Stabilizing histamine release in gut mast cells mitigates peripheral and central inflammation after stroke.

Stroke is the most common cause of long-term disability and places a high economic burden on the global healthcare system. Functional outcomes from stroke are largely determined by the extent of ischemic injury, however, there is growing recognition that systemic inflammatory responses also contribute to outcomes. Mast cells (MCs) rapidly respond to injury and release histamine (HA), a pro-inflammatory neurotransmitter that enhances inflammation. The gut serves as a major reservoir of HA. We hypothesized that cromolyn, a mast cell stabilizer that prevents the release of inflammatory mediators, would decrease peripheral and central inflammation, reduce MC trafficking to the brain, and improve stroke outcomes. We used the transient middle cerebral artery occlusion (MCAO) model of ischemic stroke in aged (18 mo) male mice to investigate the role of MC in neuroinflammation post-stroke. After MCAO we treated mice with 25 mg/kg body weight of cromolyn (MC stabilizer) by oral gavage. Cromolyn was administered at 3 h, 10 h, 24 h and every 24 h for 3 days post-stroke. Three control groups were used. One group underwent a sham surgery and was treated with cromolyn, one received sham surgery with PBS vehicle and the third underwent MCAO with PBS vehicle. Mice were euthanized at 24 h and 3 days post-stroke. Cromolyn administration significantly reduced MC numbers in the brain at both 24 h and 3 days post-stroke. Infarct volume was not significantly different between groups, however improved functional outcomes were seen at 3 days post-stroke in mice that received cromolyn. Treatment with cromolyn reduced plasma histamine and IL-6 levels in both the 24-h and 3-day cohorts. Gut MCs numbers were significantly reduced after cromolyn treatment at 24 h and 3 days after stroke. To determine if MC trafficking from the gut to the brain occurred after injury, GFP+MCs were adoptively transferred to c-kit-/- MC knock-out animals prior to MCAO. 24 h after stroke, elevated MC recruitment was seen in the ischemic brain. Preventing MC histamine release by cromolyn improved gut barrier integrity and an improvement in stroke-induced dysbiosis was seen with treatment. Our results show that preventing MC histamine release possesses prevents post-stroke neuroinflammation and improves neurological and functional outcomes.

Interlink between the gut microbiota and inflammation in the context of oxidative stress in Alzheimer's disease progression.

The microbiota-gut-brain axis is an important pathway of communication and may dynamically contribute to Alzheimer's disease (AD) pathogenesis. Pathological commensal gut microbiota alterations, termed as dysbiosis, can influence intestinal permeability and break the blood-brain barrier which may trigger AD pathogenesis via redox signaling, neuronal, immune, and metabolic pathways. Dysbiosis increases the oxidative stress. Oxidants affect the innate immune system through recognizing microbial-derived pathogens by Toll-like receptors and initiating the inflammatory process. Most of the gut microbiome research work highlights the relationship between the gut microbiota and AD, but the contributory connection between precise bacteria and brain dysfunction in AD pathology cannot be fully demonstrated. Here, we summarize the current information of the fundamental connections between oxidative stress, inflammation, and gut dysbiosis in AD. This review emphasizes on the involvement of gut microbiota in the regulation of oxidative stress, inflammation, immune responses including central and peripheral cross-talk. It provides insights for novel preventative and therapeutic approaches in AD.

Bacterial Amyloid Curli Associated Gut Epithelial Neuroendocrine Activation Predominantly Observed in Alzheimer's Disease Mice with Central Amyloid-ß Pathology.

BACKGROUND: Substantial evidence from recent research suggests an influential and underappreciated force in Alzheimer's disease (AD) pathogenesis: the pathological signals originate from outside the brain. Pathogenic bacteria produce amyloid-like proteins "curli" that form biofilms and show functional similarities to human amyloid-ß (Aß). These proteins may contribute to neurological disease progression via signaling cascade from the gut to the brain. OBJECTIVE: We propose that curli causes neuroendocrine activation from the gut to brain that promotes central Aß pathology. METHODS: PGP9.5 and TLR2 levels in response to curli in the lumen of Tg2576 AD mice were analyzed by immunohistochemical and qRT-PCR analysis. Western blot and human 3D in vitro enteroids culture systems were also used. 16S rRNA gene sequencing was used to investigate bacterial dysbiosis. RESULTS: We found significant increase in bacterial-amyloid curli with elevated TLR2 at the mRNA level in the pre- and symptomatic Tg-AD gut compared to littermate WT controls. This data associates with increased gram-positive bacterial colonization in the ileum of the symptomatic AD mice. We found fundamental evidence for vagus nerve activation in response to bacterial curli. Neuroendocrine marker PGP9.5 was significantly elevated in the gut epithelium of symptomatic AD mice, and this was colocalized with increased TLR2 expression. Enteroids, 3D-human ileal mini-gut monolayer in vitro model system also revealed increase levels of TLR2 upon stimulation with purified bacterial curli fibrils. CONCLUSION: These findings reveal the importance of pathological changes within the gut-vagus-brain signaling in response to luminal bacterial amyloid that might play a vital role in central Aß pathogenesis seen in the AD brain.

Parietal lobe and disorganisation syndrome in schizophrenia and psychotic bipolar disorder: A bimodal connectivity study.

Given the emerging evidence in support of parietal brain stimulation to treat speech disorder in psychosis, we investigated structural and functional parietal dysconnectivity in schizophrenia (n = 34) and bipolar disorder with psychotic symptoms (n = 16). We found that both patient groups demonstrated reduced left parietal structural connectivity compared to healthy controls (n = 32). The three groups also differed significantly on the variability of left and right parietal dynamic functional connectivity. In patients with schizophrenia, parietal dysconnectivity predicted the severity of disorganisation symptoms. These findings suggest that dysconnectivity between the parietal lobe and the rest of the brain plays a key role in disorganisation symptoms of schizophrenia.

A method for independent component graph analysis of resting-state fMRI.

INTRODUCTION: Independent component analysis (ICA) has been extensively used for reducing task-free BOLD fMRI recordings into spatial maps and their associated time-courses. The spatially identified independent components can be considered as intrinsic connectivity networks (ICNs) of non-contiguous regions. To date, the spatial patterns of the networks have been analyzed with techniques developed for volumetric data. OBJECTIVE: Here, we detail a graph building technique that allows these ICNs to be analyzed with graph theory. METHODS: First, ICA was performed at the single-subject level in 15 healthy volunteers using a 3T MRI scanner. The identification of nine networks was performed by a multiple-template matching procedure and a subsequent component classification based on the network "neuronal" properties. Second, for each of the identified networks, the nodes were defined as 1,015 anatomically parcellated regions. Third, between-node functional connectivity was established by building edge weights for each networks. Group-level graph analysis was finally performed for each network and compared to the classical network. RESULTS: Network graph comparison between the classically constructed network and the nine networks showed significant differences in the auditory and visual medial networks with regard to the average degree and the number of edges, while the visual lateral network showed a significant difference in the small-worldness. CONCLUSIONS: This novel approach permits us to take advantage of the well-recognized power of ICA in BOLD signal decomposition and, at the same time, to make use of well-established graph measures to evaluate connectivity differences. Moreover, by providing a graph for each separate network, it can offer the possibility to extract graph measures in a specific way for each network. This increased specificity could be relevant for studying pathological brain activity or altered states of consciousness as induced by anesthesia or sleep, where specific networks are known to be altered in different strength.

Post-radiotherapy locoregional recurrence of hyalinizing clear cell carcinoma of palate.

Clear cell carcinoma of the salivary glands is a rare tumor that represents less than 1% of all salivary tumors and is a new disease that is only recognized in recent years. It is rare and the standard treatment is still under investigation. This tumor often follows an indolent course and treatment includes wide surgical excision with or without adjuvant radiotherapy. Recurrence of the hyalinizing clear cell carcinoma (HCCC) after complete surgical resection is uncommonly documented. We hereby report a case of post-radiotherapy locoregional recurrence of HCCC of the palate and recommend further clinicopathological study and long-term follow-up to document the biological behavior of this entity along with highlighting the role of special stains and immunohistochemistry in its diagnosis.

Infarction of a polyp within a mesenteric cyst: An unusual presentation as an acute abdomen.

A case of mesenteric cyst in a five-year-old male child who presented with acute abdomen due to an infarcted polyp present within the cyst is reported. To the best of our knowledge, such an event has never been reported in the literature previously.