Project description:Tuberculosis (TB) is a common infectious disease linked to host genetics and the innate immune response. It is vital to investigate new molecular mechanisms and efficient biomarkers for Tuberculosis because the pathophysiology of the disease is still unclear, and there aren’t any precise diagnostic tools. This study downloaded three blood datasets from the GEO database, two of which (GSE19435 and 83456) were used to build a weighted gene co-expression network for searching hub genes associated with macrophage M1 by the CIBERSORT and WGCNA algorithms. Furthermore, 994 differentially expressed genes (DEGs) were extracted from healthy and TB samples, four of which were associated with macrophage M1, naming RTP4, CXCL10, CD38, and IFI44. They were confirmed as upregulation in TB samples by external dataset validation (GSE34608) and quantitative real-time PCR analysis (qRT-PCR). CMap was used to predict potential therapeutic compounds for tuberculosis using 300 differentially expressed genes (150 downregulated and 150 upregulated genes), and six small molecules (RWJ-21757, phenamil, benzanthrone, TG-101348, metyrapone, and WT-161) with a higher confidence value were extracted. We used in-depth bioinformatics analysis to investigate significant macrophage M1-related genes and promising anti-Tuberculosis therapeutic compounds. However, more clinical trials were necessary to determine their effect on Tuberculosis.
Project description:The increasing number of implant-associated infections and of multiresistant pathogens is a major problem in the daily routine. In the field of osteomyelitis, it is difficult to manage a valid clinical study because of multiple influencing factors. Therefore, models of osteomyelitis with a simulation of the pathophysiology to evaluate treatment options for implant-associated infections are necessary. The aim of this study is to develop a standardized and reproducible osteomyelitis model in-vivo to improve treatment options. This study analyses the influence of a post-infectious implant exchange one week after infection and the infection progress afterward in combination with a systemic versus a local antibiotic treatment in-vivo. Therefore, the implant exchange, the exchange to a local drug-delivery system with gentamicin, and the implant removal are examined. Furthermore, the influence of an additional systemic antibiotic therapy is evaluated. An in-vivo model concerning the implant exchange is established that analyzes clinic, radiologic, microbiologic, histologic, and immunohistochemical diagnostics to obtain detailed evaluation and clinical reproducibility. Our study shows a clear advantage of the combined local and systemic antibiotic treatment in contrast to the implant removal and to a non-combined antibiotic therapy. Group genta/syst. showed the lowest infection rate with a percentage of 62.5% concerning microbiologic analysis, which is in accordance with the immunohistochemical, cytochemical, histologic, and radiologic analysis. Our in-vivo rat model has shown valid and reproducible results, which will lead to further investigations regarding treatment options and influencing factors concerning the therapy of osteomyelitis and implant-associated infections.
Project description:A large body of experimental and clinical evidence has strongly suggested that monoamines play an important role in regulating epileptogenesis, seizure susceptibility, convulsions, and comorbid psychiatric disorders commonly seen in people with epilepsy (PWE). However, neither the relative significance of individual monoamines nor their interaction has yet been fully clarified due to the complexity of these neurotransmitter systems. In addition, epilepsy is diverse, with many different seizure types and epilepsy syndromes, and the role played by monoamines may vary from one condition to another. In this review, we will focus on the role of serotonin, dopamine, noradrenaline, histamine, and melatonin in epilepsy. Recent experimental, clinical, and genetic evidence will be reviewed in consideration of the mutual relationship of monoamines with the other putative neurotransmitters. The complexity of epileptic pathogenesis may explain why the currently available drugs, developed according to the classic drug discovery paradigm of "one-molecule-one-target," have turned out to be effective only in a percentage of PWE. Although, no antiepileptic drugs currently target specifically monoaminergic systems, multi-target directed ligands acting on different monoaminergic proteins, present on both neurons and glia cells, may represent a new approach in the management of seizures, and their generation as well as comorbid neuropsychiatric disorders.
Project description:BackgroundParicalcitol is known to attenuate ischemic-reperfusion injury of various organs. However, it is not known whether paricalcitol prevents neuronal injury after global cerebral ischemia. The purpose of this study is to investigate the neuroprotective effect of paricalcitol in a rat model of transient global cerebral ischemia.MethodsThis is a prospective, randomized experimental study. Male Sprague-Dawley rats that survived 10 min of four-vessel occlusion were randomly assigned to two treatment groups: one group was treated with paricalcitol 1 μg/kg IP, and the other was given an equivalent volume of normal saline IP. Drugs were administered at 5 min, 1 day, 2 days, and 3 days after ischemia. Neurologic function was assessed at 2 h, 1 day, 2 days, 3 days, and 4 days after ischemia. We tested motor function 3 days after ischemia using the rotarod test. Also, we tested memory function 4 days after ischemia using the passive avoidance test. We assessed neuronal degeneration in the hippocampus of surviving rats 4 days after ischemia.ResultsEight rats were allocated to each group. No significant differences were found between the groups in terms of survival rate, motor coordination, or memory function. The neurological function score 2-h post-ischemia was significantly higher in the paricalcitol group (p = 0.04). Neuronal degeneration was significantly less in the paricalcitol group compared with the control group (p = 0.01).ConclusionsParicalcitol significantly attenuated neuronal injury in the hippocampus. Although motor coordination, memory function, and survival rate were not significantly improved by paricalcitol treatment in this study, paricalcitol remains a potential neuroprotective drug after global cerebral ischemia.
Project description:It is well-established that reperfusion following cerebral ischemic injury gives rise to secondary injury accompanied by structural and functional damage. However, it remains unclear how global genes changes in cerebral ischemia-reperfusion injury (IRI). This study investigated global gene expression in the hippocampi of Wistar rats following transient cerebral IRI using an RNA-sequencing strategy. The results revealed ≥2-fold up-regulation of 156 genes and ≥2-fold down-regulation of 26 genes at 24 h post-reperfusion. Fifteen differentially expressed genes were selected to confirm the RNA-sequencing results. Gene expression levels were dynamic, with the peak expression level of each gene occurring at different time points post-reperfusion. Gene Ontology (GO) analysis classified the differentially expressed genes as mainly involved in inflammation, stress and immune response, glucose metabolism, proapoptosis, antiapoptosis, and biological processes. KEGG pathway analysis suggested that IRI activated different signaling pathways, including focal adhesion, regulation of actin cytoskeleton, cytokine-cytokine receptor interaction, MAPK signaling, and Jak-STAT signaling. This study describes global gene expression profiles in the hippocampi of Wistar rats using the middle cerebral artery occlusion (MCAO) model. These findings provide new insights into the molecular pathogenesis of IRI and potential drug targets for the prevention and treatment of IRI in the future.
Project description:Background and Objectives: Intensive care unit-acquired weakness (ICU-AW) is one of the most frequent neuromuscular complications in critically ill patients. We conducted a global survey to evaluate the current practices of diagnostics, treatment and prevention in patients with ICU-AW. Materials and Methods: A pre-survey was created with international experts. After revision, the final survey was endorsed by the European Society of Intensive Care Medicine (ESICM) using the online platform SurveyMonkey®. In 27 items, we addressed strategies of diagnostics, therapy and prevention. An invitation link was sent by email to all ESICM members. Furthermore, the survey was available on the ESICM homepage. Results: A total of 154 healthcare professionals from 39 countries participated in the survey. An ICU-AW screening protocol was used by 20% (28/140) of participants. Forty-four percent (62/141) of all participants reported performing routine screening for ICU-AW, using clinical examination as the method of choice (124/141, 87.9%). Almost 63% (84/134) of the participants reported using current treatment strategies for patients with ICU-AW. The use of treatment and prevention strategies differed between intensivists and non-intensivists regarding the reduction in sedatives (80.0% vs. 52.6%, p = 0.002), neuromuscular blocking agents (76.4% vs. 50%, p = 0.004), corticosteroids (69.1% vs. 37.2%, p < 0.001) and glycemic control regimes (50.9% vs. 23.1%, p = 0.002). Mobilization and physical activity are the most frequently reported treatment strategies for ICU-AW (111/134, 82.9%). The availability of physiotherapists (92/134, 68.7%) and the lack of knowledge about ICU-AW within the medical team (83/134, 61.9%) were the main obstacles to the implementation of the strategies. The necessity to develop guidelines for the screening, diagnosing, treatment and prevention of ICU-AW was recognized by 95% (127/133) of participants. Conclusions: A great heterogeneity regarding diagnostics, treatment and prevention of ICU-AW was reported internationally. Comprehensive guidelines with evidence-based recommendations for ICU-AW management are needed.
Project description:Ocular dominance plasticity (ODP) following monocular deprivation (MD) is a model of activity-dependent neural plasticity that is restricted to an early critical period regulated by maturation of inhibition. Unique developmental plasticity mechanisms may improve outcomes following early brain injury. Our objective was to determine the effects of neonatal cerebral hypoxia-ischemia (HI) on ODP. The rationale extends from observations that neonatal HI results in death of subplate neurons, a transient population known to influence development of inhibition. In rodents subjected to neonatal HI and controls, maps of visual response were derived from optical imaging during the critical period for ODP and changes in the balance of eye-specific response following MD were measured. In controls, MD results in a shift of the ocular dominance index (ODI) from a baseline of 0.15 to -0.10 (p < 0.001). Neonatal HI with moderate cortical injury impairs this shift, ODI = 0.14 (p < 0.01). Plasticity was intact in animals with mild injury and in those exposed to hypoxia alone. Neonatal HI resulted in decreased parvalbumin expression in hemispheres receiving HI compared with hypoxia alone: 23.4 versus 35.0 cells/high-power field (p = 0.01), with no change in other markers of inhibitory or excitatory neurons. Despite abnormal inhibitory neuron phenotype, spontaneous activity of single units and development of orientation selective responses were intact following neonatal HI, while overall visual responses were reduced. Our data suggest that specific plasticity mechanisms are impaired following early brain injury and that the impairment is associated with altered inhibitory neuronal development and cortical activation.
Project description:Hypobaric hypoxia can produce neuropsychological disorders such as insomnia, dizziness, memory deficiencies, headache and nausea. Here we report the changes in adrenomedullin (AM) expression observed in rats exposed to hypobaric hypoxia and different times of reoxygenation. AM immunoreactivity was transiently elevated in the cerebral cortex after 7 h of exposure to a simulated altitude of 8325 m (27 000 ft). This higher expression was seen in all pyramidal cells and in a subset of small interneurons. AM-positive nonpyramidal neurons contained also calbindin and calretinin, but no parvalbumin immunoreactivity, thus identifying them as bipolar and double bouquet cells. Small blood vessels and related astroglia also became immunoreactive following the hypobaric insult. AM up-regulation decreased progressively with the time of reoxygenation, reaching almost control levels after 5 days. Real-time PCR quantification of AM mRNA and Western blotting confirmed the up-regulation of AM expression following hypobaria. In addition, hypobaria modulates alternative splicing of the AM gene resulting in a higher production of AM. Our data show that AM expression regulation constitutes a cortical response to hypobaria, suggesting that AM modulation may provide new therapeutic avenues to prevent and/or treat the symptoms produced by hypobaria.