At present, diagnosis for neurosyphilis remains a major clinical challenge. Venereal Disease Research Laboratory (VDRL) titer of the cerebrospinal fluid (CSF) is suboptimally sensitive to diagnose ...neurosyphilis, which can be negative in neurosyphilis patients, especially in asymptomatic neurosyphilis patients. In the search for biomarkers of neurosyphilis, we investigated the chemokine profile in CSF of neurosyphilis patients and found that the concentrations of CXCL13, CXCL10 and CXCL8 were selectively elevated in neurosyphilis patients and correlated with CSF protein concentration and CSF-VDRL titer. After antibiotic treatment, the concentration of these chemokines was dramatically reduced. The area under the ROC curve (AUC) of CSF CXCL13, CXCL8,CXCL10 and the CSF/serum ratio of CXCL13, CXCL8,CXCL10 in the diagnosis of neurosyphilis were 0.940, 0.899, 0.915, 0.963, 0.846 and 0.926, respectively. The corresponding sensitivities/specificities of CSF CXCL13, CXCL8,CXCL10 and the CSF/serum ratio of CXCL13, CXCL8,CXCL10 in diagnosis of neurosyphilis were 85.4%/89.1%, 79%/90.1% and 79.6%/91.1%, 86.6%/99%, 79%/73.3% and 86%/92.1%, respectively. Our results suggest that the elevated concentrations of CXCL13, CXCL8, and CXCL10 or their increasing CSF/serum ratios may be potential biomarkers of neurosyphilis, particularly for asymptomatic neurosyphilis. Reduced concentration of these chemokines may indicate the prognosis of antibiotic therapy.
Treponema pallidum infection evokes vigorous immune responses, resulting in tissue damage. Several studies have demonstrated that IL-17 may be involved in the pathogenesis of syphilis. However, the ...role of Th17 response in neurosyphilis remains unclear.
In this study, Th17 in peripheral blood from 103 neurosyphilis patients, 69 syphilis patients without neurological involvement, and 70 healthy donors were analyzed by flow cytometry. The level of IL-17 in cerebrospinal fluid (CSF) was quantified by ELISA. One-year follow up for 44 neurosyphilis patients was further monitored to investigate the role of Th17/IL-17 in neurosyphilis. We found that the frequency of Th17 cells was significantly increased in peripheral blood of patients with neurosyphilis, in comparison to healthy donors. IL-17 in CSF were detected from 55.3% neurosyphilis patients (in average of 2.29 (0-59.83) pg/ml), especially in those with symptomatic neurosyphilis (61.9%). CSF IL-17 was predominantly derived from Th17 cells in neurosyphilis patients. Levels of IL-17 in CSF of neurosyphilis patients were positively associated with total CSF protein levels and CSF VDRL (Venereal Disease Research Laboratory) titers. Notably, neurosyphilis patients with undetectable CSF IL-17 were more likely to confer to CSF VDRL negative after treatment.
These findings indicate that Th17 response may be involved in central nervous system damage and associated with clinical symptoms in neurosyphilis patients. Th17/IL-17 may be used as an alternative surrogate marker for assessing the efficacy of clinical treatment of neurosyphilis patients.
Prompt therapy with high-dose intravenous benzylpenicillin for a prolonged period is critical for neurosyphilis patients to avoid irreversible sequelae. However, life-threatening neutropenia has been ...reported as a complication of prolonged therapy with high doses of benzylpenicillin when treating other diseases. This study aimed to investigate the incidence, presentation, management and prognosis of benzylpenicillin-induced neutropenia in treating neurosyphilis based on a large sample of syphilis patients in Shanghai.
Between 1st January 2013 and 31st December 2015, 1367 patients with neurosyphilis were treated with benzylpenicillin, 578 of whom were eligible for recruitment to this study. Among patients without medical co-morbidities, the total incidence of benzylpenicillin-induced neutropenia and severe neutropenia was 2.42% (95% CI: 1.38-4.13%) and 0.35% (95% CI: 0.06-1.39%), respectively. The treatment duration before onset of neutropenia ranged from 10 to 14 days, with a total cumulative dose of between 240 and 324 megaunits of benzylpenicillin. Neutropenia was accompanied by symptoms of chills and fever (5 patients), fatigue (2 patients), cough (1 patient), sore throat (1 patient), diarrhea (1 patient) and erythematous rash (1 patient). The severity of neutropenia was not associated with age, gender or type of neurosyphilis (p>0.05). Neutropenia, even when severe, was often tolerated and normalized within one week. A more serious neutropenia did not occur when reinstituting benzylpenicillin in patients with mild or moderate neutropenia nor when ceftriaxone was used three months after patients had previously experienced severe neutropenia.
Benzylpenicillin-induced neutropenia was uncommon in our cohort of patients. Continuation of therapy was possible with intensive surveillance for those with mild or moderate neutropenia. For severe neutropenia, it is not essential to aggressively use hematopoietic growth factors or broad-spectrum antibiotics for patients in good physical condition after withdrawing anti-neurosyphilis regimen. We did not see an exacerbation of neutropenia in patients with the readministration of benzylpenicillin.
The mechanisms underlying the increase of Th17 in CNS in neurosyphilis need to be further elucidated. Because Th17 response may induce the immune-mediated CNS injury, we further evaluated the ...relationship between IL-17 and the clinical outcome of neurosyphilis. Since longer time would be required to clear a higher number of T. pallidum burden, the likelihood of normalization of CSF VDRL reactivity at the end of the observation would be lower. Because the sample size is limited (the number of subjects included in the regression analyses was only ranged from 21 to 44 patients in this study), a large sample study is needed to further understanding the true immune response at different stages of neurosyphilis and its clinical significance. ...our findings demonstrate that neurological damage in syphilis patients is associated with increased CSF Th17/IL-17 response.
•Effects of fuel injection timings and split ratio in M/D/M strategy are investigated.•Too advanced methanol injection leads to wall wetting and too delayed leads to knock.•Delayed diesel injection ...and large dwell could reduce knock intensity effectively.•Excessive split ratios at high load should be avoided to prevent knock.
To improve fuel economy and emissions of a diesel/methanol dual-fuel direct injection engine at high load, a methanol/diesel/methanol (M/D/M) strategy is proposed and investigated. This M/D/M strategy consists of injecting a portion of methanol in the compression stroke to form a certain concentration of premixed charge, then injecting diesel near the TDC to ignite the premixed methanol/air mixture, and finally injecting the rest methanol into the flame to achieve diffusion combustion. In this work, a numerical study is conducted to investigate the effects of fuel injection timings and methanol split ratio (SR) in the M/D/M strategy. The results show that too advanced methanol injection timing (MSOI) leads to wall wetting while too delayed MSOI easily leads to knock; MSOI-30 is the most suitable setting to avoid these undesirable outcomes. Delayed diesel injection timing (DSOI) and large dwell can control knock intensity effectively. Moreover, increasing SR properly helps to improve fuel economy, while an excessive SR is prone to knocking. Accounting for engine performance and emissions, a SR of 50:50 paired with a MSOI-30/DSOI-5/MSOI-3 setup is the best overall configuration.
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Emerging evidence suggests that vascular pathological changes play a pivotal role in the pathogenesis of Alzheimer's disease (AD). The dysfunction of the cerebral vasculature occurs ...in the early course of AD, characterized by alterations in vascular morphology, diminished cerebral blood flow (CBF), impairment of the neurovascular unit (NVU), vasculature inflammation, and cerebral amyloid angiopathy. Vascular dysfunction not only facilitates the influx of neurotoxic substances into the brain, triggering inflammation and immune responses but also hampers the efflux of toxic proteins such as Aβ from the brain, thereby contributing to neurodegenerative changes in AD. Furthermore, these vascular changes significantly impact drug delivery and distribution within the brain. Therefore, developing targeted delivery systems or therapeutic strategies based on vascular alterations may potentially represent a novel breakthrough in AD treatment. This review comprehensively examines various aspects of vascular alterations in AD and outlines the current interactions between nanoparticles and pathological changes of vascular.
Soluble N-ethylmaleimide sensitive factor activating protein receptor (SNARE) proteins are a large family of transmembrane proteins located in organelles and vesicles. The important roles of SNARE ...proteins include initiating the vesicle fusion process and activating and fusing proteins as they undergo exocytosis activity, and SNARE proteins are also vital for the transport regulation of membrane proteins and non-regulatory vesicles. Therefore, there is great significance in establishing a method to efficiently identify SNARE proteins. However, the identification accuracy of the existing methods such as SNARE CNN is not satisfied. In our study, we developed a method based on a support vector machine (SVM) that can effectively recognize SNARE proteins. We used the position-specific scoring matrix (PSSM) method to extract features of SNARE protein sequences, used the support vector machine recursive elimination correlation bias reduction (SVM-RFE-CBR) algorithm to rank the importance of features, and then screened out the optimal subset of feature data based on the sorted results. We input the feature data into the model when building the model, used 10-fold crossing validation for training, and tested model performance by using an independent dataset. In independent tests, the ability of our method to identify SNARE proteins achieved a sensitivity of 68%, specificity of 94%, accuracy of 92%, area under the curve (AUC) of 84%, and Matthew's correlation coefficient (MCC) of 0.48. The results of the experiment show that the common evaluation indicators of our method are excellent, indicating that our method performs better than other existing classification methods in identifying SNARE proteins.
In neonatal hypoxic-ischemic brain damage (HIBD), in addition to damage caused by hypoxia and ischemia, over-activation of inflammation leads to further deterioration of the condition, thus greatly ...shortening the optimal treatment time window. Ischemic penumbra, the edematous area encompassing the infarct core, is characterized by typical activation of microglia and overt inflammation, and prone to incorporate into the infarct core gradually after ischemia onset. If treated in time, the cells located in the penumbra can survive, thereby impeding the expansion of the infarction. We demonstrated for the first time that in the acute phase of HIBD in neonatal mice, treatment of Oxiracetam (ORC) significantly curtailed the size of ischemic penumbra together with drastic reduction of infarction. By staining various cellular markers, we found that the penumbra was defined and concentrated with activated microglia. We also analyzed transmission electron microscopy and Luminex assay results to elucidate the mechanisms involved. We further confirmed that ORC switched polarization of microglia from the inflammatory towards the alternatively activated phenotype, thus promoting microglia from being neurotoxic into neuroprotective. Meanwhile, ORC decreased proliferation of microglia; however, their functions of phagocytosis and autophagy were otherwise enhanced. Last, we clarified that ORC promoted autophagy through the AMPK/mTOR pathway, which further induced the transition of the inflammatory to the alternatively activated phenotype in microglia. The pro-inflammatory factors secretion was inhibited as well, thereby reducing the progression of the infarction. Taken together, it is concluded that Oxiracetam reduced the expansion of ischemic infarction in part via regulating the interplay between microglia activation and autophagy, which would delay the progression of HIBD and effectively prolong the time window for the clinical treatment of HIBD.
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