Paige Fox

All Publications

• Topical Antibiotic Elution in a Collagen-Rich Hydrogel is Successful for Inhibiting Bacterial Growth and Biofilm Formation in Vitro. Antimicrobial agents and chemotherapy Min, J. G., Sanchez Rangel, U. J., Franklin, A., Oda, H., Wang, Z., Chang, J., Fox, P. M. 2020

  Abstract

  BACKGROUND: Chronic wounds are a prominent concern, accounting for $25 billion of healthcare costs annually. Biofilms have been implicated in delayed wound closure, but treatment options continue to be limited and susceptible to developing antibiotic resistance. A novel collagen-rich hydrogel derived from human extracellular matrix presents an avenue for treating chronic wounds by providing appropriate extracellular proteins for healing and promoting neovascularization. Using the hydrogel as a delivery system for localized secretion of therapeutic dosage of antibiotics presents an attractive means of maximizing delivery while minimizing systemic side-effects. We hypothesize that the hydrogel can provide controlled elution of antibiotics leading to inhibition of bacterial growth and disruption of biofilm formation.METHOD: The rate of antibiotic elution from the collagen-rich hydrogel and the efficacy of biofilm disruption was assessed with Pseudomonas aeruginosa Bacterial growth inhibition, biofilm disruption, and mammalian cell cytotoxicity were quantified using in vitro models.RESULTS: The antibiotic-loaded hydrogel showed sustained release of antibiotics for up to 24 hours at therapeutic levels. The treatment inhibited bacterial growth and disrupted biofilm formation at multiple time points. The hydrogel was capable of accommodating various classes of antibiotics and did not result in cytotoxicity in mammalian fibroblasts or adipose stem cellsConclusion: An antibiotic-loaded collagen-rich hydrogel is capable of controlled antibiotic release effective for bacteria cell death without native cell death. A human-derived hydrogel that is capable of eluting therapeutic levels of antibiotic is an exciting prospect in the field of chronic wound healing.

  View details for DOI 10.1128/AAC.00136-20

  View details for PubMedID 32690648

• Measuring and Improving the Quality of Care During Global Outreach Trips: A Primer for Safe and Sustainable Surgery. The Journal of hand surgery Shapiro, L. M., Global-Quest Investigators, Shapiro, L. M., Chang, J., Fox, P. M., Kozin, S. H., Chung, K. C., Dyer, G. S., Fufa, D. T., Leversedge, F. J., Katarincic, J. A., Kamal, R. N. 2020

  Abstract

  Trauma is the leading cause of mortality in patients aged 5 years and older. Globally, trauma kills more people than malaria, tuberculosis, and HIV/AIDs combined. As the number of surgical outreach trips to low- and middle-income countries and resources provided for such trips increase, hand surgeons are uniquely positioned to address this global burden. However, the delivery of surgical care alone is insufficient without effectively evaluating the quality of care delivered. It is critical that the care provided on outreach trips improves patient and population health, does not harm patients, and develops the local health care ecosystem. An estimated 8 million lives could be saved annually in low- and middle-income countries with higher-quality health systems. Currently, data collection systems for evaluating quality during outreach trips are lacking. Insight into current methods of quality assessment and improvement in both developing and developed countries can help inform future efforts to implement innovative data collection systems. Thoughtful and sustainable collaboration with host sites in low- and middle-income countries can ensure that care delivery is culturally competent and improves population health.

  View details for DOI 10.1016/j.jhsa.2020.04.027

  View details for PubMedID 32680787

• Homing of Adipose-Derived Stem Cells to a Tendon-Derived Hydrogel: A Potential Mechanism for Improved Tendon-Bone Interface and Tendon Healing. The Journal of hand surgery Franklin, A., Gi Min, J., Oda, H., Kaizawa, Y., Leyden, J., Wang, Z., Chang, J., Fox, P. M. 2020

  Abstract

  PURPOSE: Tendons are difficult to heal owing to their hypocellularity and hypovascularity. Our laboratory has developed a tendon-derived hydrogel (tHG) that significantly improves tendon healing in an animal model. We hypothesized that a potential mechanism for improved healing with tHG is through the attraction of systemic stem cells.METHODS: Homing of systemic adipose-derived stem cells (ADSCs) to tendon injuries was assessed with acute and chronic injury models. Injury sites were treated with saline or tHG, and animals given a tail vein injection (TVI) of labeled ADSCs 1 week after treatment. One week following TVI, rats were harvested for histology. To further evaluate a potential difference in homing to tHG, a subcutaneous injection (SQI) model was used. Rats were treated with an SQI of saline, silicone, ADSCs in media, tHG, tHG+ fibroblasts (FBs), or tHG+ ADSCs on day 0. One week after SQI, rats underwent TVI with labeled ADSCs. Samples were harvested 2 or 3 weeks after SQI for analysis. Flow cytometry confirmed homing in the SQI model.RESULTS: Systemically delivered ADSCs homed to both acute tendon and chronic tendon-bone interface (TBI) injury sites. Despite their presence at the injury site, there was no difference in the number of macrophages, amount of cell proliferation, or angiogenesis 1 week after stem cell delivery.In an SQI model, ADSCs homed to tHG. There was no difference in the number of ADSCs homing to tHG alone versus tHG+ ADSCs. However, there was an increase in the number of living cells, general immune cells, and T-cells present at tHG+ ADSC versus tHG alone.CONCLUSIONS: The ADSCs home to tendon injury sites and tHG. We believe the attraction of additional systemic ADSCs is one mechanism for improved tendon and TBI healing with tHG.CLINICAL RELEVANCE: Treatment of tendon and TBI injuries with tHG can augment healing via homing of systemic stem cells.

  View details for DOI 10.1016/j.jhsa.2020.05.003

  View details for PubMedID 32605739

• A Human-Derived, Collagen-Rich Hydrogel Augments Wound Healing in a Diabetic Animal Model. Annals of plastic surgery Williams, T., Sotelo Leon, D., Kaizawa, Y., Wang, Z., Leyden, J., Chang, J., Fox, P. M. 2020

  Abstract

  Application of collagen products to wounds has been shown to improve wound healing. Using a collagen-based hydrogel (cHG) capable of cellular support previously developed by our laboratory, we hypothesize that our hydrogel will increase the speed of wound healing by providing a 3-dimensional framework for cellular support, increasing angiogenesis and cell-proliferation at the wound bed.Two, 10-mm excisional wounds were created over the dorsum of 12 male, genetically modified Zucker diabetic rats. Wounds were splinted open to limit healing by wound contracture. One wound was treated with an occlusive dressing (OD), whereas the adjacent wound was treated with an OD plus cHG. Occlusive dressings were changed every other day. Hydrogel was applied on day 2 and every 4 days after until complete wound closure. Rate of wound closure was monitored with digital photography every other day. Wounds were harvested at days 10 and 16 for histological and immunohistochemical analysis.Wound closure was significantly faster in cHG-treated wounds compared with OD-treated wounds. By day 10, cHG-treated wounds achieved 63% wound closure, compared with 55% wound closure in OD-treated wounds (P < 0.05). By day 16, cHG-treated wounds achieved 84% wound closure, compared with 68% wound closure in OD-treated wounds (P < 0.05).Histologically, wound depth was not different between the cHG and OD groups on days 10 and 16. However, wound length was significantly less in the cHG group compared with the OD group (P < 0.05) consistent with digital photographic analysis. Immunohistochemical analysis for RECA-1 demonstrated that blood vessel density in the wound bed was 2.3 times higher in the cHG group compared with the OD group (P = 0.01) on day 16. Cell proliferation was 3.8 times higher in the cHG group versus the OD group (P < 0.05) on day 10.Collagen-based hydrogel-treated wounds demonstrated significantly improved healing compared with control. The thermoresponsive feature of collagen hydrogel and its structural stability at body temperature demonstrate promising clinical potential as a vehicle for the delivery of therapeutic cells to the wound bed.

  View details for DOI 10.1097/SAP.0000000000002380

  View details for PubMedID 32349080

• Patient Willingness to Pay for Faster Return to Work or Smaller Incisions. Hand (New York, N.Y.) Alokozai, A., Lindsay, S. E., Eppler, S. L., Fox, P. M., Ladd, A. L., Kamal, R. N. 2019: 1558944719890039

  Abstract

  Background: Value-based health care models such as bundled payments and accountable care organizations can penalize health systems and physicians for excess costs leading to low-value care. Health systems can minimize these extra costs by constraining diagnostic (eg, magnetic resonance imaging utilization) or treatment options with debatable necessity in the setting of clinical equipoise. Instead of restricting more expensive treatments, it is plausible that health systems could instead recoup the extra costs of these treatments by charging patients supplementary out-of-pocket charges (cost sharing). The primary aim of this exploratory study was to assess hand surgery patient willingness to pay supplementary out-of-pocket charges for a procedure that theoretically leads to an earlier return to work or smaller incisions when there are 2 procedures that lead to similar results (clinical equipoise). Methods: A total of 122 patients completed a questionnaire that included demographic information, a financial distress assessment, a series of scenarios asking patients the degree to which they are willing to pay extra for the procedure choice, as well as their perspective of how much insurers should be responsible for these additional costs. Results: Patients were willing to pay out-of-pocket to some degree for a procedure that leads to earlier return to work and smaller incision size when compared with a similar alternative procedure, but noted that insurers should bear a greater burden of costs. Approximately 10% of patients were willing to pay maximum amounts ($2500+) for earlier return to work (3, 7, and 14 days earlier) and smaller incision sizes of any length. Conclusions: Some patients may be willing to pay out-of-pocket and cost share for procedures that lead to earlier return to work and smaller incisions in the setting of clinical equipoise. As such, when developing and implementing alternative payment models, health systems could potentially offer services with debatable necessity in the setting of equipoise for a supplementary out-of-pocket charge.

  View details for DOI 10.1177/1558944719890039

  View details for PubMedID 31791156

• A Novel Technology for Free Flap Monitoring: Pilot Study of a Wireless, Biodegradable Sensor. Journal of reconstructive microsurgery Oda, H., Beker, L., Kaizawa, Y., Franklin, A., Min, J. G., Leyden, J., Wang, Z., Chang, J., Bao, Z., Fox, P. M. 2019

  Abstract

  BACKGROUND: Accurate monitoring of free flap perfusion after complex reconstruction is critical for early recognition of flap compromise. Surgeons use a variety of subjective and objective measures to evaluate flap perfusion postoperatively. However, these measures have some limitations. We have developed a wireless, biodegradable, and flexible sensor that can be applied to real-time postoperative free flap monitoring. Here we assess the biocompatibility and function of our novel sensor.METHODS: Seven Sprague-Dawley (SD) rats were used for biocompatibility studies. The sensor was implanted around the femoral artery near the inguinal ligament on one leg (implant side) and sham surgery was performed on the contralateral leg (control side). At 6 and 12 weeks, samples were harvested to assess the inflammation within and around the implant and artery. Two animals were used to assess sensor function. Sensor function was evaluated at implantation and 7 days after the implantation. Signal changes after venous occlusion were also assessed in an epigastric artery island flap model.RESULTS: In biocompatibility studies, the diameter of the arterial lumen and intima thickness in the implant group were not significantly different than the control group at the 12-week time point. The number of CD-68 positive cells that infiltrated into the soft tissue, surrounding the femoral artery, was also not significantly different between groups at the 12-week time point. For sensor function, accurate signaling could be recorded at implantation and 7 days later. A change in arterial signal was noted immediately after venous occlusion in a flap model.CONCLUSION: The novel wireless, biodegradable sensor presented here is biocompatible and capable of detecting arterial blood flow and venous occlusion with high sensitivity. This promising new technology could combat the complications of wired sensors, while improving the survival rate of flaps with vessel compromise due to its responsive nature.

  View details for DOI 10.1055/s-0039-1700539

  View details for PubMedID 31675757

• Electromyographic Analysis of Grip ORTHOPEDICS Fox, P. M., Oliver, J. D., Viet Nguyen, Hentz, V. R., Curtin, C. M. 2019; 42 (6): E555–E558

  Abstract

  This prospective cohort study used video electromyography synchronized analysis to determine the dynamic use of extrinsic and intrinsic finger flexion during grasp. Light fist formation primarily involved the flexor digitorum profundus with either the flexor digitorum superficialis or intrinsics. In contrast, both the flexor digitorum superficialis and intrinsics were recruited in all tight fist video electromyography. However, the sequence of recruitment differed between patients in tight fist formation. Injured patients demonstrated a unique pattern of recruitment based on injury. The authors conclude that the flexor digitorum profundus is the workhorse in composite fist formation but the roles of the flexor digitorum superficialis and the intrinsic muscles are less consistent across patients. [Orthopedics. 2019; 42(6):e555-e558.].

  View details for DOI 10.3928/01477447-20190812-06

  View details for Web of Science ID 000498511000012

  View details for PubMedID 31408520

• Human TendoneDerived Collagen Hydrogel Significantly Improves Biomechanical Properties of the Tendon-Bone Interface in a Chronic Rotator Cuff Injury Model JOURNAL OF HAND SURGERY-AMERICAN VOLUME Kaizawa, Y., Leyden, J., Behn, A. W., Tulu, U., Franklin, A., Wang, Z., Abrams, G., Chang, J., Fox, P. M. 2019; 44 (10)

  View details for DOI 10.1016/j.jhsa.2018.11.021

  View details for Web of Science ID 000488505800013

• Augmentation of chronic rotator cuff healing using adipose-derived stem cell-seeded human tendon-derived hydrogel JOURNAL OF ORTHOPAEDIC RESEARCH Kaizawa, Y., Franklin, A., Leyden, J., Behn, A. W., Tulu, U. S., Leon, D., Wang, Z., Abrams, G. D., Chang, J., Fox, P. M. 2019; 37 (4): 877–86

  View details for DOI 10.1002/jor.24250

  View details for Web of Science ID 000467082100008

• Quality of Randomized Controlled Trials for Surgical Treatment of Carpal Tunnel Syndrome: A Systematic Review. Plastic and reconstructive surgery Long, C., Azad, A. D., desJardins-Park, H. E., Fox, P. M. 2019; 143 (3): 791–99

  Abstract

  BACKGROUND: Randomized controlled trials are considered the gold standard in evidence-based medicine. The authors conducted a systematic review to evaluate the quantity, quality, and trends of randomized controlled trials that assess surgical treatment of carpal tunnel syndrome.METHODS: The authors identified randomized controlled trials comparing two or more surgical interventions for carpal tunnel syndrome in PubMed, Cochrane, Scopus, Google Scholar, and Clinicaltrials.gov. Two independent reviewers evaluated articles for inclusion, extracted data, and assessed randomized controlled trial quality using the Jadad score.RESULTS: Of 2253 identified studies, 58 met full inclusion criteria. They were published between 1985 and 2015, with a significant increase over time (p = 0.003). They were most frequently published in Journal of Hand Surgery (European Volume) [n = 15 (25.9 percent)]. Most randomized controlled trials were single-center studies [n = 54 (93.1 percent)] conducted in the United Kingdom [n = 13 (22.4 percent)] or the United States [n = 10 (17.2 percent)], with a mean study size of 80.1 ± 55.5 patients. Funding source was unknown in 62.1 percent (n = 36). Three-quarters [n = 44 (75.9 percent)] of randomized controlled trials did not define the primary outcome measure(s). Less than 30 percent (n = 17) of randomized controlled trials conducted a power analysis. Only four studies with patients reported lost to follow-up provided an explanation for each patient. Six randomized controlled trials (10.3 percent) conducted intention-to-treat analysis. The mean Jadad score was 2.14 ± 1.26, with no significant improvement over time (p = 0.245).CONCLUSIONS: Despite the significant increase in the number of randomized controlled trials published studying surgical treatment of carpal tunnel syndrome over time, a mean Jadad score of 2.14 with no change over time indicates a need for improvement in quality. Proper study design is key to avoiding introduction of bias and ensuring the validity of conclusions drawn.

  View details for PubMedID 30822284

• Patient Preferences for Shared Decision Making: Not All Decisions Should Be Shared. The Journal of the American Academy of Orthopaedic Surgeons E Lindsay, S., Alokozai, A., Eppler, S. L., Fox, P., Curtin, C., Gardner, M., Avedian, R., Palanca, A., Abrams, G. D., Cheng, I., Kamal, R. N. 2019

  Abstract

  To assess bounds of shared decision making in orthopaedic surgery, we conducted an exploratory study to examine the extent to which patients want to be involved in decision making in the management of a musculoskeletal condition.One hundred fifteen patients at an orthopaedic surgery clinic were asked to rate preferred level of involvement in 25 common theoretical clinical decisions (passive [0], semipassive [1 to 4], equally shared involvement between patient and surgeon [5], semiactive [6 to 9], active [10]).Patients preferred semipassive roles in 92% of decisions assessed. Patients wanted to be most involved in scheduling surgical treatments (4.75 ± 2.65) and least involved in determining incision sizes (1.13 ± 1.98). No difference exists in desired decision-making responsibility between patients who had undergone orthopaedic surgery previously and those who had not. Younger and educated patients preferred more decision-making responsibility. Those with Medicare desired more passive roles.Despite the importance of shared decision making on delivering patient-centered care, our results suggest that patients do not prefer to share all decisions.

  View details for DOI 10.5435/JAAOS-D-19-00146

  View details for PubMedID 31567900

• Biodegradable and flexible arterial-pulse sensor for the wireless monitoring of blood flow NATURE BIOMEDICAL ENGINEERING Boutry, C. M., Beker, L., Kaizawa, Y., Vassos, C., Tran, H., Hinckley, A. C., Pfattner, R., Niu, S., Li, J., Claverie, J., Wang, Z., Chang, J., Fox, P. M., Bao, Z. 2019; 3 (1): 47–57

  View details for DOI 10.1038/s41551-018-0336-5

  View details for Web of Science ID 000455123800011

• Biodegradable and flexible arterial-pulse sensor for the wireless monitoring of blood flow. Nature biomedical engineering Boutry, C. M., Beker, L., Kaizawa, Y., Vassos, C., Tran, H., Hinckley, A. C., Pfattner, R., Niu, S., Li, J., Claverie, J., Wang, Z., Chang, J., Fox, P. M., Bao, Z. 2019; 3 (1): 47–57

  Abstract

  The ability to monitor blood flow is critical to patient recovery and patient outcomes after complex reconstructive surgeries. Clinically available wired implantable monitoring technology requires careful fixation for accurate detection and needs to be removed after use. Here, we report the design of a pressure sensor, made entirely of biodegradable materials and based on fringe-field capacitor technology, for measuring arterial blood flow in both contact and non-contact modes. The sensor is operated wirelessly through inductive coupling, has minimal hysteresis, fast response times, excellent cycling stability, is highly robust, allows for easy mounting and eliminates the need for removal, thus reducing the risk of vessel trauma. We demonstrate the operation of the sensor with a custom-made artificial artery model and in vivo in rats. This technology may be advantageous in real-time post-operative monitoring of blood flow after reconstructive surgery.

  View details for PubMedID 30932072

• Quality of surgical randomized controlled trials in hand surgery: a systematic review. The Journal of hand surgery, European volume Long, C., desJardins-Park, H. E., Popat, R., Fox, P. M. 2018: 1753193418780184

  Abstract

  We assessed the quantity, quality and trends of randomized controlled trials comparing hand surgical interventions. Study characteristics were collected for 125 randomized controlled trials comparing hand surgical interventions. The Jadad scale (0-5), which assesses methodological quality of trials, was calculated. Logistic regressions were conducted to determine associations with the Jadad score. The studies were published between 1981 and 2015, with an increase over time, most often in Journal of Hand Surgery (European). Mean study size was 68 patients. Mean Jadad score was 2.1, without improvement over time. Thirty percent conducted a power analysis and 8% an intention-to-treat analysis. Studies conducted in the United Kingdom and with smaller sample sizes, power analysis and intention-to-treat analysis were associated with a higher Jadad score. The quantity of trials has increased over time while methodological quality has remained low, indicating a need to improve quality of trials in hand surgery literature.

  View details for PubMedID 29896997

• Treating the Proximal Interphalangeal Joint in Swan Neck and Boutonniere Deformities. Hand clinics Fox, P. M., Chang, J. 2018; 34 (2): 167–76

  Abstract

  Swan neck and boutonniere deformities of the proximal interphalangeal (PIP) joint are challenging to treat. In a swan neck deformity, the PIP joint is hyperextended with flexion at the distal interphalangeal (DIP) joint. In a boutonniere deformity, there is flexion the PIP joint with hyperextension of the DIP joint. When the deformities are flexible, treatment begins with splinting. However, when the deformity is fixed, serial casting or surgery is often necessary to restore joint motion before surgical correction. Many surgical techniques have been described to treat both conditions. Unfortunately, incomplete correction and deformity recurrence are common.

  View details for PubMedID 29625636

• Intratendinous Injection of Hydrogel for Reseeding Decellularized Human Flexor Tendons. Plastic and reconstructive surgery Long, C., Galvez, M. G., Legrand, A., Joubert, L., Wang, Z., Chattopadhyay, A., Chang, J., Fox, P. M. 2017; 139 (6): 1305e-1314e

  Abstract

  Decellularized cadaveric tendons are a potential source for reconstruction. Reseeding to enhance healing is ideal; however, cells placed on the tendon surface result in inadequate delivery. The authors used an injection technique to evaluate intratendinous cell delivery.Decellularized tendons were reseeded with adipose-derived stem cells in culture, and injected with fetal bovine serum or hydrogel. PKH26-stained cells in cross-section were quantified. To evaluate cell viability, the authors delivered luciferase-labeled cells and performed bioluminescent imaging. To evaluate synthetic ability, the authors performed immunohistochemistry of procollagen. Adipose-derived stem cells' ability to attract tenocytes was assessed using transwell inserts. Cell-to-cell interaction was assessed by co-culturing, measuring proliferation and collagen production, and quantifying synergy. Finally, tensile strength was tested.Both fetal bovine serum (p < 0.001) and hydrogel (p < 0.001) injection led to more cells inside the tendon compared with culturing. Hydrogel injection initially demonstrated greater bioluminescence than culturing (p < 0.005) and fetal bovine serum injection (p < 0.05). Injection groups demonstrated intratendinous procollagen staining correlating with the cells' location. Co-culture led to greater tenocyte migration (p < 0.05). Interaction index of proliferation and collagen production assays were greater than 1 for all co-culture ratios, demonstrating synergistic proliferation and collagen production compared with controls (p < 0.05). There were no differences in tensile strength.Hydrogel injection demonstrated the greatest intratendinous seeding efficiency and consistency, without compromising tensile strength. Intratendinous cells demonstrated synthetic capabilities and can potentially attract tenocytes inside the tendon, where synergy would promote intrinsic tendon healing.Therapeutic, V.

  View details for DOI 10.1097/PRS.0000000000003359

  View details for PubMedID 28538572

• De Novo Upper Extremity Lymphedema After Elective Hand Surgery in Breast Cancer Survivors. Annals of plastic surgery Baltzer, H. L., Harvey, J., Fox, P. M., Moran, S. L. 2017

  Abstract

  The safety of elective hand surgery in breast cancer (BC) survivors is controversial because of concerns of developing upper extremity lymphedema. This study aimed to evaluate the risk of developing lymphedema after elective hand surgery among patients that underwent ipsilateral axillary lymph node dissection (ALND), sentinel lymph node biopsy (SLNB), and/or radiation therapy (RT).A retrospective cohort of BC patients treated with ALND, SLNB, and/or RT was identified (1997-2012). Patients with subsequent ipsilateral elective hand surgery were included if greater than 1 year of follow-up and no preexisting lymphedema. The primary outcome was lymphedema after hand surgery. Comparisons between patients with and without lymphedema were made to identify potential lymphedema risk factors. Dichotomous and continuous variables were compared with Fisher exact and Student t tests, respectively.The analysis included 103 patients, of which 4 (3.8%) had documented lymphedema after hand surgery. Lymphedema developed early and was self-limited. Lymphedema was not related to age and type of hand surgery. Tourniquet time was longer in the nonlymphedema group. The lymphedema group all received adjuvant chemotherapy and RT with either ALND or SLNB. Patients with lymphedema had a shorter interval between hand surgery and completion of BC surgery (2.1 vs 6.2 years) and RT (2.0 vs 3.3 years).Lymphedema is uncommon after elective hand surgery among survivors and was not associated with tourniquet use. The combination of adjuvant therapies and axillary procedures and a short temporal relationship of these to hand surgery may increase lymphedema risk.

  View details for DOI 10.1097/SAP.0000000000000986

  View details for PubMedID 28187025

• Tendon Tissue Engineering: Mechanism and Effects of Human Tenocyte Coculture With Adipose-Derived Stem Cells. The Journal of hand surgery Long, C., Wang, Z., Legrand, A., Chattopadhyay, A., Chang, J., Fox, P. M. 2017

  Abstract

  Adipose-derived stem cells (ASCs) are a potential candidate for cell-based therapy targeting tendon injury; however, their therapeutic benefit relies on their ability to interact with native tenocytes. This study examines the mechanism and effects of coculturing human tenocytes and ASCs.Tenocytes (T) were directly cocultured with either ASCs (A) or fibroblasts (F) (negative control) in the following ratios: 50% T/50% A or F; 25% T/75% A or F; and 75% T/25% A or F. Cells were indirectly cocultured using a transwell insert that allowed for exchange of soluble factors only. Proliferation and collagen I production were measured and compared with monoculture controls. Synergy was quantified using the interaction index (II), which normalizes measured values by the expected values assuming no interaction (no synergy when II = 1). The ability of ASCs to elicit tenocyte migration was examined in vitro using a transwell migration assay and ex vivo using decellularized human flexor tendon explants.Compared with monoculture controls, II of proliferation was greater than 1 for all tenocyte and ASC direct coculture ratios, but not for tenocyte and fibroblast direct coculture ratios or for tenocyte and ASC indirect coculture. The ASCs elicited greater tenocyte migration in vitro and ex vivo. The II of collagen I production was greater than 1 for direct coculture groups with 25% T/75% A and 75% T/25% A.Direct coculture of ASCs and tenocytes demonstrated synergistic proliferation and collagen I production, and ASCs elicited tenocyte migration in vitro and ex vivo. These interactions play a key role in tendon healing and were absent when ASCs were replaced with fibroblasts, supporting the use of ASCs for cell-based therapy targeting tendon injuries.When ASCs are delivered for cell-based therapy, they directly interact with native tenocytes to increase cell proliferation, collagen I production, and tenocyte migration, which may enhance tendon healing.

  View details for PubMedID 28888566

• Molecular Biology of Flexor Tendon Healing in Relation to Reduction of Tendon Adhesions. The Journal of hand surgery Legrand, A., Kaufman, Y., Long, C., Fox, P. M. 2017

  Abstract

  Tendon injuries are encountered after major and minor hand trauma. Despite meticulous repair technique, adhesion formation can occur, limiting recovery. Although a great deal of progress has been made toward understanding the mechanism of tendon healing and adhesions, clinically applicable solutions to prevent adhesions remain elusive. The goal of this paper is to review the most recent literature relating to the tendon healing and adhesion prevention.

  View details for PubMedID 28709791

• Access to surgical upper extremity care for people with tetraplegia: an international perspective SPINAL CORD Fox, P. M., Suarez, P., Hentz, V. R., Curtin, C. M. 2015; 53 (4): 302-305

  Abstract

  Survey.To determine whether upper extremity reconstruction in patients with tetraplegia is underutilized internationally and, if so, what are the barriers to care.International-attendees of a meeting in Paris, France.One hundred and seventy attendees at the Tetrahand meeting in Paris in 2010 were sent a 13-question survey to determine the access and utilization of upper limb reconstruction in tetraplegic patients in their practice.Respondents ranged the globe including North America, South America, Europe, Asia and Australia. Fifty-nine percent of respondents had been practicing for more than 10 years. Sixty-four percent of respondents felt that at least 25% of people with tetraplegia would be candidates for surgery. Yet the majority of respondents found that <15% of potential patients underwent upper extremity reconstruction. Throughout the world direct patient referral was the main avenue of surgeons meeting patients with peer networking a distant second. Designated as the top three barriers to this care were lack of knowledge of surgical options by patients, lack of desire for surgery and poor referral patterns to appropriate upper extremity surgeons.The results of this survey, of a worldwide audience, indicate that many of the same barriers to care exist regardless of the patient's address. This was a preliminary opinion survey and thus the results are subjective. However, these results provide a roadmap to improving access to care by improving patient education and interdisciplinary physician communication.

  View details for DOI 10.1038/sc.2015.3

  View details for Web of Science ID 000352725500008

  View details for PubMedID 25687516

• Grafting the alar rim: application as anatomical graft. Plastic and reconstructive surgery Gruber, R. P., Fox, P., Peled, A., Belek, K. A. 2014; 134 (6): 880e-7e

  Abstract

  Alar rim contour and alar rim grafts have become essential components of rhinoplasty. Ideally, grafts of the nose should be anatomical in shape. So doing might make grafts of the alar rim more robust. The authors considered doing that by applying the graft as a continuous extension of the lateral crus.Twelve patients (two men and 10 women) constituted the study group (seven primary and five secondary cases). Of those, there were five concave rims, two concave rims with rim retraction, two boxy tips, and three cephalically oriented lateral crura. Surgical technique included the following: (1) an open approach was used; (2) a marginal incision that ignored the caudal margin of the lateral crus (the incision went straight posteriorly to a point 5 to 6 mm from the rim margin) was used; (3) a triangular graft was made to cover the exposed vestibular skin; (4) it was secured end to end to the caudal border of the lateral crus; and (5) the poster end was allowed to sit in a small subcutaneous pocket.Follow-up was 11 to 19 months. All 12 patients exhibited good rims as judged by a blinded panel. Rim retraction was not fully corrected in one patient, but no further treatment was required. One patient did require a secondary small rim graft for residual rim concavity.The concept of grafting the alar rim is strongly supported by the authors' results. The modifications the authors applied by designing the graft to be anatomical in shape has been a technical help.

  View details for DOI 10.1097/PRS.0000000000000764

  View details for PubMedID 25415110

• Management of Frontal Sinus Fractures: Treatment Modality Changes at a Level I Trauma Center JOURNAL OF CRANIOFACIAL SURGERY Fox, P. M., Garza, R., Dusch, M., Hwang, P. H., Girod, S. 2014; 25 (6): 2038-2042

  Abstract

  The optimal management of frontal sinus fractures remains controversial, and previously accepted indications for surgical intervention are being challenged. The goals of this study were to determine how frontal sinus fracture management has changed at a single institution across multiple disciplines and to evaluate the long-term outcomes of operative and nonoperative treatment modalities.Patients treated for a frontal sinus fracture at Stanford Hospital and Clinics between June 1998 and June 2009 were included in the study. Inpatient records, clinic notes, operative reports, and radiographic studies were reviewed. The patients were invited for a follow-up clinic visit, physical examination, and focused sinus computed tomography. For a period of 11 years, 124 patients were treated for a frontal sinus fracture by physicians from 3 surgical subspecialties: otolaryngology, plastic surgery, and neurosurgery. A low short-term complication rate was observed (5.6%), and there was a trend toward nonsurgical management within the study population. Ten patients returned for a long-term follow-up. Of these, the 2 patients who underwent cranialization experienced as many or more long-term complications compared with the patients treated by other modalities. These complications included abnormal frontal bone contour with bony discontinuity and altered sensation in the distribution of the trigeminal nerve.The demonstrated trend toward nonsurgical management of frontal sinus fractures seems to be safe. In the limited group of patients who returned for follow-up, more long-term complications were observed in the patients who underwent cranialization. However, a larger long-term follow-up cohort will be necessary to elucidate the relationship between treatment modality and long-term outcomes and complications.

  View details for DOI 10.1097/SCS.0000000000001105

  View details for Web of Science ID 000345012000054

• Management of frontal sinus fractures: treatment modality changes at a level I trauma center. journal of craniofacial surgery Fox, P. M., Garza, R., Dusch, M., Hwang, P. H., Girod, S. 2014; 25 (6): 2038-2042

  Abstract

  The optimal management of frontal sinus fractures remains controversial, and previously accepted indications for surgical intervention are being challenged. The goals of this study were to determine how frontal sinus fracture management has changed at a single institution across multiple disciplines and to evaluate the long-term outcomes of operative and nonoperative treatment modalities.Patients treated for a frontal sinus fracture at Stanford Hospital and Clinics between June 1998 and June 2009 were included in the study. Inpatient records, clinic notes, operative reports, and radiographic studies were reviewed. The patients were invited for a follow-up clinic visit, physical examination, and focused sinus computed tomography. For a period of 11 years, 124 patients were treated for a frontal sinus fracture by physicians from 3 surgical subspecialties: otolaryngology, plastic surgery, and neurosurgery. A low short-term complication rate was observed (5.6%), and there was a trend toward nonsurgical management within the study population. Ten patients returned for a long-term follow-up. Of these, the 2 patients who underwent cranialization experienced as many or more long-term complications compared with the patients treated by other modalities. These complications included abnormal frontal bone contour with bony discontinuity and altered sensation in the distribution of the trigeminal nerve.The demonstrated trend toward nonsurgical management of frontal sinus fractures seems to be safe. In the limited group of patients who returned for follow-up, more long-term complications were observed in the patients who underwent cranialization. However, a larger long-term follow-up cohort will be necessary to elucidate the relationship between treatment modality and long-term outcomes and complications.

  View details for DOI 10.1097/SCS.0000000000001105

  View details for PubMedID 25377963

• Fascia-only anterolateral thigh flap for extremity reconstruction. Annals of plastic surgery Fox, P., Endress, R., Sen, S., Chang, J. 2014; 72: S9-S13

  Abstract

  The ability to use the anterolateral thigh (ALT) flap as a vascularized fascial flap, without skin or muscle, was first documented by Koshima et al in 1989. The authors mention the possibility of using the fascia alone for dural reconstruction. Despite its description more than 20 years ago, little literature exists on the application of the ALT flap as a vascularized fascial flap. In our experience, the ALT flap can be used as a fascia-only flap for thin, pliable coverage in extremity reconstruction.After approval from the institutional review board, the medical records and photographs of patients who had undergone fascia-only ALT free flaps for extremity reconstruction were reviewed. Photographic images of patients were then matched to patients who had undergone either a muscle-only or a fasciocutaneous free flap reconstruction of an extremity. Photographs of the final reconstruction were then given to medical and nonmedical personnel for analysis, focusing on aesthetics including color and contour.Review of cases performed over a 2-year period demonstrated similar ease of harvest for fascia-only ALT flaps compared to standard fasciocutaneous ALT flaps. Fascia-only flaps were used for thin, pliable coverage in the upper and lower extremities. There was no need for secondary procedures for debulking or aesthetic flap revision. In contrast to muscle flaps, which require muscle atrophy over time to achieve their final appearance, there was a similar flap contour from approximately 1 month postoperatively throughout the duration of follow-up. When a large flap is required, the fascia-only ALT has the advantage of a single-line donor-site scar. Photograph comparison to muscle flaps with skin grafts and fasciocutaneous flaps demonstrated improved color, contour, and overall aesthetic appearance of the fascia-only ALT over muscle and fasciocutaneous flaps.The fascia-only ALT flap provides reliable, thin, and pliable coverage with improved contour and color over muscle and fasciocutaneous flaps. The fascia-only ALT is another excellent option for reconstructive surgery of the extremities.

  View details for DOI 10.1097/SAP.0000000000000146

  View details for PubMedID 24691305

• Human flexor tendon tissue engineering: in vivo effects of stem cell reseeding. Plastic and reconstructive surgery Schmitt, T., Fox, P. M., Woon, C. Y., Farnebo, S. J., Bronstein, J. A., Behn, A., Pham, H., Chang, J. 2013; 132 (4): 567e-76e

  View details for DOI 10.1097/PRS.0b013e3182a033cf

  View details for PubMedID 24076704

• Management of the hand in systemic sclerosis. journal of hand surgery Fox, P., Chung, L., Chang, J. 2013; 38 (5): 1012-1016

  View details for DOI 10.1016/j.jhsa.2013.02.012

  View details for PubMedID 23561724

• White light spectroscopy for free flap monitoring MICROSURGERY Fox, P. M., Zeidler, K., Carey, J., Lee, G. K. 2013; 33 (3): 198-202

  Abstract

  White light spectroscopy non-invasively measures hemoglobin saturation at the capillary level rendering an end-organ measurement of perfusion. We hypothesized this technology could be used after microvascular surgery to allow for early detection of ischemia and thrombosis. The Spectros T-Stat monitoring device, which utilizes white light spectroscopy, was compared with traditional flap monitoring techniques including pencil Doppler and clinical exam. Data were prospectively collected and analyzed. Results from 31 flaps revealed a normal capillary hemoglobin saturation of 40-75% with increase in saturation during the early postoperative period. One flap required return to the operating room 12 hours after microvascular anastomosis. The T-stat system recorded an acute decrease in saturation from ~50% to less than 30% 50 min prior to identification by clinical exam. Prompt treatment resulted in flap salvage. The Spectros T-Stat monitor may be a useful adjunct for free flap monitoring providing continuous, accurate perfusion assessment postoperatively.

  View details for DOI 10.1002/micr.22069

  View details for Web of Science ID 000316335400005

  View details for PubMedID 23280724

• Computed tomography angiography in microsurgery: indications, clinical utility, and pitfalls. Eplasty Lee, G. K., Fox, P. M., Riboh, J., Hsu, C., Saber, S., Rubin, G. D., Chang, J. 2013; 13

  Abstract

  Computed tomographic angiography (CTA) can be used to obtain 3-dimensional vascular images and soft-tissue definition. The goal of this study was to evaluate the reliability, usefulness, and pitfalls of CTA in preoperative planning of microvascular reconstructive surgery.A retrospective review of patients who obtained preoperative CTA in preparation for planned microvascular reconstruction was performed over a 5-year period (2001-2005). The influence of CTA on the original operative plan was assessed for each patient, and CTA results were correlated to the operative findings.Computed tomographic angiography was performed on 94 patients in preparation for microvascular reconstruction. In 48 patients (51%), vascular abnormalities were noted on CTA. Intraoperative findings correlated with CTA results in 97% of cases. In 42 patients (45%), abnormal CTA findings influenced the original operative plan, such as the choice of vessels, side of harvest, or nature of the reconstruction (local flap instead of free tissue transfer). Technical difficulties in performing CTA were encountered in 5 patients (5%) in whom interference from external fixation devices was the main cause.This large study of CTA obtained for preoperative planning of reconstructive microsurgery at both donor and recipient sites study demonstrates that CTA is safe and highly accurate. Computed tomographic angiography can alter the surgeon's reconstructive plan when abnormalities are noted preoperatively and consequently improve results by decreasing vascular complication rates. The use of CTA should be considered for cases of microsurgical reconstruction where the vascular anatomy may be questionable.

  View details for PubMedID 24023972

• Decellularized human tendon-bone grafts for composite flexor tendon reconstruction: a cadaveric model of initial mechanical properties. The Journal of hand surgery Fox, P. M., Farnebo, S., Lindsey, D., Chang, J., Schmitt, T., Chang, J. 2013; 38 (12): 2323–28

  Abstract

  After complex hand trauma, restoration of tendon strength is challenging. Tendon insertion tears typically heal as fibrous scars after surgical reconstruction and create a weak point at the tendon-bone interface. In addition, major tendon loss may overwhelm the amount of available autograft for reconstruction. An off-the-shelf product may help address these challenges. We hypothesized that decellularized human flexor digitorum profundus and distal phalanx tendon-bone composite grafts were a feasible option for flexor tendon reconstruction after complex hand trauma. By replacing the entire injured composite segment, the need for tendon repair within the tendon sheath, reconstruction of the tendon-bone interface, and use of limited autograft could be eliminated.Paired human cadaver forearms were dissected to obtain the flexor digitorum profundus tendon with an attached block of distal phalanx. Tendon-bone grafts were pair-matched and divided into 2 groups: decellularized grafts (n = 12) and untreated (control) grafts (n = 11). Grafts in the decellularized group were subjected to physiochemical decellularization. Pair-matched tendon-bone grafts (decellularized and untreated) were placed back into the flexor tendon sheath and secured distally using a tie-over button and proximally by weaving the graft into the flexor digitorum superficialis tendon in the distal forearm. The ultimate load, location of failure, and excursion were determined.Decellularized tendon-bone composite grafts demonstrated no significant difference in ultimate failure load or stiffness compared with untreated grafts. Both groups eventually failed in varied locations along the repair. The most common site of failure in both groups was the tie-over button. The decellularized group failed at the tendon-bone insertion in 3 specimens (25%) compared with none in the untreated group. Both groups demonstrated an average tendon excursion of approximately 82 mm before failure.Decellularization of human flexor tendon-distal phalanx tendon-bone constructs did not compromise initial strength despite chemical and mechanical decellularization in a cadaveric model. At the time of repair, decellularized flexor tendon-bone grafts can exceed the strength and excursion needed for hand therapy immediately after reconstruction.These tendon-bone grafts may become an option for complex hand reconstruction at or near tendon-bone insertions and throughout the tendon sheath. Further work is required to assess the role of reseeding in an in vivo model.

  View details for PubMedID 24055133

• Tissue expander with acellular dermal matrix for breast reconstruction infected by an unusual pathogen: Candida parapsilosis JOURNAL OF PLASTIC RECONSTRUCTIVE AND AESTHETIC SURGERY Fox, P. M., Lee, G. K. 2012; 65 (10): E286-E289

  Abstract

  Infections occur in approximately 2-5% percent of women undergoing breast reconstruction by tissue expansion depending on patient characteristics and timing of reconstruction. Bacteria, specifically Staphylococci, are the most common pathogens. Treatment varies depending on the surgeon and the aggressiveness of the infection. We report a case of unilateral tissue expander infection with Candida parapsilosis in an otherwise healthy female undergoing immediate tissue expander placement after bilateral nipple-sparing mastectomies. The patient was treated with a one-stage irrigation, debridement, and tissue expander exchange as well as a 21-day course of oral antifungal therapy. Her infection resolved and she was able to complete her implant-based reconstruction. C. parapsilosis is usually responsible for infections in critically ill patients found in association with central lines, peritoneal dialysis catheters and prosthetic heart valves. The affinity of C. parapsilosis for foreign material makes it a causative agent worth considering in difficult to treat tissue expander infections.

  View details for DOI 10.1016/j.bjps.2012.04.049

  View details for Web of Science ID 000308995700003

  View details for PubMedID 22633394

• Supercharged Free Fibula for Complex Ankle Arthrodesis A Case Report ANNALS OF PLASTIC SURGERY Fox, P. M., Chou, L., Lee, G. K. 2012; 68 (4): 342-345

  Abstract

  We report the successful use of a supercharged free fibula for tibial reconstruction and ankle arthrodesis. A 28-year-old woman underwent resection of a giant cell tumor of the distal tibia and reconstruction using a methyl methacrylate cement spacer 12 years prior. The spacer eroded into her ankle joint causing significant pain with ambulation. Therefore, she required ankle arthrodesis but lacked distal tibia bone stock. The ipsilateral fibula was harvested for reconstruction and transferred on its distal blood supply into the bony tibial defect. The proximal blood supply of the fibula flap was then anastomosed to the posterior tibial vessels to supercharge the blood supply. An Ilizarov was placed for external fixation. The combination of a supercharged free fibula and stable external fixation for tibial reconstruction led to timely bony union and ambulation, as well as avoiding the potential complications that can occur with other reconstructive options.

  View details for DOI 10.1097/SAP.0b013e31824189d0

  View details for PubMedID 22421475

• Spontaneous deletion of the methicillin resistance determinant, mecA, partially compensates for the fitness cost associated with high-level vancomycin resistance in Staphylococcus aureus ANTIMICROBIAL AGENTS AND CHEMOTHERAPY Noto, M. J., Fox, P. M., Archer, G. L. 2008; 52 (4): 1221-1229

  Abstract

  Treatment of infections caused by Staphylococcus aureus is often confounded by the bacterium's ability to develop resistance to chemotherapeutic agents. Methicillin-resistant S. aureus (MRSA) arises through the acquisition of staphylococcal chromosomal cassette mec (SCCmec), a genomic island containing the methicillin resistance determinant, mecA. In contrast, resistance to vancomycin can result from exposure to the drug, a mechanism that is not dependent upon a gene acquisition event. Here we describe three MRSA strains that became resistant to vancomycin during passage in the presence of increasing concentrations of the drug. In each case two derivative strains were isolated, one that had lost mecA and one that retained mecA during passage. Strain 5836VR lost mecA by the site-specific chromosomal excision of SCCmec, while the other two strains (strains 3130VR and VP32) deleted portions of their SCCmec elements in a manner that appeared to involve IS431. Conversion to vancomycin resistance caused a decrease in the growth rate that was partially compensated for by the deletion of mecA. In mixed-culture competition experiments, vancomycin-resistant strains that lacked mecA readily outcompeted their mecA-containing counterparts, suggesting that the loss of mecA during conversion to vancomycin resistance was advantageous to the organism.

  View details for DOI 10.1128/AAC.01164-07

  View details for Web of Science ID 000254881900003

  View details for PubMedID 18212094

  View details for PubMedCentralID PMC2292509

• Lack of relationship between purine biosynthesis and vancomycin resistance in Staphylococcus aureus: a cautionary tale for microarray interpretation ANTIMICROBIAL AGENTS AND CHEMOTHERAPY Fox, P. M., Climo, M. W., Archer, G. L. 2007; 51 (4): 1274-1280

  Abstract

  Previous microarray data (E. Mongodin, J. Finan, M. W. Climo, A. Rosato, S. Gill, and G. L. Archer, J. Bacteriol. 185:4638-4643, 2003) noted an association in two vancomycin-intermediate Staphylococcus aureus (VISA) strains between high-level, passage-induced vancomycin resistance, a marked increase in the transcription of purine biosynthetic genes, and mutation of the putative purine regulator purR. Initial studies to report on the possible association between vancomycin resistance and alterations in purine metabolism in one of these strains (VP-32) confirmed, by Western analysis, an increase in the translation of PurH and PurM, two purine pathway enzymes. In addition, PurR was identified, by knockout and complementation in a vancomycin-susceptible strain, as a repressor of the purine biosynthetic operon in S. aureus, and the PurR missense mutation was shown to inactivate the repressor. However, despite the apparent relationship between increased purine biosynthesis and increased vancomycin resistance in VP-32, neither the addition of exogenous purines to a defined growth medium nor the truncation or inactivation of purR improved the growth of vancomycin-susceptible S. aureus in the presence of vancomycin. Furthermore, the passage of additional vancomycin-susceptible and VISA strains to high-level vancomycin resistance occurred without changes in cellular purine metabolism or mutation of purR despite the development of thickened cell walls in passaged strains. Thus, we could confirm neither a role for altered purine metabolism in the development of vancomycin resistance nor its requirement for the maintenance of a thickened cell wall. The failure of biochemical and physiological studies to support the association between transcription and phenotype initially found in careful microarray studies emphasizes the importance of follow-up investigations to confirm microarray observations.

  View details for DOI 10.1128/AAC.01060-06

  View details for Web of Science ID 000245416500022

  View details for PubMedID 17242154

  View details for PubMedCentralID PMC1855472

• Vancomycin-intermediate Staphylococcus aureus strains have impaired acetate catabolism: Implications for polysaccharide intercellular adhesin synthesis and autolysis ANTIMICROBIAL AGENTS AND CHEMOTHERAPY Nelson, J. L., Rice, K. C., Slater, S. R., Fox, P. M., Archer, G. L., Bayles, K. W., Fey, P. D., Kreiswirth, B. N., Somerville, G. A. 2007; 51 (2): 616-622

  Abstract

  The most common mechanism by which Staphylococcus aureus gains resistance to vancomycin is by adapting its physiology and metabolism to permit growth in the presence of vancomycin. Several studies have examined the adaptive changes occurring during the transition to vancomycin-intermediate resistance, leading to a model of vancomycin resistance in which decreased cell wall turnover and autolysis result in increased cell wall thickness and resistance to vancomycin. In the present study, we identified metabolic changes common to vancomycin-intermediate S. aureus (VISA) strains by assessing the metabolic and growth characteristics of two VISA strains (vancomycin MICs of 8 microg/ml) and two isogenic derivative strains with vancomycin MICs of 32 microg/ml. Interestingly, we observed the parental strains had impaired catabolism of nonpreferred carbon sources (i.e., acetate), and this impairment became more pronounced as vancomycin resistance increased. To determine if acetate catabolism impairment is common to VISA strains, we assessed the ability of VISA and vancomycin-sensitive S. aureus (VSSA) clinical isolates to catabolize acetate. As expected, a significantly greater percentage of VISA strains (71%) had impaired acetate catabolism relative to VSSA (8%). This is an important observation because staphylococcal acetate catabolism is implicated in growth yield and antibiotic tolerance and in regulating cell death and polysaccharide intercellular adhesin synthesis.

  View details for DOI 10.1128/AAC.01057-06

  View details for Web of Science ID 000243900600030

  View details for PubMedID 17130298

  View details for PubMedCentralID PMC1797750

• Successful therapy of experimental endocarditis caused by vancomycin-resistant Staphylococcus aureus with a combination of vancomycin and beta-lactam antibiotics ANTIMICROBIAL AGENTS AND CHEMOTHERAPY Fox, P. M., Lampert, R. J., Stumpf, K. S., Archer, G. L., Climo, M. W. 2006; 50 (9): 2951-2956

  Abstract

  VRS1 is the first isolated strain of vancomycin-resistant Staphylococcus aureus (VRSA) found to carry the vanA gene complex previously described in Enterococcus. Under vancomycin pressure, VRS1 makes aberrant cell walls consisting of stem tetrapeptide and depsipeptide that lack the terminal D-Ala-D-Ala residues targeted by vancomycin. Previous data have suggested that this aberrant cell wall is not cross-linked by PBP2a, the enzyme responsible for cell wall transpeptidation in the presence of beta-lactam antibiotics. We examined the efficacy of treating VRS1 with a combination of vancomycin and beta-lactam antibiotics in vitro and in vivo. We found that the MIC of oxacillin for VRS1 decreased from >256 microg/ml to <1 microg/ml in the presence of vancomycin. Using the rabbit model of endocarditis, we treated VRS1-infected rabbits with nafcillin alone, vancomycin alone, or a combination of nafcillin and vancomycin. Treatment with nafcillin in combination with vancomycin cleared bloodstream infections within 24 h and sterilized 12/13 spleens (92%), as well as 8/13 kidneys (62%), following 3 days of treatment. Mean aortic valve vegetation counts were reduced 3.48 log(10) CFU/g with the combination therapy (compared to untreated controls) and were significantly lower than with either vancomycin or nafcillin given alone. VRS1 was extremely virulent in this model, as no untreated rabbits survived the 3-day trial. Treatment of clinical infections due to VRSA with the combination of vancomycin and beta-lactams may be an option, based on these results.

  View details for DOI 10.1128/AAC.00232-06

  View details for Web of Science ID 000240297000008

  View details for PubMedID 16940087

  View details for PubMedCentralID PMC1563512

• The up-regulation of ferritin expression using a small-molecule ligand to the native mRNA PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Tibodeau, J. D., Fox, P. M., Ropp, P. A., Theil, E. C., Thorp, H. H. 2006; 103 (2): 253-257

  Abstract

  The binding of small molecules to distinctive three-dimensional structures in mRNA provides a new dimension in RNA control, previously limited to the targeting of secondary structures with antisense and RNA interference; such targeting can modulate mRNA function and rates of protein biosynthesis. Small molecules that selectively bind the iron-responsive element (IRE), a specific three-dimensional structure in the noncoding region of the ferritin mRNA model that is recognized by the iron-regulatory protein repressor, were identified by using chemical footprinting. The assay used involved an oxoruthenium(IV) complex that oxidizes guanine bases in RNA sequences. Small molecules that blocked oxidation of guanines in the internal loop region were expected to selectively increase the rate of ferritin synthesis, because the internal loop region of the ferritin IRE is distinctive from those of other IREs. The natural product yohimbine was found (based on gel mobility shifts) to block cleavage of the internal loop RNA site by >50% and seemed to inhibit protein binding. In the presence of yohimbine, the rate of biosynthesis of ferritin in a cell-free expression system (rabbit reticulocyte lysate) increased by 40%. Assignment of the IRE-yohimbine interaction as the origin of this effect was supported by a similar increase in synthesis of luciferase protein in a chimera of the IRE and luciferase gene. The identification of a small, drug-like molecule that recognizes a naturally occurring three-dimensional mRNA structure and regulates protein biosynthesis rates raises the possibility that small molecules can regulate protein biosynthesis by selectively binding to mRNA.

  View details for DOI 10.1073/pnas.0509744102

  View details for Web of Science ID 000234624100002

  View details for PubMedID 16381820

  View details for PubMedCentralID PMC1326178