Glymphatic System Dysfunction in Mild Traumatic Brain Injury

ObjectiveTo assess the clinical role of the glymphatic system in mild traumatic brain injury (mTBI) and post-concussive syndrome (PCS).BackgroundClinical manifestations of mTBI, or concussion, involve a wide array of cognitive, behavioral, and mechanical impairments that commonly spontaneously resolve within weeks. When these symptoms persist, it defines a class of mTBI known as post-concussive syndrome. A multifaceted approach for diagnosing concussion and PCS, heavily reliant on a neurocognitive screening, has become the standard in suspected cases. Conventional imaging protocols are occasionally implemented for exclusion of structural injury, rarely revealing substantial evidence in otherwise uncomplicated mTBI. A CNS-specific lymphatic network, termed glymphatic, has shown to play a critical role in immune surveillance and drainage of cellular debris. Moreover, recent evidence points to glymphatic dysfunction in TBI, including mild cases, as its anatomical layout becomes better understood. Here, we review the current literature on glymphatic function and imaging modalities, with an emphasis on implications in mTBI.Design/MethodsLiterature was compiled primarily using various keyword searches (glymphatic + imaging, meningeal lymphatics, glymphatic + concussion, etc.) via Pubmed and the NIH/NLM archive. Inclusion criteria involved limiting to studies on human patients or tissue.ResultsThe glymphatic system displays critical function in healthy patients and in disease, with activity that suggests a diurnal sleep-cycle. Advanced imaging methodologies, most notably, the use of various MRI techniques, have identified impairments in meningeal lymphatic dysfunction in TBI, however, the clinical application of glymphatic imaging has yet to be well-studied and shows challenges in providing definitive data. Nonetheless, the potential for glymphatic imaging to expand our understanding of mTBI and PCS warrants further investigation.ConclusionsAnatomical and functional properties of the glymphatic network make an appealing target for concussion diagnosis, observing recovery, and exposing impact-related microstructural injuries, however the implementation of imaging in a clinical setting has yet to be well-characterized.

Quantification of Total HIV DNA as a Marker to Measure Viral Reservoir: Methods and Potential Implications for Clinical Practice

The focus of this review is to examine the importance of quantifying total HIV DNA to target the HIV reservoir and the clinical implications and challenges involved in its future application in clinical practice. Despite intrinsic limitations, the quantification of total HIV DNA is currently the most widely used marker for exploring the HIV reservoir. As it allows estimating all forms of HIV DNA in the infected cells, total HIV DNA load is the biomarker of the HIV reservoir that provides most of the insights into HIV pathogenesis. The clinical role of total HIV-DNA in both untreated and treated patients is extensively supported by important lines of evidence. Thus, predictive models that include total HIV DNA load together with other variables could constitute a prognostic tool for use in clinical practice. To date, however, this marker has been primarily used in experimental evaluations. The main challenge is technical. Although the implementation of droplet digital PCR could improve analytical performance over real-time PCR, the lack of standardization has made cross-comparisons of the data difficult. An effort by investigators to compare protocols is needed. Furthermore, the main effort now should be to involve the biomedical industry in the development of certified assays for in vitro diagnostics use.

The Roles of Cardiovascular H2-Histamine Receptors Under Normal and Pathophysiological Conditions

This review addresses pharmacological, structural and functional relationships among H2-histamine receptors and H1-histamine receptors in the mammalian heart. The role of both receptors in the regulation of force and rhythm, including their electrophysiological effects on the mammalian heart, will then be discussed in context. The potential clinical role of cardiac H2-histamine-receptors in cardiac diseases will be examined. The use of H2-histamine receptor agonists to acutely increase the force of contraction will be discussed. Special attention will be paid to the potential role of cardiac H2-histamine receptors in the genesis of cardiac arrhythmias. Moreover, novel findings on the putative role of H2-histamine receptor antagonists in treating chronic heart failure in animal models and patients will be reviewed. Some limitations in our biochemical understanding of the cardiac role of H2-histamine receptors will be discussed. Recommendations for further basic and translational research on cardiac H2-histamine receptors will be offered. We will speculate whether new knowledge might lead to novel roles of H2-histamine receptors in cardiac disease and whether cardiomyocyte specific H2-histamine receptor agonists and antagonists should be developed.

Role of tissue molecular pathogens in development of acute chronic liver failure in alcoholic liver cirrhosis

The aim of the study was to assess the pathogenetic, diagnostic and clinical role of tissue molecular pathogens – fragments of cytokeratin-18 in the development of acute chronic liver failure (ACLF) in decompensated alcoholic liver cirrhosis (ALC).Materials and methods. 80 patients with ALC were examined: 30 without signs of ACLF and 50 with signs of ACLF and 36 healthy individuals. Hepatic functional tests were determined, a marker of hepatocyte apoptosis – fragments of cytokeratin-18 (FCK-18) (Biotech, Sweden) by the enzyme immunoassay, ACLF scores were calculated using an on-line calculator at www.efclif.com/scientific-activity/score-calculators/ clif-c-aclf.Results. With ACLF, a high level of FCK-18 was detected – 1505.4 ± 446.9 U/L, more than 20 times higher than that in healthy individuals – 71.5 ± 19.6 U/L (p < 0.05) and three times higher than the level of FCK-18 in patients with ALC without ACLF – 489.4 ± 490.2 U/L. The levels of aminotransferases, bilirubin, creatinine, INR were significantly higher in patients with ACLF compared with patients without ACLF, and the level of albumin was lower. FCK-18 level directly correlated with ALT – r = 0.61 (p < 0.05), AST – r = 0.68 (p < 0.05), with bilirubin level – r = 0.41 (p < 0, 05) and the ACLF score – r = 0.48 (p < 0.05) and inversely correlated with the albumin level r = –0.51 (p < 0.05).Conclusion. Apoptosis of hepatocytes and tissue molecular pathogens released during it – fragments of cytokeratin-18 – play a role in the development of acute chronic liver failure in decompensated alcoholic liver cirrhosis.

The Role of Neurophysiological Biomarkers in Obsessive-Compulsive Disorder

Background: Obsessive-compulsive disorder is a highly debilitating psychiatric disorder with a high rate of treatment resistance. Biomarkers for obsessive-compulsive disorder may assist clinicians by predicting response to treatments and prognosis. Objective: To review the literature with regards to two of the more easily ascertainable and relatively inexpensive physiological biomarkers, i.e. heart rate variability and electroencephalography. Methods: Narrative review of the literature. Results: Decreased heart rate variability has been associated with increased symptom severity of obsessive-compulsive disorder. Findings from electroencephalography have also predicted response to pharmacotherapy and it is likely that biomarkers for OCD will have their greatest utility in predicting response to different pharmacological agents. However, the number of studies is small and results are inconsistent. Conclusions: More research is required to determine whether heart rate variability and electrophysiological studies have a clinical role as biomarkers for obsessive-compulsive disorder.

Discoidin Domain-Containing Receptor 2 Is Present in Human Atherosclerotic Plaques and Involved in the Expression and Activity of MMP-2

Discoidin domain-containing receptor 2 (DDR2) has been suggested to be involved in atherosclerotic progression, but its pathological role remains unknown. Using immunochemical staining, we located and compared the expression of DDR2 in the atherosclerotic plaques of humans and various animal models. Then, siRNA was applied to knock down the expression of DDR2 in vascular smooth muscle cells (VSMCs), and the migration, proliferation, and collagen Ι-induced expression of matrix metalloproteinases (MMPs) were evaluated. We found that an abundance of DDR2 was present in the atherosclerotic plaques of humans and various animal models and was distributed around fatty and necrotic cores. After incubation of oxidized low-density lipoprotein (ox-LDL), DDR2 was upregulated in VSMCs in response to such a proatherosclerotic condition. Next, we found that decreased DDR2 expression in VSMCs inhibited the migration, proliferation, and collagen Ι-induced expression of matrix metalloproteinases (MMPs). Moreover, we found that DDR2 is strongly associated with the protein expression and activity of MMP-2, suggesting that DDR2 might play a role in the etiology of unstable plaques. Considering that DDR2 is present in the atherosclerotic plaques of humans and is associated with collagen Ι-induced secretion of MMP-2, the clinical role of DDR2 in cardiovascular disease should be elucidated in further experiments.

An updated review of the pre-clinical role of microRNAs and their contribution to colorectal cancer

: Colorectal cancer (CRC) is one of the main causes of malignancy-related mortality worldwide. It was well-identified that microRNAs (miRNAs) decisively participate in cellular biological pathways; in a way that their deregulated expression causes CRC progression. miRNAs can control the translation and degradation of mRNAs by binding to various molecular targets involved in different biological processes, including growth, apoptosis, cell cycle, autophagy, angiogenesis, metastasis, etc. The functions of these dysregulated miRNAs may be either oncogenic or tumor-suppressive. Therefore, these miRNAs can be contributed to prognostic, diagnostic, and therapeutic approaches in CRC. In this study, we reviewed the tumor-suppressive and oncogenic functions of miRNAs in CRC and assessed their molecular activities in CRC development. However, further investigation for the involvement of dysregulated miRNAs in CRC progression is required.

The Complex Network between Inflammation and Colorectal Cancer: A Systematic Review of the Literature

Background: colorectal cancer (CRC) has a multifactorial etiology which comprises microbiota, genetic predisposition, diet, environmental factors, and last but not least, a substantial contribution by inflammation. The aim of this study is to conduct a systematic review of the literature regarding the strong link between inflammation and colorectal cancer. Methods: A systematic review of the literature on PubMed (Medline), Scopus, Cochrane and EMBase databases was performed, following the PRISMA 2020 guidelines. Each paper was reviewed by two groups of researchers in a single-blind format by using a pre-planned Microsoft© Excel® grid. Results: Using automated research filters, 14,566 studies were included, but 1% was found significant by the reviewers. Seventy pathways of inflammation were described in the sequence of inflammation-carcinogenesis, and anti-tumorigenic molecules were also found. Conclusion: several studies suggest a strong role of inflammation in the tumorigenesis of colorectal cancer through different pathways: this may have a diagnostic and clinical role and also therapeutic purpose in preventing carcinogenesis by treating inflammation. In vitro tests support this theory, even if many other clinical trials are necessary. The present paper was registered in the OpenScience Framework registry (Identifier: DOI 10.17605/OSF.IO/2KG7T).

The relationship of blood CDC42 level with Th1 cells, Th17 cells, inflammation markers, disease risk/activity, and treatment efficacy of rheumatoid arthritis

Background Cell division control protein 42 (CDC42) is reported to be involved in multiple inflammation processes by regulating T cell differentiation, maintaining immune cell homeostasis, and altering their function, while no relevant studies explored its clinical role in patients with rheumatoid arthritis (RA). Therefore, this study aimed to explore the correlation of CDC42 with Th1 and Th17 cells and its association with disease risk, activity, and treatment outcomes of RA. Methods After the enrollment of 95 active RA patients and 50 healthy subjects (HC), their CDC42, Th1 cells, and Th17 cells were assayed by RT-qPCR and flow cytometry, accordingly. For RA patients only, CDC42 was also detected at W6, and W12 after treatment. The treatment response and remission status were evaluated at W12. Results Compared to HC, CDC42 was reduced (P < 0.001), while Th1 cells (P = 0.021) and Th17 cells (P < 0.001) were increased in RA patients. Besides, CDC42 was negatively correlated with Th17 cells (P < 0.001), erythrocyte sedimentation rate (ESR) (P = 0.012), C-reactive protein (P = 0.002), and disease activity score in 28 joints (DAS28) (P = 0.007), but did not relate to Th1 cells or other disease features (all P > 0.05) in RA patients. Furthermore, CDC42 was elevated during treatment in RA patients (P < 0.001). Moreover, CDC42 increment at W12 correlated with treatment response (P = 0.004). Besides, CDC42 elevation at W0 (P = 0.038), W6 (P = 0.001), and W12 (P < 0.001) also linked with treatment remission. Conclusion CDC42 has the potential to serve as a biomarker to monitor disease activity and treatment efficacy in patients with RA.

Staphylococcus aureus isolates from Eurasian Beavers (Castor fiber) carry a novel phage-borne bicomponent leukocidin related to the Panton-Valentine leukocidin

Staphylococcus aureus can be a harmless coloniser, but it can also cause severe infections in humans, livestock and wildlife. Regarding the latter, only few studies have been performed and knowledge on virulence factors is insufficient. The aim of the present study was to study S. aureus isolates from deceased wild beavers (Castor fiber). Seventeen isolates from eleven beavers, found in Germany and Austria, were investigated. Antimicrobial and biocide susceptibility tests were performed. Isolates were characterised using S. aureus-specific DNA microarrays, spa typing and whole-genome sequencing. From two isolates, prophages were induced by mitomycin C and studied by transmission electron microscopy. Four isolates belonged to clonal complex (CC) 8, CC12, and CC398. Twelve isolates belonged to CC1956 and one isolate was CC49. The CC49 and CC1956 isolates carried distinct lukF/S genes related to the Panton-Valentine leukocidin (PVL) from human isolates of S. aureus. These genes were located on related, but not identical, Siphovirus prophages. The beavers, from which those isolates originated, suffered from abscesses, purulent organ lesions and necrotising pneumonia, i.e., clinical manifestations resembling symptoms of severe PVL-associated disease in humans. It might thus be assumed that the “Beaver Leukocidin (BVL, lukF/S-BV)”-positive strains are beaver-specific pathogens, and further studies on their clinical role as well as on a possible transmissibility to other species, including humans, are warranted.