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Papers by Gregory Jay

Journal of Orthopaedic Research®

Treatment of the injured joint with rhPRG4 is based on recent observations that inflammation dimi... more Treatment of the injured joint with rhPRG4 is based on recent observations that inflammation diminishes expression of native PRG4. Re-establishing lubrication between pressurized and sliding cartilage surfaces during locomotion promotes the nascent expression of PRG4 and thus intra-articular (IA) treatment strategies should be supported by pharmacokinetic evidence establishing the residence time of rhPRG4. A total of 21 Yucatan minipigs weighing $55 kg each received 4 mg of 131 I-rhPRG4 delivered by IA injection 5 days following surgical ACL transection. Animals were sequentially euthanized following IA rhPRG4 at 10 min (time zero), 24, 72 h, 6, 13 and 20 days later. The decay of the 131 I-rhPRG4 was measured relative to a non-injected aliquot and normalized to the weight of cartilage samples, menisci and synovium, and known cartilage volumes from each compartment surface obtained from representative Yucatan minipig knees. Decay of 131 I-rhPRG4 from joint tissues best fit a two-compartment model with an a half-life (t 1/ 2a) of 11.28 h and b half-life (t 1/2b) of 4.81 days. The tibial and femoral cartilage, meniscii, and synovium retained 7.7% of dose at 24 h. High concentrations of rhPRG4 were found in synovial fluid (SF) that was non-aspiratable and resided on the articular surfaces, removable by irrigation, at 10 min following 131 I-rhPRG4 injection. Synovial fluid K21 exceeded K12 and SF t 1/2b was 28 days indicating SF is the reservoir for rhPRG4 following IA injection. Clinical Significance: rhPRG4 following IA delivery in a traumatized joint populates articular surfaces for a considerable period and may promote the native expression of PRG4.

Arthritis research & therapy, Jan 29, 2018

Gout is an inflammatory arthritis caused by monosodium urate monohydrate (MSU) crystals' join... more Gout is an inflammatory arthritis caused by monosodium urate monohydrate (MSU) crystals' joint deposition. MSU phagocytosis by resident macrophages is a key step in gout pathogenesis. MSU phagocytosis triggers nuclear factor kappa B (NFκB) activation and production of cytokines and chemokines. Proteoglycan-4 (PRG4) is a glycoprotein produced by synovial fibroblasts and exerts an anti-inflammatory effect in the joint mediated by its interaction with cell surface receptor CD44. PRG4 also binds and antagonizes TLR2 and TLR4. The objective of this study is to evaluate the efficacy of recombinant human PRG4 (rhPRG4) in suppressing MSU-induced inflammation and mechanical allodynia in vitro and in vivo. THP-1 macrophages were incubated with MSU crystals ± rhPRG4 or bovine submaxillary mucin (BSM), and crystal phagocytosis, cytokines and chemokines expression and production were determined. NFκB p65 subunit nuclear translocation, NLRP3 induction, caspase-1 activation and conversion of p...

Comparison of Autograft and Allograft with Surface Modification for Flexor Tendon Reconstruction: A Canine in Vivo Model

The Journal of bone and joint surgery. American volume, Jan 4, 2018

Flexor tendon injury is common, and tendon reconstruction is indicated clinically if the primary ... more Flexor tendon injury is common, and tendon reconstruction is indicated clinically if the primary repair fails or cannot be performed immediately after tendon injury. The purpose of the current study was to compare clinically standard extrasynovial autologous graft (EAG) tendon and intrasynovial allogeneic graft (IAG) that had both undergone biolubricant surface modification in a canine in vivo model. Twenty-four flexor digitorum profundus (FDP) tendons from the second and fifth digits of 12 dogs were used for this study. In the first phase, a model of failed FDP tendon repair was created. After 6 weeks, the ruptured FDP tendons with a scarred digit were reconstructed with the use of either EAG or IAG tendons treated with carbodiimide-derivatized hyaluronic acid and lubricin. At 12 weeks after tendon reconstruction, the digits were harvested for functional, biomechanical, and histologic evaluations. The tendon failure model was a clinically relevant and reproducible model for tendon ...

Journal of immunology (Baltimore, Md. : 1950), Jan 15, 2018

Osteoarthritis (OA) is a low-grade chronic inflammatory joint disease. Innate immunity contribute... more Osteoarthritis (OA) is a low-grade chronic inflammatory joint disease. Innate immunity contributes to OA progression, mediated by TLR2 and TLR4. We evaluated the role of cluster determinant 44 (CD44), a transmembrane glycoprotein, in regulating TLR2-linked macrophage activation and resultant proinflammatory responses. TLR2 stimulation was performed on differentiated THP-1 macrophages in the presence or absence of a CD44-specific Ab or hyaluronan (HA). NF-κB nuclear translocation, IL-1 β and TNF-α gene expression, and protein concentrations were determined. Anti-CD44 Ab and HA treatments reduced NF-κB translocation, IL-1β and TNF-α expression, and production ( < 0.001). Inhibition of proinflammatory response in macrophages by HA was mediated by CD44. Protein phosphatase 2A mediated the reduction in NF-κB translocation by HA. CD44 knockdown reduced NF-κB nuclear translocation and downstream IL-1β and TNF-α protein production following TLR2 receptor stimulation ( < 0.001). murine...

cAMP Attenuates TGF-β's Profibrotic Responses in Osteoarthritic Synoviocytes: Involvement of Hyaluronan and PRG4

American journal of physiology. Cell physiology, Jan 13, 2018

Osteoarthritis (OA) is characterized by synovitis and synovial fibrosis. Synoviocytes are fibrobl... more Osteoarthritis (OA) is characterized by synovitis and synovial fibrosis. Synoviocytes are fibroblast-like resident cells of the synovium that are activated by TGF-β to proliferate, migrate and produce extracellular matrix. Synoviocytes secrete hyaluronan (HA) and proteoglycan-4 (PRG4). HA reduced synovial fibrosis in vivo and the Prg4 mouse exhibits synovial hyperplasia. We investigated the antifibrotic effects of increased intracellular cAMP in TGF-β stimulated human OA synoviocytes. TGF-β1 stimulated collagen I (COL1A1), α-SMA, TIMP-1, PLOD2 expression and procollagen I, α-SMA, HA and PRG4 production, migration and proliferation of OA synoviocytes were measured. Treatment of OA synoviocytes with forskolin (10μM) increased intracellular cAMP levels and reduced TGF-β1 stimulated COL1A1, α-SMA and TIMP-1 expression, with no change in PLOD2 expression. Forskolin also reduced TGF-β1 stimulated procollagen I and α-SMA content, as well as synoviocyte migration and proliferation. Forskoli...

Preclinical Animal Studies of Intravesical Recombinant Human Proteoglycan 4 (rhPRG4) as a Novel Potential Therapy for Diseases Resulting From Increased Bladder Permeability

Urology, Jan 12, 2018

To test in an animal model the hypothesis that rhPRG4 (lubricin), a highly O-glycosylated mucin-l... more To test in an animal model the hypothesis that rhPRG4 (lubricin), a highly O-glycosylated mucin-like glycoprotein, may be a novel surface-active therapeutic for treating bladder permeability with co-morbid bowel permeability. Previously we showed that inducing bladder permeability in rats with dilute protamine sulfate (PS) produced colonic permeability and visceral hypersensitivity, suggesting increased bladder permeability could represent an etiologic factor in both Interstitial Cystitis/Bladder Pain Syndrome (IC/BPS) and Irritable Bowel Syndrome (IBS). We used an animal model of catheterized ovariectomized female rats instilled intravesically with 1 mg/ml PS for 10 min that after 24 hr were treated with 1.2 mg/ml lubricin or with vehicle alone. After 24 h the bladder and colon were removed and permeability assessed electrophysiologically with the Ussing chamber to measure the transepithelial electrical resistance (TEER). A second set of rats was treated identically, except permeab...

Public reporting burden for this collection of information is estimated to average 1 hour per res... more Public reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing this collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden to Department of Defense, Washington Headquarters Services, Directorate for Information Operations and Reports (0704-0188), 1215 Jefferson Davis Highway, Suite 1204, Arlington, VA 22202-4302. Respondents should be aware that notwithstanding any other provision of law, no person shall be subject to any penalty for failing to comply with a collection of information if it does not display a currently valid OMB control number.

Liquid-crystal materials find a new order

Nature India

International journal of molecular sciences, Jan 11, 2017

Deficiency of PRG4 (lubricin), the boundary lubricant in mammalian joints, contributes to increas... more Deficiency of PRG4 (lubricin), the boundary lubricant in mammalian joints, contributes to increased joint friction accompanied by superficial and upper intermediate zone chondrocyte caspase-3 activation, as shown in lubricin-null (Prg4(-/-)) mice. Caspase-3 activity appears to be reversible upon the restitution of Prg4 either endogenously in vivo, in a gene trap mouse, or as an applied lubricant in vitro. In this study we show that intra-articular injection of human PRG4 in vivo in Prg4(-/-) mice prevented caspase-3 activation in superficial zone chondrocytes and was associated with a modest decrease in whole joint friction measured ex vivo using a joint pendulum method. Non-lubricated Prg4(-/-) mouse cartilage shows caspase cascade activation caused by mitochondrial dysregulation, and significantly higher levels of peroxynitrite (ONOO(-) and (-)OH) and superoxide (O(-)₂) compared to Prg4(+/+) and Prg4(+/-) cartilage. Enzymatic activity levels of caspase 8 across Prg4 mutant mice we...

Degradation of proteoglycan 4/lubricin by cathepsin S: Potential mechanism for diminished ocular surface lubrication in Sjögren's syndrome

Experimental eye research, Aug 23, 2017

Sjögren's syndrome (SS) is an autoimmune disease affecting the lacrimal and salivary glands w... more Sjögren's syndrome (SS) is an autoimmune disease affecting the lacrimal and salivary glands with hallmark clinical symptoms of dry eye and dry mouth. Recently, markedly increased cathepsin S (CTSS) activity has been observed in the tears of SS patients. Proteoglycan 4 (PRG4), also known as lubricin, is an effective boundary lubricant that is naturally present on the ocular surface. While PRG4 is susceptible to proteolytic digestion, the potential effect of CTSS on PRG4 remains unknown. The objective of this study was to assess the ability of CTSS to enzymatically degrade purified PRG4, and PRG4 naturally present in human tears, and alter ocular surface boundary lubricating properties. To assess the potential time course and dose-dependency of PRG4 digestion by CTSS, full-length recombinant human PRG4 (rhPRG4) was incubated at 37 °C with or without CTSS in an enzymatic digestion buffer. Digestion of PRG4 by CTSS was also examined within normal human tear samples, both with and wi...

Arthritis research & therapy, May 8, 2017

Lubricin/proteoglycan 4 (PRG4) is a mucinous glycoprotein secreted by synovial fibroblasts and su... more Lubricin/proteoglycan 4 (PRG4) is a mucinous glycoprotein secreted by synovial fibroblasts and superficial zone chondrocytes. Recently, we showed that recombinant human PRG4 (rhPRG4) is a putative ligand for CD44 receptor. rhPRG4-CD44 interaction inhibits cytokine-induced rheumatoid arthritis synoviocyte proliferation. The objective of this study is to decipher the autocrine function of PRG4 in regulating osteoarthritic synoviocyte proliferation and expression of catabolic and pro-inflammatory mediators under basal and interleukin-1 beta (IL-1β)-stimulated conditions. Cytosolic and nuclear levels of nuclear factor kappa B (NFκB) p50 and p65 subunits in Prg4 (+/+) and Prg4 (-/-) synoviocytes were studied using western blot. Nuclear translocation of p50 and p65 proteins in osteoarthritis (OA) fibroblast-like synoviocytes (FLS) in response to IL-1β stimulation in the absence or presence of rhPRG4 was studied using DNA binding assays. OA synoviocyte (5000 cells per well) proliferation f...

Interdisciplinary Development of an Improved Emergency Department Procedural Work Surface Through Iterative Design and Use Testing in Simulated and Clinical Environments

Annals of emergency medicine, Jan 14, 2016

A stable and readily accessible work surface for bedside medical procedures represents a valuable... more A stable and readily accessible work surface for bedside medical procedures represents a valuable tool for acute care providers. In emergency department (ED) settings, the design and implementation of traditional Mayo stands and related surface devices often limit their availability, portability, and usability, which can lead to suboptimal clinical practice conditions that may affect the safe and effective performance of medical procedures and delivery of patient care. We designed and built a novel, open-source, portable, bedside procedural surface through an iterative development process with use testing in simulated and live clinical environments. The procedural surface development project was conducted between October 2014 and June 2016 at an academic referral hospital and its affiliated simulation facility. An interdisciplinary team of emergency physicians, mechanical engineers, medical students, and design students sought to construct a prototype bedside procedural surface out ...

Characterization of a bovine synovial fluid lubricating factor III. The interaction with hyaluronic acid

Although hyaluronate is not a boundary lubricant in cartilaginous and latex:glass bearings, a dis... more Although hyaluronate is not a boundary lubricant in cartilaginous and latex:glass bearings, a distinct interaction with purified synovial lubricating factor (PSLF) was demonstrated by three means: 1) enhancement of lubricating ability in an artificial test system; 2) viscometry; 3) electron microscopy. The interaction was of a physical rather than a specific chemical type; it varied with the degree of purification of PSLF and of hyaluronate. The interaction accounts for retention of the relatively small PSLF molecule (approximately 280 kDa) with the synovial mucin on a 0.22 microns filter. The data provide evidence that hyaluronate and PSLF act synergistically in the boundary lubricating activity of animal joints.

A Transition from Aviation Crew Resource Management to Hospital Emergency Departments: The Medteams Story

... now focuses on behaviorally-oriented, risk management skill training (Helmreich, Merritt, &am... more ... now focuses on behaviorally-oriented, risk management skill training (Helmreich, Merritt, & Wilhelm, 1999; Leedom & Simon, 1995). ... example of team concepts from the management perspective is the differentiation of parallel, project, and management teams (Fried, Topping, ...

Emergency department design after 9/11/2001

Medicine and Health Rhode Island, Aug 1, 2003

Background and objectives Medical simulation and human factors engineering (HFE) may help investi... more Background and objectives Medical simulation and human factors engineering (HFE) may help investigate and improve clinical telemetry systems. Investigators sought to (1) determine the baseline performance characteristics of an Emergency Department (ED) telemetry system implementation at detecting simulated arrhythmias and (2) improve system performance through HFE-based intervention. Methods The prospective study was conducted in a regional referral ED over three 2-week periods from 2010 to 2012. Subjects were clinical providers working at the time of unannounced simulation sessions. Three-minute episodes of sinus bradycardia (SB) and of ventricular tachycardia (VT) were simulated. An experimental HFE-based multi-element intervention was developed to (1) improve system accessibility, (2) increase system relevance and utility for ED clinical practice and (3) establish organisational processes for system maintenance and user base cultivation. The primary outcome variable was overall simulated arrhythmia detection. Pre-intervention system characterisation, post-intervention end-user feedback and real-world correlates of system performance were secondary outcome measures. Results Baseline HFE assessment revealed limited accessibility, suboptimal usability, poor utility and general neglect of the telemetry system; one simulated VT episode (5%) was detected during 20 pre-intervention sessions. Systems testing during intervention implementation recorded detection of 4 out of 10 arrhythmia simulations (p=0.03). Twenty post-intervention sessions revealed more VT detections (8 of 10) than SB detections (3 of 10) for a 55% overall simulated arrhythmia detection rate (p=0.001). Conclusions Experimental investigations helped reveal and mitigate weaknesses in an ED clinical telemetry system implementation. In situ simulation and HFE methodologies can facilitate the assessment and abatement of patient safety hazards in healthcare environments.

The American Journal of Emergency Medicine, May 31, 1995

A study was conducted to determine the accuracy of tympanic thermometers for measuring the temper... more A study was conducted to determine the accuracy of tympanic thermometers for measuring the temperature of warmed fluids in fluid bags and in tubing at the delivery site (ie, beside the intravenous [IV] catheter). One-liter 0.9% saline bags were warmed in a microwave oven. A thermocouple electronic temperature probe was then used to measure the reference temperature. The probe was inserted into each bag and bathed in the fluid. Temperature changes were recorded simultaneously over a 20-minute period using the probe and a First Temp Tympanic Thermometer (intelligent Medical Systems, Inc, Carlsbad, CA). The warmed fluid was then allowed to run through microdrip IV tubing. Temperature of the effluent was measured in the tubing using the tympanic thermometer externally and the probe internally at the same point. The two measures were compared using linear regression and Student's t tests. Overall, the correlation between the two probes was r = 0.99 for both the fluid bags and the IV tubing. The overall mean differences were small, 0.7°C and 1.2°C for the bags and tubing, respectively, but they were statistically different (P > ,05). Data were analyzed in three temperature ranges: <36°C, 36°C to 41°C, and >41°C. Again, small differences were found on the order of 1°C. it was concluded that infrared thermometry is an accurate method for measuring the initial and delivery temperature of warmed fluids. Although tympanic thermometer measurements were statistically different from reference readings in certain temperature ranges, these differences were small and not clinically significant. Tympanic thermometers can measure the temperature of warmed fluid bags and lavage and IV effluent adjacent to the catheter site, ensuring that hypothermic patients receive fluid at therapeutic temperatures.

Portable hyperbaric oxygen therapy in the emergency department with the modified Gamow bag

Annals of Emergency Medicine, Jan 12, 1995

To compare oxygen administration by means of an inflatable portable hyperbaric chamber with that ... more To compare oxygen administration by means of an inflatable portable hyperbaric chamber with that through a nonrebreather mask for the elimination of carboxyhemoglobin (COHb). Double-crossover prospective analysis. University emergency department, Level I trauma center. Twelve healthy paid adult volunteers, all smokers. Each subject smoked five cigarettes within 60 minutes. COHb levels were measured before and after smoking by means of cooximetry. Subjects then breathed hyperbaric and normobaric oxygen in separate trials for 40 minutes. Normobaric oxygen was administered through a nonrebreather face mask at 15 L/minute outside the Gamow bag. Hyperbaric oxygen was delivered inside the Gamow bag with a demand valve regulator mask at a pressure of 1.58 atmospheres absolute pressure (8.5 psi). Venous blood (.5 mL) was sampled every 5 minutes. The specimens were iced and assayed for COHb in triplicate. A significant increase in the elimination of COHb was observed for each subject in the Gamow bag (P &amp;lt; .05, repeated-measures ANOVA). The average half-life for COHb elimination was 27.5 +/- 1.08 minutes (mean +/- SE) (n = 10). IV access failure occurred in two patients, with incomplete data as a result. The modified Gamow bag eliminated COHb more quickly than did nonrebreather mask oxygen and proved simple to operate and maintain. No complications were noted for any of the subjects. One subject experienced claustrophobia, but it abated after the bag was inflated.

Alterations in pharmacokinetics of carboxyhemoglobin produced by oxygen under pressure

Undersea Hyperbaric Medicine Journal of the Undersea and Hyperbaric Medical Society Inc, Sep 1, 1997

The pharmacokinetic effect of elevated oxygen partial pressures in the elimination of carboxyhemo... more The pharmacokinetic effect of elevated oxygen partial pressures in the elimination of carboxyhemoglobin (COHb) by O2 administration was studied in an inflatable hyperbaric chamber. A double crossover prospective analysis between the modified Gamow bag and non-rebreather (NRB) mask O2 was conducted among 12 healthy, adult volunteers who smoked five cigarettes sequentially within a 60-min period. COHb levels were measured using co-oximetry before and after smoking. Subjects inspired hyperbaric oxygen (HBO2) and normobaric oxygen (NBO2) in separate trials for 40 min. Mean COHb levels (1.16 +/- 0.28 g/dl) post-smoking were representative of low-level poisoning. NBO2 consisted of a NRB mask at a rate of 15 liter/min outside the Gamow bag. HBO2 was delivered inside the Gamow bag with a demand valve regulator mask at a Po2 of 1.58 atm abs. A significant increase in the half-life (t 1/2) of COHb was observed for each subject in the Gamow bag (P &amp;lt; 0.05; repeated measures analysis of variance). Average t 1/2 for COHb was 26.3 +/- 3.7 min (n = 12) and 71.3 +/- 9.9 min (n = 12) while breathing HBO2 and NBO2, respectively. Pharmacokinetic modeling was performed using PCNONLIN software for each subject. Both zero and first order elimination kinetics were tested and the model of best fit determined using the Akaike Information Criterion for each subject. A significant shift in COHb elimination from a zero to first order mechanism with elevation in O2 partial pressure was observed (P = 0.002; McNemar&amp;#39;s test). HBO2 provides a pharmacokinetic advantage over NRB mask O2 in eliminating mild carboxyhemoglobinemia.

Polymer Brushes that Mimic Repulsive Properties of the Boundary Lubricant Glycoprotein Lubricin

This is a report on the design of tailored functional groups which mimic the repulsive forces at ... more This is a report on the design of tailored functional groups which mimic the repulsive forces at work in the natural-joint boundary lubricant known as \textit{lubricin}. \textit{Lubricin}, an amphiphilic polyelectrolyte biomolecule, decreases friction and \textit{cellular adhesion} by exhibiting ...