Thrombotic microangiopathy following systemic AAV administration is dependent on anti-capsid antibodies.

BACKGROUNDSystemic administration of adeno-associated virus (AAV) can trigger life-threatening inflammatory responses, including thrombotic microangiopathy (TMA), acute kidney injury due to atypical hemolytic uremic syndrome-like complement activation, immune-mediated myocardial inflammation, and hepatic toxicity.METHODSWe describe the kinetics of immune activation following systemic AAV serotype 9 (AAV9) administration in 38 individuals following 2 distinct prophylactic immunomodulation regimens. Group 1 received corticosteroids and Group 2 received rituximab plus sirolimus in addition to steroids to prevent anti-AAV antibody formation.

Biodistribution of Adeno-Associated Virus Gene Therapy Following Cerebrospinal Fluid-Directed Administration.

Adeno-associated virus (AAV)-based gene therapies, exemplified by the approved therapy for spinal muscular atrophy, have the potential to deliver disease-course-altering treatments for central nervous system (CNS) indications. However, several clinical trials have reported severe adverse events, including patient deaths following high-dose systemic administration for muscle-directed gene transfer, highlighting the need to explore approaches utilizing lower doses when targeting the CNS. Animal models of disease provide insight into the response to new AAV therapies.

Corneal stem cells niche and homeostasis impacts in regenerative medicine; concise review.

The limbal stem cells niche (LSCN) is an optimal microenvironment that provides the limbal epithelial stem cells (LESCs) and strictly regulates their proliferation and differentiation. Disturbing the LSCN homeostasis can lead to limbal stem cell dysfunction (LSCD) and subsequent ocular surface aberrations, such as corneal stromal inflammation, persistent epithelial defects, corneal neovascularisation, lymphangiogenesis, corneal opacification, and conjunctivalization. As ocular surface disorders are considered the second main cause of blindness, it becomes crucial to explore different therapeutic strategies for restoring the functions of the LSCN.

SLC13A5 Deficiency Disorder: From Genetics to Gene Therapy.

Epileptic encephalopathies may arise from single gene variants. In recent years, next-generation sequencing technologies have enabled an explosion of gene identification in monogenic epilepsies. One such example is the epileptic encephalopathy SLC13A5 deficiency disorder, which is caused by loss of function pathogenic variants to the gene SLC13A5 that results in deficiency of the sodium/citrate cotransporter.

Immune Responses and Immunosuppressive Strategies for Adeno-Associated Virus-Based Gene Therapy for Treatment of Central Nervous System Disorders: Current Knowledge and Approaches.

Adeno-associated viruses (AAVs) are being increasingly used as gene therapy vectors in clinical studies especially targeting central nervous system (CNS) disorders. Correspondingly, host immune responses to the AAV capsid or the transgene-encoded protein have been observed in various clinical and preclinical studies. Such immune responses may adversely impact patients' health, prevent viral transduction, prevent repeated dosing strategies, eliminate transduced cells, and pose a significant barrier to the potential effectiveness of AAV gene therapy.

Transcriptomic Profiling of Human Limbus-Derived Stromal/Mesenchymal Stem Cells-Novel Mechanistic Insights into the Pathways Involved in Corneal Wound Healing.

Limbus-derived stromal/mesenchymal stem cells (LMSCs) are vital for corneal homeostasis and wound healing. However, despite multiple pre-clinical and clinical studies reporting the potency of LMSCs in avoiding inflammation and scarring during corneal wound healing, the molecular basis for the ability of LMSCs remains unknown. This study aimed to uncover the factors and pathways involved in LMSC-mediated corneal wound healing by employing RNA-Sequencing (RNA-Seq) in human LMSCs for the first time.

Nanosized paclitaxel-loaded niosomes: formulation, in vitro cytotoxicity, and apoptosis gene expression in breast cancer cell lines.

Background: In this study, the optimized niosomal formulation containing paclitaxel using non-ionic surfactants and cholesterol was designed and its cytotoxic effects against different breast cancer cell lines and apoptosis gene expression analysis were also investigated.

Methods And Results: Due to enhancing equation variables, the Box-Behnken method has been applied. Lipid/drug molar ratio, the amounts of Span 60, and cholesterol were selected as the target for optimization.

Burden of mild haemophilia A: Systematic literature review.

Introduction: Although the clinical manifestations of severe haemophilia A (HA) are well studied, the challenges, if any, of living with mild HA are not clearly delineated to date.

Aim: To assess available evidence of clinical risks and societal/economic impacts of disease in adult patients with mild HA using a systematic literature review.

Methods: Prespecified study selection criteria were applied in a comprehensive literature search.

Limbal Epithelial and Mesenchymal Stem Cell Therapy for Corneal Regeneration.

Corneal pathologies are a major cause of blindness and visual impairment, especially in the developing world. However, not only is there a global shortage of donor corneal tissue, but a significant proportion of these blinding pathologies also carry an unfavourable long-term prognosis for conventional corneal transplantation. In the last few decades, there has been a spurt of research on developing alternate approaches to address corneal blindness, including stem cell therapy.

The Effect of Spinal versus General Anesthesia on Quality of Life in Women Undergoing Cesarean Delivery on Maternal Request.

Introduction The proportion of women electing for cesarean delivery has increased in both developed and developing countries. Cesarean delivery on maternal request (CDMR) refers to a primary cesarean delivery performed because the mother requests this method of delivery in the absence of standard medical/obstetrical indications. Several studies compared anesthesia modalities in cesarean section regarding clinical outcomes such as maternal mortality, post-operative pain and bleeding, but only a few compared health-related quality of life (HRQoL) of women undergoing general anesthesia versus spinal anesthesia.

Effect of LaF: Ag fluorescent nanoparticles on photodynamic efficiency and cytotoxicity of Protoporphyrin IX photosensitizer.

LaF: Ag nanoparticles (NPs) were synthesized by the co-precipitation method. The produced NPs were characterized by X-ray diffraction (XRD) pattern, scanning electron microscope (SEM), dynamic light scattering (DLS) and Fourier transform infrared spectroscopy (FTIR). The emission spectrum of LaF:Ag NPs is mostly overlapped with the absorption band of protoporphyrin IX (PpIX) and their conjugation was confirmed by studying fluorescence resonance energy transfer (FRET) from LaF:Ag donor to protoporphyrin IX acceptor.

Analysis and analytical characterization of bioheat transfer during radiofrequency ablation.

Understanding thermal transport and temperature distribution within biological organs is important for therapeutic aspects related to hyperthermia treatments such as radiofrequency ablation (RFA). Unlike surface heating, the RFA treatment volumetrically heats up the biological media using a heating probe which provides the input energy. In this situation, the shape of the affected region is annular, which is described by an axisymmetric geometry.

Effects of External and Internal Hyperthermia on LDL Transport and Accumulation Within an Arterial Wall in the Presence of a Stenosis.

Effects of hyperthermia on transport of low-density lipoprotein (LDL) through a stenosed arterial wall are analyzed comprehensively in the present work. The realistic and pertinent aspects of an arterial wall is represented by a multi-layer model, with a proper representation of the thickened intima region due to the atherosclerotic plaque formation. Effects of external and internal hyperthermia on LDL concentration levels are established along with the range of influence of these effects.

A phase I dose-escalation study of MEDI-575, a PDGFRα monoclonal antibody, in adults with advanced solid tumors.

Purpose: The purpose of the study was to evaluate safety and determine the maximum tolerated dose (MTD) of MEDI-575, a fully human monoclonal antibody that selectively binds to platelet-derived growth factor receptor-α (PDGFRα), in patients with advanced solid tumors.

Methods: This phase I multicenter, open-label, single-arm study enrolled adults in a 3 + 3 dose escalation design to receive MEDI-575 (3, 6, 9, 12, or 15 mg/kg) once weekly (QW) until toxicity or disease progression occurred. One 0.

Effect of uremic serum and uremic toxins on drug metabolism in human microsomes.

There is increasing evidence that renal impairment modifies nonrenal drug clearance through drug metabolizing cytochrome P450 (CYP) enzymes. In this study, the direct inhibitory effect of serum from chronic renal failure (CRF) patients receiving dialysis was evaluated in CYP3A4 (testosterone) and CYP2B6 (bupropion) metabolism assays. Human liver microsomes were incubated with ultrafiltered serum collected pre- and post-hemodialysis from ten CRF patients.

Bacillus anthracis endospores regulate ornithine decarboxylase and inducible nitric oxide synthase through ERK1/2 and p38 mitogen-activated protein kinases.

Interactions between Bacillus anthracis (B. anthracis) and host cells are of particular interest given the implications of anthrax as a biological weapon. Inhaled B.

Preload dependence of Doppler tissue imaging-derived indices in adolescents.

Doppler tissue imaging (DTI) has been proposed as a tool for evaluation of diastolic function. Controversy exists regarding whether DTI measurements are influenced by preload. To determine the influence of preload reduction on DTI, we studied 17 patients (mean age 17 +/- 1.

Effect of transfusion on cerebral oxygenation, flow velocity in a patient with sickle cell anemia and Moyamoya disease: a case report.

Vascular occlusive diseases affect brain blood flow, brain metabolism and are associated with arterial ischemic stroke. This study was designed to measure the brain blood flow velocity, brain oxygenation, hemoglobin concentrations, hematocrit, and cell free hemoglobin at pre- and post-exchange red cell transfusion in an 18 year old male patient with sickle cell disease and moyamoya syndrome (MMS). Exchange transfusion increased cerebral oxygen saturation 12%, total hemoglobin concentration 2%, hemoglobin AA 80%, and reduced sickle (SS) hemoglobin 12%, arterializations 33%, and cell free hemoglobin 33%.

Effects of hydroxyurea and L-arginine on the production of nitric oxide metabolites in cultures of normal and sickle erythrocytes.

Previous in vitro studies suggest that erythrocytes may be a source of nitric oxide (NO) produced by nitric oxide synthase (NOS) or by oxyhemoglobin-mediated oxidation of hydroxyurea (HU). This study was performed to determine the roles of HU and NOS in the production of NO by normal and sickle erythrocytes. Red blood cells (RBCs) from normal adult hemoglobin (HbAA) and homozygous sickle cell subjects (HbSS) were incubated with PBS containing 0.

Effects of hydroxyurea treatment on cerebral oxygenation in adult patients with sickle cell disease: an open-label pilot study.

Background: In patients with sickle cell disease (SCD), cerebral oxygen saturation (rSO(2)) has been reported to be below normal and to increase after red blood cell transfusion.

Objective: This study was designed to determine the effects of long-term and short-term hydroxyurea (HU) treatment on cerebral oxygenation in patients with SCD.

Methods: This open-label pilot study was conducted at the Department of Anesthesiology and the Center for Sickle Cell Disease, College of Medicine, Howard University, Washington, DC.

Plasma levels of TNF-alpha in sickle cell patients receiving hydroxyurea.

Hydroxyurea (HU), a chemotherapeutic agent, used increasingly in the treatment of sickle cell disease (SCD) stimulates the release of a tumor necrosis factor (TNF-alpha) from human macrophages in vitro and the concentration of TNF-alpha is greater than normal in subjects affected by SCD. It is widely accepted that HU may inhibit vaso-occlusive crisis (VOC) by stimulating the production of fetal hemoglobin (HbF) and nitric oxide (NO) in SCD; however, the beneficial effects of HU in vivo may be counteracted by the release of TNF-alpha and, in turn, the expression of a vascular cell adhesion molecule (VCAM-1) on leukocytes. Previous studies have shown that the severity of SCD increases with the leukocyte count.

Cerebral oximetry in patients with sickle cell disease.

Background: There is limited information concerning the brain's oxygen supply and demand in patients with sickle cell disease.

Design: We measured near-infrared spectroscopy of brain oxygenation in 27 patients with sickle cell disease regardless of vaso-occlusive crisis, 14 normal healthy controls, and five anaemic patients without sickle cell disease. We also measured pre- and post-transfusion cerebral oximetry in 14 additional sickle cell disease patients who were on transfusion programmes.

Arterialization of venous blood for differentiation of sickle cell subjects in vaso-occlusive crisis.

These studies were designed as two experiments. Experiment 1 was performed to validate the hypothesis that oxygen saturation of the venous blood may be a marker for vaso-occlusive crisis (VOC) in sickle cell patients undergoing hydroxyurea (HU) treatments. Experiment 2 was performed to test the hypothesis that an acute increase in the blood nitric oxide (NO) concentration by administering HU modulates the perception of pain in sickle cell subjects in VOC.

Nitric oxide and cyclic GMP levels in sickle cell patients receiving hydroxyurea.

Recent studies suggest that nitric oxide (NO) may partly be responsible for the beneficial effect of hydroxyurea (HU) in sickle cell disease (SCD) patients. NO stimulates cyclic guanosine monophosphate (cGMP) production, which mediates vasodilatation. We investigated the association between NO, cGMP and fetal haemoglobin (HbF) levels after HU administration.

Arterialization of peripheral venous blood in sickle cell disease.

Arterialization of the venous blood is thought to be indicative of cutaneous shunting, and occurs in patients with sickle cell disease (SCD) during vaso-occlusive crisis (VOC). We performed the present study to quantify the amount of shunting that occurs in sickle cell patients presenting at the Howard University Sickle Cell Center, Washington, D.C.