bluuebunny/crossref_metadata_2025 huggingface dataset:
Clonidine premedication effects on inhaled induction with sevoflurane in adults: a prospective, double‐blind, randomized study
Authors: Watanabe T. , Inagaki Y. , Ishibe Y.
Published: January 2006

Background:  The purpose of this study was to evaluate whether oral clonidine premedication becomes an alternative to N2O in terms of shortening the induction time and attenuation of the adrenergic response to tracheal intubation during inhalation induction with sevoflurane, and to evaluate the quality of anesthetic induction according to the patient's satisfaction.

Methods:  We studied 84 female patients who were randomly allocated into four study groups: Groups I and II received a placebo orally, and Groups III and IV received clonidine at 150 and 300 µg, respectively, 90 min before induction of anaesthesia. Patients were anesthetized using a triple‐deep‐breath technique with 5% sevoflurane in Groups I, III and IV, and with 60% N2O−5% sevoflurane in group II.

Results:  Induction time was significantly longer (P < 0.05) in Group I. Increases in mean blood pressure and heart rate after tracheal intubation were significantly suppressed in Groups III and IV but not in Group II compared with Group I. Comfort and impression of anesthesia was better in Groups III and IV than in Groups I and II.

Conclusion:  In volatile anesthetic induction, pre‐anesthetic clonidine may become an alternative to N2O and may provide more comfort than with N2O.
Suppression of the human spinal H‐reflex by propofol: a quantitative analysis
Authors: Baars J. H. , Dangel C. , Herold K. F. , Hadzidiakos D. A. , Rehberg B.
Published: January 2006

Background:  The spinal cord is an important site of anaesthetic action because it mediates surgical immobility. During anaesthesia with volatile anaesthetics, it has been shown that the suppression of the spinal H‐reflex correlates with surgical immobility. To evaluate whether the H‐reflex could also be a possible candidate for monitoring immobility during propofol anaesthesia, this study assessed the concentration‐dependent suppression of the H‐reflex by propofol. To discriminate different effect sites, the individual concentration response‐curves and the t1/2ke0 of the H‐reflex have been compared with those of two EEG parameters.

Methods:  In 18 patients, anaesthesia was induced and maintained with propofol infused using a target‐controlled infusion pump at stepwise increasing and decreasing plasma concentrations between 0.5 and 4.5 mg/l. The H‐reflex of the soleus muscle was recorded at a frequency of 0.1 Hz. Calculated propofol concentrations and H‐reflex amplitude were analysed in terms of a pharmacokinetic‐pharmacodynamic (PKPD) model with a sigmoid concentration‐response function.

Results:  For slowly increasing propofol concentrations, computer fits of the PKPD model for H‐reflex suppression by propofol yielded the following median parameters: EC50 1.1 (0.8–1.7) mg/l, slope parameter 2.4 (2.0–3.7), and a t1/2ke0 of 6.7 (2.8–7.5, 25–75% quantiles) min. For the bispectral index, the t1/2ke0 was 2.2 (1.8–3.1) min and for the spectral edge frequency at the 95th percentile of the power spectrum 2.8 (1.9–3.2) min.

Conclusions:  Propofol, unlike sevoflurane, suppresses the spinal H‐reflex at concentrations far lower than the C50 skin incision. The differences in t1/2ke0‐values indicate the presence of different effect compartments for effects on the H‐reflex and the EEG.
Epidural morphine analgesia compared with intravenous morphine for oral cancer surgery with pectoralis major myocutaneous flap reconstruction
Authors: Singhal A. K. , Mishra S. , Bhatnagar S. , Singh R.
Published: January 2006

Background:  Oral cancer surgery with reconstruction is a complex operative procedure with morbidities such as respiratory complications and post‐operative pain. These morbidities may be reduced with appropriate operative and post‐operative pain management. Epidural analgesia provides better pain control than intravenous opioids after major thoraco‐abdominal surgical procedures. We planned to undertake a prospective study to compare the efficacy and side‐effects of epidural morphine analgesia vs. intravenous morphine in patients undergoing oral cancer surgery with pectoralis major myocutaneous flap reconstruction.

Methods:  Sixty patients undergoing a major surgical procedure for oral cancer with pectoralis major myocutaneous flap reconstruction were prospectively randomized to receive either epidural morphine or intravenous morphine in the post‐operative period. The intensity of pain was assessed daily using a 100‐mm visual analogue scale. The post‐operative side‐effects, time to ambulation, time to tolerate first nasogastric feed, total length of hospital stay and global satisfaction score were recorded.

Results:  The epidural morphine group had statistically significant lower pain scores at the three evaluation times through the post‐operative 48 h (P < 0.05). However, the mean visual analogue scores were always below 35 in the intravenous morphine group. Patients in the epidural morphine group ambulated and accepted nasogastric feed significantly earlier than those in the intravenous morphine group. The incidence of nausea/vomiting or pruritus, the length of hospital stay and the global satisfaction score were not statistically different between the groups.

Conclusion:  This study illustrates that epidural morphine offers better pain control than intravenous morphine after oral cancer surgery with pectoralis major myocutaneous flap reconstruction. Nevertheless, both methods appear to provide very good pain relief, and perhaps the extra risks inherent to epidural catheter insertion are not outweighed by the benefits in this type of surgery.
Effects of aprotinin on plasma coagulation kinetics determined by thrombelastography: role of Factor XI
Authors: Nielsen V. G.
Published: January 2006

Background:  Aprotinin is commonly administered in settings involving cardiopulmonary bypass and liver transplantation to decrease peri‐operative bleeding. Thrombelastography has been utilized to monitor coagulation in these settings, and aprotinin delays clot initiation, presumably by inhibiting kallikrein; however, aprotinin also inhibits Factor XI (FXI), a contact system protein. Thus, it was hypothesized that celite‐activated thrombelastography coagulation kin‐etics would be decreased via aprotinin‐mediated FXI inhibition.

Methods:  Citrated normal plasma and prekallikrein‐deficient (<1% normal activity) plasma were exposed to 0, 200, 400 or 800 kallikrein inhibitory units (KIU)/ml (n = 6 per condition). Samples were recalcified and celite‐activated in a thrombelastograph, with clot initiation (R, s) determined. To confirm contact system specificity, additional prekallikrein‐deficient samples with 0 or 800 KIU/ml aprotinin were activated with tissue factor (n = 4 per condition).

Results:  Exposure of celite‐activated, normal plasma to aprotinin 0, 200, 400 or 800 KIU/ml resulted in R values of 167 ± 14, 253 ± 10, 293 ± 22 and 349 ± 21 s, respectively, which were significantly different from one another (P < 0.05). Exposure of celite‐activated, prekallikrein‐deficient plasma to aprotinin 0, 200, 400 or 800 KIU/ml resulted in R values of 366 ± 15, 630 ± 64, 698 ± 46 and 850 ± 47 s, respectively, which were significantly different from one another (P < 0.05). There were no significant differences in R values between tissue factor‐activated, prekallikrein‐deficient plasma samples with 0 or 800 KIU/ml aprotinin.

Conclusions:  These data support a role for the inhibition of FXI as the mechanism for aprotinin‐mediated delayed contact system clot initiation determined by thrombelastography.
Comparison of tracheal tube cuff diameters with internal transverse diameters of the trachea in children
Authors: Dullenkopf A. , Kretschmar O. , Knirsch W. , Tomaske M. , Hug M. , Stutz K. , Berger F. , Weiss M.
Published: January 2006

Background:  In this study, we evaluated the ratio of the cuff diameters of the Microcuff paediatric tracheal tube (Microcuff PET, Weinheim, Germany) to fluoroscopically measured internal transverse tracheal diameters in children from birth to adolescence.

Methods:  With Institutional Ethics Committee approval and parental consent, we measured the internal transverse tracheal diameters from fluoroscopy images in children undergoing cardiac catheterization requiring general anaesthesia with oro‐tracheal intubation. Minimal tracheal sealing pressures were assessed at standardized respirator settings. Internal transverse tracheal diameters were compared with cuff diameters at 20 cmH2O cuff pressure. Linear regression analysis was employed to assess the correlation of tracheal diameters with age, height and weight, and to assess the correlation of the cuff/tracheal diameter ratio with sealing pressures. For all tests, P < 0.05 was considered to be statistically significant.

Results:  One hundred and forty‐five patients were studied (62 girls; 83 boys). Transverse tracheal diameters correlated well with age (r = 0.890; P < 0.0001), height (r = 0.900; P < 0.0001) and weight (r = 0.882; P < 0.0001). Tracheal sealing pressures ranged from 4 to 18 cmH2O. The ratio of the tracheal tube cuff diameter to the internal transverse tracheal diameter ranged from 1.06 in tubes with internal diameters of 6.0 and 4.5 mm to 2.01 in a tube with an internal diameter of 3.5 mm (median, 1.43), and did not correlate with tracheal sealing pressures (r = 0.021, P = 0.7999).

Conclusions:  The residual diameters of the Microcuff paediatric tracheal tube cuffs were sufficient to cover the measured internal transverse tracheal diameters of children from birth to adolescence. This allowed the internal tracheal mucosal surface to be draped and the trachea to be sealed at very low cuff pressures.
Factors associated with anaesthesia‐related maternal mortality in a tertiary hospital in Nigeria
Authors: Enohumah K. O. , Imarengiaye C. O.
Published: January 2006

Background:  Maternal mortality related to anaesthesia is low compared with that resulting from obstetric factors in developed countries. The role of anaesthesia in maternal mortality in developing countries is obscure. The purposes of this study were to determine the incidence of maternal mortality related to anaesthesia, to analyse the causes and to suggest measures to improve anaesthetic safety for parturients.

Methods:  The hospital surgical registry was reviewed from 1 January 1991 to 31 December 2000 to identify patients who had undergone surgical procedures in pregnancy or puerperium. Data were obtained from the surgical registry in the Labour and Delivery Suite, Intensive Care Unit records and maternal mortality database to determine the demographic characteristics and anaesthetic technique. Maternal mortality after surgical procedures was further scrutinized to evaluate the anaesthetic care and the contribution of anaesthesia to mortality.

Results:  A total of 12,394 deliveries occurred in the hospital during the period under review. Caesarean section accounted for 2323 deliveries (18.7%). Eighty‐four maternal mortalities were recorded, with a maternal mortality rate of 678 per 100,000 deliveries. Infection, haemorrhage, pre‐eclampsia/eclampsia and anaesthesia were the leading causes of maternal mortality. Anaesthesia was the sole cause of six maternal deaths. The patients received general anaesthesia for the surgical procedure.

Conclusion:  Difficult airway management during general anaesthesia, inadequate supervision of trainee anaesthetists and a lack of appropriate monitors were the major anaesthetic reasons for maternal mortality. Recommendations have been made to ensure that parturients and the unborn child receive the best anaesthetic care attainable in the hospital.
Organ system dysfunction following open cholecystectomy for acute acalculous cholecystitis in critically ill patients
Authors: Laurila J. , Laurila P. A. , Saarnio J. , Koivukangas V. , Syrjälä H. , Ala‐Kokko T. I.
Published: January 2006

Background:  Acute acalculous cholecystitis (AAC) refers to cholecystitis without gallstones and is a serious complication of critical illness. We describe the time course of organ system dysfunction associated with cholecystectomy in critically ill patients with AAC.

Methods:  The data of all intensive care unit (ICU) patients who had operatively confirmed AAC during their ICU stay between 2003 and 2004 were analyzed. Patients who also had other intra‐abdominal pathologies were excluded. The Sequential Organ Failure Assessment (SOFA) scores were recorded 3 days before, on the day of operation and on the first, second, third and seventh post‐operative day after cholecystectomy. The impact of open cholecystectomy on organ dysfunction was evaluated on the basis of the change in the total and individual organ SOFA scores.

Results:  Twenty‐four patients underwent open cholecystectomy for AAC with no other intra‐abdominal pathology. Sepsis was the most common admission diagnosis, followed by cardiovascular surgery. The mean (standard deviation, SD) Acute Physiology and Chronic Health Evaluation (APACHE II), Simplified Acute Physiology Score (SAPS) II and SOFA scores on admission were 24.7 (5.8), 44.3 (12.3) and 9.4 (3.2), respectively. The median (25th, 75th percentiles) total SOFA score 3 days before cholecystectomy was 7.5 (1.3, 8.0), which increased to 10.5 (8.3, 13.0) (P < 0.0001) by the day of cholecystectomy, indicating developing multiorgan dysfunction. After the operation, the score decreased to 5.5 (3.3, 10.8) (P = 0.004) by the seventh post‐operative day. The change was most obvious in cardiovascular and respiratory SOFA scores.

Conclusions:  AAC is associated with multiorgan dysfunction in critically ill patients. Open cholecystectomy seems to alter the course of multiorgan dysfunction in these patients.
Chorotypes of seaweeds from the western Mediterranean Sea and the Adriatic Sea: An analysis based on the genera Audouinella (Rhodophyta), Cystoseira (Phaeophyceae) and Cladophora (Chlorophyta)
Authors: Báez José C. , Real Raimundo , Vargas J. Mario , Flores‐Moya Antonio
Published: January 2006

The aim of the present paper is to identify the possible existence of groups of species in the genera Audouinella (Rhodophyta), Cystoseira (Phaeophyceae) and Cladophora (Chloropyta) with significantly similar distribution patterns (chorotypes), in the western Mediterranean Sea and the Adriatic Sea. Of the 98 species studied, 59 were grouped into 11 chorotypes, whereas 39 species remained ungrouped. Thirty‐eight species were included in a generalist chorotype, whereas 6 chorotypes were monospecific. The relationships with the environmental factors that could explain the chorotypes are discussed.
Heterocapsa psammophila sp. nov. (Peridiniales, Dinophyceae), a new sand‐dwelling marine dinoflagellate
Authors: Tamura Maiko , Iwataki Mitsunori , Horiguchi Takeo
Published: January 2006

A new armored dinoflagellate species, Heterocapsa psammophila Tamura, Iwataki et Horiguchi sp. nov. is described from Kenmin‐no‐hama beach, Hiroshima, Japan using light and electron microscopy. This dinoflagellate possesses the typical thecal plate arrangement of the genus Heterocapsa, Po, cp, 5′, 3a, 7′′, 6c, 5s, 5′′′, 2′′′′; and the 3‐D body scales of Heterocapsa on the plasma membrane. The cell shape is ovoidal. The spherical nucleus and the pyrenoid are situated in the hypotheca and the epitheca, respectively. The ultrastructure of H. psammophila is typical of dinoflagellates and the pyrenoid is invaginated by cytoplasmic tubules. H. psammophila is distinguished from all other hitherto‐described Heterocapsa species by the cell shape, the relative position of the nucleus and pyrenoid and the structure of the body scale. The habitat and behavior of this new species in culture suggest that the organism is truly a sand‐dwelling species.
Paradoxical effects of prodynorphin gene deletion on basal and cocaine‐evoked dopaminergic neurotransmission in the nucleus accumbens
Authors: Chefer V. I. , Shippenberg T. S.
Published: January 2006

Quantitative and conventional microdialysis were used to investigate the effects of constitutive deletion of the prodynorphin gene on basal dopamine (DA) dynamics in the nucleus accumbens (NAc) and the responsiveness of DA neurons to an acute cocaine challenge. Saline‐ and cocaine‐evoked locomotor activity were also assessed. Quantitative microdialysis revealed that basal extracellular DA levels were decreased, while the DA extraction fraction, an indirect measure of DA uptake, was unchanged in dynorphin (DYN) knockout (KO) mice. The ability of cocaine to increase NAc DA levels was reduced in KO. Similarly, cocaine‐evoked locomotor activity was decreased in KO. The selective kappa opioid receptor agonist U‐69593 decreased NAc dialysate DA levels in wildtype mice and this effect was enhanced in KO. Administration of the selective kappa opioid receptor (KOPr) antagonist nor‐binaltorphimine to KO mice attenuated the decrease in cocaine‐induced DA levels. However, it was ineffective in altering the decreased locomotor response to cocaine. These studies demonstrate that constitutive deletion of prodynorphin is associated with a reduction of extracellular NAc DA levels and a decreased responsiveness to acute cocaine. Data regarding the effects of U‐69593 and nor‐binaltorphimine in KO suggest that the kappa opioid receptor is up‐regulated as a consequence of prodynorphin gene deletion and that this adaptation underlies the decrease in basal DA dynamics and cocaine‐evoked DA levels observed in DYN KO mice. These findings suggest that the phenotype of DYN KO mice is not solely due to loss of endogenous opioid peptide but also reflects developmental compensations that occur at the level of the opioid receptor.
Neurons in dopamine‐rich areas of the rat medial midbrain predominantly encode the outcome‐related rather than behavioural switching properties of conditioned stimuli
Authors: Wilson David I. G. , Bowman E. M.
Published: January 2006

Midbrain dopamine neurons are phasically activated by a variety of sensory stimuli. It has been hypothesized that these activations contribute to reward prediction or behavioural switching. To test the latter hypothesis we recorded from 131 single neurons in the ventral tegmental area and retrorubral field of thirsty rats responding during a modified go/no‐go task. One‐quarter (n = 33) of these neurons responded to conditioned stimuli in the task, which varied according to the outcome with which they were associated (saccharin or quinine solution) and according to whether they triggered a switch in the ongoing sequence of the animal's behaviour (‘behavioural switching’). Almost half the neurons (45%) responded differentially to saccharin‐ vs. quinine‐conditioned stimuli; the activity of a minority (15%) correlated with an aspect of behavioural switching (mostly exhibiting changes from baseline activity in the absence of a behavioural switch) and one‐third (33%) encoded various outcome–switch combinations. The strongest response was excitation to the saccharin‐conditioned stimulus. Additionally, a proportion (38%) of neurons responded during outcome delivery, typically exhibiting inhibition during saccharin consumption. The neurons sampled did not fall into distinct clusters on the basis of their electrophysiological characteristics. However, most neurons that responded to the outcome‐related properties of conditioned stimuli had long action potentials (> 1.2 ms), a reported characteristic of dopamine neurons. Moreover, responses to saccharin‐conditioned stimuli were functionally akin to dopamine responses found in the macaque and rat nucleus accumbens responses observed within the same task. In conclusion, our data are more consistent with the reward‐prediction than the behavioural switching hypothesis.
Neurogenic niche modulation by activated microglia: transforming growth factor β increases neurogenesis in the adult dentate gyrus
Authors: Battista Daniela , Ferrari Carina C. , Gage Fred H. , Pitossi Fernando J.
Published: January 2006

Adult neural stem cells (NSC) proliferate and differentiate depending on the composition of the cellular and molecular niche in which they are immersed. Until recently, microglial cells have been ignored as part of the neurogenic niche. We studied the dynamics of NSC proliferation and differentiation in the dentate gyrus of the hippocampus (DG) and characterized the changes of the neurogenic niche in adrenalectomized animals (ADX). At the cellular level, we found increased NSC proliferation and neurogenesis in the ADX animals. In addition, a morphologically distinct subpopulation of NSC (Nestin+/GFAP–) with increased proliferating profile was detected. Interestingly, the number of microglial cells at stages 2 and 3 of activation correlated with increased neurogenesis (r2 = 0.999) and the number of Nestin‐positive cells (r2 = 0.96). At the molecular level, transforming growth factor beta (TGF‐β) mRNA levels were increased 10‐fold in ADX animals. Interestingly, TGF‐β levels correlated with the amount of neurogenesis detected (r2 = 0.99) and the number of stage 2 and 3 microglial cells (r2 = 0.94). Furthermore, blockade of TGF‐β biological activity by administration of an anti‐TGF‐β type II receptor antibody diminished the percentage of 5‐bromo‐2′‐deoxyuridine (BrdU)/PSA‐NCAM‐positive cells in vivo. Moreover, TGF‐β was able to promote neurogenesis in NSC primary cultures. This work supports the idea that activated microglial cells are not pro‐ or anti‐neurogenic per se, but the balance between pro‐ and anti‐inflammatory secreted molecules influences the final effect of this activation. Importantly, we identified an anti‐inflammatory cytokine, TGF‐β, with neurogenic potential in the adult brain.
An identified central pattern‐generating neuron co‐ordinates sensory‐motor components of respiratory behavior in Lymnaea
Authors: Haque Zara , Lee Thomas K. M. , Inoue Takuya , Luk Collin , Hasan Shabih U. , Lukowiak Ken , Syed Naweed I.
Published: January 2006

Defining the attributes of individual central pattern‐generating (CPG) neurons underlying various rhythmic behaviors are fundamental to our understanding of how the brain controls motor programs, such as respiration and locomotion. To this end, we have explored a simple invertebrate preparation in which the neuronal basis of respiratory rhythmogenesis can be investigated from the whole animal to a single cell level. An identified dopaminergic neuron, termed right pedal dorsal 1 (RPeD1), is a component of the CPG network which controls hypoxia‐driven, aerial respiration in the fresh water snail Lymnaea stagnalis. Using intact, semi‐intact and isolated brain preparations, we have discovered that in addition to its role as a respiratory CPG neuron, RPeD1 co‐ordinates sensory‐motor input from the pneumostome (the respiratory orifice) at the water/air interface to initiate respiratory rhythm generation. An additional, novel role of RPeD1 was also found. Specifically, direct intracellular stimulation of RPeD1 induced pneumostome openings, in the absence of motor neuronal activity. To determine further the role of RPeD1 in the respiratory behavior of intact animals, either its axon was severed or the soma selectively killed. Many components of the respiratory behavior in the intact animals were found to be perturbed following RPeD1 axotomy or ‘somatomy’ (soma removed). Taken together, the data presented provide a direct demonstration that RPeD1 is a multifunctional CPG neuron, which also serves many additional roles in the control of breathing behavior, ranging from co‐ordination of mechanosensory input to the motor control of the respiratory orifice.
Hitting Ras where it counts: Ras antagonism in the basolateral amygdala inhibits long‐term fear memory
Authors: Merino Stephen M. , Maren Stephen
Published: January 2006

Several studies have implicated the Ras/mitogen‐activated protein kinase (MAPK) pathway in Pavlovian fear conditioning. RasGRF1 knockout mice show significant deficits in acquisition of long‐term fear memories and long‐term potentaition (LTP) in the basolateral amygdala (BLA). MAPK kinase inhibition also impairs fear conditioning and amygdaloid LTP. However, there is no direct evidence to date for the involvement of Ras itself in fear conditioning. To address this issue, we examined the effects of intra‐amygdala infusions of the selective Ras antagonist farnesylthiosalicylic acid (FTS) on the acquisition and expression of conditional freezing in rats. Micro‐infusions of FTS into the BLA prior to contextual fear conditioning significantly impaired acquisition of long‐term contextual fear memory in a dose‐dependent manner. Post‐training FTS infusions had no effect on acquisition of long‐term fear memory. The effects of FTS on fear conditioning were specific for the BLA. Finally, intra‐amygdala infusions of FTS inhibited MAPK activation in BLA. Collectively, these results provide further evidence for the involvement of amygdaloid Ras in the acquisition of long‐term conditional fear memory.
Caspase‐like activity is essential for long‐term synaptic plasticity in the terrestrial snail Helix
Authors: Bravarenko N. I. , Onufriev M. V. , Stepanichev M. Yu , Ierusalimsky V. N. , Balaban P. M. , Gulyaeva N. V.
Published: January 2006

Although caspase activity in the nervous system of mollusks has not been described before, we suggested that these cysteine proteases might be involved in the phenomena of neuroplasticity in mollusks. We directly measured caspase‐3 (DEVDase) activity in the Helix lucorum central nervous system (CNS) using a fluorometrical approach and showed that the caspase‐3‐like immunoreactivity is present in the central neurons of Helix. Western blots revealed the presence of caspase‐3‐immunoreactive proteins with a molecular mass of 29 kDa. Staurosporin application, routinely used to induce apoptosis in mammalian neurons through the activating cleavage of caspase‐3, did not result in the appearance of a smaller subunit corresponding to the active caspase in the snail. However, it did increase the enzyme activity in the snail CNS. This suggests differences in the regulation of caspase‐3 activity in mammals and snails. In the snail CNS, the caspase homolog seems to possess an active center without activating cleavage typical for mammals. In electrophysiological experiments with identified snail neurons, selective blockade of the caspase‐3 with the irreversible and cell‐permeable inhibitor of caspase‐3 N‐benzyloxycarbonyl‐Asp(OMe)‐Glu(OMe)‐Val‐Asp‐(OMe)‐fluoro‐methylketone prevented development of the long‐term stage of synaptic input sensitization, suggesting that caspase is necessary for normal synaptic plasticity in snails. The results of our study give the first direct evidence that the caspase‐3‐like activity is essential for long‐term plasticity in the invertebrate neurons. This activity is presumably involved in removing inhibitory constraints on the storage of long‐term memory.
Blockade of mGluR5 glutamate receptors in the subthalamic nucleus ameliorates motor asymmetry in an animal model of Parkinson's disease
Authors: Phillips Janice M. , Lam Hoa A. , Ackerson Larry C. , Maidment Nigel T.
Published: January 2006

It has been suggested that Group I metabotropic glutamate receptor antagonists could have potential therapeutic value in the treatment of Parkinson's disease. There is evidence that when given systemically, 2‐methyl‐6‐(phenylethynyl)‐pyridine (MPEP), a metabotropic glutamate receptor type 5 (mGluR5) antagonist, produces anti‐parkinsonian effects in animal models, but the site of action has not been directly established. In the present study, we examined whether the subthalamic nucleus (STN) and its output structures may mediate such an effect using a unilateral rat model of Parkinson's disease. A battery of simple behavioral tests, reliably sensitive to dopamine depletion, was applied consecutively: (i) prior to surgery; (ii) 3 weeks following a unilateral 6‐hydroxydopamine lesion of the substantia nigra pars compacta; (iii) at 1 h, 24 h and 4 days following a microinjection of MPEP, via an indwelling cannula, into the STN, entopeduncular nucleus (EP) or substantia nigra zona reticulata. Unilaterally dopamine‐depleted animals typically had severe motor and sensorimotor asymmetries 3 weeks following surgery. Microinjection of 25 nmol MPEP into the STN of these animals significantly attenuated these asymmetries relative to vehicle. Further microinjections of lower doses (5 and 10 nmol) revealed a dose–response effect. Microinjection of MPEP into either the EP or substantia nigra zona reticulata was without effect. These data suggest that MPEP may act at the level of the STN to reduce glutamatergic overactivity and thereby induce anti‐parkinsonian effects.
Temporal memory deficits in Alzheimer's mouse models: rescue by genetic deletion of BACE1
Authors: Ohno Masuo , Chang Lei , Tseng Wilbur , Oakley Holly , Citron Martin , Klein William L. , Vassar Robert , Disterhoft John F.
Published: January 2006

Transgenic mouse models of Alzheimer's disease (AD) exhibit amyloid‐β (Aβ) accumulation and related cognitive impairments. Although deficits in hippocampus‐dependent place learning have been well characterized in Alzheimer's transgenic mice, little is known about temporal memory function in these AD models. Here, we applied trace fear conditioning to two different Alzheimer's mouse models and investigated the relationship between pathogenic Aβ and temporal memory deficits. This behavioral test requires hippocampus‐dependent temporal memory processing as the conditioned and unconditioned stimuli are separated by a trace interval of 30 s. We found that both amyloid precursor protein (APP) transgenic (Tg2576) and APP/presenilin (PS)1 transgenic (Tg6799) mice were impaired in memorizing this association across the time gap. Both transgenic groups performed as well as wild‐type control mice in delay fear conditioning when the trace interval was removed, indicating that the trace conditioning deficits are hippocampus‐specific. Importantly, Tg6799 mice engineered to lack the major Alzheimer's β‐secretase (β‐site APP‐cleaving enzyme 1: BACE1) showed behavioral rescue from temporal memory deficits. Elevated levels of soluble Aβ oligomers found in Tg6799+ mouse brains returned to wild‐type control levels without changes in APP/PS1 transgene expression in BACE1–/–·Tg6799+ bigenic mouse brains, suggesting Aβ oligomers as potential mediators of memory loss. Thus, trace fear conditioning is a useful assay to test the mechanisms and therapeutic interventions for Aβ‐dependent deficits in temporal associative memory. Our gene‐based approach suggests that lowering soluble Aβ oligomers by inhibiting BACE1 may be beneficial for alleviating cognitive disorders in AD.
Long‐lasting modulation of the induction of LTD and LTP in rat hippocampal CA1 by behavioural stress and environmental enrichment
Authors: Artola Alain , Von Frijtag Josefien C. , Fermont Patrick C. J. , Gispen Willem Hendrik , Schrama Loes H. , Kamal Amer , Spruijt Berry M.
Published: January 2006

Behavioural experience (e.g. chronic stress, environmental enrichment) can have long‐lasting effects on cognitive functions. Because activity‐dependent persistent changes in synaptic strength are believed to mediate memory processes in brain areas such as hippocampus, we tested whether behaviour has also long‐lasting effects on synaptic plasticity by examining the induction of long‐term potentiation (LTP) and long‐term depression (LTD) in slices of hippocampal CA1 obtained from rats either 7–9 months after social defeat (behavioural stress) or 3–5 weeks after 5‐week exposure to environmental enrichment. Compared with age‐matched controls, defeated rats showed markedly reduced LTP. LTP was even completely impaired but LTD was enhanced in defeated and, subsequently, individually housed (during the 7–9‐month period after defeat) rats. However, increasing stimulus intensity during 100‐Hz stimulation resulted in significant LTP. This suggests that the threshold for LTP induction is still raised and that for LTD lowered several months after a short stressful experience. Both LTD and LTP were enhanced in environmentally enriched rats, 3–5 weeks after enrichment, as compared with age‐matched controls. Because enrichment reduced paired‐pulse facilitation, an increase in presynaptic release, facilitating both LTD and LTP induction, might contribute to enhanced synaptic changes. Consistently, enrichment reduced the number of 100‐Hz stimuli required for inducing LTP. But enrichment may also actually enhance the range of synaptic modification. Repeated LTP and LTD induction produced larger synaptic changes in enriched than in control rats. These data reveal that exposure to very different behavioural experiences can produce long‐lasting effects on the susceptibility to synaptic plasticity, involving pre‐ and postsynaptic processes.
Developmental changes of CaMKII localization, activity and function during postembryonic CNS remodelling in Manduca sexta
Authors: Burkert P. , Duch C.
Published: January 2006

Insect metamorphosis is a compelling example of postembryonic remodelling of neuronal structure and synaptic connectivity as larval and adult behaviours place distinct demands on the CNS. Holometabolous insects such as the moth Manduca sexta have long served as suitable models for the study of steroid effects on CNS remodelling, but activity and calcium‐dependent mechanisms have been found to act in concert with hormonal signals. This study examines developmental changes in the localization and the activational state of CaMKII during postembryonic Manduca CNS remodelling. Western blotting, CaMKII purification and autophosphorylation with γ32P‐ATP indicate that the lepidopteran CNS may contain only one CaMKII isoform. In situ immunohistochemistry reveals developmental changes in the expression patterns of CaMKII in different types of thoracic neurons and in different neuronal compartments. Early pupal life is characterized by an increase in postsynaptic CaMKII localization, which coincides with a developmental increase in CaMKII activation. Both events correlate temporally with motoneuron dendritic filopodia collapse and rapid synaptogenesis, indicating a possible functional role for CaMKII for the postembryonic development of invertebrate motor circuitry. Substrate phosphorylation assays demonstrate that CaMKII activity in the ventral nerve cord reflects changes in calcium influx through voltage‐activated channels as occurring in vivo during normal development.
Neurogenesis in the adult spinal cord in an experimental model of multiple sclerosis
Authors: Danilov Alexandre I. , Covacu Ruxandra , Moe Morten C. , Langmoen Iver A. , Johansson Clas B. , Olsson Tomas , Brundin Lou
Published: January 2006

Multiple sclerosis is an inflammatory disease of the central nervous system characterized by inflammation, demyelination, axonal degeneration and accumulation of neurological disability. Previously, we demonstrated that stem cells constitute a possible endogenous source for remyelination. We now addressed the question of whether neurogenesis can occur in neuroinflammatory lesions. We demonstrated that, in experimental autoimmune encephalomyelitis, induced in rats 1,1′‐dioctadecyl‐6,6′‐di(4sulphopentyl)‐3,3,3′,3′tetramethylindocarbocyanin(DiI)‐labelled ependymal cells not only proliferated but descendants migrated to the area of neuroinflammation and differentiated into cells expressing the neuronal markers β‐III‐tubulin and NeuN. Furthermore, these cells were immunoreactive for bromodeoxyuridine and PCNA, markers for cells undergoing cell proliferation. Using the whole‐cell patch‐clamp technique on freshly isolated 1, DiI‐labelled cells from spinal cord lesions we demonstrated the ability of these cells to fire overshooting action potentials similar to those of immature neurones. We thus provide the first evidence for the initiation of neurogenesis in neuroinflammatory lesions in the adult spinal cord.
Serotonergic modulation of neuronal responses to behavioural inhibition and reinforcing stimuli: an fMRI study in healthy volunteers
Authors: Völlm Birgit , Richardson Paul , McKie Shane , Elliott Rebecca , Deakin J. F. W. , Anderson Ian M.
Published: January 2006

Serotonin (5‐HT) has been implicated in the aetiology of a number of psychiatric conditions, including depression, anxiety and antisocial personality disorder. The development of these disorders may arise from alterations in underlying motivational and cognitive processes such as emotional recognition, reinforcement processing and central inhibitory control. This study aimed to localize where in the brain 5‐HT modulates neuropsychological processes relevant to putative 5‐HT disorders, using functional magnetic resonance imaging. We examined the effect of the antidepressant mirtazapine on brain activations associated with behavioural inhibition and reinforcement processing in healthy subjects. Forty‐five men were randomly allocated to receiving mirtazapine or placebo in a double‐blind fashion. A Go/No‐Go, Reward/No‐Reward and Loss/No‐loss task were performed during functional magnetic resonance imaging using a 1.5 Tesla Philips Gyroscan scanner. Blood oxygenation level dependent (BOLD) responses were analysed using SPM2. Task activations were largely consistent with previous findings. Mirtazapine modulated brain activations in the Go/No‐Go and Reward/No‐Reward task. During behavioural inhibition, enhanced activations were observed in the right orbitofrontal cortex (BA47). Increased activations in bilateral parietal cortex were found during the Reward task while no significant interaction was observed in the Loss task. Our results support the suggestion of an important role of serotonin in modulating basic processes involved in psychiatric disorders. Combining drug challenge with fMRI (pharmacoMRI; pMRI) is a promising tool for investigating these processes in healthy as well as patient groups.
Intraischemic mild hypothermia prevents neuronal cell death and tissue loss after neonatal cerebral hypoxia–ischemia
Authors: Zhu Changlian , Wang Xiaoyang , Xu Falin , Qiu Lin , Cheng Xiuyong , Simbruner George , Blomgren Klas
Published: January 2006

The effectiveness of hypothermia in preventing ischemic brain damage depends on when it is started. The purpose of this study was to investigate the effects of temperature reduction during a hypoxic–ischemic (HI) insult on brain injury and signalling pathways of neuronal cell death and survival. Seven‐day‐old mice were subjected to left common carotid artery ligation and hypoxia (10% oxygen) at different temperatures (37, 36 or 34 °C) for 50 min. Brain injury at 7 days post‐HI was significantly reduced from 67.4% at 37 °C to 31.6% at 36 °C and 10% at 34 °C, with no observable injury in the cortex of the 34 °C group. Cytochrome c release, caspase‐3 activation and apoptosis‐inducing factor translocation from mitochondria to nuclei were all significantly inhibited after intraischemic temperature reduction. Concurrently, the cell survival signalling pathway involving Akt was significantly sustained (the phosphorylated form of Akt was maintained) when the hypoxia temperature was decreased. These results indicate that intraischemic hypothermia diminished apoptosis through inhibition of both caspase‐dependent and caspase‐independent neuronal cell death pathways and promoted cell survival by inhibition of phosphorylated Akt dephosphorylation in the neonatal brain, thereby preventing neuronal cell death.
Intracellular acidification in neurons induced by ammonium depends on KCC2 function
Authors: Titz Stefan , Hormuzdi Sheriar , Lewen Andrea , Monyer Hannah , Misgeld Ulrich
Published: January 2006

The Cl–‐extruding neuron‐specific K+–Cl– cotransporter KCC2, which establishes hyperpolarizing inhibition, can transport NH4+ instead of K+. It is, however, not clear whether KCC2 provides the only pathway for neuronal NH4+ uptake. We therefore investigated NH4+ uptake in cultured rat brain neurons. In neurons cultured for > 4 weeks, the response to NH4Cl applications (5 mm) consisted of an alkaline shift which reversed to an acid shift within seconds. Rebound acid shifts which followed brief applications of NH4Cl were blocked by furosemide (100 µm). They were rather insensitive to bumetanide (1 and 100 µm), in contrast to those induced in cultured glial cells. Rebound acid shifts persisted in the presence of 1 mm Ba2+ and in Na+‐free solution but were inhibited by extracellular K+. In neurons with depolarizing GABA responses, indicating the absence of functional KCC2, applications of NH4Cl barely induced an acidosis. However, large rebound acid shifts occurred in neurons that had changed their GABA response from Ca2+ increases to Ca2+ decreases. Rebound acid shifts continued to increase even after the change in the GABA response had occurred and could be induced earlier in neurons transfected with KCC2 cDNA. We conclude that KCC2 provides the main pathway for fast neuronal NH4+ uptake. Therefore, NH4Cl‐induced rebound acid shifts can be used to indicate the development of KCC2 function. Further, the well known up‐regulation of KCC2 function during development has the inevitable consequence of opening a major pathway for NH4+ influx, which can be relevant under pathophysiological conditions.
Long‐term depression of neuron to glial signalling in rat cerebellar cortex
Authors: Bellamy Tomas C. , Ogden David
Published: January 2006

Bergmann glial cells enclose synapses throughout the molecular layer of the cerebellum and express extrasynaptic AMPA receptors and glutamate transporters. Accordingly, stimulation of parallel fibres leads to the generation of inward currents in the glia due to AMPA receptor activation and electrogenic uptake of glutamate. Elimination of AMPA receptor Ca2+ permeability leads to the withdrawal of glial processes and synaptic dysfunction, suggesting that AMPA receptor‐mediated Ca2+ signalling is essential for glial support of the neuronal network. Here we show that glial extrasynaptic currents (ESCs) exhibit activity‐dependent plasticity, specifically, long‐term depression during repetitive stimulation of parallel fibres at low frequencies (0.033–1 Hz) − conditions in which Purkinje neuron excitatory postsynaptic currents (EPSCs) remain stable. Both the rate of onset and the magnitude of ESC depression increased with stimulation frequency. Depression was reversible following brief periods of stimulation, but became increasingly persistent as the duration of repetitive stimulation increased. All glial currents − AMPA receptors, glutamate transporter and a recently discovered slow 1,2,3,4‐tetrahydro‐6‐nitro‐2,3‐dioxo‐benzo[f]quinoxaline‐7‐sulphonamide (NBQX)‐sensitive current − were depressed. Increasing presynaptic release probability by doubling external Ca2+ concentration did not affect the time course of depression, suggesting that neither decreased release probability nor fatigue of release sites contribute to depression. Inhibition of glutamate uptake caused a dramatic enhancement of the rate of depression, implicating glutamate in the underlying mechanism. The strength of neuron to glial signalling in the cerebellum is therefore dynamically regulated, independently of adjacent synapses, by the frequency of parallel fibre activity.
Unstable in More Ways Than One: Reaction Time Variability and the Neuroticism/Distress Relationship
Authors: Robinson Michael D. , Wilkowski Benjamin M. , Meier Brian P.
Published: January 2006

ABSTRACT
The authors hypothesized that a greater degree of stimulus‐response variability could either serve adaptive or maladaptive control purposes, depending on levels of Neuroticism. Specifically, a more variable relation between stimulus and response may be emotionally beneficial if such flexibility is used to support non‐neurotic forms of self‐regulation, but costly if it is used to support neurotic forms of self‐regulation. To investigate these ideas, the authors asked 232 college undergraduates within three studies to perform several choice reaction time (RT) tasks. On the basis of performance, we could quantify stimulus‐response variability in terms of RT variability from trial to trial. Such a measure of stimulus‐response variability interacted with Neuroticism in predicting momentary negative affect (Study 1), informant judgments of negative affect (Study 2), and informant judgments of anxious symptoms (Study 3). As hypothesized, greater stimulus‐response variability tended to be associated with less distress among individuals low in Neuroticism, but more distress among individuals high in Neuroticism. The results highlight the manner in which Neuroticism may “taint” control functions, in turn reinforcing Neuroticism‐linked outcomes.
Immunological and virological responses to highly active antiretroviral therapy in a non‐clinical trial setting in a developing Caribbean country
Authors: Kilaru KR , Kumar A , Sippy N , Carter AO , Roach TC
Published: January 2006

Objective

Few data exist on the efficacy of antiretroviral therapy in individuals infected with HIV in the Caribbean. We evaluated the virological and immunological responses of HIV‐infected adults starting highly active antiretroviral therapy (HAART).

Design

This was a prospective observational cohort study.

Methods

A total of 158 antiretroviral‐naive patients who initiated HAART between January 2002 and March 2003, and completed at least 6 months of treatment and follow up, were included in the analysis. The response to therapy was assessed by changes in CD4 cell counts and viral loads from baseline. The mean increase in CD4 cell count, the rate of virological success (a viral load of <50 HIV‐1 RNA copies/mL) and the rate of immunological success (an increase in CD4 cell count of≥50 cells/μL over the baseline value) after commencing HAART were measured.

Results

In total, 82% of patients (123 of 150) achieved viral loads of <50 copies/mL after 6 months of therapy. Viral success rate after 6 months of HAART was similar irrespective of gender, pre‐HAART CD4 cell count and pre‐HAART viral load. However, patients older than 40 years were significantly more likely to achieve virorological success than those younger than 40 years. At 6 months after starting HAART, 79.5% of patients were estimated to have achieved immunological success and 17.9% had an increase in CD4 cell count of ≥200 cells/μL over the baseline value. The median increase in CD4 cell count for the 156 patients who had CD4 cell counts at baseline and at 6 months of therapy was 122 cells/μL.

Conclusion

In this cohort of antiretroviral‐naive HIV‐infected adults, there was a high rate of virological and immunological success after 6 months of HAART, irrespective of the pre‐HAART viral load and CD4 cell count.