Reactive microglia are the major source of tumor necrosis factor alpha and contribute to astrocyte dysfunction and acute seizures in experimental temporal lobe epilepsy.

Extensive microglia reactivity has been well described in human and experimental temporal lobe epilepsy (TLE). To date, however, it is not clear whether and based on which molecular mechanisms microglia contribute to the development and progression of focal epilepsy. Astroglial gap junction coupled networks play an important role in regulating neuronal activity and loss of interastrocytic coupling causally contributes to TLE. Here, we show in the unilateral intracortical kainate (KA) mouse model of TLE that reactive microglia are primary producers of tumor necrosis factor (TNF)α and contribute to astrocyte dysfunction and severity of status epilepticus (SE). Immunohistochemical analyses revealed pronounced and persistent microglia reactivity, which already started 4 h after KA-induced SE. Partial depletion of microglia using a colony stimulating factor 1 receptor inhibitor prevented early astrocyte uncoupling and attenuated the severity of SE, but increased the mortality of epileptic mice following surgery. Using microglia-specific inducible TNFα knockout mice we identified microglia as the major source of TNFα during early epileptogenesis. Importantly, microglia-specific TNFα knockout prevented SE-induced gap junction uncoupling in astrocytes. Continuous telemetric EEG recordings revealed that during the first 4 weeks after SE induction, microglial TNFα did not significantly contribute to spontaneous generalized seizure activity. Moreover, the absence of microglial TNFα did not affect the development of hippocampal sclerosis but attenuated gliosis. Taken together, these data implicate reactive microglia in astrocyte dysfunction and network hyperexcitability after an epileptogenic insult

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

Dataset supporting the University of Southampton Doctoral Thesis "Characterisation of the human microglial Profile identified with translocator protein (TSPO) and its role in the pathophysiology and progression of Alzheimer’s disease"

Dataset supporting the University of Southampton Doctoral Thesis &quot;Characterisation of the human microglial Profile identified with translocator protein (TSPO) and its role in the pathophysiology and progression of Alzheimer&rsquo;s disease&quot; The data includes 4 excel files that are accessible via CC BY license: Pathology_data.xlsx - collected via ImageJ macro for pixel intensity and collated in an Excel spreadsheet. Cell_counts.xlsx - collected via positive cell detection tool in QuPath software, collated in an Excel Spreadsheet. EmmaGenotyping_data_230123.xlsx - collected via qPCR using TaqMan genotyping kit, collated in an Excel spreadsheet. MSD_excel_data.xlsx - collected via MSD assay, collated in an Excel spreadsheet. Related projects/Funders: PhD Studentship from Alzheimer&#39;s Research UK (ARUK-PhD2019-016) </span

A systematic review of the cell death mechanisms in retinal pigment epithelium cells and photoreceptors after subretinal hemorrhage – Implications for treatment options

Humans rely on vision as their most important sense. This is accomplished by photoreceptors (PRs) in the retina that detect light but cannot function without the support and maintenance of the retinal pigment epithelium (RPE). In subretinal hemorrhage (SRH), blood accumulates between the neurosensory retina and the RPE or between the RPE and the choroid. Blood breakdown products subsequently damage PRs and the RPE and lead to poor vision and blindness. Hence, there is a high need for options to preserve the retina and visual functions. We conducted a systematic review of the literature in accordance with the PRISMA guidelines to identify the cell death mechanisms in RPE and PRs after SRH to deepen our understanding of the pathways involved. After screening 736 publications published until November 8, 2022, we identified 19 records that assessed cell death in PRs and/or RPE in experimental models of SRH. Among the different cell death mechanisms, apoptosis was the most widely investigated mechanism (11 records), followed by ferroptosis (4), whereas necroptosis, pyroptosis, and lysosome-dependent cell death were only assessed in one study each. We discuss different therapeutic options that were assessed in these studies, including the removal of the hematoma/iron chelation, cytoprotection, anti-inflammatory agents, and antioxidants. Further systematic investigations will be necessary to determine the exact cell death mechanisms after SRH with respect to different blood breakdown components, cell types, and time courses. This will form the basis for the development of novel treatment options for SRH

Examining the microglial TSPO phenotype in Alzheimer’s disease

Background: neuroinflammation is a key pathological feature of Alzheimer’s disease (AD), with microglia being the main inflammatory cell type in the CNS. In order to examine these cells in vivo, PET ligands targeting the microglial translocator protein (TSPO) have been developed. However, it remains unclear the specific target of these ligands, whether this is all microglia or a subset of cells. We aim to elucidate this by identifying the microglial phenotype most associated with TSPO in humans.Method: human post-mortem sections of temporal lobe (TL) and cerebellum (Cb) from cases classified by Braak stage (0-II, III-IV, V-VI; each n = 10) were immunostained for pan-Aß, pTau, and microglial markers TSPO, Iba1 and HLA-DR with protein load quantified. Double immunofluorescent staining was performed with TSPO and microglial markers HLA-DR and CD68 with positive cells counted.Result: TL showed an increase in Aβ (P&lt;0.0001), pTau (P&lt;0.0001) and TSPO (P&lt;0.0001) protein load, but not Iba1 or HLA-DR, with progressing Braak stage. Aβ (P = 0.0008) and Iba1 (P = 0.012) load increased in the Cb, but not pTau, TSPO or HLA-DR. Of note, TSPO load in TL was associated with pTau. In both areas, no difference was found in number of HLA+ or CD68+ cells, though TL TSPO+ cell number increased significantly (P = 0.0347). There was no difference in the number of HLA-DR+/TSPO+ or CD68+/TSPO+ cells with progressing Braak stage. However, significantly more CD68+/TSPO+ than HLA-DR+/TSPO+ cells were detected in both the TL (P&lt;0.0001) and Cb (P = 0.009) regions.Conclusion: the results suggest that TSPO expression is related to late stage disease (pTau) and microglial phagocytosis (CD68), a function we have previously identified associated with the presence of dementia, cognitive decline and tau pathology. Further additional analysis with other microglial markers is currently ongoing

The management of acute venous thromboembolism in clinical practice - study rationale and protocol of the European PREFER in VTE Registry

Background: Venous thromboembolism (VTE) is a major health problem, with over one million events every year in Europe. However, there is a paucity of data on the current management in real life, including factors influencing treatment pathways, patient satisfaction, quality of life (QoL), and utilization of health care resources and the corresponding costs. The PREFER in VTE registry has been designed to address this and to understand medical care and needs as well as potential gaps for improvement. Methods/design: The PREFER in VTE registry was a prospective, observational, multicenter study conducted in seven European countries including Austria, France Germany, Italy, Spain, Switzerland, and the UK to assess the characteristics and the management of patients with VTE, the use of health care resources, and to provide data to estimate the costs for 12 months treatment following a first-time and/or recurrent VTE diagnosed in hospitals or specialized or primary care centers. In addition, existing anticoagulant treatment patterns, patient pathways, clinical outcomes, treatment satisfaction, and health related QoL were documented. The centers were chosen to reflect the care environment in which patients with VTE are managed in each of the participating countries. Patients were eligible to be enrolled into the registry if they were at least 18 years old, had a symptomatic, objectively confirmed first time or recurrent acute VTE defined as either distal or proximal deep vein thrombosis, pulmonary embolism or both. After the baseline visit at the time of the acute VTE event, further follow-up documentations occurred at 1, 3, 6 and 12 months. Follow-up data was collected by either routinely scheduled visits or by telephone calls. Results: Overall, 381 centers participated, which enrolled 3,545 patients during an observational period of 1 year. Conclusion: The PREFER in VTE registry will provide valuable insights into the characteristics of patients with VTE and their acute and mid-term management, as well as into drug utilization and the use of health care resources in acute first-time and/or recurrent VTE across Europe in clinical practice. Trial registration: Registered in DRKS register, ID number: DRKS0000479

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical science. © The Author(s) 2019. Published by Oxford University Press