Cryptococcal meningitis has high mortality. Flucytosine is a key treatment but is expensive and rarely available. The anticancer agent tamoxifen has synergistic anti-cryptococcal activity with ...amphotericin in vitro. It is off-patent, cheap, and widely available. We performed a trial to determine its therapeutic potential.
Open label randomized controlled trial. Participants received standard care - amphotericin combined with fluconazole for the first 2 weeks - or standard care plus tamoxifen 300 mg/day. The primary end point was Early Fungicidal Activity (EFA) - the rate of yeast clearance from cerebrospinal fluid (CSF). Trial registration https://clinicaltrials.gov/ct2/show/NCT03112031.
Fifty patients were enrolled (median age 34 years, 35 male). Tamoxifen had no effect on EFA (-0.48log10 colony-forming units/mL/CSF control arm versus -0.49 tamoxifen arm, difference -0.005log10CFU/ml/day, 95% CI: -0.16, 0.15, p=0.95). Tamoxifen caused QTc prolongation.
High-dose tamoxifen does not increase the clearance rate of
from CSF. Novel, affordable therapies are needed.
The trial was funded through the Wellcome Trust Asia Programme Vietnam Core Grant 106680 and a Wellcome Trust Intermediate Fellowship to JND grant number WT097147MA.
Tau protein can be released by neurons, an event linked to the propagation of Tau pathology in Alzheimer'disease (AD). Neuronal hyperexcitability was shown to significantly increase Tau release by ...neurons. We confirmed this in the present study. In a previous study, it was demonstrated that hyperexcitability induces Golgi apparatus dynamics resulting in its fragmentation. Our present results revealed that the increase of Tau secretion upon hyperexcitability could be significantly reduced by preventing Golgi dynamics through the inactivation of cdk5. We then verified whether a Golgi fragmentation not induced by hyperexcitability could also increase Tau secretion. The suppression of Rab1A, Rab GTPase associated with the Golgi membranes, known to induce a Golgi fragmentation increased Tau secretion by both neurons and HeLa cells. Although it remains to be demonstrated whether the Golgi is directly involved in Tau secretion, the present results demonstrate that its dynamics are correlated to a modulation of Tau secretion.
It is well documented that neurofibrillary tangles composed of aggregated tau protein propagate in a predictable pattern in Alzheimer's disease (AD). The mechanisms underlying the propagation of tau ...pathology are still poorly understood. Recent studies have provided solid data demonstrating that in several neurodegenerative diseases including AD, the spreading of misfolded protein aggregates in the brain would result from prion‐like cell‐to‐cell transmission. Consistent with this new concept, recent studies have reported that human tau can be released in the extracellular space by an active process of secretion, and can be endocytosed both in vitro and in vivo. Most importantly, it was reported that the spreading of tau pathology was observed along synaptically connected circuits in a transgenic mouse model where human tau overexpression was restricted in the entorhinal cortex. This indicates that secretion of tau by presynaptic neurons and its uptake by postsynaptic neurons could be the sequential events leading to the propagation of tau pathology in the brain.
The present review focuses on the new concept that the spreading of tau pathology in Alzheimer brain would result from a cell‐to‐cell transmission of tau aggregates. Consistent with this concept, recent studies have reported that tau can be released by an active process of secretion and can be taken up by endocytosis by both non‐neuronal and neuronal cells.
The axonal microtubule‐associated protein TAU, involved in Alzheimer's disease (AD), can be found in the extracellular space where it could be taken up by neurons, an event that is believed to ...contribute to the propagation of tau pathology in the brain. Since the small GTPase Rab7A is involved in the trafficking of endosomes, autophagosomes, and lysosomes, and RAB7A gene expression and protein levels are up‐regulated in AD patients, we tested the hypothesis that Rab7A was involved in tau secretion. We previously reported that both primary cortical neurons and HeLa cells over‐expressing human TAU can release tau. Using these two cellular systems, we demonstrated that Rab7A regulates tau secretion. Upon Rab7A deletion, tau secretion was decreased. Consistent with this, the over‐expression of a dominant negative and a constitutively active form of Rab7A decreased and increased tau secretion, respectively. A partial co‐localization of tau and Rab7‐positive structures in both neurons and HeLa cells indicated that a late endosomal compartment could be involved in its secretion. Collectively, the present data indicate that Rab7A regulates tau secretion and therefore the up‐regulation of RAB7A reported in AD, could contribute to the extracellular accumulation of pathological TAU species that could result in the propagation of tau pathology in the AD brain.
Our data demonstrate that Rab7A involved in endocytosis and autophagy regulates the secretion of tau protein linked to Alzheimer's disease (AD). The suppression or inactivation of Rab7A decreases tau secretion, whereas the over‐expression of a constitutively active form of Rab7A increases it. tau is found in Rab7‐positive structures indicating that late endosomes could be involved in its secretion. Our data indicate that the up‐regulation of Rab7A noted in AD, could contribute to the release of pathological tau species responsible for the propagation of tau pathology in the AD brain.
It is well established that tau pathology propagates in a predictable manner in Alzheimer's disease (AD). Moreover, tau accumulates in the cerebrospinal fluid (CSF) of AD's patients. The mechanisms ...underlying the propagation of tau pathology and its accumulation in the CSF remain to be elucidated. Recent studies have reported that human tau was secreted by neurons and non-neuronal cells when it was overexpressed indicating that tau secretion could contribute to the spreading of tau pathology in the brain and could lead to its accumulation in the CSF. In the present study, we showed that the overexpression of human tau resulted in its secretion by Hela cells. The main form of tau secreted by these cells was cleaved at the C-terminal. Surprisingly, secreted tau was dephosphorylated at several sites in comparison to intracellular tau which presented a strong immunoreactivity to all phospho-dependent antibodies tested. Our data also revealed that phosphorylation and cleavage of tau favored its secretion by Hela cells. Indeed, the mimicking of phosphorylation at 12 sites known to be phosphorylated in AD enhanced tau secretion. A mutant form of tau truncated at D421, the preferential cleavage site of caspase-3, was also significantly more secreted than wild-type tau. Taken together, our results indicate that hyperphosphorylation and cleavage of tau by favoring its secretion could contribute to the propagation of tau pathology in the brain and its accumulation in the CSF.
Scope
This study evaluates the effects of a chronic high protein diet (HPD) on kidney injury, intestinal permeability and gut microbiota perturbations in a mouse model.
Method and results
Mice are ...fed a diet containing either 20% or 52% energy from protein for 24 weeks; protein displaced an equivalent amount of wheat starch. The HPD does not alter glycemic control or body weight. The HPD induces kidney injury as evidenced by increase in albuminuria, urinary kidney injury molecule‐1, blood urea nitrogen, urinary isoprostanes and renal cortical NF‐κB p65 gene expression. HPD decreases intestinal occludin gene expression, increases plasma endotoxin and plasma monocyte chemoattractant protein‐1, indicating intestinal leakiness and systemic inflammation. Cecal microbial analysis reveals that HPD feeding does not alter alpha diversity; however, it does alter beta diversity, indicating an altered microbial community structure with HPD feeding. Predicted metagenome pathway analysis demonstrates a reduction in branched‐chain amino acid synthesis and an increase of the urea cycle with consumption of a HPD.
Conclusion
These results demonstrate that long term HPD consumption in mice causes albuminuria, systemic inflammation, increase in gastrointestinal permeability and is associated with gut microbiome remodeling with an increase in the urea cycle pathway, which may contribute to renal injury.
A high protein diet is fed to mice for 24 weeks. This resulted in a change in the gut bacteria and functional pathways. There is increased leakiness of the gut, inflammation, and kidney injury. This study shows that the effect that high protein diets have on the gut bacteria may lead to kidney damage.
This study addresses the problem of Alzheimer's disease (AD) diagnosis with Electroencephalography (EEG). The use of EEG as a tool for AD diagnosis has been widely studied by comparing EEG signals of ...AD patients only to those of healthy subjects. By contrast, we perform automated EEG diagnosis in a differential diagnosis context using a new database, acquired in clinical conditions, which contains EEG data of 169 patients: subjective cognitive impairment (SCI) patients, mild cognitive impairment (MCI) patients, possible Alzheimer's disease (AD) patients, and patients with other pathologies. We show that two EEG features, namely epoch-based entropy (a measure of signal complexity) and bump modeling (a measure of synchrony) are sufficient for efficient discrimination between these groups. We studied the performance of our methodology for the automatic discrimination of possible AD patients from SCI patients and from patients with MCI or other pathologies. A classification accuracy of 91.6% (specificity = 100%, sensitivity = 87.8%) was obtained when discriminating SCI patients from possible AD patients and 81.8% to 88.8% accuracy was obtained for the 3-class classification of SCI, possible AD and other patients.
Bone morphogenetic protein-2 (BMP-2) is currently the only Food and Drug Administration (FDA)-approved osteoinductive growth factor used as a bone graft substitute. However, with increasing clinical ...use of BMP-2, a growing and well-documented side effect profile has emerged. This includes postoperative inflammation and associated adverse effects, ectopic bone formation, osteoclast-mediated bone resorption, and inappropriate adipogenesis. Several large-scale studies have confirmed the relative frequency of adverse events associated with the clinical use of BMP-2, including life-threatening cervical spine swelling. In fact, the FDA has issued a warning of the potential life-threatening complications of BMP-2. This review summarizes the known adverse effects of BMP-2, including controversial areas such as tumorigenesis. Next, select animal models that replicate BMP-2's adverse clinical effects are discussed. Finally, potential molecules to mitigate the adverse effects of BMP-2 are reviewed. In summary, BMP-2 is a potent osteoinductive cytokine that has indeed revolutionized the bone graft substitute market; however, it simultaneously has accrued a worrisome side effect profile. Better understanding of these adverse effects among both translational scientists and clinicians will help determine the most appropriate and safe use of BMP-2 in the clinical setting.
Each year, 10 million people worldwide survive the neurologic injury associated with a stroke. Importantly, stroke survivors have more than twice the risk of subsequently developing dementia compared ...with people who have never had a stroke. The link between stroke and the later development of dementia is not understood. There are reports of oligoclonal bands in the CSF of stroke patients, suggesting that in some people a B-lymphocyte response to stroke may occur in the CNS. Therefore, we tested the hypothesis that a B-lymphocyte response to stroke could contribute to the onset of dementia. We discovered that, in mouse models, activated B-lymphocytes infiltrate infarcted tissue in the weeks after stroke. B-lymphocytes undergo isotype switching, and IgM, IgG, and IgA antibodies are found in the neuropil adjacent to the lesion. Concurrently, mice develop delayed deficits in LTP and cognition. Genetic deficiency, and the pharmacologic ablation of B-lymphocytes using an anti-CD20 antibody, prevents the appearance of delayed cognitive deficits. Furthermore, immunostaining of human postmortem tissue revealed that a B-lymphocyte response to stroke also occurs in the brain of some people with stroke and dementia. These data suggest that some stroke patients may develop a B-lymphocyte response to stroke that contributes to dementia, and is potentially treatable with FDA-approved drugs that target B cells.
Weed invasions pose a threat to agricultural productivity. Weed recognition and detection play an important role in controlling weeds. The challenging problem of weed detection is how to discriminate ...between crops and weeds with a similar morphology under natural field conditions such as occlusion, varying lighting conditions, and different growth stages. In this paper, we evaluate a novel algorithm, filtered Local Binary Patterns with contour masks and coefficient k (k-FLBPCM), for discriminating between morphologically similar crops and weeds, which shows significant advantages, in both model size and accuracy, over state-of-the-art deep convolutional neural network (CNN) models such as VGG-16, VGG-19, ResNet-50 and InceptionV3. The experimental results on the "bccr-segset" dataset in the laboratory testbed setting show that the accuracy of CNN models with fine-tuned hyper-parameters is slightly higher than the k-FLBPCM method, while the accuracy of the k-FLBPCM algorithm is higher than the CNN models (except for VGG-16) for the more realistic "fieldtrip_can_weeds" dataset collected from real-world agricultural fields. However, the CNN models require a large amount of labelled samples for the training process. We conducted another experiment based on training with crop images at mature stages and testing at early stages. The k-FLBPCM method outperformed the state-of-the-art CNN models in recognizing small leaf shapes at early growth stages, with error rates an order of magnitude lower than CNN models for canola-radish (crop-weed) discrimination using a subset extracted from the "bccr-segset" dataset, and for the "mixed-plants" dataset. Moreover, the real-time weed-plant discrimination time attained with the k-FLBPCM algorithm is approximately 0.223 ms per image for the laboratory dataset and 0.346 ms per image for the field dataset, and this is an order of magnitude faster than that of CNN models.
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