Inhibition of visceral adipose tissue-derived pathogenic signals by activation of adenosine A2AR improves hepatic and cardiac dysfunction of NASH mice.

A2AR-disrupted mice is characterized by severe systemic and visceral adipose tissue (VAT) inflammation. Increasing adenosine cyclase (AC), cAMP, and protein kinase A (PKA) formation through A2AR activation suppress systemic/VAT inflammation in obese mice. This study explores the effects of 4 wk A2AR agonist PSB0777 treatment on the VAT-driven pathogenic signals in hepatic and cardiac dysfunction of nonalcoholic steatohepatitis (NASH) obese mice. Among NASH mice with cardiac dysfunction, simultaneous decrease in the A2AR, AC, cAMP, and PKA levels were observed in VAT, liver, and heart. PSB0777 treatment significantly restores AC, cAMP, PKA, and hormone-sensitive lipase (HSL) levels, decreased SREBP-1/FASN, MCP-1, and CD68 levels, reduces infiltrated CD11b+ F4/80+ cells and adipogenesis in VAT of NASH + PSB0777 mice. The changes in VAT were accompanied by the suppression of hepatic and cardiac lipogenic/inflammatory/injury/apoptotic/fibrotic markers, the normalization of cardiac contractile [sarco/endoplasmic reticulum Ca2+ ATPase (SERCA2)] marker, and cardiac dysfunction. The in vitro approach revealed that conditioned media (CM) of VAT of NASH mice (CMnash) trigger palmitic acid (PA)-like lipotoxic (lipogenic/inflammatory/apoptotic/fibrotic) effects in AML-12 and H9c2 cell systems. Significantly, A2AR agonist pretreatment-related normalization of A2AR-AC-cAMP-PKA levels was associated with the attenuation of CMnash-related upregulation of lipotoxic markers and the normalization of lipolytic (AML-12 cells) or contractile (H9C2 cells) marker/contraction. The in vivo and in vitro experiments revealed that A2AR agonists are potential agent to inhibit the effects of VAT inflammation-driven pathogenic signals on the hepatic and cardiac lipogenesis, inflammation, injury, apoptosis, fibrosis, hypocontractility, and subsequently improve hepatic and cardiac dysfunction in NASH mice.NEW & NOTEWORTHY Protective role of adenosine A2AR receptor (A2AR) and AC-cAMP-PKA signaling against nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH) possibly via its actions on adipocytes is well known in the past decade. Thus, this study evaluates pharmacological activities of A2AR agonist PSB0777, which has already demonstrated to treat NASH. In this study, the inhibition of visceral adipose tissue-derived pathogenic signals by activation of adenosine A2AR with A2AR agonist PSB0777 improves the hepatic and cardiac dysfunction of high-fat diet (HFD)-induced NASH mice.

Preservation of vascular endothelial glycocalyx and barrier by activation of adenosine A2A receptor (A2AR) improved renal dysfunction in cirrhotic rats.

Cirrhosis-related hepatic and renal endothelial dysfunction is characterized by macrophage-endothelium adhesion-mediated inflammation, glycocalyx/barrier damage, and impaired vasodilation. Activation of adenosine A2A receptor (A2AR) protects cirrhotic rats from impairment of hepatic microcirculation post hepatectomy. This study evaluates the effects of A2AR activation on the cirrhosis-related hepatic and renal endothelial dysfunction in biliary cirrhotic rats receiving two weeks of A2AR agonist PSB0777 [bile duct ligated (BDL)+PSB0777] treatment. Endothelial dysfunction in cirrhotic liver, renal vessels, and kidney is characterized by downregulation of the A2AR expressions, decreased vascular endothelial vasodilatory (p-eNOS)/anti-inflammatory (IL-10/IL-10R)/barrier [VE-cadherin (CDH5) and ß-catenin (CTNNB1)]/glycocalyx [syndecan-1 (SDC1) and hyaluronan synthase-2 (HAS2)] markers, and increased leukocyte-endothelium adhesion molecules (F4/80, CD68, ICAM-1, and VCAM-1). In BDL rats, PSB0777 treatment improves hepatic and renal endothelial dysfunction, ameliorates portal hypertension, and attenuates renal hypoperfusion by restoring of the vascular endothelial anti-inflammatory, barrier, glycocalyx markers and vasodilatory response as well as inhibiting the leukocyte-endothelium adhesion. In an in vitro study, conditioned medium (CM) of bone marrow-derived macrophage (BMDM) of BDL rats [BMDM-CM (BDL)] induced barrier/glycocalyx damage, which was reversed by the PSB0777 pre-treatment. The A2AR agonist is a potential agent that can simultaneously correct cirrhosis-related hepatic and renal endothelial dysfunction, portal hypertension, renal hypoperfusion, and renal dysfunction.

Liquid Biopsy Serial Monitoring of Treatment Responses and Relapse in Advanced Esophageal Squamous Cell Carcinoma.

(1) Background: Early predictive markers to track treatment responses are needed for advanced esophageal squamous cell carcinoma (ESCC) patients. We examined the prognostication and risk stratification role of liquid biopsy serial monitoring for this deadly cancer. (2) Methods: Circulating tumor cells (CTCs) and plasma cell-free DNA (cfDNA) were isolated from 60 ESCC patients treated by chemotherapy (CT) at five serial timepoints: baseline (CTC1/cfDNA1), CT pre-cycle III (CTC2/cfDNA2), CT post-cycle IV, end of CT and relapse. (3) Results: In 45/57 ESCC patients with evaluable CTC counts at CT pre-cycle III, positive CTC2 (≥3 CTCs) is independently associated with response at interim reassessment and progression-free survival (PFS) in multivariate analysis. In 42/57 ESCC patients with changes of CTC1/CTC2 and cfDNA1/cfDNA2, patients categorized into four risk groups based on the number of favorable and unfavorable changes of CTC1/CTC2 and cfDNA1/cfDNA2, were independently associated with overall survival (OS) by multivariate analysis. (4) Conclusions: CTC counts at pre-cycle III are independently associated with response at interim reassessment and PFS. Combined changes of CTC counts and cfDNA levels from baseline to pre-cycle III are independently associated with OS. Longitudinal liquid biopsy serial monitoring provides complementary information for prediction and prognosis for CT responses in advanced ESCC.

Histopathological and Behavioral Assessments of Aging Effects on Stem Cell Transplants in an Experimental Traumatic Brain Injury.

Traumatic brain injury (TBI) displays cognitive and motor symptoms following the initial injury which can be exacerbated by secondary cell death. Aging contributes significantly to the morbidity of TBI, with higher rates of negative neurological and behaviors outcomes. In the recent study, young and aged animals were injected intravenously with human adipose-derived mesenchymal stem cells (hADSCs) (Tx), conditioned media (CM), or vehicle (unconditioned media) following TBI. The beneficial effects of hADSCs were analyzed using various molecular and behavioral techniques. More specially, DiR-labeled hADSCs were used to observe the biodistribution of the transplanted cells. In addition, a battery of behavior tests was conducted to evaluate the neuromotor function for each treatment group and various regions of the brain were analyzed utilizing Nissl, hematoxylin and eosin (H&E), and human nuclei (HuNu) staining. Finally, flow cytometry was also performed to determine the levels of various proteins in the spleen. Here, we discuss the protocols for characterizing the histopathological and behavioral effects of transplanted stem cells in an animal model of TBI, with an emphasis on the role of aging in the therapeutic outcomes.

An update on intracerebral stem cell grafts.

INTRODUCTION: Primary neurological disorders are notoriously debilitating and deadly, and over the past four decades stem cell therapy has emerged as a promising treatment. Translation of stem cell therapies from the bench to the clinic requires a better understanding of delivery protocols, safety profile, and efficacy in each disease. Areas covered: In this review, benefits and risks of intracerebral stem cell transplantation are presented for consideration. Milestone discoveries in stem cell applications are reviewed to examine the efficacy and safety of intracerebral stem cell transplant therapy for disorders of the central nervous system and inform design of translatable protocols for clinically feasible stem cell-based treatments. Expert commentary: Intracerebral administration, compared to peripheral delivery, is more invasive and carries the risk of open brain surgery. However, direct cell implantation bypasses the blood-brain barrier and reduces the first-pass effect, effectively increasing the therapeutic cell deposition at its intended site of action. These benefits must be weighed with the risk of graft-versus-host immune response. Rigorous clinical trials are underway to assess the safety and efficacy of intracerebral transplants, and if successful will lead to widely available stem cell therapies for neurologic diseases in the coming years.

Intravenously Transplanted Human Bone Marrow Endothelial Progenitor Cells Engraft Within Brain Capillaries, Preserve Mitochondrial Morphology, and Display Pinocytotic Activity Toward Blood-Brain Barrier Repair in Ischemic Stroke Rats.

Stroke is a life-threatening disease with limited therapeutic options. Cell therapy has emerged as an experimental stroke treatment. Blood-brain barrier (BBB) impairment is a key pathological manifestation of ischemic stroke, and barrier repair is an innovative target for neurorestoration in stroke. Here, we evaluated via electron microscopy the ability of transplanted human bone marrow endothelial progenitor cells (hBMEPCs) to repair the BBB in adult Sprague-Dawley rats subjected to transient middle cerebral artery occlusion (tMCAO). ß-galactosidase prelabeled hBMEPCs were intravenously transplanted 48 hours post-tMCAO. Ultrastructural analysis of microvessels in nontransplant stroke rats revealed typical BBB pathology. At 5 days post-transplantation with hBMEPCs, stroke rats displayed widespread vascular repair in bilateral striatum and motor cortex, characterized by robust cell engraftment within capillaries. hBMEPC transplanted stroke rats exhibited near normal morphology of endothelial cells (ECs), pericytes, and astrocytes, without detectable perivascular edema. Near normal morphology of mitochondria was also detected in ECs and perivascular astrocytes from transplanted stroke rats. Equally notable, we observed numerous pinocytic vesicles within engrafted cells. Robust engraftment and intricate functionality of transplanted hBMEPCs likely abrogated stroke-altered vasculature. Preserving mitochondria and augmenting pinocytosis in cell-based therapeutics represent a new neurorestorative mechanism in BBB repair for stroke. Stem Cells 2017;35:1246-1258.

Inactivation of Bacteria on Explanted Dialysis Catheter Lumens with Fiber Optically Delivered Ultraviolet Light.

PURPOSE: To evaluate the germicidal effect of fiber optically delivered ultraviolet (UV) light on colonized explanted dialysis catheters. MATERIALS AND METHODS: Explanted dialysis catheters were screened for intraluminal colonization by culturing 1 mL of a saline flush. Catheters growing >10 colony-forming units were treated with doses of fiber optically delivered UV light (range, 40-1,300 mJ/cm2). For each UV-treated catheter, an unexposed segment was first cut and set aside as a control sample. A sterile optical fiber was inserted into the catheter hub and advanced to the catheter tip. The fiber was slowly withdrawn at a constant rate while exposing the inner lumen to UV light. A second UV-exposed segment was then removed. The UV-exposed and control segments were split and sonicated to remove the adherent bacteria. The bacteria were counted and identified. RESULTS: There were 14 colonized catheters treated with UV light. The catheters were primarily colonized with coagulase-negative staphylococci (60%) and Staphylococcus aureus (33%). There was a significant reduction in viable bacteria between the UV-treated versus untreated segments of each infected catheter (P = .04). In the seven treated catheters with >100,000 colony-forming units per cm2 of luminal surface area, there was a >99.5% reduction of viable bacteria in all UV-exposed samples, with no residual viable bacteria in four of seven (57%) of the samples. CONCLUSIONS: This study demonstrates the technical feasibility and benchtop efficacy of using fiber optics to deliver UV light into the lumen of a colonized dialysis catheter and inactivating bacteria on the intraluminal surface.

Ultrasound findings of incidental adnexal and ovarian lesions on emergency CT scans.

A search through 6076 nontraumatic emergency computed tomography (CT) scans of female patients yielded 266 (4.4%) CT scans with an incidentally detected adnexal lesion and ultrasound follow-up within 7days. The population was 87% premenopausal and 13% postmenopausal. Follow-up ultrasound yielded an ultrasound diagnosis 32% of the time. Potentially serious diagnoses included pelvic infection (3%) and suspected malignancy (2%). Benign diagnoses included normal ovaries (16%), hemorrhagic cyst (6%), and benign cyst (5%). The remaining 68% of cases were equivocal, requiring further evaluation.

Percutaneous CT-guided cryoablation for the treatment of refractory pudendal neuralgia.

PURPOSE: To evaluate the safety and efficacy of percutaneous CT-guided cryoablation of the pudendal nerve for the treatment of refractory pudendal neuralgia. MATERIALS AND METHODS: Eleven patients were selected to undergo percutaneous CT-guided cryoablation of the pudendal nerve based on established diagnostic criteria. Brief Pain Inventory questionnaires were administered prior to the procedure, during the immediate 24 h post procedure, and 45 days and 6 months following the procedure. RESULTS: Prior to treatment, the average level of pain on a scale from 0 (no pain) to 10 (worst pain imaginable) was 7.6, with pain described as "burning" (80%), "pulling" (37.5%), "crushing" (50%), "pressure" (84.5%), "throbbing" (50%), "knife-life" (52%), and "other" (60%). At 24 h, 45 days, and 6 months post-treatment, pain intensity dropped to 2.6, 3.5, and 3.1, respectively (p < 0.005). There were no procedure-related complications. CONCLUSIONS: CT-guided percutaneous cryoablation may represent a safe and efficacious option for selected patients with refractory pudendal neuralgia.

Breast striae after cosmetic augmentation.

BACKGROUND: Breast augmentation is the most popular cosmetic surgery procedure in the United States. Postoperative striae is a known but incompletely understood complication of breast augmentation. OBJECTIVES: The authors investigated their own patient population to discern risk factors for new-onset striae after cosmetic breast augmentation. METHODS: A retrospective chart review was performed for patients who underwent primary breast augmentation from 2005 to 2012 in a single-surgeon practice. Initial chart review revealed that only patients aged ≤25 years exhibited new striae; therefore, only patients from this age group were included. Potential risk factors examined included age, body mass index (BMI), oral contraceptive use, time of last menstrual period (LMP), parity, smoking and alcohol status, diabetes mellitus, and personal history of striae. Implant and surgical factors examined included implant material (silicone vs saline), volume, and location (submuscular vs subglandular placement) and the site of incision. RESULTS: Of the 549 patients included in the study, 17 (3.10%) had new-onset striae, observed at a mean of 58 days postoperatively. The risk of striae was statistically significantly higher (P<.05) among patients who were younger (3.3 times), were nulliparous (14.38 times), began their LMP>14 days before surgery (9.24 times), and had a history of striae (6.11 times). There was a strong correlation between new-onset breast striae and implant size, as well as BMI (P=.07). CONCLUSIONS: There is a strong correlation between new-onset striae and hormone levels, genetic factors, and tissue stretch components in patients who undergo cosmetic breast augmentation. This information can be utilized to better educate patients about this potential complication. LEVEL OF EVIDENCE: 4.

Screening for previous refractive surgery in eye bank corneas by using optical coherence tomography.

PURPOSE: To use optical coherence tomography (OCT) to detect previous refractive surgery in donor corneas. METHODS: We constructed a tabletop OCT scanner operating at 1310-nm wavelength. Donor corneas at the Cleveland Eye Bank were scanned while sealed within the sterile container immersed in Optisol GS. OCT scanning was performed with 7.6-mm-long lines (512 axial scans) along 8 meridians. Anterior and posterior corneal surfaces were automatically mapped using image processing software that we developed. Curvature was computed from the best parabolic fit in the central 5-mm diameter. Layered analysis of the stromal reflectivity was also performed. Twenty-nine corneas from 19 donors were examined. Five had a history of laser in situ keratomileusis (LASIK). RESULTS: The flap interfaces could not be visualized on slit-lamp or OCT images but were confirmed by histology. The death-to-scan time was 22.1 +/- 11.4 (SD) hours for normal corneas and 100.6 +/- 57.5 hours for LASIK corneas. The anterior surface power was 67.5 +/- 2.5 D in control corneas and 64.5 +/- 2.4 D in LASIK corneas (P = 0.023). There was no significance between the 2 groups in terms of posterior curvature and thickness parameters. The anterior/posterior reflectivity ratio in the central 4-mm diameter was significantly lower in post-LASIK corneas than in control (P < 0.05). CONCLUSIONS: OCT provides thickness, topography, and reflectivity maps of donor corneas without taking them out of preservation medium and container. The anterior curvature and the anterior/posterior stromal reflectivity ratio may be useful for detecting previous LASIK.