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Percutaneous and transconjunctival approaches are commonly used for fractures of the orbit and orbital rim. However, it leaves visible scarring on the face. Although previous studies reported scarring from the percutaneous approach, few reported the degree of such scarring. The authors examined the degree of scarring associated with percutaneous approaches to fractures of the orbit and orbital rim in the Japanese population. The authors reviewed photographs of patients who were treated surgically for fractures of the orbital floor, medial orbital wall, or zygomatic bone via percutaneous approaches to examine the presence of scarring and deformation. In 36% of all patients, the observers were unable to determine the side on which the surgery was performed. Furthermore, the site of scarring was identified accurately in only 20.6% of the cases in which observers were able to identify the surgical side. The authors’ study demonstrated that the subciliary approach left minimal scarring under the eyelashes. On the other hand, the medial canthal approach left depressed and wide scarring, whereas pigmentation was apparent in patients who underwent surgery via the lateral eyebrow approach. Similarly, pigmentation under the eyelashes and at the site of secondary incision was common after the subciliary approach., Journal of Craniofacial Surgery, 33 (4), pp. 1143-1146; 2022

Epistaxis after Le Fort I osteotomy is one of the relatively common postoperative complications. It can be controlled with conservative treatment, such as nasal packing, and will usually improve in a few days. However, if the epistaxis is repeated, the outcome can be life-threatening. A 22-year-old woman underwent Le Fort I osteotomy in order to correct her malocclusion. Postoperatively, pseudoaneurysm was formed in the descending palate artery, causing repeated epistaxis. Then, angiography and embolization were performed. Before the onset of epistaxis, there was discomfort around the nasal area. The patient remained asymptomatic during the 6-month follow-up. Some epistaxis after Le Fort I osteotomy is due to pseudoaneurysm formation in the maxillary artery. It is very rare. The epistaxis is delayed and recurrent. It can cause massive bleeding, and so, requires proper diagnosis and treatment. There may be signs of bleeding as in this case.

Lipodystrophy is a common complication in human immunodeficiency virus (HIV)-infected patients receiving highly active antiretroviral therapy (HAART) or antiretroviral therapy (ART). Previous studies demonstrated that endoplasmic reticulum (ER) stress-mediated unfolded protein response (UPR) is involved in lipodystrophy; however, the detailed mechanism has not been fully described in human adipogenic cell lineage. We utilized adipose tissue-derived stem cells (ADSCs) obtained from human subcutaneous adipose tissue, and atazanavir (ATV), a protease inhibitor (PI), was administered to ADSCs and ADSCs undergoing adipogenic conversion. Marked repression of adipogenic differentiation was observed when ATV was administered during 10 days of ADSC culture in adipogenic differentiation medium. Although ATV had no effect on ADSCs, it significantly induced apoptosis in differentiating adipocytes. ATV treatment also caused the punctate appearance of CCAAT-enhancer-binding (C/EBP) protein homologous protein (CHOP), and altered expression of CHOP and GRP78/Bip, which are the representation of ER stress, only in differentiating adipocytes. Administration of UPR inhibitors restored adipogenic differentiation, indicating that ER stress-mediated UPR was induced in differentiating adipocytes in the presence of ATV. We also observed autophagy, which was potentiated in differentiating adipocytes by ATV treatment. Thus, adipogenic cell atrophy leads to ATV-induced lipodystrophy, which is mediated by ER stress-mediated UPR and accelerated autophagy, both of which would cause adipogenic apoptosis. As our study demonstrated for the first time that ADSCs are unsusceptible to ATV and its deleterious effects are limited to the differentiating adipocytes, responsible target(s) for ATV-induced lipodystrophy may be protease(s) processing adipogenesis-specific protein(s)., International Journal of Molecular Sciences, 22(4), art.no.2114; 2021

MicroRNAs (miRNAs) are small noncoding RNAs that regulate protein translation by binding to complementary target mRNAs. We previously identified two mature members of the miR-142 family, miR-142-5p and miR-142-3p, as inflammation-related miRNAs with potential roles in wound healing. Here, we demonstrated that these two miRNAs are prominently expressed in wound-infiltrated neutrophils and macrophages and play central roles in wound healing. We generated miR-142−/− mice using the exchangeable gene-trap method and showed that healing of Staphylococcus aureus-infected skin wounds was significantly delayed in miR-142−/− mice compared with that in wild-type mice. MiR-142−/− mice exhibited abnormal abscess formation at S. aureus-infected skin wound sites and were also more susceptible to horizontal transmission of wound infections. MiR-142−/− neutrophils showed altered phagocytosis as a consequence of chemotactic behavior, including enhanced F-actin assembly, disturbed cell polarity, and increased cell motility. We showed that these changes were linked to cytoskeletal regulation, and that expression of the small GTPases was markedly increased in miR-142−/− neutrophils. Collectively, our data demonstrate that the miR-142 family is indispensable for protection against S. aureus infection and its clearance at wound sites. MiR-142-3p and miR-142-5p play nonredundant roles in actin cytoskeleton regulation by controlling small GTPase translation in neutrophils at wound sites.

Vascular malformations can mimic malignant tumors, and the coexistence of both types of lesions can limit and interfere with treatment. A consecutive series of vascular malformations that were treated and evaluated in a single institute and cases involving vascular anomalies combined with malignancies or malignancies that were treated as vascular anomalies were analyzed.Absolute ethanol is used in the treatment and management of vascular malformations and is sometimes administered before a definitive diagnosis has been obtained, despite the fact that some vascular lesions are subsequently revealed to be malignant tumors. This study discusses such cases.From January 2006 to August 2012, 139 patients were treated for vascular malformations at Nagasaki University Hospital and were followed up for a minimum of 1 year.Four malignant lesions coexisted with or were misdiagnosed as vascular malformations, including a malignant peripheral nerve sheath tumor located in the chest, a hemangiopericytoma of the palate, an adenoid cystic carcinoma of the cheek, and a squamous cell carcinoma of the cheek. Thus, malignant lesions were detected in 2.88% of cases in which vascular malformations were preoperatively diagnosed.When treating vascular malformations, it is advisable to be aware of the possibility of malignancy.

The forkhead box O (FOXO) family has been extensively investigated in aging and metabolism, but its role in tissue-repair processes remains largely unknown. Herein, we clarify the molecular aspect of the FOXO family in skin wound healing. We demonstrated that Foxo1 and Foxo3a were both up-regulated during murine skin wound healing. Partial knockout of Foxo1 in Foxo1 +/- mice throughout the body led to accelerated skin wound healing with enhanced keratinocyte migration, reduced granulation tissue formation, and decreased collagen density, accompanied by an attenuated inflammatory response, but we observed no wound phenotype in Foxo3a-/- mice. Fibroblast growth factor 2, adiponectin, and notch1 genes were significantly increased at wound sites in Foxo1+/- mice, along with markedly altered extracellular signal-regulated kinase 1/2 and AKT phosphorylation. Similarly, transient knockdown of Foxo1 at the wound site by local delivery of antisense oligodeoxynucleotides enhanced skin wound healing. The link between FOXO1 and scarring extends to patients, in particular keloid scars, where we see FOXO1 expression markedly increased in fibroblasts and inflammatory cells within the otherwise normal dermis. This occurs in the immediate vicinity of the keloid by comparison to the center of the mature keloid, indicating that FOXO1 is associated with the overgrowth of this fibrotic response into adjacent normal skin. Overall, our data indicate that molecular targeting of FOXO1 may improve the quality of healing and reduce pathological scarring., The American Journal of Pathology, 184(9), pp.2465-2479; 2014

Donor-site wound healing was tested with a nonadherent petrolatum- and hydrocolloid-impregnated polyester, a lipid-colloid dressing, and a nonadherent polyester dressing, supplemented with petrolatum manually by a physician onsite. Ten patients, 1 woman and 9 men (22 to 79 years old; average 58.4 ± 17.54 years), were enrolled in this prospective comparison study. The split-thickness skin graft was 14.5 ± 7.49 cm long × 8.2 ± 4.07 cm wide (5.5-27 cm long and 4.0-14.0 wide) and 14/1000 inches (0.356 mm) deep. The degree of reepithelialization in lipid-colloid dressing was significantly better than that in polyester mesh dressing, with 1.7 ± 1.00 and 2.8 ± 0.83 for the lipid-colloid dressing and polyester mesh dressing, respectively ( P < .05), and degree of pain was significantly lower in lipid-colloid dressing than that in polyester dressing, 1.7 ± 1.11 and 2.9 ± 1.12 for the lipid-colloid dressing and polyester mesh dressing, respectively ( P < .01). In moisture meter analyses, the values of effective contact coefficient and corneal thickness in lipid-colloid at wound healing was significantly smaller than those in polyester mesh (effective contact coefficient: 11.7 ± 1.87% and 15.6 ± 3.09% for lipid-colloid and polyester mesh, respectively, P < .05; corneal thickness: 31.1 ± 6.65 µm and 40.7 ± 8.69 µm for lipid-colloid and polyester mesh, respectively, P < .05). No significant difference was observed at 1 month after healing. The nonadherent lipid-colloid polyester dressing has superior wound healing and pain relief and demonstrates better corneal barrier function delineated by effective contact coefficient and corneal thickness at healing in split-thickness donors.

A paradigm shift in plastic and reconstructive surgery is brought about the usage of cell-based therapies for wound healing and regeneration. Considering the imitations in the reconstructive surgeries in restoring tissue loss and deficiency, stem cell-based therapy, in particular, has been expected to pave the way for a new solution to the regenerative approaches. Limitations in the reconstructive surgeries in restoring tissue loss and deficiency have paved the way for new regenerative approaches. Among them, adipose-derived stem/progenitor cells (ADSCs)-based therapy could be the most promising clue, since ADSCs have pluripotent differentiation capabilities not only in adipocytes but also in a variety of cell types. Accumulating evidences have indicated that the unfavorable development of adipose-tissue damage, namely, lipodystrophy, is a systemic complication, which is closely related to metabolic abnormality. Considering ADSC-based regenerative medicine should be applied for the treatment of lipodystrophy, it is inevitable to ascertain whether the ADSCs obtained from the patients with lipodystrophy are capable of being used. It will be very promising and realistic if this concept is applied to lipoatrophy, one form of lipodystrophies that deteriorates the patients&rsquo, quality of life because of excessive loss of soft tissue in the exposed areas such as face and extremities. Since lipodystrophy is frequently observed in the human immunodeficiency virus (HIV)-infected patients receiving highly active antiretroviral therapy (HAART), the present study aims to examine the biological potentials of ADSCs isolated from the HIV-infected patients with lipodystrophy associated with the HAART treatment. Growth properties, adipogenic differentiation, and mitochondrial reactive oxygen species (ROS) production were examined in ADSCs from HIV-infected and HIV-uninfected patients. Our results clearly demonstrated that ADSCs from both patients showed indistinguishable growth properties and potentials for adipocyte differentiation in vitro. Thus, although the number of cases were limited, ADSCs isolated from the patients with lipodystrophy retain sufficient physiological and biological activity for the reconstitution of adipose-tissue, suggesting that ADSCs from the patients with lipodystrophy could be used for autologous ADSC-based regenerative therapy.

Vascular anomalies comprise vascular tumours and vascular malformations. Some vascular anomalies result in ulcerations and necrosis. In vascular tumours, infantile haemangiomas are predominant and ulceration is demonstrated in up to 16%. In vascular malformations, arteriovenous malformations predominate and frequently demonstrate either primary ulceration or skin necrosis after diagnostic and therapeutic procedures. Various diagnostic and therapeutic imaging methods, such as X-ray, computed tomography (CT), magnetic resonance imaging (MRI), duplex Doppler ultrasound, and angiography, are used to visualize vascular anomalies; angiograms are required when embolization is attempted and blood flow needs to be further investigated. Duplex Doppler ultrasound is useful for routine check-ups as a therapeutic tool; however, it has limited in precision and accuracy. The aim of the present review is to give an overview of wounds related to vascular anomalies, detailing the diagnostic imaging and treatment options.

The efficacy of one-stage artificial dermis and skin grafting was tested in a nude rat model. Reconstruction with artificial dermis is usually a two-stage procedure with 2- to 3-week intermission. If one-stage use of artificial dermis and split-thickness skin grafting are effective, the overall burden on patients and the medical cost will markedly decrease. The graft take rate, contraction rate, tissue elasticity, histology, morphometric analysis of the dermal thickness, fibroblast counting, immunohistochemistry of α-smooth muscle actin, matrix metalloproteinase-2, CD31, and F4/80, as well as gelatin zymography, real-time reverse transcriptase polymerase chain reaction for matrix metalloproteinase-2, and electron microscopy, were investigated from day 3 to 3 months postoperatively. The graft take rate was good overall in one-stage artificial dermis and skin grafting groups up to 3 weeks, and the contraction rate was greater in the two-staged artificial dermis and skin grafting group than in the skin grafting alone or one stage of artificial dermis and skin grafting groups. Split-thickness skin grafting with artificial dermis and basic fibroblast growth factor at a concentration of 1 μg/cm2 showed significantly greater elasticity by Cutometer, and the dermal thickness was significantly thinner, fibroblast counting was significantly greater, and the α-smooth muscle actin expression level was more notable with a more mature blood supply in the dermis and more organized dermal fibrils by electron microscopy at 3 weeks. Thus, one-stage artificial dermis and split-thickness skin grafting with basic fibroblast growth factor show a high graft take rate and better tissue elasticity determined by Cutometer analysis, maturity of the dermis, and increased fibroblast number and blood supply compared to a standard two-stage reconstruction.

A solitary fibrous tumor is a neoplasm generally arising from the mesothelial surfaces of the pleura and mesothelium. In this paper, we describe three cases of rare solitary fibrous tumors arising from the orbit and discuss the management of the tumors, including diagnosis and treatment. All three cases were treated by surgical resection and showed satisfactory aesthetic and functional results. For a definitive diagnosis, immunohistochemical staining for proteins such as vimentin, CD34 and bcl-2 and hematoxylin and eosin (H&E) staining for identifying the morphological characteristics of spindle cell tumors with a partially storiform pattern and staghorn vessels are indispensable. The principle of treatment for orbital solitary fibrous tumor is complete resection because the prognosis depends on controlling tumor progression, which can be difficult with chemotherapy and radiotherapy alone.

Treatment of critical limb ischemia is sometimes difficult because of the patient's condition, and some novel approaches are needed.The hindlimbs of Sprague-Dawley rats, after 20-Gy x-ray irradiation and surgical occlusion, were divided into four groups: with a superficial fascial flap, 5.0 × 10 adipose-derived stromal/stem cells, and both combined. The rats were tested for laser tissue blood flow, immunohistologic blood vessel density, and foot paw punch hole wound healing. Green fluorescent protein-tagged Sprague-Dawley rats were used for further investigation by cell tracking for 2 weeks.Laser tissue blood flow demonstrated a significant increase in the combined treatment of flap and adipose-derived stem cells at both 1 and 2 weeks. There were no significant differences between the treatment groups treated with flaps alone and those treated with adipose-derived stem cells alone. Wound healing was significantly increased following combined treatment at 1 week, and there was no wound by 2 weeks except for the no-flap and no-adipose-derived stem cell group. The number of vessels depicted by von Willebrand factor showed a significant increase in the combined treatment group, at both 1 week and 2 weeks. In the cell tracking group, at 2 weeks, the green fluorescent protein-tagged adipose-derived stem cells were significantly more positive in the no-flap group than in the flap group.Adipose-derived stem cells may be a potent cell source in irradiated and occluded limbs by enhancing tissue blood flow and blood vessel density. Adipose-derived stem cells may play an important role in some difficult ischemic conditions in terms of wound healing.

Postnatally, scars occur as a consequence of cutaneous wound healing. Scarless wound healing is highly desired for patients who have undergone surgery or trauma, especially to exposed areas. Based on the properties of mesenchymal stem cells (MSCs) for tissue repair and immunomodulation, we investigated the potential of MSCs for scarless wound healing. MSCs were expanded from umbilical cord blood (UCB-MSCs) and Wharton’s jelly (WJ-MSCs) from healthy donors who underwent elective full-term pregnancy caesarean sections. UCB-MSCs expressed lower levels of the pre-inflammatory cytokines IL1A and IL1B, but higher levels of the extracellular matrix (ECM)-degradation enzymes MMP1 and PLAU compared with WJ-MSCs, suggesting that UCB-MSCs were more likely to favor scarless wound healing. However, we failed to find significant benefits for stem cell therapy in improving wound healing and reducing collagen deposition following the direct injection of 1.0 × 105 UCB-MSCs and WJ-MSCs into 5 mm full-thickness skin defect sites in nude mice. Interestingly, the implantation of UCB-MSCs tended to increase the expression of MMP2 and PLAU, two proteases involved in degradation of the extracellular matrix in the wound tissues. Based on our data, UCB-MSCs are more likely to be a favorable potential stem cell source for scarless wound healing, although a better experimental model is required for confirmation.

IgG4-related disease is an emerging disease entity characterized by elevated serum IgG4 concentration and tumefaction or tissue infiltration by IgG4-positive plasma cells. In IgG4-related disease, tumor-like lesions develop in multiple organs, such as the lacrimal gland, salivary gland, lung, pancreas, kidney, and lymph nodes. We report here three cases of IgG4-related orbital inflammation that presented as unilateral pseudotumors. The patients all were men, with an age range of 65–75 years. The patients had been pointed out unilateral intra-orbital masses, and histopathological examinations revealed marked accumulation of IgG4-positive plasma cells (IgG4/IgG ratio: 51.1–71.6 %) with fibrosis. But storiform fibrosis was seen in only one case, and no obliterative phlebitis was seen. The serum levels of IgG4 were increased to 178–670 mg/dL. The masses had well-defined homogeneous signal intensities, and they were hypo-intense on T1-weighted MR images and iso-intense on T2-weighted MR images. Gadolinium enhanced mass lesions in two cases. All orbital mass lesions responded well to corticosteroid treatment.

Objective Recent genome-wide association studies identified susceptibility loci for nonsyndromic cleft lip with or without cleft palate (NSCL±P) on 8q24.21, 10q25.3, 13q31.1, 15q13.3, 17q22, and 18q22 in populations of European origin. The purpose of this study was to determine, using DNA samples, whether 8q24.21 was a susceptibility locus for the development of NSCL±P in Japanese patients. Methods We used DNA from 167 Japanese NSCL±P patients (45 cleft lip without cleft palate and 122 cleft lip with cleft palate patients) and 190 Japanese unaffected control individuals. We performed an association study using 13 single nucleotide polymorphisms (SNPs) selected on the 8q24.21 locus. Genotyping of each SNP was carried out by direct sequencing of genomic DNA. Additionally, a haplotype block was constructed using the selected SNPs. Results The 13 selected SNPs were successfully genotyped in 357 individuals. The p values obtained were not low enough to indicate a significant association between the haplotypes and the development of NSCL±P in this population. Conclusions Our results suggest that the 8q24.21 locus is not associated with susceptibility to NSCL±P in Japanese patients and provide further evidence that ethnicity is a strong factor in determining susceptibility loci, albeit using a limited number of samples. Further studies are needed to identify regions involved in the development of NSCL±P in the Japanese population.

This review provides a thorough and clear discussion on the outcomes of stem cells in treating chronic wounds. With recent technological developments that now allow isolation and culture of stem cells, researchers are able to perform vigorous studies on somatic or adult stem cells. Human and animal stem cell studies are discussed with a focus on the basic process of stem cells in wound healing and the authors' first-hand clinical experience with stem cells used for chronic wound healing., Clinics in Plastic Surgery, 39(3), pp.281-292; 2012

Keloids are a fibroproliferative disease due to abnormal wound healing process after skin injury. They are characterized by overproduction of extracellular matrix (ECM) such as collagens. MicroRNAs (miRNAs) are noncoding small RNAs and negatively regulate protein expression. Several miRNAs that have critical roles in tissue fibrosis and ECM metabolism have been reported. However, regulation and function of miRNAs in keloid remain to be explored. The purpose of this study was to identify miRNAs involved in keloid pathogenesis. We performed miRNA microarray analysis to compare miRNA expression profiles between keloid-derived fibroblasts (KFs) and normal fibroblasts (NFs). In all, 7 upregulated and 20 downregulated miRNAs were identified. Among these, we focused on miR-196a, which showed the highest fold change. Overexpression or knockdown of miR-196a led to a decreased or increased level of secreted type I/III collagens, respectively. Reporter analysis showed direct binding of miR-196a to the 3′ untranslated region (UTR) of COL1A1 and COL3A1. In conclusion, we demonstrate for the first time that miRNA expression profile is altered in KFs compared with NFs. Downregulation of miR-196a may be one of the mechanisms by which collagens are highly deposited in keloid tissues. Our findings suggest that miR-196a could be a new therapeutic target for keloid lesions., Journal of Investigative Dermatology, 132(6), pp.1597-1604; 2012

A high dose of ionizing external radiation damage to the skin and soft tissue results in changes in function as well as in the general body condition. Once radiation surpasses the tissue safety or survival level, progressive alteration in the damaged tissue results in tissue loss and then flap loss. Local expression and action of stem cells or local growth factors in the irradiated tissue is mitigated, and external administration is sought to investigate the possibility of skin and soft tissue survival after an elevating flap. Basic fibroblast growth factor (bFGF) is primarily considered as a potent angiogenic growth factor. In burns, resurfacing with a dermal component is required, and bFGF stimulates wound healing and enhances human skin-derived mesenchymal stem cells under serum-free conditions in a dose-dependent manner. Thirty-five male, 4- to 8-week-old CLAWN miniature pigs received radiation exposure to assess the effectiveness of bFGF in terms of the progressive clinical course relevant to human skin and soft tissue. At 2 weeks following 10-Gy irradiation, tissue was preserved in the group receiving subcutaneous placement of a round-type tissue expander and bFGF. The expander plus bFGF group demonstrated significantly greater dermo-epidermal proliferation than the radiation alone, radiation plus bFGF, or expander plus radiation plus vehicle-solution groups, and new blood vessel formation was significantly increased in the expander tissue with bFGF after irradiation (p

Color changes of visible and exposed body surfaces, such as the face and extremities, after burn injury or surgery, such as skin grafting, flap, or sclerotherapy for vascular malformations, are sometimes a concern. The consequences reduce the satisfaction of both patients and physicians. An easy and reproducible method has not yet been established for an objective analysis of color changes; therefore, we tested a hand-held color analyzer (NF-333; Nippon Denshoku Co. Ltd) with data transport to a computer database and analysis software for posttreatment skin color change. The parameters included L, a, and b, which measure clarity, red, and yellow, respectively. Two groups were prospectively divided with 20 (11 females and nine males) patients per group. One group received skin grafting plus basic fibroblast growth factor (bFGF) spray daily and the other group received only skin grafting. The patients were randomized by the date of their first visit to our hospital. Patients were treated with bFGF on odd days, while patients who came on even days were included in the non-bFGF-treated group. The donor site for skin grafting was the lateral thighs and the thickness was similar in both groups. The results were compared at 1-year posttreatment follow-up. Clinical and objective assessments of the scars were performed 1 to years after complete healing. Color change differentials in comparison with the surrounding skin were lower with bFGF treatment in all parameters (p

Systemic and local radiation injuries caused by nuclear power reactor accidents, therapeutic irradiation, or nuclear terrorism should be prevented or properly treated in order to improve wound management and save lives. Currently, regenerative surgical modalities should be attempted with temporal artificial dermis impregnated and sprayed with a local angiogenic factor such as basic fibroblast growth factor, and secondary reconstruction can be a candidate for demarcation and saving the donor morbidity. Human mesenchymal stem cells and adipose-derived stem cells, together with angiogenic and mitogenic factor of basic fibroblast growth factor and an artificial dermis, were applied over the excised irradiated skin defect and were tested for differentiation and local stimulation effects in the radiation-exposed wounds. The perforator flap and artificial dermal template with growth factor were successful for reconstruction in patients who were suffering from complex underlying disease. Patients were uneventfully treated with minimal morbidities. In the experiments, the hMSCs are strongly proliferative even after 20 Gy irradiation in vitro. In vivo, 4 Gy rat whole body irradiation demonstrated that sustained marrow stromal (mesenchymal stem) cells survived in the bone marrow. Immediate artificial dermis application impregnated with cells and the cytokine over the 20 Gy irradiated skin and soft tissues demonstrated the significantly improved fat angiogenesis, architected dermal reconstitution, and less inflammatory epidermal recovery. Detailed understanding of underlying diseases and rational reconstructive procedures brings about good outcomes for difficult irradiated wound healing. Adipose-derived stem cells are also implicated in the limited local injuries for short cell harvesting and processing time in the same subject., Health Physics, 98(6), pp.858-862; 2010

BACKGROUND: The pathogenesis of keloid is poorly understood. Although vigorous investigations have attempted to elucidate the mechanisms or causative factors of keloid, there are little data on why keloids are very intractable and recur easily in each patient. METHODS: In an attempt to analyze the possible interaction between human mesenchymal stem cells and keloid-derived fibroblasts, the dual-chamber cell-migration assay, cell proliferation, ultrastructural morphology, and Western blot analysis were used to investigate the production of the extracellular matrices of the coculture. RESULTS: Cell proliferation was not significantly different between keloid-derived fibroblasts and normal dermal fibroblasts during a 4-day observation period. There was a significant cell migration of human mesenchymal stem cells when keloid-derived fibroblasts were placed in the bottom chamber, compared to when normal dermal fibroblasts were placed in the same way in 8-microm diameter pore membranes (190.6 +/- 51.45 and 32.0 +/- 6.20 cells/field, respectively, P < 0.01). With 3-microm diameter pores, the human mesenchymal stem cells migrated in the pores only when the keloid-derived fibroblasts were placed in the bottom chambers (6.4 +/- 3.84 cells/field). Monolayer coculture of human mesenchymal stem cells and keloid-derived fibroblasts demonstrated further functional differentiation, such as collagen secretion and abundant rough endoplasmic reticulum. Western blot analysis of the cells in the modified dual-chamber culture demonstrated most significantly abundant fibronectin expression when the human mesenchymal stem cells contained keloid fibroblasts. CONCLUSION: The results of this study may indicate that human mesenchymal stem cells participate and recruit in keloid pathogenesis by differentiating themselves toward keloid recalcitrant formation and progression., International Journal of Dermatology, 47(11), pp.1112-1117; 2008

Acute wounds caused by the severe and extensive infection such as alpha-hemolytic streptococci or MRSA may be life-threatening in immunocompromised hosts such as steroid users or those with venostasis in the lower legs. The principle of the treatment is the removal of the primary pathogens, however, difficulties of the lower leg reconstruction remain due to the tissue loss and the deficiency of the circulation system after extensive soft tissue debridement. For 10 immediately-developing extensive lower extremity cases, artificial skin substitutes composed of dried bilayer membranes of outer silicone membrane and inner porcine-tendon derived collagen layer (Pelnac®, Gunze Co., Ltd., Kyoto, Japan) were immediately after extensive and meticulous debridement. While the skin substitute integrated into the wound bed for maximally 3 weeks, total 20 micrograms of the basic fibroblast growth factors (bFGF)(Trafermin®, Kaken Pharmaceutical Co. Ltd, Tokyo, Japan) were applied by the 27-Gage syringe daily. The outer membranes were removed and thin partial thickness skin grafting (9–10/1,000 inches) was performed and wound healed uneventfully. The bFGF-treated skin texture was significantly softer compared to control by a durometer (Teclock®, GS-701N, Tokyo, Japan)(p

Hereditary congenital ptosis (PTOS) is defined as drooping of the upper eyelid without any other accompanying symptoms and distinguished from syndromic blepharoptosis.Two previous linkage analyses assigned a PTOS locus (PTOS1) to 1p32-p34.1 and another (PTOS2) to Xq24-q27.1. In addition, in a sporadic case with a balanced chromosomal translocation t(1;8)(p34.3;q21.12), the ZFHX4 (zinc finger homeodomain 4) gene was found to be disrupted at the 8q21.12 breakpoint, but there was no gene at the 1p34.3 breakpoint, suggesting the existence of the third PTOS locus (PTOS1) at 8q21.12. We carried out a genome-wide linkage analysis in a Japanese PTOS family and calculated two-point and multipoint LOD scores with reduced penetrance. Haplotype analysis gave three candidate disease-responsible regions, i.e., 8q21.11-q22.1, 12q24.32-q24.33 and 14q21.1-q23.2. Although the family size is too small to define one of them, 8q21.11-q22.1 is a likely candidate region, because it contains the previously reported translocation breakpoint above. We thus performed mutation, Southern-blot and methylation analyses of ZFHX4, but could not find any disease specific change in the family. Nevertheless, our data may support the localization of PTOS1., 長崎大学学位論文 学位記番号:博（医歯薬）甲第153号 博士（医学）学位授与年月日:平成20年3月19日, Journal of Human Genetics, 53(1), pp.34-41; 2008

Forward dislocation of the temporomandibular joint commonly can be easily diagnosed and successfully reduced by manual repositioning. In this report, we discuss a rare case of prolonged temporomandibular dislocation that had persisted for more than 20 years because the otolaryngologist and dentist had missed the dislocation. This patient underwent open reduction and mandibular joint plasty with preoperative orthodontic therapy. It is possible that strong pain and mouth-closing disability may gradually remit and only deviated mandibular prognathism like malocclusion may persist. Therefore, abnormal occlusion warrants careful attention to temporomandibular joint dislocation.

Various methods have been attempted for the treatment and management of keloids; however, there is little satisfactory clinical evidence in long-term follow ups. Also, there is a preference for occurrence and recurrence in anatomic location. Usually anatomic locations with higher regional tension and more sebaceous glands are inclined toward pathogenesis. Thirty-eight keloids treated with combined surgical excision and postoperative irradiation, using electron beams with only a 10-mm opening by lead shielding, were investigated at a mean follow up of 4.4 +/- 2.5 years (range, 1-9 years) at a single institute. Ten locations such as the ear (n = 6), neck (n = 3), and upper lip (n = 1) were among the craniofacial locations. The hardness of the keloids and posttreatment scars was clinically and objectively tested with the Vancouver scar scale and a durometer, which is often used for the industrial measurement of thread balls and rubber. At a mean of 4.4 +/- 2.5 years of follow up, the clinical characteristics of the scars were significantly better posttreatment as 2.6 +/- 0.5 versus 1.0 +/- 0.6, 3.7 +/- 0.7 versus 1.7 +/- 0.7, 2.9 +/- 0.4 versus 1.3 +/- 0.5, and 2.7 +/- 0.5 versus 1.3 +/- 0.5 (keloid scars versus posttreatment scars: pigmentation, pliability, height and vascularity, respectively, P < 0.01). The durometer readings were significantly lower posttreatment, 15.2 +/- 3.9 versus 7.7 +/- 2.9 (keloid scars versus posttreatment scars, P < 0.01). The recurrence rate was 21.2% overall with none in craniofacial locations. Therefore, the combined treatment of surgical excision and postoperative electron beam irradiation is effective for scar quality and reducing the recurrence rate in long-term follow up.

Skin and soft tissue radiation injuries are life-threatening as well as of esthetic concern in local tissues. As for local radiation injuries, clinically developed procedures such as local flaps and free vascularized flaps result in better and less-invasive reconstructive outcomes for victims of therapeutic radiation of malignant tumors, prolonged fluoroscopic procedures for cardiovascular diseases or possibly direct contact with radioactive waste, while systemic radiation injuries should find other solutions. In systemic radiation injuries, there is a good chance to save lives when the initial treatment is efficient, although donors of the skin grafting after debridement of the radiation-damaged tissue removal are unrealistically autogenous. Thus, exceeding certain extent and degree, systemic radiation injury-induced burns were not the medical objectives. Recent understanding and application of use in adult stem cells, however, create a new insight for severe systemic radiation injuries. Among the adult stem cells, the human mesenchymal stem cells are able to be freeze-dried, easily thawed and able to be cultured in vitro. A basic fibroblast growth factor is already of clinical use and efficient for the human mesenchymal stem cell growth both in vitro and in vivo. An artificial dermis is useful for temporal coverage of the raw surface of severe bedsores. The combined use of these successfully regenerates both dermis and epidermis after 20 Gy whole body irradiation in a nude rat model. Therefore, even severe radiation injuries, local tissue management and therapy are well-handled and systemic radiation injury may be hopeful with understanding and the specialized practice of regenerative medicine.

Aim: Secondary lymphedema is observed in common after postmalignancy treatment of the breast and the gynecologic organs but effective therapies are not established. Adipose-derived stem cells (ADSCs), which are pluripotent, regenerative in local injection, are tested for murine hindlimb secondary lymphedema by regenerative method. Methods & results: Mice were divided into four groups: no ADSCs, 1 × 106 ADSCs, 1 × 105 ADSCs and 1 × 104 ADSCs (each group, n = 20) in a stringent surgical resection and irradiation. Circumferential measurement, lymphatic flow assessment and quantification of lymphatic vessels were performed. Results: The numbers of lymphatic vessels by LYVE-1 immunohistochemistry, and VEGF-C- or VEGFR3-expressing cells were significantly increased in transplanted groups (p < 0.05). Conclusion: ADSCs can restore the lymphatic vascular network in secondary lymphedema with increased collecting vessels.

Even though the precise mechanisms related to venous malformation are still unclear, the clinical manifestations sometimes threaten vital signs such as mastication, airway and phonics. Our therapeutic modalities were reviewed, and their effectiveness and related complications were analyzed. Between March, 1998 and February, 2006, 11 patients (15-59 years old; average 32.4 +/- 13.60, 4 women and 7 men) with craniofacial venous malformation were included in this investigation. All cases experienced some kind of surgery at least once during clinical follow-up. Direct puncture scintigraphy with technetium-99m Sn colloid-labeled demonstrated low-flow malformations in all cases. Two cases underwent bone surgery and another two cases had static suspensions for facial nerve paralysis. Blood loss from surgery alone was 1352 +/- 1115.0 mL, simultaneous procedures yielded 400 +/- 244.9 mL blood loss and sclerotherapy alone resulted in 187 +/- 284.8 mL of blood loss (surgery alone versus sclerotherapy alone, P < 0.01). Excellent sclerotherapy cases were when the malformation was localized and the number of sclerotherapies was significantly fewer than good cases (1.3 +/- 0.58 times versus 3.6 +/- 1.15 times, excellent, good, respectively, P < 0.05). Although there are difficulties in understanding the mechanisms and multiple therapeutic interventions are required, there have been satisfactory outcomes so far and the development of better sclerosants or a real-time navigation system may benefit more precise therapeutic effects and lower morbidity.

Seven consecutive clinical cases of necrotising fasciitis or necrotic skin lesions (42-78 years old; average 65.0 years of age, three females and four males) due to group A Streptococcus, group B Streptococcus, methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa in the lower extremities, who demonstrated rapid systemic symptoms, were investigated for the usefulness of a bilayer artificial dermis, derived from porcine tendons, over 4 +/- 2.4 years (1-7 years). All surgical debridement was confirmed as sufficiently deep and wide for clinically infected lesions and artificial dermis was applied to all wounds. The average interval to secondary split-thickness skin grafting was about 17.5 days (17.5 +/- 2.44 days, 21 days max., 14 days min.) and the average thickness was 0.009 +/- 0.0022 in. (range: 0.006 - 0.012 in.). No clinical problems were noted during the application of the artificial dermis and the subsequent skin grafting. Since, the donated skin graft was thin, the morbidity was minimised. The use of artificial dermis after extensive surgical debridement in necrotising fasciitis was easy and effective. Local or systemic infection was negligible.

Although there are numerous investigations describing bone marrow cells or bone-marrow derived cells at the site of such injuries as bone fractures, infarction and subsequent ischemic reperfusion injury, or cutaneous wounds, little is know about the factors that affect the cells in those clinical situations. Cysteinyl leukotrienes have been extensively investigated in airway diseases that may eventually lead to lung fibrosis; while the engraftment of mesenchymal stem cells have been shown to reverse bleomycin-induced lung fibrosis in vivo. Therefore, we elucidated the involvement of cysteinyl leukotrienes in human mesenchymal stem cell proliferation and differentiation. Human mesenchymal stem cells express the cysteinyl leukotriene type 1 receptor. Various doses of pranlukast, which is a specific cysteinyl leukotriene type 1 receptor antagonist, failed to affect the proliferation of cells; however, 10(-6) M of pranlukast significantly induced cellular cytoplasmic differentiation by showing microvilli sprouting and the emersion of rough endoplasmic reticulum within a 16-hour(s) incubation. Additionally, pranlukast-induced fibronectin protein production by human mesenchymal stem cells. Therefore, attenuation of the cysteinyl leukotriene pathway contributes to human mesenchymal stem cell differentiation and may contribute to modulation of the local injury site.

Sleep apnea in craniofacial surgery was investigated. Between January 1999 and December 2003, 18 patients were measured at an at least 6-month interval before and after surgery. Eight patients underwent palatoplasty for cleft palate, and the other 10 patients underwent orthognathic surgery, syndromic craniosynostosis, and postpharyngeal flap surgery. All patients included in the study demonstrated clinical signs of obstructive sleep apnea, such as snoring and cessation of breathing during sleep. An apnomonitor was used for presurgical and postsurgical sleep apnea status by measuring: 1) position during sleep; 2) percutaneous oxygen saturation; 3) respiratory analysis, such as the type of apnea-hypopnea, frequency of the events, and duration of apnea-hypopnea; 4) heart rate; and 5) snore analysis, such as trains, time, mean, and minimal and maximal amplifications. The apnea-hypopnea index (AHI) was significantly improved after surgery, especially in cases other than palatoplasty (7.4 +/- 8.73/h and 1.6 +/- 0.43/h, before and after surgery, respectively; P0.05 excluding palatoplasty). The percentage of snoring to total sleep was also improved significantly (22.4 +/- 19.74% and 9.0 +/- 8.54%, before and after surgery, respectively; P0.01 in all patients). Therefore, changes in sleep apnea parameters were elucidated in craniofacial surgery. Palatoplasty did not necessarily worsen the sleep apnea status, although there were snoring and anatomic abnormalities. Detachment of the pharyngeal flaps improved sleep apnea, and bimaxillary advancement was effective in normalizing sleep apnea.

Background: Distraction osteogenesis has some advantages, such as less hazardous complications, less scarring, and fewer bone defects. However, it has not been fully accepted yet because of a unidirectional expansion along the distraction device. Because cranial expansion is limited by scalp tension and soft-tissue scarring, undercorrection of the cranium and relapse of the vault deformities have occasionally been seen on long-term follow-up. These patients also had so much bone defect that the donor bone was inadequate for immediate revisions, and dissection under the scalp was complicated. Methods: The authors used distraction osteogenesis to treat 12 cases of craniosynostosis. Five patients were syndromic (two cases of Pfeiffer's syndrome, two cases of Crouzon's disease, and one case of Apert's syndrome), and seven were nonsyndromic (four cases of brachycephaly, two cases of scaphocephaly, and one case of plagiocephaly). Results: After only unidirectional expansion without vertical reduction, the shape of the cranium was satisfactorily improved, which might have been an illusion caused by the relative reduction attributed to the elongation by the distraction osteogenesis and, in brachycephaly, alteration of the patient's head position resulting from inclination of the facial plane by forehead advancement. However, in scaphocephaly, the unique deformity in the occipital and frontal regions remained after simple distraction. Distraction osteogenesis should be applied for a narrow cranium because the bone defect and scalp closure could pose problems. Radical reshaping should be used in cases of sufficient donor bone and scalp closure. Although additional surgery is unavoidable for device removal, minor revisions can be performed for revision of the irregularity at that time. Conclusion: Except for prolonged treatment, based on minimally invasive operations, distraction cranioplasty might be applied extensively in cases of craniosynostosis.

Pediatric burns are frequently observed: twenty-year burn analysis was performed in a single department, and 354 cases, aged 0-6 years old. The major cause of pediatric burns was scalding (68%) and hot water comprised over half of the scald burns. At 1 year old and younger, the total burn surface area (TBSA) was significantly smaller than from 1 to 6 years old (4.8+/-9.56 versus 10.5+/-18.86%, respectively, p

To avoid hypertrophic scars in burn wounds, the simultaneous application of basic fibroblast growth factor (bFGF) with regular surgical debridement and skin grafting was investigated for skin hardness by clinical examination and instrumental measurement. As little is known about the role of bFGF in wounds, burn wound scars were tested for hardness. Burn scars in various anatomical locations at least 1 year after final wound healing clinically demonstrated a significantly lower hard score in bFGF-treated wounds than in non-bFGF wounds (0.95+/-0.51 versus 2.3+/-0.66, respectively, p

Restriction of the mouth opening from a pathologic condition outside the temporomandibular joint is called a pseudo- or extra-articular ankylosis. The authors report two cases of severe post-traumatic pseudoankylosis. One case showed fibrous degeneration of the bilateral masseter muscles without a facial bone fracture, which caused severe trismus, a mouth opening of less than 2 mm, and gradually appeared after blunt injuries to the face. The other was a rare case accompanied with the bone formation in the masseter muscle and was diagnosed as myositis ossificans traumatica, which also presented as severe trismus, with a maximal mouth opening of 5 mm after facial violence. Both were surgically treated with dissection of the affected muscles. In addition, a hemicoronoidotomy was performed in the case of myositis ossificans traumatica. Although a conservative therapy with physical rehabilitation is the basic policy for the management of pseudoankylosis of the temporomandibular joint, a surgical treatment should be considered when the origin of the problems is an osteogenic character or severe extra-articular ankylosis resistant to conservative therapy before completion of true temporomandibular joint ankylosis.

Objective To identify factors associated with relapse after maxillary advancement in cleft lip and palate patient. Subjects Seventy-one cleft lip and palate patients underwent Le Fort I maxillary advancement osteotomy between 1988 and 1998, and 58 patients (42 unilateral cleft and 16 bilateral cleft) with complete data were investigated for relapse by clinical and cephalometric analysis. The clinical follow-up period ranged from 1.5 to 8.5 years (mean 2.5 years). Results Horizontal advancement averaged 6.9 mm. There was a significant correlation between surgical movement and postoperative relapse in both the horizontal and vertical planes. In vertical repositioning, 15 patients had maxillary intrusion and 31 had inferior repositioning. There was a significant difference between the intrusion group and the inferior repositioning group. There was a significant correlation between surgical and postoperative rotation regardless of the direction. Other factors were evaluated by the horizontal relapse rate. Type of cleft and the rate of relapse were statistically associated. A relapse was more likely to occur in patients with bilateral cleft. There were no significant associations with the rate of relapse in type of operations or previous alveolar bone grafting. There was no significant correlation between the rate of relapse and the number of missing anterior teeth, postoperative overbite and overjet, and age at operation. Four of 71 patients experienced major relapse, and 3 of them underwent jaw surgery again. Conclusions Based on clinical and cephalometric analysis, two-jaw surgery should be performed in cases of severe maxillary hypoplasia, and overcorrection may be useful in inferior repositioning or surgical rotation. Special attention should be paid to the patient with bilateral cleft, multiple missing teeth, or shallow postoperative overbite.

Cleft of the soft palate (CSP) and the hard palate are subtypes of cleft palate. Patients with either condition often have difficulty with speech and swallowing. Nonsyndromic, cleft palate isolated has been reported to be associated with several genes, but to our knowledge, there have been no detailed genetic investigations of CSP. We performed a genome-wide linkage analysis using a single-nucleotide polymorphism-based microarray platform and successively using microsatellite markers in a family in which six members, across three successive generations, had CSP. A maximum LOD score of 2.408 was obtained at 2p24.2-24.1 and 2p21-p12, assuming autosomal dominant inheritance. Our results suggest that either of these regions is responsible for this type of CSP., Journal of Human Genetics, 55(2), pp.124-126; 2010

Keloids are benign dermal tumors, characterized by overgrowth of lesions, invasiveness beyond the original boundary of the insult, and recurrence of lesions. The exact etiology is unknown, however. Our hypothesis is that keloids are acquired as a result of an abnormal or prolonged wound healing process, with persistent proliferation and extracellular matrix production of fibroblasts that should otherwise discontinue in normal wound healing. In this study, we examined the response of keloid fibroblasts to proapoptotic signaling. Cell-permeable ceramide, N-acetyl-D-sphingosine, induced apoptosis of dermal fibroblasts in a dose- and time-dependent manner, which was detected by phase contrast microscopy, fluorescent microscopy, the TUNEL method, flow cytometric analysis, and WST-1 assay. In contrast, keloid fibroblasts resisted apoptosis induced by N-acetyl-D-sphingosine (percent survival with 40 mM ceramide treatment for 12 h, normal versus keloid: 9.6% +/- 6.6% vs 66.8% +/- 5.5%). Western blotting analysis showed insulin-like growth factor I receptor overexpression in keloid fibroblasts, but not in normal fibroblasts. Exogenously added insulin-like growth factor I enhanced the resistance of keloid fibroblasts to ceramide-induced apoptosis. Wort- mannin, a phosphatidylinositol 3 kinase inhibitor, suppressed the antiapoptotic action of insulin-like growth factor I in keloid fibroblasts. Our results suggest that keloid fibroblasts overexpressing insulin-like growth factor I receptor are resistant to apoptosis, thus allowing persistent proliferation and production of excessive extracellular matrix. J Invest Dermatol 115:1065-1071 2000

Congenital hemifacial hypertrophy is expressed in facial asymmetry resulting from unilateral overgrowth. We examined proliferative activity of primary cultured osteoblasts taken from the hemifacial hypertrophic side of an 18-year-old woman compared with the normal side. Both fetal calf serum and basic fibroblast growth factor stimulated osteoblast DNA synthesis, and cultured osteoblast proliferation was markedly increased in the hypertrophic side. Neutralizing antibody against basic fibroblast growth factor was effective to partially block fetal calf serum-induced DNA synthesis. These results suggest that fibroblast growth factor and its receptor signal transduction axis may be selectively involved in affected osteoblasts, leading to progression of congenital hemifacial hypertrophy.

The comparative study of neurosensory disturbance of the inferior alveolar nerve after bilateral sagittal split osteotomies was carried out. The 112 patients who underwent bilateral sagittal split osteotomies were divided into two groups: one group consisted of 62 patients (124 osteotomy sites) who received bicortical osteosynthesis using the lag screw principle (bicortical fixation group), and the other group consisted of 52 patients (104 osteotomy sites) who underwent monocortical osteosynthesis using miniplates (monocortical fixation group). The incidence of neurosensory disturbance of the inferior alveolar nerve as well as its recovery course was compared by patients' interview and Semmes-Weinstein pressure esthesiometer. Mean follow-up period was 12 months (minimum 3 months, maximum 36 months). The incidences of sensory disturbance of both groups were not significantly different at 2 weeks postoperatively. During the period 6 to 12 months postoperatively, the number of patients having light touch sensory disturbance was significantly less in the monocortical fixation group than in the bicortical fixation group. Moreover, the number of patients complaining of numbness during 6 to 18 months postoperatively was significantly less in the monocortical fixation group. These findings suggested that the monocortical osteosynthesis had less damage on the inferior alveolar nerve, leading to the better restoration of neurosensory disturbance in patients in whom the nerve damage was moderate.

A new approach to tumours in the infratemporal or pterygopalatine fossa is presented. Through a midline skin incision, one side of the face from the forehead to the neck is completely degloved. Zygomatic and mandibular osteotomies improve access. All mimic muscles and the facial nerve are included in the elevated flap. This approach provides a widely exposed field from the temporal fossa to the neck without damage to major vessels or nerves other than the supra- and infraorbital nerves. Direct access to tumours in the infratemporal or pterygopalatine fossa is facilitated, thus making tumour resection easier, safer and more reliable. Details of this approach are described.

Premature closure of cranial sutures has been known as one of the complications of juvenile or congenital hyperthyroidism. Thyroid hormone is an anabolic agent for bone formation in the early stages of childhood development. In children, excess thyroid hormone acts as an acceleration factor for the skeletal bone, whereas in adult hyperthyroidism, it causes bone mineral loss due to the high turnover rate of bone formation and consequently bone resorption. In addition, there are numerous literature descriptions concerning the interactions among bone metabolism, hormones, and growth factors, among which insulin-like growth factor I (IGF-I) is the most abundantly found growth factor in osteoblasts and in bone models in vivo. We therefore investigated whether or not the cranial sutures show accelerated closure and how the local growth factors or cytokines participate and function in local bone metabolism after administration of exogenous excess thyroid hormone in a rat model. A total of 60 female Wistar rats, aged 10 days, were divided into two groups, the triiodothyronine (T 3 )-treated group (n = 30, T 3 0.1 μg/gm of body weight per day) and the control group (n = 30, saline vehicle only), and were maintained and subsequently sacrificed at 15, 30, and 60 days. The parameters of cranial width derived from the morphologic measurements of the skull indicated that the lambda-asterion distance at 30 days and the pterion-bregma distance at 60 days in the T 3 -treated group were significantly decreased compared with those of the control group. Furthermore, the fluorescent histologic findings showed fluorescent labeling with no interruption along the suture edges, suggesting continuous bone formation, and displayed narrowing of the suture gap of the sagittal suture in the T 3 -treated group. Tartrate resistant acid phosphatase staining showed very little osteoclastic activity in the sagittal suture, especially in the T 3 -treated group. The intensity of immunohistochemical staining of IGF-I was markedly increased in the suture margins of the T 3 -treated group. There were no significant differences observed either in the skull base measurements or in the histologic and histochemical findings of the skull base or the coronal suture between the groups. More significantly, excess administration of thyroid hormone enhanced the cranial sagittal suture closure ; therefore, it was proposed that local IGF-I plays an important role in sagittal sutural bone formation.

A family with Saethre-Chotzen syndrome with or without polydactyly of the great toes is presented. Saethre-Chotzen syndrome with polydactyly of the great toes has been reported as Robinow-Sorauf syndrome. Both syndromes were observed in this family. This suggests that Saethre-Chotzen syndrome and Robinow-Sorauf syndrome fall within the same clinical spectrum, and the cause is a pleiotropic effect, which is variously expressed.