bluuebunny/crossref_metadata_2025_split huggingface dataset:
Multiple functions of GABAA and GABAB receptors during pattern processing in the zebrafish olfactory bulb
Authors: Tabor Rico , Yaksi Emre , Friedrich Rainer W. 
Published: July 2008

Abstractγ‐Aminobutyric acid (GABA)ergic synapses are thought to play pivotal roles in the processing of activity patterns in the olfactory bulb (OB), but their functions have been difficult to study during odor responses in the intact system. We pharmacologically manipulated GABAA and GABAB receptors in the OB of zebrafish and analysed the effects on odor responses of the output neurons, the mitral cells (MCs), by electrophysiological recordings and temporally deconvolved two‐photon Ca2+ imaging. The blockade of GABAB receptors enhanced presynaptic Ca2+ influx into afferent axon terminals, and changed the amplitude and time course of a subset of MC responses, indicating that GABAB receptors have a modulatory influence on OB output activity. The blockade of GABAA receptors induced epileptiform firing, enhanced excitatory responses and abolished fast oscillations in the local field potential. Moreover, the topological reorganization and decorrelation of MC activity patterns during the initial phase of the response was perturbed. These results indicate that GABAA receptor‐containing circuits participate in the balance of excitation and inhibition, the regulation of total OB output activity, the synchronization of odor‐dependent neuronal ensembles, and the reorganization of odor‐encoding activity patterns. GABAA and GABAB receptors are therefore differentially involved in multiple functions of neuronal circuits in the OB.
Pathway‐dependent modulation by P2‐purinoceptors in the mouse retina
Authors: Kaneda Makoto , Ishii Toshiyuki , Hosoya Toshihiko 
Published: July 2008

AbstractAdenosine trisphosphate (ATP) activates purinoceptors and acts as a neurotransmitter in the nervous system. In the retina, we previously reported that the immunohistochemical distribution of the subset of P2‐purinoceptors differs between the ON and OFF pathways. Here, we investigated whether ATP activates P2‐purinoceptors and modulates the physiological function of the mouse retina. We also examined if signal processing by P2‐purinoceptors is pathway specific. Results showed that ATP activated both ON‐ and OFF‐cholinergic amacrine cells. However, responses in OFF‐cholinergic amacrine cells were greater than those in ON‐cholinergic amacrine cells. Pharmacological studies in OFF‐cholinergic amacrine cells showed that the response of OFF‐cholinergic amacrine cells is mediated P2X2‐purinoceptors. Further, ATP increased γ‐aminobutyric acid (GABA)ergic inhibitory postsynaptic currents (IPSCs) in OFF‐ but not ON‐cholinergic amacrine cells. The increase in GABAergic IPSCs was mediated by P2‐purinoceptors. P2‐purinoceptor‐mediated signals suppressed OFF ganglion cells but activated ON ganglion cells. Our findings indicate that ATP physiologically modulates signal processing of the ON and OFF pathways in a pathway‐specific manner through P2‐purinoceptors.
Divergent phosphorylation pattern of tau in P301L tau transgenic mice
Authors: Deters Natasha , Ittner Lars M. , Götz Jürgen 
Published: July 2008

AbstractAggregates of hyperphosphorylated tau are prominent in brains of patients with Alzheimer’s disease or frontotemporal dementia (FTD). They have been reproduced in animal models following the identification of tau mutations in familial cases of FTD. This includes our previously generated transgenic model, pR5, which expresses FTD (P301L) mutant tau in neurons. The mice are characterized by tau aggregation including tangle (NFT) formation, memory impairment and mitochondrial dysfunction. In 8‐month‐old mice, S422 phosphorylation of tau is linked to NFT formation, however, a detailed analysis of tau solubility, phosphorylation and aggregation has not been done nor have the mice been monitored until a high age. Here, we undertook an analysis by immunohistochemistry, Gallyas impregnation and Western blotting of brains from 3 month‐ up to 20 month‐old mice. NFTs first appeared at 6 months in the amygdala, followed by the CA1 region of the hippocampus. As the mice get older, the solubility of tau is decreased as determined by sequential extractions. Histological analysis revealed increased phosphorylation at the AT180, AT270 and 12E8 epitopes with ageing. The numbers of AT8‐positive neurons increased from 3 to 6 months old. However, whereas S422 appeared only late and concomitantly with NFT formation, the only neurons left with AT8‐reactivity at 20 months were those that had undergone NFT formation. As hyperphosphorylated tau continued to accumulate, the lack of AT8‐reactivity suggests regulatory mechanisms in specifically dephosphorylating the AT8 epitope in the remaining neurons. Thus, differential regulation of phosphorylation is important for NFT formation in neurodegenerative diseases with tau pathology.
Types and synaptic connections of hippocampal inhibitory neurons reciprocally connected with the medial septum
Authors: Takács Virág T. , Freund Tamás F. , Gulyás Attila I. 
Published: July 2008

AbstractThe morphological properties and connectivity of γ‐aminobutyric acid (GABA)ergic hippocampal cells projecting to the medial septum (HS cells) were examined in the rat. Two types of HS cells are located in different layers of the hippocampus: sparsely‐spiny cells are in CA1–3 str. oriens and CA3 str. radiatum, where recurrent axons of pyramidal cells arborize. Densely‐spiny HS cells with spiny somata are located in the termination zone of granule cell axons. In the hilus, intermediate morphologies can also be found. HS cells receive GABAergic medial septal afferents in all layers where they occur, thus the connectivity of the septum and the hippocampus is reciprocal at cell level. HS cells receive extremely dense innervation, sparsely‐spiny cells are innervated by ∼19 000 excitatory inputs, while densely‐spiny cells get an even larger number (∼37 000). While 14% of the inputs are inhibitory for the sparsely‐spiny cells, it is only 2.3% in the case of densely‐spiny cells. Because a high proportion (up to 54.5% on somata and 27.5% on dendrites) of their GABAergic inputs derived from labelled septal terminals, their predominant inhibitory input probably arises from the medial septum. CA1 area HS cells possessed myelinated projecting axons, as well as local collaterals, which targeted mostly pyramidal cell dendrites and spines in str. oriens and radiatum. The synaptic organization suggests that by sampling the activity of large populations of principal cells HS cells can reliably broadcast hippocampal activity level to the medial septum.
Ephrin‐A5 acts as a repulsive cue for migrating cortical interneurons
Authors: Zimmer Geraldine , Garcez Patricia , Rudolph Judith , Niehage Ronny , Weth Franco , Lent Roberto , Bolz Jürgen 
Published: July 2008

AbstractCortical interneurons are born in the germinative zones of the ganglionic eminences in the subpallium, and migrate tangentially in spatially and temporally well‐defined corridors into the neocortex. Because ephrin‐A5 is expressed in the ventricular zone (VZ) of the ganglionic eminences at these developmental stages, we examined the possible effects of this molecule on interneuron migration. Double‐immunocytochemistry of dissociated neurons from the medial ganglionic eminences (MGE) revealed that calbindin‐positive cells express the EphA4‐receptor. In situ, EphA4 is strongly expressed in the subventricular zone of the ganglionic eminences. Using different in vitro assays, we found that ephrin‐A5 acts as a repellent cue for MGE neurons. We then examined interneuron migration in slice overlay experiments, where MGE‐derived explants from enhanced green fluorescent protein‐expressing transgenic mice were homotopically grafted into host slices from wild‐type littermate embryos. In these in vitro preparations, interneurons recapitulated in vivo cell migration in several respects. However, interneurons in brain slices also migrated in the VZ of the ganglionic eminences, a region that is strictly avoided in vivo. In situ hybridizations revealed that ephrin‐A5 became downregulated in the VZ in vitro. When recombinant ephrin‐A5‐Fc was added to the slices, it preferentially bound to the VZ, and migrating MGE neurons avoided the VZ as in vivo. The restoration of the normal migration pathway in slices required ephrin‐A5 clustering and signalling of Src family kinases. Together, these experiments suggest that ephrin‐A5 acts as an inhibitory flank that contributes to define the pathway of migrating interneurons.
Non‐stereoselective reversal of neuropathic pain by naloxone and naltrexone: involvement of toll‐like receptor 4 (TLR4)
Authors: Hutchinson Mark R. , Zhang Yingning , Brown Kimberley , Coats Benjamen D. , Shridhar Mitesh , Sholar Paige W. , Patel Sonica J. , Crysdale Nicole Y. , Harrison Jacqueline A. , Maier Steven F. , Rice Kenner C. , Watkins Linda R. 
Published: July 2008

AbstractAlthough activated spinal cord glia contribute importantly to neuropathic pain, how nerve injury activates glia remains controversial. It has recently been proposed, on the basis of genetic approaches, that toll‐like receptor 4 (TLR4) may be a key receptor for initiating microglial activation following L5 spinal nerve injury. The present studies extend this idea pharmacologically by showing that TLR4 is key for maintaining neuropathic pain following sciatic nerve chronic constriction injury (CCI). Established neuropathic pain was reversed by intrathecally delivered TLR4 receptor antagonists derived from lipopolysaccharide. Additionally, (+)‐naltrexone, (+)‐naloxone, and (−)‐naloxone, which we show here to be TLR4 antagonists in vitro on both stably transfected HEK293‐TLR4 and microglial cell lines, suppressed neuropathic pain with complete reversal upon chronic infusion. Immunohistochemical analyses of spinal cords following chronic infusion revealed suppression of CCI‐induced microglial activation by (+)‐naloxone and (−)‐naloxone, paralleling reversal of neuropathic pain. Together, these CCI data support the conclusion that neuron‐to‐glia signaling through TLR4 is important not only for initiating neuropathic pain, as suggested previously, but also for maintaining established neuropathic pain. Furthermore, these studies suggest that the novel TLR4 antagonists (+)‐naloxone and (−)‐naloxone can each fully reverse established neuropathic pain upon multi‐day administration. This finding with (+)‐naloxone is of potential clinical relevance. This is because (+)‐naloxone is an antagonist that is inactive at the (−)‐opioid selective receptors on neurons that produce analgesia. Thus, these data suggest that (+)‐opioid antagonists such as (+)‐naloxone may be useful clinically to suppress glial activation, yet (−)‐opioid agonists suppress pain.
Diabetes downregulates presynaptic proteins and reduces basal synapsin I phosphorylation in rat retina
Authors: VanGuilder Heather D. , Brucklacher Robert M. , Patel Kruti , Ellis Rhona W. , Freeman Willard M. , Barber Alistair J. 
Published: July 2008

AbstractDiabetic retinopathy can result in vision loss and involves progressive neurovascular degeneration of the retina. This study tested the hypothesis that diabetes decreases the retinal expression of presynaptic proteins involved in synaptic function. The protein and mRNA contents for synapsin I, synaptophysin, vesicle‐associated membrane protein 2, synaptosomal‐associated protein of 25 kDa and postsynaptic density protein of 95 kDa were measured by immunohistochemistry, immunoblotting and real‐time quantitative polymerase chain reaction in whole retinas and retinal synaptosomes from streptozotocin‐diabetic and control Sprague–Dawley rats. There was less presynaptic protein immunoreactivity after 1 and 3 months of diabetes than in controls. Discrete synaptophysin‐immunoreactive puncta were significantly smaller and fewer in sections from 1‐ and 3‐month diabetic rat retinas than in those from controls. The content of presynaptic proteins was significantly less in whole retinas of 1‐ and 3‐month diabetic rats, and in synaptosomes from 1‐month diabetic rats, than in controls. Whole retinas had significantly less mRNA for these genes after 3 months but not 1 month of diabetes, as compared to controls (with the exception of postsynaptic density protein of 95 kDa). In contrast, there was significantly less mRNA for synaptic proteins in synaptosomes of 1‐month diabetic rats than in controls, suggesting a localized depletion at synapses. Protein and mRNA for β‐actin and neuron‐specific enolase were unchanged by diabetes. The ratio of phosphorylated to total synapsin I was also reduced in whole retina and isolated synaptosomes from 1‐month diabetic rats, as compared to controls. These data suggest that diabetes has a profound impact on presynaptic protein expression in the retina, and may provide a mechanism for the well‐established defects in vision and the electrophysiological response of the retina in diabetes.
Omi / HtrA2 is relevant to the selective vulnerability of striatal neurons in Huntington’s disease
Authors: Inagaki Reina , Tagawa Kazuhiko , Qi Mei‐Ling , Enokido Yasushi , Ito Hikaru , Tamura Takuya , Shimizu Shigeomi , Oyanagi Kityomitsu , Arai Nobutaka , Kanazawa Ichiro , Wanker Erich E , Okazawa Hitoshi 
Published: July 2008

AbstractSelective vulnerability of neurons is a critical feature of neurodegenerative diseases, but the underlying molecular mechanisms remain largely unknown. We here report that Omi/HtrA2, a mitochondrial protein regulating survival and apoptosis of cells, decreases selectively in striatal neurons that are most vulnerable to the Huntington’s disease (HD) pathology. In microarray analysis, Omi/HtrA2 was decreased under the expression of mutant huntingtin (htt) in striatal neurons but not in cortical or cerebellar neurons. Mutant ataxin‐1 (Atx‐1) did not affect Omi/HtrA2 in any type of neuron. Western blot analysis of primary neurons expressing mutant htt also confirmed the selective reduction of the Omi/HtrA2 protein. Immunohistochemistry with a mutant htt‐transgenic mouse line and human HD brains confirmed reduction of Omi/HtrA2 in striatal neurons. Overexpression of Omi/HtrA2 by adenovirus vector reverted mutant htt‐induced cell death in primary neurons. These results collectively suggest that the homeostatic but not proapoptotic function of Omi/HtrA2 is linked to selective vulnerability of striatal neurons in HD pathology.
Emergency laparoscopic surgery for complicated diverticular disease
Authors: Titu L. V. , Zafar N. , Phillips S. M. , Greenslade G. L. , Dixon A. R. 
Published: July 2008

AbstractObjective  The aim of this study was to analyse the outcome of emergency laparoscopic surgical management of complicated diverticular disease.Method  A prospectively collected electronic database of all colorectal laparoscopic procedures between April 2001 and September 2007 has been used to identify outcomes in patients presenting with complicated diverticular disease.Results  Sixty‐six patients (28 men), median age 69 years (23–95), ASA grade II (12), III (38), IV (16) have undergone emergency surgery for complicated diverticulitis – Hinchey grades I (27), II (29), III (7) and diverticular bleeding (3) over a 6½‐year period: 43 high anterior resections, 17 Hartmann’s resections and seven low anterior resections. Diverticular fistulas were seen in 16 patients: colovaginal (7), colovesical (2), colo‐fallopian (4), entero‐colic (3). The median operation time was 110 min (45–195 min). There was one conversion to open surgery. Postoperative analgesia was provided by intravenous Paracetamol in 33 patients (50%), patient‐controlled analgesia in 24 (36%), oral Paracetamol and Oramorph (12%) and epidural opioid infusion (1.5%). The median time to normal diet was 24 h (4 h–6 days) and median hospital stay 5 days (2–30). There were two deaths (3.3%); anastomotic leak, ventricular fibrillation (VF) cardiac arrest. Other complications included: wound infection eight (12%), anastomotic leak four (8%), port‐site hernia one and one case of Clostridium difficile colitis requiring colectomy. There were five (7.5%) returns to theatre and two readmissions (3%).Conclusion  Laparoscopic resectional surgery in complicated diverticular disease is a feasible, safe and a largely predictable operation that allows for early hospital discharge and, in our opinion, improved patient care. We are encouraged to continue to offer our patients the option of an emergency laparoscopic resection.
Rectal cancer in young adults: a series of 102 patients at a tertiary care centre in India
Authors: Nath J. , Wigley C. , Keighley M. R. B. , Perakath B. 
Published: July 2008

AbstractObjective  Rectal cancer in young patients is uncommon. There is little information on rectal cancer in young adults in India. The aim of this study was to determine the relative incidence of rectal cancer in young patients in India and identify any differences in histological grade and pathological stage between younger and older cohorts.Method  All adult patients presenting at a tertiary colorectal unit with primary rectal adenocarcinoma between September 2003 and August 2007 were included. Patients were divided into two groups: 40 years and younger, and older than 40 years. Details regarding patient demographics, preoperative assessment, management and tumour grade and stage were obtained from a prospectively maintained database.Results  One hundred and two of 287 patients (35.5%) were 40 or younger at presentation. Younger patients were more likely to present with less favourable histological features (52.0%vs 20.5% (P < 0.001)) and low rectal tumours (63.0%vs 50.0%) (P = 0.043), but were equally likely to undergo curative surgery compared to the older group (P = 0.629). Younger patients undergoing surgery had a higher pathological T stage (T0–2 18.9%, T3 62.3%, T4 19.7%vs 34.5%, 56.0%, 9.5%) (P = 0.027) and more advanced pathological N stage (N0 31.1%, N1 41.0%, N2 27.9%vs 53.4%, 26.7%, 17.2%) (P = 0.014).Conclusion  The relative number of young patients with rectal cancer in this Indian series is higher than figures reported in western populations. The reasons for this are not clear. The histopathological features of rectal tumours in young patients in this study are consistent with similar studies in Western populations.
Lack of pancreatic body and tail in HNF1B mutation carriers
Authors: Haldorsen I. S. , Vesterhus M. , Ræder H. , Jensen D. K. , Søvik O. , Molven A. , Njølstad P. R. 
Published: July 2008

AbstractAims  Hepatocyte nuclear factor 1B (HNF1B) gene mutation carriers have a systemic disease characterized by congenital malformations in the urogenital tract, diabetes mellitus of maturity‐onset diabetes of the young type and dysfunction of the liver and exocrine pancreas. We aimed to investigate pancreatic structure and exocrine function in carriers of HNF1B mutations.Methods  We studied five subjects from two families with the previously reported mutation R137_K161del and the novel mutation F148L in HNF1B. All patients underwent computed tomography (CT) and magnetic resonance cholangiopancreatography (MRCP). We measured faecal elastase and serum vitamins D and E.Results  One of the mutation carriers reported abdominal symptoms. All five subjects had faecal elastase deficiency, three had vitamin D deficiency and two had vitamin E deficiency. Neither CT nor MRCP depicted tissue corresponding to the pancreatic body and tail in the five mutation carriers, indicating agenesis of the dorsal pancreas. The head of the pancreas was slightly atrophic but had normal X‐ray attenuation at CT in all patients.Conclusions  Agenesis of the pancreatic body and tail and pancreatic exocrine dysfunction are parts of the phenotype in HNF1B mutation carriers. This strengthens the evidence for a critical role of HNF1B in development and differentiation of at least the dorsal pancreas.
Ketoacidosis occurs in both Type 1 and Type 2 diabetes— a population‐based study from Northern Sweden
Authors: Wang Z. H. , Kihl‐Selstam E. , Eriksson J. W. 
Published: July 2008

AbstractAims  To determine the occurrence of diabetic ketoacidosis (DKA) in adult Type 2 and Type 1 diabetic patients in Northern Sweden and to determine whether DKA presents with a different clinical picture in Type 2 compared with Type 1 diabetic subjects.Methods  All adult patients from a hospital catchment area in Northern Sweden with diagnosed DKA episodes during 1997–2000 were included in a retrospective study. Medical records and laboratory reports were analysed.Results  During the years 1997 to 2000, the average annual incidence rate for DKA was 5.9 per 100 000 adult inhabitants. Twenty‐five patients developed DKA, eight (32%) had Type 2 diabetes, while 17 (68%) had Type 1 diabetes. Type 2 diabetic patients with DKA were older and had higher levels of C‐peptide than Type 1 diabetic patients. On admission because of DKA, a similar degree of hyperglycaemia was present in Type 1 and Type 2 patients. Metabolic acidosis was more severe in Type 1 compared with Type 2 diabetic patients. In 50% of the Type 2 diabetic patients, diabetes was diagnosed at the episode of DKA.Conclusions  DKA occurs in Caucasian Type 2 diabetic patients within a Swedish population. Although the frequency of DKA is much higher in Type 1 diabetic patients, Type 2 diabetes may account for as much as one‐third of the overall DKA cases.
New use of rosiglitazone decreased following publication of a meta‐analysis suggesting harm
Authors: Shah B. R. , Juurlink D. N. , Austin P. C. , Mamdani M. M. 
Published: July 2008

AbstractAims  It is uncertain whether meta‐analyses lead to changes in prescribing practices. We studied trends in the prescribing of glucose‐lowering therapy before and after the publication of a meta‐analysis suggesting harm from rosiglitazone.Methods  We examined the prescription records of all residents of Ontario, Canada, aged ≥ 66 years. For each week between January and December 2007, we identified new users of five categories of glucose‐lowering medications: rosiglitazone, pioglitazone, metformin, glibenclamide (glyburide) and insulin. The effect of the meta‐analysis was assessed using interventional autoregressive integrated moving‐average models.Results  Following the release of the meta‐analysis, there was a sudden decline in new users of rosiglitazone (P = 0.01), mirrored by a nearly identical but transient increase in new users of pioglitazone (P < 0.001). There was also a net decline in new users of thiazolidinediones as a class (P < 0.001). The number of new users of other glucose‐lowering medications did not change.Conclusions  A highly‐publicized meta‐analysis regarding rosiglitazone's potential harms led to an abrupt decline in new users of the drug, as well as a transient surge in new use of pioglitazone.