Akiyoshi Hirano

Malfunction of nuclease ERCC1-XPF results in diverse clinical manifestations and causes Cockayne syndrome, xeroderma pigmentosum, and Fanconi anemia.

Cockayne syndrome (CS) is a genetic disorder characterized by developmental abnormalities and photodermatosis resulting from the lack of transcription-coupled nucleotide excision repair, which is responsible for the removal of photodamage from actively transcribed genes. To date, all identified causative mutations for CS have been in the two known CS-associated genes, ERCC8 (CSA) and ERCC6 (CSB). For the rare combined xeroderma pigmentosum (XP) and CS phenotype, all identified mutations are in three of the XP-associated genes, ERCC3 (XPB), ERCC2 (XPD), and ERCC5 (XPG). In a previous report, we identified several CS cases who did not have mutations in any of these genes. In this paper, we describe three CS individuals deficient in ERCC1 or ERCC4 (XPF). Remarkably, one of these individuals with XP complementation group F (XP-F) had clinical features of three different DNA-repair disorders--CS, XP, and Fanconi anemia (FA). Our results, together with those from Bogliolo et al., who describe XPF alterations resulting in FA alone, indicate a multifunctional role for XPF.

Factors Related to Relapse After Le Fort I Maxillary Advancement Osteotomy in Patients With Cleft Lip and Palate

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.

Basic fibroblast growth factor accelerates and improves second-degree burn wound healing.

Second‐degree burns are sometimes a concern for shortening patient suffering time as well as the therapeutic choice. Thus, adult second‐degree burn patients (average 57.8 ± 13.9 years old), mainly with deep dermal burns, were included. Patients receiving topical basic fibroblast growth factor (bFGF) or no bFGF were compared for clinical scar extent, passive scar hardness and elasticity using a Cutometer, direct scar hardness using a durometer, and moisture analysis of the stratum corneum at 1 year after complete wound healing. There was significantly faster wound healing with bFGF, as early as 2.2 ± 0.9 days from the burn injury, compared with non‐bFGF use (12.0 ± 2.2 vs. 15.0 ± 2.7 days, p<0.01). Clinical evaluation of Vancouver scale scores showed significant differences between bFGF‐treated and non‐bFGF–treated scars (p<0.01). Both maximal scar extension and the ratio of scar retraction to maximal scar extension, elasticity, by Cutometer were significantly greater in bFGF‐treated scars than non‐bFGF–treated scars (0.23 ± 0.10 vs. 0.14 ± 0.06 mm, 0.59 ± 0.20 vs. 0.49 ± 0.15 mm: scar extension, scar elasticity, bFGF vs. non‐bFGF, p<0.01). The durometer reading was significantly lower in bFGF‐treated scars than in non‐bFGF–treated scars (16.2 ± 3.8 vs. 29.3 ± 5.1, p<0.01). Transepidermal water loss, water content, and corneal thickness were significantly less in bFGF‐treated than in non‐bFGF–treated scars (p<0.01).

Mesenchymal stem cell therapy for cutaneous radiation syndrome.

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.

The quality of pediatric burn scars is improved by early administration of basic fibroblast growth factor.

Pediatric burn wounds can be problematic because an accurate evaluation is difficult as the result of anatomically immature vasculature or immobilization failure, especially in patients with second-degree burns, and because the burn surface areas and the burn depth tend to worsen over the course of time. Delayed wound healing results in unsightly scarring, such as hypertrophic scars, which are problematic both esthetically and functionally. Among cytokines and growth factors, basic fibroblast growth factor (bFGF) is clinically proven, having demonstrated accelerated acute and chronic wound healing. Accelerated wound healing may lead to improved scarring. To elucidate the effects of bFGF on second-degree pediatric burn wounds, a comparative study was performed. A total of 20 pediatric patients ranging from 8 month to 3 years (average 1 year, 3 months ± 6 months) who suffered from the burns by various causes were divided into two groups, conventional (n = 10) and treatment with bFGF (n = 10). A moisture meter, used to objectively measure the stratum corneum and epithelial—mesenchymal functions, was used to assess scars at least 1 year after wound healing. Clinical evaluation of pigmentation, pliability, height, and vascularity demonstrated significant differences between conventional and bFGF-treated scars (1.7 ± 0.55 vs 0.7 ± 0.58, 2.4 ± 0.82 vs 1.1 ± 0.69, 1.8 ± 0.66 vs 0.5 ± 0.57, 1.9 ± 0.63 vs 0.8 ± 0.68; conventional vs bFGF-treated, pigmentation, pliability, height, and vascularity, respectively, P < .01). The effective contact coefficient was significantly greater in conventional wounds than bFGF-treated wounds (14.6 ± 1.68 % vs 8.7 ± 2.82 %; conventional vs bFGF, P < .01) and bFGF-treated wounds demonstrated significantly less transepidermal water loss values than conventional treatment (8.3 ± 1.90 g/m2/h vs 5.7 ± 1.85 g/m2/hr; conventional vs bFGF, P < .01). Pediatric burn patients treated with bFGF showed less damaging function of the stratum corneum after healing both in clinical assessment and moisture meter analysis.

Noncultured autologous adipose-derived stem cells therapy for chronic radiation injury.

Increasing concern on chronic radiation injuries should be treated properly for life-saving improvement of wound management and quality of life. Recently, regenerative surgical modalities should be attempted with the use of noncultured autologous adipose-derived stem cells (ADSCs) with temporal artificial dermis impregnated and sprayed with local angiogenic factor such as basic fibroblast growth factor, and secondary reconstruction can be a candidate for demarcation and saving the donor morbidity. Autologous 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 tested for Patients who were uneventfully healed with minimal donor-site morbidity, which lasts more than 1.5 years.

PAX9 and TGFB3 are linked to susceptibility to nonsyndromic cleft lip with or without cleft palate in the Japanese: population-based and family-based candidate gene analyses

AbstractThe prevalence of nonsyndromic cleft lip with or without cleft palate (CL/P) and cleft palate only (CPO) are believed to be higher in the Japanese than in Americans, Europeans or Africans. The purpose of this study was to investigate, in a Japanese population, relationships between CL/P or CPO and seven candidate genes (TGFB3, DLX3, PAX9, CLPTM1, TBX10, PVRL1, TBX22) that showed positive associations in other populations and are expressed in the oral/lip region in developing mice. We first searched for mutations in these genes among 112 CL/P and 16 CPO patients, and found a heterozygous missense mutation (640A>G, S214G) in exon 3 of PAX9 in two sibs with CL/P and their phenotypically normal mother from a Japanese family. A population-based case-control analysis and a family-based transmission disequilibrium test (TDT), using single nucleotide polymorphisms (SNPs), and two-SNP haplotypes of the genes, between the 112 CL/P cases with their parents and 192 controls indicated a significant association at one SNP site, IVS1+5321, in TGFB3 with a P-value of 0.0016. Population-based haplotyping revealed that the association was most significant for haplotype “A/A” consisting of IVS1+5321 and IVS1−1572; TDT also gave a P-value of 0.0252 in this haplotype.

A strong association of axillary osmidrosis with the wet earwax type determined by genotyping of the ABCC11 gene

BackgroundTwo types of cerumen occur in humans: the wet type with brownish, sticky earwax, and the dry type with a lack of or reduced ceruminous secretion. The wet type is common in populations of European and African origin, while the dry type is frequently seen in Eastern Asian populations. An association between axillary odor and the wet-type earwax was first identified approximately 70 years ago. The data were based on a phenotypical analysis of the two phenotypes among the Japanese by a researcher or by self-declaration of the subjects examined, and were not obtained using definite diagnostic methods. Recently, we identified a single-nucleotide polymorphism (SNP; rs17822931) of the ABCC11 gene as the determinant of the earwax types. In the present study, to determine whether the SNP can serve as a diagnostic marker for axillary osmidrosis (AO), we examined genotypes at rs17822931 in 79 Japanese AO individuals. AO was defined here as a clinical condition of individuals with a deep anxiety regarding axillary odor and had undergone the removal of bilateral axillary apocrine glands.ResultsA comparison of the frequencies of genotypes at rs17822931 in the 79 AO individuals and in 161 Japanese from the general population showed that AO was strongly associated with the wet earwax genotype. A total of 78 (98.7%) of 79 AO patients had either the GG or GA genotype, while these genotypes were observed in 35.4% (57/161) of the subjects from the general population (p < 1.1 × 10-24, by Fishers exact test).ConclusionThe strong association between the wet-earwax associated ABCC11- genotypes (GG and GA) and AO identified in this study indicates that the genotypes are good markers for the diagnosis of AO. In addition, these results suggest that having the allele G is a prerequisite for the axillary odor expression. In other words, the ABCC11 protein may play a role in the excretory function of the axillary apocrine gland. Together, these results suggest that when an AO individual visiting a hospital is diagnosed with dry-type earwax by ABCC11-genotyping, surgical removal of their axillary glands may not be indicated.

A Basic Fibroblast Growth Factor Improves Lower Extremity Wound Healing With a Porcine-Derived Skin Substitute

BACKGROUND Although a number of cytokine or growth factor therapies for wound acceleration have been reported, few mentioned the quality of the outcome. The lower extremity is important in esthetics as well as in function, because it is exposed. Recently, a growth factor, namely basic growth factor (bFGF) is widely used for difficult wound healing with a porcine-derived bilayered artificial dermis for better wound closure. Thus, their combination use was tested clinically. METHODS Sequential lower extremity reconstruction by an artificial dermis with or without bFGF administration and secondary split-thickness skin grafting was measured for hardness using a durometer, and the moisture parameters assessed such as effective contact coefficient, transepidermal water loss (TEWL), water content and thickness using a moisture meter for at least 6 months after the final procedure and compared with normal skin control. RESULTS There was significantly less skin hardness using a durometer in bFGF treatment compared with non-bFGF treatment (16.2 +/- 3.83 vs. 29.2 +/- 4.94, p < 0.01). Effective contact coefficient, TEWL, water content, and thickness in non-bFGF treatment were all significantly greater than those in bFGF treatment, whereas water content and thickness in bFGF treatment were comparable with those of the control. CONCLUSION The use of bFGF as artificial dermis for extensive and deeper tissue loss coverage demonstrated better reconstruction quality in terms of hardness using a durometer and the function of the stratum corneum by moisture analysis.

Cranial vault distraction: its illusionary effect and limitation.

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 Pfeiffers syndrome, two cases of Crouzons disease, and one case of Aperts 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 patients 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.