bluuebunny/crossref_metadata_2025 huggingface dataset:
Intravenous pamidronate in the treatment and prevention of osteoporosis
Authors: Chan S. S. Y. , Nery L. M. , McElduff A. , Wilmshurst E. G. , Fulcher G. R. , Robinson B. G. , StIel J. N. , Gunton J. E. , Clifton‐Bligh P. B.
Published: December 2004

Abstract

Background : Potent oral bisphosphonates are the mainstay of therapy for osteoporosis. However, there are patients who cannot have oral bisphosphonates (e.g. because of gastrointestinal side‐effects). Therefore, we wanted to examine the effects of intermittent i.v. pamidronate (APD) on bone mineral density (BMD) in patients who needed bisphosphonate therapy but could not have oral bisphosphonates.

Aim : To assess BMD before and after intermittent i.v. APD in patients requiring a bisphosphonate either for the prevention of osteoporosis on concurrent steroid therapy or for the treatment of osteoporosis.

Methods:  This was a retrospective audit of 84 consecutive patients at risk of fractures commencing APD between October 1997 and May 2000. Patients were treated with intermittent i.v. APD. BMD as measured by dual‐energy X‐ray absorptiometry before and after APD was the main outcome.

Results:  The mean length of treatment and mean total APD dose were 16.8 ± 7.0 months and 186.1 ± 79.5 mg respectively. The reasons for using APD were failure to qualify for oral bisphosphonates on the pharmaceutical benefits scheme due to lack of documented minimal trauma fractures (58%), symptomatic gastro‐­oesophageal disease (20%), intolerance of oral bisphosphonates (18%) and lack of efficacy of calcitriol (4%). Mean baseline T‐score at lumbar (L) 2−4 spine and femoral neck were −1.54 ± 1.22 and − 2.87 ± 1.19, respectively.

From baseline to after APD treatment, there was a significant increase in L2−4 BMD (0.883 ± 0.175 vs 0.912 ± 0.176 g/cm2, P < 0.001, mean increase +3.5%), in femoral neck BMD (0.667 ± 0.137 vs 0.680 ± 0.134 g/cm2, P= 0.001, mean increase +2.1%) and in trochanteric BMD (0.549 ± 0.129 vs 0.566 ± 0.132 g/cm2, P < 0.001, mean increase +3.1%). One‐third of the patients were on oral glucocorticoids at the time of the present study and they had a similar increase in BMD compared to patients not on gluco­corticoids. Mild side‐effects occurred in seven patients, none of whom discontinued treatment.

Conclusion : Intermittent APD increases BMD and may be a suitable alternative for patients who cannot have oral bisphosphonates. (Intern Med J 2004; 34: 162−166)
Long‐term potentiation of mGluR1 activity by depolarization‐induced Homer1a in mouse cerebellar Purkinje neurons
Authors: Minami Itsunari , Kengaku Mineko , Smitt Peter Sillevis , Shigemoto Ryuichi , Hirano Tomoo
Published: December 2004

Metabotropic glutamate receptor 1 (mGluR1) plays a crucial role in synaptic plasticity and motor learning in the cerebellum. We have studied activity‐dependent changes in mGluR1 function in mouse cultured Purkinje neurons. Depolarizing stimulation potentiated Ca2+ and current responses to an mGluR1 agonist for several hours in the cultured Purkinje neurons. It also blocked internalization of mGluR1 and increased the number of mGluR1s on the cell membrane. We found that depolarization simultaneously increased transcription of Homer1a in Purkinje neurons. Homer1a inhibited internalization and increased cell‐surface expression of mGluR1 when coexpressed in human embryonic kidney (HEK)‐293 cells. Depolarization‐induced Homer1a expression in Purkinje neurons was blocked by a mitogen‐activated protein kinase (MAPK) inhibitor. Changes in internalization and mGluR1‐mediated Ca2+ response were also blocked by inhibition of MAPK activity, suggesting that localization and activity of mGluR1 were regulated in the same signalling pathway as Homer1a expression. It is thus suggested that depolarization of the Purkinje neuron leads to the increment in mGluR1 responsiveness through MAPK activity and induction of Homer1a expression, which increases active mGluR1 on the cell surface by blocking internalization of mGluR1.
Does luminance‐contrast contribute to a saliency map for overt visual attention?
Authors: Einhäuser Wolfgang , König Peter
Published: December 2004

In natural environments, humans select a subset of visual stimuli by directing their gaze to locations attended. In previous studies it has been found that at fixation points luminance‐contrast is higher than average. This led to the hypothesis that luminance‐contrast makes a major contribution to a saliency map of visual overt attention, consistent with a computation of stimulus saliency in early visual cortical areas. We re‐evaluate this hypothesis by using natural and modified natural images to uncover the causal effects of luminance‐contrast to human overt visual attention and: (i) we confirm that when viewing natural images, contrasts are elevated at fixation points. This, however, only holds for low spatial frequencies and in a limited temporal window after stimulus onset; (ii) however, despite this correlation between overt attention and luminance‐contrast, moderate modifications of contrast in natural images do not measurably affect the selection of fixation points. Furthermore, strong local reductions of luminance‐contrast do not repel but attract fixation; (iii) neither contrast nor contrast modification is correlated to fixation duration; and (iv), even the moderate contrast modifications used fall into the physiologically relevant range, and subjects are well able to detect them in a forced choice paradigm. In summary, no causal contribution of luminance‐contrast to a saliency map of human overt attention is detectable. In conjunction with recent results on the relation of contrast sensitivity of neuronal activity to the level in the visual cortical hierarchy, the present study provides evidence that, for natural scenes, saliency is computed not early but late during processing.
Nucleus accumbens β‐endorphin levels are not elevated by brain stimulation reward but do increase with extinction
Authors: Zangen Abraham , Shalev Uri
Published: December 2004

β‐Endorphin is an endogenous opioid peptide implicated in reward processes, but the brain sites directly involved in its putative role in reward have not been identified. Here we used in vivo microdialysis in rats to study the effect of a potent reinforcer, lateral hypothalamus self‐stimulation (LHSS), on the extracellular levels of β‐endorphin in the nucleus accumbens (NAS). The NAS is involved in the reinforcing effects of natural and artificial rewards, has high density of opioid receptors and is innervated by arcuate nucleus β‐endorphin neurons. LHSS had no effect on extracellular levels of β‐endorphin in the NAS. Surprisingly, extinction of the self‐stimulation behaviour induced a rapid increase in NAS β‐endorphin levels. In a subsequent experiment in rats previously trained to self‐administer heroin for 10 days, β‐endorphin levels also were increased during a test for extinction of the heroin‐reinforced behaviour. Finally, the increase in extracellular β‐endorphin levels in the NAS was also observed during exposure to an aversive stimulus, intermittent footshock (20 min). These results indicate a possible role for increased levels of NAS β‐endorphin in the organism's adaptive response to stress and frustration.
Actions of neuropeptide Y and growth hormone secretagogues in the arcuate nucleus and ventromedial hypothalamic nucleus
Authors: Kumarnsit Ekkasit , Johnstone Louise E. , Leng Gareth
Published: December 2004

Systemic or central administration of growth‐hormone secretagogues (GHS) induces dense Fos expression in the arcuate nucleus but little or no Fos expression in the ventromedial hypothalamic nucleus, although both sites show intense expression of mRNA for the GHS receptor. Here, we recorded the electrical activity of single neurons from the arcuate nucleus and from the ventromedial hypothalamic nucleus in a rat hypothalamic slice preparation, and compared responses of these two populations to GHS. At both sites, the predominant neuronal response to GHS was a long‐lasting excitation, indicating that GHS receptors at both sites are functional and similarly coupled to electrical excitation. We also tested neurons at both sites for their responses to neuropeptide Y and to somatostatin; at both sites the predominant response to each of these peptides was inhibitory. The arcuate cells that are activated by GHS include neuropeptide Y cells and growth hormone‐releasing hormone cells. It seems possible that neuropeptide Y released in the ventromedial hypothalamus from the terminals of arcuate neurons counteracts the activation of ventromedial hypothalamic neurons by GHS in vivo, or that somatostatin released following liberation of growth hormone may do so.
Glucocorticoid‐induced impairment of declarative memory retrieval is associated with reduced blood flow in the medial temporal lobe
Authors: De Quervain Dominique J.‐F. , Henke Katharina , Aerni Amanda , Treyer Valerie , McGaugh James L. , Berthold Thomas , Nitsch Roger M. , Buck Alfred , Roozendaal Benno , Hock Christoph
Published: December 2004

Previous work indicates that stress levels of circulating glucocorticoids can impair retrieval of declarative memory in human subjects. Several studies have reported that declarative memory retrieval relies on the medial temporal lobe. The present study used \mathrm{H}^{15}_{2}O‐positron emission tomography to investigate whether acutely elevated glucocorticoid levels affect regional cerebral blood flow in the medial temporal lobe, as well as in other brain regions, during declarative memory retrieval in healthy male human subjects. When measured over four different declarative memory retrieval tasks, a single, stress‐level dose of cortisone (25 mg) administered orally 1 h before retention testing, induced a large decrease in regional cerebral blood flow in the right posterior medial temporal lobe, the left visual cortex and the cerebellum. The decrease in the right posterior medial temporal lobe was maximal in the parahippocampal gyrus, a region associated with successful verbal memory retrieval. Cortisone administration also significantly impaired cued recall of word pairs learned 24 h earlier, while drug effects on performance in the other tasks (verbal recognition, semantic generation and categorization) were not significant. The present results provide further evidence that acutely elevated glucocorticoid levels can impair declarative memory retrieval processes and suggest that such impairments may be related to a disturbance of medial temporal lobe function.
Involvement of calcineurin in the neurotoxic effects induced by amyloid‐beta and prion peptides
Authors: Agostinho Paula , Oliveira Catarina Resende
Published: December 2004

It is usually accepted that prion and amyloid‐beta (Aβ) peptides induce apoptotic cell death. However, the mechanisms that trigger neuronal death, induced by these amyloidogenic peptides, remain to be clarified. In the present study we analysed the neurotoxic effects of the synthetic prion and Aβ peptides, PrP106‐126 and Aβ25−35, in primary cultures of rat brain cortical cells. PrP106‐126 and Aβ25−35 incubated at a concentration of 25 µm for 24 h, did not affect cell membrane integrity, but decreased the metabolic capacity of the cells. The intracellular free Ca2+ concentration and reactive oxygen species levels increased significantly after 24 h treatment with PrP106‐126 and Aβ25−35. Furthermore, these peptides (after 24 h exposure) also induced cytochrome c release from mitochondria and increased caspase‐3‐like activity. FK506, an inhibitor of the Ca2+/calmodulin‐dependent phosphatase, calcineurin, was able to prevent cytochrome c release, caspase‐3 activation and cell death induced by Aβ25−35 or PrP106‐126 peptides. Taken together these data suggest that calcineurin is involved in Aβ25−35 and PrP106‐126 neurotoxicity.
Inhibition of rostral basal forebrain neurons promotes wakefulness and induces FOS in orexin neurons
Authors: Satoh Shinsuke , Matsumura Hitoshi , Nakajima Tomoko , Nakahama Ken‐ichi , Kanbayashi Tuyoshi , Nishino Seiji , Yoneda Hiroshi , Shigeyoshi Yasufumi
Published: December 2004

The present study examined whether the activities of the rostral basal forebrain neurons alter the activities of the orexin (also known as hypocretin) neurons in the tuberal part of the hypothalamus in rats. We performed microdialysis perfusion of the ventromedial portion of the rostral basal forebrain with the GABAA receptor agonist muscimol to inhibit focally the neuronal activities in the rostral basal forebrain. Then, we monitored sleep/wake behaviour and investigated the pattern of activities of orexin neurons by examining the expression of FOS as an indicator of cellular activation. Bilateral perfusion with muscimol (5, 15, and 50 µm) produced a dose‐dependent decrease in the amount of sleep. This perfusion with muscimol at 50 µm produced FOS‐like immunoreactivity in 37% of the orexin neurons located in the tuberal part of the hypothalamus, whereas the FOS‐like immunoreactivity was sparse in orexin neurons of the sleeping control rats (P = 0.001 by Mann–Whitney U‐test). Unilateral perfusion with muscimol (50 µm) also suppressed sleep. In this case, FOS‐like immunoreactivity was seen in 40% of the orexin neurons on the side ipsilateral to the perfusion site but only in 10% of orexin neurons on the contralateral side (P = 0.018 by Wilcoxon signed rank test). These functional data suggested that a sleep‐generating element in the ventromedial part of the rostral basal forebrain provides an inhibitory influence on the activities of the orexin neurons in the tuberal part of the hypothalamus.
Periodic absence of nursing mothers phase‐shifts circadian rhythms of clock genes in the suprachiasmatic nucleus of rat pups
Authors: Ohta Hidenobu , Honma Sato , Abe Hiroshi , Honma Ken‐ichi
Published: December 2004

Effects of absence of nursing mothers on the circadian pacemaker of their offspring were examined by measuring clock genes, the rat Per1 (rPer1) and rPer2 expression rhythms in the pup suprachiasmatic nuclei (SCN). Neonate rats born to mothers kept under a 12‐h light : 12‐h dark cycle (LD) were blinded immediately after birth and exposed to periodic maternal deprivation where pups were deprived of their mothers during the light phase of 12‐h for the first week of life. At postnatal day 6, the periodic maternal deprivation completely phase‐reversed the circadian rhythms in expression of the clock genes in the pup SCN and in spontaneous locomotor activity after the pups were weaned at postnatal day 21. The periodic maternal absence also altered the patterns of stress‐related gene expressions such as corticotropine‐releasing hormone, arginine vasopressin, and glucocorticoid receptor in particular brain areas of the mother‐deprived pups at P6. These findings indicate that periodic absence of the nursing mother in the first week of life produces a resetting effect on the neonatal circadian clock and induces stress responses in the hypothalamus–pituitary–adrenal axis.
Mineralocorticoid receptor expression and increased survival following neuronal injury
Authors: Macleod Malcolm R. , Johansson Inga‐Maj , Söderström Ingegerd , Lai Maggie , Gidö Gunilla , Wieloch Tadeusz , Seckl Jonathan R. , Olsson Tommy
Published: December 2004

Glucocorticoids, acting via the mineralocorticoid receptor, are required for granule neuronal survival in the rat dentate gyrus. Whether this mineralocorticoid receptor‐mediated neuroprotective effect has more general applicability is unknown. Here we report increased mineralocorticoid receptor expression in rat hippocampal and cortical neurons exposed in vitro to low levels of staurosporine and in rat hippocampal pyramidal neurons exposed in vivo to hypothermic transient global ischaemia. In both the cell culture system and the in vivo system increased mineralocorticoid receptor expression is associated with increased neuronal survival, and this increase is reversed by mineralocorticoid receptor antagonism. Modulation of mineralocorticoid receptor gene expression may therefore be an important target for reduction of brain injury in conditions caused by cerebral ischaemia including brain damage following cardiac arrest and stroke.
Calcium‐dependent phosphorylation processes control brain aromatase in quail
Authors: Balthazart J. , Baillien M. , Charlier T. D. , Ball G. F.
Published: December 2004

Increased gene transcription activated by the binding of sex steroids to their cognate receptors is one important way in which oestrogen synthase (aromatase) activity is regulated in the brain. This control mechanism is relatively slow (hours to days) but recent data indicate that aromatase activity in quail preoptic‐hypothalamic homogenates is also rapidly (within minutes) affected by exposure to conditions that enhance Ca2+‐dependent protein phosphorylation. We demonstrate here that Ca2+‐dependent phosphorylations controlled by the activity of multiple protein kinases including PKC, and possibly also PKA and CAMK, can rapidly down‐regulate aromatase activity in brain homogenates. These phosphorylations directly affect the aromatase molecule itself. Western blotting experiments on aromatase purified by immunoprecipitation reveal the presence on the enzyme of phosphorylated serine, threonine and tyrosine residues in concentrations that are increased by phosphorylating conditions. Cloning and sequencing of the quail aromatase identified a 1541‐bp open reading frame that encodes a predicted 490‐amino‐acid protein containing all the functional domains that have been previously described in the mammalian and avian aromatase. Fifteen predicted consensus phosphorylation sites were identified in this sequence, but only two of these (threonine 455 and 486) match the consensus sequences corresponding to the protein kinases that were shown to affect aromatase activity during the pharmacological experiments (i.e. PKC and PKA). This suggests that the phosphorylation of one or both of these residues represents the mechanism underlying, at least in part, the rapid changes in aromatase activity.
The transient depression of hippocampal CA1 LTP induced by chronic intermittent ethanol exposure is associated with an inhibition of the MAP kinase pathway
Authors: Roberto M. , Nelson T. E. , Ur C. L. , Brunelli M. , Sanna P. P. , Gruol D. L.
Published: December 2004

Using electrophysiological and biochemical approaches, we investigated the effects of chronic, intermittent ethanol (CIE) treatment on activation of the mitogen activated protein kinase (MAPK), also known as extracellular signal regulated protein kinase 1 and 2. In hippocampal slices taken from control rats, brief high‐frequency stimulation to Schaffer collateral fibers induced a large post‐tetanic potentiation (PTP) in the CA1 region that decayed to stable long‐term potentiation (LTP) of field extracellular postsynaptic potentials. Western blot analyses showed that phosphorylation of MAPK was increased during PTP and returned to baseline levels during LTP. In slices from the rats removed immediately from CIE treatment, PTP and MAPK activation during the PTP was significantly less than that observed in control slices and LTP was absent. In slices from rats subjected to 1 day withdrawal from CIE treatment, both the reduction in MAPK phosphorylation during PTP and the impairment of PTP and LTP were still evident. Recovery of PTP and partial recovery of LTP was observed in slices obtained from 5‐day withdrawn rats. However, MAPK activation during PTP was still attenuated significantly. Interestingly, MAPK activation was enhanced significantly during LTP in 5‐day withdrawn rats as well as the sensitivity to MAPK inhibitor PD 098059. In addition to these changes in HFS‐induced MAPK activation, we also observed a significant reduction in the basal phosphorylation of MAPK in slices removed from rats immediately after CIE treatment. These results implicate the MAPK signal transduction pathway as a potential cellular target of ethanol. Alterations in MAPKs could play an important role in the alcohol‐induced changes in synaptic plasticity associated with the effects of alcohol abuse on learning and memory processes.
Influence of auditory deprivation upon the tonopic organization in the inferior colliculus: a Fos immunocytochemical study in the rat
Authors: Wu Han‐Chiang , Lecain Eric , Chiappini Ilaria , Yang Ting‐Hua , Tran Ba Huy Patrice
Published: December 2004

The frequency organization in the inferior colliculus of neonatally‐deafened rats was investigated using electrical stimulation of the cochlea and immunoreactivity for Fos as a marker of neuronal activity. An electrode implanted either at the base or at the apex of the right cochlea delivered a unique 45‐min stimulation at two different level intensities and at two time points, i.e. either at 4 weeks or at 4 months. In 4‐week‐old rats stimulated at 5× threshold, a site‐for‐site organization was observed since basal or apical stimulation induced a strong labelling in the ventro‐medial or in the dorsolateral part of the left inferior colliculus, respectively. In 4‐month‐old rats, stimulation of the base induced an extremely weak Fos labelling without any specific location in the left inferior colliculus while stimulation of the apex induced a diffuse labelling with two discrete bands being distinguishable in the left inferior colliculus. In 4‐week‐old rats stimulated at 15× threshold, basal stimulation elicited a diffuse Fos‐like immunoreactivity in the left inferior colliculus while apical stimulation yielded a response restricted to the dorsal part of the left inferior colliculus. In 4‐month‐old rats, no response was detected in the left inferior colliculus after stimulation of the basal part of the cochlea. Stimulation of the apex could still induce a labelling in the dorsolateral left inferior colliculus. Thus, the inferior colliculus exhibits an adult‐like tonotopic organization early on independently of any acoustic stimulation. Prolonged absence of auditory input dramatically alters this organization in the inferior colliculus, especially for high frequencies. From a clinical standpoint, these results could argue for early implantation in deaf children.
Action of tachykinins in the rat hippocampus: modulation of inhibitory synaptic transmission
Authors: Ogier R. , Raggenbass M.
Published: December 2004

Substance P and other neuropeptides of the tachykinin family can powerfully excite CA1 hippocampal interneurons present in the CA1 region. In the present work we show that, by exciting hippocampal interneurons, tachykinins can indirectly inhibit pyramidal neurons. We found that tachykinins caused a decrease in the inhibitory synaptic current interval and an increase in the inhibitory synaptic current amplitude in almost all pyramidal neurons tested. This effect was tetrodotoxin sensitive. Tachykinins did not alter the frequency or amplitude of miniature inhibitory synaptic currents and were without effect on evoked inhibitory synaptic currents. Thus, these neuropeptides acted at the somatodendritic membrane of GABAergic interneurons, rather than at their axon terminals. The effect of substance P on spontaneous inhibitory synaptic currents could be mimicked by a selective agonist of NK1 receptors, but not by selective agonists of NK2 and NK3 receptors. It was suppressed by an NK1 receptor antagonist. In CA1 interneurons located in stratum radiatum, substance P generated a sustained tetrodotoxin‐insensitive inward current or induced membrane depolarization and action potential firing. This direct excitatory action was mediated by NK1 receptors. Current–voltage relationships indicate that the net tachykinin‐evoked current reversed in polarity at or near the K+ equilibrium potential, suggesting that a suppression of a resting K+ conductance was involved. By increasing the excitability of CA1 GABAergic interneurons, tachykinins can powerfully facilitate the inhibitory synaptic input to pyramidal neurons. This indirect inhibition could play a role in regulating short‐term and/or long‐term synaptic plasticity, promoting neuronal circuit synchronization or, in some physiopathological situations, influencing epileptogenesis.
Anticonvulsant pharmacology of voltage‐gated Na+ channels in hippocampal neurons of control and chronically epileptic rats
Authors: Remy Stefan , Urban Bernd W. , Elger Christian E. , Beck Heinz
Published: December 2004

Voltage‐gated Na+ channels are a main target of many first‐line anticonvulsant drugs and their mechanism of action has been extensively investigated in cell lines and native neurons. Nevertheless, it is unknown whether the efficacy of these drugs might be altered following chronic epileptogenesis. We have, therefore, analysed the effects of phenytoin (100 µm), lamotrigine (100 µm) and valproate (600 µm) on Na+ currents in dissociated rat hippocampal granule neurons in the pilocarpine model of chronic epilepsy. In control animals, all three substances exhibited modest tonic blocking effects on Na+ channels in their resting state. These effects of phenytoin and lamotrigine were reduced (by 77 and 64%) in epileptic compared with control animals. Phenytoin and valproate caused a shift in the voltage dependence of fast inactivation in a hyperpolarizing direction, while all three substances shifted the voltage dependence of activation in a depolarizing direction. The anticonvulsant effects on Na+ channel voltage dependence proved to be similar in control and epileptic animals. The time course of fast recovery from inactivation was potently slowed by lamotrigine and phenytoin in control animals, while valproate had no effect. Interestingly, the effects of phenytoin on fast recovery from inactivation were significantly reduced in chronic epilepsy. Taken together, these results reveal that different anticonvulsant drugs may exert a distinct pattern of effects on native Na+ channels. Furthermore, the reduction of phenytoin and, to a less pronounced extent, lamotrigine effects in chronic epilepsy raises the possibility that reduced pharmacosensitivity of Na+ channels may contribute to the development of drug resistance.
Molecular cloning and expression regulation of PRG‐3, a new member of the plasticity‐related gene family
Authors: Savaskan Nicolai E. , Bräuer Anja U. , Nitsch Robert
Published: December 2004

Phospholipid‐mediated signalling on neurons provokes diverse responses such as neurogenesis, pattern formation and neurite remodelling. We have recently uncovered a novel set of molecules in the mammalian brain, named plasticity‐related genes (PRGs), which mediate lipid phosphate phosphatase activity and provide evidence for their involvement in mechanisms of neuronal plasticity. Here, we report on a new member of the vertebrate‐specific PRG family, which we have named plasticity‐related gene‐3 (PRG‐3). PRG‐3 is heavily expressed in the brain and shows a specific expression pattern during brain development where PRG‐3 expression is found predominantly in neuronal cell layers and is already expressed at embryonic day 16. In the mature brain, strongest PRG‐3 expression occurs in the hippocampus and cerebellum. Overexcitation of neurons induced by kainic acid leads to a transient down‐regulation of PRG‐3. Furthermore, PRG‐3 is expressed on neurite extensions and promotes neurite growth and a spreading‐like cell body in neuronal cells and COS‐7 cells. In contrast to previously described members of the PRG family, PRG‐3 does not perform its function through enzymatic phospholipid degradation. In summary, our findings feature a new member of the PRG family which shows dynamic expression regulation during brain development and neuronal excitation.
Tissue plasminogen activator in primary afferents induces dorsal horn excitability and pain response after peripheral nerve injury
Authors: Yamanaka Hiroki , Obata Koichi , Fukuoka Tetsuo , Dai Yi , Kobayashi Kimiko , Tokunaga Atsushi , Noguchi Koichi
Published: December 2004

The extracellular protease cascade of plasminogen activators and plasminogen are known to regulate neuronal plasticity and extracellular matrix modification, and to be important factors involved in producing long‐term potentiation in the CNS. The purpose of this study is to examine the expression of plasminogen activators in primary afferents and its role in nociceptive pathways after peripheral nerve injury. We found the induction of mRNAs for tissue type plasminogen activator (tPA) and urokinase plasminogen activator (uPA) in the rat dorsal root ganglia following sciatic nerve transection. Immunoreactivity for tPA was increased in laminae I and II of the dorsal horn and, importantly, the increase in proteolytic activity mediated by tPA was observed in the same area. As neither immunoreactivity for uPA nor uPA‐mediated proteolysis was observed, we further examined the effects of tPA on dorsal horn excitability and neuropathic pain behaviour. Intrathecal injection of a specific inhibitor of tPA decreased electrical stimulation‐induced Fos expression in dorsal horn neurons following axotomy, and also prevented the development of thermal hyperalgesia following partial sciatic nerve ligation. These findings suggest that the increased tPA in the dorsal horn due to mRNA expression in the dorsal root ganglia increases the dorsal horn excitability and has an important role in pain behaviour after peripheral nerve injury. The tPA‐mediated hypersensitivity in dorsal horn neurons may be a novel molecular mechanism of neuropathic pain.
Richness dependence and climatic forcing as regulating processes of coastal fish‐species richness
Authors: Lekve Kyrre , Stenseth Nils Chr. , Johansen Rune , Lingjærde Ole Chr. , Gjøsæter Jakob
Published: December 2004

The maintenance of species diversity is influenced by processes originating both within and outside the ecological community of concern. Along the Norwegian Skagerrak coast, the number of fish species displays variability around a rather stable long‐time average. Using a mechanistically based first‐order autoregressive model with environmental forcing for the species number, we demonstrate for this system the presence of richness‐dependent regulation of species diversity. We explicitly model the niche space as a carrying capacity of species diversity and the intrinsic community feedback as a richness‐dependent regulation. Wind stress, temperature and the North Atlantic Oscillation (NAO) are used as environmental variables. This general and flexible model successfully captures the community dynamics of fish in the coastal areas of the Norwegian Skagerrak coast and thereby demonstrates the validity of developing general models of biodiversity patterns.
Sympathetic dysfunction of central origin in patients with ALS
Authors: Karlsborg M. , Andersen E. B. , Wiinberg N. , Gredal O. , Jørgensen L. , Mehlsen J.
Published: December 2004

Amyotrophic lateral sclerosis (ALS) is a severe, progressive disease affecting both the central and peripheral parts of the motor nervous system. Some studies have shown unequivocal indications of a more disseminated disease also affecting the autonomic nervous system. We therefore evaluated the centrally and peripherally mediated autonomic vascular reflexes by (i) the local 133‐Xenon washout technique, and (ii) the head‐up tilt table test. The results correlated to clinical scores. We examined nine ALS patients and 15 age‐matched controls. The 133‐Xenon washout test showed a significant reduction in the centrally mediated sympathetic vasoconstrictor response, but a preserved locally mediated response in the patients. In the head‐up tilt table test, the patients had a significantly higher mean arterial blood pressure (MAP) compared with controls, probably due to a general increase in vascular resistance. There were no correlations between the ALS Severity Scores and blood flow changes, diastolic blood pressure or MAP. Our study supports previous results, but indicates abnormalities consistent with a solely centrally located sympathetic dysfunction in ALS, independent of the stage of the disease.
Cognitive impairment: classification by 1H magnetic resonance spectroscopy
Authors: Martínez‐Bisbal M. C. , Arana E. , Martí‐Bonmatí L. , Mollá E. , Celda B.
Published: December 2004

1H magnetic resonance spectroscopy (MRS) allows accurate and non‐invasive in vivo metabolic study, and is a useful tool for the diagnosis of different forms of dementias. Cognitive impairment pathologies have been almost exclusively studied with MRS by comparison with healthy without a global comparison amongst Alzheimer disease (AD), vascular dementia, mild cognitive impairment (MCI) and major depression patients with cognitive impairment. Whereas decrease of N‐acetylaspartate (NAA) and increase myo‐Inositol (mI) at different brain locations by 1H MRS are common features of AD, Choline (Cho) alterations have been inconclusive. In our study, 64 patients with cognitive impairment were evaluated by 1H MRS using two echo times (31 and 136 ms). There were statistical differences between dementia (AD and vascular dementia) and non‐dementia (MCI and depression) spectra at posterior cingulate gyrus. Cho/Cr, mI/Cr and NAA/Cr have been valuables for the differentiation amongst the different cognitive impairment entities. NAA/mI provides the best area under the ROC curve with the highest sensitivity (82.5%) and specificity (72.7%) in diagnosing AD. NAA/mI and mI/Cr ratios differed amongst the four cognitive impairment degenerative pathologies. Metabolic MRS differences found amongst patients with cognitive impairment entities can be useful to differentiate between AD, vascular dementia, MCI and depression.
Selenium Deficiency Associated with Cardiomyopathy: A Complication of the Ketogenic Diet
Authors: Bergqvist A. G. Christina , Chee Claire M. , Lutchka Lisa , Rychik Jack , Stallings Virginia A.
Published: December 2004

Summary:  Purpose: The ketogenic diet (KD) is an efficacious treatment for intractable epilepsy, associated with infrequent side effects. The KD is known to be deficient in most vitamins and minerals and may be deficient in trace minerals. We report biochemical selenium deficiency in nine patients on the KD, including one who developed cardiomyopathy.

Methods: A whole‐blood selenium level was obtained on the symptomatic patient after noting the patient's poor appearance on physical examination. Children already treated and children beginning the KD were then evaluated prospectively for selenium status by measuring whole‐blood or serum selenium as part of routine laboratory evaluation every 3 months.

Results: The index case had no detectable whole‐blood selenium. Cardiac physical examination and ECG were normal, but the echocardiogram revealed cardiomyopathy. Thirty‐nine additional children had the selenium status evaluated. Eight had selenium levels below the normal range (six initially, and two developed low selenium levels on serial testing). They were referred for cardiology evaluations, which were normal. Selenium supplementation improved levels in all children. Low levels were seen in some children after only a few months of treatment.

Conclusions: The nutrient adequacy of the currently used KD has not been fully evaluated. The nutrient content of KD with usual supplements may not meet Recommended Dietary Allowances (RDA) for selenium and may not provide other trace minerals in adequate amounts. At our center, selenium deficiency was found in 20% of the patients evaluated. Screening for selenium deficiency is suggested if the patient KD regimen does not meet ≥75% of the RDA or if the child is symptomatic. Nutrient supplementation should provide adequate trace elements for children treated with the KD. The KD requires close monitoring of the overall nutritional status.
A Kindling Model of Pharmacoresistant Temporal Lobe Epilepsy in Sprague–Dawley Rats Induced by Coriaria Lactone and Its Possible Mechanism
Authors: Wang Ying , Zhou Dong , Wang Bing , Li Huaisu , Chai Huixia , Zhou Qiao , Zhang Shangfu , Stefan Hermann
Published: December 2004

Summary:  Purpose: The aim of this study was to develop a new animal model of pharmacoresistant temporal lobe epilepsy (TLE) by repeated intramuscular injection of Coriaria lactone (CL) at subthreshold dosages and to explore the mechanisms that might be involved.

Methods: Healthy male Sprague–Dawley rats (n = 160) were randomized into four groups during the kindling process: three groups (n = 50 for each group) received CL injection at subthreshold dosages (1.25, 1.5, and 1.75 mg/kg, respectively), and ten received normal saline (NS) injection as a control group. The maximal human adult dosage of carbamazepine (CBZ), valproate (VPA), and phenytoin (PHT) was administered as monotherapy to different groups of kindled rats for 1 month (n = 20 for each group). Changes in EEG recording, seizure number, intensity (expressed as grade 1–5 according to Racine stage), and duration, including spontaneous seizures during different interventions, were compared. The expression of P‐170, a multiple drug resistance gene (MDR1) encoding P‐glycoprotein, was measured in brain samples from different groups of experimental rats by using an image analysis and measurement system (ImagePro‐Plus 4.0).

Results: A total of 70 (46.7%) rats were fully kindled with a median of 15 (seven to 20) CL injections. Electrocorticogram (ECoG) including hippocampal (EHG) monitoring revealed the temporal lobe origins of epileptiform potentials, which were consistent with the behavioral changes observed. Spontaneous seizures occurred with frequency and diurnal patterns similar to those of human TLE. The antiepileptic drugs (AEDs) tested lacked a satisfactory seizure control. The maximal P‐170 expression was in the kindled rats with AED treatment; the next highest was in the kindled rats without AED intervention. Nonkindled SD rats with CL injection also had increased P‐170 expression compared with control SD rats.

Conclusions: The study provided a simple and stable animal TLE kindling model with pharmacoresistant properties. The pharmacoresistance observed in the kindled rats to CBZ, VPA, and PHT at maximal human adult dosages together with the increased P‐170 expression was a distinct feature of this model. This model might be used in further investigations of the mechanisms involved in pharmacoresistant TLE and for developing new AEDs.
Posttraumatic Epilepsy: Neuroradiologic and Neuropsychological Assessment of Long‐term Outcome
Authors: Mazzini Letizia , Cossa Federico Maria , Angelino Elisabetta , Campini Riccardo , Pastore Ilaria , Monaco Francesco
Published: December 2004

Summary:   Purpose: We sought to detect the incidence and the risk factors of posttraumatic epilepsy (PTE) in rehabilitation patients; to define the influence of PTE for late clinical and functional outcome; and to assess the cognitive and behavioral features of the patients with PTE.

Methods: Patients were examined with (a) cognitive and behavioral examinations, which included a clinical interview and psychometric tests performed by an expert clinical psychologist; (b) single‐photon emission computed tomography (SPECT) and magnetic resonance imaging (MRI); and (c) functional evaluation including the Glasgow Outcome Scale (GOS) and the Functional Independence Measure (FIM).

Results: Of the 143 patients examined in this study, in 27 (19%), seizures developed after a mean time from trauma of 11.9 ± 8.6 months. The occurrence of PTE was significantly correlated with the hypoperfusion in temporal lobes (p < 0.004), the degree of hydrocephalus (p < 0.04), the evidence of intracerebral hematoma (p < 0.01), and operative brain injury (p < 0.001). Patients with epilepsy showed a significantly higher incidence of personality disorders than did patients without epilepsy. The disinhibited behavior, irritability, and agitated and aggressive behavior were significantly more frequent and severe in PTE patients. The psychometric tests intended to explore memory, language, intelligence, attention, and spatial cognition did not show any significant difference between those with and without epilepsy. PTE also was significantly correlated with a worse functional outcome 1 year after the trauma.

Conclusions: The degrees of hydrocephalus and of hypoperfusion in the temporal lobes are significant risk factors for late PTE. Another main finding of our study is the absence of influence of epilepsy on cognitive disorders; its influence on neurobehavioral disorders and functional outcome is discussed.
Neocortical Temporal FDG‐PET Hypometabolism Correlates with Temporal Lobe Atrophy in Hippocampal Sclerosis Associated with Microscopic Cortical Dysplasia
Authors: Diehl Beate , LaPresto Eric , Najm Imad , Raja Shanker , Rona Sabine , Babb Thomas , Ying Zhong , Bingaman William , Lüders Hans O. , Ruggieri Paul
Published: December 2004

Summary:  Purpose: Medically intractable temporal lobe epilepsy (TLE) due to hippocampal sclerosis (HS), with or without cortical dysplasia (CD), is associated with atrophy of the hippocampal formation and regional fluorodeoxyglucose positron‐emission tomography (FDG‐PET) hypometabolism. The relation between areas of functional and structural abnormalities is not well understood. We investigate the relation between FDG‐PET metabolism and temporal lobe (TL) and hippocampal atrophy in patients with histologically proven isolated HS and HS associated with CD.

Methods: Twenty‐three patients underwent en bloc resection of the mesial and anterolateral neocortical structures. Ten patients were diagnosed with isolated HS; 13 patients had associated microscopic CD. Temporal lobe volumes (TLVs) and hippocampal volumes were measured. Magnetic resonance imaging (MRI) and PET were co‐registered, and regions of interest (ROIs) determined as gray matter of the mesial, lateral, and anterior temporal lobe.

Results: All patients (HS with or without CD) had significant ipsilateral PET hypometabolism in all three regions studied (p < 0.0001). In patients with isolated HS, the most prominent hypometabolism was in the anterior and mesial temporal lobe, whereas in dual pathology, it was in the lateral temporal lobe. TLVs and hippocampal volumes were significantly smaller on the epileptogenic side (p < 0.05). The PET asymmetries ipsilateral/contralateral to the epileptogenic zone and TLV asymmetries correlated significantly for the anterior and lateral temporal lobes (p < 0.05) in the HS+CD group, but not in the isolated HS group. Mesial temporal hypometabolism was not significantly different between the two groups.

Conclusions: Temporal neocortical microscopic CD with concurrent HS is associated with more prominent lateral temporal metabolic dysfunction compared with isolated HS in TL atrophy. Further studies are needed to confirm these findings and correlate the PET hypometabolic patterns with outcome data in patients operated on for HS with or without CD.
Mapping of the Rat's Motor Area after Hemispherectomy: The Hemispheres as Potentially Independent Motor Brains
Authors: Machado André G. G. , Shoji Alexandre , Ballester Gerson , Marino Raul
Published: December 2004

Summary:  Purpose: The remarkable motor recovery observed after hemispherectomy in patients and experimental animals has puzzled investigators, as it defies classic jacksonian neurology. Several mechanisms for this phenomenon have been considered, such as neuronal sprouting to subcortical structures, neurochemical changes, and cerebellar diaschisis. The spared hemisphere may, however, play a crucial part in this functional recovery.

Methods: In this study, seven Wistar rats were submitted to right hemisphere motor area mapping. In the same anesthetic time, a left microsurgical hemispherectomy was performed, and the animal allowed to recover for 2 weeks. After then, the right hemisphere was again stimulated for its motor area.

Results: Four rats had, after 2 weeks of observation, bilateral body movements with stimulation of only the right hemisphere. The same segments on both sides had symmetric and simultaneous movements.

Conclusions: The results suggest that each motor area has the latent capacity to control motricity bilaterally, and that such capacity is brought into function after removal of the opposite hemisphere. The same neuronal population that gives afference to one segment contralaterally seems to give afference to the same segment ipsilaterally.
Long‐term Effects of Status Epilepticus in the Immature Brain Are Specific for Age and Model
Authors: Cilio Maria Roberta , Sogawa Yoshimi , Cha Byung‐Ho , Liu Xianzeng , Huang Li‐Tung , Holmes Gregory L.
Published: December 2004

Summary:  Purpose: Status epilepticus (SE) is more common in children than adults and has a high mortality and morbidity rate. SE in adult rats results in long‐term disturbances in learning and memory, as well as an enhanced seizure susceptibility to further seizures. In contrast, a number of studies suggest that the immature brain is less vulnerable to the morphologic and physiologic alterations after SE. The goal of this study was to determine whether the long‐term consequences of SE during development on hippocampal plasticity and cognitive function are age and model specific.

Methods: We used lithium‐pilocarpine (Li‐PC) to induce SE at different age points during development (P12, P16, P20) and evaluated the effects of this abnormal neural activity on spatial memory performance and seizure susceptibility in the animals beginning at P55, corresponding to young adulthood.

Results: We demonstrated that SE at P12 did not result in any structural or functional changes detectable in adulthood, whereas SE at both P16 and P20 induced cell loss and mossy fiber sprouting within the hippocampus and cognitive impairment when the animals were tested as adults.

Conclusions: Whereas the seizure threshold to generalized seizures was not altered, animals with SE at P20 showed an increased susceptibility to kindling in adulthood.
Effect of Topiramate or Carbamazepine on the Pharmacokinetics of an Oral Contraceptive Containing Norethindrone and Ethinyl Estradiol in Healthy Obese and Nonobese Female Subjects
Authors: Doose Dennis R. , Wang Shean‐Sheng , Padmanabhan Mukund , Schwabe Stefan , Jacobs David , Bialer Meir
Published: December 2004

Summary:  Purpose: To study the pharmacokinetics of a combination oral contraceptive (OC) containing norethindrone and ethinyl estradiol during OC monotherapy, concomitant OC and topiramate (TPM) therapy, and concomitant OC and carbamazepine (CBZ) therapy in order to comparatively evaluate the pharmacokinetic interaction, which may cause contraceptive failure.

Methods: This randomized, open‐label, five‐group study included two 28‐day cycles. Five groups of female subjects received oral doses of ORTHO‐NOVUM 1/35 alone (cycle 1) and then concomitant with TPM or CBZ (cycle 2). The treatment groups were group 1, TPM, 50 mg/day; group 2, TPM, 100 mg/day; group 3, TPM, 200 mg/day; group 4, TPM, 200 mg/day (obese women); and group 5, CBZ, 600 mg/day. Group 4 comprised obese women whose body mass index (BMI) was between 30 and 35 kg/m2. The BMI of the remaining four groups was ≤27 kg/m2.

Results: Coadministration of TPM at daily doses of 50, 100, and 200 mg (nonobese) and 200 mg (obese) nonsignificantly (p > 0.05) changed the mean area under the curve (AUC) of ethinyl estradiol by –12%, +5%, –11%, and –9%, respectively, compared with OC monotherapy. A similar nonsignificant difference was observed with the plasma levels and AUC values of norethindrone (p > 0.05). CBZ (600 mg/day) significantly (p < 0.05) decreased the AUC values of norethindrone and ethinyl estradiol by 58% and 42%, respectively, and increased their respective oral clearance by 69% and 127% (p < 0.05). Because CBZ induces CYP 3A–mediated and glucuronide conjugation metabolic pathways, the significant increase in the oral clearance of ethinyl estradiol and norethindrone was anticipated.

Conclusions: TPM, at daily doses of 50–200 mg, does not interact with an OC containing norethindrone and ethinyl estradiol. The lack of the TPM–OC interaction is notable when it is compared with the CBZ–OC interaction.