Publications by authors named "Lisa M Pierce"

32 Publications

Antibiofilm activity of chitosan/epsilon-poly-L-lysine hydrogels in a porcine ex vivo skin wound polymicrobial biofilm model.

Wound Repair Regen 2021 Mar 22;29(2):316-326. Epub 2021 Jan 22.

Department of Clinical Investigation, Tripler Army Medical Center, Honolulu, Hawaii, USA.

As antibiotic resistance continues to increase globally, there is an urgency for novel, non-antibiotic approaches to control chronic drug-resistant infections, particularly those associated with polymicrobial biofilm formation in chronic wounds. Also needed are clinically relevant polymicrobial biofilm models that can be utilized to assess the efficacy of innovative therapeutics against mature biofilms. We successfully developed a highly reproducible porcine ex vivo skin wound polymicrobial biofilm model using clinical isolates of multidrug-resistant Pseudomonas aeruginosa, methicillin-resistant Staphylococcus aureus, and Candida albicans. This ex vivo biofilm model was then used to assess the antimicrobial and antibiofilm properties of an easily fabricated chitosan hydrogel incorporating the natural antimicrobial peptide epsilon-poly-L-lysine. Antimicrobial activity was evaluated against planktonic cultures in vitro and against mature biofilms ex vivo. The antibiofilm efficiency of the hydrogels was especially pronounced against Pseudomonas aeruginosa, whose counts were reduced by 99.98% after 2 hours in vitro and by 99.94% after treatment for 24 hours when applied to 24 hour ex vivo polymicrobial wound biofilms. The activity of the hydrogels was lower against Staphylococcus aureus and ineffective against Candida albicans. Gram, Hucker-Twort staining of paraffin sections revealed balanced polymicrobial communities in mature 48 hour untreated biofilms. Treatment of 48 or 72 hour biofilms for 2 or 3 days with hydrogels that were applied within 5 hours after inoculation resulted in an impressive 96% and 97% reduction in biofilm thickness compared to untreated biofilms, respectively (P < .001). Likewise, topical gel treatment for 24 hours reduced biofilm thickness by 84% and 70%, respectively, when applied to mature biofilms at 24 and 48 hours after inoculation (P < .001). Thus, this ex vivo wound biofilm model provides a useful means to assess the efficacy of novel treatments to prevent and eradicate polymicrobial biofilms consisting of multidrug-resistant Pseudomonas aeruginosa, methicillin-resistant Staphylococcus aureus, and Candida albicans.
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http://dx.doi.org/10.1111/wrr.12890DOI Listing
March 2021

Transitioning an Advanced Practice Fellowship Curriculum to eLearning During the COVID-19 Pandemic.

J Nurs Educ 2020 Sep;59(9):514-517

Background: The COVID-19 global pandemic brought mandatory shelter-in-place orders, disrupting traditional face-to-face teaching methods for advanced practice fellowship programs nationally, creating a challenge for fellowship program directors to preserve curriculum using nontraditional methods.

Method: Using a variety of both web-based and app-based virtual platforms, a nationally accredited fellowship program converted traditional in-seat learning modalities to elearning platforms using both synchronous and asynchronous education.

Results: Preliminary data indicate that knowledge acquisition and perceived fellow satisfaction are preserved despite the abrupt change to program delivery. Programmatic modifications were submitted to the American Nurse Credentialing Center for compliance and deemed as creative, innovative, and collaborative.

Conclusion: Curriculum for advanced practice fellowship programs can be favorably converted to elearning using virtual platforms during a crisis. Through prompt reevaluation and restructuring, virtual platforms can replace in-seat didactic lectures, patient case studies, mentoring, and even simulation, while ensuring program continuation and compliance with accreditation standards. [J Nurs Educ. 2020;59(9):514-517.].
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http://dx.doi.org/10.3928/01484834-20200817-07DOI Listing
September 2020

Oxidative Stress Alters Angiogenic and Antimicrobial Content of Extracellular Vesicles and Improves Flap Survival.

Plast Reconstr Surg Glob Open 2019 Dec 19;7(12):e2588. Epub 2019 Dec 19.

Department of Clinical Investigation, Tripler Army Medical Center, Honolulu, Hawaii.

Extracellular vesicles (EVs) secreted from adipose-derived mesenchymal stem cells (ADSCs) (ADSC-EVs) improve flap survival after ischemia-reperfusion injury. Exposure of parent ADSCs to oxidative stress has been shown to enhance this effect, but mechanisms are unclear. We aimed to determine whether angiogenesis-promoting protein and microRNA (miRNA) content is altered in EVs after preconditioning with hydrogen peroxide (HO ADSC-EVs) and whether HO ADSC-EVs can increase viability of random pattern skin flaps.

Methods: EVs secreted by human ADSCs were isolated after culture in EV-depleted medium ± HO. Nanoparticle tracking analysis determined size and concentration of purified EVs. Mass spectrometry and small RNA next-generation sequencing were performed to compare proteomic and miRNA profiles. ADSC-EVs, HO ADSC-EVs, or vehicle were injected into random pattern skin flaps of BALB/c mice (4-5 mice per group). Viable and necrotic areas were measured on day 7, and tissues underwent histologic analysis.

Results: Angiogenic and antimicrobial protein content of EVs was altered with HO preconditioning. Functional enrichment analysis identified constitutive photomorphogenesis 9 signalosome (known to direct vascular endothelial growth factor production) as the major enriched Gene Ontology term unique to HO ADSC-EVs. Two miRNAs were increased, and 12 (including 10 antiangiogenic miRNAs) were reduced in HO ADSC-EVs. Enhanced viability ( < 0.05) of flaps treated with HO ADSC-EVs compared with vehicle corresponded to increased capillary density in the HO group ( < 0.001).

Conclusion: Altered protein and miRNA content in ADSC-EVs after HO pretreatment likely contributes to enhanced therapeutic effects on flap survival observed in preclinical models.
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http://dx.doi.org/10.1097/GOX.0000000000002588DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7288884PMC
December 2019

Inhibition of microRNA-124-3p as a novel therapeutic strategy for the treatment of Gulf War Illness: Evaluation in a rat model.

Neurotoxicology 2019 03 29;71:16-30. Epub 2018 Nov 29.

Department of Clinical Investigation, Tripler Army Medical Center, 1 Jarrett White Road, Honolulu, Hawaii, 96859, USA. Electronic address:

Gulf War Illness (GWI) is a chronic, multisymptom illness that continues to affect up to 30% of veterans deployed to the Persian Gulf during the 1990-1991 Gulf War. After nearly 30 years, useful treatments for GWI are lacking and underlying cellular and molecular mechanisms involved in its pathobiology remain poorly understood, although exposures to pyridostigmine bromide (PB) and pesticides are consistently identified to be among the strongest risk factors. Alleviation of the broad range of symptoms manifested in GWI, which involve the central nervous system, the neuroendocrine system, and the immune system likely requires therapies that are able to activate and inactivate a large set of orchestrated genes. Previous work in our laboratory using an established rat model of GWI identified persistent elevation of microRNA-124-3p (miR-124) levels in the hippocampus whose numerous gene targets are involved in cognition-associated pathways and neuroendocrine function. This study aimed to investigate the broad effects of miR-124 inhibition in the brain 9 months after completion of a 28-day exposure regimen of PB, DEET (N,N-diethyl-3-methylbenzamide), permethrin, and mild stress by profiling the hippocampal expression of genes known to play a critical role in synaptic plasticity, glucocorticoid signaling, and neurogenesis. We determined that intracerebroventricular infusion of a miR-124 antisense oligonucleotide (miR-124 inhibitor; 0.05-0.5 nmol/day/28 days), but not a negative control oligonucleotide, into the lateral ventricle of the brain caused increased protein expression of multiple validated miR-124 targets and increased expression of downstream target genes important for cognition and neuroendocrine signaling in the hippocampus. Off-target cardiotoxic effects were revealed in GWI rats receiving 0.1 nmol/day as indicated by the detection in plasma of 5 highly elevated protein cardiac injury markers and 6 upregulated cardiac-enriched miRNAs in plasma exosomes determined by next-generation sequencing. Results from this study suggest that in vivo inhibition of miR-124 function in the hippocampus is a promising, novel therapeutic approach to improve cognition and neuroendocrine dysfunction in GWI. Additional preclinical studies in animal models to assess feasibility and safety by developing a practical, noninvasive drug delivery system to the brain and exploring potential adverse toxicologic effects of miR-124 inhibition are warranted.
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http://dx.doi.org/10.1016/j.neuro.2018.11.008DOI Listing
March 2019

Evaluation of a Novel Hybrid Viable Bioprosthetic Mesh in a Model of Mesh Infection.

Plast Reconstr Surg Glob Open 2017 Aug 10;5(8):e1418. Epub 2017 Aug 10.

Department of General Surgery, Tripler Army Medical Center, Honolulu, H.I.; and Department of Clinical Investigation, Tripler Army Medical Center, Honolulu, H.I.

Background: The reported incidence of mesh infection in contaminated operative fields is as high as 30% regardless of material used. Our laboratory previously showed that augmenting acellular bioprosthetic mesh with allogeneic mesenchymal stem cells (MSC) enhances resistance to bacterial colonization in vivo and preserves mesh integrity. This study's aim was to determine whether augmentation of non-crosslinked porcine dermis (Strattice) with commercially available, cryopreserved, viable MSC-containing human placental tissue (Stravix) similarly improves infection resistance after inoculation with () using an established mesh infection model.

Methods: Stravix was thawed per manufacturer's instructions and 2 samples were tested for cell viability using a Live/Dead Cell assay at the time of surgery. Rats (N = 20) were implanted subcutaneously with 1 piece of Strattice and 1 piece of hybrid mesh (Strattice + Stravix sutured at the corners). Rats were inoculated with either sterile saline or 10 colony-forming units of before wound closure (n = 10 per group). At 4 weeks, explants underwent microbiologic and histologic analyses.

Results: In -inoculated animals, severe or complete mesh degradation concurrent with abscess formation was observed in 100% (10/10) hybrid meshes and 90% (9/10) Strattice meshes. Histologic evaluation determined that meshes inoculated with exhibited severe acute inflammation, which correlated with bacterial recovery ( < 0.001). Viability assays performed at the time of surgery failed to verify the presence of numerous live cells in Stravix.

Conclusions: Stravix cryopreserved MSC-containing human umbilical tissue does not improve infection resistance of a bioprosthetic mesh in vivo in rats after inoculation with .
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http://dx.doi.org/10.1097/GOX.0000000000001418DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5585427PMC
August 2017

Bone Marrow-Derived Mesenchymal Stem Cells Enhance Bacterial Clearance and Preserve Bioprosthetic Integrity in a Model of Mesh Infection.

Plast Reconstr Surg Glob Open 2016 Jun 17;4(6):e751. Epub 2016 Jun 17.

Departments of General Surgery and Clinical Investigation, Tripler Army Medical Center, Honolulu, HI.

Background: The reported incidence of mesh infection in contaminated operative fields is as high as 30% regardless of the material used. Recently, mesenchymal stem cells (MSCs) have been shown to possess favorable immunomodulatory properties and improve tissue incorporation when seeded onto bioprosthetics. The aim of this study was to evaluate whether seeding noncrosslinked bovine pericardium (Veritas Collagen Matrix) with allogeneic bone marrow-derived MSCs improves infection resistance in vivo after inoculation with Escherichia coli (E. coli).

Methods: Rat bone marrow-derived MSCs at passage 3 were seeded onto bovine pericardium and cultured for 7 days before implantation. Additional rats (n = 24) were implanted subcutaneously with MSC-seeded or unseeded mesh and inoculated with 7 × 10(5) colony-forming units of E. coli or saline before wound closure (group 1, unseeded mesh/saline; group 2, unseeded mesh/E. coli; group 3, MSC-seeded mesh/E. coli; 8 rats per group). Meshes were explanted at 4 weeks and underwent microbiologic and histologic analyses.

Results: MSC-seeded meshes inoculated with E. coli demonstrated superior bacterial clearance and preservation of mesh integrity compared with E. coli-inoculated unseeded meshes (87.5% versus 0% clearance; p = 0.001). Complete mesh degradation concurrent with abscess formation was observed in 100% of rats in the unseeded/E. coli group, which is in contrast to 12.5% of rats in the MSC-seeded/E. coli group. Histologic evaluation determined that remodeling characteristics of E. coli-inoculated MSC-seeded meshes were similar to those of uninfected meshes 4 weeks after implantation.

Conclusions: Augmenting a bioprosthetic material with stem cells seems to markedly enhance resistance to bacterial infection in vivo and preserve mesh integrity.
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http://dx.doi.org/10.1097/GOX.0000000000000765DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4956863PMC
June 2016

Long-term epigenetic alterations in a rat model of Gulf War Illness.

Neurotoxicology 2016 07 11;55:20-32. Epub 2016 May 11.

Department of General Surgery, Tripler Army Medical Center, 1 Jarrett White Road, Honolulu, HI 96859, USA.

Gulf War Illness (GWI) is a chronic, multisymptom illness that affects 25% of the 700,000 US veterans deployed to the Persian Gulf during the 1990-1991 Gulf War. Central nervous system impairments are among the most common symptoms reported, including memory dysfunction and depression. After 25 years, the diagnosis remains elusive, useful treatments are lacking, and the cause is poorly understood, although exposures to pyridostigmine bromide (PB) and pesticides are consistently identified to be among the strongest risk factors. Epigenetic changes including altered microRNA (miRNA) expression and DNA methylation play an important role in learning, memory, and emotion regulation and have been implicated in various neurological disorders. In this study, we used an established rat model of GWI to determine whether 1) chronic alterations in miRNA expression and global DNA methylation and DNA hydroxymethylation are mechanisms involved in the pathobiology of GWI, and 2) plasma exosome small RNAs may serve as potential noninvasive biomarkers of this debilitating disease. One year after a 28-day exposure regimen of PB, DEET (N,N-diethyl-3-methylbenzamide), permethrin, and mild stress, expression of 84 mature miRNAs and global 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) content were analyzed in the brains of GWI rats and vehicle controls by PCR array and enzyme-linked immunosorbent assay, respectively. Plasma exosome RNA next-generation sequencing analysis was performed in pooled samples to discover potential noninvasive biomarkers. We found that combined exposure to low doses of GW-related chemicals and mild stress caused epigenetic modifications in the brain that persisted one year after exposure, including increased expression of miR-124-3p and miR-29b-3p in the hippocampus and regional alterations in global 5mC and 5hmC content. GW-relevant exposures also induced the differential expression of two piwi-interacting RNAs (piRNAs) in circulation (piR-007899 and piR-019162). Results from this study implicate a role for epigenetic alterations in GWI. Evaluation of the diagnostic potential of plasma exosome RNAs in veterans with GWI is warranted.
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http://dx.doi.org/10.1016/j.neuro.2016.05.007DOI Listing
July 2016

Evaluation of Six Split-thickness Skin Graft Donor-site Dressing Materials in a Swine Model.

Plast Reconstr Surg Glob Open 2013 Dec 6;1(9):e84. Epub 2014 Jan 6.

Department of General Surgery, Tripler Army Medical Center, Honolulu, Hawaii; and Department of Clinical Investigation, Tripler Army Medical Center, Honolulu, Hawaii.

Background: Numerous dressings for split-thickness skin graft donor sites are commercially available with no conclusive evidence-based consensus regarding the optimal dressing choice. This study was conducted to identify which of 5 commonly used materials promotes wound healing most effectively for use on split-thickness donor sites in comparison with our standard dressing, Xeroform (petrolatum gauze).

Methods: Twenty-four partial-thickness wounds were created on the backs of 4 pigs using a dermatome. Wounds (n = 4 per dressing type per pig) were treated with Xeroform, Opsite (polyurethane film), Kaltostat ( calcium sodium alginate), DuoDERM (hydrocolloid), Aquacel (hydrofiber), and Mepilex (silicone foam). Full-thickness skin samples were excised at 3 or 5 days and evaluated histologically for reepithelialization and inflammation. Comparisons also included incidence of infection, ease of use, and cost analyses.

Results: DuoDERM elicited the greatest percent reepithelialization (81%) and Mepilex the lowest (33%) after 3 days (P = 0.004). All dressings demonstrated complete reepithelialization except Mepilex (85%) at 5 days. There were no infections and inflammation was mild among all treatments. Mepilex was easiest to use, whereas Aquacel, Kaltostat, and Opsite were most difficult (P = 0.03). Xeroform was most cost-effective and Aquacel most expensive. Combined scoring revealed DuoDERM = Xeroform > Opsite = Mepilex > Kaltostat > Aquacel.

Conclusions: DuoDERM and Xeroform were most effective overall. DuoDERM tended to outperform all dressings in reepithelialization at 3 days, while Xeroform was least expensive, easy to use, and demonstrated rapid reepithelialization. These findings suggest that Xeroform may be preferred for use on large donor-site areas. DuoDERM may be more appropriate for small donor sites when healing time is a priority.
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http://dx.doi.org/10.1097/GOX.0000000000000031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4174104PMC
December 2013

An experimental comparison of the effects of bacterial colonization on biologic and synthetic meshes.

Hernia 2015 Apr 1;19(2):197-205. Epub 2014 Aug 1.

Department of General Surgery, Tripler Army Medical Center, 1 Jarrett White Road, Honolulu, HI, 96859, USA.

Purpose: Biologic meshes are being used with increasing frequency to repair contaminated abdominal wall defects despite high long-term recurrence and infection rates associated with their use. Recent clinical reports describing the success of lightweight, macroporous synthetic meshes in contaminated ventral hernia repairs have led some surgeons to challenge the belief that synthetics are contraindicated in contaminated fields. We aimed to determine whether a frequently used biologic mesh (Strattice(TM)) is more resistant to bacterial colonization than macroporous synthetic mesh (Parietex(TM) Progrip(TM)) after inoculation with two common pathogens.

Methods: Rats (n = 48) were implanted subcutaneously with Strattice(TM) or Progrip(TM). Meshes were inoculated with sterile saline or a suspension containing 10(6) colony-forming units of Staphylococcus aureus or Escherichia coli prior to wound closure (n = 8 per subgroup). Meshes were explanted at 4 weeks and underwent microbiologic and histologic analyses.

Results: Progrip(TM) demonstrated superior bacterial clearance compared to Strattice(TM) (E. coli, 88 vs. 17% clearance, p = 0.03; S. aureus, 75 vs. 50%, p = 0.61; combined bacterial strains, 81 vs. 36%, p = 0.02; respectively). In the Strattice(TM) group, severely degraded meshes were observed in 100% of animals inoculated with E. coli (but 0% inoculated with S. aureus). In contrast, all Progrip(TM) meshes remained intact regardless of inoculum. Scores for neovascularization were higher in the synthetic group irrespective of contamination (p < 0.05).

Conclusions: Biologic meshes may not be more resistant to bacterial colonization than reduced-weight synthetics, and their resistance may differ in response to different pathogens. The routine use of biologics in contaminated ventral hernia repair should be questioned, particularly in the presence of E. coli.
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http://dx.doi.org/10.1007/s10029-014-1290-0DOI Listing
April 2015

Effect of cross-linked and non-cross-linked acellular dermal matrices on the expression of mediators involved in wound healing and matrix remodeling.

Plast Reconstr Surg 2013 Apr;131(4):697-705

Honolulu, Hawaii From the Departments of General Surgery and Clinical Investigation, Tripler Army Medical Center.

Background: Molecular mechanisms that direct the extent of the foreign body reaction to implanted biological meshes and their subsequent incorporation are poorly understood. The purpose of this study was to compare the influence of non-cross-linked human dermis (AlloDerm) with that of cross-linked porcine dermis (Permacol) on the expression of genes critical for wound healing and tissue remodeling in a rat ventral hernia model.

Methods: Full-thickness abdominal wall defects were repaired with AlloDerm, Permacol, or suture repair with no mesh (n = 10 rats per group). Explants were harvested 90 days after repair and divided for histologic, immunohistochemical, and gene expression analyses. Real-time quantitative polymerase chain reaction arrays were used to profile the expression of 84 wound healing-associated genes at the tissue/mesh interface.

Results: Both meshes induced the differential expression (≥ 3-fold change relative to suture repair, p ≤ 0.01) of extracellular matrix components, remodeling enzymes, and inflammatory cytokines. Genes most markedly up-regulated included matrix metalloproteinase-9 (Permacol, 66-fold; AlloDerm, 19-fold) and chemokine (C-C motif) ligand 12 (Permacol, 24-fold; AlloDerm, 71-fold). Immunohistochemistry using antibodies against matrix metalloproteinase-9 and chemokine (C-C motif) ligand 12 confirmed differential expression at the protein level (p < 0.001). Histologically, AlloDerm demonstrated overall better remodeling characteristics than Permacol.

Conclusions: Permacol elicits increased protease expression and reduced cellular and vascular infiltration compared with AlloDerm 90 days after implantation, indicative of delayed remodeling induced by cross-linking. Increased understanding of the host response to implanted materials ultimately will enable the development of improved meshes with enhanced wound healing properties and fewer graft-related complications.
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http://dx.doi.org/10.1097/PRS.0b013e3182818a3dDOI Listing
April 2013

Biocompatibility comparison of novel soft tissue implants vs commonly used biomaterials in a pig model.

Otolaryngol Head Neck Surg 2012 Sep 11;147(3):456-61. Epub 2012 Jun 11.

Department of Otolaryngology, Tripler Army Medical Center, Honolulu, Hawaii 96859, USA.

Objective: To develop a model to evaluate biocompatibility, integration, and substrate independence of novel porous bioscaffolds for maxillofacial and plastic reconstruction using sphere-templated angiogenic regeneration technology compared with currently available synthetic and biologic soft tissue implants.

Study Design: A prospective pilot study using animals.

Setting: Military medical center.

Subjects And Methods: Five pigs underwent dorsal subcutaneous implantation of a polypropylene-based material coated with precision pore silicone granules (sphere-templated scaffold), expanded polytetrafluoroethylene, human dermis, and porcine dermis. Sham and undissected sites were also used as controls. Specimens were harvested 7, 21, 90, and 180 days after surgery and evaluated histologically for inflammation, neovascularization, and collagen deposition.

Results: All materials and sham sites induced a mild to moderate inflammation that decreased over time, except for human dermis, which elicited a moderate to severe inflammatory response. The responses were varied and measurable using subjective scoring methods. The sphere-templated scaffold demonstrated numerous foreign body giant cells adjacent to the silicone granules, which were not seen in any of the other specimens.

Conclusion: Subjective scoring of pathology slides and measurement of capsule thickness appeared to show differences between the materials, but these differences require a larger number of subjects and proper statistical analysis to assess. The robust foreign body reaction elicited by the polypropylene/silicone-based scaffold argues against the use of this material in future studies. The authors advocate using inert biodegradable substances for future bioscaffold constructs.
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http://dx.doi.org/10.1177/0194599812450855DOI Listing
September 2012

Influence of a new monofilament polyester mesh on inflammation and matrix remodeling.

J Invest Surg 2012 Oct 9;25(5):330-9. Epub 2012 May 9.

Department of General Surgery, Tripler Army Medical Center, Honolulu, Hawaii 96859, USA.

ABSTRACT Synthetic mesh is widely used for hernia repairs, but mesh-induced chronic inflammatory responses may lead to postoperative complications. We previously showed an elevated response to multifilament polyester (PE) versus monofilament polypropylene (PP) and polytetrafluoroethylene (PTFE) meshes, but it is unclear whether this discrepancy is due to the differences in chemical composition or filament structure. This study compares the influence of a newly available monofilament PE mesh to that of multifilament PE, monofilament PP, and monofilament PTFE on the expression of genes important in inflammation and extracellular matrix remodeling in a rat model. Full thickness abdominal wall defects were corrected with onlay repair or suture repair with no mesh. Explants were harvested 7 or 90 days after repair and divided for histology and mRNA analyses using real-time quantitative polymerase chain reaction arrays to profile expression at the tissue-mesh interface. Monofilament PE elicited a reduced foreign body reaction compared to multifilament PE, corresponding with reduced mRNA expression of important inflammatory cytokines and matrix metalloproteinases (MMPs). Unexpectedly, monofilament PE also resulted in markedly reduced mRNA expression of tumor necrosis factor and MMPs 3 and 9 compared to the widely-used monofilament PP mesh. Findings from this study revealed that both chemical composition and filament structure are important mesh characteristics that may affect a patient's wound healing response and clinical outcome, and should be considered by the surgeon when choosing a particular mesh. Although clinical studies are warranted, results in a rodent model suggest that monofilament PE may be more beneficial than the multifilament form for certain hernia repairs.
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http://dx.doi.org/10.3109/08941939.2011.639848DOI Listing
October 2012

Pulmonary toxicity after exposure to military-relevant heavy metal tungsten alloy particles.

Toxicol Appl Pharmacol 2012 Feb 16;259(1):74-86. Epub 2011 Dec 16.

Department of General Surgery, Tripler Army Medical Center, Honolulu, HI 96859, USA.

Significant controversy over the environmental and public health impact of depleted uranium use in the Gulf War and the war in the Balkans has prompted the investigation and use of other materials including heavy metal tungsten alloys (HMTAs) as nontoxic alternatives. Interest in the health effects of HMTAs has peaked since the recent discovery that rats intramuscularly implanted with pellets containing 91.1% tungsten/6% nickel/2.9% cobalt rapidly developed aggressive metastatic tumors at the implantation site. Very little is known, however, regarding the cellular and molecular mechanisms associated with the effects of inhalation exposure to HMTAs despite the recognized risk of this route of exposure to military personnel. In the current study military-relevant metal powder mixtures consisting of 92% tungsten/5% nickel/3% cobalt (WNiCo) and 92% tungsten/5% nickel/3% iron (WNiFe), pure metals, or vehicle (saline) were instilled intratracheally in rats. Pulmonary toxicity was assessed by cytologic analysis, lactate dehydrogenase activity, albumin content, and inflammatory cytokine levels in bronchoalveolar lavage fluid 24h after instillation. The expression of 84 stress and toxicity-related genes was profiled in lung tissue and bronchoalveolar lavage cells using real-time quantitative PCR arrays, and in vitro assays were performed to measure the oxidative burst response and phagocytosis by lung macrophages. Results from this study determined that exposure to WNiCo and WNiFe induces pulmonary inflammation and altered expression of genes associated with oxidative and metabolic stress and toxicity. Inhalation exposure to both HMTAs likely causes lung injury by inducing macrophage activation, neutrophilia, and the generation of toxic oxygen radicals.
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http://dx.doi.org/10.1016/j.taap.2011.12.008DOI Listing
February 2012

Alterations in pelvic floor muscles and pelvic organ support by pregnancy and vaginal delivery in squirrel monkeys.

Int Urogynecol J 2011 Sep 13;22(9):1109-16. Epub 2011 May 13.

Department of Obstetrics, Scott and White Memorial Hospital and Clinic, 2401 South 31st Street, Temple, TX 76508, USA.

Introduction And Hypothesis: The objective of this study was to measure the effects of pregnancy and parturition on pelvic floor muscles and pelvic organ support.

Methods: Levator ani, obturator internus, and coccygeus (COC) muscle volumes and contrast uptake were assessed by MRI of seven females prior to pregnancy, 3 days, and 4 months postpartum. Bladder neck and cervix position were measured dynamically with abdominal squeezing.

Results: The sides of three paired muscles were similar (p > 0.66). COC volumes were greater (p < 0.004) after parturition than before pregnancy or after recovery. COC contrast uptake increased (p < 0.02) immediately after delivery. Bladder neck position both in the relaxed state and abdominal pressure descended (p < 0.04) after delivery and descended further (p < 0.001) after recovery. Cervical position in the relaxed state before delivery was higher (p < 0.001) than postpartum but was unchanged (p = 0.50) with abdominal pressure relative to delivery.

Conclusion: In squirrel monkeys, coccygeus muscles demonstrate the greatest change related to parturition, and parturition-related bladder neck descent seems permanent.
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http://dx.doi.org/10.1007/s00192-011-1443-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4128415PMC
September 2011

Inflammatory cytokine and matrix metalloproteinase expression induced by collagen-coated and uncoated polypropylene meshes in a rat model.

Am J Obstet Gynecol 2011 Jul 23;205(1):82.e1-9. Epub 2011 Feb 23.

Department of Clinical Investigation, Tripler Army Medical Center, Honolulu, HI, USA.

Objective: The objective of the study was to compare the influence of collagen-coated vs uncoated polypropylene meshes on the expression of genes critical for wound healing.

Study Design: In 54 rats, abdominal wall defects were created, repaired by polypropylene sutures, and covered by an overlay of coated polypropylene (n = 20), uncoated polypropylene (n = 18), or no mesh (n = 16). Explants were harvested 7 or 90 days after repair and divided for histological, immunohistochemical, and messenger ribonucleic acid (mRNA) analyses. Real-time quantitative polymerase chain reaction arrays were used to profile the expression of 84 genes at the tissue-mesh interface.

Results: One week after implantation, coated mesh elicited a slightly greater inflammatory response and increased mRNA expression of 4 proinflammatory cytokines compared with uncoated mesh. Both materials, however, induced a comparable expression of cytokines and matrix metalloproteinases relative to suture repair 90 days after implantation.

Conclusion: Collagen-coated polypropylene mesh induces elevated inflammatory cytokine expression compared with uncoated mesh early in the healing process, but the response to both meshes is similar 90 days after implantation.
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http://dx.doi.org/10.1016/j.ajog.2011.02.045DOI Listing
July 2011

Influence of mesh materials on the expression of mediators involved in wound healing.

J Invest Surg 2011 ;24(2):87-98

Department of General Surgery, Tripler Army Medical Center, Honolulu, Hawaii 96859, USA.

The use of synthetic mesh for ventral hernia repair is widely accepted, but mesh-induced inflammatory responses may lead to postoperative complications. Molecular mechanisms that direct the extent of the foreign body reaction to implanted materials are poorly understood. This study compares the influence of three macroporous meshes on the expression of genes critical for wound healing and extracellular matrix remodeling in a rat model. Full thickness abdominal wall defects were corrected with polypropylene, polyester, polytetrafluoroethylene (PTFE), or suture repair with no mesh. Explants were harvested 7 or 90 days after repair and were divided for histological, immunohistochemical, and mRNA analyses. Real-time quantitative polymerase chain reaction arrays were used to profile the expression of 84 genes involved in angiogenesis at the tissue-mesh interface. Evaluation of gene expression profiles and histologic specimens revealed that polypropylene and polyester induced a greater and more persistent inflammatory response than PTFE, which elicited a response most similar to that induced by suture repair. Mesh implantation induced the differential expression (>3-fold change and p < .01) of genes encoding inflammatory cytokines, growth factors, and extracellular matrix proteins relative to suture repair without mesh. Genes most markedly upregulated included the neutrophil chemoattractant CXCL2 and matrix metalloproteinases 3 and 9. Polyester induced the greatest number of differentially expressed genes relative to suture repair both at 7 and 90 days after implantation. Results from this study suggest that the particular type of mesh used in a hernia repair may affect the patient's wound healing response and clinical outcome.
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http://dx.doi.org/10.3109/08941939.2010.548904DOI Listing
June 2011

Effect of estrogen replacement on the histologic response to polypropylene mesh implanted in the rabbit vagina model.

Am J Obstet Gynecol 2009 Nov 15;201(5):505.e1-9. Epub 2009 Aug 15.

Department of Obstetrics and Gynecology, Scott & White Memorial Hospital and Clinic, Texas A&M University Health Science Center College of Medicine, Temple, TX, USA.

Objective: The aim of this study was to determine the effect of estrogen replacement after ovariectomy on the histologic response to polypropylene mesh implanted in rabbit vagina.

Study Design: Thirty rabbits were assigned to 5 groups: sham laparotomy, ovariectomy, ovariectomy-preoperative estrogen, ovariectomy-postoperative estrogen, or ovariectomy-preoperative and postoperative estrogen. Rabbits underwent sham surgery or ovariectomy and were infused with vehicle or 17beta-estradiol (200 microg/d) for 4 weeks ("preoperative" estrogen). Polypropylene mesh was implanted in the posterior vaginal wall, and rabbits were infused with vehicle or "postoperative" estrogen for an additional 8 weeks. Grafts were harvested and underwent histologic evaluation.

Results: Vaginal atrophy in ovariectomized rabbits was reversed by estrogen replacement. Scores for inflammation (P = .33) and neovascularization (P = .23) at the graft site were not different among estrogen replacement groups, but estrogen administration was associated with increased collagen deposition (P = .005).

Conclusion: Estrogen replacement administered for 8 weeks postoperatively increases collagen deposition into polypropylene mesh.
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http://dx.doi.org/10.1016/j.ajog.2009.05.050DOI Listing
November 2009

Long-term histologic response to synthetic and biologic graft materials implanted in the vagina and abdomen of a rabbit model.

Am J Obstet Gynecol 2009 May 16;200(5):546.e1-8. Epub 2009 Mar 16.

Department of Obstetrics and Gynecology, Scott & White Memorial Hospital and Clinic, Texas A&M University Health Science Center College of Medicine, Temple, TX, USA.

Objective: We sought to evaluate the effects of graft type, site of implantation, and ovariectomy on the long-term histologic response to graft materials used in pelvic reconstructive surgery.

Study Design: In all, 45 rabbits underwent ovariectomy or sham laparotomy and were implanted with polypropylene (PP) mesh (n = 23) or cross-linked porcine dermis (PS) (n = 22) in the vagina and abdomen. Grafts were harvested 9 months later and were processed for histology to evaluate the host inflammatory response and degree of tissue incorporation within the grafts.

Results: Polypropylene induced a milder (P < .007), more uniform response than PS, whereas PS elicited a more variable response and degraded by 9 months. Vaginal grafts had higher scores for inflammation (P = .005) and neovascularization (P < .001), and had lower scores for fibroblastic proliferation (P < .001) than abdominal grafts. Ovariectomy had no effect (P > .05).

Conclusion: Synthetic and biologic grafts evoke different foreign body responses, which may have implications for surgical outcomes in women.
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http://dx.doi.org/10.1016/j.ajog.2008.12.040DOI Listing
May 2009

Biomechanical properties of synthetic and biologic graft materials following long-term implantation in the rabbit abdomen and vagina.

Am J Obstet Gynecol 2009 May 14;200(5):549.e1-8. Epub 2009 Mar 14.

Department of Obstetrics and Gynecology, Scott & White Memorial Hospital and Clinic, Texas A&M University Health Science Center College of Medicine, Temple, TX, USA.

Objective: We sought to evaluate the effects of anatomic location and ovariectomy on biomechanical properties of synthetic and biologic graft materials after long-term implantation.

Study Design: A total of 35 rabbits underwent ovariectomy or sham laparotomy and were implanted with polypropylene (PP) mesh (n = 17) or cross-linked porcine dermis (PS) (n = 18) in the vagina and abdomen. Grafts were harvested 9 months later and underwent mechanical properties testing.

Results: After implantation, PS was similar in strength (P = .52) but was twice as stiff as PP (P = .04) and had a maximal elongation only half that of PP (P < .001). Degradation of PS was associated with decreased ultimate tensile strength (P = .03) and elastic modulus (P = .046). Vaginal PP grafts shrunk more (P < .001) and were less stiff than abdominal PP grafts (P = .049) but were not different in strength (P = .19). Ovariectomy had no effect (P > .05).

Conclusion: Cross-linked PS undergoes long-term degradation resulting in compromised biomechanical properties and thus is likely inferior to lightweight PP meshes for pelvic organ prolapse and incontinence procedures.
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http://dx.doi.org/10.1016/j.ajog.2008.12.041DOI Listing
May 2009

Morphological and functional heterogeneity of the mouse intrahepatic biliary epithelium.

Lab Invest 2009 Apr 9;89(4):456-69. Epub 2009 Feb 9.

Scott and White Digestive Diseases Research Center, Temple, TX, USA.

Rat and human biliary epithelium is morphologically and functionally heterogeneous. As no information exists on the heterogeneity of the murine intrahepatic biliary epithelium, and with increased usage of transgenic mouse models to study liver disease pathogenesis, we sought to evaluate the morphological, secretory, and proliferative phenotypes of small and large bile ducts and purified cholangiocytes in normal and cholestatic mouse models. For morphometry, normal and bile duct ligation (BDL) mouse livers (C57/BL6) were dissected into blocks of 2-4 microm(2), embedded in paraffin, sectioned, and stained with hematoxylin and eosin. Sizes of bile ducts and cholangiocytes were evaluated by using SigmaScan to measure the diameters of bile ducts and cholangiocytes. In small and large normal and BDL cholangiocytes, we evaluated the expression of cholangiocyte-specific markers, keratin-19 (KRT19), secretin receptor (SR), cystic fibrosis transmembrane conductance regulator (CFTR), and chloride bicarbonate anion exchanger 2 (Cl(-)/HCO(3)(-) AE2) by immunofluorescence and western blot; and intracellular cyclic adenosine 3',5'-monophosphate (cAMP) levels and chloride efflux in response to secretin (100 nM). To evaluate cholangiocyte proliferative responses after BDL, small and large cholangiocytes were isolated from BDL mice. The proliferation status was determined by analysis of the cell cycle by fluorescence-activated cell sorting, and bile duct mass was determined by the number of KRT19-positive bile ducts in liver sections. In situ morphometry established that the biliary epithelium of mice is morphologically heterogeneous, with smaller cholangiocytes lining smaller bile ducts and larger cholangiocytes lining larger ducts. Both small and large cholangiocytes express KRT19 and only large cholangiocytes from normal and BDL mice express SR, CFTR, and Cl(-)/HCO(3)(-) exchanger and respond to secretin with increased cAMP levels and chloride efflux. Following BDL, only large mouse cholangiocytes proliferate. We conclude that similar to rats, mouse intrahepatic biliary epithelium is morphologically and functionally heterogeneous. The mouse is therefore a suitable model for defining the heterogeneity of the biliary tree.
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http://dx.doi.org/10.1038/labinvest.2009.6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2662046PMC
April 2009

Transverse cystocele repair with uterine preservation using native tissue.

Int Urogynecol J Pelvic Floor Dysfunct 2008 Sep 8;19(9):1275-81. Epub 2008 May 8.

Department of Obstetrics & Gynecology, Scott and White Memorial Hospital and Clinic, Texas A&M University Health Science Center College of Medicine, 2401 South 31st Street, Temple, TX 76508, USA.

The goals of this study were to describe the surgical procedure of the transverse cystocele repair with uterine preservation using native tissue and to examine the surgical complications and short-term anatomical outcomes of this operation. Patients who underwent transverse cystocele repair with uterine preservation at our institution were identified by retrospective chart review for the interval from January 2001 to September 2006. Sixty-nine patients were identified. Median point for first postoperative visit was 6.1 weeks (range 3-101 weeks). Average age was 66.6 +/- 13.1 years (range 33-89). Patients undergoing this procedure had no intraoperative complications and high frequency of initial anatomic success (defined as Baden-Walker halfway system grade 0 or 1 for anterior compartment) during a relatively short follow-up interval. Preoperatively, bladder grade averaged 2.6 with postoperative grade averaging 0.02. Based on our initial anatomical findings, we conclude that this surgical approach has merit for a subset of patients with adequate uterine support.
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http://dx.doi.org/10.1007/s00192-008-0629-4DOI Listing
September 2008

Effects of bilateral levator ani nerve injury on pelvic support in the female squirrel monkey.

Am J Obstet Gynecol 2008 May 7;198(5):585.e1-8. Epub 2008 Mar 7.

Department of Obstetrics and Gynecology, Scott & White Memorial Hospital and Clinic, Texas A&M University Health Science Center College of Medicine, Temple, TX 76508, USA.

Objective: To determine whether experimental denervation of the levator ani (LA) and its subsequent atrophy contribute to the development of pelvic organ prolapse in the squirrel monkey.

Study Design: Thirty-seven female monkeys were evaluated including 7 that underwent bilateral LA neurectomy (bLAN), 17 nulliparous monkeys without prolapse, 7 parous monkeys without prolapse, and 6 parous monkeys with prolapse. Magnetic resonance imaging was used to calculate LA muscle volumes and obtain measurements of the position of bladder and cervix. Repeat observations in bLAN females occurred at different times in relation to parturition.

Results: LA volumes were reduced in bLAN monkeys (P = .02). Bladder (P = .03) and cervix (P = .04) positions varied between groups, with nulliparous females having the most cephalad positions and females with prolapse having the most caudal positions. Bladder descent was observed in a subset of 4 bLAN females that experienced vaginal parturition (P = .04) and correlated with external findings of vaginal prolapse.

Conclusion: Bilateral transection of the LA nerve results in atrophy of denervated LA muscles but not a loss of pelvic support in nulliparous monkeys, suggesting that connective tissue components compensate for weakened pelvic floor muscles. LA denervation may accelerate the onset of vaginal prolapse subsequent to parturition.
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http://dx.doi.org/10.1016/j.ajog.2007.12.001DOI Listing
May 2008

Histologic response of porcine collagen-coated and uncoated polypropylene grafts in a rabbit vagina model.

Am J Obstet Gynecol 2008 May 4;198(5):582.e1-7. Epub 2008 Mar 4.

Department of Obstetrics & Gynecology, Scott & White Memorial Hospital and Clinic, Texas A&M University Health Science Center College of Medicine, Temple, TX 76508, USA.

Objective: The purpose of this study was to determine whether the host tissue response in the rabbit vagina differs for 2 synthetic graft materials that are used in pelvic reconstructive surgery.

Study Design: One strip of porcine collagen-coated or uncoated polypropylene mesh was implanted adjacent to a sham operative site into the posterior vagina of 10 New Zealand white rabbits and harvested 12 weeks later. Rabbits were assigned randomly to group 1 (coated; n = 5), group 2 (uncoated; n = 5), or group 3 (unoperated; n = 4). Full-thickness sagittal sections of posterior vaginal wall and rectum were scored for inflammation, neovascularization, and fibroblastic proliferation.

Results: Erosion of grafts did not occur in any animal. Coated and uncoated meshes induced a mild inflammatory response with minimal fibrosis and good host tissue incorporation within the grafts. Few apoptotic and proliferating cells were seen for both graft types.

Conclusion: Both coated and uncoated polypropylene meshes elicit a mild foreign body reaction and minimal fibrotic response without evidence of vaginal epithelial erosion.
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http://dx.doi.org/10.1016/j.ajog.2007.12.029DOI Listing
May 2008

Levator ani muscle and connective tissue changes associated with pelvic organ prolapse, parity, and aging in the squirrel monkey: a histologic study.

Am J Obstet Gynecol 2007 Jul;197(1):60.e1-9

Department of Obstetrics and Gynecology, Scott & White Hospital, Temple, TX 76508, USA.

Objective: This study was undertaken to evaluate histologically the levator ani muscle and paravaginal attachments in squirrel monkeys with and without pelvic organ prolapse.

Study Design: Serial sections from 19 females were processed with routine histology stains. Fiber typing was performed with antifast (type II) and antislow (type I) skeletal myosin antibodies, and apoptotic nuclei were examined by dUTP nick-end labeling (TUNEL).

Results: Gross disruption of the levator ani muscle and its innervation was not observed in animals with or without visible support defects. Myogenic changes occurred more frequently in the pubocaudalis than iliocaudalis muscles, and a significant association was found with aging (P < .05, Fisher exact test) but not with pelvic organ prolapse or parity. Neurogenic changes were observed in 3 of 13 multiparous monkeys. Myocyte diameter increased in animals with pelvic organ prolapse compared with age-, weight-, and parity-matched animals without pelvic organ prolapse (P = .005) and correlated with levator ani muscle wet weight (R = 0.76; P = .0006). In the paravaginal attachments, the numbers of fibroblasts and apoptotic nuclei were not different between animals with and without pelvic organ prolapse, but parity was associated with increased apoptosis (P = .025).

Conclusion: Vaginal prolapse in the squirrel monkey does not result from atrophy or gross disruption of the levator ani muscle or its innervation. As in women, myogenic changes are a common finding in the levator ani muscle and increase with aging, whereas denervation with subsequent reinnervation occurs in some multiparous monkeys.
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http://dx.doi.org/10.1016/j.ajog.2007.02.037DOI Listing
July 2007

Magnetic resonance imaging of the levator ani in the squirrel monkey: a comparison of muscle volume between a cohort with pelvic organ prolapse and matched normals.

Am J Obstet Gynecol 2006 May;194(5):1467-71

Department of Obstetrics and Gynecology, Scott and White Memorial Hospital and Clinic, Texas A&M University System Health Science Center College of Medicine, Temple, TX, USA.

Objective: Magnetic resonance imaging was used to test whether squirrel monkeys with pelvic organ prolapse have reduced pelvic muscle volumes, compared with matched normals.

Study Design: Levator ani and obturator internus volumes obtained from T1-weighted axial scans of matched groups were measured. Muscle volumes and weights were compared for animals necropsied after magnetic resonance imaging.

Results: Two observers concurred on measures of levator ani and obturator internus (Kendal tau > or = 0.60 with P < .003). Levator ani volume was related to mass (R2 = 0.62, P = .0009). Animals with pelvic organ prolapse did not differ (P = .67, Wilks multivariate test) from those without pelvic organ prolapse in age, parity, and weight. Levator ani differed between groups (pelvic organ prolapse = 520 mm3 versus normals = 392 mm3, P = .015) and not sides (P = .80). The obturator internus did not differ between groups (P = .29) or sides (P = .72).

Conclusion: Magnetic resonance imaging demonstrates that levator ani volumes in parous squirrel monkeys with pelvic organ prolapse were not reduced, suggesting that prolapse is not related to pelvic muscle size reduction in this species.
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http://dx.doi.org/10.1016/j.ajog.2006.01.062DOI Listing
May 2006

Distribution and immunohistochemical characterization of primary afferent neurons innervating the levator ani muscle of the female squirrel monkey.

Am J Obstet Gynecol 2006 Oct 25;195(4):987-96. Epub 2006 Apr 25.

Department of Obstetrics and Gynecology, Scott & White Hospital, Temple, TX 76508, USA.

Objective: This study was undertaken to examine the neurofilament and neurochemical composition of subpopulations of primary afferent neurons innervating the levator ani muscle by combining retrograde tracing and triple labeling immunofluorescence in the female squirrel monkey.

Study Design: Cholera toxin B subunit (CTB) was injected unilaterally into the levator ani muscle of 3 monkeys to identify primary sensory neurons in the dorsal root ganglia (DRG) and their central projections in the spinal cord. L7-S2 DRG were processed for dual or triple labeling immunofluorescence 3 days after injection to examine labeling of the 200 kD neurofilament marker RT97 (a marker of myelinated neurons), calcitonin gene-related peptide (CGRP; a marker of peptidergic neurons), isolectin B4 (IB4; a marker of small, unmyelinated neurons), and nerve growth factor receptor (TrkA) in CTB-positive neurons.

Results: RT97-negative (C-fiber) neurons were more numerous (74% of total CTB-labeled neurons) and smaller in size than RT97-positive (A-fiber) afferent neurons (26% of CTB-labeled neurons). IB4 labeling was almost exclusively found in RT97-negative afferent neurons. Approximately 43% of all CTB-labeled DRG neurons expressed CGRP, and the majority of these were small. The distribution and sizes of CTB-labeled TrkA-positive DRG neurons were similar to those of CTB-labeled CGRP-positive DRG neurons.

Conclusion: The levator ani muscle is innervated by 3 major subpopulations of primary afferent neurons consisting of cells with large, neurofilament-rich soma and A fibers (putative proprioceptive neurons) and those with small, peptidergic or nonpeptidergic, neurofilament-poor soma and C fibers (putative nociceptive, mechanoreceptive, ergoreceptive, and thermoreceptive neurons). Future investigation is needed to elucidate the relationship between primary sensory neuron subpopulations and changes in neuropeptide and neurotrophin expression on experimental levator ani nerve damage, childbirth, and aging.
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http://dx.doi.org/10.1016/j.ajog.2006.02.042DOI Listing
October 2006

Immunohistochemical evidence for the interaction between levator ani and pudendal motor neurons in the coordination of pelvic floor and visceral activity in the squirrel monkey.

Am J Obstet Gynecol 2005 May;192(5):1506-15

Department of Obstetrics and Gynecology, Scott & White Hospital, Temple, Tex 76508, USA.

Objective: The purpose of this study was to characterize the spinal distribution of afferent and efferent pathways that innervate the levator ani (LA) muscle in the female squirrel monkey.

Study Design: Cholera toxin B (CTB) was injected unilaterally into the LA muscle of 5 monkeys to identify primary sensory neurons in the dorsal root ganglia (DRG) and motor neurons in the spinal cord that contribute fibers to the LA nerve. Fluoro-Gold (FG) was injected into the external anal sphincter of 2 of these animals to label pudendal motor neurons (1 of these animals underwent unilateral LA neurectomy before CTB injection). Spinal cord and DRG were processed for immunofluorescence 3 to 7 days after injections.

Results: Retrograde transport of CTB from the LA muscle labeled primary afferent neurons in the ipsilateral DRG, their central projections, and motor neurons in the medial portion of the ipsilateral ventral horn of the spinal cord (L7-S2 segments). Injection of FG into the external anal sphincter labeled cells in Onuf's nucleus, primarily in L7. Importantly, CTB-labeled LA motor neurons were virtually absent in Onuf's nucleus, where all pudendal motor neurons are located. CTB-labeled processes were observed within Onuf's nucleus, adjacent to FG-labeled pudendal motor neurons, and appeared to derive from dendrites of LA motor neurons that project into Onuf's nucleus.

Conclusion: The LA muscle has a distinct innervation with very little or no contribution from the pudendal nerve. The intriguing labeling of LA neural elements within a nucleus that innervates the external urethral and anal sphincters (involved in pelvic visceral control) may represent a neuroanatomic substrate for physiologic integration of spinal and supraspinal inputs for the coordination of pelvic floor and visceral activity.
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http://dx.doi.org/10.1016/j.ajog.2004.10.607DOI Listing
May 2005

Evaluation of the aged female baboon as a model of pelvic organ prolapse and pelvic reconstructive surgery.

Am J Obstet Gynecol 2005 May;192(5):1395-8

Department of Obstetrics and Gynecology, Scott and White Clinic, Texas A&M University System Health Science Center College of Medicine, Temple 76508, USA.

Objective: This study examines the baboon as an animal model of pelvic organ prolapse (POP) by describing the pelvic floor anatomy and adapting human clinical assessment tools.

Study Design: The pelvic anatomy of an adult female baboon was observed at necropsy, and comparisons were made to the human and squirrel monkey. The pelvic organ prolapse quantification (POP-Q) system was used to assess vaginal support in 12 living adult baboons, including 6 young, reproductive-age, nulligravid females (4.8 +/- 0.5 years) and 6 older, multiparous females (23.0 +/- 0.5 years).

Results: The female baboon pelvic anatomy was found to have similar architecture to the human and squirrel monkey female. Six multiparous females with mean parity of 5 (range 2-8) showed no evidence of POP or differences in POP-Q measurements from 6 nulliparous females.

Conclusion: The POP-Q system can be used to assess female baboon vaginal support. In a sample of baboons, pelvic support loss consistent with POP was not identified. As the pelvic anatomy is similar to the human female, the baboon may prove useful for evaluating surgical materials and for modeling pelvic floor reconstructive surgeries.
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http://dx.doi.org/10.1016/j.ajog.2004.12.046DOI Listing
May 2005

Innervation of the levator ani muscles in the female squirrel monkey.

Am J Obstet Gynecol 2003 May;188(5):1141-7

Department of Obstetrics and Gynecology, Scott and White Clinic, 2401 W. 31st Street, Temple, TX 76508, USA.

Objective: The purpose of this study was to characterize the innervation of the levator ani muscles in the female squirrel monkey and to investigate its usefulness as an animal model of pelvic organ prolapse.

Study Design: Eleven nulliparous female squirrel monkeys with no pelvic organ prolapse were used in this study. Detailed pelvic dissections were conducted (n = 3), and the Koelle stain for acetylcholinesterase was used to identify the motor endplate zone in the levator ani muscles (n = 2). Unilateral levator ani (n = 4) and pudendal (n = 2) neurectomies were performed; changes in levator ani muscle mass and myocyte diameter were examined 14 days after neurectomy. Nerve biopsy specimens from each animal were processed for microscopy.

Results: The levator ani nerve originated from the S2 spinal root and entered the pelvic cavity adjacent to the pelvic nerve between the flexor caudalis brevis and iliocaudalis muscles. The levator ani nerve then projected caudally and bifurcated to penetrate the iliocaudalis and pubocaudalis. A single motor endplate zone in each muscle correlated with the point of levator ani nerve penetration. The pudendal nerve originated from the S1-S2 spinal roots to innervate the urethral and anal sphincters, clitoris, and perineum, but not the iliocaudalis or pubocaudalis. Significant atrophy and myocyte shrinkage occurred in the iliocaudalis and pubocaudalis ipsilateral to the levator ani nerve transection (P <.05). Pudendal neurectomy produced no levator ani muscle changes.

Conclusion: Intrapelvic skeletal muscles in the female squirrel monkey are similar to humans and have distinct innervation with no contribution from the pudendal nerve. The squirrel monkey is likely to be a useful model of pelvic organ prolapse and warrants further study.
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http://dx.doi.org/10.1067/mob.2003.329DOI Listing
May 2003

The effect of fetal acidemia on fetal-placental vascular tone and production of the inflammatory cytokines interleukin-6 and tumor necrosis factor-alpha.

Am J Obstet Gynecol 2002 Oct;187(4):894-7

Division of Maternal-Fetal Medicine, Madigan Army Medical Center, Ft. Lewis, WA, USA.

Objective: Our purpose was to determine the effects of fetal acidemia on placental vascular tone and production of interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha).

Study Design: With use of an ex vivo placental perfusion model, the maternal and fetal circulation of two cotyledons from five human placentas were perfused for 4 hours. The fetal circulation of one cotyledon was perfused with acidemic (pH 6.90) Hanks' balanced salt solution (HBSS), whereas the fetal circulation of the other cotyledon was perfused with physiologic (pH 7.35) HBSS. Fetal venous effluents were collected hourly, and IL-6 and TNF-alpha concentrations were determined by enzyme-linked immunosorbent assay. Cotyledon perfusion pressures were recorded every 10 minutes. Paired t tests were used to compare differences in cytokine production and perfusion pressure between the cotyledons.

Results: Fetal-placental vascular perfusion pressure was consistently reduced from baseline under acidemic, but not physiologic, conditions with statistical significance achieved from 20 minutes onward (P <.05). IL-6 and TNF-alpha increased exponentially over time for both conditions (P <.05). There was no difference in cytokine production when acidemic conditions were compared with physiologic conditions (P <.05).

Conclusion: Fetal-placental vasodilation may be a compensatory mechanism to improve acidemic conditions. Unlike fetal hypoperfusion or fetal hyperoxia, fetal acidemia does not result in elevated placental cytokine levels.
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http://dx.doi.org/10.1067/mob.2002.127455DOI Listing
October 2002