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1.  Hypertrophic scar contracture is mediated by the TRPC3 mechanical force transducer via NFkB activation 
Scientific Reports  2015;5:11620.
Wound healing process is a complex and highly orchestrated process that ultimately results in the formation of scar tissue. Hypertrophic scar contracture is considered to be a pathologic and exaggerated wound healing response that is known to be triggered by repetitive mechanical forces. We now show that Transient Receptor Potential (TRP) C3 regulates the expression of fibronectin, a key regulatory molecule involved in the wound healing process, in response to mechanical strain via the NFkB pathway. TRPC3 is highly expressed in human hypertrophic scar tissue and mechanical stimuli are known to upregulate TRPC3 expression in human skin fibroblasts in vitro. TRPC3 overexpressing fibroblasts subjected to repetitive stretching forces showed robust expression levels of fibronectin. Furthermore, mechanical stretching of TRPC3 overexpressing fibroblasts induced the activation of nuclear factor-kappa B (NFκB), a regulator fibronectin expression, which was able to be attenuated by pharmacologic blockade of either TRPC3 or NFκB. Finally, transplantation of TRPC3 overexpressing fibroblasts into mice promoted wound contraction and increased fibronectin levels in vivo. These observations demonstrate that mechanical stretching drives fibronectin expression via the TRPC3-NFkB axis, leading to intractable wound contracture. This model explains how mechanical strain on cutaneous wounds might contribute to pathologic scarring.
doi:10.1038/srep11620
PMCID: PMC4479825  PMID: 26108359
2.  Noncontact, Low-Frequency Ultrasound Therapy Enhances Neovascularization and Wound Healing in Diabetic Mice 
Plastic and reconstructive surgery  2014;134(3):402e-411e.
Background
Chronic wounds are a major source of morbidity for patients and represent a significant health burden. Implementing noninvasive techniques that accelerate healing of these wounds would provide great benefit. Ultrasound appears to be an effective modality for the treatment of chronic wounds in humans. MIST Therapy is a noncontact, low-frequency ultrasound treatment delivered through a saline mist. A variety of mechanisms have been proposed to explain the efficacy of ultrasound therapy, but the underlying molecular and cellular pathways impacted by this technique remain unclear. The in vivo effect of noncontact, low-frequency ultrasound was therefore examined in a humanized excisional wound model.
Methods
The treatment group received noncontact, low-frequency ultrasound therapy three times per week, whereas the control group received a standard dressing change. Wounds were photographed at regular intervals to calculate healing kinetics. Wound tissue was harvested and processed for histology, quantitative polymerase chain reaction, and enzyme-linked immunosorbent assay.
Results
The MIST group demonstrated significantly accelerated wound healing, with 17.3 days to wound closure compared with 24 days in the controls (p < 0.05). This improvement became evident by day 9, with healing evidenced by significantly decreased mean wound area relative to original size (68 percent versus 80 percent; p < 0.01). Expression of markers of neovascularization (stromal cell-derived factor 1, vascular endothelial growth factor, and CD31) was also increased in the wound beds of noncontact, low-frequency ultrasound–treated mice compared with controls.
Conclusion
Noncontact, low-frequency ultrasound treatment improves neo-vascularization and wound closure rates in excisional wounds for diabetic mice, likely because of the stimulated release of angiogenic factors.
doi:10.1097/PRS.0000000000000467
PMCID: PMC4422103  PMID: 25158717
3.  Tracking the elusive fibrocyte: Identification and characterization of collagen producing hematopoietic lineage cells during murine wound healing 
Stem cells (Dayton, Ohio)  2014;32(5):1347-1360.
Fibrocytes are a unique population of circulating cells reported to exhibit characteristics of both hematopoietic and mesenchymal cells, and play an important role in wound healing. However putative fibrocytes have been found to lose expression of hematopoietic surface markers such as CD45 during differentiation, making it difficult to track these cells in vivo with conventional methodologies. In this study, to distinguish hematopoietic and non-hematopoietic cells without surface markers, we took advantage of the gene vav 1, which is expressed solely on hematopoietic cells but not on other cell types, and established a novel transgenic mouse, in which hematopoietic cells are irreversibly labeled with green fluorescent protein (GFP) and non-hematopoietic cells with red fluorescent protein (RFP). Use of single-cell transcriptional analysis in this mouse model revealed two discrete types of collagen I (Col I) expressing cells of hematopoietic lineage recruited into excisional skin wounds. We confirmed this finding on a protein level, with one subset of these Col I synthesizing cells being CD45+ and CD11b+, consistent with the traditional definition of a fibrocyte, while another was CD45− and Cd11b−, representing a previously unidentified population. Both cell types were found to initially peak, then reduce post-healing, consistent with a disappearance from the wound site and not a loss of identifying surface marker expression. Taken together we have unambiguously identified two cells of hematopoietic origin that are recruited to the wound site and deposit collagen, definitively confirming the existence and natural time-course of fibrocytes in cutaneous healing.
doi:10.1002/stem.1648
PMCID: PMC4096488  PMID: 24446236
Fibrocytes; wound healing; hematopoietic cells; surface markers; collagen
4.  Physiological ER Stress Mediates the Differentiation of Fibroblasts 
PLoS ONE  2015;10(4):e0123578.
Recently, accumulating reports have suggested the importance of endoplasmic reticulum (ER) stress signaling in the differentiation of several tissues and cells, including myoblasts and osteoblasts. Secretory cells are easily subjected to ER stress during maturation of their secreted proteins. Skin fibroblasts produce and release several proteins, such as collagens, matrix metalloproteinases (MMPs), the tissue inhibitors of metalloproteinases (TIMPs) and glycosaminoglycans (GAGs), and the production of these proteins is increased at wound sites. Differentiation of fibroblasts into myofibroblasts is one of the key factors for wound healing and that TGF-β can induce fibroblast differentiation into myofibroblasts, which express α-smooth muscle actin. Well-differentiated myofibroblasts show increased production of collagen and TGF-β, and bring about wound healing. In this study, we examined the effects of ER stress signaling on the differentiation of fibroblasts, which is required for wound healing, using constitutively ER stress-activated primary cultured fibroblasts. The cells expressed positive α-smooth muscle actin signals without TGF-β stimulation compared with control fibroblasts. Gel-contraction assays suggested that ER stress-treated primary fibroblasts caused stronger shrinkage of collagen gels than control cells. These results suggest that ER stress signaling could accelerate the differentiation of fibroblasts to myofibroblasts at injured sites. The present findings may provide important insights for developing therapies to improve wound healing.
doi:10.1371/journal.pone.0123578
PMCID: PMC4416017  PMID: 25928708
6.  Comparison of FSH and hMG on ovarian stimulation outcome with a GnRH antagonist protocol in younger and advanced reproductive age women 
Purpose
To compare the embryo outcomes of in vitro fertilization/intra-cytoplasmic sperm injection with a gonadotropin-releasing hormone (GnRH) antagonist protocol with follicle stimulating hormone (FSH) and with human menopausal gonadotropin (hMG).
Methods
We performed a retrospective cohort study in 465 patients. Stimulation was started by daily FSH injection, and either FSH was continued (FSH alone group) or hMG was administrated (FSH-hMG group) after administration of a GnRH antagonist. Primary outcomes were the embryo profile (number of retrieved, mature, and fertilized eggs, and morphologically good embryos on day 3) and endocrine profile. Secondary outcomes were the doses and durations of gonadotropin. Data were stratified by the patients’ age into two groups: <35 years and ≥35 years.
Results
In patients aged <35 years, the number of retrieved oocytes in the FSH alone group was significantly increased than that in the FSH-hMG group (13.7 vs 9.2, P = 0.04), while there was no difference at other age groups. The FSH-hMG group required a significantly greater amount of gonadotropins at any age (all ages, P < 0.001; <35 years, P = 0.013; ≥35 years, P < 0.001).
Conclusions
Exogenous FSH alone is probably sufficient for follicular development and hMG may not improve the embryo profile in a GnRH antagonist protocol across all age.
doi:10.1007/s12522-014-0186-0
PMCID: PMC4300428  PMID: 25620883
Embryo profile; Endocrine profile; FSH; GnRH Antagonist; hMG
7.  Infrared venography of the hand in Apert syndrome 
As well as craniofacial synostosis, complex syndactyly of hands is a distinctive feature of Apert syndrome. Consideration of blood flow to the digits is very important in separation surgery. Several reports offer information about arterial distribution in Apert's hands. Though, venous pattern has not been well discussed. Infrared venography offers a real-time image with minimal invasion. An Apert syndrome patient underwent a series of finger splitting surgeries. Infrared venography was carried out to assess veins. There was a palmar venous arch, placing distally to the metacarpophalangeal joint. The arch had to be cut to divide fused fingers sufficiently. As well as arterial abnormality, venous uniqueness should be noted in Apert syndactyly surgeries. Infrared venography, which can be carried out easily, offers good information that surgeon require.
doi:10.4103/0970-0358.122027
PMCID: PMC3897110  PMID: 24459355
Anomaly; Apert syndrome; hand; infrared; syndactyly; vein
8.  Comparative Study of Antibacterial Effects and Bacterial Retentivity of Wound Dressings 
Eplasty  2013;13:e5.
Objectives: We are often confused on selecting a suitable wound dressing for the treatment of infected wounds from huge number of available wound dressings. Then, to help clinicians easily select a wound dressing, we compared the antibacterial effects and bacterial retentivity (ie, potency of keeping absorbed bacteria inside wound dressings and preventing them from leaking out) of wound dressings. Methods: Five wound dressings with antibacterial constituents were compared to research antibacterial effects against nonpathogenic Escherichia coli using an in vitro model. The 5 other wound dressings with no antibacterial constituent were compared to research bacterial retentivity. The relative amount of E coli was determined using cell proliferation reagent WST-1 (11644807001, Roche Applied Science, United States) with time. Results: The results have shown that the antibacterial effects and bacterial retentivity differed among various wound dressings. Silver ions quickly exerted a very strong antibacterial effect, and hydrofibers had a high potency of bacterial retentivity by gelling the absorbed bacteria in wound dressings. Conclusions: The present study indicated the differences of antibacterial strength, time of onset and duration of the antibacterial effect, and bacterial retentivity between each wound dressing. Clinicians should use appropriate wound dressings according the wound condition in consideration of the different characteristics of wound dressings. The present results are helpful for clinicians to select appropriate wound dressing.
PMCID: PMC3556601  PMID: 23372860
9.  Supplementation of bone marrow aspirate-derived platelet-rich plasma for treating radiation-induced ulcer after cardiac fluoroscopic procedures: A preliminary report 
Background:
The frequency of encountering radiodermatitis caused by X-ray fluoroscopic procedures for ischaemic heart disease is increasing. In severe cases, devastating ulcers with pain, for which conservative therapy is ineffective, emerge. Radiation-induced ulcers are notorious for being difficult to treat. Simple skin grafting often fails because of the poor state of the wound bed. A vascularized flap is a very good option. However, the non-adherence of the well-vascularized flap with the irradiated wound bed is frequently experienced.
Aim:
To ameliorate the irradiated wound bed, bone marrow-derived platelet-rich plasma (bm-PRP) was delivered during the surgery.
Materials and Methods:
Four patients with severe cutaneous radiation injury accompanied by unbearable pain after multiple fluoroscopic procedures for ischaemic heart disease were treated. Wide excision of the lesion and coverage with a skin flap supplemented with bm-PRP injection was performed.
Results:
All patients obtained wound closure and were relieved from pain. No complication concerning the bone marrow aspiration and delivery of bm-PRP was observed.
Conclusions:
Supplementation of bm-PRP can be an option without major complications, time, and cost to improve the surgical outcome for irradiated wounds.
doi:10.4103/0970-0358.96599
PMCID: PMC3385373  PMID: 22754164
Bone marrow; cardiac fluoroscopy; platelet-rich plasma; radiation ulcer; skin flap
10.  bFGF Regulates PI3-Kinase-Rac1-JNK Pathway and Promotes Fibroblast Migration in Wound Healing 
PLoS ONE  2010;5(8):e12228.
Fibroblast proliferation and migration play important roles in wound healing. bFGF is known to promote both fibroblast proliferation and migration during the process of wound healing. However, the signal transduction of bFGF-induced fibroblast migration is still unclear, because bFGF can affect both proliferation and migration. Herein, we investigated the effect of bFGF on fibroblast migration regardless of its effect on fibroblast proliferation. We noticed involvement of the small GTPases of the Rho family, PI3-kinase, and JNK. bFGF activated RhoA, Rac1, PI3-kinase, and JNK in cultured fibroblasts. Inhibition of RhoA did not block bFGF-induced fibroblast migration, whereas inhibition of Rac1, PI3-kinase, or JNK blocked the fibroblast migration significantly. PI3-kinase-inhibited cells down-regulated the activities of Rac1 and JNK, and Rac1-inhibited cells down-regulated JNK activity, suggesting that PI3-kinase is upstream of Rac1 and that JNK is downstream of Rac1. Thus, we concluded that PI3-kinase, Rac1, and JNK were essential for bFGF-induced fibroblast migration, which is a novel pathway of bFGF-induced cell migration.
doi:10.1371/journal.pone.0012228
PMCID: PMC2923192  PMID: 20808927
11.  Human Chorionic Gonadotropin Combined with Progesterone for Luteal Support Improves Pregnancy Rate in Patients with Low Late-Midluteal Estradiol Levels in IVF Cycles 
Purpose: To investigate how late-midluteal estradiol levels relate to the pregnancy outcome in IVF cycles, and to assess whether human chorionic gonadotropin (hCG) for luteal support benefits the pregnancy outcome of patients with low late-midluteal estradiol levels.
Methods: The pregnancy rate of 436 women undergoing first IVF cycles with long protocol and luteal support with progesterone alone were analyzed. Unsuccessful women with low late-midluteal estradiol levels (<100 pg/mL) proceeded with the exploratory second IVF cycles where they were randomly given with either progesterone alone (P protocol) or hCG +progesterone (P+hCG protocol) for luteal support.
Results: Pregnancy rate in women with low late-midluteal estradiol levels was significantly lower compared to that with medium (100–500 pg/mL) and high (>500 pg/mL) levels (13.3, 26.8, and 36.3%, respectively). P+hCG protocol increased late-midluteal estradiol levels and produced a significantly higher pregnancy rate (31.7%) than P protocol (13.7%).
Conclusions: hCG in combination with progesterone for luteal support was suggested to benefit women undergoing IVF with low late-midluteal estradiol levels.
doi:10.1023/A:1021207014429
PMCID: PMC3455835  PMID: 12503886
Estradiol; hCG; IVF-ET; luteal support; progesterone

Results 1-11 (11)