Focused Ultrasound as a Novel Non-Invasive Method for the Delivery of Gold Nanoparticles to Retinal Ganglion Cells.

Purpose: The blood-retinal barrier (BRB) restricts the delivery of intravenous therapeutics to the retina, necessitating innovative approaches for treating retinal disorders. This study sought to explore the potential of focused ultrasound (FUS) to non-invasively deliver intravenously administered gold nanoparticles (AuNPs) across the BRB. FUS-BRB modulation can offer a novel method for targeted retinal therapy. Methods: AuNPs of different sizes and shapes were characterized, and FUS parameters were optimized to permeate the BRB without causing retinal damage in a rodent model. The delivery of 70-kDa dextran and AuNPs to the retinal ganglion cell (RGC) layer was visualized using confocal and two-photon microscopy, respectively. Histological and statistical analyses were conducted to assess the effectiveness and safety of the procedure. Results: FUS-BRB modulation resulted in the delivery of dextran and AuNPs to the RGC and inner nuclear layer. Smaller AuNPs reached the retinal layers to a greater extent than larger ones. The delivery of dextran and AuNPs across the BRB with FUS was achieved without significant retinal damage. Conclusions: This investigation provides the first evidence, to our knowledge, of FUS-mediated AuNP delivery across the BRB, establishing a foundation for a targeted and non-invasive approach to retinal treatment. The results contribute to developing promising non-invasive therapeutic strategies in ophthalmology to treat retinal diseases. Translational Relevance: Modifying the BRB with ultrasound offers a targeted and non-invasive delivery strategy of intravenous therapeutics to the retina.

Vantris vs. deflux for treatment of paediatric vesicoureteral reflux: Efficacy and obstruction risk.

INTRODUCTION: The aim was to compare the efficacy of polyacrylate polyalcohol copolymer (PPC) injections and dextranomer/hyaluronic acid (Dx/Ha) injections for the endoscopic treatment of vesicoureteral reflux in children. MATERIAL: This retrospective cohort study included 189 young patients who had endoscopic treatment for vesicoureteral reflux from January 2012 to December 2019 in our center. Among them, 101 had PCC injections and 88 had Dx/Ha injections. Indications for treatment were vesicoureteral reflux with breakthrough urinary tract infection or vesicoureteral reflux with renal scarring on dimercaptosuccinic acid (DMSA) renal scan. Endoscopic injection was performed under the ureteral meatus. Early complications, recurrence of febrile urinary tract infection and vesicoureteral reflux after endoscopic injection, ureteral obstruction and reintervention were evaluated and compared between groups. RESULTS: Endoscopic treatment was successful in 90.1% of patients who had PPC injection and in 82% of patients who had Dx/Ha injection. Four patients presented a chronic ureteral obstruction after PPC injection, one with a complete loss of function of the dilated kidney. One patient in the Dx/Ha group presented a postoperative ureteral dilatation after 2 injections. CONCLUSION: Despite a similar success rate after PPC and Dx/Ha injections for endoscopic treatment of VUR, there may be a greater risk of postoperative ureteral obstruction after PPC injections. The benefit of using PPC to prevent febrile UTI and renal scarring in children with low-grade VUR does not seem to outweigh the risk of chronic ureteral obstruction.

An injectable fluorescent and iodinated hydrogel for preoperative localization and dual image-guided surgery of pulmonary nodules.

The widespread use of video-assisted thoracoscopic surgery (VATS) has triggered the rapid expansion in the field of computed tomography (CT)-guided preoperative localization and near-infrared (NIR) fluorescence image-guided surgery. However, its broader application has been hindered by the absence of ideal imaging contrasts that are biocompatible, minimally invasive, highly resolvable, and perfectly localized within the diseased tissue. To achieve this goal, we synthesize a dextran-based fluorescent and iodinated hydrogel, which can be injected into the tissue and imaged with both CT and NIR fluorescence modalities. By finely tuning the physical parameters such as gelation time and composition of iodinated oil (X-ray contrast agent) and indocyanine green (ICG, NIR fluorescence dye), we optimize the hydrogel for prolonged localization at the injected site without losing the dual-imaging capability. We validate the effectiveness of the developed injectable dual-imaging platform by performing image-guided resection of pulmonary nodules on tumor-bearing rabbits, which are preoperatively localized with the hydrogel. The injectable dual-imaging marker, therefore, can emerge as a powerful tool for surgical guidance.

Macropinocytic dextran facilitates KRAS-targeted delivery while reducing drug-induced tumor immunity depletion in pancreatic cancer.

Background: Pancreatic cancer comprises not only cancer cells but also a collection of cross-talking noncancerous cells within tumor. Therefore, selective delivery of cytotoxic agents towards cancer cells and limiting the collateral damage to tumor suppressive benign cells, such as effector lymphocytes in the tumor microenvironment, is of great value. Methods: Pancreatic cancer cells harbor oncogenic KRAS which induces a constitutively high level of macropinocytosis. Inspired by such uniquity, we sought to explore the targeting potential of dextran, a biomaterial presumed to be endocytosed in the macropinocytosis dependent manner. Cell entry preference, mechanism and subcellular sorting of dextran with different molecular weights were firstly examined. Triptolide (TP), a potent cytotoxin was then set as the model payload for dextran conjugation. KRAS selectivity and the therapeutic effects of dextran-conjugated TP were investigated via both in vitro cellular studies and in vivo tumor model assessment. Results: Dextran, with a specific molecular weight of 70 kDa rather than other weights, was identified as a robust KRAS-responsive intracellular delivery carrier with enhanced entry upon KRAS mutation. The 70 kDa dextran-conjugated TP (DEX-TP) displayed greater efficacy and cellular deposition efficiency towards KRAS mutant cells than KRAS wild-type cells. Treatment with DEX-TP suppressed tumor progression in KRAS mutant pancreatic cancer orthotopic mouse models with reduced toxicity and significantly extended mouse survival time. Furthermore, the conjugate attained a more favorable therapeutic outcome in the tumor immune microenvironment than the free drug, preserving the fraction of T cells and their effector cytokines. Conclusions: In summary, macropinocytic dextran was able to provide drug delivery selectivity towards KRAS mutant cancer cells and reduce tumor immunity depletion caused by the cytotoxic drug in pancreatic cancer.

The Study of Efficiency of the Approach to Prevent the Adhesions in the Abdominal Cavity of Rats.

Adhesions in rat abdominal cavity were studied after laparotomy and subsequent single intraperitoneal injection of 2 ml of 5% aqueous solution of oxidized dextran (OD) with a molecular weight of 40 kDa (oxidation degree 10%). On days 7 and 21 after laparotomy, the number of adhesions in OD-treated rats was lower by 7.5 and 4 times than in animals not receiving OD. The number of neutrophils in adhesions on day 21 was manyfold lower in OD-treated rats. In 7 and 21 days after laparotomy, the number of fibroblasts in the adhesions of rats receiving and not receiving OD was similar, but 2-fold higher than in the peritoneum of non-operated rats. The content of collagen in adhesions on day 21 after laparotomy in OD-treated rats was 10-fold lower than in animals no receiving OD.

Does 99mTc-tilmanocept, as next generation radiotracer, meet with the requirements for improved sentinel node imaging?

INTRODUCTION AND OBJECTIVES: To evaluate the migration of 99mTc-tilmanocept from the injection site (IS) as well as the uptake in sentinel nodes (SNs) and non-SNs for lymphatic mapping in patients with breast cancer and melanoma, scheduled for SN biopsy after interstitial tracer administration. MATERIALS AND METHODS: For 29 primary tumours in 28 patients (mean age: 62y, range: 45-81y) scheduled for SN biopsy planar images were acquired 10 and 120min after administration of 74MBq 99mTc-tilmanocept, in order to evaluate lymphatic drainage as well as uptake ratios between injection site (IS), SN and non-SN. SPECT-CT was performed immediately after delayed planar images to enable anatomical lymph node localization. RESULTS: SNs were visualized in all patients (100%) with drainage to 34 basins. Uptake in non-SNs was perceived in 16 basins (47%). Number of SNs was concordant between early and delayed images in all basins excepting five (86%). In 24 patients tracer migrated to one lymph node basin (LNB), in three to 2 and in one to 4. When IS was included (N=29) on image, IS/SN ratio could be measured per LNB. The IS/SN ratio at 2h compared to 15min decreased with an average of 66% (range: 15-96%). SN/non-SN 2h ratio in LNBs with visible non-SNs averaged 6.6 (range: 2.3-15.6). In 9 patients with two SNs SN1/SN2 ratio averaged 1.9 on delayed images. At histopathology, SNs were found to be tumour positive in 7 basins (20%). CONCLUSION: 99mTc-tilmanocept appears to meet the requirements for improved SN imaging in breast cancer and melanoma on the basis of early and persistent SN visualization frequently accompanied by no or markedly less non-SN uptake. This is associated to rapid migration from the injection site together with increasing SN uptake and retention as expressed by decreasing IS/SN and persistently high SN/non-SN ratios. Further head-to-head comparison of 99mTc-tilmanocept with standard SN radiotracers in larger series of patients is necessary.

Dextran-Curcumin Nanosystems Inhibit Cell Growth and Migration Regulating the Epithelial to Mesenchymal Transition in Prostate Cancer Cells.

Functional nanocarriers which are able to simultaneously vectorize drugs to the site of interest and exert their own cytotoxic activity represent a significant breakthrough in the search for effective anticancer strategies with fewer side effects than conventional chemotherapeutics. Here, we propose previously developed, self-assembling dextran-curcumin nanoparticles for the treatment of prostate cancer in combination therapy with Doxorubicin (DOXO). Biological effectiveness was investigated by evaluating the cell viability in either cancer and normal cells, reactive oxygen species (ROS) production, apoptotic effect, interference with the cell cycle, and the ability to inhibit cell migration and reverse the epithelial to mesenchymal transition (EMT). The results proved a significant enhancement of curcumin efficiency upon immobilization in nanoparticles: IC50 reduced by a half, induction of apoptotic effect, and improved ROS production (from 67 to 134%) at low concentrations. Nanoparticles guaranteed a pH-dependent DOXO release, with a more efficient release in acidic environments. Finally, a synergistic effect between nanoparticles and Doxorubicin was demonstrated, with the free curcumin showing additive activity. Although in vivo studies are required to support the findings of this study, these preliminary in vitro data can be considered a proof of principle for the design of an effective therapy for prostate cancer treatment.

PDGF-BB/SA/Dex injectable hydrogels accelerate BMSC-mediated functional full thickness skin wound repair by promoting angiogenesis.

Wound healing is a well-orchestrated dynamic and interactive process, which needs a favorable microenvironment and suitable angiogenesis. Platelet derived growth factor-BB (PDGF-BB) plays a crucial role in wound healing. However, the short half-life of PDGF-BB limits its efficacy. In the present study, we successfully synthesized an injectable hydrogel with sodium alginate (SA) and dextran (Dex) as a delivery system to simultaneously deliver PDGF-BB and bone marrow-derived mesenchymal stem cells (BMSCs) in the wound. Our work demonstrates that the PDGF-BB protein enhanced the survival, migration and endothelial cell (EC) differentiation of BMSCs in vitro. The PDGF-BB/SA/Dex hydrogels could sustainably release PDGF-BB with excellent biocompatibility in vitro and in vivo. Besides, these composite hydrogels loaded with BMSCs could accelerate wound healing by improving epithelialization and collagen deposition. In addition, the PDGF-BB/SA/Dex hydrogels promoted the EC-differentiation of transplanted BMSCs and proliferation of hair follicle stem cells in the wound. Furthermore, the expressions of angiogenesis-specific markers, PDGFR-ß, p-PI3K, p-Akt, and p-eNOS, were obviously increased in the PDGF-BB/SA/Dex/BMSCs group. In conclusion, the PDGF-BB/SA/Dex injectable hydrogels could accelerate BMSC-mediated skin wound healing by promoting angiogenesis via the activation of the PDGF-BB/PDGFR-ß-mediated PI3K/Akt/eNOS pathway, which may provide a new therapeutic strategy for stem cell therapy in wound healing.

Insulin- and cholic acid-loaded zein/casein-dextran nanoparticles enhance the oral absorption and hypoglycemic effect of insulin.

Diabetes mellitus is the most common metabolic disease in the world. Herein, insulin- and cholic acid-loaded zein nanoparticles with dextran surfaces were fabricated to enhance the oral absorptions of insulin in the intestine and in the liver which is the primary action organ of endogenous insulin. In the nanoparticles, zein acted as cement to embed insulin, cholic acid and casein by hydrophobic interactions. The hydrophilic dextran conjugated to casein by the Maillard reaction was located on the nanoparticle surface. The nanoparticles had an insulin loading efficiency of 74.6%, a cholic acid loading efficiency of 55.1% and a hydrodynamic diameter of 267 nm. The dextran significantly increased the disperse stability of the nanoparticles, protected the loaded insulin from hydrolysis in digestive juices, and increased the trans-mucus permeability of the insulin. The embedded cholic acid molecules were consecutively exposed to the surface when the nanoparticles were gradually eroded by proteases. The exposed cholic acid promoted the absorptions of the nanoparticles in the ileum and liver via bile acid transporters. The effect of pretreated lymphatic transport inhibitor cycloheximide revealed that about half of the nanoparticles were transported via the intestinal lymphatic transport pathway and the other half of the nanoparticles were transported via portal blood absorption. The oral pharmacological bioavailability of the nanoparticles in type I diabetic mice was 12.5-20.5%. This study demonstrates that nanoparticles are a promising oral delivery system for insulin.

The clinical effects of sodium hyaluronate, polyethylene glycol, and dextran-70 eye drops in relieving dry eye after phacoemulsification.

ABSTRACT: To compare the clinical efficacy of sodium hyaluronate eye drops, polyethylene glycol eye drops, and compound dextran eye drops in the treatment of dry eye after phacoemulsification of cataract.A total of 99 patients with dry eye after cataract phacoemulsification combined with intraocular lens implantation were treated in our hospital. Patients were divided into group A (sodium hyaluronate eye drops), group B (polyethylene glycol eye drops), and group C (dextran-70 eye drops). The clinical effect, tear film breakup time, basic tear secretion, corneal staining score, dry eye symptom score, and the incidence of ocular irritation were assessed.On the 3rd, 15th, 30th, and 60th day after operation, the tear film breakup time, corneal staining score, Schirmer I test, and dry eye symptom score in group A and group B were better than those in group C (P < .05). In addition, there were no significant differences in tear breakdown time, corneal staining score, Schirmer I test, and dry eye symptom score between group A and group B (P > .05). At 3 days to 60 days after operation, the incidence of dry eye in group A (12.12%) and group B (18.18%) was lower than that in group C (39.39%), and the incidence of dry eye in group A was significantly lower than that in group B (P < .05).The effect of sodium hyaluronate eye drops elicited a greater beneficial impact as compared to polyethylene glycol eye drops and dextran-70 eye drops.

Audio-vestibular disorders and pregnancy: A systematic review.

PURPOSE: During pregnancy a woman's body undergoes many physiological changes that involve all systems and organs, including sensory ones. We conducted this systematic review to highlight current evidence and treatment options in pregnant women with audio-vestibular disorders. MATERIALS AND METHODS: A search was made on the following databases: PubMed, PubMed Central, Web of Science and Scopus. This research protocol was deposited in the PROSPERO Database. RESULTS: After application of inclusion-exclusion criteria, 30 manuscripts were included in the review. Many authors (14/15) found a slight alteration of audiometric tests during pregnancy, with a reported recovery postpartum in most of the studies (5/7). Regarding sudden sensorineural hearing loss (SSNHL), we found four articles for a total of 69 patients: the treatment of choice was intravenous Dextran 40 and intra-tympanic corticosteroids. Most included studies (4/6) found neither clinical nor epidemiological associations between otosclerosis and pregnancy in large-based sample studies. Few investigations regarded Eustachian tube function and vertigo. CONCLUSIONS: According to our results, many variations of hearing acuity during pregnancy are slight and transient and require only clinical observation. In large samples, otosclerosis appeared not to be associated with pregnancy. Clinicians should consider intra-tympanic steroids in managing SSNHL during pregnancy. Further more accurate research is needed to deepen and clarify the association between pregnancy and audio-vestibular disorders.

Nattokinase Attenuates Retinal Neovascularization Via Modulation of Nrf2/HO-1 and Glial Activation.

Purpose: Nattokinase (NK), an active ingredient extracted from traditional food Natto, has been studied for prevention and treatment of cardiovascular diseases due to various vasoprotective effects, including fibrinolytic, antihypertensive, anti-atherosclerotic, antiplatelet, and anti-inflammatory activities. Here, we reported an antineovascular effect of NK against experimental retinal neovascularization. Methods: The inhibitory effect of NK against retinal neovascularization was evaluated using an oxygen-induced retinopathy murine model. Expressions of Nrf2/HO-1 signaling and glial activation in the NK-treated retinae were measured. We also investigated cell proliferation and migration of human umbilical vein endothelial cells (HUVECs) after NK administration. Results: NK treatment significantly attenuated retinal neovascularization in the OIR retinae. Consistently, NK suppressed VEGF-induced cell proliferation and migration in a concentration-dependent manner in cultured vascular endothelial cells. NK ameliorated ischemic retinopathy partially via activating Nrf2/HO-1. In addition, NK orchestrated reactive gliosis and promoted microglial activation toward a reparative phenotype in ischemic retina. Treatment of NK exhibited no cell toxicity or anti-angiogenic effects in the normal retina. Conclusions: Our results revealed the anti-angiogenic effect of NK against retinal neovascularization via modulating Nrf2/HO-1, glial activation and neuroinflammation, suggesting a promising alternative treatment strategy for retinal neovascularization.

Antireflux endoscopic injection therapy in post-pubertal patients via techniques adopted for the dilated ureteral orifice: a retrospective single-center study.

BACKGROUND: To investigate the efficacy and safety of endoscopic injection therapy for vesicoureteral reflux in post-pubertal patients with dilated ureteral orifice via modified hydrodistension implantation techniques. METHODS: We retrospectively reviewed medical records including operational procedure and clinical course of all consecutive patients over 12 years old with a history of injection therapy. Endoscopic injection of dextranomer/hyaluronic acid copolymer was performed under hydrodistension implantation technique with some modifications in order to inject through dilated ureteral orifice align with the intramural ureter. Technical selections were done according to hydrodistension grade of the ureteral orifice. Voiding cystourethrography was evaluated at 3 months postoperatively. Hydronephrosis was evaluated using ultrasonography preoperatively until 6 months postoperatively. RESULTS: From 2016 to 2019, 12 patients (all female, 16 ureteral units; median age 32 [range 15-61] years) underwent endoscopic injection therapy at one of our institutions. We have identified grade II vesicoureteral reflux in 5 ureters, grade III in 8, and grade IV in 3 ureters. Grade 3 ureteral-orifice dilation were presented in 12 ureters (75%), grade 2 in 3 and grade 1 in 1 ureter in the present cases. Postoperatively, vesicoureteral reflux was diminished to grade 0 in 12 ureteral units (75%), decreased to grade I in 3 (9%), and remained grade III in 1 (6%). Three patients reported dull flank pain for several days postoperatively and there was 1 case of acute pyelonephritis. Temporary hydronephrosis was confirmed in 3 ureteral units (19%) at 1 month postoperatively. Median follow-up duration was 23 (range 13-63) months long. Although, 3 patients were experienced f-UTI 1-2 times, repeated VCUG showed no VUR recurrence. CONCLUSIONS: According to hydrodistension grade of the ureteral orifice, endoscopic injection therapy via modified hydrodistension implantation technique is an effective and safe treatment for vesicoureteral reflux in post-pubertal female patients with dilated ureteral orifice. While ureteral deformities or a history of anti-reflux surgery may increase the risks, these can be managed with appropriate methods that ensure sufficient mound appearance and height.

Patterns of use, effectiveness and safety of gadolinium contrast agents: a European prospective cross-sectional multicentre observational study.

BACKGROUND: The EU gadolinium-based contrast agents (GBCA) market has changed in recent years due to the European Medicines Agency decision to suspend the marketing authorisation of linear GBCA and the marketing authorisation of new generic macrocyclic GBCA. The study aims to understand the patterns of (GBCA) use, and to study the effectiveness and safety of GBCA in routine practice across Europe. METHODS: Prospective, cross-sectional, multicentre, observational study in patients undergoing contrast-enhanced magnetic resonance. Reported usage patterns included indication, referral and examination details. Assessment of effectiveness included changes in radiological diagnosis, diagnostic confidence and image quality. Safety data were collected by spontaneous patient adverse event (AE) reporting. RESULTS: 2118 patients were included from 8 centres across 5 European countries between December 2018 and November 2019. Clariscan, Dotarem (gadoteric acid), Gadovist (gadobutrol) and ProHance (gadoteridol) were utilised in 1513 (71.4%), 356 (16.8%), 237 (11.2%) and 12 (0.6%) patients, respectively. Most were performed in CNS-related indications (46.2%). Mean GBCA doses were 0.10 mmol/kg body weight, except for Gadovist (mean 0.12 mmol/kg). GBCA use increased confidence in diagnosis in 96.2% of examinations and resulted in a change in radiological diagnosis in 73.9% of patients. Image quality was considered excellent or good in 96.1% of patients and across all GBCA. Four patients reported AEs (0.19%), with only 1 (0.05%) considered serious. CONCLUSIONS: This European study confirmed that GBCAs are used appropriately in Europe for a wide range of indications. The study demonstrated a significant increase in diagnostic confidence after GBCA use and confirmed the good safety profile of GBCAs, with comparable results for all agents used.

Transepithelial versus epithelium-off corneal crosslinking for progressive keratoconus.

BACKGROUND: Keratoconus is the most common corneal dystrophy. It can cause loss of uncorrected and best-corrected visual acuity through ectasia (thinning) of the central or paracentral cornea, irregular corneal scarring, or corneal perforation. Disease onset usually occurs in the second to fourth decade of life, periods of peak educational attainment or career development. The condition is lifelong and sight-threatening. Corneal collagen crosslinking (CXL) using ultraviolet A (UVA) light applied to the cornea is the only treatment that has been shown to slow progression of disease. The original, more widely known technique involves application of UVA light to de-epithelialized cornea, to which a photosensitizer (riboflavin) is added topically throughout the irradiation process. Transepithelial CXL is a recently advocated alternative to the standard CXL procedure, in that the epithelium is kept intact during CXL. Retention of the epithelium offers the putative advantages of faster healing, less patient discomfort, faster visual rehabilitation, and less risk of corneal haze. OBJECTIVES: To assess the short- and long-term effectiveness and safety of transepithelial CXL compared with epithelium-off CXL for progressive keratoconus. SEARCH METHODS: To identify potentially eligible studies, we searched the Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Trials Register) (2020, Issue 1); Ovid MEDLINE; Embase.com; PubMed; Latin American and Caribbean Health Sciences Literature database (LILACS); ClinicalTrials.gov; and World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP). We did not impose any date or language restrictions. We last searched the electronic databases on 15 January 2020. SELECTION CRITERIA: We included randomized controlled trials (RCTs) in which transepithelial CXL had been compared with epithelium-off CXL in participants with progressive keratoconus. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methodology. MAIN RESULTS: We included 13 studies with 723 eyes of 578 participants enrolled; 13 to 119 participants were enrolled per study. Seven studies were conducted in Europe, three in the Middle East, and one each in India, Russia, and Turkey. Seven studies were parallel-group RCTs, one study was an RCT with a paired-eyes design, and five studies were RCTs in which both eyes of some or all participants were assigned to the same intervention. Eleven studies compared transepithelial CXL with epithelium-off CXL in participants with progressive keratoconus. There was no evidence of an important difference between intervention groups in maximum keratometry (denoted 'maximum K' or 'Kmax'; also known as steepest keratometry measurement) at 12 months or later (mean difference (MD) 0.99 diopters (D), 95% CI -0.11 to 2.09; 5 studies; 177 eyes; I2 = 41%; very low certainty evidence). Few studies described other outcomes of interest. The evidence is very uncertain that epithelium-off CXL may have a small (data from two studies were not pooled due to considerable heterogeneity (I2 = 92%)) or no effect on stabilization of progressive keratoconus compared with transepithelial CXL; comparison of the estimated proportions of eyes with decreases or increases of 2 or more diopters in maximum K at 12 months from one study with 61 eyes was RR 0.32 (95% CI 0.09 to 1.12) and RR (non-event) 0.86 (95% CI 0.74 to 1.00), respectively (very low certainty). We did not estimate an overall effect on corrected-distance visual acuity (CDVA) because substantial heterogeneity was detected (I2 = 70%). No study evaluated CDVA gain or loss of 10 or more letters on a logarithm of the minimum angle of resolution (logMAR) chart. Transepithelial CXL may result in little to no difference in CDVA at 12 months or beyond. Four studies reported that either no adverse events or no serious adverse events had been observed. Another study noted no change in endothelial cell count after either procedure. Moderate certainty evidence from 4 studies (221 eyes) found that epithelium-off CXL resulted in a slight increase in corneal haze or scarring when compared to transepithelial CXL (RR (non-event) 1.07, 95% CI 1.01 to 1.14). Three studies, one of which had three arms, compared outcomes among participants assigned to transepithelial CXL using iontophoresis versus those assigned to epithelium-off CXL. No conclusive evidence was found for either keratometry or visual acuity outcomes at 12 months or later after surgery. Low certainty evidence suggests that transepithelial CXL using iontophoresis results in no difference in logMAR CDVA (MD 0.00 letter, 95% CI -0.04 to 0.04; 2 studies; 51 eyes). Only one study examined gain or loss of 10 or more logMAR letters. In terms of adverse events, one case of subepithelial infiltrate was reported after transepithelial CXL with iontophoresis, whereas two cases of faint corneal scars and four cases of permanent haze were observed after epithelium-off CXL. Vogt's striae were found in one eye after each intervention. The certainty of the evidence was low or very low for the outcomes in this comparison due to imprecision of estimates for all outcomes and risk of bias in the studies from which data have been reported. AUTHORS' CONCLUSIONS: Because of lack of precision, frequent indeterminate risk of bias due to inadequate reporting, and inconsistency in outcomes measured and reported among studies in this systematic review, it remains unknown whether transepithelial CXL, or any other approach, may confer an advantage over epithelium-off CXL for patients with progressive keratoconus with respect to further progression of keratoconus, visual acuity outcomes, and patient-reported outcomes (PROs). Arrest of the progression of keratoconus should be the primary outcome of interest in future trials of CXL, particularly when comparing the effectiveness of different approaches to CXL. Furthermore, methods of assessing and defining progressive keratoconus should be standardized. Trials with longer follow-up are required in order to assure that outcomes are measured after corneal wound-healing and stabilization of keratoconus. In addition, perioperative, intraoperative, and postoperative care should be standardized to permit meaningful comparisons of CXL methods. Methods to increase penetration of riboflavin through intact epithelium as well as delivery of increased dose of UVA may be needed to improve outcomes. PROs should be measured and reported. The visual significance of adverse outcomes, such as corneal haze, should be assessed and correlated with other outcomes, including PROs.

Comparison of Subureteral Endoscopic Injection of Dextranomer/Hyaluronic Acid and Lich-Gregoir Ureteral Reimplantation in the Treatment of Pediatric Primary Vesicoureteral Reflux: A Prospective Randomized Study.

Background: The gold standard of surgical intervention of vesicoureteral reflux (VUR) is open ureteral reimplantation with high success and low complication rates. However, in recent years, endoscopic injection, dextranomer/hyaluronic acid (Dx/HA), has become an effective therapy for VUR. It is noted that limited prospective randomized trials compare the different surgical techniques of especially endoscopic injection versus open procedures. We aimed to compare the outcomes of endoscopic injection of Dx/HA and Lich-Gregoir open technique of ureteral reimplantation for grades III and IV primary VUR in pediatric patients. Materials and Methods: Between January 2016 and December 2018, 60 pediatric patients with grades III and IV primary VUR were included in a prospective randomized trial. Thirty cases with 45 refluxing ureters managed by endoscopic injection of Dx/HA comprised group A. Open Lich-Gregoir technique used in the other 30 cases with 48 refluxing ureters composed of group B. Renal ultrasound, voiding cystourethrography, and renal scintigraphy were used for follow-up. The surgical success rate, cost-effectiveness, and occurrence of complications were evaluated and compared in both groups. Results: Sixty pediatric patients with 93 refluxing ureters (41 females and 19 males) were included in the trial. The mean follow-up for all patients was 17.7 ± 7.1 months. Overall reflux resolution was 80% (36/45) of the ureters in group A after a single injection and 93.75% (45/48) of the ureters in group B. The difference between the two groups was not statistically significant concerning clinical or anatomical preoperative factors and surgical success rate. There was a statistically significant difference between the two groups in terms of operative time and hospital stay. Conclusion: This comparative study demonstrated a high success rate of open ureteral reimplantation (Lich-Gregoir) procedure over the endoscopic injection of Dx/HA therapy to manage primary VUR grades III-IV. Clinical Trial Number: NCT04798443.

The effect of hypergravity in intestinal permeability of nanoformulations and molecules.

The oral administration of drugs remains a challenge due to rapid enzymatic degradation and minimal absorption in the gastrointestinal tract. Mechanical forces, namely hypergravity, can interfere with cellular integrity and drug absorption, and there is no study describing its influence in the intestinal permeability. In this work, it was studied the effect of hypergravity on intestinal Caco-2 cells and its influence in the intestinal permeability of different nanoformulations and molecules. It was shown that the cellular metabolic activity and integrity were maintained after exposure to different gravity-levels (g-levels). Expression of important drug transporters and tight junctions' proteins was evaluated and, most proteins demonstrated a switch of behavior in their expression. Furthermore, paracellular transport of FITC-Dextran showed to significantly increase with hypergravity, which agrees with the decrease of transepithelial electrical resistance and the increase of claudin-2 at higher g-levels. The diffusion of camptothecin released from polymeric micelles revealed a significant decrease, which agrees with the increased expression of the P-gp observed with the increase in g-levels, responsible for pumping this drug out. The neonatal Fc receptor-mediated transport of albumin-functionalized nanoparticles loaded with insulin showed no significant changes when increasing the g-levels. Thus, this study supports the effect of hypergravity on intestinal permeability is dependent on the molecule studied and the mechanism by which it is absorbed in the intestine.

Transdermal electroosmotic flow generated by a porous microneedle array patch.

A microneedle array is an attractive option for a minimally invasive means to break through the skin barrier for efficient transdermal drug delivery. Here, we report the applications of solid polymer-based ion-conductive porous microneedles (PMN) containing interconnected micropores for improving iontophoresis, which is a technique of enhancing transdermal molecular transport by a direct current through the skin. The PMN modified with a charged hydrogel brings three innovative advantages in iontophoresis at once: (1) lowering the transdermal resistance by low-invasive puncture of the highly resistive stratum corneum, (2) transporting of larger molecules through the interconnected micropores, and (3) generating electroosmotic flow (EOF). In particular, the PMN-generated EOF greatly enhances the transdermal molecular penetration or extraction, similarly to the flow induced by external pressure. The enhanced efficiencies of the EOF-assisted delivery of a model drug (dextran) and of the extraction of glucose are demonstrated using a pig skin sample. Furthermore, the powering of the PMN-based transdermal EOF system by a built-in enzymatic biobattery (fructose / O2 battery) is also demonstrated as a possible totally organic iontophoresis patch.

Non-invasive intranasal administration route directly to the brain using dendrimer nanoplatforms: An opportunity to develop new CNS drugs.

There are several routes of administration to the brain, including intraparenchymal, intraventricular, and subarachnoid injections. The blood-brain barrier (BBB) impedes the permeation and access of most drugs to the central nervous system (CNS), and consequently, many neurological diseases remain undertreated. For past decades, to circumvent this effect, several nanocarriers have been developed to deliver drugs to the brain. Importantly, intranasal (IN) administration can allow direct delivery of drugs into the brain through the anatomical connection between the nasal cavity and brain without crossing the BBB. In this regard, dendrimers may possess great potential to deliver drugs to the brain by IN administration, bypassing the BBB and reducing systemic exposure and side effects, to treat diseases of the CNS. In this original concise review, we highlighted the few examples advocated regarding the use of dendrimers to deliver CNS drugs directly via IN. This review highlighed the few examples of the association of dendrimer encapsulating drugs (e.g., small compounds: haloperidol and paeonol; macromolecular compounds: dextran, insulin and calcitonin; and siRNA) using IN administration. Good efficiencies were observed. In addition, we will present the in vivo effects of PAMAM dendrimers after IN administration, globally, showing no general toxicity.

Paeonol alleviates dextran sodium sulfate induced colitis involving Candida albicans-associated dysbiosis.

Inflammatory bowel disease (IBD), which consists of ulcerative colitis (UC) and Crohn's disease (CD), is a chronic inflammatory disorder of the gastrointestinal tract. Occurrence and development of UC have been associated with multiple potential causative factors, which include fungal dysbiosis. Growing evidence reveals that Candida albicans-associated dysbiosis is correlated with clinical deterioration in UC. Paeonol (PAE) is a commonly used traditional medicine with multiple reported properties including effective alleviation of UC. In this study, a murine UC model was established by colonizing mice with additional C. albicans via gavage prior to dextran sodium sulfate (DSS) administration. Effects of PAE treatment were also assessed at initiation and in preestablished C. albicans-associated colitis. The results showed that C. albicans supplementation could aggravate disease activity index (DAI), compromise mucosal integrity, exacerbate fecal and tissue fungal burdens, increase serum ß-glucan and anti-Saccharomyces cerevisiae antibody (ASCA) levels, promote serum and colonic tissue pro-inflammatory cytokine secretion (tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, IL-6, and IL-8) and decrease the anti-inflammatory cytokine IL-10 level. It also stimulated Dectin-1, TLR2 and TLR4 as well as expression of their downstream effector NF-κB in colonic tissue. After PAE treatment, the adverse impacts of C. albicans on colitis were relieved, via decreased receptor-associated local and systemic inflammation. Our study suggests that PAE should be a candidate for treatment of fungal dysbiosis-associated UC and may act through the Dectin-1/NF-κB pathway in collaboration with TLR2 and TLR4. LAY SUMMARY: Candida albicans is believed to be an important stimulator in ulcerative colitice (UC) development. Suppressing the growth of intestinal C. albicans can be contributory to the amelioration of UC. Paeonol (PAE) is a commonly used traditional medicine with multiple biological functions. In this study, we observed that PAE could alleviate symptoms in mice UC model accompanying with burden reduction of C. albicans. Therefore, we suppose that PAE can be a candidate in the treatment of C. albicans-associated UC.