bluuebunny/crossref_metadata_2025 huggingface dataset:
Varenicline for smoking cessation: A placebo‐controlled, randomized study
Authors: WANG Chen , XIAO Dan , CHAN Kenneth Ping Wah , POTHIRAT Chaicharn , GARZA Dahlia , DAVIES Simon
Published: January 2009

Background and objective:  Varenicline tartrate, a novel, selective, nicotinic acetylcholine receptor partial agonist, has been developed specifically as a smoking cessation drug. This study evaluated the efficacy of a standard regimen of varenicline compared with placebo for smoking cessation in 333 subjects in China, Singapore and Thailand.

Methods:  This 24‐week, randomized, double‐blind, placebo‐controlled trial of varenicline, 1 mg bd, consisted of a 12‐week treatment period followed by a 12‐week non‐treatment follow‐up period. The primary study end‐point was the 4‐week continuous abstinence rate defined as the proportion of subjects who reported total abstinence from smoking and other nicotine products from weeks 9–12. A key secondary end‐point was the continuous abstinence rate from weeks 9–24, defined as the proportion of subjects who achieved the primary end‐point as well as total abstinence from all tobacco products from weeks 13–24.

Results:  Both end‐points were achieved by a significantly higher proportion of subjects in the varenicline group than in the placebo group. The 4‐week continuous abstinence end‐point was achieved by 50.3% and 31.6% in the varenicline and placebo groups, respectively (P = 0.0003), while continuous abstinence from weeks 9–24 was achieved by 38.2% and 25.0% of subjects, respectively (P = 0.0080). The treatment effect was generalizable by treatment centre and country. Varenicline was safe and appeared to be well tolerated by most subjects.

Conclusion:  Varenicline was significantly more efficacious for smoking cessation than placebo over a 12‐week treatment period and a further 12‐week non‐treatment follow‐up period in smokers from China, Singapore and Thailand. No significant side‐effects were noted.
Zinc ions are endogenous modulators of neurotransmitter‐stimulated capacitative Ca2+ entry in both cultured and in situ mouse astrocytes
Authors: Kresse Wolfgang , Sekler Israel , Hoffmann Anja , Peters Oliver , Nolte Christiane , Moran Arie , Kettenmann Helmut
Published: January 2009

Astrocytes express a variety of metabotropic receptors and their activation leads to a biphasic Ca2+ response due to Ca2+ release from intracellular stores and subsequent capacitative Ca2+ entry. We performed Ca2+ imaging with Fura‐2 on cultured mouse astrocytes and showed that extracellular zinc reversibly blocks the capacitative Ca2+ entry following application of the metabotropic ligands ATP, glutamate and endothelin‐1. Zinc blocked the plateau phase of the ligand‐triggered Ca2+ responses. When ligands were repetitively applied in the presence of zinc the calcium responses progressively decayed and even disappeared, indicating that capacitative Ca2+ entry is required to refill the stores. Zinc inhibited the capacitative Ca2+ entry with a Ki of ≈ 6 µm, which is well within the physiological concentration range of zinc found in the brain. Application of the reducing agent DTT prevented the blocking effect by zinc ions but not the inhibition elicited by the nonphysiological metal ions Gd3+ and La3+, indicating that zinc has a distinct binding site. To monitor the capacitative Ca2+ entry in astrocytes in situ and to determine the effect of zinc on this pathway we utilized X‐rhod‐1 imaging in hippocampal slices of a transgenic mouse line with green fluorescent astrocytes. Zinc affected the repetitive metabotropic Ca2+ response in the following fashion: (i) after depleting stores in Ca2+‐free solution, re‐addition of Ca2+ led to an influx of Ca2+ via a zinc‐sensitive Ca2+ entry route; (ii) with repetitive application of metabotropic ligands, Ca2+ responses became smaller and even disappeared in the presence of zinc. We conclude that zinc, which is coreleased from glutamatergic synaptic vesicles upon neuronal activity, has a major impact on shaping the astrocytic calcium responses.
Activity in human medial temporal lobe associated with encoding process in spatial working memory revealed by magnetoencephalography
Authors: Campo Pablo , Maestú Fernando , Capilla Almudena , Fernández Santiago , Fernández Alberto , Ortiz Tomás
Published: January 2009

Animal studies have suggested that working memory may be affected after lesions in the medial temporal lobe, although this assumption has not been corroborated by neuropsychological studies in humans. However, very recently, several functional neuroimaging studies in humans have successfully observed activation of the medial temporal lobe during working memory tasks. The main aim of this study was to investigate the contribution of the medial temporal lobe to the encoding process in spatial working memory. To address this issue we registered the neuromagnetic brain patterns of eight adult volunteers while they performed a spatial working memory task and more perceptual task using identical stimuli. After a initial phase (between 200 and 400 ms) without differences in activation, the medial temporal lobe showed a sustained activity, more evident in the right hemisphere, lasting up to 800 ms during the encoding stage of the spatial working memory task, while the activation in the perceptual task terminated earlier (∼400 ms after stimulus onset). The finding of a continued activation of the medial temporal lobe strongly suggests the contribution of this brain region to encoding operations in working memory.
Spinal cord injury‐induced lesional expression of the repulsive guidance molecule (RGM)
Authors: Schwab Jan M. , Conrad Sabine , Monnier Philippe P. , Julien Sylvie , Mueller Bernhard K. , Schluesener Hermann J.
Published: January 2009

The repulsive guidance molecule (RGM) is involved in the formation of the central nervous system (CNS) during development by modulating guidance of growing axons. However, a role of RGM in CNS injury remains to be established. We studied the expression of RGM in the spinal cord of rats with spinal cord injury (SCI). After SCI, RGM+ cells accumulated in lesions and peri‐lesional areas. During the first days after SCI, RGM expression was confined to neurons, ballooned neurite fibers/retraction bulbs, smooth muscle/endothelial cells, and to leucocytes infiltrating the lesion. Lesional RGM expression was frequently confined to hypertrophic β‐APP+ and RhoA+ neurites/retraction bulbs. With maturation of the lesion, we observed RGM expression by components of the developing scar tissue (cicatrix), such as fibroblastoid cells, reactive astrocytes and in addition a pronounced extracellular RGM deposition resembling neo‐laminae. Frequent RGM+, RhoA+ coexpression by lesional retraction bulbs represent first preliminary evidence of RGM to exert growth inhibitory effects by the second messenger system RhoA. To date, RGM is one of the most potent axonal growth inhibitors identified and present in axonal growth impediments (i) oligodendrocytes; (ii) the plexus choroideus and (iii) components of the developing scar.
Migration of cells from primary transplants of allo‐ and xenografted foetal striatal tissue in the adult rat brain
Authors: Hurelbrink Carrie B. , Barker Roger A.
Published: January 2009

Primary neural cells derived from human xenografts migrate extensively following transplantation into the adult rat CNS. However, it is unknown whether cells from allografts have the same capability to migrate within the adult rat brain. Moreover, it is unclear whether human‐derived cells migrate to this extent as an inherent property of being in a xenograft environment, or whether it is due to the large size of the developed human brain compared with the adult rat brain. In order to address these issues we have designed an experimental paradigm to investigate the potential for cells derived from grafts of primary rat, mouse and human foetal striatal tissue to migrate following intrastriatal transplantation in an adult rat model of Huntington's disease (HD). Green fluorescent protein (GFP)‐expressing rat and mouse donors and an antibody specific to human nuclear antigen enabled identification of graft‐derived cells within the host brain, and double‐labelling with GFP and neuronal nuclear antigen or immunostaining with human‐specific tau identified graft‐derived neurons. Twelve weeks post‐transplantation, cells had migrated throughout the host in all groups; however, human cells and neurons had migrated significantly more than rat or mouse cells. These results demonstrate that neural cells derived from allografts are capable of migrating in the adult rat CNS and that the extent of migration is most likely determined by the size of the mature donor adult brain. This has important implications for the use of allo‐ and xenogeneic tissue as a source for transplantation in treating diffuse neurodegenerative disorders such as HD.
Regulation of miRNA expression during neural cell specification
Authors: Smirnova Lena , Gräfe Anja , Seiler Andrea , Schumacher Stefan , Nitsch Robert , Wulczyn F. Gregory
Published: January 2009

MicroRNA (miRNA) are a newly recognized class of small, noncoding RNA molecules that participate in the developmental control of gene expression. We have studied the regulation of a set of highly expressed neural miRNA during mouse brain development. Temporal control is a characteristic of miRNA regulation in C. elegans and Drosophila, and is also prominent in the embryonic brain. We observed significant differences in the onset and magnitude of induction for individual miRNAs. Comparing expression in cultures of embryonic neurons and astrocytes we found marked lineage specificity for each of the miRNA in our study. Two of the most highly expressed miRNA in adult brain were preferentially expressed in neurons (mir‐124, mir‐128). In contrast, mir‐23, a miRNA previously implicated in neural specification, was restricted to astrocytes. mir‐26 and mir‐29 were more strongly expressed in astrocytes than neurons, others were more evenly distributed (mir‐9, mir‐125). Lineage specificity was further explored using reporter constructs for two miRNA of particular interest (mir‐125 and mir‐128). miRNA‐mediated suppression of both reporters was observed after transfection of the reporters into neurons but not astrocytes. miRNA were strongly induced during neural differentiation of embryonic stem cells, suggesting the validity of the stem cell model for studying miRNA regulation in neural development.
Neurons expressing relaxin 3/INSL 7 in the nucleus incertus respond to stress
Authors: Tanaka Masaki , Iijima Norio , Miyamoto Yasumasa , Fukusumi Shoji , Itoh Yasuaki , Ozawa Hitoshi , Ibata Yasuhiko
Published: January 2009

Relaxin 3/INSL 7 has recently been identified as a new member of the insulin/relaxin superfamily. Although it was reported to be dominantly expressed in the brain, its detailed distribution and function in the central nervous system are still obscure. In the present study we demonstrated that in the rat relaxin 3 was mainly expressed in neurons of the nucleus incertus (NI) of the median dorsal tegmental pons. Other relaxin 3‐expressing neurons were scattered in the pontine raphe nucleus, the periaqueductal gray and dorsal area to the substantia nigra in the midbrain reticular formation. Relaxin 3‐immunoreactive fibers projected particularly densely in the septum, hippocampus, lateral hypothalamus and intergeniculate leaflet of the thalamus. Ultrastructural examination revealed that relaxin 3 was localized in the dense‐cored vesicles in the perikarya and was also observed in the synaptic terminals of axons. As almost all relaxin 3‐containing neurons express corticotropin‐releasing factor (CRF) type 1 receptor in the NI, we examined the response of relaxin 3 neurons to intracerebroventricular administration of CRF; 65% of relaxin 3 neurons expressed c‐Fos 2 h after intracerebroventricular administration of 1 µg CRF. We then confirmed that c‐Fos was induced in 60% of relaxin 3 neurons in the NI and the expression of relaxin 3 mRNA increased significantly in the NI after water‐restraint stress. Collectively, these results suggest that relaxin 3 produced in the NI is released from nerve endings and is involved in the regulation of the stress response.
Involvement of NMDA and AMPA/KA receptors in the nucleus accumbens core in instrumental learning guided by reward‐predictive cues
Authors: Giertler Christian , Bohn Ines , Hauber Wolfgang
Published: January 2009

The use of reward‐predictive cues to guide behavior critically involves the nucleus accumbens. However, little is known regarding the role of ionotropic glutamate receptors in the core subregion of the nucleus accumbens (AcbC) in instrumental learning guided by reward‐predictive cues. Here we examined the effects of an intra‐AcbC blockade of NMDA and AMPA/KA receptors on the acquisition of an instrumental response in a reaction time (RT) task in rats. In this task, discriminative cues signaled in advance the upcoming reward magnitude (5 or 1 food pellet) associated with a lever release. During early acquisition (days 1–6) rats received daily bilateral injections of either the NMDA receptor antagonist AP5 (5.0 µg per side, n = 14), the AMPA/KA receptor antagonist CNQX (2.5 µg per side, n = 14) or vehicle (0.5 µL per side, n = 19). No treatment was given during late acquisition (days 7–12). The main result was that rats which received intra‐AcbC injections of AP5 or CNQX during early acquisition exhibited a general RT increase of responses to high and low reward. However, treatment with AP5 and CNQX did not interfere with discriminative guidance of RTs by cue‐associated reward magnitudes, i.e. during acquisition RTs of responses to expected high reward became significantly faster than RTs of responses to expected low reward. Our findings suggest that NMDA and AMPA/KA receptors in the AcbC play a critical role in invigorating responding during instrumental learning, but seem less important in guiding responding according to reward‐predictive cues.
Adult gaze influences infant attention and object processing: implications for cognitive neuroscience
Authors: Reid Vincent M. , Striano Tricia
Published: January 2009

Infants follow others' gaze toward external objects from early in ontogeny, but whether they use others' gaze in processing information about objects remains unknown. In Experiment 1, 4‐month‐old infants viewed a video presentation of an adult gazing toward one of two objects. When presented with the same objects alone a second time, infants looked reliably less at the object to which the adult had directly gazed (cued object). This suggests that the uncued object was perceived as more novel than the object previously cued by the adult's gaze. In Experiment 2, adult gaze was not directed towards any object. In this control experiment, infants looked at both objects equally in the test phase. These findings show that adult eye gaze biases infant visual attention and information processing. Implications of the paradigm for cognitive neuroscience are presented and the results are discussed in terms of neural structures and change over ontogeny.
Autonomic arousal in an appetitive context in primates: a behavioural and neural analysis
Authors: Braesicke Katrin , Parkinson John A. , Reekie Yvonna , Man Mei‐See , Hopewell Lucy , Pears Andrew , Crofts Harriet , Schnell Christian R. , Roberts Angela C.
Published: January 2009

Central to many emotional responses is the accompanying peripheral somatic and autonomic arousal, feedback from which has been hypothesized to enhance emotional memory and to contribute to appraisal processes and decision making, and dysfunction of which may contribute to antisocial behaviour. Whilst peripheral arousal may accompany both positive and negative emotional contexts, its relationship with the former is poorly understood, as are the neural mechanisms underlying such a relationship. The purpose of the present study was to determine the autonomic correlates of anticipation, as well as consumption, of high incentive food, in the freely moving common marmoset and to investigate the contribution of the amygdala to such effects. Blood pressure (BP) and heart rate (HR) were measured remotely by a telemetric device implanted into the descending aorta and behavioural responses were monitored whilst marmosets viewed preferred or non‐preferred foods and were then allowed access to eat those foods. A marked rise in blood pressure in unrestrained marmosets was observed in response both to the sight of highly preferred foods (anticipatory period) as well as during the actual consumption of those foods (consummatory period). Excitotoxic lesions of the amygdala abolished the autonomic arousal in the anticipatory period, but spared both the behavioural arousal in the anticipatory period and the autonomic arousal in the consummatory period. Together these data serve as an important step towards understanding the role of autonomic arousal in emotion and its neural underpinnings.
Regulation of corticosteroid receptors in the rat brain: the role of serotonin and stress
Authors: Robertson D. A. F. , Beattie J. E. , Reid I. C. , Balfour D. J. K.
Published: January 2009

It has been suggested that physiological resistance to repeated stress is associated with increased 5‐hydroxytryptamine (5‐HT) release in the dorsal hippocampus and that dysregulation of this neuroadaptation may be implicated in the psychopathology of depression. This study used 5,7‐dihydroxytryptamine lesions to investigate the role of 5‐HT projections to the hippocampus in physiological responses to repeated stress and putative changes in corticosteroid receptor immunoreactivity in the brain. Repeated exposure to elevated open platform stress (1 h/day) caused regionally selective changes in glucocorticoid and mineralocorticoid receptor immunoreactivity in the dorsal hippocampus that were not observed in ventral hippocampus, frontal cortex, hypothalamus or parietal cortex. Glucocorticoid receptor immunoreactivity in the dorsal hippocampus was decreased after 5 days but increased after 20 days of stress. Mineralocorticoid receptor immunoreactivity was increased after 5 or 10 days of stress. The increases in glucocorticoid and mineralocorticoid receptor immunoreactivity, evoked by repeated stress, were abolished by lesions of the principal 5‐HT projections to the hippocampus. The lesions abolished the increased defecation observed in stressed animals, but had no effects on the plasma corticosterone response to the stressor or the habituation of this response observed following repeated stress. The experiments have revealed a dissociation in the regulation of corticosteroid receptor expression in the dorsal and ventral hippocampus by repeated stress and 5‐HT. The data suggest that adaptation to inescapable stress is associated with regionally selective changes in corticosteroid receptor expression in dorsal hippocampus that are largely 5‐HT‐dependent, although these changes do not mediate habituation of the pituitary adrenocortical response to the stressor.
Two populations of glutamatergic axons in the rat dorsal raphe nucleus defined by the vesicular glutamate transporters 1 and 2
Authors: Commons Kathryn G. , Beck Sheryl G. , Bey Vincent W.
Published: January 2009

Most glutamatergic neurons in the brain express one of two vesicular glutamate transporters, vGlut1 or vGlut2. Cortical glutamatergic neurons highly express vGlut1, whereas vGlut2 predominates in subcortical areas. In this study immunohistochemical detection of vGlut1 or vGlut2 was used in combination with tryptophan hydroxylase (TPH) to characterize glutamatergic innervation of the dorsal raphe nucleus (DRN) of the rat. Immunofluorescence labeling of both vGlut1 and vGlut2 was punctate and homogenously distributed throughout the DRN. Puncta labeled for vGlut2 appeared more numerous then those labeled for vGlut1. Ultrastructural analysis revealed axon terminals containing vGlut1 and vGlut2 formed asymmetric‐type synapses 80% and 95% of the time, respectively. Postsynaptic targets of vGlut1‐ and vGlut2‐containing axons differed in morphology. vGlut1‐labeled axon terminals synapsed predominantly on small‐caliber (distal) dendrites (42%, 46/110) or dendritic spines (46%, 50/110). In contrast, vGlut2‐containing axons synapsed on larger caliber (proximal) dendritic shafts (> 0.5 µm diameter; 48%, 78/161). A fraction of both vGlut1‐ or vGlut2‐labeled axons synapsed onto TPH‐containing dendrites (14% and 34%, respectively). These observations reveal that different populations of glutamate‐containing axons innervate selective dendritic domains of serotonergic and non‐serotonergic neurons, suggesting they play different functional roles in modulating excitation within the DRN.
Molecular and functional characterization of an Ih‐channel from lobster olfactory receptor neurons
Authors: Gisselmann Günter , Marx Thomas , Bobkov Yuriy , Wetzel Christian H. , Neuhaus Eva M. , Ache Barry W. , Hatt Hanns
Published: January 2009

We isolated a cDNA named PAIH encoding a member of the Ih‐channel family expressed in olfactory receptor neurons (ORNs) of the spiny lobster Panulirus argus. Functional expression of recombinant PAIH in HEK293 cells generated a slowly activating, noninactivating inward current under whole‐cell voltage‐clamp to hyperpolarizing voltage steps, the amplitude and activation rate of which increase with increasing hyperpolarization. The channel is weakly selective for K+. Intracellular cAMP or cGMP shifts activation of the current to less negative potentials in a concentration‐dependent manner. Finally, the channel is blocked by the Ih‐channel blocker ZD7288. An Ih‐channel sharing the properties of the recombinant channel occurs in cultured lobster ORNs. PAIH immunoreactivity localizes the protein to the transduction compartment of the ORNs in situ, and selectively applying the blocker to the transduction compartment reduces spontaneous activity in the ORN. Collectively, these results implicate for the first time a functional role for an Ih‐channel in olfactory signal transduction.
Enhancement of learning behaviour by a potent nitric oxide‐guanylate cyclase activator YC‐1
Authors: Chien Wei‐Lin , Liang Keng‐Chen , Teng Che‐Ming , Kuo Sheng‐Chu , Lee Fang‐Yu , Fu Wen‐Mei
Published: January 2009

Memory is one of the most fundamental mental processes, and various approaches have been used to understand the mechanisms underlying this process. Nitric oxide (NO), cGMP and protein kinase G (PKG) are involved in the modulation of synaptic plasticity in various brain regions. YC‐1, which is a benzylindazole derivative, greatly potentiated the response of soluble guanylate cyclase to NO (up to several hundreds fold). We have previously shown that YC‐1 markedly enhances long‐term potentiation in hippocampal and amygdala slices via NO‐cGMP‐PKG‐dependent pathway. We here further investigated whether YC‐1 promotes learning behaviour in Morris water maze and avoidance tests. It was found that YC‐1 shortened the escape latency in the task of water maze, increased and decreased the retention scores in passive and active avoidance task, respectively. Administration of YC‐1 30 min after foot‐shock stimulation did not significantly affect retention scores in response to passive avoidance test. Administration of scopolamine, a muscarinic antagonist, markedly impaired the memory acquisition. Pretreatment of YC‐1 inhibited the scopolamine‐induced learning deficit. The enhancement of learning behaviour by YC‐1 was antagonized by intracerebroventricular injection of NOS inhibitor L‐NAME and PKG inhibitors of KT5823 and Rp‐8‐Br‐PET‐cGMPS, indicating that NO‐cGMP‐PKG pathway is also involved in the learning enhancement action of YC‐1. YC‐1 is thus a good drug candidate for the improvement of learning and memory.
The neuroprotective effect of progesterone after traumatic brain injury in male mice is independent of both the inflammatory response and growth factor expression
Authors: Jones Nigel C. , Constantin Despina , Prior Malcolm J. W. , Morris Peter G. , Marsden Charles A. , Murphy Sean
Published: January 2009

Previous studies suggest that progesterone may possess neuroprotective properties after traumatic insult but, with the exception of reduced formation of cerebral oedema, limited experimental evidence has been presented to support this claim. In the present study we focused on the effect of progesterone treatment on structural and functional deficits in an experimental model of traumatic brain injury. Female mice exhibited significantly (P = 0.0445) reduced lesion volumes compared with males after aseptic cryogenic cerebral injury (ACI), suggesting that female sex steroids provide protection against this injury. In male mice, progesterone treatment after injury (three intraperitoneal doses of 8 mg/kg) reduced lesion volume (P = 0.0429) and improved performance in a spatial cognitive task (Morris water maze; P = 0.0014). However, progesterone had no demonstrable effect on the formation of oedema as measured using T2‐weighted magnetic resonance imaging, nor did it affect brain water content. The pro‐inflammatory cytokines TNF‐α and IL‐1β, and growth factors BDNF and G‐CSF, were all strongly transcriptionally activated after ACI. However, progesterone administration did not affect expression of these genes. This study provides strong evidence that progesterone possesses neuroprotective properties in a mouse model of traumatic brain injury, but suggests that the steroid achieves this effect through mechanism(s) independent of the inflammatory response or growth factor up‐regulation.
Vasopressin facilitates glycinergic and GABAergic synaptic transmission in developing hypoglossal motoneurons
Authors: Reymond‐Marron I. , Raggenbass M. , Zaninetti M.
Published: January 2009

The hypoglossal nucleus of young rats contains vasopressin binding sites and vasopressin can directly excite hypoglossal motoneurons. In addition, indirect evidence suggests that vasopressin can enhance the synaptic input to motoneurons. We have characterized this latter effect by using brainstem slices and whole‐cell recordings. We found that, in the presence of blockers of fast glutamatergic transmission, vasopressin strongly facilitated inhibitory synaptic activity. On average, vasopressin caused a six‐fold increase in the frequency and a 1.5‐fold increase in the amplitude of GABAergic postsynaptic currents. The effect of vasopressin on glycinergic postsynaptic currents was similar in magnitude. Vasopressin did not affect the frequency of GABAergic or glycinergic miniature postsynaptic currents, indicating that the peptide‐induced facilitation of inhibitory transmission was mediated by receptors located on the somatodendritic region rather than on axon terminals of presynaptic neurons. The pharmacological profile of these receptors was determined by using d[Cha4]AVP and dVDAVP, selective agonists of V1b and V2 vasopressin receptors, respectively, and Phaa‐D‐Tyr‐(Et)‐Phe‐Gln‐Pro‐Arg‐Arg‐NH2, a selective antagonist of V1a vasopressin receptors. The two agonists had no effect on the frequency of inhibitory postsynaptic currents. By contrast, the antagonist suppressed the vasopressin‐induced facilitation of these currents, indicating that the receptors involved were exclusively of the V1a type. Thus, vasopressin exerts a dual action on hypoglossal motoneurons: a direct excitatory action and an indirect action mediated by GABAergic and glycinergic synapses. By virtue of this dual effect, vasopressin could alter the input–output properties of these motoneurons. Alternatively, it could play a role in generating or modulating specific motor patterns.
Translation of an integral membrane protein in distal dendrites of hippocampal neurons
Authors: Grigston Jeffrey C. , VanDongen Hendrika M. A. , McNamara II James O. , VanDongen Antonius M. J.
Published: January 2009

Maintenance of synaptic plasticity requires protein translation. Because changes in synaptic strength are regulated at the level of individual synapses, a mechanism is required for newly translated proteins to specifically and persistently modify only a subset of synapses. Evidence suggests this may be accomplished through local translation of proteins at or near synapses in response to plasticity‐inducing patterns of activity. A number of proteins important for synaptic function are integral membrane proteins, which require a specialized group of organelles, proteins and enzymatic activities for proper synthesis. Dendrites appear to contain machinery necessary for the proper production of these proteins, and mRNAs for integral membrane proteins have been found localized to dendrites. Experiments are described that investigate the local translation of membrane proteins in the dendrites of cultured rat hippocampal neurons, using fluorescence recovery after photobleaching. Neurons were transfected with cDNAs encoding a fluorescently labeled transmembrane protein, TGN‐38. Under conditions where the transport of this reporter construct was inhibited, the appearance of newly synthesized protein was observed via fluorescent microscopy. The dendritic translation of this protein required activation of glutamate receptors. The results demonstrate a functional capacity for activity‐dependent synthesis of integral membrane proteins for distal dendrites in hippocampal neurons.
Down‐regulation of amygdala preprotachykinin A mRNA but not3H‐SP receptor binding sites in subjects affected by mood disorders and schizophrenia
Authors: Carletti Renzo , Corsi Mauro , Melotto Sergio , Caberlotto Laura
Published: January 2009

Increasing evidence suggests that substance P (SP) neurokinin‐1 (NK1) receptors are involved in stress and emotional responses, representing a potential target for the treatment of anxiety and depression in humans. Given the important role of the amygdaloid complex in the regulation of emotional behavior, we examined the mRNA levels of preprotachykinin A [PPT‐A, a precursor of both SP and neurokinin A (NKA)] and3H‐SP binding sites in the amygdala of patients affected by bipolar disorder, major depression or schizophrenia as compared with matched control individuals. By means ofin situhybridization, a significant reduction of PPT‐A mRNA expression levels was detected in the three diagnostic groups, mainly in the basal, lateral and accessory basal amygdaloid nuclei, but not in the temporal cortical area proximal to the amygdala. Receptor autoradiography performed on adjacent sections showed no change in3H‐SP binding sites as compared with controls. No significant correlation was found between levels of PPT‐A mRNA expression or binding sites and subject age, gender, hemisphere side, cause of death or history of substance misuse (marijuana, alcohol, cocaine/amphetamine). An inverse relationship between PPT‐A mRNA expression levels and lifetime antipsychotic treatment (Fluphenazine) in the schizophrenic and bipolar disorder groups was found. Post‐mortem delay was also negatively correlated with NK1 binding sites. The results confirm an involvement of the tachykinins in psychiatric disorders, suggesting there is a generalized impairment of the SP system in the amygdala in mood disorders and schizophrenia rather than this being a disease‐related phenomenon.
Right ear advantage for conspecific calls in adults and subadults, but not infants, California sea lions (Zalophus californianus): hemispheric specialization for communication?
Authors: Böye M. , Güntürkün O. , Vauclair J.
Published: January 2009

This paper explores functional hemispheric asymmetries in the perception of auditory signals in a marine mammal species, the sea lion. Using a head‐orienting task toward sounds we found a right ear – left hemisphere – advantage for conspecific calls in adult and subadult California sea lions (Zalophus californianus) that was absent in infants. Non‐conspecific sounds did not elicit lateralized reactions in any age group. These findings show that maturational steps regarding communication in the brain of pinnipeds are similar to those described in primates. Such a result in a semi‐aquatic species distant from primates on the phylogenetic tree speaks for a stability and an ancient emergence of the left hemispheric specialization for vocal communication. The origin of what seems to be a widespread brain feature might be searched in the temporal and spectral communicative sound's characteristics rather than in its semantic value.
Volume‐sensitive chloride channels in mouse cortical neurons: characterization and role in volume regulation
Authors: Inoue Hana , Mori Shin‐ichiro , Morishima Shigeru , Okada Yasunobu
Published: January 2009

Because persistent swelling causes cell damage and often results in cell death, volume regulation is an important physiological function in both neuronal and non‐neuronal cells. Brain cell swelling has been observed not only in various pathological conditions but also during physiological synaptic transmissions. Volume‐sensitive anion channels have been reported to play an important role in the regulatory volume decrease occurring after osmotic swelling in many cell types. In this study, using a two‐photon laser scanning microscope and patch‐clamp techniques, we found that mouse cortical neurons in primary culture exhibit regulatory volume decrease after transient swelling and activation of Cl– currents during exposure to a hypotonic solution. The regulatory volume decrease was inhibited by Cl– channel blockers or K+ channel blockers. Swelling‐activated Cl– currents exhibited outward rectification, time‐dependent inactivation at large positive potentials, a low‐field anion permeability sequence, an intermediate unitary conductance and sensitivity to known blockers of volume‐sensitive Cl– channels. Thus, it is concluded that the activity of the volume‐sensitive outwardly rectifying Cl– channel plays a role in the control of cell volume in cortical neurons.
The dependence of the auditory evoked N1m decrement on the bandwidth of preceding notch‐filtered noise
Authors: Okamoto H. , Kakigi R. , Gunji A. , Kubo T. , Pantev C.
Published: January 2009

The auditory evoked response is known to be changed by a preceding sound. In this study we investigated by means of magnetoencephalography how a preceding notch‐filtered noise (NFN) with different bandwidths influences the human auditory evoked response elicited by the following test stimulus. We prepared white noise (WN) and four NFNs which were derived from WN by suppressing frequency regions around 1 kHz with 1/8‐, 1/4‐, 1/2‐ and 1‐octave bandwidths. Stimulation for 3 s with this set of noises resulted in differences in responsiveness to a 1‐kHz test tone presented 500 ms after the offset of the noises. The N1m response to the 1‐kHz test tone stimulus was at a minimum when the preceding NFN had 1/4‐octave stop‐band frequencies as compared with 1/8‐, 1/2‐ and 1‐octave NFN and WN. This N1m decrement is explained by the imbalanced neural activities caused by habituation and lateral inhibition in the auditory system. The results contribute to understanding of the inhibitory system in the human auditory cortex.
Central nucleus of amygdala projections to rostral ventrolateral medulla neurones activated by decreased blood pressure
Authors: Saha Sikha , Drinkhill Mark J. , Moore Jonathan P. , Batten Trevor F. C.
Published: January 2009

The central nucleus of amygdala (CeA) participates in cardiovascular regulation during emotional behaviour but it has not been established whether any of these effects are mediated through its direct connections to blood pressure‐regulating neurones in the rostral ventrolateral medulla (RVLM). The RVLM contains barosensitive neurones that maintain resting blood pressure via their projections to sympathetic preganglionic neurones in the thoracic spinal cord. In this study on rats, we used combined anterograde neuronal tracing of CeA projections with confocal and electron microscopic immunohistochemical detection of phenylethanolamine‐N‐methyltransferase, the adrenaline‐synthesizing enzyme present in C1 catecholamine neurones of the RVLM, and Fos, the protein product of thec‐fosproto‐oncogene. Fos expression in barosensitive neurones was stimulated by an intravenous infusion of the hypotensive agent sodium nitroprusside. Injection of the tracer biotin dextran amine (10‐kDa form) into the CeA resulted in anterograde labelling of axons and varicosities throughout the RVLM without retrograde labelling of somata in any brain area. With confocal microscopy, presumptive CeA terminals were found in close apposition to adrenergic (phenylethanolamine‐N‐methyltransferase‐immunoreactive) and non‐adrenergic neurones that displayed Fos‐immunoreactive nuclei in response to decreased blood pressure. Electron microscopic analysis confirmed that some labelled terminals of CeA axons made synaptic contact withc‐fos‐activated adrenergic neurones. The results provide evidence that cardiovascular influences elicited from the CeA during stressful events may be mediated, at least in part, via monosynaptic neural projections to barosensitive sympathetic blood pressure‐regulating neurones in the RVLM.
Recapitulating emotional context: activity of amygdala, hippocampus and fusiform cortex during recollection and familiarity
Authors: Fenker Daniela B. , Schott Björn H. , Richardson‐Klavehn Alan , Heinze Hans‐Jochen , Düzel Emrah
Published: January 2009

The amygdala is thought to enhance long‐term memory for emotionally arousing events by modulating memory formation and storage in the hippocampus and in neocortical areas. Recent animal studies have raised the possibility that cooperativity between amygdala and hippocampus contributes to the retrieval of fear memories. The functional contributions of the amygdala to the retrieval of emotional memories in humans are less well known. Here, in a functional magnetic resonance imaging experiment, 20 healthy subjects studied neutral words in the context of a fearful or a neutral human face. In a subsequent test, they made ‘remember’ (conscious recollection of the study context), ‘know’ (familiarity in the absence of conscious recollection) and ‘new’ judgements on the studied and newly presented neutral words, in the absence of face stimuli. At test, bilateral amygdala, hippocampus and fusiform face area (FFA) were more strongly activated during recollection than during familiarity. Higher activity for fearful than for neutral study context was found in bilateral FFA during recollection but not during familiarity. This difference recapitulated higher activity for fearful than for neutral context in the FFA during study. These data suggest that the amygdalae and hippocampi contribute to the retrieval of emotion‐laden context memories by coordinating the reactivation of stored representations in neocortical areas, such as the FFA. However, there also was a recapitulation of emotional study context in the right amygdala during familiarity only, which might therefore be related to affective implicit memory.
Determination of the pharmacodynamic interaction of propofol and dexmedetomidine during esophagogastroduodenoscopy in children
Authors: HAMMER GREGORY B. , SAM WAI JOHNN , CHEN MICHAEL I. , GOLIANU BRENDA , DROVER DAVID R.
Published: January 2009

Objectives:  Propofol is a sedative‐hypnotic drug commonly used to anesthetize children undergoing esophagogastroduodenoscopy (EGD). Dexmedetomidine is a highly selective alpha‐2 adrenergic receptor agonist that has been utilized in combination with propofol to provide anesthesia. There is currently no information regarding the effect of intravenous dexmedetomidine on the propofol plasma concentration–response relationship during EGD in children. This study aimed to investigate the pharmacodynamic interaction of propofol and dexmedetomidine when used in combination for children undergoing EGD.

Methods:  A total of 24 children undergoing EGD, ages 3–10 years, were enrolled in this study. Twelve children received dexmedetomidine 1 μg·kg−1 given over 10 min as well as a continuous infusion of propofol delivered by a computer‐assisted target‐controlled infusion (TCI) system with target plasma concentrations ranging from 2.8 to 4.0 μg·ml−1 (DEX group). Another group of 12 children undergoing EGD also received propofol administered by TCI targeting comparable plasma concentrations without dexmedetomidine (control group). We used logistic regression to predict plasma propofol concentrations at which 50% of the patients exhibited minimal response to stimuli (EC50 for anesthesia).

Results:  The EC50 ± se values in the control and DEX groups were 3.7 ± 0.4 μg·ml−1 and 3.5 ± 0.2 μg·ml−1, respectively. There was no significant shift in the propofol concentration–response curve in the presence of dexmedetomidine.

Conclusion:  The EC50 of propofol required to produce adequate anesthesia for EGD in children was unaffected by a concomitant infusion of dexmedetomidine 1 μg·kg−1 given over 10 min.
A left paraglossal approach for oral intubation in children scheduled for bilateral orofacial cleft reconstruction surgery – a prospective observational study
Authors: SEN INDU , KUMAR SUSHIL , BHARDWAJ NEERJA , WIG JYOTSNA
Published: January 2009

Background:  Children with orofacial cleft defects are expected to have difficult airways. Conventional midline laryngoscopic approach of oral intubation can lead to iatrogenic tissue trauma. In this study, we evaluated the feasibility of left paraglossal laryngoscopy as a primary technique for airway management in these children.

Methods:  After institutional ethical committee approval and informed consent, we enrolled 21 children with uncorrected bilateral lip and palate deformities (BL CL/P). Anesthesia was induced with halothane (0.5–4%) in 100% oxygen. After obtaining intravenous access, fentanyl 1.5 μg·kg−1 and atracurium 0.5 mg·kg−1 were administered. Endotracheal intubation was performed with Miller’s straight blade laryngoscope, introduced using left paraglossal approach. Difficulty of intubation was scored according to modified Intubation Difficulty Scale.

Results:  Data consists of 21 children (15 males and six females), mean age 1.31 ± 1.18 years and weight 9.27 ± 2.57 kg. Laryngoscopic view obtained was CL II (7[33.3%]) and CL I (14[66.6%]) respectively (Figure 1). All the children could be easily intubated using left paraglossal approach, only 2/3 of them needed optimal external laryngeal manipulation to help achieving it. Though intubation could be done in the first attempt in 19 children, two infants (9½ and 11 months) required one size smaller endotracheal tube and were intubated in the second attempt using left paraglossal approach. Perioperative course was uneventful in all the children.

 Distribution of Intubation Difficulty scale (IDS) Score in BL CL/P patients. n (%) IDS: 0 (intubation without difficulty), IDS: 1 (slight difficulty; OELM applied/additional intubation attempt), IDS: >5 (Moderate to Major difficulty), IDS: = α (Impossible intubation).

image

Conclusion:  Keeping in mind midline tissue support loss in cleft deformities, we propose routine use of left paraglossal laryngoscopic approach for intubating children with uncorrected BL CL/P anomalies.
Reduced neorectal capacitance is a more important factor for impaired defecatory function after rectal resection than the anal sphincter pressure
Authors: Schuld J. , Kreissler‐Haag D. , Remke M. , Steigemann N. , Schilling M. , Scheingraber S.
Published: January 2009

Objective  The role of the diverse anorectal diagnostic tools like manometry and determination of the preception threshold and the maximal tolerable volume is still a matter of debate. Currently, there is a scarcity of physiological data in the long‐term follow‐up of patients who underwent sphincter‐preserving rectal resection. The aim of this study was therefore to perform these anorectal physiological measurements and to correlate the determined parameters with a faecal incontinence score.

Method  In 45 patients, anorectal manometry, electromyography (EMG) and neorectal volume measurements were performed 21.6 ± 1.4 months after rectal resection. Additionally, patients answered questions to help in the determination of a modified faecal incontinence score.

Results  More than half of the patients had more than four bowel movements per day and suffered from defecatory urgency, evacuation and discrimination problems. Manometric data were not related to any functional deficits. In contrast, perception threshold and maximal tolerable volume were correlated with the faecal incontinence score.

Conclusion  Defecatory problems especially after radiochemotherapy are still common after rectal resection and the satisfactory functionality post resection should not be oversimplified to just the number of bowel movements. A precondition of an adequate defecation is not only the integrity of the sphincter muscles, but also the recovery of the rectal reservoir function.
Hand‐assisted laparoscopic surgery may be a useful tool for surgeons early in the learning curve performing total abdominal colectomy
Authors: Ozturk E. , Kiran R. P. , Remzi F. , Geisler D. , Fazio V.
Published: January 2009

Objective  We evaluated outcomes after hand‐assisted (HALC) and straight laparoscopic (LC) techniques for the initial laparoscopic total abdominal colectomy (TAC) procedures performed by surgeons starting their laparoscopic careers.

Method  The first eight HALC cases of two surgeons performing TAC by this technique (Group A) were compared with the first (Group B) and last eight (Group C) TAC cases of three surgeons performing LC. Groups A and B were compared with a matched group of open total colectomy cases (Group D) and to the eight cases performed by an experienced surgeon (Group E). Demographics, intra‐operative and postoperative outcomes including operation time, morbidity, conversion and readmission rates and length of hospital stay (LOS) were compared using Wilcoxon or Chi‐squared tests.

Results  Demographics of the patients were similar. Groups A, B C and E had similar operating time (P = 0.10) which was significantly longer than Group D (P < 0.0001). Morbidity (P = 0.75) and readmission rates were similar (P = 0.89). Conversion rate was significantly higher for Group B (Group B: 41.7%vs Group A: 0%, P = 0.008), in the early period. LOS was comparable between minimally invasive groups but significantly shorter than open surgery group (P = 0.0005). For Groups A and C, operating time (P = 0.55), conversion rate (P = 0.11), morbidity (P = 0.83) and LOS (P = 0.12) were similar.

Conclusions  Hand‐assisted laparoscopic colectomy may be associated with a significantly shorter learning curve for TAC as results are better than early LC and comparable with LC performed by experienced laparoscopic surgeons. It may be a better option for surgeons early in their laparoscopic career.
The role of SMAD4 in early‐onset colorectal cancer
Authors: Royce S. G. , Alsop K. , Haydon A. , Mead L. , Smith L. D. , Tesoriero A. A. , Giles G. G. , Jenkins M. A. , Hopper J. L. , Southey M. C.
Published: January 2009

Objective  Chromosomal loss within the region of 18q and loss of SMAD4 expression have been reported to be frequent somatic events during colorectal cancer tumour progression; however, their associations with age at onset have not been widely studied.

Method  We analysed 109 tumours from a population‐based case‐family study based on colorectal cancers diagnosed before the age of 45 years. These patients with early‐onset colorectal cancer had been previously screened for germ‐line mismatch repair gene mutations, microsatellite instability (that included the mononucleotide repeat in TGFβRII) and somatic k‐ras mutations. We measured SMAD4 protein expression using immunohistochemistry and SMAD4 copy number using quantitative real‐time PCR.

Results  Loss of SMAD4 protein expression was observed in 27/109 (25%) of cancers tested and was more commonly observed in rectal tumours (15/41, 36%) when compared with tumours arising in the colon (11/66, 17%) (P = 0.04). There was no association between SMAD4 protein expression and TGFβR11 mutation status, SMAD4 copy number, family history, MSI status, tumour stage or grade.

Conclusion  Loss of SMAD4 expression is a common feature of early‐onset colorectal tumours as it is in colorectal cancers diagnosed in other age‐groups. Taken together, the molecular pathways (genetic and epigenetic) now known to be involved in early‐onset colorectal cancer only explain a small proportion of the disease and require further exploration.