bluuebunny/crossref_metadata_2025 huggingface dataset:
Functional role of a high mol mass protein complex in the sea urchin yolk granule
Authors: Perera Aruni , Davis Philip , Robinson John J.
Published: April 2004

We have investigated the biochemical and functional characteristics of the major protein constituents of the yolk granule organelle present in sea urchin eggs and embryos. Compositional analysis, using sodium dodecyl sulfate polyacrylamide gel electrophoresis, revealed distinctly different polypeptide patterns under reducing and non‐reducing conditions. In the presence of reducing agent, a 240 kDa species dissociated into polypeptides of apparent mol mass 160, 120 and 90 k. The relatedness of these polypeptides to the 240 kDa species was demonstrated in protein gel blot and peptide mapping analyses. The profile of yolk granule polypeptides was dynamic during embryonic development with the disappearance of the 160 kDa species and the coincidental appearance of lower mol mass polypeptides. However, the 240 kDa complex was detected even after the disappearance of the 160 kDa polypeptide. The 240 kDa complex was released from yolk granules in the absence of calcium and the purified species was shown to bind liposomes in a calcium‐dependent manner. In addition, the 240 kDa complex possessed a calcium‐dependent, liposome aggregating activity. The 240 kDa species could also induce the aggregation of yolk granules, previously denuded of the complex following treatment with either ethylenediaminetetraacetic acid or trypsin. Collectively, these results demonstrate the dynamic characteristics of the yolk granule 240 kDa protein complex and offer insights into a possible functional role.
Differentiation of slow and fast fibers in tentacles of Sepia officinalis (Mollusca)
Authors: Grimaldi Annalisa , Tettamanti Gianluca , Brivio Maurizio F. , Valvassori Roberto , De Eguileor Magda
Published: April 2004

The tentacles of Sepia officinalis are cylindrical muscular structures that can be quickly everted and elongated to capture prey. The combination of both velocity and extensive elongation of the tentacles is due to the presence of both cross‐striated and helical muscles. The complex organization and differentiation of different fibers has been studied in cuttlefish extracted from egg gel coats at different developmental stages, and in completely developed animals. Tentacle muscles start to differentiate centrifugally from the area close to the axial nervous system, where two types of myocytes can be recognized. These populations of myocytes, which may be distinguished morphologically and which express different myosin isoforms, give rise to fast and slow muscles.

The presence in molluscs of slow and fast muscles arising from different populations of myocytes, as in vertebrate muscle development, could be considered as an example of evolutionary conservation.
Northern New Zealand Rhegmatogenous Retinal Detachment Study: epidemiology and risk factors
Authors: Polkinghorne Philip J , Craig Jennifer P
Published: April 2004

Background: The incidence of retinal detachment in New Zealand is not currently documented in the literature. This study sought to determine the annual incidence of rhegmatogenous retinal detachment (RRD) and associated risk factors in northern New Zealand.

Methods: Epidemiological and clinical data were collected for all patients presenting with a RRD in a 12‐month interval in a confined geographical area of New Zealand.

Results: One hundred and forty‐one patients presented between May 1997 and April 1998 with a RRD. Five patients presented with bilateral RRD. The mean age at presentation was 53.9 years and the annual incidence for RRD was 11.8 cases per 100 000 people. RRD was more common in males than in females (1.3:1). Ocular trauma, high myopia and cataract extraction were found to be significant risk factors in the development of RRD.

Conclusions: The annual incidence of RRD in northern New Zealand is comparable to values reported for other parts of the world and, consistent with previous studies, the incidence of RRD was found to increase with age, and in association with trauma, high myopia and cataract surgery.
Sympathetic ophthalmia following ciliary body laser cyclophotocoagulation for rubeotic glaucoma
Authors: Kumar Nikhil , Chang Andrew , Beaumont Paul
Published: April 2004

A 60‐year‐old Asian man presented with left rubeotic glaucoma secondary to a central retinal vein occlusion. He was successfully treated with laser diode cyclophotocoagulation of the ciliary body. Nine months later he developed right progressive visual loss, headache, corneal oedema, anterior chamber cells, flare, mutton fat keratic precipitates, a swollen disc, and a minimal inferior visual field defect. A diagnosis of sympathetic ophthalmia was made, which was confirmed by characteristic findings seen on fluorescein and indocyanine green angiography.
Deposits in artificial corneas: risk factors and prevention
Authors: Hicks Celia R , Chirila Traian V , Werner Liliana , Crawford Geoffrey J , Apple David J , Constable Ian J
Published: April 2004

Purpose: To identify risk factors for calcium deposition and pigmented staining within AlphaCor artificial corneas.

Methods: Retrospective analysis of data from 72 AlphaCor implantations was conducted. Histological analysis of explants was performed.

Results: Eight cases of either intraoptic calcium or pigment deposition occurred in AlphaCor patients between 2.5 and 21 months after implantation. Four cases had diffuse white deposits, confirmed to be calcium and associated with prior coadministration of topical steroids and beta‐blockers. The other four cases had brown deposits, associated with cigarette smoking and topical levobunolol.

Conclusion: These findings led to changes in patient management protocols, surgeon training and patient information so as to minimize the risk of further occurrences. No further cases of white deposition have occurred after warning surgeons of the risk associated with certain topical therapy combinations. The risk of brown staining may be difficult to remove completely as it appears that environmental exposure to chemicals may cause deposition in addition to personal smoking habits and topical medications.
Clinical Case Notes
Authors: Landers John , Tang K C , Hing Stephen
Published: April 2004

The visual field can be affected by disorders involving any part of the visual pathway, from the retina to the striate cortex. The pattern of visual field damage can indicate the location of the disorder. The case is presented here of an 8‐year‐old girl with congenital glaucoma. Initial perimetry appeared consistent with glaucomatous field loss; however, this evolved into a homonymous quadrantanopia, indicating the presence of a cerebral lesion as the cause. Computed tomography and magnetic resonance imaging scans detected a large middle cranial fossa arachnoid cyst. Postoperatively there was resolution of the visual field defects secondary to the arachnoid cyst. The pattern of field loss was pivotal in this patient's management. Attention must be paid when caring for the patient with a chronic disease to ensure that concurrent conditions are diagnosed.
Clinical Case Notes
Authors: Garrott Helen M , Walland Mark J
Published: April 2004

Raised intraocular pressure and glaucoma have rarely been associated with use of periorbital corticosteroids for dermatological conditions such as blepharitis and eczema. Three cases are described in which periorbital topical corticosteroids appear to have resulted in raised intraocular pressure or glaucoma. Topical corticosteroids used for dermatological conditions around the face and eyes are often regarded as being fairly innocuous with regard to ocular side‐effects. This case series demonstrates that secondary open‐angle glaucoma can be a sight‐threatening consequence, and periorbital steroids should therefore be used cautiously and sparingly, particularly in those with a family history of glaucoma. Intraocular pressure may not always return to normal upon cessation of the drug.
Clinical Case Notes
Authors: Riley Andrew F , Aburn Neil S
Published: April 2004

A case is reported of a patient with bilateral central retinal artery occlusion secondary to giant cell arteritis. After treatment the vision recovered in one eye but remained poor in the other eye. Treatments employed are discussed with particular attention drawn to differences in the treatment of each eye and suggestions are made for treatment of similar cases.
Systemic autonomic function in subjects with primary angle‐closure glaucoma: a comparative study of symptomatic and asymptomatic disease presentation
Authors: Yong Vernon KY , Umapathi Thirugnanam , Aung Tin , Tan Nigel CK , Lee Jong‐Jian , Liew Geok‐Cheng , Yip Chee‐Chew , Foster Paul J , Chew Paul TK
Published: April 2004

Background: Autonomic dysfunction is thought to be a contributory factor in primary angle‐closure glaucoma (PACG) by precipitating pupil block in anatomically predisposed eyes. This study aimed to compare systemic autonomic function between subjects who had suffered a previous episode of acute angle closure (symptomatic PACG), those who had asymptomatic PACG, and age and sex‐matched controls.

Methods: Tests for systemic parasympathetic function included the heart‐rate response to standing (30:15 ratio), heart‐rate variation during deep breathing, and the ratio of the heart rate at phases IV and II of the Valsalva manoeuvre (Valsalva ratio). For assessment of the sympathetic nervous system, blood pressure was recorded supine and then after 2 and 5 min of standing. A modified sweat test, the sympathetic skin response, was recorded on the palm and sole.

Results: A total of 30 subjects were examined: eight previous symptomatic PACG, eight asymptomatic PACG and 14 control subjects. The mean ages were similar, and all except one subject were Chinese. None of the subjects had evidence of systemic dysautonomia. There was no significant difference found between the groups for the 30:15 ratio, heart‐rate variation during deep respiration and the Valsalva ratio. No significant orthostatic hypotension was detected in subjects with PACG. Abnormal sympathetic skin response was not more common in PACG subjects compared to control subjects.

Conclusions: This study identified no systemic autonomic dysfunction in people with PACG.
Sub‐Tenon infiltration or classical analgesic drugs to relieve postoperative pain
Authors: Calenda Emile , Muraine Marc , Quintyn Jean Claude , Brasseur Gérard
Published: April 2004

Background: In a prospective randomized double‐blind study, the analgesic effect produced by sub‐Tenon infiltration was compared with classic analgesic drugs in patients scheduled for posterior segment surgery under general anaesthesia.

Methods: One hundred patients were randomized into two groups of 50. One group received sub‐Tenon infiltration (group 1) with 3 mL of bupivacaine 0.50% by the surgeon before the end of the surgery and the other (group 2) received only classical analgesic drugs postoperatively. A visual analogue scale (VAS) (graded from 1 to 10) was used to assess pain. For both groups, when VAS was between 1 and 3 paracetamol (3 g/24 h) associated with ketoprofen (200 mg/24 h) was given; between 3 and 6 nalbuphine (0.2 mg/kg slowly intravenously repeated every 4 h if necessary) was given; and over 6 morphine was given. Morphine 1 mg was injected every 2 min until VAS below 3 was obtained.

Results: All patients in group 2 (control) experienced pain in the recovery room period; however, no patient in group 1 required analgesic drugs in the first 6 h after the sub‐Tenon infiltration. In the recovery room period, the VAS pain score in patients who received sub‐Tenon infiltration (group 1) was 0.6 ± 1.3 (mean ± SD) compared to 3.4 ± 2.2 in group 2. The difference was statistically significant (P = 0.000001). All patients in group 2 asked for analgesic drugs in the recovery room, some of whom required morphine. Despite the administration of drugs the pain score was statistically higher in group 2. Between the end of the recovery room period and the 6th hour, the VAS pain score in group 1 was statistically lower. From the 6th until the 24th hour, the pain score was not statistically significantly different between the groups. Regarding consumption of analgesic drugs from the recovery room until the 24th hour, the consumption of level 1 analgesic drugs (paracetamol, ketoprofen) and level 3 (morphine) was statistically lower in group 1 (P = 0.0009). The difference was not significant for level 2, probably because the number of patients was not sufficient.

Conclusion: Sub‐Tenon infiltration with 3 mL of bupivacaine 0.50% offers excellent postoperative analgesia for about 6 h and is an excellent alternative to classical drugs. Furthermore, it is highly reliable and safe.
A retrospective review of the associations between amblyopia type, patient age, treatment compliance and referral patterns
Authors: Chua Brian E‐G , Johnson Kim , Frank Martin FRANZCO
Published: April 2004

Aim: To review presenting ages, referral sources, amblyopia type and treatment compliance in children attending a typical public hospital ophthalmology clinic with no formal amblyopia screening program in place.

Methods: One hundred and twenty‐seven children attending the outpatients clinics of The Children's Hospital at Westmead for amblyopia management between January 2001 and May 2003 were reviewed. Presenting age, amblyopia type, referral source, treatment prescribed and compliance achieved were analysed using means, 95% confidence intervals (CI), and Mantel−Haenszel χ2 statistic.

Results: General practitioners and paediatricians provided most referrals. The mean presenting age was 32.9 (95% CI 29.0−36.9) months. There was no significant association between presenting age and amblyopia type (χ2 = 6.00, P = 0.11, d.f. = 3), but a trend was found with deprivation amblyopia identified earliest, and pure anisometropic amblyopia identified latest (χ2 = 5.65, P = 0.02, d.f. = 1). Compliance to patching did not differ significantly between sexes, with calculated aggregate compliance of 67.3% (95% CI: 59−75%) for boys and 66.3% (95% CI: 60−73%) for girls. Compliance to patching also did not differ significantly between amblyopia types (χ2 = 3.61, P = 0.3, d.f. = 3). Compliance was best among younger and older children, and worst among those aged 15−30 months. There was no association between patching compliance and treatment duration.

Conclusion: Amblyopia is a preventable form of blindness. A multidisciplinary approach must be taken. Resources and education should be targeted at general practitioners and paediatricians who have the greatest opportunities to perform amblyopia screening. Teachers are an important resource in identifying cases missed at previous informal screening opportunities. Amblyopia treatment must be intensified and individualized between the ages of 15−30 months when compliance is poorest.
Diode laser treatment of pre‐threshold and threshold retinopathy of prematurity
Authors: Lee Graham A , Hilford David J , Gole Glen A
Published: April 2004

Purpose: Retinopathy of prematurity (ROP) is a sight‐threatening condition of premature infants. This study aimed to investigate the efficacy of diode laser photocoagulation in the treatment of pre‐threshold and threshold ROP.

Methods: A retrospective review was conducted of patients who underwent diode laser treatment for ROP by one author (GAG) from 1992 to 2000. During this time, 2137 babies <1500 g birthweight or <32 weeks post‐conception age were examined.

Results: Seventy‐six eyes in 40 infants (20 male, 20 female) were treated for ROP. Treatment was performed on average at 37 weeks post‐conception age (range 31−50 weeks, SD = 3.2). The number of burns per eye for the first session of laser ranged between 193 and 1937 (mean 933), with power ranging from 200 to 1000 mW (mean 484). Eighteen (45.0%) of these 40 infants underwent a second session of laser (mean number of burns 683, range 167−1618), which was performed in 29 (38.2%) of the 76 eyes that initially underwent laser treatment. Complete regression was observed in 61 eyes (80.3%), occurring on average at 39 weeks post‐conception age (range 35−45, SD = 2.2). Six (7.9%) eyes progressed to stage IVA disease, two (2.6%) to stage IVB and three (3.9%) to stage V ROP. In the latter part of the study as the number of laser burns per eye increased it was found that the number of patients requiring a second session of laser treatment decreased, with no adverse outcomes observed in the last 3 years of the study. At last follow up, the average refractive error in the treated eyes was −0.40 D spherical equivalent (range −12.75 D to +4.25 D, SD = 3.0). The degree of myopia induced showed no significant correlation with the number of laser burns administered.

Conclusion: Diode laser treatment is able to stop progression of ROP in the majority of cases.
Medial canthal tendon repair for moderate to severe tendon laxity
Authors: Clement Colin I , O'Donnell Brett A
Published: April 2004

Background: Medial canthal tendon laxity is a common cause of epiphora and ocular irritation. It is difficult to treat due to the proximity of the lower canaliculus and punctum to the tendon.

Methods: The results of a prospective series of patients with involutional medial canthal tendon laxity between 1997 and 2002 were reviewed. Symptoms and measured laxity were recorded before and after medial canthal tendon repair. The medial canthal tendon was routinely repaired through a cut along the lid margin extending from the punctum medially. This avoids a vertical cut onto the anterior lamella of the eyelid, which is useful if a skin graft is required.

Results: Twenty lower eyelid medial canthal tendon repairs were performed on 17 patients. Preoperatively, the lower punctum in all patients was able to be distracted to the medial limbus or further and in 50% of cases, the lower lid punctum was able to be distracted to the pupil midline or further. Postoperatively all patients had reduction of their medial canthal tendon laxity. Postoperatively in 85% of cases the lower punctum was not able to be distracted beyond the medial limbus; however, 15% of cases still had significant residual laxity. Eighty‐five per cent of patients reported improvement in symptoms.

Conclusions: This is an effective procedure in the majority of patients with moderate to severe medial canthal tendon laxity; however, residual lower lid laxity persisted in some patients.
Effect of scan repetition on the reproducibility of optic nerve head topographic measurements with the Top SS
Authors: Akar Yusuf , Bozkurt Banu , Irkeç Murat , Orhan Mehmet , Karaağaoglu Ergun
Published: April 2004

Purpose: To determine the effect of scan repetition during a single visit for improved reproducibility of optic nerve head topographic measurements.

Methods: One randomly selected eye of 20 healthy subjects with no systemic or ocular disease was evaluated. Half of the subjects were under 30 years of age and the other half were older than 60 years. Five independent image series, each consisting of 10 newly recorded consecutive images, were obtained for each subject over a period of 10 weeks with a confocal scanning laser ophthalmoscope, the Top SS. Subjects were divided into two groups according to disc area being either smaller or larger than 2 mm2. Reproducibility of the measurements in three parameters (volume below, half depth area and the average depth) were calculated for each set of scans. The coefficient of variation (standard deviation divided by the mean) was taken as the measure of reproducibility. Repeated measures of analysis of variation and independent sample t‐test were used for statistical analysis. Statistical significance was set as P < 0.05.

Results: Both age groups were found to be equally distributed with respect to sex. There were no significant intergroup differences in keratometry, pupil diameter or refractive error. Increasing the scan repetition per visit up to five improved the reproducibility of the measurements. Further increases in scans per visit reduced the reproducibility. Subjects with larger discs and older age were found to have lower coefficients of variation for topographic measurements.

Conclusions: Normal subjects should be examined at least three to four times per visit to have significantly improved reliability of measurements of optic nerve head topography. Factors associated with decreased reproducibility included older age, smaller discs, and more than five scans per visit. Sex, refraction and pupil diameter were shown to have no effect on the reproducibility.
Effect of hinged lamellar keratotomy on post‐keratoplasty astigmatism and vision
Authors: Walker Nathan J , Apel Andrew JG
Published: April 2004

Purpose: To show that hinged lamellar keratotomy alone affects refraction and vision in post‐keratoplasty eyes.

Methods: A retrospective, non‐comparative, interventional case series was conducted on 28 eyes of 26 patients who had two‐stage laser in situ keratomileusis (LASIK) after penetrating keratoplasty. Records were reviewed with respect to the hinged lamellar keratotomy component of the procedure. The interval between keratoplasty and keratotomy was at least 1 year, and the follow‐up period averaged 29 ± 10 days. The Automated Corneal Shaper with nasal hinge was used. In addition to basic empirical astigmatism calculations, the Alpins method of astigmatism analysis was also employed to ensure that the influence of changes in cylinder axis were correctly taken into account when calculating the refractive change.

Results: Surgically induced astigmatism from hinged lamellar keratotomy was not statistically significant in this series; however, the range in values (−9.06 to +7.57 D) has potential clinical ramifications. Nearly 70% of cases studied experienced surgically induced astigmatism of at least 2 D. Mean preoperative uncorrected vision was logMAR 1.06 ± 0.41, which improved marginally postoperatively to logMAR 1.03 ± 0.44 (P = 0.36). Best spectacle‐corrected visual acuity averaged logMAR 0.21 ± 0.16 preoperatively, improving to logMAR 0.09 ± 0.15 (range −0.18 to 0.42) postoperatively, which was a statistically significant improvement (P < 0.01). No difference in refractive or visual outcomes was identified when those with keratoconus were compared to those with other underlying corneal disease processes.

Conclusion: Although mean surgically induced astigmatism was not statistically significant, hinged lamellar keratotomy caused considerable changes in astigmatism in nearly 70% of post‐keratoplasty eyes studied. This suggests that clinically significant inaccuracies may result if a one‐stage LASIK procedure is performed on such patients. The authors suggest that reassessment of refraction after keratotomy may improve refractive outcomes.
Morphological changes in keratoconus: pathology or pathogenesis
Authors: Sherwin Trevor , Brookes Nigel H
Published: April 2004

Keratoconus was first discriminated from other corneal ectatic diseases in 1854. Since that time the morphological characteristics of keratoconic progression have been invaluable in the diagnosis of the condition. The key clinical features used to identify keratoconus have remained essentially the same since the introduction of the slit‐lamp biomicroscope. Only relatively recently has the development of computerized corneal topography revolutionized the diagnosis of early keratoconus. Analysis of peer‐reviewed literature databases revealed a steady chronological increase in pathological research into the progress of keratoconus. This overview describes the recent advances in our understanding of keratoconic pathology and highlights the interactions within the cornea that may be important in the pathogenesis of this condition.
Pseudoexfoliation syndrome: pathological manifestations of relevance to intraocular surgery
Authors: Conway R Max , Schlötzer‐Schrehardt Ursula , Küchle Michael , Naumann Gottfried OH
Published: April 2004

Pseudoexfoliation syndrome (PEX) is a common ocular condition often associated with the need for intraocular surgery. Although results of cataract and glaucoma filtering surgery in eyes with PEX in the early stages of the disease may be comparable to those in eyes without PEX, in the later stages morbidity is significantly increased due to periocular surgical complications and the outcome is worse. Surgical and postoperative difficulties are often multifactorial and are directly related to the pathological changes of PEX on intraocular structures. Recent years have seen a large increase in the understanding of the effects of PEX on the various ocular tissues. Although the visible areas of the anterior capsule are most obviously involved, this is only a small part of the picture and of least significance. Biomicroscopically invisible changes of the zonules and their attachments are of greatest consequence. There is also distinct, often active, involvement of almost all tissues of the anterior segment of the eye, many of which have important implications for the anterior segment surgeon including iridopathy, iris vasculopathy (including persistent breakdown of the blood−aqueous barrier and anterior segment hypoxia), ciliary body involvement and keratopathy. Trabecular dysfunction is evident by the deposition of PEX material derived from bothin situand extra‐trabecular production as well as protein and melanin deposition. These changes should be kept in mind by all intraocular surgeons as a source of potential difficulties in the perioperative period. Additionally, in light of these changes, patients need to be given realistic expectations regarding the increased risk of complications and more prolonged expected recovery time. In this short review, current reports relating to PEX pathological changes of practical interest to the intraocular surgeon are summarized.
Cooperation and biased competition model can explain attentional filtering in the prefrontal cortex
Authors: Szabo Miruna , Almeida Rita , Deco Gustavo , Stetter Martin
Published: April 2004

Recent neurophysiological experimental results suggest that the prefrontal cortex plays an important role in filtering out unattended visual inputs. Here we propose a neurodynamical computational model of a part of the prefrontal cortex to account for the neural mechanisms defining this attentional filtering effect. Similar models have been employed to explain experimental results obtained during the performance of attention and working memory tasks. In this previous work the principle of biased competition was shown to successfully account for the experimental data. To model the attentional filtering effect, the biased competition model was extended to enable cooperation between stimulus selective neurons. We show that, in a biological relevant minimal model, competition and cooperation between the neurons are sufficient conditions for reproducing the attentional effect. Furthermore, a characterization of the parameter regime where the cooperation effect is observed is presented. Finally, we also reveal parameter regimes where the network has different modes of operation: selective working memory, attentional filtering, pure competition and noncompetitive amplification.
Repositioning of charged I–II loop amino acid residues within the electric field by β subunit as a novel working hypothesis for the control of fast P/Q calcium channel inactivation
Authors: Sandoz Guillaume , Lopez‐Gonzalez Ignacio , Stamboulian Séverine , Weiss Norbert , Arnoult Christophe , De Waard Michel
Published: April 2004

We have investigated the contribution of the Cavβ subunits to the process of inactivation dependent of the I–II loop of Cavα2.1. Two amino acid residues located in the alpha1 interaction domain (AID) of the I–II loop of Cavα2.1 (Arg387 and Glu388) have been directly implicated in voltage‐dependent inactivation of this channel. Various point mutations of these residues disrupt the interaction between the I–II loop and the III–IV loop, and thereby modify the inactivation properties of the channel by accelerating its kinetics and shifting the steady‐state inactivation curve towards hyperpolarized potentials. A similar disruption is produced by Cavβ4 subunit association with the I–II loop. Moreover, in the presence of Cavβ4 subunit, introducing negatively charged residues at positions 387 or 388 slows inactivation kinetics down, whereas introducing positive charges has the opposite effect. The shift of the steady‐state inactivation curve is also amino acid charge‐dependent. In contrast, mutation of Arg387 or Glu388 does not alter the differential regulation of the different Cavβ isoforms on inactivation. These results suggest that the expression of Cavβ4 alters the contribution of charged residues at positions 387 and 388 to inactivation. We discuss these results with regard to the actual hypotheses on the mechanisms of calcium channel inactivation. We introduce the working concept that Cavβ‐subunits produce a conformational repositioning of charged AID residues within the electric field.
Transcriptional response to circumscribed cortical brain ischemia: spatiotemporal patterns in ischemic vs. remote non‐ischemic cortex
Authors: Küry Patrick , Schroeter Michael , Jander Sebastian
Published: April 2004

Focal brain infarcts are surrounded by extended perilesional zones that comprise the partially ischemic penumbra but also completely non‐ischemic cortex of the remote ipsilateral hemisphere. To delineate the impact of lesion‐associated vs. remote processes on transcriptional programming after focal ischemia, we used cDNA array analysis, quantitative real‐time polymerase chain reaction and immunohistochemistry in the photothrombosis model of circumscribed cortical ischemia in rats. At an early stage of 4 h after ischemia, gene induction occurred to a similar extent in the ischemic infarct and remote non‐ischemic cortex of the ipsilateral hemisphere. Among the genes induced in non‐ischemic cortex we found the NGF‐inducible genes PC3, VGF and Arc, the transcriptional regulators IκB‐α and Stat3, and the β‐chemokine MIP‐1α (CCL3). At 3 days, the spatial pattern of gene expression had changed dramatically with brain fatty acid‐binding protein as the only gene significantly induced in non‐ischemic ipsilateral cortex. In contrast, numerous genes were exclusively regulated at the lesion site, comprising genes involved in cell cycle regulation, proteolysis, apoptosis, lipid homeostasis and anti‐inflammatory counter‐regulation. Cortical spreading depression was identified as the main mechanism underlying gene induction in remote non‐ischemic cortex. Our data demonstrate a dynamic spatiotemporal pattern of gene induction, which may contribute to delayed progression of damage or, alternatively, mediate neuroprotection, tissue remodeling and functional compensation.
The interplay between oxidative stress and brain‐derived neurotrophic factor modulates the outcome of a saturated fat diet on synaptic plasticity and cognition
Authors: Wu Aiguo , Ying Zhe , Gomez‐Pinilla Fernando
Published: April 2004

A diet high in saturated fat (HF) decreases levels of brain‐derived neurotrophic factor (BDNF), to the extent that compromises neuroplasticity and cognitive function, and aggravates the outcome of brain insult. By using the antioxidant power of vitamin E, we performed studies to determine the role of oxidative stress as a mediator for the effects of BDNF on synaptic plasticity and cognition caused by consumption of the HF diet. Male adult rats were maintained on a HF diet for 2 months with or without 500 IU/kg of vitamin E. Supplementation of the HF diet with vitamin E dramatically reduced oxidative damage, normalized levels of BDNF, synapsin I and cyclic AMP‐response element‐binding protein (CREB), caused by the consumption of the HF diet. In addition, vitamin E supplementation preserved the process of activation of synapsin I and CREB, and reversed the HF‐impaired cognitive function. It is known that BDNF facilitates the synapse by modulating synapsin I and CREB, which have been implicated in synaptic plasticity associated to learning and memory. These results show that oxidative stress can interact with the BDNF system to modulate synaptic plasticity and cognitive function. Therefore, studies appear to reveal a mechanism by which events classically related to the maintenance of energy balance of the cell, such as oxidative stress, can interact with molecular events that modulate neuronal and behavioural plasticity.
Differences between brain structures in nuclear translocation and DNA binding of the glucocorticoid receptor during stress and the circadian cycle
Authors: Kitchener Pierre , Di Blasi Francesco , Borrelli Emiliana , Piazza Pier Vincenzo
Published: April 2004

Glucocorticoid receptors (GRs) are transcription factors that, upon activation by glucocorticoids, translocate to the cell nucleus, and bind to specific response elements (GREs) in the promoter region of target genes. We analysed stress‐ and circadian‐induced changes in nuclear translocation and GRE binding of GRs in the hippocampus and the prefrontal cortex of the rat brain. Nuclear translocation and binding to GRE were measured in nuclear extracts by Western blot and gel shift, respectively. When glucocorticoid levels were low, as during the light period of the circadian cycle, nuclear GRs and GRE binding were almost undetectable. However, the increase in glucocorticoid levels observed during the dark phase of the circadian cycle or after stress induced a massive nuclear translocation of GRs and GRE binding. These effects were corticosterone‐dependent because they were suppressed by adrenalectomy and restored by the injection of corticosterone. Furthermore, GR translocation and GRE binding were of higher amplitude or lasted longer in the hippocampus than in the prefrontal cortex. By contrast, extracellular levels of glucocorticoids, measured by microdialysis in freely moving animals, were identical in the two structures. These results suggest that specific intracellular regulations of GR activity contribute to differentiate the effects of glucocorticoids in different regions of the brain.
Mice deficient for the synaptic vesicle protein Rab3a show impaired spatial reversal learning and increased explorative activity but none of the behavioral changes shown by mice deficient for the Rab3a regulator Gdi1
Authors: D'Adamo Patrizia , Wolfer David P. , Kopp Caroline , Tobler Irene , Toniolo Daniela , Lipp Hans‐Peter
Published: April 2004

Rab proteins are small GTPases involved in intracellular trafficking. Among the 60 different Rab proteins described in mammals, Rab3a is the most abundant in brain, where it is involved in synaptic vesicle fusion and neurotransmitter release. Rab3a constitutive knockout mice (Rab3a−/−) are characterized by deficient short‐ and long‐term synaptic plasticity in the mossy fiber pathway and altered circadian motor activity, while no effects on spatial learning have been reported so far for these mice. The goals of this study were to analyse possible behavioral consequences of the lack of synaptic plasticity in the mossy fiber pathway using a broad battery of sensitive behavioral measures that has been used previously to analyse the behavior of Gdi1 mice lacking a protein thought to regulate Rab3a. Rab3a−/− mice showed normal acquisition but moderately impaired platform reversal learning in the water maze including reference memory and episodic‐like memory tasks. A mild deficit in spatial working memory was also observed when tested in the radial maze. Analysis of explorative behavior revealed increased locomotor activity and enhanced exploratory activity in open field, O‐maze, dark/light box and novel object tests. Spontaneous activity in normal home cage settings was unaffected but Rab3a−/− mice showed increased motor activity when the home cage was equipped with a wheel. No differences were found for delayed and trace fear conditioning or for conditioned taste aversion learning. Congruent with earlier data, these results suggest that Rab3a‐dependent synaptic plasticity might play a specific role in the reactivity to novel stimuli and behavioral stability rather than being involved in memory processing. On the other hand, the phenotypic changes in the Rab3a−/− mice bore no relation to the behavioral changes as observed in the Gdi1 mice. Such divergence in phenotypes implies that the putative synaptic interaction between Gdi1 and Rab3a should be reconsidered and re‐analysed.
Cocaine‐experienced rats exhibit learning deficits in a task sensitive to orbitofrontal cortex lesions
Authors: Schoenbaum Geoffrey , Saddoris Michael P. , Ramus Seth J. , Shaham Yavin , Setlow Barry
Published: April 2004

Addictive drugs, such as cocaine, cause long‐lasting neural changes in prefrontal cortex. It has been hypothesized that these changes affect the behavioural control mediated by orbitofrontal cortex. To test this hypothesis, rats were given injections of cocaine (30 mg/kg/d, i.p.) or vehicle for 14 days and then trained after a 2‐week withdrawal period in an odor discrimination task sensitive to the effects of orbitofrontal cortex lesions. We found that cocaine‐treated rats, who demonstrated long‐lasting sensitization to the locomotor activating effects of cocaine, failed to show normal changes in response latency during discrimination learning and were also slower than controls to acquire serial reversals. These behavioural impairments are identical to the effects of orbitofrontal cortex lesions in this task and show that cocaine exposure in rats can cause long‐lasting effects on orbitofrontal‐dependent functions. Notably, these effects were not correlated with increases in locomotor activity linked to cocaine‐induced psychomotor sensitization observed before or after training, suggesting that the brain changes underlying the behavioural effects in the discrimination task are different from those mediating psychomotor sensitization.
The peptide sequence Arg‐Glu‐Arg, present in the amyloid precursor protein, protects against memory loss caused by Aβ and acts as a cognitive enhancer
Authors: Mileusnic R. , Lancashire C. L. , Rose S. P. R.
Published: April 2004

Amino acid sequences containing the palindromic tripeptide RER, matching amino acids 328–330 of the amyloid precursor protein APP, when injected intracerebrally prior to or just after training, protect against memory loss induced by amyloid‐beta (Aβ) in a one‐trial passive avoidance task in the young chick. RER also acts as a cognitive enhancer, strengthening memory for a weak version of the task. N‐terminal acylation of RER protects it against rapid degradation, and AcRER is effective in restoring memory if administered peripherally. Biotinylated RER binds to chick neuronal perikarya in an APP‐displaceable manner via 66 and ≈ 110 kDa neuronal cell membrane proteins. We suggest that RER binding is likely to exert effects on memory retention via receptor‐mediated events that include activation of second messenger pathways. These findings suggest that RER and its derivatives may offer a novel approach to enhancing the neuroprotective effects of APP and alleviating the effects of memory loss in the early stages of Alzheimer's disease.
Functional MRI of the immediate impact of transcranial magnetic stimulation on cortical and subcortical motor circuits
Authors: Bestmann Sven , Baudewig Jürgen , Siebner Hartwig R. , Rothwell John C. , Frahm Jens
Published: April 2004

Recent studies indicate that the cortical effects of transcranial magnetic stimulation (TMS) may not be localized to the site of stimulation, but spread to other distant areas. Using echo‐planar imaging with blood‐oxygenation‐level‐dependent (BOLD) contrast at 3 Tesla, we measured MRI signal changes in cortical and subcortical motor regions during high‐frequency (3.125 Hz) repetitive TMS (rTMS) of the left sensorimotor cortex (M1/S1) at intensities above and below the active motor threshold in healthy humans. The supra‐ and subthreshold nature of the TMS pulses was confirmed by simultaneous electromyographic monitoring of a hand muscle. Suprathreshold rTMS activated a network of primary and secondary cortical motor regions including M1/S1, supplementary motor area, dorsal premotor cortex, cingulate motor area, the putamen and thalamus. Subthreshold rTMS elicited no MRI‐detectable activity in the stimulated M1/S1, but otherwise led to a similar activation pattern as obtained for suprathreshold stimulation though at reduced intensity. In addition, we observed activations within the auditory system, including the transverse and superior temporal gyrus, inferior colliculus and medial geniculate nucleus. The present findings support the notion that re‐afferent feedback from evoked movements represents the dominant input to the motor system via M1 during suprathreshold stimulation. The BOLD MRI changes in motor areas distant from the site of subthreshold stimulation are likely to originate from altered synaptic transmissions due to induced excitability changes in M1/S1. They reflect the capability of rTMS to target both local and remote brain regions as tightly connected constituents of a cortical and subcortical network.
Addictive and non‐addictive drugs induce distinct and specific patterns of ERK activation in mouse brain
Authors: Valjent Emmanuel , Pagès Christiane , Hervé Denis , Girault Jean‐Antoine , Caboche Jocelyne
Published: April 2004

A major goal of research on addiction is to identify the molecular mechanisms of long‐lasting behavioural alterations induced by drugs of abuse. Cocaine and delta‐9‐tetrahydrocannabinol (THC) activate extracellular signal‐regulated kinase (ERK) in the striatum and blockade of the ERK pathway prevents establishment of conditioned place preference to these drugs. However, it is not known whether activation of ERK in the striatum is specific for these two drugs and/or this brain region. We studied the appearance of phospho‐ERK immunoreactive neurons in CD−1 mouse brain following acute administration of drugs commonly abused by humans, cocaine, morphine, nicotine and THC, or of other psychoactive compounds including caffeine, scopolamine, antidepressants and antipsychotics. Each drug generated a distinct regional pattern of ERK activation. All drugs of abuse increased ERK phosphorylation in nucleus accumbens, lateral bed nucleus of the stria terminalis, central amygdala and deep layers of prefrontal cortex, through a dopamine D1 receptor‐dependent mechanism. Although some non‐addictive drugs moderately activated ERK in a few of these areas, they never induced this combined pattern of strong activation. Antidepressants and caffeine activated ERK in hippocampus and cerebral cortex. Typical antipsychotics mildly activated ERK in dorsal striatum and superficial prefrontal cortex, whereas clozapine had no effect in the striatum, but more widespread effects in cortex and amygdala. Our results outline a subset of structures in which ERK activation might specifically contribute to the long‐term effects of drugs of abuse, and suggest mapping ERK activation in brain as a way to identify potential sites of action of psychoactive drugs.
Corticotropin‐releasing factor and urocortin differentially modulate rat Purkinje cell dendritic outgrowth and differentiation in vitro
Authors: Swinny J. D. , Metzger F. , IJkema‐Paassen J. , Gounko N. V. , Gramsbergen A. , Van Der Want J. J. L.
Published: April 2004

The precise outgrowth and arborization of dendrites is crucial for their function as integrators of signals relayed from axons and, hence, the functioning of the brain. Proper dendritic differentiation is particularly resonant for Purkinje cells as the intrinsic activity of this cell‐type is governed by functionally distinct regions of its dendritic tree. Activity‐dependent mechanisms, driven by electrical signaling and trophic factors, account for the most active period of dendritogenesis. An as yet unexplored trophic modulator of Purkinje cell dendritic development is corticotropin‐releasing factor (CRF) and family member, urocortin, both of which are localized in climbing fibers. Here, we use rat organotypic cerebellar slice cultures to investigate the roles of CRF and urocortin on Purkinje cell dendritic development. Intermittent exposure (12 h per day for 10 days in vitro) of CRF and urocortin induced significantly more dendritic outgrowth (45% and 70%, respectively) and elongation (25% and 15%, respectively) compared with untreated cells. Conversely, constant exposure to CRF and urocortin significantly inhibited dendritic outgrowth. The trophic effects of CRF and urocortin are mediated by the protein kinase A and mitogen‐activating protein kinase pathways. The study shows unequivocally that CRF and urocortin are potent regulators of dendritic development. However, their stimulatory or inhibitory effects are dependent upon the degree of expression of these peptides. Furthermore, the effects of CRF and urocortin on neuronal differentiation and re‐modeling may provide a cellular basis for pathologies such as major depression, which show perturbations in the expression of these stress peptides.
Modulation of photic resetting in rats by lesions of projections to the suprachiasmatic nuclei expressing p75 neurotrophin receptor
Authors: Erhardt Christine , Galani Rodrigue , Jeltsch Hélène , Cassel Jean‐Christophe , Klosen Paul , Menet Jérôme S. , Pévet Paul , Challet Etienne
Published: April 2004

The suprachiasmatic nuclei of the hypothalamus (SCN) are the site of the master circadian clock in mammals. The SCN clock is mainly entrained by the light–dark cycle. Light information is conveyed from the retina to the SCN through direct, retinohypothalamic fibres. The SCN also receive other projections, like cholinergic fibres from basal forebrain. To test whether cholinergic afferents are involved in photic resetting, lesions of cholinergic projections were performed in rats with intracerebroventricular (i.c.v.) injections or intra‐SCN microinjections of 192 IgG‐saporin. When injected in the SCN, this immunotoxin destroys the cholinergic projections and retinohypothalamic afferents that express p75 low‐affinity nerve growth factor (p75NGF) receptors. The extent of lesions in the basal forebrain and SCN was assessed by acetylcholinesterase histochemistry, p75NGF receptor, choline acetyl‐transferase, calbindin‐D28K and VIP immunocytochemistry. The intra‐SCN treatment reduced light‐induced phase advances by 30%, and induced a complete loss of forebrain and retinal afferents expressing p75NGF receptors within the SCN and a decrease of forebrain cholinergic neurons, most likely those projecting to the SCN. The i.c.v. treatment reduced light‐induced phase advances by 40%, increased phase delays and led to extensive damage of forebrain p75NGF‐expressing neurons, while sparing half of the fibres expressing p75NGF receptors (retinal afferents?) in the SCN. Because the integrity of forebrain p75NGF‐expressing neurons appears to be critical in mediating the effects on light‐induced phase advances, we therefore suggest that anterior cholinergic projections expressing p75NGF receptors modulate the sensitivity of the SCN clock to the phase advancing effects of light.