Hyperosmotic Agents Research Articles

Clinical Impact of Standardized Interpretation and Reporting of Multimodality Neuromonitoring Data.

Evaluate the consistency and clinical impact of standardized multimodality neuromonitoring (MNM) interpretation and reporting within a system of care for patients with severe traumatic brain injury (sTBI). Retrospective, observational historical case-control study. Single-center academic level I trauma center. Standardized interpretation of MNM data summarized within daily reports. Consecutive patients with sTBI undergoing MNM were included. Historical controls were patients monitored before implementation of standardized MNM interpretation; cases were defined as patients with available MNM interpretative reports. Patient characteristics, physiologic data, and clinical outcomes were recorded, and clinical MNM reporting elements were abstracted. The primary outcome was the Glasgow Outcome Scale score 3-6 months postinjury. One hundred twenty-nine patients were included (age 42 ± 18 yr, 82% men); 45 (35%) patients were monitored before standardized MNM interpretation and reporting, and 84 (65%) patients were monitored after that. Patients undergoing standardized interpretative reporting received fewer hyperosmotic agents (3 [1-6] vs. 6 [1-8]; p = 0.04) and spent less time above an intracranial threshold of 22 mm Hg (22% ± 26% vs. 28% ± 24%; p = 0.05). The MNM interpretation cohort had a lower proportion of anesthetic days (48% [24-70%] vs. 67% [33-91%]; p = 0.02) and higher average end-tidal carbon dioxide during monitoring (34 ± 6 mm Hg vs. 32 ± 6 mm Hg; p < 0.01; d = 0.36). After controlling for injury severity, patients undergoing standardized MNM interpretation and reporting had an odds of 1.5 (95% CI, 1.37-1.59) for better outcomes. Standardized interpretation and reporting of MNM data are a novel approach to provide clinical insight and to guide individualized critical care. In patients with sTBI, independent MNM interpretation and communication to bedside clinical care teams may result in improved intracranial pressure control, fewer medical interventions, and changes in ventilatory management. In this study, the implementation of a system for management, including standardized MNM interpretation, was associated with a significant improvement in outcome.

Comparing equiosmolar hypertonic saline and mannitol for achieving brain relaxation in elective craniotomy patients: A systematic review and meta-analysis.

This study strives to provide a current and thorough assessment of the comparative efficacy and safety between equiosmolar quantities of hypertonic saline (HS) and mannitol in facilitating brain relaxation for patients undergoing elective craniotomies. This systematic review and meta-analysis, following preferred reporting items for systematic reviews and meta-analyses guidelines, compared the efficacy and safety of equiosmolar concentrations of mannitol and HS in elective craniotomies. PubMed, Scopus, Cochrane Library, ScienceDirect, and Proquest databases were searched using keywords related to mannitol, HS, and craniotomy. Results were analyzed through a random-effects model using Mantel-Haenszel risk ratio and standard mean difference. P < 0.05 was considered significant. Thirteen randomized controlled trials encompassing 965 patients (516 in the HS group and 448 in the mannitol group) were analyzed. The quality of studies was moderate-to-high, and no significant publication bias was observed. The primary outcome, brain relaxation, favored HS over mannitol without significant heterogeneity. Mannitol was associated with increased urine output compared to HS, irrespective of dose, with high heterogeneity. HS was linked to significantly reduced fluid input, confirmed by subgroup analysis with lower heterogeneity. No significant difference was found in serum osmolality between the two agents. Serum sodium (Na+) levels favored HS, whereas arterial blood Na+ levels also favored HS despite considerable heterogeneity. Maximum mean arterial pressure was higher with HS, but it displayed significant heterogeneity. Maximum central venous pressure showed no significant difference between the two agents, with moderate heterogeneity. HS appears more effective than mannitol in achieving brain relaxation, and it may offer advantages in fluid management and Na+ balance. Clinicians should consider these findings when selecting hyperosmotic agents for neurosurgical procedures. Further research is needed to address heterogeneity in certain outcomes and guide clinical practice.

DMSO synergized with sugars: optical clearing agent modulation of optical coherence tomography of skin tissues.

The stratum corneum of the outermost skin is an important barrier impeding transdermal permeation, and permeation enhancers can reduce the barrier resistance of the stratum corneum and enhance the permeation of drugs in tissues. The optical imaging depth, signal intensity, and scattering coefficient variation rules of skin tissues in time dimension are obtained by using optical coherence tomography (OCT). The effect of optical clearing agents (OCAs) on OCT imaging is obtained by quantitatively analyzing the changes in the optical properties of tissues. D-fructose, one of the monosaccharides, and sucrose, one of the disaccharides, were selected for the ex vivo optical clearing experiments on pig skin tissues utilizing the dimethyl sulfoxide (DMSO) carrier effect. We find that DMSO synergized with sugars applied to skin tissue has a more significant increase in the optical imaging depth and signal intensity, and a reduction in the scattering coefficient with an increasing concentration of DMSO. DMSO with a high concentration and D-fructose with saturated concentration (10:1; v/v) effectively reduce light attenuation in OCT imaging and improve the image quality. This operation will also shorten the application time to minimize skin damage from hyperosmotic agents.

A Review of the Management of Fuchs Endothelial Corneal Dystrophy

Fuchs Endothelial Corneal Dystrophy leads to progressive visual deterioration that may cause acutely painful episodes. Medical management has been limited to prescribing hyperosmotic agents. The advancement in therapeutic and surgical management has led to earlier intervention, better visual prognosis, and improved quality of life for patients affected by FECD. Optometrists play a role in the management of this condition’s diagnosis, treatment, and postsurgical care.

Enhancing paracellular and transcellular permeability using nanotechnological approaches for the treatment of brain and retinal diseases.

Paracellular permeability across epithelial and endothelial cells is, in large part, regulated by apical intercellular junctions also referred to as tight junctions (TJs). These junctions contribute to the spatial definition of different tissue compartments within organisms, separating them from the outside world as well as from inner compartments, with their primary physiological role of maintaining tissue homeostasis. TJs restrict the free, passive diffusion of ions and hydrophilic small molecules through paracellular clefts and are important for appropriate cell polarization and transporter protein localisation, supporting the controlled transcellular diffusion of smaller and larger hydrophilic as well as hydrophobic substances. This traditional diffusion barrier concept of TJs has been challenged lately, owing to a better understanding of the components that are associated with TJs. It is now well-established that mutations in TJ proteins are associated with a range of human diseases and that a change in the membrane fluidity of neighbouring cells can open possibilities for therapeutics to cross intercellular junctions. Nanotechnological approaches, exploiting ultrasound or hyperosmotic agents and permeation enhancers, are the paradigm for achieving enhanced paracellular diffusion. The other widely used transport route of drugs is via transcellular transport, allowing the passage of a variety of pro-drugs and nanoparticle-encapsulated drugs via different mechanisms based on receptors and others. For a long time, there was an expectation that lipidic nanocarriers and polymeric nanostructures could revolutionize the field for the delivery of RNA and protein-based therapeutics across different biological barriers equipped with TJs (e.g., blood-brain barrier (BBB), retina-blood barrier (RBB), corneal TJs, etc.). However, only a limited increase in therapeutic efficiency has been reported for most systems until now. The purpose of this review is to explore the reasons behind the current failures and to examine the emergence of synthetic and cell-derived nanomaterials and nanotechnological approaches as potential game-changers in enhancing drug delivery to target locations both at and across TJs using innovative concepts. Specifically, we will focus on recent advancements in various nanotechnological strategies enabling the bypassing or temporally opening of TJs to the brain and to the retina, and discuss their advantages and limitations.

Optical Modulation of the Blood-Brain Barrier for Glioblastoma Treatment.

The blood-brain barrier (BBB) is a major obstacle to the diagnostics and treatment of many central nervous system (CNS) diseases. A prime example of this challenge is seen in glioblastoma (GBM), the most aggressive and malignant primary brain tumor. The BBB in brain tumors, or the blood-brain-tumor barrier (BBTB), prevents the efficient delivery of most therapeutics to brain tumors. Current strategies to overcome the BBB for therapeutic delivery, such as using hyperosmotic agents (mannitol), have impeded progress in clinical translation limited by the lack of spatial resolution, high incidences of complications, and potential for toxicity. Focused ultrasound combined with intravenously administered microbubbles enables the transient disruption of the BBB and has progressed to early-phase clinical trials. However, the poor survival with currently approved treatments for GBM highlights the compelling need to develop and validate treatment strategies as well as the screening for more potent anticancer drugs. In this protocol, we introduce an optical method to open the BBTB (OptoBBTB) for therapeutic delivery via ultrashort pulse laser stimulation of vascular targeting plasmonic gold nanoparticles (AuNPs). Specifically, the protocol includes the synthesis and characterization of vascular-targeting AuNPs and a detailed procedure of optoBBTB. We also report the downstream characterization of the drug delivery and tumor treatment efficacy after BBB modulation. Compared with other barrier modulation methods, our optical approach has advantages in high spatial resolution and minimally invasive access to tissues. Overall, optoBBTB allows for the delivery of a variety of therapeutics into the brain and will accelerate drug delivery and screening for CNS disease treatment. Key features • Pulsed laser excitation of vascular-targeting gold nanoparticles non-invasively and reversibly modulates the blood-brain barrier permeability. • OptoBBTB enhances drug delivery in clinically relevant glioblastoma models. • OptoBBTB has the potential for drug screening and evaluation for superficial brain tumor treatment.

Critical Emergency Department Interventions and Clinical Deterioration in Children With Nonsevere Traumatic Intracranial Hemorrhage.

Substantial practice variation exists in the management of children with nonsevere traumatic intracranial hemorrhage (tICH). A comprehensive understanding of rates and timing of clinically important tICH, including critical interventions and deterioration, along with associated clinical and neuroradiographic characteristics, will inform accurate risk stratification. We conducted a single-center retrospective cohort study of children aged younger than 18 years evaluated in the emergency department (ED) from May 1, 2014 to February 28, 2020 with tICH and initial Glasgow Coma Scale (GCS) score of higher than 8. We determined rates of clinically important tICH after injury and within 96 hours of ED arrival, defined as immediate ED interventions (intubation, hyperosmotic agents, or neurosurgery within 4 hours of arrival) or clinically important deterioration (signs/symptoms with change in management). Associations between outcome and clinical and neuroradiographic characteristics were calculated using individual logistic regression models. Our sample included 135 children. Clinically important tICH was observed in 13.3% (n = 18); 9 (6.7%) underwent immediate ED interventions and 9 (6.7%) developed deterioration. Most (93.3%, n = 127) presented with an initial GCS ≥ 14, including all children who later deteriorated. Initial GCS ( P = 0.001) and nonaccidental trauma ( P = 0.024) mechanism were associated with the outcome. None of the 71 (52.6%) children with initial GCS ≥ 14, isolated, nonepidural hemorrhage after accidental injury developed clinically important tICH. Clinically important tICH occurred in 13% of children with nonsevere tICH, and 7% of children who did not undergo immediate ED interventions later deteriorated, all of whom had an initial GCS ≥ 14. However, a subgroup of children was identified as low risk based on clinical and neuroradiographic characteristics.

Management of Fuchs endothelial corneal dystrophy (FECD): a case series

Background: Fuchs endothelial corneal dystrophy (FECD) is the most common corneal dystrophy and often results in visual loss. This study aims to discuss the etiology, pathophysiology, diagnosis, and management of FECD. Case presentations: We reported three cases of FECD. The first patient was 60 years old female diagnosed with corneal scar post-penetrating keratoplasty (PK) and pseudophakia in the right eye (RE) and FECD grade II in the left eye (LE). The right and left eye (RLE) visual acuity was 6/18 and 6/12, respectively. The patient was managed thrice a day with lubricant eye drops in the RE and Phacoemulsification and Descemet membrane endothelial keratoplasty (DMEK) in the LE. The second patient was 80 years old female with RLE FECD grade II, LE Pseudophakia, and RE Immature Cataract. Visual acuity was light perception in the right eye and 1/60 in the LE. She was managed with Siloxane eye drop 2x1, Oculenta gel 1x1 in RLE, and DMEK in LE. The third patient was 73 years old male with pseudophakia, FECD grade III, and corneal neovascularization in the RE. Visual acuity in RE was hand movement, and LE was 6/6. He was planned for PK on RE, Diquafosol sodium (Diquas®) eye drop twice a day, and eye fresh plus eye drops 4x1 in RLE. Conclusion: FECD is the most common endothelial dystrophy and the main indication for corneal transplantation in the presence of visual disturbances. Medical therapy in the form of topical hyperosmotic agents can be given in the early phase and is useful for reducing corneal edema. The preferred management of FECD is currently Endothelial Keratoplasty (EK), such as DMEK, which has demonstrated excellent corneal clearance. Although the graft rejection rate in DMEK is low, there is a risk of rejection with the discontinuation of topical corticosteroids.

376 Neurologic Deterioration in Children with Non-Severe Traumatic Intracranial Hemorrhage: A Multicenter Cross-Sectional Study

OBJECTIVES/GOALS: Children with traumatic intracranial hemorrhage are monitored closely for deterioration and need for intervention. Data on risk factors for deterioration in nonsevere head injury are limited. Our objective was to identify children with hemorrhage from non-severe head injury who are at risk for deterioration. METHODS/STUDY POPULATION: We conducted a 10-site cross-sectional study of children 8. Our primary outcome was clinically important hemorrhage after injury and within 96 hours of ED arrival, defined as ED interventions (intubation, hyperosmotic agents, or neurosurgery within 4 hours of arrival) or clinically important deterioration (new or worsening signs/symptoms with an acute change in management). After testing model assumptions, we used logistic regression to identify clinical and neuroradiographic factors associated with clinically important hemorrhage. RESULTS/ANTICIPATED RESULTS: We studied 763 children with intracranial hemorrhage, with a median (IQR) age of 3.0 (0.4, 10.5) years. Initial GCS was mild (14-15) in 89.4% (n=682) and moderate (9-13) in 10.6% (n=81). Clinically important hemorrhage was observed in 19.5% (n=149), and 7.8% (n=59) developed clinically important deterioration. Median (IQR) time to deterioration was 17.6 (4.6, 37.9) hours. In our sample, 16.3% (n=124) underwent critical interventions, 54.9% (n=419) were admitted to an ICU, and 50.1% (n=382) underwent repeat neuroimaging. We found older age (OR 1.6; 95% CI 1.3, 1.9), lower GCS (OR 5.0; 95% CI 2.9, 8.5), and epidural hemorrhage (OR 3.3; 95% CI 2.0, 5.5) was associated with clinically important hemorrhage. DISCUSSION/SIGNIFICANCE: Clinically important hemorrhage occurred in one in five children with non-severe head injury. Clinical and neuroradiographic factors associated with ED interventions and deterioration were identified. Risk stratification algorithms using these data will be developed to assist clinicians caring for children with head injury.

Catheter failure in the administration of hyperosmotic drugs through a peripheral vein and vascular selection: A retrospective cohort study.

This study aimed to determine whether the placement of a peripheral intravenous catheter (PIVC) in the cephalic vein of the forearm could prevent PIVC failure in patients receiving hyperosmotic drugs through the peripheral vein. This retrospective cohort study included patients aged ≥ 20 years who had received infusion therapy via a PIVC in our institution between July and November 2017. Patients were divided into groups according to PIVC insertion into the cephalic, basilic, and medial veins. PIVCs used to administer drugs with osmotic pressure ratios > 2.0 were included. The primary outcome was survival time to catheter failure. Catheter failure was defined as accidental and unplanned catheter removal. We set the cephalic vein and other veins, including the medial and basilic veins, in the forearm as cohort groups. We used the Kaplan-Meier survival curves to compare the time until catheter failure in the cohort groups. The Cox proportional hazard models were fitted, and the hazard ratios were calculated. A total of 46 catheters with hyperosmotic agents were included in the analysis. Catheter failure was observed in 25 (54.3%) cases. Time to catheter failure in patients receiving high-dose drugs via the cephalic vein was significantly longer than that in the other two groups (p < 0.01). Thus, the cephalic vein, which has a high blood flow, is the ideal site of PIVC insertion in patients receiving high drug concentrations to prevent catheter failure.

Potentially Detrimental Effects of Hyperosmolality in Patients Treated for Traumatic Brain Injury.

Hyperosmotic therapy is commonly used to treat intracranial hypertension in traumatic brain injury patients. Unfortunately, hyperosmolality also affects other organs. An increase in plasma osmolality may impair kidney, cardiac, and immune function, and increase blood–brain barrier permeability. These effects are related not only to the type of hyperosmotic agents, but also to the level of hyperosmolality. The commonly recommended osmolality of 320 mOsm/kg H2O seems to be the maximum level, although an increase in plasma osmolality above 310 mOsm/kg H2O may already induce cardiac and immune system disorders. The present review focuses on the adverse effects of hyperosmolality on the function of various organs.

Verticalization for Refractory Intracranial Hypertension: A Case Series.

Severe intracranial hypertension is strongly associated with mortality. Guidelines recommend medical management involving sedation, hyperosmotic agents, barbiturates, hypothermia, and surgical intervention. When these interventions are maximized or are contraindicated, refractory intracranial hypertension poses risk for herniation and death. We describe a novel intervention of verticalization for treating intracranial hypertension refractory to aggressive medical treatment. This study was a single-center retrospective review of six cases of refractory intracranial hypertension in a tertiary care center. All patients were treated with a standard-of-care algorithm for lowering intracranial pressure (ICP) yet maintained an ICP greater than 20mmHg. They were then treated with verticalization for at least 24h. We compared themedian ICP, the number of ICP spikes greater than 20mmHg, and the percentage of ICP values greater than 20mmHg in the 24h before verticalization vs. after verticalization. We assessed the use of hyperosmotic therapies and any changes in the mean arterial pressure and cerebral perfusion pressure related with the intervention. Five patients were admitted with subarachnoid hemorrhage and one with intracerebral hemorrhage. All patients had ICP monitoring by external ventricular drain. The median opening pressure was 30mmHg (25th-75th interquartile range 22.5-30mmHg). All patients demonstrated a reduction in ICP after verticalization, with a significant decrease in the median ICP (12 vs. 8mmHg; p < 0.001), the number of ICP spikes (12 vs. 2; p < 0.01), and the percentage of ICP values greater than 20mmHg (50% vs. 8.3%; p < 0.01). There was a decrease in total medical interventions after verticalization (79 vs. 41; p = 0.05) and a lower total therapy intensity level score after verticalization. The most common adverse effects included asymptomatic bradycardia (n = 3) and pressure wounds (n = 4). Verticalization is an effective noninvasive intervention for lowering ICP in intracranial hypertension that is refractory to aggressive standard management and warrants further study.

Reduced deliquescency of isosorbide by cocrystallization and mechanisms for hygroscopicity

Isosorbide (ISO) is an effective hyperosmotic agent that can be administrated orally and is used as a therapeutic agent for brain pressure drop, glaucoma, and Meniere’s disease. However, the critical relative humidity (CRH) of ISO is about 48% RH at 25 °C, and it deliquesces in humid environments. In this study, we attempted to reduce the deliquescence of ISO using cocrystallization and analyze the water adsorption mechanism from the crystal structure. Four new ISO cocrystals with piperazine (PZ), hydrochlorothiazide (HCT), 3,5-dihydroxybenzoic acid (35DHBA), or gallic acid (GA) were identified. The dynamic vapor sorption analyses demonstrated that all the cocrystals showed higher CRHs than the ISO crystal. Although water adsorption below the CRH was observed for all cocrystals, the water molecules adsorbed in the ISO-PZ and ISO-GA cocrystals were lower than those in the ISO crystal. Investigation of the crystal structures suggested that the amount of water adsorbed might be related to the degree of exposure of the ISO hydroxyl groups on the crystal surface. Given the CRH, water adsorption below the CRH, thermal stability, apparent dissolution rate, and toxicity level of the coformer, the ISO-GA cocrystal is the most suitable for preparing a solid formulation of ISO.

Efficacy and safety of inhaled dry-powder mannitol in adults with cystic fibrosis: An international, randomized controlled study

Background: Mannitol is a mucoactive hyperosmotic agent used as add-on therapy in patients with cystic fibrosis (CF), administered twice-daily (BID) via a small, portable, breath-actuated dry-powder inhaler. This study was conducted to provide confirmatory evidence of mannitol's efficacy and safety in adults. Methods: This multicenter, double-blind, randomized, parallel-group, controlled clinical trial recruited adults (aged ≥18 years) with CF, and forced expiratory volume in 1 second (FEV1) 40–90% predicted. Subjects received either mannitol 400 mg or mannitol 50 mg (control), BID via dry-powder inhaler for 26 weeks. Primary endpoint: FEV1 averaged over the 26-week treatment period. Results: Of 423 subjects randomized (209 or 214 receiving mannitol 400 mg BID or control, respectively), 373 (88.2%) completed the study, with a similar proportion completing in the two groups. For FEV1 averaged over 26 weeks, mannitol 400 mg BID was statistically superior to control (adjusted mean difference 54 mL [95% CI 8, 100 mL]; p = 0.020). This was supported by sensitivity analyses of the primary endpoint, and by observed improvements in secondary pulmonary function endpoints (eg, absolute adjusted mean difference in percent predicted FEV1 averaged over 26 weeks 1.21% [0.07%, 2.36%]; p = 0.037). Adverse events were mainly mild or moderate in severity, with treatment-related adverse events in 15.5 and 12.2% of subjects receiving mannitol 400 mg BID and control, respectively. Conclusions: In adults with CF, mannitol 400 mg BID inhaled as a dry-powder statistically significantly improved lung function (FEV1) compared with control, with this improvement supported by sensitivity analyses and secondary pulmonary function endpoints. Mannitol had a good overall safety and tolerability profile. ClinicalTrials.gov: NCT02134353.

Trends and variation in repeat neuroimaging for children with traumatic intracranial hemorrhage.

ObjectivesWe aimed to determine trends and institutional variation in repeat neuroimaging in children with traumatic intracranial hemorrhage and to identify factors associated with neuroimaging modality (subsequent magnetic resonance imaging [MRI] vs computed tomography [CT]).MethodsWe conducted a retrospective cross‐sectional study of 35 hospitals in the Pediatric Health Information System database. We included children <18 years of age hospitalized from 2010–2019 with intracranial hemorrhage and who underwent a brain CT. We calculated repeat neuroimaging rates by modality and used regression analyses to examine temporal trends. We used hierarchical logistic regression to identify factors associated with subsequent MRI versus repeat CT, controlling for hospital.ResultsWe identified 12,714 children with intracranial hemorrhage, of which 5072 with repeat neuroimaging were studied. Of the 5072 children with repeat neuroimaging, repeat CT was performed in 67.6% (n = 3429) and subsequent MRI in 32.4% (n = 1643). Overall repeat neuroimaging with either a CT or MRI remained similar from 2010–2019 (P = 0.431); however, repeat CT scans significantly decreased (P = 0.001); whereas, MRIs significantly increased (P < 0.001). Repeat neuroimaging by hospital ranged from 20%–80%. After controlling for institution, subsequent MRI was more likely to be used in younger children and children who did not receive hyperosmotic agents, neurosurgical interventions, or intensive care unit admission (all P‐values <0.001).ConclusionsWe found that repeat neuroimaging rates for children with intracranial hemorrhage vary substantially by institution. We also found that although MRI was increasingly used to re‐image these children, overall repeat neuroimaging rates (CT or MRI) have not decreased over the past decade. Future work to implement optimal utilization of neuroimaging in these children is needed.

Optimal hyperosmotic agents for tissue immersion optical clearing in terahertz biophotonics.

In this work, a thorough analysis of hyperosmotic agents for the immersion optical clearing (IOC) in terahertz (THz) range was performed. It was aimed at the selection of agents for the efficient enhancement of penetration depth of THz waves into biological tissues. Pulsed spectroscopy in the frequency range of 0.1 to 2.5 THz was applied for investigation of the optical properties of common IOC agents. Using the collimated transmission spectroscopy in visible range, binary diffusion coefficients of tissue water and agent in ex vivo rat brain tissue were measured. IOC agents were objectively compared using two-dimensional nomogram, accounting for their THz-wave absorption coefficients and binary diffusion coefficients. The results of this study demonstrate an interplay between the penetration depth enhancement and the diffusion rate and allow for pointing out glycerol as an optimal agent among the considered ones for particular applications in THz biophotonics.

Update on the Surgical Management of Fuchs Endothelial Corneal Dystrophy.

Fuchs endothelial corneal dystrophy (FECD) is the most common posterior corneal dystrophy and the leading indication for corneal transplantation in the United States. FECD is slowly progressive, and patients develop gradual corneal endothelial decompensation, eventually resulting in failure of the endothelium to maintain corneal deturgescence. Medical management consists of topical hyperosmotic agents to facilitate dehydration of the cornea, but surgical intervention is often required to regain corneal clarity. The surgical management of FECD has evolved over the past two decades as corneal transplantation techniques have allowed for more selective keratoplasty and replacement of only the diseased layers of the cornea. Prior surgical management consisted of penetrating keratoplasty (PK) that carried significant intraoperative risks associated with “open sky” as well as postoperative risks of graft rejection, wound dehiscence, postoperative astigmatism, and prolonged visual rehabilitation. In the past 15 years, endothelial keratoplasty (EK) has become the treatment of choice for endothelial disease, significantly reducing the risks associated with the surgical treatment of FECD. Here we discuss the current surgical management of FECD, including the introduction of Descemet stripping only (DSO), and highlight future investigative efforts.

Optical Properties of Hyperosmotic Agents for Immersion Clearing of Tissues in Terahertz Spectroscopy

We measured the transmission spectra of the most common hyperosmotic agents, such as pure glycerol, propylene glycol (PG), dimethyl sulfoxide (DMSO), polyethylene glycol (PEG) with molecular weights of 200, 300, 400, and 600 Da, their aqueous solutions, and aqueous solutions of sucrose, glucose, fructose, and dextran 40 and 70. The experiments were carried out using a THz pulsed spectrometer with an evacuated measuring compartment to eliminate the effect of water vapor on spectral measurements. We reconstructed the dielectric characteristics of hyperosmotic agents in the spectral range from 0.1 to 2.5 THz and plotted a dependence of the amplitude absorption coefficient on the concentration of the considered agents at a frequency of 0.5 THz. The results are useful for selecting optimal agents for immersion optical clearing in the THz range.

P1133XYLITOL-BASED PERITONEAL DIALYSIS SOLUTIONS MITIGATED IN VITRO MESOTHELIAL AND ENDOTHELIAL TO MESENCHYMAL TRANSITION

Abstract Background and Aims Fibrosis, angiogenesis and microvascular alteration are main pathogenetic mechanisms involved in the progressive loss of the peritoneal ultrafiltration capacity in patients undergoing peritoneal dialysis (PD). Main cause of this condition is the continuous peritoneal exposure to hyperosmotic and hyperglycaemic agents. High glucose level activates the Mesothelial to Mesenchymal Transition (MMT) and the Endothelial-to-Mesenchymal (EndMT) program, which are responsible for the development of fibrosis/chronic peritoneal damage. Moreover, the high glucose content of PD solution may induce the VEGF production with consequent neo-angiogenesis. Therefore, the introduction of more biocompatible solutions in clinical practice is necessary for preserving the long-term peritoneal membrane. To this purpose we tested the in vitro effects of a new commercially available PD solutions containing xylitol, carnitine and reduced glucose, at comparable osmotic strength (XyloCore). Method Human vein microvascular endothelial cells (HMVEC) were cultured in EGM™-2MV medium (Lonza) and Human peritoneal mesothelial cell line (HMrSV5) were cultured in Dulbecco's Modified Eagle Medium (DMEM; Gibco) containing 10% fetal bovine serum. Cells were cultured to confluence and then treated for 3 hours with serum free medium, XyloCore 0.7 (0.5% Glucose, 0.7% Xylitol and 0.02% L-carnitine), XyloCore 1.5 (0.5% Glucose, 1.5% Xylitol and 0.02% L-carnitine) and commercially available glucose-based solutions (Fixioneal) 1.36% and 2.27% Glucose. Gene expression of MMT/EndMT, apoptosis, inflammation, extracellular remodeling and angiogenesis markers was evaluated by real-time PCR. Cell viability was assayed by MTS assay. Results Our in vitro results demonstrated that XyloCore solutions, by influencing only partially the mesothelial and endothelial cells viability, demonstrated a good biocompatible profile. Then, gene expression analysis of HMVEC and HMrSV5 treated with XyloCore solutions revealed a significant down-regulation of transcripts encoding for MMT and EndMT biomarkers (Zinc finger protein SNAI1, TGF-beta, alpha-SMA and vimentin), and pivotal biological elements involved in apoptosis (Bcl-2), extracellular matrix remodeling (matrix metallopeptidases), inflammation (IL-1beta, IL-6) and angiogenesis (Vascular endothelial growth factor) compared to glucose-based solutions with comparable osmotic strength. Conclusion These in vitro results demonstrated, for the first time, that XyloCore solutions have a better biocompatible impact and less pro-fibrotic potentials compared to conventional glucose-based solutions. These effects, if confirmed in in vivo studies, could have interesting clinical potentials.

Optimized skin optical clearing for optical coherence tomography monitoring of encapsulated drug delivery through the hair follicles.

Hair follicles (HF) represent a drug delivery reservoir for improved treatment of skin disorders. Although various particulate systems play an important role in HF-targeting, their optical monitoring in skin is challenging due to strong light scattering. Optical clearing is an effective approach allowing the increasing of particle detection depth in skin. The enhancement of optical probing depth (OPD) and optical detection depth (ODD) of particle localization using optical coherence tomography (OCT) was evaluated under application of various optical clearing agents (OCAs) together with skin permeability enhancers ex vivo in rats. Efficient OPD increasing was demonstrated for all investigated OCAs. However, skin dehydration under action of hyperosmotic agents led to the worsening of OCT-contrast in dermis decreasing the ODD. Lipophilic agents provided optical clearing of epidermis without its dehydration. The highest ODD was obtained at application of a PEG-400/oleic acid mixture. This OCA was tested in vivo showing beneficial ODD and OPD enhancement.