julilili42/papers huggingface dataset:
Cytomegalovirus seropositivity is associated with glucose regulation in the oldest old. Results from the Leiden 85-plus Study
2012-08-28

Abstract Background Cytomegalovirus (CMV) infection has been reported to contribute to the pathogenesis of type 1 diabetes and post-transplantation diabetes. However, CMV infection has not been evaluated as a possible risk factor for type 2 diabetes. Our aim was to investigate potential associations between CMV seropositivity, CMV IgG antibody level and glucose regulation in the oldest old. Results CMV seropositive subjects were more likely to have type 2 diabetes (17.2% vs 7.9%, p = 0.016), had a higher level of HbA1c (p = 0.014) and higher non-fasting glucose (p = 0.024) in the oldest olds. These associations remained significant after adjustment for possible confounders. CMV IgG antibody level was not significantly associated with glucose regulation (all p &gt; 0.05). Conclusions In the oldest old, CMV seropositivity is significantly associated with various indicators of glucose regulation. This finding suggests that CMV infection might be a risk factor for the development of type 2 diabetes in the elderly.
Impairment of GLP1 ‐induced insulin secretion: role of genetic background, insulin resistance and hyperglycaemia
2012-08-28

One major risk factor of type 2 diabetes is the impairment of glucose‐induced insulin secretion which is mediated by the individual genetic background and environmental factors. In addition to impairment of glucose‐induced insulin secretion, impaired glucagon‐like peptide ( GLP )1‐induced insulin secretion has been identified to be present in subjects with diabetes and impaired glucose tolerance, but little is known about its fundamental mechanisms. The state of GLP1 resistance is probably an important mechanism explaining the reduced incretin effect observed in type 2 diabetes. In this review, we address methods that can be used for the measurement of insulin secretion in response to GLP1 in humans, and studies showing that specific diabetes risk genes are associated with resistance of the secretory function of the β‐cell in response to GLP1 administration. Furthermore, we discuss other factors that are associated with impaired GLP1 ‐induced insulin secretion, for example, insulin resistance. Finally, we provide evidence that hyperglycaemia per se , the genetic background and their interaction result in the development of GLP1 resistance of the β‐cell. We speculate that the response or the non‐response to therapy with GLP1 analogues and/or dipeptidyl peptidase‐4 ( DPP‐IV ) inhibitors is critically dependent on GLP1 resistance.
Quinocetone triggers oxidative stress and induces cytotoxicity and genotoxicity in human peripheral lymphocytes of both genders
2012-08-28

Abstract Background Quinocetone has been widely used as an animal growth promoter in China. However, available data showed that QCT has potential genotoxicity. This study was conducted to investigate the cytotoxicity and genotoxicity of QCT in human lymphocytes. Results CCK ‐8 assay demonstrated the severe inhibitory effects by QCT in a dose‐ and time‐dependent manner. DNA damage analysis using alkalic Comet assay revealed a pronounced increase of DNA fragmentation in cells. In contrast, DNA damage was significantly decreased after incubation with S9 mix. This finding demonstrated that the intermediate metabolites of this drug exerted lower genotoxicity than its parent drugs. We further described chromosomal damage induced by this drug employing cytokinesis‐block micronucleus assay. The micronucleus frequency was significantly increased in quinocetone groups as compared to controls. Similar to the observation in Comet assay, incorporation of S9 mix in the cytokinesis‐block micronucleus assay could markedly alleviate the chromosomal damage. Moreover, QCT could invoke increase of reactive oxygen species generation in cells. Intriguingly, the toxicity of QCT was more prominent in samples from males than those from females under the same conditions. Conclusion QCT could induce potential cytotoxicity and genotoxicity in human lymphocytes.
Towards motivation-based adaptation of difficulty in e-learning programs
2012-08-28

&lt;span&gt;The objective of this study was to investigate if an e-learning environment may use measurements of the user's current motivation to adapt the level of task difficulty for more effective learning. In the reported study, motivation-based adaptation was applied randomly to collect a wide range of data for different adaptations in a variety of motivational states. This data was then utilised to extract rules for an adequate motivation-based adaptation to maximise expected learning success. A learning classifier system was used for the data analysis, generating rules for suitable and unsuitable adaptations based on current user motivation data. We extracted a set of twelve rules which suggest particular adaptation strategies based on real-world data. These rules could generally be embedded into existing psychological theories, namely the Zone of Proximal Development and the Yerkes-Dodson Law. In future research, we intend to evaluate these rules on further studies and develop concrete sets of adaptation strategies based on user motivation measurements.&lt;/span&gt;
Role of K ATP channels in β‐cell resistance to oxidative stress
2012-08-28

The importance of K ATP channels in stimulus‐secretion coupling of β‐cells is well established, although they are not indispensable for the maintenance of glycaemic control. This review article depicts a new role for K ATP channels by showing that genetic or pharmacological ablation of these channels protects β‐cells against oxidative stress. Increased production of oxidants is a crucial factor in the pathogenesis of type 2 diabetes mellitus ( T2DM ). T2DM develops when β‐cells can no longer compensate for the high demand of insulin resulting from excess fuel intake. Instead β‐cells start to secrete less insulin and β‐cell mass is diminished by apoptosis. Both, reduction of insulin secretion and β‐cell mass induced by oxidative stress, are prevented by deletion or inhibition of K ATP channels. These findings may open up new insights into the early treatment of T2DM .
Homeostatic metaplasticity of corticospinal excitatory and intracortical inhibitory neural circuits in human motor cortex
2012-08-29

Key points Homeostatic metaplasticity is an important mechanism for maintaining overall synaptic weight of a neuronal network in the physiological range. Homeostatic metaplasticity has been demonstrated, so far largely exclusively, for excitatory synaptic neurotransmission. New non‐invasive transcranial magnetic theta burst stimulation (TBS) experiments at the systems level of human motor cortex demonstrate for the first time that homeostatic metaplasticity is also present in inhibitory intracortical circuits. In addition, manipulation of intracortical inhibition by priming TBS contributes to the homeostatic regulation of metaplasticity in the corticospinal excitatory pathway. Findings are important for therapeutic applications of non‐invasive brain stimulation that aim at correcting excitatory or inhibitory neurotransmission outside the physiological range in humans with neuropsychiatric disorders. Abstract Homeostatic metaplasticity, a fundamental principle for maintaining overall synaptic weight in the physiological range in neuronal networks, was demonstrated at the cellular and systems level predominantly for excitatory synaptic neurotransmission. Although inhibitory networks are crucial for regulating excitability, it is largely unknown to what extent homeostatic metaplasticity of inhibition also exists. Here, we employed intermittent and continuous transcranial magnetic theta burst stimulation (iTBS, cTBS) of the primary motor cortex in healthy subjects for induction of long‐term potentiation (LTP)‐like and long‐term depression (LTD)‐like plasticity. We studied metaplasticity by testing the interactions of priming TBS with LTP/LTD‐like plasticity induced by subsequent test TBS. Changes in excitatory neurotransmission were measured by the input–output curve of motor‐evoked potentials (IO‐MEP), and changes in GABA A ergic inhibitory neurotransmission by the IO of short‐interval intracortical inhibition (IO‐SICI, four conditioning stimulus intensities of 70–100% active motor threshold, interstimulus interval 2.0 ms). Non‐primed iTBS increased IO‐MEP, while non‐primed cTBS decreased IO‐MEP. Pairing of identical protocols (iTBS→iTBS, cTBS→cTBS) resulted in suppression of the non‐primed TBS effects on IO‐MEP, and pairing of different protocols (cTBS→iTBS, iTBS→cTBS) enhanced the test TBS effects on IO‐MEP. While non‐primed TBS did not result in significant changes of IO‐SICI, iTBS→iTBS resulted in IO‐SICI decrease, and cTBS→cTBS in IO‐SICI increase compared with the non‐primed conditions. The changes in SICI induced by priming TBS correlated with the changes in MEP induced by subsequent test TBS. Findings demonstrate that plasticity in both excitatory and inhibitory circuits in the human motor cortex are regulated by homeostatic metaplasticity, and that priming effects on inhibition contribute to the homeostatic regulation of metaplasticity in excitatory circuits.
Randomized, double‐blind, placebo‐controlled study of safety and efficacy of miltefosine in antihistamine‐resistant chronic spontaneous urticaria
2012-08-29

Abstract Background Chronic spontaneous urticaria (CSU), a mast cell‐driven condition, is debilitating, common, and hard to treat. Miltefosine, a lipid raft modulator, can inhibit mast cell responses in vivo . Objective To study the safety and efficacy of systemic miltefosine treatment in CSU patients resistant to standard‐dosed antihistamines. Methods In this investigator‐initiated multicentre, randomized, double‐blind, placebo‐controlled study, CSU patients were treated for 4 weeks with daily doses of up to 150‐mg miltefosine ( n = 47) or placebo ( n = 26). Disease activity was assessed using the urticaria activity score. Safety and tolerability of miltefosine were also assessed. Results After 4 weeks of treatment, Urticaria Activity Score (UAS7) levels were substantially more reduced in miltefosine‐treated patients (−6.3 vs. −3.5 in placebo‐treated patients; P = 0.05). Also, the number of weals, but not the intensity of pruritus, was significantly reduced in miltefosine‐treated patients vs. placebo‐treated patients ( P = 0.02). In general, adverse events were frequent in both groups (miltefosine: 88%, placebo: 65% of patients) but mostly mild to moderate in severity. We did not observe any serious adverse events. Conclusions The results of this study indicate that miltefosine is an effective and safe treatment option for CSU patients who do not respond to standard‐dosed antihistamines.
Synchronous spontaneous cerebrospinal fluid leaks in the nose and ear
2012-08-29

Abstract Objective: The majority of spontaneous cerebrospinal fluid leaks occur at the anterior skull base; few cases at the temporal bone have been described. There have been no previous reports of synchronous leaks at the anterior skull base and temporal bone in the same patient. Methods: Case report and brief review of management of spontaneous cerebrospinal fluid leaks in the nose and ear. Case report: A 34-year-old, pregnant woman presented with watery nasal discharge and unilateral middle-ear effusion. The nasal and ear secretions both proved to be cerebrospinal fluid. Radiological imaging showed defects in both the ethmoid roof and the mastoid roof (middle cranial fossa). These defects were surgically closed using duraplasties. Conclusion: A literature review indicated that this is the first reported case of synchronous spontaneous cerebrospinal fluid leaks via the anterior skull base and temporal bone.
P06 Olesoxime improves specific features of the HD pathology
2012-08-29

<h3>Background</h3> Olesoxime, a cholesterol-oxime, is a neuroprotective compound initially developed for the treatment of ALS (Bordet <i>et al</i> 2007). It interacts with proteins on the outer membrane of mitochondria (OMM) and inhibits the opening of the mitochondrial permeability transition pore (mPTP). Furthermore, it was found to accelerate oligodendrocyte maturation, thereby enhancing myelination (Magalon <i>et al</i> 2012). Since both mitochondrial function and myelination are impaired in HD (Lin &amp; Beal, 2006; Xiang <i>et al</i> 2010), we evaluated the effect of olesoxime on the behavioural and neuropathological phenotype of the BACHD rat. <h3>Methods</h3> BACHD rats and their wild type littermates were fed ad libitum with either an olesoxime-containing or a control diet beginning at 5 weeks of age (n=15/group). Behavioural observations were carried out during a 12 months study period and neuropathology and mitochondrial function were investigated subsequently (n=4–6/group). <h3>Results</h3> Olesoxime treatment improved the cognitive and psychiatric phenotype in BACHD rats, which might be associated with a reduced mhtt accumulation found in the prelimbic cortex that is involved in learning and emotionality. It further increased the width of axon bundles in the striatum, which was significantly decreased in BACHD rats compared to wild types, possibly due to an improved myelination. Olesoxime was further capable of restoring mitochondrial respiratory chain function, rescuing a deficit in the expression of OMM proteins and normalise mitochondrial membrane fluidity. <h3>Conclusions</h3> Olesoxime did not improve motor and metabolic function but it ameliorated the cognitive, psychiatric and mitochondrial pathology in the BACHD rat.
B12 The influence of kalirin-7 deficiency on the phenotype of YAC128 mice
2012-08-29

<h3>Background</h3> The guanine-nucleotide exchange factor kalirin is a key regulator of spine morphogenesis and important for synaptic function and glutamatergic transmission. <i>Kalirin-7</i>-knockout mice (Kal7KO) deficient for the most abundant isoform of <i>kalirin</i> in the adult brain show a decrease in hippocampal spine density and specific behavioural changes. In Huntington9s disease (HD) there is evidence for abnormalities in synaptic plasticity and transmission in several brain regions in patients and mouse models. These alterations are supposed to account for cognitive and motoric deficits in HD. <h3>Aims</h3> To analyse the interaction between Huntingtin and proteins involved in synaptic plasticity in vivo on a behavioural and molecular level we generated a mouse model lacking <i>kalirin-7 (Kal7)</i> while overexpressing the human <i>huntingtin (htt)</i> with 128 CAGs (YAC128). The YAC128 mice show motor deficits, cognitive impairment and a striatal degeneration reproducing symptoms of the human disease. <h3>Methods</h3> The Kal7KO-YAC128 mouse model was first analysed in a set of behavioural tests. Kal7KO-YAC128 mice were compared with littermates heterozygous for <i>htt</i> (YAC128), homozygous deficient for <i>Kal7</i> (Kal7KO) and wildtype controls. 13–15 males of each group were repeatedly tested from 4 to 15 months in Rotarod, Simple swimming test, Elevated plus maze (EPM) and the automated home cage system LabMaster (LM; TSE Systems). The influence of <i>kalirin-7</i> deficiency on the expression of mutant huntingtin, the glutamatergic NMDA receptor subunits NR1, NR2A and NR2B as well as on the level of synaptic proteins like PSD-95 were analysed by immunoblotting and immunohistochemistry in cortex, striatum and hippocampus. Moreover we examined in the same brain regions the morphology of neurons and the synaptic morphology by electron microscopy. <h3>Results</h3> The motoric deficit of the YAC128 was not changed by the Kalirin 7-deficiency. No significant difference in anxiety could be found between YAC128 and Kal7KO-YAC128. Results of the Simple swimming test and LM are still under analysis. First results of the biochemical analysis are going to be presented. <h3>Conclusions</h3> Preliminary results indicate that <i>kalirin-7</i> deletion does not influence the behavioural phenotype of YAC128 mice.
C05 A novel BACHD transgenic rat exhibits characteristic neuropathological features of Huntington disease
2012-08-29

<h3>Background</h3> Huntington disease (HD) is an inherited progressive neurodegenerative disorder, characterised by motor, cognitive and psychiatric deficits as well as neurodegeneration and brain atrophy beginning in the striatum and the cortex and extending to other subcortical brain regions. The genetic cause is an expansion of the CAG repeat stretch in the <i>HTT</i> gene encoding huntingtin protein (htt). <h3>Methods</h3> Here, we generated and characterised a HD transgenic rat model using a human bacterial artificial chromosome (BAC) which contains the full-length <i>HTT</i> genomic sequence with 97 CAG/CAA repeats and all regulatory elements. <h3>Results</h3> BACHD transgenic rats display a robust, early-onset and progressive HD-like phenotype including motor deficits and anxiety-related symptoms. The phenotype is characterised by striatal dysfunction associated with an imbalance in the striosome and matrix compartments in early stages of the disease. This was, in addition to reduced dopamine receptor binding, readily detectable by in vivo imaging. Neuropathologically, the distribution of neuropil aggregates and nuclear accumulations of N-terminal mutant huntingtin in BACHD rats is similar to that seen in HD patients. Neuropil aggregates in the sensorimotor circuit may be associated with motor dysfunction and aggregates in the limbic-based circuits could be related to anxiety changes and thus render this model suitable for the ongoing research in how these circuits are affected in HD. <h3>Conclusion</h3> Taken together, our data demonstrate that this transgenic BACHD rat line may be a valuable model for further understanding the disease mechanisms and for preclinical pharmacological studies.
C07 Skinner box test for strategy shifting impairments in BACHD rats
2012-08-29

<h3>Background</h3> The BACHD rat is a novel animal model of Huntington disease expressing the full-length human huntingtin gene with 97 CAG/CAA repeats. We are investigating whether these rats are impaired during strategy shifts, as this is common among Huntington disease patients. We have previously found that BACHD rats are impaired during reversal learning in the simple swimming test. <h3>Aims</h3> We aim at further characterising the phenotype found in the simple swimming test. <h3>Methods/techniques</h3> We compared BACHD and wild-type rats in a Skinner box test that used multiple shifts. The boxes contained two cue lights with associated levers placed on either side of a food crib. One of the cue lights, randomly picked, would shine during trials. Rats were initially trained to respond either on the lever situated below the shining cue light, or on the lever of a particular side regardless of whether the cue light above it shined or not. Rats from both groups where then trained on a reversal of the original setting and finally on a shift to the setting of the other group. <h3>Results/outcome</h3> All rats learnt the initial tasks at a similar rate. There was a trend indicating that BACHD rats were impaired during side reversal, while no differences were seen in the light reversal. BACHD rats were faster than wild-type rats at switching from side- to light-based strategy, while no differences where seen when the shift was made in the opposite direction. At certain steps, there were indications that BACHD rats were less motivated to work for the food reward. <h3>Conclusions</h3> The results are not conclusive and it is unclear if BACHD rats are impaired during reversals and strategy shifts. There are however indications of other relevant phenotypes, such as a lowered or more sensitive motivational state.
C06 Phenor: data exploration for automated homecage system
2012-08-29

<h3>Background</h3> Automated behavioural assessment is gaining a greater presence in the field of neurodegenerative disease research. It provides objectivity and a wide scope of uses in phenotyping but conversely presents difficulties due to the very advantages it presents: mainly, that the researcher is presented with a large amount of data which must be collated, prepared, explored and tested. Manual preparation of this data can also increase the risk of mistakes and thus decrease the reliability of results. <h3>Aims</h3> In order to facilitate the exploration and analysis of data produced by the Labmaster and Phenomaster automated homecage system (TSE Systems), we undertook to create a system that would aggregate and process the raw data produced, present the results in an intuitive and visual manner to aid discovery and provide some additional tools to facilitate data analysis. <h3>Methods</h3> The R Statistics software (R Development Core Team (2009)) was used to create a script to provide all the processing and analysis functions. For our analysis, we limited the variables analysed from the homecage output since not all are relevant or are coincide with the observations of other variables. Where inferential tests were applied, we used False Discovery Rate to adjust for multiple testing. The Manipulate package was used to give interactive functionality and the PLS package provided functions for partial least square regression. <h3>Outcome</h3> The script we generated was able to produce the necessary aggregation and reduction of data from the csv files containing raw Labmaster/Phenomaster data, automatically adjusting for occasions when the metabolic attachment was present. The amount of time necessary to prepare, graph and export data was greatly reduced, while facilitating exploration of the data by use of multivariate analysis. We illustrate the outcomes from this analysis method with results from different rodent models of HD and HD-like diseases and experiments.
C10 Generation and characterisation of a transgenic rat model of huntington's disease-like 4 (HDL4), also called spinocerebellar ataxia type 17 (SCA17)
2012-08-29

Huntington9s disease-like 4 (HDL4), also called spinocerebellar ataxia type 17, is an autosomal-dominant, late-onset neurodegenerative disorder caused by CAG repeat expansions in the TATA-box-binding protein (TBP), an ubiquitously expressed transcription factor. The clinical features of HDL4 closely resembled those of Huntington9s disease, including uncontrolled movements, emotional problems, and loss of thinking ability. To further investigate this devastating disease and additionally find a good model for treatment studies, we generated the first transgenic rat model of HDL4, which carries a full human cDNA fragment of the TBP gene with 64 CAG repeats under the control of the murine prion protein promoter (PrP-TBP64Q). In total we obtained ten positive founder animals, whereof only five transmitted the transgene. On the basis of the expression level of mutant TBP as well as the distribution of mutant TBP in the different brain regions we chose one of these five lines (line 8.4) for further characterisation. This line shows a strong expression of the mutant TBP protein in the cerebellum and a moderate expression in the olfactory bulb, brainstem and cortex. HDL4 rats showed an ataxia-like phenotype and impaired motor coordination and balance capabilities in the beam walking test. Additionally, HDL4 rats had a significantly lower body weight than their wildtype littermates and showed decreased activity. At the age of 10 months neuropathological changes, such as misshaped Purkinje cells, degenerated dendrites as well as missing basket and stellate neurons were observed in the cerebellum of heterozygous transgenic HDL4 rats compared to wildtype littermates. By electron microscopy we demonstrated dark cell degeneration as well as moderate fibre degeneration in the striatum. Moreover, we observed decreased levels of dopamine receptor (D<sub>2</sub>R) by performing PET imaging. Altogether the present data shows that this animal model exhibits symptoms which mimic well the human HDL4 phenotype indicating that this rat model will be of great value for further studies of pathomechanisms in Huntington9s disease-like 4 and for therapeutic trials.