Dampened Inflammation and Improved Survival After CXCL5 Administration in Murine Lupus via Myeloid and Neutrophil Pathways.

OBJECTIVE: To determine the efficacy of CXCL5 administration in lupus-prone MRL/lpr (Faslpr ) mice and elucidate its working mechanisms. METHODS: CXCL5 expression in blood (obtained from SLE patients and Faslpr mice) and major internal organs (obtained from Faslpr mice) was examined by Luminex, real-time polymerase chain reaction, and immunofluorescent staining analyses. Pharmacokinetic studies were performed in Faslpr mice and healthy Institute of Cancer Research mice. Efficacy of CXCL5 administration was demonstrated in Faslpr mice, and the working mechanism of CXCL5 treatment was elucidated by flow cytometry, Luminex, and RNA sequencing. RESULTS: In SLE patients, serum CXCL5 levels were significantly lower than in healthy individuals (P < 0.0001) and negatively correlated with disease activity (P = 0.004). In Faslpr mice, disease severity progressed with age and was negatively associated with plasma CXCL5 levels. Intravenous administration of CXCL5 to Faslpr mice restored endogenous circulatory CXCL5, improved mice survival, and reduced anti-double-stranded DNA antibodies, proteinuria, lupus nephritis activity and chronicity indices, renal complements, and neutrophil extracellular traps over short-term (10 weeks) and long-term (2 years) time periods. In vitro and in vivo assays demonstrated that CXCL5 dictated neutrophil trafficking and suppressed neutrophil activation, degranulation, proliferation, and renal infiltration. Renal and splenic RNA sequencing further showed that CXCL5-mediated immunomodulation occurred by promoting energy production in renal-infiltrated immune cells, activating certain T cells, and reducing tissue fibrosis, granulocyte extravasation, complement components, and interferons. Further factorial design results indicated that CXCL5 appears to enhance host tolerability to cyclophosphamide in vulnerable individuals. CONCLUSION: We found that serum CXCL5 levels were significantly lower in SLE patients than in healthy individuals and were negatively correlated with disease activity. By administering CXCL5 intravenously in a mouse model of lupus, mouse survival improved, and indices of disease activity reduced significantly. Taken together, these findings indicate CXCL5 administration may represent a novel myeloid/neutrophil-targeting therapy for SLE.

Intraperitoneally Delivered Umbilical Cord Lining Mesenchymal Stromal Cells Improve Survival and Kidney Function in Murine Lupus via Myeloid Pathway Targeting.

To determine the therapeutic efficacy of human umbilical cord lining mesenchymal stromal cells (CL-MSCs) (US Patent number 9,737,568) in lupus-prone MRL/lpr (Faslpr) mice and elucidate its working mechanisms. A total of 4 doses of (20-25) × 106 cells/kg of CL-MSCs was given to 16-week-old female Faslpr mice by intraperitoneal injection. Three subsequent doses were given on 17 weeks, 18 weeks, and 22 weeks, respectively. Six-week-old Faslpr mice were used as disease pre-onset controls. Mice were monitored for 10 weeks. Mouse kidney function was evaluated by examining complement component 3 (C3) deposition, urinary albumin-to-creatinine ratio (ACR), and lupus nephritis (LN) activity and chronicity. Working mechanisms were elucidated by flow cytometry, Luminex/ELISA (detection of anti-dsDNA and isotype antibodies), and RNA sequencing. CL-MSCs improved mice survival and kidney function by reducing LN activity and chronicity and lymphocyte infiltration over 10 weeks. CL-MSCs also reduced urinary ACR, renal complement C3 deposition, anti-dsDNA, and isotype antibodies that include IgA, IgG1, IgG2a, IgG2b, and IgM. Immune and cytokine profiling demonstrated that CL-MSCs dampened inflammation by suppressing splenic neutrophils and monocytes/macrophages, reducing plasma IL-6, IL-12, and CXCL1 and stabilizing plasma interferon-γ and TNF-α. RNA sequencing further showed that CL-MSCs mediated immunomodulation via concerted action of pro-proinflammatory cytokine-induced chemokines and production of nitric oxide in macrophages. CL-MSCs may provide a novel myeloid (neutrophils and monocytes/macrophages)-targeting therapy for SLE.

Transverse Colostomy Differs in Outcomes Compared to Sigmoid Colostomy: A Cohort Analysis.

PURPOSE: Our aim was to identify any differences in outcomes following transverse versus sigmoid colostomy creation for management of cancer. METHODS: Transverse and sigmoid colostomies are used to manage cancer-related complications including obstruction, perforation, and fistulation. The decision to use either colostomy is largely based on the surgeon's preference and the location of the cancer complication. All patients treated for cancer complications with the use of a sigmoid or transverse colostomy at National University Hospital between January 2011 and December 2016 were included. Patient characteristics and distribution frequencies were reported based on the operation performed. Post procedure morbidity and mortality was compared. Univariate and subgroup analysis were performed. RESULTS: This was a single-center, retrospective cohort study of 93 patients who underwent a colostomy creation over a 5-year duration. Of the 93 patients included, 56 underwent a transverse colostomy (median age 59, 26 male, 30 female) and 37 a sigmoid colostomy (median age 64, 20 male, 17 female). According to univariate analysis, higher rates of stoma prolapse were seen patients with transverse colostomies. There were no differences in complications between a laparoscopic or open approach. There were no differences in the rate of other postoperative complications. CONCLUSION: Sigmoid colostomies were associated with a lower prolapse rate compared to transverse colostomies for cancer management. The manner of surgical approach did not affect rate of postoperative complications.

Afterthoughts on colonoscopy. Was it that bad?

OBJECTIVES: Colorectal cancer is among the top three most common cancers globally. In order to reduce the health burden, it is important to improve the uptake of colorectal cancer screening by understanding the barriers and facilitators encountered. There are numerous reports in the literature on the views of the general public on cancer screening. However, the experiences of colonoscopy patients are not as well studied. This paper maps their perceptions. METHODS: Keyword searches for terms such as 'colorectal', 'colonoscopy' and 'qualitative' were conducted on 3 December 2019 in five databases: Medline, Embase, CINAHL, PsycINFO and Web of Science Core Collection. Qualitative articles that quoted colonoscopy-experienced patients with no prior history of colorectal cancer were included for the thematic analysis. The systematic review was then synthesized according to PRISMA guidelines. RESULTS: The major themes were distilled into three categories: pre-procedure, during and post-procedure. The factors identified in the pre-procedure phase include the troublesome bowel preparation, poor quality of information provided and the dynamics within a support network. Perceptions of pain, emotional discomfort and the role of providers mark the experience during the procedure. The receipt of results, opportunities given for discussion and finances relating to colonoscopy are important post-procedure events. CONCLUSION: Understanding colorectal cancer screening behaviour is fundamental for healthcare providers and authorities to develop system and personal level changes for the improvement of colorectal cancer screening services. The key areas include patient comfort, the use of clearer instructional aids and graphics, establishing good patient rapport, and the availability of individualized options for sedation and the procedure.

Isoform-specific upregulation of FynT kinase expression is associated with tauopathy and glial activation in Alzheimer's disease and Lewy body dementias.

Cumulative data suggest the involvement of Fyn tyrosine kinase in Alzheimer's disease (AD). Previously, our group has shown increased immunoreactivities of the FynT isoform in AD neocortex (with no change in the alternatively spliced FynB isoform) which associated with neurofibrillary degeneration and reactive astrogliosis. Since both the aforementioned neuropathological features are also variably found in Lewy Body dementias (LBD), we investigated potential perturbations of Fyn expression in the post-mortem neocortex of patients with AD, as well as those diagnosed as having one of the two main subgroups of LBD: Parkinson's disease dementia (PDD) and dementia with Lewy bodies (DLB). We found selective upregulation of FynT expression in AD, PDD, and DLB which also correlated with cognitive impairment. Furthermore, increased FynT expression correlated with hallmark neuropathological lesions, soluble ß-amyloid, and phosphorylated tau, as well as markers of microglia and astrocyte activation. In line with the human post-mortem studies, cortical FynT expression in aged mice transgenic for human P301S tau was upregulated and further correlated with accumulation of aggregated phosphorylated tau as well as with microglial and astrocytic markers. Our findings provide further evidence for the involvement of FynT in neurodegenerative dementias, likely via effects on tauopathy and neuroinflammation.

Organic Nanoparticles with Aggregation-Induced Emission for Bone Marrow Stromal Cell Tracking in a Rat PTI Model.

Stem-cell based therapy is an emerging therapeutic approach for ischemic stroke treatment. Bone marrow stromal cells (BMSCs) are in common use as a cell source for stem cell therapy and show promising therapeutic outcomes for stroke treatment. One challenge is to develop a reliable tracking strategy to monitor the fate of BMSCs and assess their therapeutic effects in order to improve the success rate of such treatment. Herein, TPEEP, a fluorogen with aggregation-induced emission characteristics and near-infrared emission are designed and synthesized and further fabricated into organic nanoparticles (NPs). The obtained NPs show high fluorescence quantum yield, low cytotoxicity with good physical and photostability, which display excellent tracking performance of BMSCs in vitro and in vivo. Using a rat photothrombotic ischemia model as an example, the NP-labeled BMSCs are able to migrate to the stroke lesion site to yield bright red fluorescence. Immunofluorescence staining shows that the NP labeling does not affect the normal function of BMSCs, proving their good biocompatibility in vivo. These merits make TPEEP NP a potential cell tracker to evaluate the fate of BMSCs in cell therapy.

A High-Dimensional Atlas of Human T Cell Diversity Reveals Tissue-Specific Trafficking and Cytokine Signatures.

Depending on the tissue microenvironment, T cells can differentiate into highly diverse subsets expressing unique trafficking receptors and cytokines. Studies of human lymphocytes have primarily focused on a limited number of parameters in blood, representing an incomplete view of the human immune system. Here, we have utilized mass cytometry to simultaneously analyze T cell trafficking and functional markers across eight different human tissues, including blood, lymphoid, and non-lymphoid tissues. These data have revealed that combinatorial expression of trafficking receptors and cytokines better defines tissue specificity. Notably, we identified numerous T helper cell subsets with overlapping cytokine expression, but only specific cytokine combinations are secreted regardless of tissue type. This indicates that T cell lineages defined in mouse models cannot be clearly distinguished in humans. Overall, our data uncover a plethora of tissue immune signatures and provide a systemic map of how T cell phenotypes are altered throughout the human body.

Peripheral sensory stimulation is neuroprotective in a rat photothrombotic ischemic stroke model.

Ischemic stroke is one of the leading causes of death and disability in the world. Thrombolytic therapy using recombinant tissue plasminogen activator (rtPA), the only FDA-approved drug for acute ischemia, is limited by a narrow therapeutic time window and risk of hemorrhage. There is a serious need for a neuroprotective therapy which is clinically viable. We earlier demonstrated that peripheral sensory stimulation (PSS) is a potential therapeutic intervention for hyperacute ischemia resulting in recovery of neurovascular functions when administered immediately following ischemia onset in a rat model. Here, we investigated the potential neuroprotective effect of PSS during the hyperacute phase of stroke in a rat photothrombotic ischemia (PTI) model. We employed electrocorticography (ECoG) to image cortical neural activity responses pre-and post-ischemia. Results showed that the neural activity including somatosensory evoked potentials (SSEPs) and alpha-to-delta ratio (ADR) were restored following administration of PSS. Further, immunohistochemistry and TTC staining also indicated the neuroprotective effect of PSS intervention, protecting more neurons and reduced infarct. Overall, the study demonstrated that PSS administered immediately following ischemia induction in a rat PTI model can significantly promote neuroprotection via inhibition of peri-infarct expansion and enhanced cortical neural activity functions, suggesting effective recovery. Future work utilizing multimodal imaging to probe changes in neurovascular functions, will explore application of PSS as an adjuvant intervention for improving rtPA thrombolysis therapy.

The anatomy of failures following the ligation of intersphincteric tract technique for anal fistula: a review of 93 patients over 4 years.

BACKGROUND: Although the ligation of intersphincteric tract technique is a promising sphincter-preserving option in managing anal fistulas, failures are still seen. OBJECTIVE: This study aimed to illustrate the patterns of failures and recurrences following the ligation of intersphincteric tract procedure for anal fistulas. DESIGN: This study is a retrospective review. SETTINGS: This study was conducted at the Division of Colorectal Surgery, University Surgical Cluster, National University Health System, Singapore, from April 2006 to September 2010. PATIENTS: Ninety-three patients were evaluated. INTERVENTIONS: All patients underwent the ligation of intersphincteric tract procedure for anal fistulas. MAIN OUTCOME MEASURES: Failure was defined as nonhealing of the surgical wound or fistula. Recurrence was defined as the reappearance of the fistula after initial healing. RESULTS: After a median follow-up of 23 (range, 1-85) weeks, there were 7 failures and 6 recurrences. The median time to healing was 4 (range, 1-12) weeks. The freedom from failure or recurrence at 1 year following the ligation of intersphincteric tract procedure was 78% (95% CI: 66%-90%). All 7 failures had discharge at the intersphincteric wound. Four had an unhealed internal opening, and 3 had isolated failures at the intersphincteric wound. Endoanal ultrasonography revealed a less complicated anatomy that enabled successful treatment with either local application of silver nitrate (n = 3) or fistulotomy (n = 4). All 6 recurrences had a demonstrable tract from the previous internal opening to an external opening with healing of the intersphincteric wound. The median time to recurrence was 22 (range, 15-33) weeks from the ligation of the intersphincteric tract procedure. Fistulotomy, repeat ligation of intersphincteric tract, or anocutaneous advancement flap procedure was successfully performed subsequently. CONCLUSION: In patients with early failures, the medialization of the external opening to the intersphincteric wound simplified subsequent management. All recurrences should be reevaluated and managed accordingly.