the decreased phosphorylation of ATF2 and consequent increased expression of the melanocyte survival gene Sox10 resulting in a higher DDR threshold required to engage melanoma cell death. In the setting of normal melanocyte behavior, this regulatory relationship may facilitate appropriate epidermal melanization in response to UV-induced DNA damage. However, pathologic pathway activation during oncogenic transformation produces a tumor that is intrinsically resistant to chemotherapy and has the propensity to accumulate additional mutations. These findings identify DNA damage agents and pharmacologic inhibitors of RhoJ/PAK1 as novel synergistic agents that can be used to treat melanomas that are resistant to conventional chemotherapies. Cancer Res; 72(21); 5516–28. ©2012 AACR.
Efficacy of Cetuximab in Metastatic Castration-Resistant Prostate Cancer Might Depend on EGFR and PTEN Expression: Results from a Phase II Trial (SAKK 08/07)
Authors: Cathomas Richard , Rothermundt Christian , Klingbiel Dirk , Bubendorf Lukas , Jaggi Rolf , Betticher Daniel C. , Brauchli Peter , Cotting Denise , Droege Cornelia , Winterhalder Ralph , Siciliano Daniele , Berthold Dominik R. , Pless Miklos , Schiess Ralph , von Moos Roger , Gillessen Silke ,   for the Swiss Group for Clinical Cancer Research (SAKK)
Published: September 2012

Purpose: The EGF receptor (EGFR) is overexpressed in the majority of metastatic castration-resistant prostate cancers (mCRPC) and might represent a valid therapeutic target. The combination of docetaxel and cetuximab, the monoclonal antibody against EGFR, has not been tested in patients with prostate cancer.

Experimental Design: Patients with mCRPC progressing during or within 90 days after at least 12 weeks of docetaxel were included in this phase II trial. Treatment consisted of docetaxel (75 mg/m2 every 3 weeks or 35 mg/m2 on days 1, 8, 15 every 4 weeks) in combination with cetuximab (400 mg/m2 on day 1 and then 250 mg/m2 weekly). The primary endpoint was progression-free survival (PFS) at 12 weeks defined as the absence of prostate-specific antigen (PSA), radiographic, or clinical progression. Evaluation of known biomarkers of response and resistance to cetuximab (EGFR, PTEN, amphiregulin, epiregulin) was conducted.

Results: Thirty-eight patients were enrolled at 15 Swiss centers. Median age was 68 years and median PSA was 212 ng/mL. PFS at 12 weeks was 34% [95% confidence interval (CI), 19%–52%], PFS at 24 weeks was 20%, and median overall survival (OS) was 13.3 months (95% CI, 7.3–15.4). Seven patients (20%) had a confirmed ≥50% and 11 patients (31%) a confirmed ≥30% PSA decline. About 47% of enrolled patients experienced grade 3 and 8% grade 4 toxicities. A significantly improved PFS was found in patients with overexpression of EGFR and persistent activity of PTEN.

Conclusions: EGFR inhibition with cetuximab might improve the outcome of patients with mCRPC. A potential correlation between EGFR overexpression, persistent expression of PTEN, and EGFR inhibition should be investigated further. Clin Cancer Res; 18(21); 6049–57. ©2012 AACR.
8-Amino-Adenosine Activates p53-Independent Cell Death of Metastatic Breast Cancers
Authors: Polotskaia Alla , Hoffman Sandy , Krett Nancy L. , Shanmugam Mala , Rosen Steven T. , Bargonetti Jill
Published: September 2012

8-Amino-adenosine (8-NH2-Ado) is a ribose sugar nucleoside analogue that reduces cellular ATP levels and inhibits mRNA synthesis. Estrogen receptor-negative (ER−) metastatic breast cancers often contain mutant p53; therefore, we asked if 8-NH2-Ado could kill breast cancer cells without activating the p53-pathway. Regardless of the breast cancer subtype tested or the p53 status of the cells, 8-NH2-Ado was more cytotoxic than either gemcitabine or etoposide. 8-NH2-Ado treatment inhibited cell proliferation, activated cell death, and did not activate transcription of the p53 target gene p21 or increase protein levels of either p53 or p21. This occurred in the estrogen receptor-positive (ER+) MCF-7 cells that express wild-type p53, the ER+ T47-D cells that express mutant p53, and the ER− MDA-MB-468 cells or MDA-MB-231 cells that both express mutant p53. 8-NH2-Ado induced apoptotic death of MCF-7 cells and apoptosis was not inhibited by knockdown of functional p53. Moreover, the pan-caspase inhibitor Z-VAD blocked the 8-NH2-Ado–induced MCF-7 cell death. Interestingly, 8-NH2-Ado caused the MDA-MB-231 cells to detach from the plate with only limited evidence of apoptotic cell death markers and the cell death was not inhibited by Z-VAD. Inhibition of MDA-MB-231 cell autophagy, by reduction of ATG7 or 3-methyladenine treatment, did not block this 8-NH2-Ado–mediated cytotoxicity. Importantly 8-NH2-Ado was highly cytotoxic to triple-negative breast cancer cells and worked through a pathway that did not require wild-type p53 for cytoxicity. Therefore, 8-NH2-Ado should be considered for the treatment of triple-negative breast cancers that are chemotherapy resistant. Mol Cancer Ther; 11(11); 2495–504. ©2012 AACR.
Photodynamic Properties of Vital Dyes for Vitreoretinal Surgery
Authors: Brockmann Tobias , Steger Claudia , Dawczynski Jens
Published: September 2012

The purpose of this study was to evaluate photodynamic properties of indocyanine green (ICG), brilliant blue G (BBG) and trypan blue (TB) as currently used vital dyes for chromovitrectomy. Under consideration of intraoperative illumination intensities and dye concentrations, a simulative in vitro investigation was set up. Therefore, standardized dilutions of original ICG, BBG and TB vials were irradiated at a wavelength of 366 nm with an intensity of 14 µW/cm2 between 0 and 48 h. After this, all samples were measured spectroscopically in a 220- to 750-nm bandwidth. Analyzing the vital dyes over the time course, an exponential photolysis was observed for ICG, whereas BBG and TB presented photostable properties. Regarding ICG, 5% of the concentration was degraded to toxic metabolites every 20 min. For this reason, our study provides evidence that intraocular dye concentrations and modern endoillumination systems alone cannot fully prevent ICG photodegradation.
Intrasilicone Bevacizumab Injection for Iris Neovascularization after Vitrectomy for Proliferative Diabetic Retinopathy
Authors: Salman Abdelrahman G.
Published: September 2012

Purpose: To evaluate the efficacy and safety of intrasilicone injection of bevacizumab for the treatment of iris neovascularization after vitrectomy for proliferative diabetic retinopathy. Methods: Bevacizumab 1.25 mg/0.05 ml was injected into silicone oil in 15 eyes of 11 patients with iris neovascularization which had developed 2.5–6 months after vitrectomy and silicone oil tamponade. The main outcome measures were regression of iris neovascularization, intraocular pressure elevation, and visual acuity. Results: In all eyes, iris neovascularization regressed and postinjection intraocular pressure was controlled within 7 days postinjection. Visual acuity improved in 12 eyes. In 4 patients, iris neovascularization recurred within 10 weeks after the injection and they were successfully treated with a second intrasilicone bevacizumab injection of the same dose. Conclusion: Intrasilicone injection of bevacizumab is safe and effective in the treatment of patients with iris neovascularization after vitrectomy for advanced proliferative diabetic retinopathy. Further studies on greater numbers of patients and more advanced neovascularization are recommended.
Gene-Targeted Analysis of Copy Number Variants Identifies 3 Novel Associations With Coronary Heart Disease Traits
Authors: Costelloe Seán J. , El-Sayed Moustafa Julia S. , Drenos Fotios , Palmen Jutta , Qiao Li , Whiting Stephen , Thomas Michael , Kivimaki Mika , Kumari Meena , Hingorani Aroon D. , Tzoulaki Ioanna , Marjo-Riitta Järvelin , Aimo Ruokonen , Hartikainen Anna-Liisa , Pouta Anneli , Walters Robin G. , Blakemore Alexandra I.F. , Humphries Steve E. , Coin Lachlan J. M. , Talmud Philippa J.
Published: September 2012

Background—

Copy number variants (CNVs) are a major form of genomic variation, which may be implicated in complex disease phenotypes. However, investigation of the role of CNVs in coronary heart disease (CHD) traits has been limited.

Methods and Results—

We examined the use of the cnvHap algorithm for CNV detection, using data for 2500 men from the Second Northwick Park Heart Study (NPHS-II). An Illumina custom chip, including 722 single-nucleotide polymorphisms covering 76 coronary heart disease-trait genes, was used. Common CNVs were significantly associated (at
P
<0.05, after correction) with coronary heart disease phenotypes in 5 genes. Novel associations of CNVs in toll-like receptor-4 with apolipoprotein AI were replicated (
P
<0.05) in the Whitehall II cohort (4887 subjects), whereas newly described associations of CNVs in sterol regulatory element-binding protein with apolipoprotein AI and associations of interleukin-6 signal transducer with apolipoprotein B were replicated in the data from 3546 subjects from the North Finnish Birth Cohort 1966 (
P
<0.05).

Conclusions—

This study supports the use of CNV detection algorithms such as cnvHap as potential tools for the identification of novel CNVs, some of which show significant association and replication with coronary heart disease risk phenotypes. However, the functional basis for these associations requires further substantiation.