bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical Case Notes
Authors: Patel Dipika V , Phang Kian Liun , Grupcheva Christina N , Best Stephen J , McGhee Charles NJ
Published: November 2004

A 90‐year‐old woman developed a large circular capsulorhexis‐like defect in Descemet's membrane as a complication of small incision cataract surgery. Nine months post‐surgery, in vivo confocal microscopic examination of the temporal mid‐peripheral cornea revealed an endothelial cell density of 934 ± 69 cells/mm2 (normal range 1566–3088 cells/mm2). Endothelial pigmented deposits were visible as scattered hyper‐reflective areas on the posterior endothelial surface. Descemet's folds were also noted. In vivo confocal microscopy performed 3 years later showed the temporal mid‐peripheral corneal endothelial density (in the region of the break) was 948 ± 66 cells/mm2. A reduction of endothelial polymegathism and pleomorphism was observed. Imaging in the region of the temporal portion of the original Descemet's defect showed well‐defined linear structures with hyper‐reflective edges. Compared to 3 years previously, the cornea at the level of Descemet's membrane appeared to have greater reflectivity. This case demonstrates how microstructural changes in the cornea can be described and analysed over time with the assistance of in vivo confocal microscopy.
Clinical Case Notes
Authors: Thiagalingam Sureka , Fernando Glen T , Tan Kimberley , O'Donnell Brett A , Weeks Kerry , Branley Michael
Published: November 2004

Orbital apex syndrome secondary to mucormycosis in immuno­compromised patients is well described; however, few reports exist of a paranasal sinus mycetoma resulting in this presentation in the immuno­competent patient. The case is reported of a 92‐year‐old man who developed orbital apex syndrome secondary to a sphen­oidal sinus mycetoma of Pseudallescheria boydii.
Amniotic membrane grafting in the surgical management of primary pterygium
Authors: Essex Rohan W , Snibson Grant R , Daniell Mark , Tole Derek M
Published: November 2004

Background: To evaluate the efficacy of amniotic membrane transplantation in primary pterygium surgery.

Methods: Patients presenting to the outpatient clinic of the Royal Victorian Eye and Ear Hospital with primary pterygium requiring surgical management were included in this study. The pterygia were excised to bare sclera and the conjunctival defects were closed with amniotic membrane grafts. The primary outcome was pterygium recurrence.

Results: Twenty‐eight pterygia of 26 patients were included. Twenty‐three patients (88%, 25 eyes) completed 12 months follow up. By 12 months postoperatively 16 of these eyes (64%) had developed corneal recurrence and a further two had developed a limbal recurrence (9%). Five required repeat surgery during the 12 month follow‐up period. No association was found between pterygium recurrence and pterygium size (P = 0.33), amniotic membrane graft dimension (P = 0.12), patient age (P = 0.53) or patient sex (P = 0.63).

Conclusion: Amniotic membrane grafting for primary pterygium was associated with an unacceptably high recurrence rate in this population.
Quantification of amino acid neurochemistry secondary to NMDA or betaxolol application
Authors: Sun Daniel , Kalloniatis Michael
Published: November 2004

Background: Alterations in retinal amino acid neurochemistry are an indicator of metabolic function. Glutamate is the primary excitatory amino acid neurotransmitter within the retina, and excessive levels of glutamate can potentially cause excitotoxicity, in particular, through the N‐methyl‐D‐aspartate (NMDA) subtype of glutamate receptor. Anomalies in NMDA receptor function have been implicated as causing many neurodegenerative disorders, and overactivation leads to neuronal death secondary to metabolic insult. Several pharmaceutical agents have been proposed as potential neuroprotective agents against excitotoxicity (e.g. betaxolol), yet any effects such drugs have on retinal neurochemistry have not been determined. Therefore, the aim of this study was to quantify the changes in retinal amino acid neurochemistry secondary to the application of NMDA with and without betaxolol.

Methods: Functional NMDA channel activation was confirmed in both amacrine and ganglion cells by quantifying the entry into these neurones of a channel permeable probe (agmatine: 1‐amino‐4‐guanidobutane [AGB]). By probing serial thin sections with immunoglobulins targeting AGB, glutamate, γ‐aminobutyric acid (GABA) and glycine, it was possible to simultaneously study the neurochemical characteristic as well as the NMDA‐evoked AGB responses of different neurochemical populations of inner retinal neurones.

Results: The authors have previously shown no accumulation of glutamate or GABA within Müller cells following NMDA application. Herein they report altered GABA and glycine immunoreactivity, but not glutamate immunoreactivity within neurones of the amacrine and ganglion cell layers following NMDA application. Finally, the addition of betaxolol did not significantly alter the normal neurochemistry of the retina.

Conclusion: The retina possesses intrinsic mechanisms that allow it to maintain metabolic integrity during short periods of high NMDA application.
A tribute to Charles David Kelman MD: ophthalmologist, inventor and pioneer of phacoemulsification surgery
Authors: Pandey Suresh K , Milverton E John , Maloof Anthony J
Published: November 2004

Charles David Kelman was born in Brooklyn, New York, USA, on 23 May 1930 and passed away in Boca Raton, Florida, USA, on 1 June 2004 at the age of 74 years after a long battle with cancer. He received a Bachelor of Science degree from Tufts University in 1950 and completed medical studies at the University of Geneva, Switzerland, in 1956. He was Clinical Professor of Ophthalmology at New York Medical College and an Attending Surgeon at New York Eye and Ear Infirmary and Manhattan Eye, Ear and Throat Hospital. Although a prolific inventor, he will be best remembered for developing phacoemulsification, following his realization while sitting in a dentist's chair, that ultrasonic vibrations could be used to emulsify the aged crystalline lens through a very small incision. His pioneering work revolutionized cataract surgery. He also pioneered cryo‐extraction of cataracts, the use of freezing for the repair of retinal detachments and designed numerous ophthalmic instruments and intraocular lenses. Dr Kelman received numerous awards, including the American Academy of Ophthalmology Achievement Award (1970), the Ridley Medal from the International Congress of Ophthalmology (1990), and the Inventor of the Year Award from The New York Patent, Trademark and Copyright Law Association (1992). Most recently (2003), Dr Kelman was honoured by the American Academy of Ophthalmology with the Laureate Recognition award. Dr Kelman was also an accomplished Broadway producer, composer and jazz saxophonist. With his demise, the ophthalmic and medical community lost a famed inventor with multifaceted talents and one of the great ophthalmologists of the twentieth century.
HIV and tuberculosis co‐infection in south‐western Sydney: experience from a case series
Authors: Limaye S , Quin J , Steele R. H
Published: November 2004

Abstract

A case series of six patients with HIV and Mycobacterium tuberculosis co‐infection is presented. All patients were overseas‐born and in all but one there was profound immunodeficiency. We recommend HIV screening of all cases of M. tuberculosis and a high degree of suspicion of tuberculosis in immigrants with HIV infection from endemic areas. Management problems included delayed diagnosis, rapid progression, paradoxical reactions and requirement for surgical intervention in three patients. Therapeutic complications included possible drug malabsorption, adverse events and drug interactions. M. tuberculosis was fully drug sensitive in all cases. (Intern Med J 2004; 34: 203−206)
Nonalcoholic fatty liver disease: is all the fat bad?
Authors: Clouston A. D. , Powell E. E.
Published: November 2004

Abstract

Nonalcoholic fatty liver disease is now a major cause of liver disease in developed countries, largely as a result of an epidemic of obesity, diabetes and sedentary lifestyles. This has resulted in raised clinical awareness and diagnostic refinement. The entity encompasses several histologic patterns from benign steatosis to nonalcoholic steatohepatitis, the latter having a significant risk of progressive fibrosis and the development of cirrhosis. Labor­atory tests and imaging are not able to distinguish steatosis from steatohepatitis, which requires liver biopsy. However following an assessment of several risk factors, patients can be stratified for the potential risk of fibrosis, allowing the rational use of liver biopsy. This review will describe the various patterns of nonalcoholic fatty liver disease and relate this to disease pathogenesis and progression. Strategies for management, including experimental interventions, will be discussed. (Intern Med J 2004; 34: 187−191)
A chronic disease management programme can reduce days in hospital for patients with chronic obstructive pulmonary disease
Authors: Rea H. , McAuley S. , Stewart A. , Lamont C. , Roseman P. , Didsbury P.
Published: November 2004

Background:  A steady increase in chronic obstructive pulmonary disease (COPD) admissions was addressed by enhancing primary care to provide intensive chronic disease management.

Aim:  To compare the effect of a disease management programme, including a COPD management guideline, a patient‐specific care plan and collaboration between patients, general practitioners, practice nurses, hospital physicians and nurse specialists with conventional care, on hospital admissions and quality of life.

Methods:  One hundred and thirty‐five patients with a clinical diagnosis of moderate to severe COPD were identified from hospital admission data and general practice records. General practices were randomized to either conventional care (CON), or the intervention (INT). Pre‐ and post‐study assessment included spirometry, Shuttle Walk Test, Short Form‐36, and the Chronic Respiratory Questionnaire (CRQ). Admission data were compared for 12 months prior to and during the trial.

Results: For respiratory conditions, mean hospital bed days per patient per year for the INT group were reduced from 2.8 to 1.1, whereas those for the CON group increased from 3.5 to 4.0 (group difference, P = 0.030) The INT group also showed an improvement for two dimensions of the CRQ, fatigue (P = 0.010) and mastery (P = 0.007).

Conclusions: A chronic disease management programme for COPD patients that incorporated a variety of interventions, including pulmonary rehabilitation and implemented by primary care, reduced admissions and hospital bed days. Key elements were patient participation and information sharing among healthcare providers. (Intern Med J 2004; 34: 608−614)
Dynamic regulation of spine–dendrite coupling in cultured hippocampal neurons
Authors: Korkotian Eduard , Holcman David , Segal Menahem
Published: November 2004

We investigated the role of dendritic spine morphology in spine–dendrite calcium communication using novel experimental and theoretical approaches. A transient rise in [Ca2+]i was produced in individual spine heads of Fluo‐4‐loaded cultured hippocampal neurons by flash photolysis of caged calcium. Following flash photolysis in the spine head, a delayed [Ca2+]i transient was detected in the parent dendrites of only short, but not long, spines. Delayed elevated fluorescence in the dendrite of the short spines was also seen with a membrane‐bound fluorophore and fluorescence recovery from bleaching of a calcium‐bound fluorophore had a much slower kinetics, indicating that the dendritic fluorescence change reflects a genuine diffusion of free [Ca2+]i from the spine head to the parent dendrite. Calcium diffusion between spine head and the parent dendrite was regulated by calcium stores as well as by a Na–Ca exchanger. Spine length varied with the recent history of the [Ca2+]i variations in the spine, such that small numbers of calcium transients resulted in elongation of spines whereas large numbers of calcium transients caused shrinkage of the spines. Consequently, spine elongation resulted in a complete isolation of the spine from the dendrite, while shrinkage caused an enhanced coupling with the parent dendrite. These studies highlight a dynamically regulated coupling between a dendritic spine head and its parent dendrite.
A single high dose of cocaine induces behavioural sensitization and modifies mRNA encoding GluR1 and GAP‐43 in rats
Authors: Grignaschi Giuliano , Burbassi Silvia , Zennaro Eleonora , Bendotti Caterina , Cervo Luigi
Published: November 2004

Neuroadaptive changes underlying repeated exposure to cocaine‐induced behavioural sensitization have been related to modification in the pattern of synaptic connectivity and excitatory transmission. Remarkably, even a single exposure to abused drugs is sufficient to elicit lasting behavioural sensitization. The present study investigated whether in Sprague–Dawley rats a single, behavioural sensitizing dose of cocaine is sufficient to induce changes in the mRNA levels of growth‐associated protein 43 (GAP‐43), an important protein in mediating experience‐dependent plasticity and synaptic reorganization, and of glutamate receptor 1 (GluR1), a subunit of AMPA glutamate receptors, a protein that is up‐regulated with repeated cocaine. Single exposure to 20, but not 10 mg/kg cocaine induced locomotor sensitization to a second injection of 10 mg/kg cocaine, observed at 24 h, 48 h and 7 days. Single dose of 20 but not 10 mg/kg cocaine 48 h before scheduled death significantly enhanced GluR1 and GAP‐43 mRNA expression in the nucleus accumbens (NAc), both shell and core subregions, and ventral tegmental area (VTA). No changes were found in the levels of mRNA for GluR1 and GAP‐43 in the frontal cortex, caudate putamen, dentate gyrus of hippocampus and basolateral nucleus of the amygdala after the single dose of 20 mg/kg cocaine. These results further strengthen the involvement of NAc and VTA in the behavioural sensitization and suggest a role of GAP‐43 in the synaptic reorganization associated to drug abuse.
Δ9‐tetrahydrocannabinol decreases somatic and motivational manifestations of nicotine withdrawal in mice
Authors: Balerio Graciela N. , Aso Ester , Berrendero Fernando , Murtra Patricia , Maldonado Rafael
Published: November 2004

The possible interactions between Δ9‐tetrahydrocannabinol (Δ9‐THC) and nicotine remain unclear in spite of the current association of cannabis and tobacco in humans. The aim of the present study was to explore the interactions between these two drugs of abuse by evaluating the consequences of Δ9‐THC administration on the somatic manifestations and the aversive motivational state associated with nicotine withdrawal in mice. Acute Δ9‐THC administration significantly decreased the incidence of several nicotine withdrawal signs precipitated by mecamylamine or naloxone, such as wet‐dog‐shakes, paw tremor and scratches. In both experimental conditions, the global withdrawal score was also significantly attenuated by acute Δ9‐THC administration. This effect of Δ9‐THC was not due to possible adaptive changes induced by chronic nicotine on CB1 cannabinoid receptors, as the density and functional activity of these receptors were not modified by chronic nicotine administration in the different brain structures investigated. We also evaluated the consequences of Δ9‐THC administration on c‐Fos expression in several brain structures after chronic nicotine administration and withdrawal. c‐Fos was decreased in the caudate putamen and the dentate gyrus after mecamylamine precipitated nicotine withdrawal. However, acute Δ9‐THC administration did not modify c‐Fos expression under these experimental conditions. Finally, Δ9‐THC also reversed conditioned place aversion associated to naloxone precipitated nicotine withdrawal. Taken together, these results indicate that Δ9‐THC administration attenuated somatic signs of nicotine withdrawal and this effect was not associated with compensatory changes on CB1 cannabinoid receptors during chronic nicotine administration. In addition, Δ9‐THC also ameliorated the aversive motivational consequences of nicotine withdrawal.
A soluble Nogo receptor differentially affects plasticity of spinally projecting axons
Authors: MacDermid V. E. , McPhail L. T. , Tsang B. , Rosenthal A. , Davies A. , Ramer M. S.
Published: November 2004

In the central nervous system, regeneration of injured axons and sprouting of intact axons are suppressed by myelin‐derived molecules that bind to the Nogo receptor (NgR). We used a soluble form of the NgR (sNgR), constructed as an IgG of the human NgR extracellular domain, to manipulate plasticity of uninjured primary afferent and descending monoaminergic projections to the rat spinal cord following dorsal rhizotomy. Rats with quadruple dorsal rhizotomies were treated with intrathecal sNgR or saline, or were left untreated for 2 weeks. Rhizotomy alone resulted in sprouting of serotonergic axons and to a lesser extent, tyrosine‐hydroxylase (TH)‐expressing axons, while axons expressing dopamine‐β‐hydroxylase (DβH) were unaffected. Human IgG immunohistochemistry revealed that sNgR infused into the intrathecal space penetrated approximately 300 µm into spinal white and grey matter. Separate axonal populations differed in their responses to intrathecal sNgR: TH‐expressing and DβH‐expressing axons responded most and least vigorously, respectively. Serotonergic axons were identified by serotonin (5‐HT) or serotonin transporter (SERT) immunohistochemistry. Interestingly, a large increase in 5‐HT compared to SERT‐positive axons density in both saline and sNgR‐treated rats indicated that serotonergic axons both sprouted and increased their transmitter content in response to rhizotomy and sNgR treatment. Calcitonin gene‐related peptide‐positive axons were largely depleted ipsilaterally by rhizotomy, and sNgR increased axon density only in deeper contralateral laminae (III–V). GAP‐43 immunohistochemistry revealed a small increase in axon density following dorsal rhizotomy that was further augmented by sNgR treatment. These results reveal a differential effect of myelin antagonism on distinct populations of spinally projecting axons.
The cortically evoked secondary depolarization affects the integrative properties of thalamic reticular neurons
Authors: Fuentealba Pablo , Crochet Sylvain , Steriade Mircea
Published: November 2004

Corticothalamic terminals on thalamic reticular (RE) neurons account for most synapses from afferent pathways onto this nucleus and these inputs are more powerful than those from axon collaterals of thalamocortical neurons. Given the supremacy of cortical inputs, we analysed here the characteristics and possible mechanisms underlying a secondary component of the cortically elicited depolarization in RE neurons, recorded in cats under barbiturate anesthesia. Electrical stimulation of corticothalamic axons in the internal capsule evoked fixed and short‐latency excitatory postsynaptic potentials (EPSPs) that, by increasing stimulation intensity and at hyperpolarized levels (< −70 mV), developed into low‐threshold spikes and spindle oscillations. The threshold for spindle oscillations was 60% higher than that required for evoking minimal EPSPs. The evoked EPSPs included a secondary depolarizing component, which appeared ∼ 5 ms after the peak of the initial component and was voltage dependent, i.e. most prominent between −70 mV and −85 mV, while being greatly reduced or absent at more hyperpolarized levels. The secondary depolarizing component was sensitive to QX‐314 in the recording micropipette. We suggest that the secondary component of cortically evoked EPSPs in RE neurons is due to the dendritic activation of T‐currents, with a probable contribution of the persistent Na+ current. This late component affected the integrative properties of RE neurons, including their spiking output and temporal summation of incoming cortical inputs.
Hippocampal BDNF mediates the efficacy of exercise on synaptic plasticity and cognition
Authors: Vaynman Shoshanna , Ying Zhe , Gomez‐Pinilla Fernando
Published: November 2004

We found that a short exercise period enhanced cognitive function on the Morris water maze (MWM), such that exercised animals were significantly better than sedentary controls at learning and recalling the location of the platform. The finding that exercise increased brain‐derived neurotrophic factor (BDNF), a molecule important for synaptic plasticity and learning and memory, impelled us to examine whether a BDNF‐mediated mechanism subserves the capacity of exercise to improve hippocampal‐dependent learning. A specific immunoadhesin chimera (TrkB‐IgG), that mimics the BDNF receptor, TrkB, to selectively bind BDNF molecules, was used to block BDNF in the hippocampus during a 1‐week voluntary exercise period. After this, a 2‐trial‐per‐day MWM was performed for 5 consecutive days, succeeded by a probe trial 2 days later. By inhibiting BDNF action we blocked the benefit of exercise on cognitive function, such that the learning and recall abilities of exercising animals receiving the BDNF blocker were reduced to sedentary control levels. Inhibiting BDNF action also blocked the effect of exercise on downstream systems regulated by BDNF and important for synaptic plasticity, cAMP response‐element‐binding protein (CREB) and synapsin I. Specific to exercise, we found an association between CREB and BDNF expression and cognitive function, such that animals who were the fastest learners and had the best recall showed the highest expression of BDNF and associated CREB mRNA levels. These findings suggest a functional role for CREB under the control of BDNF in mediating the exercise‐induced enhancement in learning and memory. Our results indicate that synapsin I might also contribute to this BDNF‐mediated mechanism.
Intrinsic and spontaneous neurogenesis in the postnatal slice culture of rat hippocampus
Authors: Kamada Maki , Li Ren‐Yong , Hashimoto Mika , Kakuda Masaaki , Okada Hiroshi , Koyanagi Yoshio , Ishizuka Toru , Yawo Hiromu
Published: November 2004

Organotypic slice culture preserves the morphological and physiological features of the hippocampus of live animals for a certain time. The hippocampus is one of exceptional regions where neurons are generated intrinsically and spontaneously throughout postnatal life. We investigated the possibility that neurons are generated continuously at the dentate granule cell layer (GCL) in slice culture of the rat hippocampus. Using 5‐bromodeoxyuridine (BrdU) labelling and retrovirus vector transduction methods, the phenotypes of the newly generated cells were identified immunohistochemically. At 4 weeks after BrdU exposure, BrdU‐labelled cells were found in the GCL and were immunoreactive with a neuronal marker, anti‐NeuN. There were fibrils immunoreactive with anti‐glial fibrillary acidic protein (GFAP), an astrocyte marker, in the layer covering the GCL and occasionally encapsulated BrdU‐labelled nuclei. When the newly divided cells were marked with the enhanced green fluorescent protein (EGFP) using a retrovirus vector, these cells had proliferative abilities throughout the following 4‐week cultivation period. Four weeks after the inoculation, the EGFP‐expressing cells consisted of various phenotypes of both early and late stages of differentiation; some were NeuN‐positive cells with appearances of neurons in the GCL and some were immunoreactive with anti‐Tuj1, a marker of immature neurons. Some EGFP‐expressing cells were immunoreactive with anti‐GFAP or anti‐nestin, a marker of neural progenitors. The present study suggests that slice cultures intrinsically retain spontaneous neurogenic abilities for their cultivation period. The combination of slice culture and retrovirus transduction methods enable the newly divided cells to be followed up for a long period.
Are switches in perception of the Necker cube related to eye position?
Authors: Einhäuser Wolfgang , Martin Kevan A. C. , König Peter
Published: November 2004

The issue of the relation of eye position to perceptual reversals of the ambiguous figure of the ‘Necker cube’ dates back to Necker's original article [L.A. Necker (1832) The London & Edinburgh Philosophical Magazine and Journal of Science, 1, 329–337]. Despite the investigations of many distinguished psychophysicists since then, the question of whether perceptual switching is a cause or a consequence of associated changes in eye position has remained a matter of debate. In the present study we overcame methodological problems that have bedevilled many previous studies. We avoided any instruction that could interfere with the human subjects' free viewing of the Necker cube, tracked the eye position precisely and used biased versions of the cube that produced unambiguous percepts to determine how each subject actually looked at the cube. We show that, under these free‐viewing conditions, there is a close link between the perception of the Necker cube and eye position. The average eye position of most subjects is at an extreme value at about the time when the subject's perception switches. From the biased cube trials we can infer that the polarity of the extreme corresponds to the percept which the subject had before the switch. These data indicate a bidirectional coupling between eye position and perceptual switching so that, after a subject's perceptual state changes, their eye position shifts to view the newly established percept. When the eye position approaches the corresponding extreme, the percept, in turn, becomes more and more likely to switch. This result suggests that the changed eye position itself might provide a negative feedback signal that suppresses the percept.
BM88 is an early marker of proliferating precursor cells that will differentiate into the neuronal lineage
Authors: Koutmani Yassemi , Hurel Catherine , Patsavoudi Evangelia , Hack Michael , Gotz Magdalena , Thomaidou Dimitra , Matsas Rebecca
Published: November 2004

Progression of progenitor cells towards neuronal differentiation is tightly linked with cell cycle control and the switch from proliferative to neuron‐generating divisions. We have previously shown that the neuronal protein BM88 drives neuroblastoma cells towards exit from the cell cycle and differentiation into a neuronal phenotype in vitro. Here, we explored the role of BM88 during neuronal birth, cell cycle exit and the initiation of differentiation in vivo. By double‐ and triple‐labelling with the S‐phase marker BrdU or the late G2 and M‐phase marker cyclin B1, antibodies to BM88 and markers of the neuronal or glial cell lineages, we demonstrate that in the rodent forebrain, BM88 is expressed in multipotential progenitor cells before terminal mitosis and in their neuronal progeny during the neurogenic interval, as well as in the adult. Further, we defined at E16 a cohort of proliferative progenitors that exit S phase in synchrony, and by following their fate for 24 h we show that BM88 is associated with the dynamics of neuron‐generating divisions. Expression of BM88 was also evident in cycling cortical radial glial cells, which constitute the main neurogenic population in the cerebral cortex. In agreement, BM88 expression was markedly reduced and restricted to a smaller percentage of cells in the cerebral cortex of the Small eye mutant mice, which lack functional Pax6 and exhibit severe neurogenesis defects. Our data show an interesting correlation between BM88 expression and the progression of progenitor cells towards neuronal differentiation during the neurogenic interval.
A role for ERKII in synaptic pattern selectivity on the time‐scale of minutes
Authors: Ajay Sriram M. , Bhalla Upinder S.
Published: November 2004

Stimulus reinforcement strengthens learning. Intervals between reinforcement affect both the kind of learning that occurs and the amount of learning. Stimuli spaced by a few minutes result in more effective learning than when massed together. There are several synaptic correlates of repeated stimuli, such as different kinds of plasticity and the amplitude of synaptic change. Here we study the role of signalling pathways in the synapse on this selectivity for spaced stimuli. Using the in vitro hippocampal slice technique we monitored long‐term potentiation (LTP) amplitude in CA1 for repeated 100‐Hz, 1‐s tetani. We observe the highest LTP levels when the inter‐tetanus interval is 5–10 min. We tested biochemical activity in the slice following the same stimuli, and found that extracellular signal‐regulated kinase type II (ERKII) but not CaMKII exhibits a peak at about 10 min. When calcium influx into the slice is buffered using AM‐ester calcium dyes, amplitude of the physiological and biochemical response is reduced, but the timing is not shifted. We have previously used computer simulations of synaptic signalling to predict such temporal tuning from signalling pathways. In the current study we consider feedback and feedforward models that exhibit temporal tuning consistent with our experiments. We find that a model incorporating post‐stimulus build‐up of PKM zeta acting upstream of mitogen‐activated protein kinase is sufficient to explain the observed temporal tuning. On the basis of these combined experimental and modelling results we propose that the dynamics of PKM activation and ERKII signalling may provide a mechanism for functionally important forms of synaptic pattern selectivity.
Cellular prion protein/laminin receptor: distribution in adult central nervous system and characterization of an isoform associated with a subtype of cortical neurons
Authors: Baloui Hasna , Von Boxberg Ysander , Vinh Joëlle , Weiss Stefan , Rossier Jean , Nothias Fatiha , Stettler Olivier
Published: November 2004

The 67‐kDa LR protein was originally discovered as a non‐integrin laminin receptor. Several more recent in vitro studies demonstrated the function of 67‐kDa LR and its related ‘precursor’ form 37‐kDa LRP as receptors of cellular prion protein and their implication in abnormal prion protein propagation in vitro. In addition, expression of both proteins was shown to increase considerably in the brain of scrapie‐infected mice and hamsters. While LRP/LR are thus likely to play important roles in neuronal cell adhesion, survival and homeostasis and during pathological disorders, little is known so far about their fine cellular distribution in adult central nervous system. Using immunocytochemistry and western blotting, we show here that the 67‐kDa LR is the major receptor form in adult rat brain and spinal cord, expressed within the cytoplasm and at the plasma membrane of most neurons and in a subset of glial cells. The overall distribution of LR correlates well with that reported for laminin‐1 but also with brain regions classically associated with prion‐related neurodegeneration. In contrast to LR, the 37‐kDa LRP form is much less abundant in adult than in postnatal central nervous system. Characterization of a novel antibody allowed us to study the distribution across tissues of cell membrane‐associated LRP. Interestingly, this form is almost exclusively found on a subclass of parvalbumin‐immunoreactive cortical interneurons known to degenerate during the early stages of Creutzfeldt‐Jakob disease. Our demonstration of local differences in the expression of particular LRP/LR isoforms may be a first step towards unraveling their specific molecular interactions.
Distribution and signaling of TREM2/DAP12, the receptor system mutated in human polycystic lipomembraneous osteodysplasia with sclerosing leukoencephalopathy dementia
Authors: Sessa Giuseppina , Podini Paola , Mariani Margherita , Meroni Alessandra , Spreafico Roberto , Sinigaglia Francesco , Colonna Marco , Panina Paola , Meldolesi Jacopo
Published: November 2004

Together with its adaptor protein, the adaptor protein of 12 kDa also known as KARAP and TYROBP (DAP12), triggering r (TREM2) is a stimulatory membrane receptor of the immunoglobulin/lectin‐like superfamily, well known in myeloid cells. In humans, however, loss‐of‐function mutations of TREM2/DAP12 leave myeloid cells unaffected but induce an autosomal recessive disease characterized, together with bone cysts, by a spectrum of pathological lesions in the cortex, thalamus and basal ganglia with clinical symptoms of progressive dementia (polycystic lipomembraneous osteodysplasia with sclerosing leukoencephalopathy). Nothing was known about the role of TREM2/DAP12 in brain cell biology and physiology. By confocal immunocytochemistry we demonstrate that, in both human and mouse cerebral cortex, TREM2/DAP12, strongly expressed by microglia, is also present in a fraction of neurons but not in astrocytes and oligodendrocytes. In contrast, in the hippocampal cortex TREM2‐expressing neurons are rare. Both in neurons and microglia the receptor appears to be located mostly intracellularly in a discrete compartment(s) partially coinciding with (or adjacent to) the Golgi complex/trans‐Golgi network. Four nerve cell lines were identified as expressing the intracellular receptor system. In living human microglia CHME‐5 and glioblastoma T98G cells, activation of TREM2 by its specific antibody induced [Ca2+]i responses, documenting its surface expression and functioning. Surface expression of TREM2, low in resting CHME‐5 and T98G cells, increases significantly and transiently (60 min) when cells are stimulated by ionomycin, as revealed by both surface biotinylation and surface immunolabeling. Our results provide the first information about the expression, distribution (mostly intracellular) and functioning of TREM2/DAP12 system in nerve cells, a necessary step in the understanding of the cellular mechanisms affected in polycystic lipomembraneous osteodysplasia with sclerosing leukoencephalopathy.
Altered morphological and electrophysiological properties of Cajal–Retzius cells in cerebral cortex of embryonic Presenilin‐1 knockout mice
Authors: Kilb Werner , Hartmann Dieter , Saftig Paul , Luhmann Heiko J.
Published: November 2004

Mutations of Presenilin‐1 are the major cause of familial Alzheimer's disease. Presenilin‐1 knockout (PS1–/–) mice develop severe cortical dysplasia related to human type 2 lissencephaly. This overmigration syndrome has been attributed to the premature loss of Cajal–Retzius cells (CRcs), pioneer neurons required for the termination of radial neuronal migration. To elucidate the potential cellular mechanisms responsible for this premature neuronal loss, we investigated the morphological and electrophysiological properties of visually identified CRcs of wild‐type (WT) and PS1–/– mouse brains at embryonic day 16.5. The density of CRcs was substantially reduced in the cerebral cortex of PS1–/–. In PS1–/– CRcs the number of axonal branches was significantly increased to 12.5 ± 4.9 (n = 8; WT, 4.0 ± 1.4, n = 12), while no differences in dendritic branching and total length of dendritic and axonal compartments were observed. Additionally, the resting membrane potential of PS1–/– CRcs was significantly depolarized (−48.3 ± 1.7 mV; n = 23) in contrast to WT CRcs (−57.9 ± 2.1 mV; n = 38). Active membrane properties were not affected by PS1 deficiency. CRcs of both genotypes showed spontaneous postsynaptic currents that could be completely blocked by 100 µm bicuculline and were unaffected by glutamatergic antagonists, suggesting that they were mediated by GABAA receptors. These results demonstrate that axonal branching and resting membrane potential of CRcs was affected in embryonic cerebral cortex of PS1–/– mice. The depolarized membrane potential observed in PS1–/– CRcs may increase the susceptibility to neuronal death, thus facilitating the premature loss of CRcs in PS1–/– mice.
Acute improvement of hand sensibility after selective ipsilateral cutaneous forearm anaesthesia
Authors: Björkman Anders , Rosén Birgitta , Lundborg Göran
Published: November 2004

The cortical representation of body parts is constantly modulated in response to the afferent input, and acute deafferentation of a body part results in bilateral cortical reorganization. To study the effects on hand function of right forearm anaesthesia, we investigated ten human subjects (group 1) for perception of touch, tactile discrimination and grip strength in the right (ipsilateral) and left (contralateral) hand before, during and 24 h after forearm skin anaesthesia with a local anaesthetic cream (EMLA®). Ten age‐matched controls (group 2) were investigated in the same way but received placebo. In group 1 a significant improvement was seen in tactile discrimination in the ipsilateral hand compared to base line (P = 0.009) and compared to group 2 (P = 0.006). The improvement in tactile discrimination remained for at least 24 h after anaesthesia. Perception of touch, was improved during anaesthesia compared to baseline values in group 1 (P = 0.046) and remained for at least 24 h. Grip strength did not change. These findings suggest that transient selective deafferentation of an extremity results in enhanced sensory functions of the functionally preserved parts of the same extremity, presumably as a result of expansion of adjacent cortical territories. Such rapid functional changes suggest unmasking of pre‐existing synaptic connections as the mechanism underlying the acute modulation of sensory functions in the hand. Our findings open new perspectives for sensory re‐education and rehabilitation following injury to the peripheral and central nervous system.
Post‐training intrabasolateral amygdala infusions of dopamine modulate consolidation of inhibitory avoidance memory: involvement of noradrenergic and cholinergic systems
Authors: LaLumiere Ryan T. , Nguyen Linda T. , McGaugh James L.
Published: November 2004

There is extensive evidence that several neurotransmitter systems within the basolateral amygdala (BLA) influence memory consolidation. The present study investigated the influence of dopamine (DA) in the BLA on the consolidation of memory for inhibitory avoidance (IA) training. Male Sprague–Dawley rats (≈300 g) were trained on a step‐through IA task and, 48 h later, tested for retention as indexed by their latencies to enter the shock compartment on the test day. Drugs were infused into the BLA or central amygdala nucleus (CEA) immediately or 3 h after training via bilateral cannulae. DA infused into the BLA immediately after training enhanced retention, whereas DA infused into the BLA 3 h after training or into the CEA did not affect retention. Infusions of the dopaminergic antagonist cis‐Flupenthixol together with DA blocked the DA‐induced memory enhancement. Immediate post‐training intra‐BLA infusions of the D1 receptor antagonist SCH 23390 or the D2 receptor antagonist sulpiride impaired retention. β‐adrenergic or muscarinic cholinergic receptor antagonists coinfused into the BLA with DA blocked the memory enhancing effects of DA. These findings indicate that dopaminergic activation within the BLA modulates memory consolidation and that the modulation involves activation of both D1 and D2 receptors and concurrent activation of β‐adrenergic and cholinergic influences within the BLA.
Altered sensorimotor development in a transgenic mouse model of amyotrophic lateral sclerosis
Authors: Amendola Julien , Verrier Bernard , Roubertoux Pierre , Durand Jacques
Published: November 2004

Most neurodegenerative diseases become manifest at an adult age but abnormalities or pathological symptoms appear earlier. It is important to identify the initial mechanisms underlying such progressive neurodegenerative disease in both humans and animals. Transgenic mice expressing the familial amyotrophic lateral sclerosis (ALS)‐linked mutation (G85R) in the enzyme superoxide dismutase 1 (SOD1) develop motor neuron disease at 8–10 months of age. We address the question of whether the mutation has an early impact on spinal motor networks in postnatal mutant mice. Behavioural tests showed a significant delay in righting and hind‐paw grasping responses in mutant SOD1G85R mice during the first postnatal week, suggesting a transient motor deficit compared to wild‐type mice. In addition, extracellular recordings from spinal ventral roots in an in vitro brainstem–spinal cord preparation demonstrated different pharmacologically induced motor activities between the two strains. Rhythmic motor activity was difficult to evoke with N‐methyl‐dl‐aspartate and serotonin at the lumbar levels in SOD1G85R mice. In contrast to lumbar segments, rhythmic activity was similar in the sacral roots from the two strains. These results strongly support the fact that the G85R mutation may have altered lumbar spinal motor systems much earlier than previously recognized.
Identified spinal motoneurons of young rats possess nicotinic acetylcholine receptors of the heteromeric family
Authors: Ogier R. , Liu X. , Tribollet E. , Bertrand D. , Raggenbass M.
Published: November 2004

The aim of the present study was to determine whether, in young rats, spinal motoneurons possess functional nicotinic acetylcholine receptors. Motoneurons were identified either by retrograde labelling or by choline acetyltransferase immunohistochemistry. Whole‐cell recordings were performed in spinal cord slices cut at the lumbar level. In voltage clamp, acetylcholine evoked a rapidly activating inward current. In current clamp, it depolarized the motoneuron membrane and induced action potential firing. The acetylcholine‐evoked current was strongly reduced by d‐tubocurarine or dihydro‐β‐erythroidine, broad spectrum nicotinic antagonists, but was almost insensitive to methyllycaconitine, a nicotinic antagonist selective for receptors containing the α7 subunit. Moreover, exo‐2‐(2‐pyridyl)‐7‐azabicyclo[2.2.1]heptane, an α7‐specific agonist, was without effect. In young animals, light‐microscopic autoradiography showed that in the central grey matter all laminae were intensely and equally labelled by [3H]epibatidine. A dense [125I]‐α‐bungarotoxin binding was also found in all laminae, with slightly lower levels in the superficial layers of the dorsal horns and in the ventral part of the grey matter. In adults, the density of [3H]epibatidine binding sites was much lower in the entire grey matter, except in layer 2 of the dorsal horn, and [125I]‐α‐bungarotoxin binding sites were present only in some selected areas. Our data indicate that spinal motoneurons possess functional nicotinic receptors of the heteromeric type and suggest that nicotinic cholinergic transmission may play a significant role in the developing spinal cord.
Clinical and biochemical effects of propofol EDTA vs sevoflurane in healthy infants and young children1
Authors: Cohen Ira T. , Finkel Julia C. , Hannallah Raafat S. , Goodale David B.
Published: November 2004

Background : Propofol is frequently used for the induction and maintenance of anaesthesia in children aged 3 years and older. The present study compared the clinical and chemical effects of propofol containing disodium edetate (Diprivan®) with that of sevoflurane in children younger than 3 years of age.

Methods : This was an open‐label, comparative, parallel‐group study. Fifty‐six healthy children were randomly assigned to receive either propofol (n = 28; mean age 14.7 months) or sevoflurane (n = 28; mean age 13.2 months) for ambulatory surgical procedures. Anaesthesia was induced with nitrous oxide (60%), oxygen and sevoflurane (8%). In the propofol group, it was followed by an intravenous infusion of propofol at a rate of 200 μg·kg−1·min−1. For the sevoflurane group, anaesthesia was maintained with sevoflurane (1.5–2.5%). Haemodynamic measurements, recovery time and side‐effects were recorded. Ionized calcium and magnesium concentrations in blood were measured. Statistical analysis was performed using ancova and the Fisher's exact test.

Results : The effects of propofol were similar to those of sevoflurane with respect to haemodynamic profile, recovery times (20 min vs 19.4 min) and side‐effects (i.e. vomiting 10.7% vs 7.1%). Throughout the study, there were no significant differences between the mean ionized calcium and ionized magnesium concentrations in the two groups.

Conclusions : In children younger than 3 years of age, propofol containing ethylenediaminetetraacetic acid has a similar profile to sevoflurane with respect to haemodynamic effects, recovery times, side‐effects, ionized calcium and ionized magnesium levels.
The clinical effect of mixing different proportions of rocuronium and mivacurium
Authors: Fletcher James E. , Heard Christopher M.B.
Published: November 2004

Background : A synergistic effect has been described when rocuronium (Roc) and mivacurium (Miv) are combined in equal (i.e. 1 : 1) ED95 proportions at various total doses. We have investigated the effect of Roc or Miv alone and four different ratios (1 : 4, 2 : 3, 3 : 2 and 4 : 1) of Roc and Miv mixed to a total dose of 1.33 × ED95. The primary outcome is the ratio producing the maximum enhancement of duration of clinical effect.

Methods : Sixty‐eight healthy children were anaesthetized with propofol, nitrous oxide and fentanyl. They then randomly received either Roc 0.4 (mg·kg−1), Miv 0.133 (mg·kg−1) or one of four Roc + Miv combinations (mg·kg−1): Roc 0.32 + Miv 0.027; Roc 0.24 + Miv 0.053; Roc 0.16 + Miv 0.08; and Roc 0.08 + Miv 0.106. The mechanical response of the adductor pollicis muscle to supramaximal stimulation of the ulnar nerve at the wrist was recorded.

Results : Duration of effect was greater in the combination groups than that predicted from the duration of Roc or Miv used alone. Duration was maximally increased around a 1 : 1 ratio (2 : 3 and 3 : 2) of Roc and Miv. The likelihood of achieving 100% block was greater in combination groups compared with Roc or Miv used alone.

Conclusions : Combinations of Roc and Miv show a synergistic effect, which appears maximal as the mixture approaches a 1 : 1 ratio of their ED95s. This combination acted as if a larger effective dose of a single (new) drug had been given, but did not offer the advantage of both rapid onset and short duration of effect.
Incidence and risk factors of perioperative respiratory adverse events in children undergoing elective surgery
Authors: Mamie Chantal , Habre Walid , Delhumeau Cécile , Barazzone Argiroffo Constance , Morabia Alfredo
Published: November 2004

Background:  Adverse respiratory events remain one of the major causes of morbidity during anaesthesia, especially in children. The purpose of this prospective study was to determine the incidence of perioperative respiratory adverse events (PRAE) during elective paediatric surgery and to identify the risk factors for these events.

Methods:  Potential risk factors (atopy, eczema, rhinitis, food allergy, previous allergic tests, pollens or animal allergy, passive smoking, obstructive sleep disorders) were assessed using the International Society on Allergy and Asthma (ISAAC) questionnaire, which was submitted to the parents during preoperative anaesthetic assessment. Anaesthetic and surgical conditions were systematically recorded. A multivariate logistic regression explaining PRAE was developed in 800 children.

Results:  The intraoperative incidence of respiratory adverse events was 21% and the incidence in the postanesthetic care unit was 13%. According to the multivariate analysis, children not anaesthetized by a specialist paediatric anaesthesiologist have 1.7 increased risk to present PRAE (95% CI = 1.13–2.57). Children anaesthetized for ear, nose, throat (ENT) surgery had a 1.57‐fold higher risk of PRAE compared with other procedures (95% CI = 1.01–2.44). Furthermore, there was a synergistic interaction when two risk factors: residents and ENT surgery, were concomitant: the odds ratio (OR) of PRAE during non‐ENT surgical procedures was 1.43 (95% CI = 0.91–2.24), but increased to 2.74‐fold (95% CI = 1.15–4.32) for ENT surgery. The risk of PRAE was significantly lower when the anaesthetic technique included tracheal intubation with relaxants (OR = 0.6, 95% CI = 0.45–0.95) and decreased by 8% with each increasing year of age.

Conclusions:  This study demonstrates a high incidence of PRAE in paediatric surgical patients without respiratory tract infections, which appears to be primarily determined by the age of the child and the anaesthetic care rather than by the child's medical history.