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Best podcasts about methods to

Latest podcast episodes about methods to

PaperPlayer biorxiv neuroscience
Proteomics and phosphoproteomics profiling in glutamatergic neurons and microglia in an iPSC model of Jansen de Vries Syndrome

PaperPlayer biorxiv neuroscience

Play Episode Listen Later Jul 8, 2023


Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.07.08.548192v1?rss=1 Authors: Aguilan, J., Pedrosa, E., Dolstra, H., Nur Baykara, R., Barnes, J., Zhang, J., Sidoli, S., Lachman, H. Abstract: Background: Jansen de Vries Syndrome (JdVS) is a rare neurodevelopmental disorder (NDD) caused by gain-of-function (GOF) truncating mutations in PPM1D exons 5 or 6. PPM1D is a serine/threonine phosphatase that plays an important role in the DNA damage response (DDR) by negatively regulating TP53 (P53). JdVS-associated mutations lead to the formation of a truncated PPM1D protein that retains catalytic activity and has a GOF effect because of reduced degradation. Somatic PPM1D exons 5 and 6 truncating mutations are well-established factors in a number of cancers, due to excessive dephosphorylation and reduced function of P53 and other substrates involved in DDR. Children with JdVS have a variety of neurodevelopmental, psychiatric, and physical problems. In addition, a small fraction has acute neuropsychiatric decompensation apparently triggered by infection or severe non-infectious environmental stress factors. Methods: To understand the molecular basis of JdVS, we developed an induced pluripotent stem cell (iPSC) model system. iPSCs heterozygous for the truncating variant (PPM1D+/tr), were made from a patient, and control lines engineered using CRISPR-Cas9 gene editing. Proteomics and phosphoprotemics analyses were carried out on iPSC-derived glutamatergic neurons and microglia from three control and three PPM1D+/tr iPSC lines. We also analyzed the effect of the TLR4 agonist, lipopolysaccharide, to understand how activation of the innate immune system in microglia could account for acute behavioral decompensation. Results: One of the major findings was the downregulation of POGZ in unstimulated microglia. Since loss-of-function variants in the POGZ gene are well-known causes of autism spectrum disorder, the decrease in PPM1D+/tr microglia suggests this plays a role in the neurodevelopmental aspects of JdVS. In addition, neurons, baseline, and LPS-stimulated microglia show marked alterations in the expression of several E3 ubiquitin ligases, most notably UBR4, and regulators of innate immunity, chromatin structure, ErbB signaling, and splicing. In addition, pathway analysis points to overlap with neurodegenerative disorders. Limitations: Owing to the cost and labor-intensive nature of iPSC research, the sample size was small. Conclusions: Our findings provide insight into the molecular basis of JdVS and can be extrapolated to understand neuropsychiatric decompensation that occurs in subgroups of patients with ASD and other NDDs. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

PaperPlayer biorxiv neuroscience
Evidence for glutamate excitotoxicity that occurs before the onset of cell loss and motor symptoms in an ovine Huntington's Disease model.

PaperPlayer biorxiv neuroscience

Play Episode Listen Later Jun 24, 2023


Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.06.20.545648v1?rss=1 Authors: Jiang, A., Lehnert, K., You, L., Hawkins, V., Reid, S. J., Handley, R. R., Jacobsen, J. C., Patassini, S., Rudiger, S. R., McLaughlan, C. J., Kelly, J. M., Verma, P. J., Bawden, C. S., Gusella, J. F., MacDonald, M. E., Waldvogel, H. J., Faull, R. L. M., Snell, R. G. Abstract: Background Huntington's disease (HD) is a neurodegenerative genetic disorder caused by an expansion in the CAG repeat tract of the huntingtin (HTT) gene resulting in a triad of behavioural, cognitive, and motor defects. Current knowledge of disease pathogenesis remains incomplete, and no disease course modifying interventions are in clinical use. We have previously reported the development and characterisation of the OVT73 transgenic sheep model of HD. OVT73 captures an early prodromal phase of the disease with an absence of motor symptomatology even at 5-years of age and no detectable striatal cell loss. Methods To better understand the disease initiating events we have undertaken a single nuclei transcriptome study of the striatum of an extensively studied cohort of 5-year-old OVT73 HD sheep and age matched wild type controls. Results We have identified transcriptional upregulation from genes encoding N-methyl-D-aspartate (NMDA), -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and kainate receptors in OVT73 medium spiny neurons, the cell type preferentially lost early in the disease. This observation supports the glutamate excitotoxicity hypothesis as an early neurodegeneration cascade initiating process. Moreover, the downstream consequences of excitotoxicity including a downregulation of transcription of components for the oxidative phosphorylation complexes was also observed. We also found that pathways that have been proposed to act to reduce excitotoxicity including the activity of the CREB family of transcription factors (CREB1, ATF2, ATF4 and ATF7) were transcriptionally downregulated. Conclusions To our knowledge, the OVT73 model is the very first large mammalian HD model that exhibits transcriptomic signatures of an excitotoxic process that occurs in the absence of cell loss. Our results indicate that glutamate excitotoxicity is a disease initiating process. Addressing this biochemical defect early may prevent any cell loss and avoid the more complex secondary consequential challenges due to cell death. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

PaperPlayer biorxiv neuroscience
Amyloid fibril proteomics of AD brains reveals modifiers of aggregation and toxicity

PaperPlayer biorxiv neuroscience

Play Episode Listen Later Mar 3, 2023


Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.03.03.530975v1?rss=1 Authors: Upadhyay, A., Chhangani, D., Rao, N. R., Kofler, J., Vassar, R., Rincon-Limas, D. E., Savas, J. N. Abstract: Background: The accumulation of amyloid beta (Abeta) peptides in fibrils is prerequisite for Alzheimer's disease (AD). Our understanding of the proteins that promote Abeta fibril formation and mediate neurotoxicity has been limited due to technical challenges in isolating pure amyloid fibrils from brain extracts. Methods: To investigate how amyloid fibrils form and cause neurotoxicity in AD brain, we developed a robust biochemical strategy. We benchmarked the success of our purifications using electron microscopy, amyloid dyes, and a large panel of Abeta immunoassays. Tandem mass-spectrometry based proteomic analysis workflows provided quantitative measures of the amyloid fibril proteome. These methods allowed us to compare amyloid fibril composition from human AD brains, three amyloid mouse models, transgenic Abeta42 flies, and Abeta42 seeded cultured neurons. Results: Amyloid fibrils are primarily composed by Abeta42 and unexpectedly harbor Abeta38 but generally lack Abeta40 peptides. Multidimensional quantitative proteomics allowed us to redefine the fibril proteome by identifying 17 new amyloid-associated proteins. Notably, we confirmed 126 previously reported plaque-associated proteins. We validated a panel of these proteins as bona fide amyloid-interacting proteins using antibodies and orthogonal proteomic analysis. One metal-binding chaperone metallothionein-3 is tightly associated with amyloid fibrils and modulates fibril formation in vitro. Lastly, we used a transgenic Abeta42 fly model to test if knock down or over-expression of fibril-interacting gene homologues modifies neurotoxicity. Eight RNAi lines suppressed and 11 enhanced Abeta42 toxicity. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

PaperPlayer biorxiv neuroscience
Transcranial direct current stimulation elevates the baseline activity while sharpening the spatial tuning of the human visual cortex

PaperPlayer biorxiv neuroscience

Play Episode Listen Later Feb 8, 2023


Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.02.07.527461v1?rss=1 Authors: Ahn, J., Ryu, J., Lee, S., Lee, C., Im, C.-H., Lee, S.-H. Abstract: Background: Although transcranial direct current stimulation (tDCS) is widely used to affect various kinds of human cognition, behavioral studies on humans have produced highly inconsistent results. This requires a clear understanding of how tDCS impacts the system-level neural activity, a prerequisite for the principled application of tDCS to human cognition. Objective: Here, we aim to gain such understanding by probing the spatial and temporal cortical activity of the human early visual cortex (EVC) in diverse aspects while controlling the polarity and presence of tDCS. We target EVC to capitalize on its well-established anatomical and functional architecture that is readily accessible with non-invasive quantitative neuroimaging methods. Methods: To create an electric field in EVC precisely and effectively, we tailored high-definition stimulation montages for 15 individual brains by running electric field simulations. We then conducted an fMRI (functional magnetic neuroimaging)-tDCS experiment on each brain with a sham-controlled crossover design over multiple days. We quantified tDCS effects with eight measures, tested their significance with mixed ANOVA, and further validated their robustness to across-voxel and across-subject variability. Results: The anodal application of tDCS gradually elevated baseline BOLD activity of EVC and sharpened its spatial tuning by augmenting surround suppression without affecting its evoked activity. Conclusions: Comparisons of our and previous findings suggest the fundamental differences in tDCS effects between the visual and motor cortices, inhibitory and excitatory effects predominant in the former and latter, respectively. This calls for considering the differences in the excitatory-inhibitory recurrent network between brain regions in predicting or interpreting tDCS effects. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

PaperPlayer biorxiv neuroscience
Overlap in the cortical representation of hand and forearm muscles as assessed by navigated TMS

PaperPlayer biorxiv neuroscience

Play Episode Listen Later Jan 28, 2023


Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.01.27.525857v1?rss=1 Authors: Jin, F., Bruijn, S. M., Daffertshofer, A. Abstract: Background: The representation of upper limb muscles in the motor cortex is complex. It contains areas of excitability that may overlap between muscles. Objective/Hypothesis: We expected the cortical representations of synergistic muscle pairs to overlap more than those of non-synergistic muscles. Methods: To detail this, we used navigated transcranial magnetic stimulation in eight hand and forearm muscles of twenty healthy participants. We transformed the cortical representations of muscles to a template MRI to allow for group analysis. Results: We found that the amount of overlap in cortical representations differed significantly between within-hand and within-forearm muscle combinations. Most synergistic muscle pairs, both within the hand, within the forearm and between them, had a larger overlap than non-synergistic muscle pairs. Conclusions: Our study supports the largely overlapping nature of cortical representations of upper limb muscles. We can particularly underscore that the overlap is elevated in muscles that usually act in a synergistic manner. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

PaperPlayer biorxiv neuroscience
Protocol for mapping of the supplementary motor area using repetitive navigated transcranial magnetic stimulation

PaperPlayer biorxiv neuroscience

Play Episode Listen Later Jan 24, 2023


Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.01.23.525160v1?rss=1 Authors: Engelhardt, M. J., Kern, G., Karhu, J., Picht, T. Abstract: Background: Damage to the supplementary motor area (SMA) for example during surgery can lead to impairments of motor and language function. A detailed preoperative mapping of functional boarders of the SMA could therefore aid preoperative diagnostics in these patients. Objective: The aim of this study was the development of a repetitive nTMS protocol for non-invasive functional mapping of the SMA while assuring effects are indeed caused by SMA stimulation rather than activation of M1. Methods: To this purpose the SMA in the dominant hemisphere of twelve healthy subjects (28.2 +- 7.7 years, 6 females) was mapped using repetitive nTMS at 20 Hz (120% RMT), while subjects performed a finger tapping task. The location of induced errors was marked in each subjects individual MRI. To further validate the protocol, effects of SMA stimulation were directly compared to effects of M1 stimulation in four different tasks. Results: Mapping of the SMA was possible for all subjects, yet varying effect sizes were observed. Stimulation of the SMA led to a significant reduction of finger taps compared to baseline (BL: 45 taps, SMA: 35.5 taps; p less than 0.01). Line tracing, writing and targeting of circles was less accurate during SMA compared to M1 stimulation. Conclusion: Mapping of the SMA using repetitive nTMS is feasible. While errors induced in the SMA are not entirely independent of M1 due to the proximity of both regions, disruption of the SMA induces functionally distinct errors. These error maps can aid preoperative diagnostics in patients with SMA related lesions. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

PaperPlayer biorxiv neuroscience
Intragastric administration of low-dose rotenone post-colitis exacerbates damage to the nigrostriatal dopaminergic system in Parkinson's disease: The pace accelerates even more

PaperPlayer biorxiv neuroscience

Play Episode Listen Later Dec 22, 2022


Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.12.22.521569v1?rss=1 Authors: Sharma, N., Sharma, M., Thakkar, D., Kumar, H., Smetanova, S., Buresova, L., Andrla, P., Khairnar, A. Abstract: Background: The contribution of gastrointestinal (GI) inflammation and local exposure to neurotoxins in the gut offers the most in-depth explanation of Parkinson's disease (PD) etiopathogenesis through abnormal accumulation and spreading of alpha-synuclein (-syn) aggregates from the gut to the brain. Objectives: This study was designed to investigate whether dextran sodium sulfate (DSS)-mediated colitis may have lasting effects on dopaminergic pathways in the brain and whether or not colitis exacerbated susceptibility to later exposure to the neurotoxin rotenone. Methods: To induce chronic colitis, 10 months old C57BL/6 mice were pre-exposed to 3 cycles of 7 days of 1% (w/v) DSS administration in drinking water followed by 14 days of regular drinking water. After colitis-induction, animals received a low dose of intragastric rotenone for the next 8 weeks, followed by testing for Parkinsonian behavior and GI phenotypes of inflammation. At the end of the 8th week after colitis, colon, brain stem, and midbrain tissue were isolated and analyzed for -syn, inflammatory markers, and dopaminergic neuronal loss. Gut microbial composition was assessed by 16S rRNA sequencing analysis. Results: We found that local rotenone exposure for 8 weeks did not affect colitis severity and colonic tight junction (TJ) protein expression (ZO-1, Occludin, and Claudin-1). On the other hand, we found that while eight weeks of chronic rotenone administration led to an increase in inflammatory markers, the presence of pre-existing colitis resulted in a considerable change in gut microbiota composition and a decrease in TJ's protein expression. In addition, the administration of rotenone in mice post-colitis caused gastrointestinal function impairment and poor behavioral performances. Itworsened rotenone-induced -syn pathology in the colon, which extended upward and resulted in severe dopaminergic neuron loss and significant astroglia activation in the dorsal motor nucleus of the vagus (DMV), locus coeruleus, substantia nigra as well as in striatum. Interestingly, in the case of rotenone alone, we found that -syn induced ChAT+ neuronal death is restricted to the DMV. These findings indicate that long-term rotenone exposure in conjunction with early inflammatory intestinal milieu exacerbates the progression of -syn pathology and aggravates neurodegeneration in the intragastric mouse PD model. Conclusions: This work provides detailed insight into the involvement of GI inflammation triggered after a neurotoxic insult in the colon and explores their potential to impact central dopaminergic degeneration in PD. This way, we can identify potential therapeutic targets that stop the enteric inflammatory processes involved in progressing PD. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

PaperPlayer biorxiv cell biology
Effect of flavonoids hydroxygenkwanin on vascular smooth muscle cell proliferation, migration, and neointimal formation

PaperPlayer biorxiv cell biology

Play Episode Listen Later Dec 20, 2022


Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.12.20.521220v1?rss=1 Authors: Chen, C.-C., Lin, M.-S., Chen, P.-Y., Leu, Y.-L., Wang, S.-H. Abstract: Background: Restenosis and atherosclerosis are chronic inflammatory disease. Abnormal vascular smooth muscle cell (VSMC) proliferation and migration play crucial roles in neointimal hyperplasia and restenosis progression in response to stimulation with various inflammatory cytokines, such as platelet-derived growth factor-BB (PDGF-BB) and tumour necrosis factor- (TNF-). Hydroxygenkwanin (HGK) exerts remarkable anti-inflammatory, antitumour, antiproliferative and antimigratory effects. The aim of the study was to evaluate and elucidate the therapeutic effect and regulatory mechanism of HGK on neointimal hyperplasia. Methods: To determine the therapeutic effects of HGK in PDGF-BB- or TNF--treated VSMCs, MTT assays, Western blotting analysis, cell cycle analysis, BrdU incorporation assay, wound healing assay and adhesion assay were performed in vitro. A docking assay was also used to elucidate the mechanism underlying the regulatory effect of HGK. Histological and immunohistochemical staining of denuded femoral arteries was conducted to elucidate the therapeutic effect of HGK in an in vivo assay. Results: HGK inhibited the abnormal proliferation, migration, and inflammation of PDGF-BB-or TNF--treated VSMCs through regulation of the PDK1/AKT/mTOR pathway. In addition, HGK promoted circulating endothelial progenitor cell (EPC) chemotaxis. In an in vivo assay, HGK dramatically enhanced re-endothelization and reduced neointimal hyperplasia after femoral artery denudation with a guide wire in mice. Conclusions: In the present study, HGK decreased the PDGF-BB- or TNF--induced abnormal proliferation, migration and inflammation in VSMCs and improved re-endothelialization and neointimal hyperplasia in denuded femoral arteries. These results provide a novel potential treatment for restenosis in the future. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

PaperPlayer biorxiv neuroscience
Spontaneous activation of cortical somatosensory networks depresses their excitability in preterm human neonates

PaperPlayer biorxiv neuroscience

Play Episode Listen Later Dec 9, 2022


Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.12.08.519675v1?rss=1 Authors: Whitehead, K., Rupawala, M., Laudiano-Dray, M. P., Meek, J., Olhede, S., Fabrizi, L. Abstract: Introduction: The activity of the developing cortex is characteristically discontinuous where sudden high amplitude bursts interrupt periods of quiescent background. While the functional importance of this activity is clear, its aetiology is not known. Here, we hypothesise that this alternating pattern arises because of 'refractoriness' of cortical networks following spontaneous activation. Methods: To test this hypothesis, we assessed whether spontaneous activity in sensory networks depressed their excitability by measuring the impact of ongoing activity on the response to an external sensory stimulus. We recorded cortical activity before and after mechanical tactile stimulation of hands and feet in 35 preterm infants of median 32 weeks post-menstrual age. Results: Mechanical stimulation evoked wideband energy increases with two distinct peaks within the delta and alpha-beta band. The delta activity engaged extended cortical areas, while the faster activity engaged local somatotopically specific areas. By then characterising the spectro-spatial properties of the spontaneous activity preceding stimulation, we showed that baseline energy with a distribution and spectral profile similar to that of somatosensory-evoked activity dampened the energy changes elicited by touching the body. Discussion: Sensory-evoked activity in preterm human neonates likely represents the coordinated activation of extended (tangential) and local (e.g. columnar) cortical aggregates. The occurrence of spontaneous cortical events in the same cortical regions depresses their excitability preventing their immediate re-engagement. This 'refractoriness' offers the first etiological explanation to the cyclical burst-quiescence pattern typical of preterm cortical activity. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

PaperPlayer biorxiv neuroscience
Single-cell RNA-seq reveals alterations in peripheral CX3CR1 and nonclassical monocytes in familial tauopathy

PaperPlayer biorxiv neuroscience

Play Episode Listen Later Oct 30, 2022


Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.10.28.514304v1?rss=1 Authors: Sirkis, D. W., Warly Solsberg, C., Johnson, T. P., Bonham, L. W., Sturm, V. E., Lee, S. E., Rankin, K. P., Rosen, H. J., Boxer, A. L., Seeley, W. W., Miller, B. L., Geier, E. G., Yokoyama, J. S. Abstract: Background: Emerging evidence from mouse models is beginning to elucidate the brain's immune response to tau pathology, but little is known about the nature of this response in humans. In addition, it remains unclear to what extent tau pathology and the local inflammatory response within the brain influence the broader immune system. Methods: To address these questions, we performed single-cell RNA sequencing (scRNA-seq) of peripheral blood mononuclear cells (PBMCs) from carriers of pathogenic variants in MAPT, the gene encoding tau. Results: Analysis of ~181,000 individual PBMC transcriptomes from MAPT pathogenic variant carriers (n = 8) and healthy non-carrier controls (n = 8) demonstrated striking differential expression in monocytes and natural killer (NK) cells. We observed a marked reduction in the expression of CX3CR1 - the gene encoding the fractalkine receptor that is known to modulate tau pathology in mouse models - in monocytes and NK cells. We also observed a significant reduction in the abundance of nonclassical monocytes and dysregulated expression of nonclassical monocyte marker genes, including FCGR3A. Finally, we identified reductions in TMEM176A and TMEM176B, genes thought to be involved in the inflammatory response in human microglia. We confirmed differential expression of select biologically relevant genes dysregulated in our scRNA-seq data using droplet digital PCR as an orthogonal technique for quantitative validation. Conclusions: Our results suggest that human peripheral immune cell expression and abundance are modulated by tau-associated pathophysiologic changes. CX3CR1 and nonclassical monocytes in particular will be a focus of future work exploring the role of these peripheral signals in additional tau-associated neurodegenerative diseases. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

PaperPlayer biorxiv neuroscience
A Cre-Driver Rat Model for Anatomical and Functional Analysis of Glucagon (Gcg)-Expressing Cells in the Brain and Periphery

PaperPlayer biorxiv neuroscience

Play Episode Listen Later Oct 13, 2022


Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.10.10.511573v1?rss=1 Authors: Zheng, H., Lopez-Ferreras, L., Krieger, J.-P., Fasul, S., Cea Salazar, V., Valderrama Pena, N., Skibicka, K. P., Rinaman, L. Abstract: Objective: The glucagon gene (Gcg) encodes preproglucagon, which is cleaved to form glucagon-like peptide 1 (GLP1) and other mature signaling molecules implicated in metabolic functions. To date there are no transgenic rat models available for precise manipulation of GLP1-expressing cells in the brain and periphery. Methods: To visualize and manipulate Gcg-expressing cells in rats, CRISPR/Cas9 was used to express iCre under control of the Gcg promoter. Gcg-Cre rats were bred with tdTomato reporter rats to tag Gcg-expressing cells. Cre-dependent AAVs and RNAscope in situ hybridization were used to evaluate the specificity of iCre expression by GLP1 neurons in the caudal nucleus of the solitary tract (cNTS) and intermediate reticular nucleus (IRt), and by intestinal and pancreatic secretory cells. Food intake was assessed in heterozygous (Het) Gcg-Cre rats after chemogenetic stimulation of cNTS GLP1 neurons expressing an excitatory DREADD. Results: While genotype has minimal effect on body weight or composition in chow-fed Gcg-Cre rats, homozygous (Homo) rats have lower plasma glucose levels. In neonatal and adult Gcg-Cre/tdTom rats, reporter-labeled cells are present in the cNTS and IRt, and in additional brain regions (e.g., basolateral amygdala, piriform cortex) that lack detectable Gcg mRNA in adults but display transient developmental or persistently low Gcg expression. Compared to wildtype (WT) rats, hindbrain Gcg mRNA and GLP1 protein in brain and plasma are markedly reduced in Homo Gcg-Cre rats. Chemogenetic stimulation of cNTS GLP1 neurons reduced overnight chow intake in males but not females, the effect in males was blocked by antagonism of central GLP1 receptors, and hypophagia was enhanced when combined with a subthreshold dose of cholecystokinin-8 to stimulate gastrointestinal vagal afferents. Conclusions: Gcg-Cre rats are a novel and valuable experimental tool for analyzing the development, anatomy, and function of Gcg-expressing cells in the brain and periphery. In addition, Homo Gcg-Cre rats are a unique model for assessing the role of Gcg-encoded proteins in glucose homeostasis and energy metabolism. Copy rights belong to original authors. Visit the link for more info Podcast created by PaperPlayer

PaperPlayer biorxiv neuroscience
Quotidian Profile of Vergence Angle in Ambulatory Subjects Monitored with Wearable Eye Tracking Glasses

PaperPlayer biorxiv neuroscience

Play Episode Listen Later Sep 18, 2022


Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.09.14.506830v1?rss=1 Authors: Dilbeck, M. D., Gentry, T. N., Economides, J. R., Horton, J. C. Abstract: PURPOSE: Wearable tracking glasses record eye movements and fixations as ambulatory subjects navigate their environment. We tested the performance of eye tracking glasses under laboratory and real world conditions, to characterize the vergence behavior of normal individuals engaged in their customary daily pursuits. METHODS: To define the accuracy and variability of the eye tracking glasses, 4 subjects fixated with the head stabilized at a series of distances corresponding to vergence demands of: 0.25, 0.50, 1, 2, 4, 8, 16, and 32{degrees}. Then, 10 subjects wore the eye tracking glasses for prolonged periods while carrying out their normal activities. Vergence profiles were compiled for each subject and compared with interpupillary distance. RESULTS: In the laboratory the eye tracking glasses were comparable in accuracy to remote video eye trackers, outputting a mean vergence value within 1{degrees} of demand at all angles except 32{degrees}. In ambulatory subjects the glasses were less accurate, due to tracking interruptions and measurement errors, only partly mitigated by application of data filters. Nonetheless, a useful record of vergence behavior was obtained in every subject. Vergence angle often had a bimodal distribution, reflecting a preponderance of activities at near (mobile phone, computer) or far (driving, walking). Vergence angle was highly correlated with interpupillary distance. CONCLUSIONS: Wearable eye tracking glasses provide a history of vergence angle and the corresponding scene witnessed by ambulatory subjects. They offer insight into the diversity of human ocular motor behavior and may become useful for diagnosis of disorders that affect vergence, such as convergence insufficiency, Parkinson disease, and strabismus. Copy rights belong to original authors. Visit the link for more info Podcast created by PaperPlayer

PaperPlayer biorxiv neuroscience
A parabrachial-to-amygdala circuit that determines hemispheric lateralization of somatosensory processing

PaperPlayer biorxiv neuroscience

Play Episode Listen Later Sep 8, 2022


Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.09.06.506763v1?rss=1 Authors: Allen, H. N., Chaudhry, S., Hong, V. M., Lewter, L. A., Sinha, G. P., Carrasquillo, Y., Taylor, B., Kolber, B. J. Abstract: Background: The central amygdala (CeA) is a bilateral hub of pain and emotional processing with well-established functional lateralization. We reported that optogenetic manipulation of neural activity in the left and right CeA has opposing effects on bladder pain. Methods: To determine the influence of calcitonin gene-related peptide (CGRP) signaling from the parabrachial nucleus (PBN) on this diametrically opposed lateralization, we administered CGRP and evaluated the activity of CeA neurons in acute brain slices as well as the behavioral signs of bladder pain in the mouse. Results: We found that CGRP increased firing in both the right and left CeA neurons. Furthermore, we found that CGRP administration in the right CeA increased behavioral signs of bladder pain and decreased bladder pain-like behavior when administered in the left CeA. Conclusions: These studies reveal a parabrachial-to-amygdala circuit driven by opposing actions of CGRP that determines hemispheric lateralization of visceral pain. Copy rights belong to original authors. Visit the link for more info Podcast created by PaperPlayer

PaperPlayer biorxiv neuroscience
Human iPSC-derived astrocytes transplanted into the mouse brain display three morphological responses to amyloid-β plaques

PaperPlayer biorxiv neuroscience

Play Episode Listen Later Nov 20, 2020


Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.11.19.389023v1?rss=1 Authors: Preman, P., TCW, J., Calafate, S., Snellinx, A., Alfonso-Triguero, M., Corthout, N., Munck, S., Thal, D. R., Goate, A. M., De Strooper, B., Arranz, A. M. Abstract: Background: Increasing evidence for a direct contribution of astrocytes to neuroinflammatory and neurodegenerative processes causing Alzheimer's disease comes from molecular studies in rodent models. However, these models may not fully recapitulate human disease as human and rodent astrocytes differ considerably in morphology, functionality, and gene expression. Methods: To address these challenges, we established an approach to study human astroglia within the context of the mouse brain by transplanting human induced pluripotent stem cell (hiPSC)-derived glia progenitors into neonatal brains of immunodeficient mice. Results: Xenografted (hiPSC)-derived glia progenitors differentiate into astrocytes that integrate functionally within the mouse host brain and mature in a cell-autonomous way retaining human-specific morphologies, unique features and physiological properties. In Alzheimer's chimeric brains, transplanted hiPSC-derived astrocytes respond to the presence of amyloid plaques with various morphological changes that seem independent of the APOE allelic background. Conclusion: In sum, this chimeric model has great potential to analyze the role of patient-derived and genetically modified astroglia in Alzheimer's disease. Copy rights belong to original authors. Visit the link for more info

PaperPlayer biorxiv bioinformatics
Design and implementation of an intelligent framework for supporting evidence-based treatment recommendations in precision oncology

PaperPlayer biorxiv bioinformatics

Play Episode Listen Later Nov 17, 2020


Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.11.15.383448v1?rss=1 Authors: Lin, F. P. Abstract: BACKGROUND: The advances in genome sequencing technologies have provided new opportunities for delivering targeted therapy to patients with advanced cancer. However, these high-throughput assays have also created a multitude of challenges for oncologists in treatment selection, demanding a new approach to support decision-making in clinics. METHODS: To address this unmet need, this paper describes the design of a symbolic reasoning framework using the method of hierarchical task analysis. Based on this framework, an evidence-based treatment recommendation system was implemented for supporting decision-making based on a patient's clinicopathologic and biomarker profiles. RESULTS: This intelligent framework captures a six-step sequential decision process: (1) concept expansion by ontology matching, (2) evidence matching, (3) evidence grading and value-based prioritisation, (4) clinical hypothesis generation, (5) recommendation ranking, and (6) recommendation filtering. The importance of balancing evidence-based and hypothesis-driven treatment recommendations is also highlighted. Of note, tracking history of inference has emerged to be a critical step to allow rational prioritisation of recommendations. The concept of inference tracking also enables the derivation of a novel measure -- level of matching -- that helps to convey whether a treatment recommendation is drawn from incomplete knowledge during the reasoning process. CONCLUSIONS: This framework systematically encapsulates oncologist's treatment decision-making process. Further evaluations in prospective clinical studies are warranted to demonstrate how this computational pipeline can be integrated into oncology practice to improve outcomes. Copy rights belong to original authors. Visit the link for more info

PaperPlayer biorxiv bioinformatics
Differential gene expression in the interactome of the Human Dopamine transporter in the context of Parkinson's disease

PaperPlayer biorxiv bioinformatics

Play Episode Listen Later Oct 12, 2020


Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.10.12.336388v1?rss=1 Authors: NAVARRO, R. C., Ligia Scott, A., Allison Philot, E., Atencio, L., Fernandez Ponce, C., Aroca Martinez, G., Cadena Bonfanti, A., Gomez Escorcia, l., Navarro Quiroz, E. Abstract: Abstract: Background: The human dopamine transporter is the main regulator of dopamine tone and an intricate network exists to regulate the expression, conformation, and kinetics of the hDAT. hDAT dysfunction is directly related to Parkinson's disease. The objective of this work is to evaluate the differential gene expression in the interactome of the Dopamine transporter in the context of Parkinson's disease. Methods:To do this, we evaluated hDAT interaction data in string-db, mint.bio, IntAct, reactome, hprd and BioGRID, subsequently, data was obtained from the differential gene expression of mRNA and miRNAs for this hDAT interactome in the context of PD. Results: The analysis of the differential expression changes of genes of the hDAT interactome in tissues of patients with PD compared with tissues of individuals without PD, allowed to identify an expression pattern of 32 components of the hDAT interactome, of which 31 presented a negative change proportion in PD. Conclusions: We found a total of 90 miRNAs that could regulate the expression of 27 components of the hDAT interactome, at the same time, 39 components of the hDAT interactome may participate in 40 metabolic pathways. Together, these findings show a systematic effect on the hDAT-mediated dopamine internalization process in patients with Parkinson's, which would contribute to a greater susceptibility to neuronal oxidative stress in PD patients. Copy rights belong to original authors. Visit the link for more info

PaperPlayer biorxiv biochemistry
The Epidermal Barrier is Indispensable for Systemic Energy Homeostasis

PaperPlayer biorxiv biochemistry

Play Episode Listen Later Sep 3, 2020


Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.09.01.277723v1?rss=1 Authors: Neess, D., Kruse, V., Marcher, A.-B., Waede, M. R., Vistisen, J., Moeller, P. M., Petersen, R., Brewer, J. R., Ma, T., Colleluori, G., Severi, I., Cinti, S., Gerhart-Hines, Z., Mandrup, S., Faergeman, N. J. Abstract: Objectives: Homeostatic regulation of body temperature is fundamental to mammalian physiology and is controlled by acute and chronic responses of local, endocrine and neuronal regulators. Although the skin is the largest sensory organ of the human body, and plays a fundamental role in regulating body temperature, it is surprising that adaptive alterations in skin functions and morphology only vaguely have been associated with physiological responses to cold stress or sensation of ambient temperatures. Methods: To unravel the physiological responses to a compromised epidermal barrier in detail we have used animal models with either defects in skin lipid metabolism (ACBP-/- and skin-specific ACBP-/- knockout mice) or defects in skin structural proteins (ma/ma Flg ft/ft). The primary objective was to clarify how defects in epidermal barrier function affect 1) energy expenditure by indirect calorimetry, 2) response to high fat feeding and a high oral glucose load and 3) expression of brown-selective gene programs by quantitative PCR in inguinal WAT (iWAT). Results: We show that mice with a compromised epidermal barrier function exhibit increased energy expenditure, increased food intake, browning of the iWAT, and resistance to diet-induced obesity. The metabolic phenotype, including browning of the iWAT, is reversed by housing the mice at thermoneutrality (30C) or by pharmacological beta-adrenergic blocking. These findings show that a compromised epidermal barrier induces a beta-adrenergic response that increases energy expenditure and browning of the white adipose tissue to maintain a normal body temperature. Conclusion: Our findings show that the epidermal barrier plays a key role in maintaining systemic metabolic homeostasis. Copy rights belong to original authors. Visit the link for more info

PaperPlayer biorxiv genetics
Variants in RABL2A causing male infertility and ciliopathy

PaperPlayer biorxiv genetics

Play Episode Listen Later Aug 11, 2020


Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.08.11.246611v1?rss=1 Authors: Ding, X., Fragoza, R., Singh, P., Zhang, S., Yu, H., Schimenti, J. C. Abstract: Purpose: Approximately 7% of men suffer from infertility worldwide and sperm abnormalities are the major cause. Though genetic defects are thought to underlie a substantial fraction of all male infertility cases, the actual molecular bases are usually undetermined. Because the consequences of most genetic variants in populations are unknown, this complicates genetic diagnosis even after genome sequencing of patients. Some patients with ciliopathies, including primary ciliary dyskinesia (PCD) and Bardet-Biedl syndrome (BBS), also suffer from infertility because sperm flagella, which share several characteristics with cilia, are also affected in these patients. Methods: To identify infertility-causing genetic variants in human populations, we used in silico predictions to identify potentially deleterious SNP (single nucleotide polymorphism) alleles of RABL2A, a gene essential for normal cilia and flagella function. Candidate variants were assayed for protein stability in vitro, and the destabilizing variants were modeled in mice using CRISPR/Cas9-mediated genome editing. The resulting mice were characterized phenotypically for reproductive and developmental defects. Results: Two of the SNP alleles, Rabl2L119F (rs80006029) and Rabl2V158F (rs200121688), destabilized the protein. Mice bearing these alleles exhibited PCD- and BBS-associated disorders including male infertility, early growth retardation, excessive weight gain in adulthood, heterotaxia, pre-axial polydactyly, neural tube defects (NTD) and hydrocephalus. Conclusion: Our study identified and validated pathogenicity of two variants causing ciliopathies and male infertility in human populations, and identified phenotypes not previously described for null alleles of Rabl2. Copy rights belong to original authors. Visit the link for more info

PaperPlayer biorxiv neuroscience
Transcriptome alterations are enriched for synapse-associated genes in the striatum of subjects with obsessive-compulsive disorder

PaperPlayer biorxiv neuroscience

Play Episode Listen Later Jul 24, 2020


Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.07.23.216697v1?rss=1 Authors: Piantadosi, S. C., McClain, L. L., Klei, L., Wang, J., Springer, S., Chamberlain, B. L., Lewis, D. A., Devlin, B., Ahmari, S. E. Abstract: Background: Obsessive compulsive disorder (OCD) is a chronic and severe psychiatric disorder for which effective treatment options are limited. Structural and functional neuroimaging studies have consistently implicated the orbitofrontal cortex (OFC) and striatum in the pathophysiology of the disorder. Recent genetic evidence points to involvement of components of the excitatory synapse in the etiology of OCD. However, the transcriptional alterations that could link genetic risk to known structural and functional abnormalities remain mostly unknown. Methods: To assess potential transcriptional changes in the OFC and two striatal regions (caudate nucleus and nucleus accumbens) of OCD subjects relative to unaffected comparison subjects, we sequenced messenger RNA transcripts from these brain regions. Results: In a joint analysis of all three regions, 904 transcripts were differentially expressed between 7 OCD versus 8 unaffected comparison subjects. Region-specific analyses highlight a smaller number of differences, which concentrate in caudate and nucleus accumbens. Pathway analyses of the 904 differentially expressed transcripts showed enrichment for genes involved in synaptic signaling, with these synapse-associated genes displaying lower expression in OCD subjects relative to unaffected comparison subjects. Finally, we estimate that cell type fractions of medium spiny neurons are lower whereas vascular cells and astrocyte fractions are higher in tissue of OCD subjects. Conclusions: Together, these data provide the first unbiased examination of differentially expressed transcripts in both OFC and striatum of OCD subjects. These transcripts encode synaptic proteins more often than expected by chance, and thus implicate the synapse as a vulnerable molecular compartment for OCD. Copy rights belong to original authors. Visit the link for more info

PaperPlayer biorxiv neuroscience
Brain transcriptome analysis reveals subtle effects on mitochondrial function and iron homeostasis of mutations in the SORL1 gene implicated in early onset familial Alzheimers disease

PaperPlayer biorxiv neuroscience

Play Episode Listen Later Jul 17, 2020


Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.07.17.207787v1?rss=1 Authors: Barthelson, K., Pederson, S. M., Newman, M., Lardelli, M. Abstract: Background: To prevent or delay the onset of Alzheimers disease (AD), we must understand its molecular basis. The great majority of AD cases arise sporadically with a late onset after 65 years of age (LOAD). However, rare familial cases of AD can occur due to dominant mutations in a small number of genes that cause an early onset prior to 65 years of age (EOfAD). As EOfAD and LOAD share similar pathologies and disease progression, analysis of EOfAD genetic models may give insight into both subtypes of AD. Sortilin-related receptor 1 (SORL1) is genetically associated with both EOfAD and LOAD and provides a unique opportunity to investigate the relationships between both forms of AD. Currently, the role of SORL1 mutations in AD pathogenesis is unclear. Methods: To understand the molecular consequences of SORL1 mutation, we performed targeted mutagenesis of the orthologous gene in zebrafish. We generated an EOfAD-like mutation, V1482Afs, and a putatively null mutation, to investigate whether EOfAD-like mutations in sorl1 display haploinsufficiency by acting through loss-of-function mechanisms. We performed mRNA-sequencing on whole brains comparing normal (wild type) fish with their siblings heterozygous for EOfAD-like or complete loss-of-function mutations in sorl1 or transheterozygous for these mutations. Differential gene expression and gene set enrichment analyses identified, respectively, changes in young adult zebrafish brain transcriptomes, and putative effects on neural subcellular functions. Results: We identified subtle effects on expression of genes involved in energy production, mRNA translation and mTORC1 signalling in both the EOfAD-like and null mutant brains, implying that these effects are due to sorl1 haploinsufficiency. Surprisingly, we also observed changes to expression of genes occurring only in the EOfAD-mutation carrier brains, suggesting gain-of-function effects. Transheterozygosity for the EOfAD-like and null mutations (i.e. lacking wild type sorl1), caused apparent effects on iron homeostasis and other transcriptome changes distinct from the single-mutation heterozygous fish. Conclusions: Our results provide insight into the possible early brain molecular effects of an EOfAD mutation in human SORL1. Differential effects of heterozygosity and complete loss of normal SORL1 expression are revealed. Copy rights belong to original authors. Visit the link for more info

PaperPlayer biorxiv neuroscience
The left dorsal stream causally mediates the tone labeling in absolute pitch

PaperPlayer biorxiv neuroscience

Play Episode Listen Later Jul 16, 2020


Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.07.16.206284v1?rss=1 Authors: Rogenmoser, L., Arnicane, A., Jancke, L., Elmer, S. Abstract: Background: Absolute pitch (AP) refers to the ability of effortlessly identifying given pitches without the reliance on any reference pitch. Correlative evidence suggests that the left posterior dorsolateral prefrontal cortex (DLPFC) is responsible for the process underlying pitch labeling in AP. Objective: Here, we aimed at investigating the causal relationship between the DLPFC and the pitch-labeling process underlying AP. Methods: To address this, we measured sight-reading performance of right-handed AP possessors and matched control musicians (N=18 per sample) under cathodal and sham transcranial direct current stimulation of the left DLPFC. The participants were instructed to report visually presenting notations as accurately and fast as possible by playing with their right hand on a piano. The notations were simultaneously presented with distracting auditory stimuli that either matched or mismatched them in different semitone degrees. Results: Unlike the control participants, the AP possessors revealed an interference effect in that they responded slower in mismatching conditions than in the matching one. Under cathodal stimulation, half of the time discrepancies between matching and mismatching conditions vanished; specifically, the ones with small up to moderate deviations. Conclusions: These findings confirm that the pitch-labeling process underlying AP occurs automatically and is largely non-suppressible when triggered by tone exposure. The improvement of the AP possessors' sight-reading performance in response to the suppression of the left DLPFC using cathodal stimulation confirms a causal relationship between this brain structure and pitch labeling. Copy rights belong to original authors. Visit the link for more info

PaperPlayer biorxiv neuroscience
Differential effect of anesthesia on visual cortex neurons with diverse population coupling

PaperPlayer biorxiv neuroscience

Play Episode Listen Later Jun 14, 2020


Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.06.13.150284v1?rss=1 Authors: Lee, H., Tanabe, S., Wang, S., Hudetz, A. G. Abstract: Introduction: Firing rate (FR) and population coupling (PC) are intrinsic properties of cortical neurons. Neurons with different FR and PC have diverse excitability to stimulation, tuning curve, and synaptic plasticity. Therefore, investigation of the effect of anesthesia on neurons with different FR and PC would be important to understand state-dependent information processing in neuronal circuits. Methods: To test how anesthesia affects neurons with diverse PC and FR, we measured single-unit activities in deep layers of primary visual cortex at three levels of anesthesia with desflurane and in wakefulness. Based on PC and FR in wakefulness, neurons were classified into three distinct groups: high PC-high FR (HPHF), low PC-high FR (LPHF), and low PC-low FR (LPLF) neurons. Results: Applying repeated light flashes as visual stimuli, HPHF neurons showed the strongest early response (FR at 20-150ms post-stimulus) among the three groups, whereas the response of LPHF neurons persisted longest (up to 440ms). Anesthesia profoundly altered PC and FR, and differently affected the three neuron groups: (i) PC and FR became strongly correlated suppressing population-independent spike activity; (ii) Pairwise correlation of spikes between neurons could be predicted by a PC-based raster model suggesting uniform neuron-to-neuron coupling; (iii) Contrary to evoked-potential studies under anesthesia, the flash-induced early response of HPHF neurons was attenuated, and their spike timing was split and delayed; (iv) Late response (FR at 200-400ms post-stimulus) was suppressed both in HPHF and LPHF neurons. Conclusions: Anesthetic-induced association between PC and FR suggests reduced information content in the neural circuit. Altered response of HPHF neurons to visual stimuli suggests that anesthesia interferes with conscious sensory processing in primary sensory cortex. Copy rights belong to original authors. Visit the link for more info

PaperPlayer biorxiv neuroscience
The role of the meningeal lymphatic system in local inflammation and trigeminal nociception implicated in migraine pain

PaperPlayer biorxiv neuroscience

Play Episode Listen Later Apr 25, 2020


Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.04.25.060939v1?rss=1 Authors: Mikhailov, N., Koroleva, K., Abdollahzadeh, A., Giniatullina, R., Gafurov, O., Malm, T., Sierra Lopez, A., Tohka, J., Noe, F. M., Giniatullin, R. Abstract: Background: A system of lymphatic vessels has been recently characterized in the meninges, with a postulated role in cleaning of the brain via cerebro-spinal fluid drainage. As meninges are an important tissue involved in the origin of migraine pain, we hypothesized that malfunctioning of a cleaning lymphatic system should affect the functional properties of meningeal nociception. To test this hypothesis, we studied migraine-related nociceptive and inflammatory mechanisms in the meninges, in a mouse model of primary lymphedema (K14-VEGFR3-Ig mice) characterized by the lack of functional meningeal lymphatic system. Methods: To study the migraine-related nociceptive and inflammatory mechanisms we recorded spiking activity from meningeal fibers of the trigeminal nerve, estimated the local mast cells infiltration, calcitonin gene-related peptide (CGRP) and cytokine levels (basal and under stimulating conditions), as well as the dura mater innervation in freshly-isolated hemiskull preparations from K14-VEGFR3-Ig (K14) or wild type C57BL/6 mice (WT). Results: We found that the level of CGRP and the production of TNF , which both are implicated in migraine, were reduced in meninges of K14 mice. There was a trend of having a larger number of dural mast cells, consistent with the increased level of the mast cell activator MCP-1 found in these animals. In addition, we found an increased spontaneous and ATP-induced nociceptive firing in the meningeal afferents of mice lacking meningeal lymphatic system. However, the patterns of trigeminal innervation in meninges remained unchanged. Conclusions: In summary, the lack of meningeal lymphatic system leads to a new balance between pro- and anti-inflammatory mechanisms implicated in peripheral nociception, affecting key cellular and humoral factors implicated in migraine. Copy rights belong to original authors. Visit the link for more info

Science Says
Towards personalised molecular feedback for weight loss

Science Says

Play Episode Listen Later May 28, 2019


Background: Numerous diets, apps and websites help guide and monitor dietary behaviour with the goal of losing weight, yet dieting success is highly dependent on personal preferences and circumstances. To enable a more quantitative approach to dieting, we developed an integrated platform that allows tracking of life-style information alongside molecular biofeedback measurements (lactate and insulin). Methods: To facilitate weight loss, participants (≥18 years) omitted one main meal from the usual three-meal routine. Daily caloric intake was restricted to ~1200KCal with one optional snack ≤250KCal. A mobile health platform (personalhealth.warwick.ac.uk) was developed and used to maintain diaries of food intake, weight, urine collection and volume. A survey was conducted to understand participants’ willingness to collect samples, motivation for taking part in the study and reasons for dropout. Results: Meal skipping resulted in weight loss after a 24 h period in contrast to 3-meal control days regardless of the meal that was skipped, breakfast, lunch or dinner (p 

Medizinische Fakultät - Digitale Hochschulschriften der LMU - Teil 19/19
External validation of decision-analytic models based on claims data of health insurance funds

Medizinische Fakultät - Digitale Hochschulschriften der LMU - Teil 19/19

Play Episode Listen Later Mar 16, 2016


Background: Decision-analytic models are used in the context of economic evaluation to bring together the best available evidence and to support the decision on the adoption of a health technology. A decision model’s credibility is, however, diminished by uncertainty which, to large part, stems from parameter uncertainty. Especially when novel technologies are evaluated, high quality evidence may not be available at the point of coverage decision making. A decision model incorporating uncertain parameter values eventually simulates uncertain effectiveness and cost outcomes. To enhance credibility of decision models, external validation of uncertain parameter values is vital. Data sources for external validation should be able to reflect the model’s study design and patient cohort, and estimate real-world effectiveness and costs. Objective: This study assesses whether claims data of health insurance funds are suitable to externally validate decision-analytic models. Methods: To answer the research question, a validation approach is developed which highlights critical steps in the validation of decision models based on claims data. The validation steps are: 1) selection of the validation level, 2) selection of the claims dataset, study design, and patient cohort, 3) selection of disease-relevant health technologies and costs, 4) statistical analysis of claims data, 5) changes to the decision model, 6) comparison between model and claims data, and 7) sensitivity analyses. The validation approach is exemplarily applied in the validation of a Markov model comparing treatment of localized prostate cancer (active surveillance and radical prostatectomy) in a German health care context, based on claims data of the German AOK statutory health insurance fund. An external validation of resource use, probability of utilization, and cost parameters is chosen, because these parameters are afflicted by a high degree of uncertainty in the decision model. Two different approaches to the analysis of relevant health technologies for prostate cancer treatment are presented in claims data analysis: an excess approach and a disease-related approach. Results: The decision model assumes that resource use and unit costs are identical in the two treatment groups; this is, however, not observed in claims data analysis. Excess cost analysis and disease-related cost analysis of AOK claims data as well as model analysis show that, overall, active surveillance is the less costly strategy compared to radical prostatectomy, with total incremental costs of €-6,611, €-6,260, and €-7,486 respectively. When testing differences between model and outcomes of claims data analysis, p-values of 0.61 (excess approach) and 0.18 (disease-related approach) indicate an agreement that is sufficient to assume that the decision model simulates real-world costs validly. Discussion: This study reveals general strengths and limitations of claims data based model validation. Claims data are able to provide evidence on real-world resource utilization and, with limitations regarding clinical information, effectiveness of a wide range of indications and treatments for a large patient cohort. Validation based on claims data is especially suitable when the decision maker, interested in the validity of the model in question, is the insurance fund providing access to the claims data. Suitability of claims data based validation is, however, limited concerning the replication of decision models’ structure and patient cohort. For one, the identification of distinct health states is limited, because clinical information is not included in sufficient detail. Secondly, due to non-randomization and a restricted number of variables available to adjust for confounding, comparability of treatment groups is limited in claims data analysis. Thirdly, distinct identification of health technology utilization and corresponding costs is not possible if the technology of interest is not specifically coded. Finally, claims data are, generally, collected for billing purposes; diagnoses and technology utilization are only coded if they are relevant for reimbursement by the insurance fund, which biases outcomes of model validation in cases where treatment is not covered by the insurance fund. Conclusion: The presented validation approach indicates critical aspects of the validation based on claims data, which may support researchers and decision makers in their decision on the suitability of claims data for model validation. The suitability of claims data for the external validation of a decision model ultimately depends on the ability of the claims data source to reflect the model’s patient cohort and outcome measures.

Medizin - Open Access LMU - Teil 22/22
Next generation sequencing analysis of nine Corynebacterium ulcerans isolates reveals zoonotic transmission and a novel putative diphtheria toxin-encoding pathogenicity island

Medizin - Open Access LMU - Teil 22/22

Play Episode Listen Later Jan 1, 2014


Background: Toxigenic Corynebacterium ulcerans can cause a diphtheria-like illness in humans and have been found in domestic animals, which were suspected to serve as reservoirs for a zoonotic transmission. Additionally, toxigenic C. ulcerans were reported to take over the leading role in causing diphtheria in the last years in many industrialized countries. Methods: To gain deeper insights into the tox gene locus and to understand the transmission pathway in detail, we analyzed nine isolates derived from human patients and their domestic animals applying next generation sequencing and comparative genomics. Results: We provide molecular evidence for zoonotic transmission of C. ulcerans in four cases and demonstrate the superior resolution of next generation sequencing compared to multi-locus sequence typing for epidemiologic research. Additionally, we provide evidence that the virulence of C. ulcerans can change rapidly by acquisition of novel virulence genes. This mechanism is exemplified by an isolate which acquired a prophage not present in the corresponding isolate from the domestic animal. This prophage contains a putative novel virulence factor, which shares high identity with the RhuM virulence factor from Salmonella enterica but which is unknown in Corynebacteria so far. Furthermore, we identified a putative pathogenicity island for C. ulcerans bearing a diphtheria toxin gene. Conclusion: The novel putative diphtheria toxin pathogenicity island could provide a new and alternative pathway for Corynebacteria to acquire a functional diphtheria toxin-encoding gene by horizontal gene transfer, distinct from the previously well characterized phage infection model. The novel transmission pathway might explain the unexpectedly high number of toxigenic C. ulcerans.

Medizin - Open Access LMU - Teil 21/22
Diagnostic Value of Concentration Profiles of Glucocorticosteroids and Endocannabinoids in Hair

Medizin - Open Access LMU - Teil 21/22

Play Episode Listen Later Oct 1, 2013


Background:Endogenous corticosteroids and endocannabinoids are both known to be involved in stress adaption and anti-inflammatory and immuneregulatory effects. The application of hair as retrospective specimen for long-term recording of corticosteroids and its association with stress-induced biochemical alterations was intensively examined.Methods:To evaluate the stability and correlation of various parameters of the endocannabinoid and corticosteroid systems, a prospective study was carried out. Hair samples were collected monthly over a pregnancy cycle (sixth week of pregnancy to 9 weeks postpartum). By comparison of hair concentrations in particular segments (ie, grown in the same time span but collected at different times), an examination of analyte stability in hair was achieved. Additionally, the comparison of proximal segments provided on biochemical information that is independent of alteration due to physical instability. The detection limits of a validated procedure using solid-phase extraction cleanup and liquid chromatography-mass spectrometry proved to be suitable to identify the endogenous levels of cortisol (limits of detection = 1.6 pg/mg), cortisone (2.1 pg/mg), anandamide (AEA, 0.3 pg/mg), and 2-arachidonoylglycerol (15 pg/mg).Results:Corticosteroid concentrations in corresponding hair segments were found to be reduced with increasing hair age; an average decline of cortisol and cortisone by 50% in 4 months was estimated. Independently, an increase of cortisol and cortisone in proximal segments collected during pregnancy was confirmed, which is assumed to be stress related. Endocannabinoids proved to be by far more stable, as demonstrated by subsequent monthly collection of corresponding segments and there was hardly any washout of AEA detectable. Elevated hair concentrations of AEA and 2-arachidonoylglycerol were detected in the first-second trimester of pregnancy, which corresponds to negative correlations between AEA, cortisol, and cortisone.

Medizin - Open Access LMU - Teil 20/22
Re-focusing the ethical discourse on personalized medicine: a qualitative interview study with stakeholders in the German healthcare system

Medizin - Open Access LMU - Teil 20/22

Play Episode Listen Later Jan 1, 2013


Background: In recent years, personalized medicine (PM) has become a highly regarded line of development in medicine. Yet, it is still a relatively new field. As a consequence, the discussion of its future developments, in particular of its ethical implications, in most cases can only be anticipative. Such anticipative discussions, however, pose several challenges. Nevertheless, they play a crucial role for shaping PM's further developments. Therefore, it is vital to understand how the ethical discourse on PM is conducted, i.e. on what - empirical and normative - assumptions ethical arguments are based regarding PM's current and future developments. Methods: To gather this information, we conducted a qualitative interview study with stakeholders in the German health care system. Our purposive sample included 17 representatives of basic research, clinical research, health economics, regulatory authorities, reimbursement institutions, pharmaceutical industry, patient organizations, as well as clinicians and legal experts involved in PM developments or policy making. We used an interview guide with open-ended questions and analyzed transcriptions of the interviews by means of qualitative content analysis. Results: The respondents addressed a multitude of concerns in the context of research on as well as application of personalized preventive and therapeutic measures both on the individual and on the societal level. Interestingly, regarding future developments of PM the ethical evaluation seemed to follow the rule: the less likely its application, the more problematic a PM measure is assessed. The more likely its application, on the other hand, the less problematic it is evaluated. Conclusions: The results of our study suggest re-focusing the ethical discourse on PM in Germany towards a constructive ethical monitoring which ensures to include only, nevertheless all of the actual and/or potential concerns that are ethically relevant in order to allow balancing them against the actual and potential ethically relevant benefits of PM measures. To render this possible, we propose a strategy for evaluating ethical concerns in the context of PM.

Medizin - Open Access LMU - Teil 21/22
miR-411 is up-regulated in FSHD myoblasts and suppresses myogenic factors

Medizin - Open Access LMU - Teil 21/22

Play Episode Listen Later Jan 1, 2013


Background: Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant muscle disorder, which is linked to the contraction of the D4Z4 array at chromosome 4q35. Recent studies suggest that this shortening of the D4Z4 array leads to aberrant expression of double homeobox protein 4 (DUX4) and causes FSHD. In addition, misregulation of microRNAs (miRNAs) has been reported in muscular dystrophies including FSHD. In this study, we identified a miRNA that is differentially expressed in FSHD myoblasts and investigated its function. Methods: To identify misregulated miRNAs and their potential targets in FSHD myoblasts, we performed expression profiling of both miRNA and mRNA using TaqMan Human MicroRNA Arrays and Affymetrix Human Genome U133A plus 2.0 microarrays, respectively. In addition, we over-expressed miR-411 in C2C12 cells to determine the effect of miR-411 on myogenic markers. Results: Using miRNA and mRNA expression profiling, we identified 8 miRNAs and 1,502 transcripts that were differentially expressed in FSHD myoblasts during cell proliferation. One of the 8 differentially expressed miRNAs, miR-411, was validated by quantitative RT-PCR in both primary (2.1 fold, p

Medizin - Open Access LMU - Teil 19/22
Common variants at 12p11, 12q24, 9p21, 9q31.2 and in ZNF365 are associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers

Medizin - Open Access LMU - Teil 19/22

Play Episode Listen Later Jan 1, 2012


Introduction: Several common alleles have been shown to be associated with breast and/or ovarian cancer risk for BRCA1 and BRCA2 mutation carriers. Recent genome-wide association studies of breast cancer have identified eight additional breast cancer susceptibility loci: rs1011970 (9p21, CDKN2A/B), rs10995190 (ZNF365), rs704010 (ZMIZ1), rs2380205 (10p15), rs614367 (11q13), rs1292011 (12q24), rs10771399 (12p11 near PTHLH) and rs865686 (9q31.2). Methods: To evaluate whether these single nucleotide polymorphisms (SNPs) are associated with breast cancer risk for BRCA1 and BRCA2 carriers, we genotyped these SNPs in 12,599 BRCA1 and 7,132 BRCA2 mutation carriers and analysed the associations with breast cancer risk within a retrospective likelihood framework. Results: Only SNP rs10771399 near PTHLH was associated with breast cancer risk for BRCA1 mutation carriers (per-allele hazard ratio (HR) = 0.87, 95% CI: 0.81 to 0.94, P-trend = 3 x 10(-4)). The association was restricted to mutations proven or predicted to lead to absence of protein expression (HR = 0.82, 95% CI: 0.74 to 0.90, P-trend = 3.1 x 10(-5), P-difference = 0.03). Four SNPs were associated with the risk of breast cancer for BRCA2 mutation carriers: rs10995190, P-trend = 0.015; rs1011970, P-trend = 0.048; rs865686, 2df P = 0.007; rs1292011 2df P = 0.03. rs10771399 (PTHLH) was predominantly associated with estrogen receptor (ER)-negative breast cancer for BRCA1 mutation carriers (HR = 0.81, 95% CI: 0.74 to 0.90, P-trend = 4 x 10(-5)) and there was marginal evidence of association with ER- negative breast cancer for BRCA2 mutation carriers (HR = 0.78, 95% CI: 0.62 to 1.00, P-trend = 0.049). Conclusions: The present findings, in combination with previously identified modifiers of risk, will ultimately lead to more accurate risk prediction and an improved understanding of the disease etiology in BRCA1 and BRCA2 mutation carriers.

Medizin - Open Access LMU - Teil 19/22
A framework for assessing Health Economic Evaluation (HEE) quality appraisal instruments

Medizin - Open Access LMU - Teil 19/22

Play Episode Listen Later Jan 1, 2012


Background: Health economic evaluations support the health care decision-making process by providing information on costs and consequences of health interventions. The quality of such studies is assessed by health economic evaluation (HEE) quality appraisal instruments. At present, there is no instrument for measuring and improving the quality of such HEE quality appraisal instruments. Therefore, the objectives of this study are to establish a framework for assessing the quality of HEE quality appraisal instruments to support and improve their quality, and to apply this framework to those HEE quality appraisal instruments which have been subject to more scrutiny than others, in order to test the framework and to demonstrate the shortcomings of existing HEE quality appraisal instruments. Methods: To develop the quality assessment framework for HEE quality appraisal instruments, the experiences of using appraisal tools for clinical guidelines are used. Based on a deductive iterative process, clinical guideline appraisal instruments identified through literature search are reviewed, consolidated, and adapted to produce the final quality assessment framework for HEE quality appraisal instruments. Results: The final quality assessment framework for HEE quality appraisal instruments consists of 36 items organized within 7 dimensions, each of which captures a specific domain of quality. Applying the quality assessment framework to four existing HEE quality appraisal instruments, it is found that these four quality appraisal instruments are of variable quality. Conclusions: The framework described in this study should be regarded as a starting point for appraising the quality of HEE quality appraisal instruments. This framework can be used by HEE quality appraisal instrument producers to support and improve the quality and acceptance of existing and future HEE quality appraisal instruments. By applying this framework, users of HEE quality appraisal instruments can become aware of methodological deficiencies inherent in existing HEE quality appraisal instruments. These shortcomings of existing HEE quality appraisal instruments are illustrated by the pilot test.

Medizin - Open Access LMU - Teil 19/22
Specific guidelines for assessing and improving the methodological quality of economic evaluations of newborn screening

Medizin - Open Access LMU - Teil 19/22

Play Episode Listen Later Jan 1, 2012


Background: Economic evaluation of newborn screening poses specific methodological challenges. Amongst others, these challenges refer to the use of quality adjusted life years (QALYs) in newborns, and which costs and outcomes need to be considered in a full evaluation of newborn screening programmes. Because of the increasing scale and scope of such programmes, a better understanding of the methods of high-quality economic evaluations may be crucial for both producers/authors and consumers/reviewers of newborn screening-related economic evaluations. The aim of this study was therefore to develop specific guidelines designed to assess and improve the methodological quality of economic evaluations in newborn screening. Methods: To develop the guidelines, existing guidelines for assessing the quality of economic evaluations were identified through a literature search, and were reviewed and consolidated using a deductive iterative approach. In a subsequent test phase, these guidelines were applied to various economic evaluations which acted as case studies. Results: The guidelines for assessing and improving the methodological quality of economic evaluations in newborn screening are organized into 11 categories: "bibliographic details"

Medizin - Open Access LMU - Teil 19/22
Protective and Aggravating Effects of Nlrp3 Inflammasome Activation in IBD Models: Influence of Genetic and Environmental Factors

Medizin - Open Access LMU - Teil 19/22

Play Episode Listen Later Jan 1, 2012


Background: Inflammatory bowel disease (IBD) is characterized by chronic intestinal inflammation due to dysregulation of the mucosal immune system. The cytokines IL-1 beta and IL-18 appear early in intestinal inflammation and their pro-forms are processed via the caspase-1-activating multiprotein complex, the Nlrp3 inflammasome. Previously, we reported that the uptake of dextran sodium sulfate (DSS) by macrophages activates the Nlrp3 inflammasome and that Nlrp3(-/-) mice are protected in the acute DSS colitis model. Of note, other groups have reported opposing effects in regards to DSS susceptibility in Nlrp3(-/-) mice. Recently, mice lacking inflammasomes were found to develop a distinct intestinal microflora. Methods: To reconcile the contradicting observations, we investigated the role of Nlrp3 deficiency in two different IBD models: acute DSS colitis and TNBS (2,4,6-trinitrobenzene sulfonic acid)-induced colitis. In addition, we in-vestigated the impact of the intestinal flora on disease severity by performing cohousing experiments of wild-type and Nlrp3(-/-) mice, as well as by antibiotic treatment. Results: Nlrp3(-/-) mice treated with either DSS or TNBS exhibited attenuated colitis and lower mortality. This protective effect correlated with an increased frequency of CD103+ lamina propria dendritic cells expressing a tolerogenic phenotype in Nlrp3(-/-) mice in steady state conditions. Interestingly, after cohousing, Nlrp3(-/-) mice were as susceptible as wild-type mice, indicating that transmission of endogenous bacterial flora between the two mouse strains might increase susceptibility of Nlrp3(-/-) mice towards DSS-induced colitis. Accordingly, treatment with antibiotics almost completely prevented colitis in the DSS model. Conclusions: The composition of the intestinal microflora significantly influences disease severity in IBD models comparing wild-type and Nlrp3(-/-) mice. This observation may - at least in part - explain contradictory results concerning the role of the inflammasome in different labs. Further studies are required to define the role of the Nlrp3 inflammasome in noninflamed mucosa under steady state conditions and in IBD. Copyright (C) 2012 S. Karger AG, Basel

Medizin - Open Access LMU - Teil 17/22
Travel and migration associated infectious diseases morbidity in Europe, 2008

Medizin - Open Access LMU - Teil 17/22

Play Episode Listen Later Jan 1, 2010


Background: Europeans represent the majority of international travellers and clinicians encountering returned patients have an essential role in recognizing, and communicating travel-associated public health risks. Methods: To investigate the morbidity of travel associated infectious diseases in European travellers, we analysed diagnoses with demographic, clinical and travel-related predictors of disease, in 6957 ill returned travellers who presented in 2008 to EuroTravNet centres with a presumed travel associated condition. Results: Gastro-intestinal (GI) diseases accounted for 33% of illnesses, followed by febrile systemic illnesses (20%), dermatological conditions (12%) and respiratory illnesses (8%). There were 3 deaths recorded; a sepsis caused by Escherichia coli pyelonephritis, a dengue shock syndrome and a Plasmodium falciparum malaria. GI conditions included bacterial acute diarrhea (6.9%), as well as giardiasis and amebasis (2.3%). Among febrile systemic illnesses with identified pathogens, malaria (5.4%) accounted for most cases followed by dengue (1.9%) and others including chikungunya, rickettsial diseases, leptospirosis, brucellosis, Epstein Barr virus infections, tick-borne encephalitis (TBE) and viral hepatitis. Dermatological conditions were dominated by bacterial infections, arthropod bites, cutaneous larva migrans and animal bites requiring rabies post-exposure prophylaxis and also leishmaniasis, myasis, tungiasis and one case of leprosy. Respiratory illness included 112 cases of tuberculosis including cases of multi-drug resistant or extensively drug resistant tuberculosis, 104 cases of influenza like illness, and 5 cases of Legionnaires disease. Sexually transmitted infections (STI) accounted for 0.6% of total diagnoses and included HIV infection and syphilis. A total of 165 cases of potentially vaccine preventable diseases were reported. Purpose of travel and destination specific risk factors was identified for several diagnoses such as Chagas disease in immigrant travellers from South America and P. falciparum malaria in immigrants from sub-Saharan Africa. Travel within Europe was also associated with health risks with distinctive profiles for Eastern and Western Europe. Conclusions: In 2008, a broad spectrum of travel associated diseases were diagnosed at EuroTravNet core sites. Diagnoses varied according to regions visited by ill travellers. The spectrum of travel associated morbidity also shows that there is a need to dispel the misconception that travel, close to home, in Europe, is without significant health risk.

Medizin - Open Access LMU - Teil 15/22
Development and first assessment of a questionnaire for health care utilization and costs for cardiac patients

Medizin - Open Access LMU - Teil 15/22

Play Episode Listen Later Jan 1, 2008


Background: The valid and reliable measurement of health service utilization, productivity losses and consequently total disease-related costs is a prerequisite for health services research and for health economic analysis. Although administrative data sources are usually considered to be the most accurate, their use is limited as some components of utilization are not systematically captured and, especially in decentralized health care systems, no single source exists for comprehensive utilization and cost data. The aim of this study was to develop and test a questionnaire for the measurement of disease-related costs for patients after an acute cardiac event (ACE). Methods: To design the questionnaire, the literature was searched for contributions to the assessment of utilization of health care resources by patient-administered questionnaires. Based on these findings, we developed a retrospective questionnaire appropriate for the measurement of disease-related costs over a period of 3 months in ACE patients. Items were generated by reviewing existing guidelines and by interviewing medical specialists and patients. In this study, the questionnaire was tested on 106 patients, aging 35 - 65 who were admitted for rehabilitation after ACE. It was compared with prospectively measured data; selected items were compared with administrative data from sickness funds. Results: The questionnaire was accepted well (response rate = 88%), and respondents completed the questionnaire in an average time of 27 minutes. Concordance between retrospective and prospective data showed an intraclass correlation (ICC) ranging between 0.57 (cost of medical intake) and 0.9 (hospital days) with the other main items (physician visits, days off work, medication) clustering around 0.7. Comparison between self-reported and administrative data for days off work and hospitalized days were possible for n = 48. Respective ICCs ranged between 0.92 and 0.94, although differences in mean levels were observed. Conclusion: The questionnaire was accepted favorably and correlated well with alternative measurement approaches. This first assessment showed promising characteristics of this questionnaire in different aspects of validity for patients with ACE. However, additional research and more extensive tests in other patient groups would be worthwhile.

Medizin - Open Access LMU - Teil 15/22
Pollen grains induce a rapid and biphasic eczematous immune response in atopic eczema patients

Medizin - Open Access LMU - Teil 15/22

Play Episode Listen Later Jan 1, 2008


Introduction: Eczematous reactions to type I allergy-inducing antigens are documented in a subgroup of patients with atopic eczema. Yet, the underlying immunological mechanisms are not well understood. Material and Methods: To delineate the effect of native pollen grains on human skin of healthy and atopic individuals we performed patch tests (atopy patch test with native pollen grains, PPT). Nickel patch tests (NPT) served as an established model of contact dermatitis. Skin site biopsies were taken 6 - 96 h after allergen application and investigated immunohistochemically. Results: Histology of positive patch tests showed an influx of mononuclear cells (predominantly CD4+, CD25+, CD45RO+). This influx was detected earlier in the PPT reaction than in the immune response to nickel. A biphasic cytokine response could be detected in the PPT: IL-5 dominated in the early, IFN-gamma in the late phase. The NPT was continuously dominated by IFN-gamma. Dendritic cell subpopulations imitated the earlier kinetics of the mononuclear infiltrate. Discussion: Thus, pollen grains induce eczematous reactions in susceptible individuals. This reaction appears clinically and immunohistochemically similar to the contact hypersensitivity reaction to nickel but follows a faster kinetic and a biphasic course: Th2 and IgE in the early (24 h) and Th1 predominance in the late (96 h) phase. Copyright (c) 2007 S. Karger AG, Basel.

Medizin - Open Access LMU - Teil 14/22
Rotation frequency of human bronchial and nasal epithelial spheroids as an indicator of mucociliary function

Medizin - Open Access LMU - Teil 14/22

Play Episode Listen Later Jan 1, 2006


Background: We evaluated a new in vitro model for mucociliary transport function. Spheroids of human respiratory epithelium show beating cilia at their surface. When cultured in their own mucus, spheroids can rotate along their axis due to coordinated ciliary beating. Objective and Methods: To assess whether this setup yields meaningful results we measured rotation frequency (RF) of human bronchial or nasal epithelial spheroids under different temperatures and concentrations of isoproterenol. Isoproterenol was administered either as caged compound releasing active isoproterenol after illumination with UV light, or through a permeable membrane in a two-chamber system. Results: Under stable conditions, RF remained constant over 200 min. Between 27 and 35 C, there was a temperature-dependent increase: RF27 degrees C = 0.27 +/- 0.08 s(-1), and RF37 degrees C = 0.43 +/- 0.10 s(-1) (means +/- SEM). Isoproterenol (10(-5), 10(-4) and 10(-3) mmol/l) induced concentration-dependent increases in RF (9, 20 and 25%, respectively; medians) if applied in the two-chamber system. The experiments with caged isoproterenol did not yield conclusive results, probably because the byproducts from photolysis negatively affected ciliary function. The transport velocity at the surface of bronchial and nasal spheroids was estimated to be 2.96 and 3.62 mm/min (medians), respectively, which is in the same range as mucus transport velocity measured in vivo in humans. Conclusions: This setup can be used to study mucociliary transport function under controlled conditions in vitro, in particular as RF is likely to reflect not only ciliary beat frequency, but also the coordination of ciliary beating and the properties of the mucus. Copyright (C) 2006 S. Karger AG, Basel.

Medizin - Open Access LMU - Teil 13/22
Deep subcutaneous application of poly-L-lactic acid as a filler for facial lipoatrophy in HIV-infected patients

Medizin - Open Access LMU - Teil 13/22

Play Episode Listen Later Jan 1, 2005


Introduction: Facial lipoatrophy is a crucial problem of HIV-infected patients undergoing highly active antiretroviral therapy (HAART). Poly-L-lactic acid (PLA), provided as New-Fill(R)/Sculptra(TM), is known as one possible treatment option. In 2004 PLA was approved by the FDA as Sculptra(TM) for the treatment of lipoatrophy of the face in HIV-infected patients. While the first trials demonstrated relevant efficacy, this was to some extent linked to unwanted effects. As the depth of injection was considered relevant in this context, the application modalities of the preparation were changed. The preparation was to be injected more deeply into subcutaneous tissue, after increased dilution. Material and Methods: To test this approach we performed a pilot study following the new recommendations in 14 patients. Results: While the efficacy turned out to be about the same, tolerability was markedly improved. The increase in facial dermal thickness was particularly obvious in those patients who had suffered from lipoatrophy for a comparatively small period of time. Conclusion: With the new recommendations to dilute PLA powder and to inject it into the deeper subcutaneous tissue nodule formation is a minor problem. However, good treatment results can only be achieved if lipoatrophy is not too intense; treatment intervals should be about 2 - 3 weeks. Copyright (C) 2005 S. Karger AG, Basel.