Non-variceal upper gastrointestinal (GI) bleeding is a significant cause of morbidity and mortality. Traditionally, through-the-scope (TTS) clips, thermal therapy, and injection therapies are used to treat GI bleeding. In this review, we provide an overview of novel endoscopic treatments that can be used to achieve hemostasis. Specifically, we discuss the efficacy and applicability of over-the-scope clips, hemostatic agents, TTS doppler ultrasound, and endoscopic ultrasound, each of which offer an effective method of reducing rates of GI rebleeding.

Autoimmune optic papillitis is a rare disorder that causes progressive visual loss, often treated with rituximab (RTX). However, its use is not without risks. Here, we present a 51-year-old man who experienced vision loss because of autoimmune optic papillitis, which was well-controlled with RTX. Four years later, the patient developed abdominal pain and diarrhea and was found to have RTX-induced Crohns disease (CD). The patient failed treatment with azathioprine, but was subsequently able to achieve clinical and endoscopic remission of his CD with ustekinumab, while continuing RTX therapy for autoimmune optic papillitis. This case report describes the efficacy of the anti-interleukin 12/23 monoclonal antibody in inducing remission of RTX-induced CD.

Many diseases, including cancers, AIDS, diabetes, asthma, Parkinson's, and lymphoma, are associated with the immune cell responses of patients suffering from them. Identifying the underlying immune response in such diseases is critical to correctly diagnose their root cause and determine the correct medications to target that root cause for personal therapy and immunotherapy. This work focuses on small molecular CF dyes to conjugate with antibodies, such as CD4 and CD19, for their application in flow cytometry. The CF dyes enable the expansion of flow cytometry reagent panels to support high dimensional flow cytometry analysis of the resulting emissions of 30-40 fluorescent colors, a record in flow cytometry. The CF dyes can be used along with existing flow cytometry dyes to provide a quick, accurate, and cost-effective method for the diagnosis and immunology treatment of diseases such as minimal residual disease (MRD) after cancer therapy. The CF dyes will also be an effective tool for the clinical studies of immune response to SARS-CoV-2 and the related vaccine development.

Purpose

To investigate the immunoregulatory roles of adipose-derived mesenchymal stem cells (ADSCs) in autoimmune dacryoadenitis.

Methods

Rabbits were treated with ADSCs or phosphate-buffered solution on days 1, 3, 5, 7, and 9 after injection of activated peripheral blood lymphocytes, and clinical scores were determined by assessing tear production, break-up time, and fluorescein and hematoxylin and eosin staining. Inflammatory response was determined by measuring the expression of different mediators of inflammation in the lacrimal glands. The Th1/Th17-mediated autoreactive responses were evaluated by determining the proliferative response and the expression of cytokine genes and the lineage-determining transcription factors. The frequency of regulatory T cells (Tregs) was also examined.

Results

The ADSC-treated rabbits showed decreased autoimmune responses, and the secretory function of their lacrimal gland was restored significantly. Treatment with ADSCs downregulated the Th1 and Th17 responses but enhanced Tregs function. In addition, ADSC treatment noticeably suppressed the expression of matrix metalloproteinase (MMP)-9, MPP-2, IL-1β, and IL-6, whereas it enhanced the expression of the anti-inflammatory cytokine IL-10.

Conclusions

Our results demonstrated that ADSC administration efficiently ameliorates autoimmune dacryoadenitis mainly via modulating Th1/Th17 responses.

Pathogenic T helper (T_h)17 cells are key mediators of autoimmune diseases such as uveitis and its animal model, experimental autoimmune uveitis (EAU). However, the contribution of microRNAs (miRs) to the intrinsic control of pathogenic T_h17 cells in EAU remains largely unknown. Here, we have reported that miR-223-3p was significantly up-regulated in interphotoreceptor retinoid-binding protein-specific T_h17 cells, and its expression was enhanced by IL-23-signal transducer and activator of transcription 3 signaling. Knockdown of miR-223-3p decreased the pathogenicity of T_h17 cells in a T-cell transfer model of EAU. Mechanistic studies showed that miR-223-3p directly repressed the expression of forkhead box O3 (FOXO3), and FOXO3 negatively regulated pathogenic T_h17 cell responses partially via suppression of IL-23 receptor expression. Thus, our results reveal an important role for miR-223-3p in autoreactive T_h17 cell responses and suggest a potential therapeutic avenue for uveitis.-Wei, Y., Chen, S., Sun, D., Li, X., Wei, R., Li, X., Nian, H. miR-223-3p promotes autoreactive T_h17 cell responses in experimental autoimmune uveitis (EAU) by inhibiting transcription factor FOXO3 expression.

In this study, we showed that TLR7 activation significantly promoted interphotoreceptor retinoid-binding protein (IRBP)-specific Th17 responses by upregulating RORγt, IL-17, GM-CSF, and IL-23R expression in experimental autoimmune uveitis mice. In vivo administration of CL097 activated dendritic cells (DCs) and endowed them with an increased ability to activate IRBP-specific Th17 cells. CL097-treated DCs (CL097-DCs) formed a cytokine milieu that favored the generation and maintenance of Th17 cells by stimulating IL-1β, IL-6, and IL-23 expression. Furthermore, IRBP-specific T cells from immunized mice injected with CL097-DCs produced more IL-17 and transferred more severe experimental autoimmune uveitis than did those from mice injected with DCs. The enhanced immunostimulatory activities of CL097-DCs depended on JNK, ERK, and p38 activation. Blockade of ERK, but not p38 or JNK, completely abolished the Th17 responses induced by CL097-DCs. Collectively, our findings suggest that CL097 treatment significantly promotes autoreactive IL-17⁺ T cell responses through enhancing DC activation, which is mediated, at least in part, via the activation of ERK signaling.

Hereditary spastic paraplegias are a large, diverse group of neurological disorders (SPG1-71) with the unifying feature of prominent lower extremity spasticity, owing to a length-dependent axonopathy of corticospinal motor neurons. The most common early-onset form of pure, autosomal dominant hereditary spastic paraplegia is caused by mutation in the ATL1 gene encoding the atlastin-1 GTPase, which mediates homotypic fusion of ER tubules to form the polygonal ER network. We have identified a p.Pro342Ser mutation in a young girl with pure SPG3A. This residue is in a critical hinge region of atlastin-1 between its GTPase and assembly domains, and it is conserved in all known eukaryotic atlastin orthologs. We produced induced pluripotent stem cells from skin fibroblasts and differentiated these into forebrain neurons to generate a human neuronal model for SPG3A. Axons of these SPG3A neurons showed impaired growth, recapitulating axonal defects in atlastin-1-depleted rat cortical neurons and impaired root hair growth in loss-of-function mutants of the ATL1 ortholog rhd3 in the plant Arabidopsis. Both the microtubule cytoskeleton and tubular ER are important for mitochondrial distribution and function within cells, and SPG3A neurons showed alterations in mitochondrial motility. Even so, it is not clear whether this change is involved in disease pathogenesis. The SPG3A axon growth defects could be rescued with microtubule-binding agents, emphasizing the importance of tubular ER interactions with the microtubule cytoskeleton in hereditary spastic paraplegia pathogenesis. The prominent alterations in axon growth in SPG3A neurons may represent a particularly attractive target for suppression in screens for novel pharmacologic agents.

Bacteremia is a life-threating syndrome often caused by methicillin-resistant Staphylococcus aureus (MRSA). Thus, there is an urgent need to develop novel approaches to successfully treat this infection. Staphylococcal accessory regulator A (SarA), a global virulence regulator, plays a critical role in pathogenesis and β-lactam antibiotic resistance in Staphylococcus aureus. Hypericin is believed to act as an antibiotic, antidepressant, antiviral and non-specific kinase inhibitor. In the current study, we investigated the impact of hypericin on β-lactam antibiotics susceptibility and mechanism(s) of its activity. We demonstrated that hypericin significantly decreased the minimum inhibitory concentrations of β-lactam antibiotics (e.g., oxacillin, cefazolin and nafcillin), biofilm formation and fibronectin binding in MRSA strain JE2. In addition, hypericin significantly reduced sarA expression, and subsequently decreased mecA, and virulence-related regulators (e.g., agr RNAⅢ) and genes (e.g., fnbA and hla) expression in the studied MRSA strain. Importantly, the in vitro synergistic effect of hypericin with β-lactam antibiotic (e.g., oxacillin) translated into in vivo therapeutic outcome in a murine MRSA bacteremia model. These findings suggest that hypericin plays an important role in abrogation of β-lactam resistance against MRSA through sarA inhibition, and may allow us to repurpose the use of β-lactam antibiotics, which are normally ineffective in the treatment of MRSA infections (e.g., oxacillin).

Dry wells (gravity-fed infiltration wells) have frequently been used to recharge aquifers with stormwater, especially in urban areas, as well as manage flood risk and reduce surface water body contamination from stormwater pollutants. However, only limited assessment of their potential adverse impacts on groundwater quality exists. Dry well recharge can bypass significant portions of the filtering-capacity of the vadose zone. Stormwater and groundwater monitoring data and analysis of transport of a wide range of historic and current-use stormwater chemicals of concern is lacking. To address these gaps, two dry wells were constructed with vegetated and structural pretreatment features to assess the likelihood of stormwater contaminants reaching the aquifer. We monitored, assessed, and compared the presence of contaminants in stormwater to water quality in the vadose zone and shallow groundwater after it passed through the dry well. The dry wells were installed at a suburban residential and at a suburban commercial site. The selected sites were overlying a regional, unconsolidated, and highly heterogeneous alluvial aquifer system. Stormwater, vadose zone, and groundwater samples were collected during five storms and analyzed for over 200 contaminants of concern. Relatively few contaminants were detected in stormwater, generally at low concentrations. Prior to stormwater entering the dry well, 50-65% of contaminants were removed by vegetated pretreatment. In groundwater, metals such as aluminum and iron were detected at similar concentrations in both upgradient and downgradient wells, suggesting the source of these metals was not dry well effluent. Naturally occurring metals such as chromium and arsenic were not detected in stormwater but were found at elevated concentrations in groundwater. A modeling assessment suggests that the travel time of metals and hydrophobic organic contaminants to the water table at these sites ranges from years to centuries, whereas water soluble pesticides would likely reach the water table within days to months. The modeling assessment also showed that more vulnerable sites with higher fraction of alluvial sands would have much shorter contaminant travel times. However, none of the contaminants assessed reached concentrations that pose a risk to human health across the scenarios considered. No evidence was found, either through direct measurements or vadose zone modeling, that contaminants present in suburban stormwater degraded or would degrade groundwater quality at the studied sites and site conditions. Future work is needed to address emerging contaminants of concern.

Antibiotic-resistant H. pylori was increasingly found in infected individuals, which resulted in treatment failure and required alternative therapeutic strategies. Daphnetin, a coumarin-derivative compound, has multiple pharmacological activities. The mechanism of daphnetin on H. pylori was investigated focusing on its effect on cell morphologies, transcription of genes related to virulence, adhesion, and cytotoxicity to human gastric epithelial (GES-1) cell line. Daphnetin showed good activities against multidrug resistant (MDR) H. pylori clinical isolates, with minimal inhibitory concentration (MIC) values ranging from 25 to 100 μg/mL. In addition, daphnetin exposure resulted in H. pylori morphological changes. Moreover, daphnetin caused increased translocation of phosphatidylserine (PS), DNA damage, and recA expression, and RecA protein production vs. control group. Of great importance, daphnetin significantly decreased H. pylori adhesion to GES-1 cell line vs. control group, which may be related to the reduced expression of colonization related genes (e.g., babA and ureI). These results suggested that daphnetin has good activity against MDR H. pylori. The mechanism(s) of daphnetin against H. pylori were related to change of membrane structure, increase of DNA damage and PS translocation, and decrease of H. pylori attachment to GES-1 cells.