A mechanistically novel peptide agonist of the IL-7 receptor that addresses limitations of IL-7 cytokine therapy.

Interleukin (IL)-7 is broadly active on T-cell populations, and modified versions have been clinically evaluated for a variety of therapeutic applications, including cancer, lymphopenia, and infectious diseases; and found to be relatively well-tolerated and biologically active. Here we describe novel IL-7R agonists that are unrelated in structure to IL-7, bind to the receptor subunits differently from IL-7, but closely emulate IL-7 biology. The small size, low structural complexity, and the natural amino acid composition of the pharmacologically active peptide MDK1472 allows facile incorporation into protein structures, such as the IgG2-Fc fusion MDK-703.

Phenotypes of CF rabbits generated by CRISPR/Cas9-mediated disruption of the CFTR gene.

Existing animal models of cystic fibrosis (CF) have provided key insights into CF pathogenesis but have been limited by short lifespans, absence of key phenotypes, and/or high maintenance costs. Here, we report the CRISPR/Cas9-mediated generation of CF rabbits, a model with a relatively long lifespan and affordable maintenance and care costs. CF rabbits supplemented solely with oral osmotic laxative had a median survival of approximately 40 days and died of gastrointestinal disease, but therapeutic regimens directed toward restoring gastrointestinal transit extended median survival to approximately 80 days.

HMGB1 Antagonist, Box A, Reduces TLR4, RAGE, and Inflammatory Cytokines in the Cornea of P. aeruginosa-Infected Mice.

Purpose: High mobility group box 1 (HMGB1) contributes to adverse disease outcome in Pseudomonas aeruginosa keratitis. This study tests Box A, an HMGB1 antagonist, in a model of the disease.

Methods: C57BL/6 mice (B6) were injected subconjunctivally (1 day before infection) with Box A or phosphate-buffered saline (PBS), infected with P.

Topical Glycyrrhizin Is Therapeutic for Pseudomonas aeruginosa Keratitis.

Purpose: Glycyrrhizin (GLY), an inhibitor of high-mobility group box 1 (HMGB1) protects prophylactically against Pseudomonas aeruginosa keratitis. However, the therapeutic potential of GLY to enhance an antibiotic has not been tested and is our purpose.

Methods: C57BL/6 mice (B6) were infected with a clinical isolate (KEI 1025) of P.

Characterization of Three Ocular Clinical Isolates of P. aeruginosa: Viability, Biofilm Formation, Adherence, Infectivity, and Effects of Glycyrrhizin.

We selectively characterized three isolates from keratitis patients and how glycyrrhizin (GLY) affected them. Type III toxins were determined using polymerase chain reaction (PCR). Minimum Inhibitory Concentration (MIC) of GLY and assays for its effects on: time kill, bacterial permeability, and biofilm/adhesion were done.

Glycyrrhizin Reduces HMGB1 and Bacterial Load in Pseudomonas aeruginosa Keratitis.

Purpose: High mobility group box 1 (HMGB1) contributes to poor disease outcome in Pseudomonas aeruginosa keratitis. This study tests the prophylactic effect of treatment with HMGB1 inhibitors, glycyrrhizin (GLY) and its derivative, carbenoxolone (CBX), for Pseudomonas keratitis.

Methods: We treated C57BL/6 (B6) mice subconjunctivally with GLY or CBX, infected with a noncytotoxic clinical isolate (KEI 1025) or a cytotoxic strain (ATCC 19660) of P.

Inactivation of the miR-183/96/182 Cluster Decreases the Severity of Pseudomonas aeruginosa-Induced Keratitis.

Purpose: The microRNA-183/96/182 cluster (miR-183/96/182) plays important roles in sensory organs. Because the cornea is replete with sensory innervation, we hypothesized that miR-183/96/182 modulates the corneal response to bacterial infection through regulation of neuroimmune interactions.

Methods: Eight-week-old miR-183/96/182 knockout (ko) mice and their wild-type littermates (wt) were used.

Thrombomodulin Protects Against Bacterial Keratitis, Is Anti-Inflammatory, but Not Angiogenic.

Purpose: Thrombomodulin (TM) is a multidomain, transmembrane protein with anti-inflammatory properties. Thrombomodulin domain (D) 1 is lectin-like, interacting with Lewis Y antigen on lipopolysaccharide, and with HMGB1, while TMD23 is associated with angiogenic and anti-inflammatory functions. Thus, we tested if TM is protective against Pseudomonas aeruginosa keratitis and whether it enhanced corneal vascularity.

High-mobility group box 1: a novel target for treatment of Pseudomonas aeruginosa keratitis.

High-mobility group box 1 (HMGB1), a prototypic alarmin, mediates the systemic inflammatory response syndrome. Treatment with vasoactive intestinal peptide, an anti-inflammatory neuropeptide, downregulates proinflammatory cytokines and promotes healing in a susceptible (cornea perforates) model of Pseudomonas aeruginosa keratitis, and also significantly downregulates HMGB1 expression. Therefore, we examined targeting HMGB1 for the treatment of P.

Interleukin 17 regulates Mer tyrosine kinase-positive cells in Pseudomonas aeruginosa keratitis.

Purpose: To determine if IL-17 regulates Mer tyrosine kinase-positive (MerTK+) cells in Pseudomonas aeruginosa keratitis.

Methods: Interleukin 17 was tested in normal and infected cornea of susceptible C57BL/6 and resistant BALB/c mice. The latter were treated with recombinant mouse (rm) IL-17; both groups were treated with IL-17 neutralizing antibody.

The evolution of disease: anthropological perspectives on epidemiologic transitions.

Background: The model of epidemiologic transitions has served as a guiding framework for understanding relationships between patterns of human health and disease and economic development for the past several decades. However, epidemiologic transition theory is infrequently employed in epidemiology.

Objective: Moving beyond Omran's original formulation, we discuss critiques and modifications of the theory of epidemiologic transitions and highlight some of the ways in which incorporating epidemiologic transition theory can benefit theory and practice in epidemiology.

HGF signaling impacts severity of Pseudomonas aeruginosa keratitis.

Purpose: To determine whether rapamycin altered corneal growth factor levels to impact severity of Pseudomonas aeruginosa keratitis.

Methods: BALB/c mice were injected intraperitoneally with rapamycin or PBS and infected with P. aeruginosa.

The role of VIP in cornea.

Purpose: Exogenous vasoactive intestinal peptide (VIP) down-regulates pro-inflammatory but up-regulates anti-inflammatory cytokines, growth factors (GFs) and Toll-like receptors promoting healing in experimental Pseudomonas aeruginosa (P. aeruginosa) keratitis. Whether VIP is required for GF or GF receptor (R) expression in normal and infected corneas is unknown and is the purpose of this study.

Effects of VIP on corneal reconstitution and homeostasis following Pseudomonas aeruginosa induced keratitis.

Purpose: Studies from our laboratory have demonstrated that vasoactive intestinal peptide (VIP) directly converts the normally susceptible C57BL/6J (B6) mouse to resistant after ocular infection through modulation of the inflammatory response. This study examines mechanisms by which VIP influences the healing phase following infection--specifically reconstitution of the extracellular matrix (ECM).

Methods: B6 mice received daily intraperitoneal (IP) injections of VIP, while control mice were similarly injected with sterile phosphate buffered saline (PBS).

Dose response of Gabapentin Enacarbil versus placebo in subjects with moderate-to-severe primary restless legs syndrome: an integrated analysis of three 12-week studies.

Background: The efficacy and tolerability of gabapentin enacarbil (Horizant®; GlaxoSmithKline, Brentford, UK) has been demonstrated in several restless legs syndrome (RLS) phase II and phase III clinical studies at various doses from 600 mg to 2400 mg.

Objective: The objective of this study was to evaluate key efficacy and safety outcomes in subjects with RLS treated with once-daily gabapentin enacarbil 600 mg, 1200 mg, 1800 mg and 2400 mg, providing supportive evidence of the efficacy of gabapentin enacarbil 600 mg compared with higher doses and placebo.

Study Design: Integrated post hoc analysis of three 12-week, randomized, double-blind, placebo-controlled trials in subjects with RLS.

Substance P affects growth factors in Pseudomonas aeruginosa-infected mouse cornea.

Purpose: This study analyzed the influence of substance P (SP) on growth factors related to wound healing in mice in the presence of infectious keratitis.

Methods: Naturally resistant mice were injected intraperitoneally with SP or phosphate-buffered saline and infected with Pseudomonas aeruginosa, and corneal messenger RNA (mRNA) levels of growth factors and apoptosis genes were tested. Enzyme-linked immunosorbent assay determined the protein levels, whereas immunohistochemistry tested the distribution, macrophage phenotype, and cell quantitation.

Vasoactive intestinal peptide downregulates proinflammatory TLRs while upregulating anti-inflammatory TLRs in the infected cornea.

TLRs recognize microbial pathogens and trigger an immune response, but their regulation by neuropeptides, such as vasoactive intestinal peptide (VIP), during Pseudomonas aeruginosa corneal infection remains unexplored. Therefore, C57BL/6 (B6) mice were injected i.p.

A randomized, double-blind, placebo-controlled study to assess the efficacy and tolerability of gabapentin enacarbil in subjects with restless legs syndrome.

Study Objective: To evaluate the efficacy and tolerability of gabapentin enacarbil (GEn) 1200 mg or 600 mg compared with placebo in subjects with moderate-to-severe primary restless legs syndrome (RLS).

Methods: This 12-week, multicenter, double-blind, placebo-controlled study randomized subjects (1:1:1) to GEn 1200 mg, 600 mg, or placebo. Co-primary endpoints: mean change from baseline in International Restless Legs Scale (IRLS) total score and proportion of responders (rated as "very much" or "much" improved) on the investigator-rated Clinical Global Impression-Improvement scale (CGI-I) at Week 12 LOCF for GEn 1200 mg compared with placebo.

VIP and growth factors in the infected cornea.

Purpose: Vasoactive intestinal peptide (VIP) is an anti-inflammatory neuropeptide that downregulates proinflammatory cytokines and promotes healing in a susceptible model of P. aeruginosa keratitis. Growth factors also play a role in corneal healing and restoration of tissue homeostasis after wounding.

Testican-1 promotes resistance against Pseudomonas aeruginosa-induced keratitis through regulation of MMP-2 expression and activation.

Purpose: Testican-1 (or SPOCK) is a highly conserved chimeric proteoglycan encoded by the SPOCK1 gene. Protease regulatory activity has recently been demonstrated by this molecule and its family members testican-2 and -3. The present study tested the hypothesis that testican-1 regulates corneal matrix metalloproteinase (MMP)-2 expression, thus improving disease outcome after Pseudomonas aeruginosa-induced keratitis.

VIP promotes resistance in the Pseudomonas aeruginosa-infected cornea by modulating adhesion molecule expression.

Purpose: This study tested the hypothesis that the neuropeptide vasoactive intestinal peptide (VIP) regulates adhesion molecule expression, reduces inflammatory cell migration and infiltration into the Pseudomonas aeruginosa-infected cornea of susceptible B6 mice, and promotes corneal healing and resistance.

Methods: B6 mice received daily intraperitoneal (IP) injections of VIP from -1 through 5 days after infection. Control mice were similarly injected with sterile phosphate-buffered saline (PBS).

Long-term maintenance treatment of restless legs syndrome with gabapentin enacarbil: a randomized controlled study.

Objective: To assess maintenance of efficacy and tolerability of gabapentin enacarbil in patients with moderate to severe primary restless legs syndrome (RLS).

Patients And Methods: This study (conducted April 18, 2006, to November 14, 2007) comprised a 24-week, single-blind (SB) treatment phase (gabapentin enacarbil, 1200 mg) followed by a 12-week randomized, double-blind (DB) phase. Responders from the SB phase (patients with improvements on the International Restless Legs Scale [IRLS] and investigator-rated Clinical Global Impression-Improvement scale at week 24 and stable while taking a gabapentin enacarbil dose of 1200 mg for at least 1 month before randomization) were randomized to gabapentin enacarbil, 1200 mg, or placebo once daily at 5 pm with food.

Role of the Fas pathway in Pseudomonas aeruginosa keratitis.

Purpose: The role of the Fas pathway was tested in Pseudomonas aeruginosa-infected mouse cornea by contrasting the responses of FasL(-/-) and wild-type (WT) mice.

Methods: TUNEL staining, real-time RT-PCR, immunostaining, and ELISA assay were used.

Results: Compared with WT (resistant) mice, BALB/c FasL(-/-) exhibited significantly elevated bacterial counts and polymorphonuclear leukocyte numbers at 1 and 3 days postinfection (p.

Beta-defensins 2 and 3 together promote resistance to Pseudomonas aeruginosa keratitis.

Defensins play an important role in both innate and adaptive immunity due to their antimicrobial, regulatory, and chemotactic effects. Nonetheless, the role of murine beta-defensins (mBD) 3 and 4, the murine homologs of human beta-defensins (hBD) 2 and 3, remains unknown in Pseudomonas aeruginosa keratitis. This study explored their role in corneal infection and potential synergy with mBD2, a defensin associated with better outcome in this disease.

IL-33 shifts macrophage polarization, promoting resistance against Pseudomonas aeruginosa keratitis.

Purpose: To determine the role of IL-33 in resistance to Pseudomonas aeruginosa keratitis.

Methods: Corneal IL-33 mRNA and protein levels were tested in susceptible C57BL/6 (B6) and resistant BALB/c mice. B6 mice were injected with recombinant mouse IL-33 (rmIL-33) and disease severity, bacterial load, polymorphonuclear neutrophils (PMN) infiltrate, gene expression of inflammatory, and T-helper (Th)1/Th2 cytokines were tested by RT-PCR.