Podcasts about methods using

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.07.28.550867v1?rss=1 Authors: McIlroy, R. E., Barnett-Cowan, M. Abstract: Background: Vision can significantly impact both the perception and behaviour related to postural control. This study examines the influence of vision on the perception of postural instability onset. Previous research employing Temporal Order Judgment (TOJ) tasks to investigate the perceived timing of postural perturbation onset has not incorporated visual cues. Research question: Does the presence of visual feedback affect the point of subjective simultaneity (PSS) between postural perturbation onset and an auditory reference stimulus and does this additional sensory cue increase TOJ precision? Methods: Using a lean-and-release paradigm, 10 participants were exposed to postural perturbations in both eyes closed (EC) and eyes open (EO) conditions using a TOJ task where they indicated whether they perceived postural instability onset or sound onset as occurring first for each trial. Separate paired t-tests between EC and EO PSS and just noticeable difference (JND) values were used. One-sample t-tests were also used on PSS values for both conditions, comparing them to 0ms (true simultaneity). Results: The EC condition demonstrated a perceived delay of postural instability onset by 25.78 ms, while the EO condition showed a perceived delay of the auditory stimulus by 12.33 ms. However, no significant differences were found between the conditions or in comparison to true simultaneity. Mean JND values for EC (39.88 ms) and EO (46.48 ms) were not significantly different, suggesting visual information does not affect response precision for this task under these conditions. Significance: These findings indicate that visual information does not significantly affect the perception of postural instability onset. This suggests that visual information may play a limited role in the early perceptual stages of postural instability. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Title: ⏰ Synergy Traders #46.16: Real Trading Methods Using Harmonic Patterns + Classical Technical Analysis with Leslie Jouflas, CMT of TradingLiveOnline.com   Recorded on Tuesday, July 25th, 2023 as part of the Synergy Traders #46: "Derivatives 2023 Conference, Futures and Options Trading" event, hosted by TradeOutLoud and TimingResearch.   The full event video/podcast series and presentation notes are available here: https://timingresearch.com/blog/2023/synergy-traders-46-day-2/   Bonus... ⚡ eBook: "7 Risk Management Strategies: Top Traders Share Their Best Tips" https://timingresearch.com/LR3POD   Terms and Policies: https://timingresearch.com/policies/  

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.07.02.547427v1?rss=1 Authors: Zhao, K., Xie, H., Fonzo, G. A., Carlisle, N., Osorio, R. S., Zhang, Y. Abstract: BACKGROUND: Dementia is highly heterogeneous, with pronounced individual differences in neuropsychiatric symptoms (NPS) and neuroimaging findings. Understanding the heterogeneity of NPS and associated brain abnormalities is essential for effective management and treatment of dementia. METHODS: Using large-scale neuroimaging data from the Open Access Series of Imaging Studies (OASIS-3), we conducted a multivariate sparse canonical correlation analysis to identify functional connectivity-informed symptom dimensions. Subsequently, we performed a clustering analysis on the obtained latent connectivity profiles to reveal neurophysiological subtypes and examined differences in abnormal connectivity and phenotypic profiles between subtypes. RESULTS: We identified two reliable neuropsychiatric subsyndromes: behavioral and anxiety in the connectivity-NPS linked latent space. The behavioral subsyndrome was characterized by the connections predominantly involving the default mode and somatomotor networks and neuropsychiatric symptoms involving nighttime behavior disturbance, agitation, and apathy. The anxiety subsyndrome was mainly contributed by connections involving the visual network and the anxiety neuropsychiatric symptom. By clustering individuals along these two subsyndromes-linked connectivity latent features, we uncovered three subtypes encompassing both dementia patients and healthy controls. Dementia in one subtype exhibited similar brain connectivity and cognitive-behavior patterns to healthy individuals. However, dementia in the other two subtypes showed different dysfunctional connectivity profiles involving the default mode, frontoparietal control, somatomotor, and ventral attention networks, compared to healthy individuals. These dysfunctional connectivity patterns were associated with differences in baseline dementia severity and longitudinal progression of cognitive impairment and behavioral dysfunction. CONCLUSIONS: Our findings shed valuable insights into disentangling the neuropsychiatric and brain functional heterogeneity of dementia, offering a promising avenue to improve clinical management and facilitate the development of timely and targeted interventions for dementia patients. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.04.11.536217v1?rss=1 Authors: Chou, S., Fish, K. N., Lewis, D. A., Sweet, R. A. Abstract: Background: Individuals with schizophrenia are at elevated genetic risks for comorbid cannabis use, and often experience exacerbations of cognitive and psychotic symptoms when exposed to cannabis. These findings have led a number of investigators to examine cannabinoid CB1 receptor (CB1R) alterations in schizophrenia, though with conflicting results. We recently demonstrated the presence of CB1R in both excitatory and inhibitory boutons in the human prefrontal cortex, with differential levels of the receptor between bouton types. We hypothesized that the differential enrichment of CB1R between bouton types - a factor previously unaccounted for when examining CB1R changes in schizophrenia - may resolve prior discrepant reports and increase our insight into the effects of CB1R alterations on the pathophysiology of schizophrenia. Methods: Using co-labeling immunohistochemistry and fluorescent microscopy, we examined total CB1R levels and CB1R levels within excitatory (vGlut1-positive) and inhibitory (vGAT-positive) boutons of prefrontal cortex samples from ten pairs of individuals diagnosed with schizophrenia and non-psychiatric comparisons. Results: Significantly higher total CB1R levels were found within samples from individuals with schizophrenia. Terminal type-specific analyses identified significantly higher CB1R levels within excitatory boutons in samples from individuals with schizophrenia relative to comparisons. In contrast, CB1R levels within the subset of inhibitory boutons that normally express high CB1R levels (presumptive cholecystokinin neuron boutons) were lower in samples from individuals with schizophrenia relative to comparison samples. Conclusion: Given CB1Rs role in suppressing neurotransmission upon activation, these results suggest an overall shift in excitatory and inhibitory balance regulation toward a net reduction of excitatory activity in schizophrenia. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

HTTP (Hypertext Transfer Protocol) is a protocol used for communication between web clients (such as web browsers) and web servers. HTTP methods are the actions that can be performed on resources identified by URLs (Uniform Resource Locators) in HTTP requests. #https #http #httpinjector #httpclient #httpcustom #http_custom #httpcustom #infosectrain #HTTPmethods #cloudcomputing #cybersecurity #infosectrain Thank you for watching this video, For more details or free demo with out expert write into us at sales@infosectrain.com ➡️ Agenda for the Webinar

https://psychiatry.dev/wp-content/uploads/speaker/post-12144.mp3?cb=1677996406.mp3 Playback speed: 0.8x 1x 1.3x 1.6x 2x Download: Cognitive Remediation Works But How Should We Provide It? An Adaptive Randomized Controlled Trial of Delivery Methods Using a Patient NominatedFull EntryCognitive Remediation Works But How Should We Provide It? An Adaptive Randomized Controlled Trial of Delivery Methods Using a Patient Nominated Recovery Outcome in First-Episode Participants –

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.12.28.522119v1?rss=1 Authors: Philippi, S. M., BP, K., Raj, T., Castellano, J. M. Abstract: Background: Processes that drive Alzheimer's disease pathogenesis have long been considered to occur within the central nervous system, yet recent studies have bolstered the possibility that changes in the periphery may be relevant to the disease process. Accumulating evidence has suggested that proteins changing in the blood may be reliable indicators of disease within the brain. Recent advances in geroscience have identified potential mechanisms of blood-brain communication that modulate brain function in ways that could be harnessed for therapy. While blood-borne proteins associated with either youth or old age have been targeted to restore function to the aged brain, it remains unclear whether other dysfunctional systemic states can be exploited for similar benefits. Here we investigate whether APOE allelic variation or presence of brain amyloid are associated with distinct proteomic changes within the systemic environment and what molecular processes are associated with these changes. Methods: Using the SOMAscan assay, we measured 1,305 plasma proteins from 53 homozygous APOE3 and APOE4 subjects (mean age = 68 years; minimum = 54 years) who exhibited no cognitive impairment, some of whom can be categorized as harboring cerebral amyloid based on cerebrospinal fluid A{beta}42 measurements. Using the Dream R package for linear mixed effects modeling, we investigated possible contributions of either the APOE-{epsilon}4 allele or amyloid positivity to changes in the plasma proteome. Ontology-based pathway and module trait correlation analyses were performed to understand disrupted pathways that vary based on APOE genotype or amyloid positivity. Results: We found that expression of the APOE-{epsilon}4 allele produced distinct changes in the composition of the plasma proteome. Using both pathway enrichment analysis and weighted gene co-expression network analysis, we found that plasma proteins associated with APOE4 expression were linked to pathways related to atherosclerosis, lipid transport, the extracellular matrix, and synaptogenesis signaling. Independent of APOE4, we found that cognitively normal, amyloid-positive subjects exhibit distinct plasma proteome signatures associated with pathways previously linked to AD pathology, relative to amyloid-negative controls. Harboring brain amyloid was associated with plasma proteomic changes linked to dysfunction in blood-brain barrier and other neural cell types. Our results indicate that changes in the plasma proteome are related to possession of AD risk alleles, as well as the presence of amyloid pathology in subjects prior to the onset of symptoms. This work highlights the possibility that pathways in the systemic environment in certain risk contexts may be plausible targets to explore for modulating disease. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.11.15.516629v1?rss=1 Authors: Qi, W., Fang, Z., Luo, C., Hong, H., Long, Y., Dai, Z., Liu, J., Zeng, Y., Zhou, T., Xia, Y., Yang, X., Gao, G. Abstract: Objective: Non-alcoholic fatty liver disease (NAFLD), characterized by hepatic steatosis, is one of the most common causes of liver dysfunction. ATGL is closely related to hepatic steatosis as the speed-limited triacylglycerol lipase. Nevertheless, the expression and regulation of ATGL in NAFLD remain unclear. Methods: Using immunohistochemistry and qRT-PCR to detect the expression of ATGL and BTRC in different models with hepatic steatosis. Co-IP evaluated the binding of ATGL and BTRC. Knockdown of BTRC employed by adenoviruses and then analyzed the ATGL expression, triglyceride levels, and lipid droplets accumulation. Results: Our results revealed that ATGL protein level was decreased in animal and cellular models of hepatic steatosis and the liver tissues of cholangioma/hepatic carcinoma patients with hepatic steatosis, while the ATGL mRNA level had hardly changed; which means the decreased ATGL mainly degraded through the proteasome pathway. BTRC was identified as the E3 ligase for ATGL, up-regulated, and negatively correlated with ATGL level. Moreover, adenovirus-mediated knockdown of BTRC ameliorated hepatic steatosis via up-regulating ATGL level. Conclusions: Our study demonstrates a crucial role of elevated BTRC in hepatic steatosis through promoting ATGL proteasomal degradation as a new ATGL E3 ligase and suggests BTRC may serve as a potential therapeutic target for NAFLD. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.11.04.514246v1?rss=1 Authors: Bea-Mascato, B., Giudice, G., Pinheiro-de-Sousa, I., Petsalaki, E., Valverde, D. Abstract: BACKGROUND: The primary cilium is a sensory organelle that extends from the plasma membrane. It plays a vital role in physiological and developmental processes by controlling different signalling pathways such as WNT, Sonic hedgehog (SHh), and transforming growth factor {beta} (TGF-{beta}). Ciliary dysfunction has been related to different pathologies such as Alstrom (ALMS) or Bardet-Biedl (BBS) syndrome. The leading cause of death in adults with these syndromes is chronic kidney disease (CKD), which is characterised by fibrotic and inflammatory processes often involving the TGF-{beta} pathway. METHODS: Using genomic editing with CRISPR-CAS9 and phosphoproteomics we have studied the TGF- {beta} signalling pathway in knockout (KO) models for ALMS1 and BBS1 genes. We have developed a network diffusion-based analysis pipeline to expand the data initially obtained and to be able to determinate which processes were deregulated in TGF-{beta} pathway. Finally, we have analysed protein-protein interactions to prioritise candidate genes in the regulation of the TGF-{beta} pathway in Alstrom and Bardet-Biedl syndrome. RESULTS: Analysis of differentially phosphorylated proteins identified 10 candidate proteins in the ALMS1 KO model and 41 in the BBS1 KO model. After network expansion using a random walk with a restart model, we were able to obtain processes related to TGF-{beta} signalling such as endocytosis in the case of ALMS1 or extracellular matrix regulation in BBS1. Protein interaction analyses demonstrated the involvement of CDC42 as a central protein in the interactome in ALMS1 and CDK2 in the case of BBS1. CONCLUSION: In conclusion, the depletion of ALMS1 and BBS1 affects the TGF-{beta} signalling pathway, conditioning the phosphorylation and activation of several proteins, including CDC42 in the case of ALMS1 and CDK2 in the case of BBS1. KEYWORDS: ALMS1, BBS1, ciliopathies, TGF-{beta}, phosphoproteomics, Alstrom syndrome, Bardet-Biedl syndrome. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Do you want to conceive naturally? Acupuncture as a treatment for infertility shows great results both in man and women. Acupuncture can be considered as successful treatment in restoring fertility in the patients, by improving the sperm quality and ovaries function and balancing the endocrine system and hormones. It is also important to understand what is going on in your own body and start BBT charting.    Dr. Beck Hoehn, a Los Angeles-based Board-Certified Acupuncturist & Herbalist. She is a fertility expert and specializes in fertility acupuncture and approaches pregnancy and fertility in a wholistic way using eastern medicine principles.   Over the last 7 years she has helped frustrated couples get pregnant, stay pregnant, and enjoy their dream family.    Dr. Hoehn developed a method called The Positive Pregnancy Project that begins in January where she will introduce women to Eastern medicine principles to not only support their fertility but to enhance their soon-to-be family lives.  Today on Discovering True health we are going to learn: A radical new way to get pregnant and healthy, and avoid the expensive IVF business How acupuncture can help with fertility and mitigate pregnancy symptoms The best way to prepare our bodies for conceiving a child as well as the types of things that can affect our fertility factor How to get started on getting pregnant and avoid the pitfalls of the IVF industry Why most apps out there for cycle and ovulation tracking do nor work and tips and techniques to conceive faster How can we enjoy a safe and healthy conception once pregnant   PLEASE SUPPORT our work. It takes time and effort to make these videos. Every little bit helps!  **To donate/tip our channel, below through our Paypal. Paypal Donation Link: https://www.paypal.com/donate/?hosted_button_id=6YECDNX33L4KQ   Contact Dr. Beck Hoehn: https://www.mightyriverwellness.com   The Positive Pregnancy Project which starts in January: https://mightyriver.kartra.com/page/af-thankyou   P.S. Whenever you're ready ... here are 2 ways I can help you START YOUR DREAM FAMILY:  Grab a free copy of my BOOK, THE GET PREGNANT GUIDE. It's the roadmap to timing your fertile window:  https://www.drbeckhoehn.com/get-pregnant-guide?r_done=1   2. In this webinar, I draw out THE POSITIVE PREGNANCY PROJECT and by the end of it you'll have A CLEAR ROADMAP SO YOU CAN GET PREGNANTWatch this FREE TRAINING where I show you why you aren't pregnant yet and what to do about it: https://www.drbeckhoehn.com/get-pregnant   Stay In Touch with Us! Instagram:   @DiscoveringTrueHealth Twitter:        @DTrueHealth  Facebook:   @discoveringtruhealth Rumble:      Discoveringtruehealth   Listen On:  Apple Podcast Spotify Watch On: YouTube   www.discoveringtruehealth.com     Medical disclaimer: Discovering True Health LLC does not provide medical advice. Discovering True Health and the content available on Discovering True Health's properties (discoveringtruehealth.com, YouTube, and other channels) do not provide a diagnosis or other recommendation for treatment and are not a substitute for the professional judgment of a healthcare professional in diagnosis and treatment of any person or animal. The determination of the need for medical services and the types of healthcare to be provided to a patient are decisions that should be made only by a physician or other licensed health care provider. Always seek the advice of a physician or other qualified healthcare provider with any questions you have regarding a medical condition.

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.10.31.514510v1?rss=1 Authors: Dervinis, M., Crunelli, V. Abstract: Aims: Recurrent network activity in corticothalamic circuits generates physiological and pathological EEG waves. Many computer models have simulated spike-and-wave discharges (SWDs), the EEG hallmark of absence seizures (ASs). However, these models either provided detailed simulated activity only in a selected territory (i.e. cortical or thalamic) or did not test whether their corticothalamic networks could reproduce the physiological activities that are generated by these circuits. Methods: Using a biophysical large-scale corticothalamic model that reproduces the full extent of EEG sleep waves, including sleep spindles, delta and slow ( less than 0.1 Hz) waves, here we investigated how single abnormalities in voltage- or transmitter-gated channels in the neocortex or thalamus lead to SWDs. Results: We found that a selective increase in the tonic {gamma}-aminobutyric acid type A receptor (GABA-A) inhibition of first order thalamocortical (TC) neurons or a selective decrease in cortical phasic GABA-A inhibition are sufficient to generate ~4 Hz SWDs (as in humans) that invariably start in neocortical territories. Decreasing the leak conductance of higher order TC neurons leads to ~7 Hz SWDs (as in rodent models) while maintaining sleep spindles at 7-14 Hz. Conclusion: By challenging key features of current mechanistic views, this simulated ictal corticothalamic activity provides novel understanding of ASs and makes key testable predictions. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

The guys run through what it means to be productive in Power BI. Is it output, learning, or solutions? How to estimate your work, how to stay productive (rolling average), and how to break down your work. What methods and tools are used? Get in touch: Send in your questions or topics you want us to discuss by tweeting to @PowerBITips with the hashtag #empMailbag or submit on the PowerBI.tips Podcast Page. Visit PowerBI.tips: https://powerbi.tips/ Watch the episodes live every Tuesday and Thursday morning at 730am CST on YouTube: https://www.youtube.com/powerbitips Subscribe on Spotify: https://open.spotify.com/show/230fp78XmHHRXTiYICRLVv Subscribe on Apple: https://podcasts.apple.com/us/podcast/explicit-measures-podcast/id1568944083‎ Follow Mike: https://www.linkedin.com/in/michaelcarlo/ Follow Seth: https://www.linkedin.com/in/seth-bauer/ Follow Tommy: https://www.linkedin.com/in/tommypuglia/

Title: ⏰ Synergy Traders #31.06: Out Of The Box Methods Using RSI with Leslie Jouflas of TradingLiveOnline.com   Recorded on July 20th, 2021 as part of the "Synergy Traders #31: Day 1, Favorite Indicators" event, hosted by TradeOutLoud and TimingResearch.   The full event video/podcast series and presentation notes are available here: https://timingresearch.com/blog/2021/synergy-traders-31-day-1-favorite-indicators/   Terms and Policies: https://timingresearch.com/policies/  

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.08.19.257113v1?rss=1 Authors: Treccani, G., Yigit, H., Lingner, T., Schleussner, V., Wennstrom, M., Herzog, D. P., Fricke, M., Wegener, G., Mittmann, T., Trotter, J., Muller, M. Abstract: Background: The detrimental effects of early adversity on brain development and adult mental health are well established. While studies have identified myelination processes and oligodendrocytes as targets of early adversity across species, knowledge about the precise molecular mechanisms and cell populations involved is still lacking. NG2+ cells are oligodendrocyte precursor cells with unique properties, as they form synapses with neurons, engage in cell-cell communication and respond to stress hormones. Methods: Using an established mouse model of early life stress (ELS) we performed cell-type specific molecular profiling in hippocampal NG2 cells at early postnatal and adult stages. To further dissect the impact of glucocorticoids on ELS-induced transcriptional changes, we integrated our data with available Chip-seq data on genomic binding sites of the glucocorticoid receptor (GR). The functional relevance of one candidate gene, Scn7a, was confirmed by electrophysiological recordings in hippocampal NG2 cells. Results: ELS specifically targeted the hippocampal NG2 cell transcriptome, and the molecular changes correlated with the ELS-induced increase of corticosterone. The overlap analysis with Chip-seq data on genomic binding sites of the GR revealed nine overlapping genes. Among those Scn7a, coding for a subunit of sodium channels, remained upregulated until adulthood in ELS animals. Upregulation of Scn7a was accompanied by an increase in the density of voltage-gated sodium channel activated currents in hippocampal NG2 cells. Conclusions: Our findings indicate that ELS specifically targets the transcriptional profiles and electrophysiological properties of hippocampal NG2 glia. Considering that voltage-gated sodium channels are important for the NG2 cell-to-neuron communication, our findings may provide novel insights into the pathophysiological processes underlying stress related mental disorders. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.07.29.220350v1?rss=1 Authors: Bass, J. S., Tuo, A., Ton, L., Jankovic, M., Kapadia, P. P., Schirmer, C., Krishnan, V. Abstract: Objective: Antiepileptic drugs (AEDs) require daily ingestion for maximal seizure prophylaxis. Adverse psychiatric consequences of AEDs present as: (i) reversible changes in mood, anger, anxiety and/or irritability that often necessitate drug discontinuation, and (ii) autism and/or cognitive/psychomotor developmental delays following fetal exposure. Technical advances in quantifying naturalistic rodent behaviors may provide sensitive preclinical estimates of AED psychiatric tolerability and neuropsychiatric teratogenicity. Methods: Using instrumented home-cage monitoring, we assessed how valproic acid (VPA, dissolved in sweetened drinking water) alters home-cage behavior in adult C57BL/6J mice and in the adult offspring of VPA-exposed breeder pairs. By utilizing a pup open field assay, we also examined how prenatal VPA exposure impacts early spontaneous exploratory behavior. Results: At 500-600mg/kg/d, chronic VPA produced hyperphagia and increased wheel-running without impacting sleep, activity and measures of risk aversion. When applied chronically to breeder pairs of mice, VPA prolonged the latency to viable litters without affecting litter size. Two-week old VPA-exposed pups displayed open field hypoactivity without alterations in thigmotaxis. As adults, prenatal VPA-exposed mice displayed active state fragmentation, hypophagia and increased wheel running, together with subtle alterations in home-cage dyadic behavior. Interpretation: Through automated home-cage assessments of C57BL/6J mice, we capture an ethologically centered psychopharmacological profile of enterally administered VPA that is aligned with human clinical experience. By characterizing the effects of pangestational VPA exposure, we discover novel murine expressions of pervasive neurodevelopment. Incorporating rigorous comprehensive assessments of neuropsychiatric tolerability may inform the design of future AEDs with improved neuropsychiatric safety profiles, both for patients and their offspring. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.07.23.218446v1?rss=1 Authors: He, L., Bhat, K., Ioannidis, A., ZHANG, L., Nguyen, N. T., Allen, J. E., Nghiemphu, P. L., Cloughesy, T. F., Liau, L. M., Kornblum, H. I., Pajonk, F. Abstract: Background: Glioblastoma (GBM) is the deadliest of all brain cancers in adults. The current standard-of-care is surgery followed by radiotherapy and temozolomide, leading to a median survival time of only 15 months. GBM are organized hierarchically with a small number of glioma-initiating cells, responsible for therapy resistance and tumor recurrence, suggesting that targeting glioma-initiating cells could improve treatment response. ONC201 is a first-in-class anti-tumor agent with clinical efficacy in some forms of high-grade gliomas. Here we test its efficacy against GBM in combination with radiation. Methods: Using patient-derived GBM lines and mouse models of GBM we test the effects of radiation and ONC201 on GBM self - renewal in vitro and survival in vivo. A possible resistance mechanism is investigated using RNA-Sequencing. Results: Treatment of GBM cells with ONC201 reduced self-renewal, clonogenicity and cell viability in vitro. ONC201 exhibited anti-tumor effects on radioresistant GBM cells indicated by reduced self-renewal in secondary and tertiary glioma spheres. Combined treatment with ONC201 and radiation prolonged survival in syngeneic and patient-derived orthotopic xenograft mouse models of GBM. Subsequent transcriptome analyses after combined treatment revealed shifts in gene expression signatures related to quiescent GBM populations, GBM plasticity, and GBM stem cells. Conclusions: Our findings suggest that combined treatment with the DRD2/3 antagonist ONC201 and radiation improves the efficacy of radiation against GBM in vitro and in vivo through suppression of GICs without increasing toxicity in mouse models of GBM. A clinical assessment of this novel combination therapy against GBM is further warranted. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.07.16.207449v1?rss=1 Authors: Brown, A., Wieben, M., Murdock, S., Chang, J., Dizon, M., Dorsky, R. M., Fung, C. M. Abstract: Background: Children born with intrauterine growth restriction (IUGR) are at increased risk for cognitive impairment including learning and memory deficits. Dentate gyrus (DG) granule neurons relay cortical information into the hippocampus proper for memory formation, and their production is highly dependent on environmental signals. However, it is unknown whether IUGR affects DG neurogenesis, and thus provides a potential mechanism underlying abnormal learning and memory function. Methods: Using a hypertensive disease of pregnancy mouse model of IUGR, we assessed multiple behaviors, quantified neural stem and progenitor cells (NSPCs) and developing neurons in the DG, and characterized transcriptional effects on molecular pathways in the hippocampus. Results: We found that the predominant behavioral phenotype in IUGR offspring, short-term implicit learning and memory deficits, was associated with accelerated DG neurogenesis and NSPC depletion. Consistent with known molecular regulators of DG neurogenesis, we also found strong evidence for decreased Wnt pathway activity following IUGR. Conclusion: We have discovered that postnatal memory deficits are associated with accelerated NSPC differentiation following IUGR, a phenotype that could be explained by decreased Wnt signaling. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.04.28.065086v1?rss=1 Authors: Karcher, N., Michelini, G., Kotov, R., Barch, D. Abstract: Background: Previous research from the Adolescent Brain Cognitive Development (ABCD) study delineated and validated a hierarchical 5-factor structure with a general psychopathology (p) factor at the apex and five specific factors (internalizing, somatoform, detachment, neurodevelopmental, externalizing) using parent-reported child symptoms. The current study is the first examining associations between dimensions from a hierarchical structure and resting state functional connectivity (RSFC) networks. Methods: Using 9-11-year-old children from the ABCD baseline sample, we compared the variance explained by each hierarchy level (p factor, 2-factor, 3-factor, 4-factor, and 5-factor models) in RSFC. Analyses were first conducted in a discovery dataset (n=3790) with significant associations examined in a replication dataset (n=3791). Results: The current study found associations between p factor and lower connectivity within default mode network (DMN), although stronger effects emerged for the neurodevelopmental factor. Neurodevelopmental impairments were related to variation in RSFC networks associated with attention to internal states and external stimuli. These networks included within DMN, DMN with cingulo-opercular (CON) and Other (Unassigned) networks, CON with ventral attention and Other network, and dorsal attention with Other network. Results held when accounting for parental psychopathology. Conclusion: The hierarchical structure of psychopathology showed replicable links to RSFC alterations in middle childhood. The p factor had minimal association with altered connectivity, while the specific neurodevelopmental dimension showed robust associations with multiple RSFC impairments. Results show the utility of examining associations between intrinsic brain architecture and specific dimensions of psychopathology, revealing associations specifically with neurodevelopmental impairments. Copy rights belong to original authors. Visit the link for more info

Bitte beachten Sie auch immer den aktuellen "Haftungsausschluss (Disclaimer) und allgemeiner Hinweis zu medizinischen Themen" auf https://paleolowcarb.de/haftungsausschluss/ #geNUSS[explosion] von [næhr:sinn] - das low carb knusper nuss müsli [næhr:sinn] geNUSS[explosion] ist ein hochwertiges low-carb* Müsli und besteht zu 100% aus natürlichen Zutaten. Es ist gut als Frühstück und Snack und hat nur 13,7g verwertbaren Kohlenhydraten auf 100g. Es ist getreidefrei und sojafrei. Perfekt für den Start in den Tag. Wir verarbeiten nur hochwertigste, nährstoffreiche Zutaten, die dich länger satt machen und nachhaltig mit Energie versorgen. Wir nutzen ballaststoffreiche Kokosnuss, Erdmandel und heimische Nüsse. Mehr darüber erfährst du auf lowcarbmüsli.at oder auf Amazon.de In Folge #096 Wie viel Veränderung kann man in nur 4 Tagen erreichen? Sehr viel, schaut man sich die Studie von Sportwissenschaftler und Paleo-Experte Jens Freese an. Er hat im Rahmen seiner Doktorarbeit 28 Teilnehmer, für 4 Tage in die Natur geschickt und sie nach paleolithischem Vorbild leben lassen. Die Ergebnisse waren beeindruckend. Signifikante Veränderungen in wichtigen Gesundheitsparametern wie Blutzucker, Insulin, Körperfett und Blutfettwerten. Jens Freese erzählt in diesem Interview mehr über die Studie selbst, den Ablauf, die Ergebnisse und welche Herausforderungen die Durchführung einer solchen Studie mit sich bringt. Das Video der aktuellen Folge direkt auf Youtube öffnen Und nicht vergessen: Wenn du uns auf Youtube siehst, und wenn du es noch nicht getan hast, dann abonniere unseren Kanal „Evolution Radio Show“ Wenn du das Podcast hörst, dann findest du die Links für Apple iTunes und Android hier auf unserer Homepage Kurze Zusammenfassung Jens Freese ist Sportwissenschaftler und Psychoneuroimmunologe und zählt zu den führenden Experten des Paleo Lifestyle im deutschsprachigen Raum. Der Kölner kann auf eine über 15-jährigen Lehrtätigkeit als wissenschaftlicher Leiter der Deutschen Trainer Akademie zurückblicken, in der er mehr als 6000 Trainer in diversen Fitness- und Gesundheitsbereichen ausgebildet hat. Neben all dem, setzt er sich auch leidenschaftlich für wissenschaftliche Fragestellungen ein. Er war Mitglied einer Forschungsgruppe an der Universität Essen-Duisburg, die den Einfluss von Sport auf die Prävention von Alzheimer untersucht hat. Mit seiner aktuellen Forschungsgruppe, am Institut für Natursport und Ökologie der Deutschen Sporthochschule Köln, untersucht er die Auswirkungen einer steinzeitlich-orientierten Lebensweise auf die Prävention moderner Zivilisationserkrankungen. Jens Freese hat auch die Marke "Paleo Leben" gegründet und bietet dort eine Ausbildung zum Paleo-Coach an. Paleo Leben - Ausbildung zum Paleo-Coach http://www.paleo-leben.de/ Journal of Evolution and Health To Restore Health, “Do we Have to Go Back to the Future?” The Impact of a 4-Day Paleolithic Lifestyle Change on Human Metabolism – a Pilot Study ##Abstract On their way from the Stone Age via the Agricultural Revolution to current high-tech conditions, humans lost their primal foraging behavior. Today, energy expenditure is not necessary anymore for gathering nor hunting, and metabolic diseases are epidemically arising wherever our original Paleolithic lifestyle is turning into a modern sedentary lifestyle. In this pilot study, we followed through the concept that a radical change towards a Paleolithic hunter-gatherer lifestyle could serve as therapy against any metaflammatory disease, even in the short term. Thirteen healthy adult volunteers were transferred to the DELUX National Park (Germany and Luxembourg) for four days and three nights, where Stone Age conditions where mimicked. Thirty-eight biochemical and bioelectrical parameters were measured from participants before and after this relocation. Body weight (-3,9%), body fat (-7,5%), body mass index (-3,8%), visceral fat area (-14,4%) and metaflammation-related parameters (fasting glucose = -18,2%; fasting insulin = -50,1%; HOMA = -57,8%) decreased significantly. C-reactive protein, as the main indicator for low-grade inflammation, increased up to an average of 169,6 %. Our data show that returning to our Paleolithic roots may have positive effects on risk factors commonly associated with metabolic disorders, such as obesity and type 2 diabetes. These findings may lead the way to further research to answer the question whether the already existing metabolic conditions and/or autoimmune and neuroinflammatory diseases could be influenced by a Paleolithic lifestyle Back to the Future. Metabolic Effects of a 4-Day Outdoor Trip Under Simulated Paleolithic Conditions – New Insights from The Eifel Study ##Abstract Background: The observation that the emergence of common Western diseases takes place with much greater prevalence as societies migrate from natural-living cultures to modernized societies, has been well documented. For approximately 84,000 generations humans lived under hunter-gatherer conditions but recently endured dramatic change from our native lifestyle with the occurrence of the agricultural, industrial, and digital revolutions. The massive technological advancement that occurred within a relatively recent timeframe enabled humans to live in manner that is remarkably different than our pre-agricultural past. Consequently, the shift from a natural to a modern lifestyle likely promotes a gene-environment mismatch which causes metabolic dysregulation which causes disease. Methods: Using a within-participant design, we examined whether, compared to baseline, changes in lifestyle towards a more Paleolithic-style pattern, for a four-day and four-night period related to changes in a variety of metabolic parameters. Two groups of 14 volunteers were isolated for a period of four days and four nights in the natural park Südeifel on the borders between Germany and Luxembourg. Participants lived outdoors without tents. The daily hiking performance was 16.4 km (≈ 24963 steps/day) and the daily activity time 5.49 h/day by a mean caloric intake of 1747 kcal/day. Results: After four days of simulated Paleolithic conditions, body weight (-2.9%), body mass index (-2.7%), body fat (-10.4%), visceral fat (-13.6%) and waist-hip-ratio (-2.2%) significantly decreased, while muscle mass significantly increased (+2,3%). Additionally, fasting glucose (-6.5%), basal insulin (-44.4%), homeostasis model assessment-index (-49.3%) and fatty liver index (-41%) significantly dropped. In contrast, C-reactive protein, significantly increased (+67.1%). Conclusion: Our study indicates that a short nature trip, where modern humans adjust their behavioral patterns to simulate a more Paleolithic-like condition, could serve as an effective strategy to help prevent or improve modern metabolic disease. Particularly, the major findings of an expeditious reduction of homeostasis model assessment-index and fatty liver index scores in only four days reveal the potential for meaningful benefits with such an intervention, even when compared to the effects of longer-term, singleintervention studies such as dietary or fitness programs on similar metabolic parameters. Webseiten Jens Freese | (auf Facebook folgen) Paleo Low Carb - JULIAS BLOG | (auf Facebook folgen) Superhumanoid - PAWELS BLOG Super | (auf Facebook folgen)

Background: Multiple myeloma is characterized by clonal expansion of B cells producing monoclonal immunoglobulins or fragments thereof, which can be detected in the serum and/or urine and are ideal target antigens for patient-specific immunotherapies. Methods: Using phage particles as immunological carriers, we employed a novel chemically linked idiotype vaccine in a clinical phase I/II trial including 15 patients with advanced multiple myeloma. Vaccines composed of purified paraproteins linked to phage were manufactured successfully for each patient. Patients received six intradermal immunizations with phage idiotype vaccines in three different dose groups. Results: Phage idiotype was well tolerated by all study participants. A subset of patients (80% in the middle dose group) displayed a clinical response indicated by decrease or stabilization of paraprotein levels. Patients exhibiting a clinical response to phage vaccines also raised idiotype-specific immunoglobulins. Induction of a cellular immune response was demonstrated by a cytotoxicity assay and delayed type hypersensitivity tests. Conclusion: We present a simple, time-and cost-efficient phage idiotype vaccination strategy, which represents a safe and feasible patient-specific therapy for patients with advanced multiple myeloma and produced promising anti-tumor activity in a subset of patients.

Background: Metabolomics helps to identify links between environmental exposures and intermediate biomarkers of disturbed pathways. We previously reported variations in phosphatidylcholines in male smokers compared with non-smokers in a cross-sectional pilot study with a small sample size, but knowledge of the reversibility of smoking effects on metabolite profiles is limited. Here, we extend our metabolomics study with a large prospective study including female smokers and quitters. Methods: Using targeted metabolomics approach, we quantified 140 metabolite concentrations for 1,241 fasting serum samples in the population-based Cooperative Health Research in the Region of Augsburg (KORA) human cohort at two time points: baseline survey conducted between 1999 and 2001 and follow-up after seven years. Metabolite profiles were compared among groups of current smokers, former smokers and never smokers, and were further assessed for their reversibility after smoking cessation. Changes in metabolite concentrations from baseline to the follow-up were investigated in a longitudinal analysis comparing current smokers, never smokers and smoking quitters, who were current smokers at baseline but former smokers by the time of follow-up. In addition, we constructed protein-metabolite networks with smoking-related genes and metabolites. Results: We identified 21 smoking-related metabolites in the baseline investigation (18 in men and six in women, with three overlaps) enriched in amino acid and lipid pathways, which were significantly different between current smokers and never smokers. Moreover, 19 out of the 21 metabolites were found to be reversible in former smokers. In the follow-up study, 13 reversible metabolites in men were measured, of which 10 were confirmed to be reversible in male quitters. Protein-metabolite networks are proposed to explain the consistent reversibility of smoking effects on metabolites. Conclusions: We showed that smoking-related changes in human serum metabolites are reversible after smoking cessation, consistent with the known cardiovascular risk reduction. The metabolites identified may serve as potential biomarkers to evaluate the status of smoking cessation and characterize smoking-related diseases.

Background: Re-irradiation is a reasonable second treatment option for patients with recurrent malignant glioma (MG) after previous radio(chemo) therapy. However, only limited data is available allowing for a precise selection of patients suitable for re-treatment in regard to safety and efficacy. Methods: Using the department database, 58 patients with two courses of percutaneous radiation were identified. Besides classical dose-volume histogram (DVH) parameters equivalent uniform dose (EUD) values were calculated for the tumor and organs at risk (OARs), retrospectively analyzed and correlated to survival outcome parameters. Cumulative EUD values were also calculated in all cases where previous OAR DVHs were available. Results: Median follow-up was 265 days and no relevant toxicity was observed after re-irradiation in our patient cohort during follow-up. Time interval between first and second irradiation was regularly above 6 months. As a conservative estimation of the cumulative EUD to the OARs, the EUDs of first and second irradiation were added. Median cumulative EUD to the optic chiasm was 48.8 Gy (range, 2.5-76.5 Gy), 57.4 Gy (range, 2.7-75.3 Gy) to the brainstem, 20.9/22.1 Gy (range, 0.0-68.3 Gy) to the right/left optic nerve and 73.8 Gy (range, 64.9-77.3 Gy) to the brain. No correlation between treated volume and survival was seen. Conclusions: This study provides retrospective estimates on cumulative doses at the OARs. EUD values are derived and may serve as reference for further studies, including planning studies where specific constraints are needed.

Background: Nepal has made substantial progress in reducing under-five mortality and is on track to achieve Millennium Development Goal 4, but advances in neonatal health are less encouraging. The objectives of this study were to assess relative and absolute inequalities in neonatal mortality over time, and to review experience with major programs to promote neonatal health. Methods: Using four nationally representative surveys conducted in 1996, 2001, 2006 and 2011, we calculated neonatal mortality rates for Nepal and for population groups based on child sex, geographical and socio-economic variables using a true cohort log probability approach. Inequalities based on different variables and years were assessed using rate differences (rd) and rate ratios (rr); time trends in neonatal mortality were measured using the annual rate of reduction. Through literature searches and expert consultation, information on Nepalese policies and programs implemented since 1990 and directly or indirectly attempting to reduce neonatal mortality was compiled. Data on timeline, coverage and effectiveness were extracted for major programs. Results: The annual rate of reduction for neonatal mortality between 1996 and 2011 (2.8 percent per annum) greatly lags behind the achievements in under-five and infant mortality, and varies across population groups. For the year 2011, stark absolute and relative inequalities in neonatal mortality exist in relation to wealth status (rd = 21.4, rr = 2.2); these are less pronounced for other measures of socio-economic status, child sex and urban-rural residence, ecological and development region. Among many efforts to promote child and maternal health, three established programs and two pilot programs emerged as particularly relevant to reducing neonatal mortality. While these were designed based on national and international evidence, information about coverage of different population groups and effectiveness is limited. Conclusion: Neonatal mortality varies greatly by socio-demographic variables. This study clearly shows that much remains to be achieved in terms of reducing neonatal mortality across different socio-economic, ethnic and geographical population groups in Nepal. In moving forward it will be important to scale up programs of proven effectiveness, conduct in-depth evaluation of promising new approaches, target unreached and hard-to-reach populations, and maximize use of financial and personnel resources through integration across programs.

Tue, 17 Jul 2012 12:00:00 +0100 https://edoc.ub.uni-muenchen.de/16114/ https://edoc.ub.uni-muenchen.de/16114/1/Kuegel_Wolfgang.pdf Kügel, Wolfgang ddc:540, ddc:500, Fakultät für C

Background: Little is known as to how health-related quality of life (HRQoL) when measured by generic instruments such as EQ-5D differ across smokers, ex-smokers and never-smokers in the general population; whether the overall pattern of this difference remain consistent in each domain of HRQoL; and what implications this variation, if any, would have for economic evaluations of tobacco control interventions. Methods: Using the 2006 round of Health Survey for England data (n = 13,241), this paper aims to examine the impact of smoking status on health-related quality of life in English population. Depending upon the nature of the EQ-5D data (i.e. tariff or domains), linear or logistic regression models were fitted to control for biology, clinical conditions, socio-economic background and lifestyle factors that an individual may have regardless of their smoking status. Age-and gender-specific predicted values according to smoking status are offered as the potential `utility' values to be used in future economic evaluation models. Results: The observed difference of 0.1100 in EQ-5D scores between never-smokers (0.8839) and heavy-smokers (0.7739) reduced to 0.0516 after adjusting for biological, clinical, lifestyle and socioeconomic conditions. Heavy-smokers, when compared with never-smokers, were significantly more likely to report some/severe problems in all five domains - mobility (67%), self-care (70%), usual activity (42%), pain/discomfort (46%) and anxiety/depression (86%) -. `Utility' values by age and gender for each category of smoking are provided to be used in the future economic evaluations. Conclusion: Smoking is significantly and negatively associated with health-related quality of life in English general population and the magnitude of this association is determined by the number of cigarettes smoked. The varying degree of this association, captured through instruments such as EQ-5D, may need to be fed into the design of future economic evaluations where the intervention being evaluated affects (e. g. tobacco control) or is affected (e. g. treatment for lung cancer) by individual's (or patients') smoking status.

Background: During the last 5 years a fundamental curriculum reform was realized at the medical school of the Ludwig Maximilians University. In contrast to those efforts, the learning objectives were not defined consistently for the curriculum and important questions concerning the curriculum could not be answered. This also applied to Occupational and Environmental Medicine where teachers of both courses were faced with additional problems such as the low number of students attending the lectures. The aims of the study were to develop and analyse a curriculum map for Occupational and Environmental Medicine based on learning objectives using a web-based database. Furthermore we aimed to evaluate student perception about the curricular structure. Methods: Using a web-based learning objectives database, a curriculum map for Occupational and Environmental Medicine was developed and analysed. Additionally online evaluations of students for each course were conducted. Results: The results show a discrepancy between the taught and the assessed curriculum. For both curricula, we identified that several learning objectives were not covered in the curriculum. There were overlaps with other content domains and redundancies within both curricula. 53% of the students in Occupational Medicine and 43% in Environmental Medicine stated that there is a lack of information regarding the learning objectives of the curriculum. Conclusions: The results of the curriculum mapping and the poor evaluation results for the courses suggest a need for re-structuring both curricula.

Background: Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease characterised by accumulation of activated (myo)fibroblasts and excessive extracellular matrix deposition. The enhanced accumulation of (myo)fibroblasts may be attributed, in part, to the process of transforming growth factor textgreekb1 (TGFtextgreekb1)-induced epithelial--mesenchymal transition (EMT), the phenotypic switching of epithelial to fibroblast-like cells. Although alveolar epithelial type II (ATII) cells have been shown to undergo EMT, the precise mediators and mechanisms remain to be resolved. The objective of this study is to investigate the role of SNAI transcription factors in the process of EMT and in IPF.Methods: Using quantitative reverse transcription-PCR (RT-PCR), immunofluorescence, immunohistochemistry, western blotting, as well as gain- and loss-of-function studies and functional assays, the role of SNAI1 and SNAI2 in TGFtextgreekb1-induced EMT in ATII cells in vitro was assessed; and the expression of SNAI transcription factors was analysed in experimental and human IPF in vivo.Results: TGFtextgreekb1 treatment increased the expression and nuclear accumulation of SNAI1 and SNAI2, in concert with induction of EMT in ATII cells. SNAI overexpression was sufficient to induce EMT, and small interfering RNA (siRNA)-mediated SNAI depletion attenuated TGFtextgreekb1-induced ATII cell migration and EMT. SNAI expression was elevated in experimental and human IPF and localised to hyperplastic ATII cells in vivo.Conclusions: The results demonstrate that TGFtextgreekb1-induced EMT in ATII cells is essentially controlled by the expression and nuclear translocation of SNAI transcription factors. Increased SNAI1 and SNAI2 expression in experimental and human IPF in vivo suggests that SNAI-mediated EMT may contribute to the fibroblast pool in idiopathic pulmonary fibrosis.

Objective: There is overwhelming evidence that activation of the hypothalamic-pituitary-adrenal (HPA) system plays a major role in depression and cardiovascular disease in genetically susceptible individuals. We hypothesized that due to the multiple interactions between the sympathetic and the HPA systems via adrenoceptors, polymorphisms in these genes could have an impact on HPA axis activity in major depression. Methods: Using the dexamethasone/corticotrophin-releasing hormone (DEX/CRH) test, we investigated the association of alpha 2-adrenoceptor (ADRA2A -1291C -> G) and the beta 2-adrenoceptor gene (ADRB2 Arg16Gly) in 189 patients with major depression during the acute state of the disease and after remission. Results: Male ADRA2A -1291G allele homozygotes showed significant pretreatment HPA axis hyperactivity, with increased adrenocorticotropin (ACTH; F = 4.9, d.f. = 2, p = 0.009) and cortisol responses (F = 6.4, d.f. = 2, p = 0.003). In contrast, female ADRB2 Arg/Arg homozygotes had increased pretreatment ACTH (F = 7.17, d.f. = 2, p = 0.001) and cortisol (F = 8.95, d.f. = 2, p = 0.000) levels. Interestingly, in the respective genotypes, the stress hormones remained elevated in the second DEX/CRH test, despite a reduction in depressive symptoms. Conclusions: This study provides evidence that, depending on gender and polymorphisms, there is continuous HPA axis overdrive in a proportion of patients irrespective of the status of depression. Considering the importance of stress hormones for cardiovascular disorders, our data might suggest that these patients are at high risk of comorbidity between depression and cardiovascular disorders. Copyright (c) 2008 S. Karger AG, Basel

Background: Liquid chromatography tandem-mass spectrometry (LC-MS/MS) is an efficient technology for routine determination of immunosuppressants in whole blood; however, time-consuming manual sample preparation remains a significant limitation of this technique. Methods: Using a commercially available robotic pipetting system (Tecan Freedom EVO), we developed an automated sample-preparation protocol for quantification of tacrolimus in whole blood by LC-MS/MS. Barcode reading, sample resuspension, transfer of whole blood aliquots into a deep-well plate, addition of internal standard solution, mixing, and protein precipitation by addition of an organic solvent is performed by the robotic system. After centrifugation of the plate, the deproteinized supernatants are submitted to on-line solid phase extraction, using column switching prior to LC-MS/MS analysis. The only manual actions within the entire process are decapping of the tubes, and transfer of the deep-well plate from the robotic system to a centrifuge and finally to the HPLC autosampler. Whole blood pools were used to assess the reproducibility of the entire analytical system for measuring tacrolimus concentrations. Results: A total coefficient of variation of 1.7% was found for the entire automated analytical process (n=40; mean tacrolimus concentration, 5.3 mu g/L). Close agreement between tacrolimus results obtained after manual and automated sample preparation was observed. Conclusions: The analytical system described here, comprising automated protein precipitation, on-line solid phase extraction and LC-MS/MS analysis, is convenient and precise, and minimizes hands-on time and the risk of mistakes in the quantification of whole blood immunosuppressant concentrations compared to conventional methods.

Background/Aims: The expression of transporters involved in bile acid homeostasis is differentially regulated during obstructive cholestasis. Since the drug efflux transporter breast cancer resistance protein (BCRP) is known to transport bile acids, we investigated whether duodenal BCRP expression could be altered during cholestasis. Methods: Using real-time RT-PCR analysis we determined mRNA expression levels in duodenal tissue of 19 cholestatic patients. Expression levels were compared to 14 healthy subjects. BCRP protein staining was determined in biopsies of 6 cholestatic and 6 healthy subjects by immunohistochemistry. Results: We found that in patients with obstructive cholestasis mean duodenal BCRP mRNA levels were significantly reduced to 53% and mean protein staining was reduced to 57%. Conclusions: BCRP, a transporter for bile acids and numerous drugs, appears to be down-regulated in the human duodenum during cholestasis. The clinical impact of these results has to be investigated in further studies. Copyright (c) 2006 S. Karger AG, Basel.

Background/Aims: Pharmacological and morphological studies suggest that the gut mucosal immune system and local neuropeptide-containing neurones interact. We aimed to determine whether gut immune cells are targets for calcitonin gene-related peptide (CGRP), which has potent immune regulatory properties. Methods: Using density gradient centrifugation, rat lamina propria mononuclear cells (LP-MNCs) and intra-epithelial lymphocytes (IELs) were isolated. RT-PCR was employed for the detection of mRNA of rat calcitonin receptor-like receptor (CRLR), which is considered to represent the pharmacologically defined CGRP receptor-1 subtype, as well as mRNA of the receptor activity-modifying proteins, which are essential for CRLR function and determine ligand specificity. A radioreceptor assay was employed for the detection of specific CGRP binding sites. Results: RT-PCR and DNA sequencing showed that LP-MNCs and IELs express CRLR. Incubation of isolated LP-MNCs with radiolabelled alphaCGRP revealed the existence of specific binding sites for CGRP. Conclusion: These novel data indicate that mucosal immune cells of the rat gut are a target for CGRP and provide significant evidence that CGRP functions as an immune regulator in the gut mucosa. Copyright (C) 2002 S. Karger AG, Basel.