Bilateral blepharoptosis in a juvenile.

In adults, aponeurotic blepharoptosis is the most common type of ptosis. However, myogenic ptosis is the predominant cause, and bilateral aponeurotic ptosis is very rare among children. Here, we report a previously healthy 10-year-old Japanese girl with bilateral aponeurotic blepharoptosis who presented initially with bilateral blepharoptosis for about 4years. This case report shows that history taking and careful observation of the patient lead to an accurate diagnosis, and aponeurotic ptosis should be considered in the differential diagnosis of bilateral blepharoptosis among children.

Therapeutic potential of human adipose tissue-derived multi-lineage progenitor cells in liver fibrosis.

INTRODUCTION: Liver fibrosis is characterized by excessive accumulation of extracellular matrix. In a mouse model of liver fibrosis, systemic injection of bone marrow mesenchymal stem cells (BM-MSCs) was considered to rescue the diseased phenotype. The aim of this study was to assess the effectiveness of human adipose tissue-derived multi-lineage progenitor cells (hADMPCs) in improving liver fibrosis. METHODS AND RESULTS: hADMPCs were isolated from subcutaneous adipose tissues of healthy volunteers and expanded. Six week-old male nude mice were treated with carbon tetra-chloride (CCl4) by intraperitoneal injection twice a week for 6 weeks, followed by a tail vein injection of hADMPCs or placebo control. After 6 more weeks of CCl4 injection (12 weeks in all), nude mice with hADMPCs transplants exhibited a significant reduction in liver fibrosis, as evidenced by Sirius Red staining, compared with nude mice treated with CCl4 for 12 weeks without hADMPCs transplants. Moreover, serum glutamic pyruvate transaminase and total bilirubin levels in hADMPCs-treated nude mice were lower levels than those in placebo controls. Production of fibrinolytic enzyme MMPs from hADMPCs were examined by ELISA and compared to that from BM-MSCs. MMP-2 levels in the culture media were not significantly different, whereas those of MMP-3 and -9 of hADMPCs were higher than those by BM-MSCs. CONCLUSION: These results showed the mode of action and proof of concept of systemic injection of hADMPCs, which is a promising therapeutic intervention for the treatment of patients with liver fibrosis.

Orbital Compartment Syndrome in Eosinophilic Angiocentric Fibrosis.

A 43-year-old man reported right visual loss after biopsy of an intranasal mass, which improved after treatment at another hospital. On first examination at our hospital, his visual acuity was 1.2 OD, and MRI showed a right intraorbital mass involving the ethmoid sinus. His visual acuity decreased to 0.08 OD 12 days after orbital biopsy, with right globe tenting shown by MRI. An emergent lateral canthotomy and cantholysis were performed. The histopathological diagnosis was eosinophilic angiocentric fibrosis, and treatment with intravenous methylprednisolone (125 mg/day) and oral diaminophenyl sulfone (75 mg/day) was started immediately after surgery. One month later, the diaminophenyl sulfone was discontinued and cyclophosphamide (50 mg/day) was started. The methylprednisolone and cyclophosphamide doses were tapered over 9 months and 7 months, respectively. At the 1.5-year follow-up examination, his visual acuity was 1.0 OD. The lesions did not grow in size.

Congenital entropion: outcome of posterior layer advancement of lower eyelid retractors and histological study of orbicularis oculi muscle hypertrophy.

PURPOSE: To examine surgical outcomes of the posterior layer advancement of the lower eyelid retractors (LER) in patients with congenital entropion and to ascertain whether the pretarsal orbicularis oculi muscle (OOM) was hypertrophic or not. MATERIALS AND METHODS: This retrospective study included three Japanese patients with congenital entropion who underwent posterior layer advancement of the LER. We reviewed the surgical outcomes and postoperative complications, such as lower eyelid ectropion and retraction for each patient. We also measured the diameters of the pretarsal OOM fibers in these patients and compared them with those measured in the previously reported 67 eyelids of 41 Japanese patients with congenital epiblepharon. RESULTS: Congenital entropion was successfully corrected in all three patients without recurrence during 12-months of follow-up. No patient exhibited lower eyelid ectropion or lower eyelid retraction. The mean diameter of the pretarsal OOM fibers was 21.9 µm (range, 20.5-23.7 µm), which was not significantly different from that of the congenital epiblepharon (25.3 µm; range, 18.1-34.7 µm; p = 0.272, Mann-Whitney U test). CONCLUSIONS: The surgical outcomes in the present study suggest that posterior layer advancement of the LER is a useful surgical option for treatment of congenital entropion. No histological evidence of pretarsal OOM hypertrophy was shown in congenital entropion, which demonstrated that debulking of the pretarsal OOM may not be significant for correction of this entity.

Comparison of bony nasolacrimal canal narrowing with or without primary acquired nasolacrimal duct obstruction in a Japanese population.

PURPOSE: To compare the minimum diameter of the nasolacrimal canal and its location between patients with or without primary acquired nasolacrimal duct obstruction (NLDO) in a Japanese population. METHODS: One hundred one patients with unilateral primary acquired NLDO (Group A, 101 affected sides; Group B, 101 unaffected sides) and 50 non-NLDO patients (Group C, 100 sides) were included. Anteroposterior and transverse diameters were measured at the canal entrance and the shortest point using contiguous 1-mm axial computed tomographic images. Canal shapes were classified into 2 types: the "funnel" type (a canal with both minimum diameters at the canal entrance) and the "hourglass" type (a canal with at least one minimum diameter in the canal). The distance from the entrance to the part with the shortest diameter was measured on sides with the hourglass type. RESULTS: The funnel type was found more frequently in Groups A and B than in Group C (p<0.050), although a difference was not found between Groups A and B (p=0.778). The distance of the transverse diameter was significantly shorter in Groups A and B than Group C (p<0.050), although no significant difference was found in this distance between Groups A and B (p=1.000). There were no significant differences between the groups for each value except for the above mentioned (p>0.050). CONCLUSIONS: Primary acquired NLDO patients exhibited the funnel type more frequently or there was a shorter distance from the entrance to the part with the shortest diameter than non-NLDO patients, which may enhance the risk of primary acquired NLDO.

Anatomy of anterior ethmoidal foramen, medial canthal tendon, and lacrimal fossa for transcutaneous anterior ethmoidal nerve block in Japanese individuals.

PURPOSE: To examine the anatomical relationships of the anterior ethmoidal foramen (AEF), medial canthal tendon (MCT), and lacrimal fossa (LF) in Japanese individuals. METHODS: Thirty-eight orbits from 19 Japanese cadavers (7 men and 12 women; average age at death, 89.3 years) were used in this experimental anatomical study. The AEF, MCT, and superior border of the LF were exposed. The following distances were then measured: 1) from the point at the medial orbital rim directly anterior to the AEF to the superior border of the MCT (AEF-MCT), and 2) from the superior border of the LF to the superior border of the MCT (LF-MCT). RESULTS: (AEF-MCT) and (LF-MCT) distances were 9.40±1.92 (mean±standard deviation) and 4.21±1.18 mm, respectively. No values of (LF-MCT) exceeded the mean (AEF-MCT) (9.40 mm). CONCLUSIONS: The transcutaneous anterior ethmoidal nerve block can be reliably performed without injury to the lacrimal sac by inserting a needle approximately 9 mm superior to the superior border of the MCT.

Comparison of surgical outcomes between simple posterior layer advancement of lower eyelid retractors and combination with a lateral tarsal strip procedure for involutional entropion in a Japanese population.

AIMS: To compare the effectiveness of simple posterior layer advancement of the lower eyelid retractor (LER) and combination surgery of posterior layer advancement of the LER with a lateral tarsal strip procedure for involutional lower eyelid entropion in a Japanese population. METHODS: 46 eyelids of 37 patients with horizontal laxity (Group A) and 47 eyelids of 42 patients without horizontal laxity (Group B) that underwent simple posterior layer advancement of the LER, and 47 eyelids of 37 patients with horizontal laxity that had the combination surgery (Group C) were retrospectively reviewed. RESULTS: All eyelids were judged as successfully corrected without recurrence in Groups B and C. On the other hand, although 42 eyelids (91.3%) were successfully altered in Group A, four eyelids (8.7%) showed recurrence at a mean period of 7.6 months postoperatively. Surgical success rates in Groups B and C tended to be higher than in Group A (p=0.056). CONCLUSIONS: The combination surgery in Group C and simple posterior layer advancement of the LER in Group B provided complete surgical success. The present study suggests the importance of preoperative evaluation of horizontal laxity, allowing surgeons to perform the least amount of surgery to achieve success.

Role of notch signaling in the maintenance of human mesenchymal stem cells under hypoxic conditions.

Human adipose tissue-derived multilineage progenitor cells (hADMPCs) are attractive for cell therapy and tissue engineering because of their multipotency and ease of isolation without serial ethical issues. However, their limited in vitro lifespan in culture systems hinders their therapeutic application. Some somatic stem cells, including hADMPCs, are known to be localized in hypoxic regions; thus, hypoxia may be beneficial for ex vivo culture of these stem cells. These cells exhibit a high level of glycolytic metabolism in the presence of high oxygen levels and further increase their glycolysis rate under hypoxia. However, the physiological role of glycolytic activation and its regulatory mechanisms are still incompletely understood. Here, we show that Notch signaling is required for glycolysis regulation under hypoxic conditions. Our results demonstrate that 5% O2 dramatically increased the glycolysis rate, improved the proliferation efficiency, prevented senescence, and maintained the multipotency of hADMPCs. Intriguingly, these effects were not mediated by hypoxia-inducible factor (HIF), but rather by the Notch signaling pathway. Five percent O2 significantly increased the level of activated Notch1 and expression of its downstream gene, HES1. Furthermore, 5% O2 markedly increased glucose consumption and lactate production of hADMPCs, which decreased back to normoxic levels on treatment with a γ-secretase inhibitor. We also found that HES1 was involved in induction of GLUT3, TPI, and PGK1 in addition to reduction of TIGAR and SCO2 expression. These results clearly suggest that Notch signaling regulates glycolysis under hypoxic conditions and, thus, likely affects the cell lifespan via glycolysis.

Combination of nasolabial v-y advancement flap and glabellar subcutaneous pedicled flap for reconstruction of medial canthal defect.

A 77-year-old woman presented with a 1-year history of a right medial canthal tumor, which was histopathologically diagnosed as a basal cell carcinoma. After removal of the tumor with a 4-mm safety margin, the defect occupied the areas superior and inferior to the medial canthal tendon. We first reconstructed the lower part of the defect using a nasolabial V-Y advancement flap to make an elliptic defect in the upper part. We then created a glabellar subcutaneous pedicled flap to match the residual upper elliptic defect with the major axis set along a relaxed skin tension line. The pedicled glabellar flap was passed through a subcutaneous tunnel to the upper residual defect. At 6 months postoperatively, the patient showed no tumor recurrence and a good cosmetic outcome.

Intraocular pressure change with eye positions before and after orbital decompression for thyroid eye disease.

PURPOSE: To examine intraocular pressure (IOP) changes in primary and upward gazes before and after orbital decompression in patients with thyroid eye disease. METHODS: Seventy-eight orbits of 40 patients who underwent orbital decompression between June 2010 and September 2012 were retrospectively reviewed. Subjects were divided in 2 groups according to the number of orbital walls removed: deep lateral orbital wall decompression group (Group A) or balanced decompression group (Group B). IOP was measured using Goldmann applanation tonometry in primary gaze and a 20° upward gaze before and 3 months after surgery. RESULTS: Preoperative IOP in upward gaze (18.7 mm Hg) was higher than in primary gaze (15.7 mm Hg, p < 0.001). Postoperative IOP reduction in upward gaze (3.8 mm Hg) was greater than in primary gaze (1.7 mm Hg, p < 0.001). Although the overall postoperative IOP in upward gaze (14.9 mm Hg) remained higher than in primary gaze (14.0 mm Hg, p = 0.038), the gaze-related IOP demonstrated no significant difference in all subgroups (Group A, p = 0.091; Group B, p = 0.332). CONCLUSIONS: IOP in upward gaze was higher prior to orbital decompression, but reduction was greater postoperatively and approximated the IOP in primary gaze.

Topical rebamipide treatment for superior limbic keratoconjunctivitis in patients with thyroid eye disease.

PURPOSE: To evaluate efficacy of topical rebamipide for superior limbic keratoconjunctivitis (SLK) in patients with thyroid eye disease. DESIGN: Retrospective, observational case series. METHODS: Thirty-three eyes from 20 thyroid eye disease patients with SLK who received topical rebamipide (Mucosta ophthalmic suspension unit dose 2%; Otsuka Pharmaceutical Co, Ltd; chemical name, (2RS)-2-(4-chlorobenzoylamino)-3-(2-oxo-1, 2-dihydroquinolin-4-yl) propanoic acid) were included. The following items were evaluated before and 4 weeks after the start of treatments: presence or absence of SLK, rose bengal staining score, area and density classification of fluorescein staining, Schirmer test I results (without topical anesthesia), tear film break-up time, Hertel exophthalmometry values, and margin reflex distances 1 and 2. RESULTS: Twenty-eight eyes showed complete disappearance of SLK after treatment (84.8%; P < .001). The other 5 eyes (15.2%) demonstrated significant improvement, but had residual punctate rose bengal staining and fluorescein staining near the superior corneal limbus. All 5 eyes exhibited at least 1 of the following findings: proptosis of more than 17.7 mm and upper or lower eyelid retractions or both. Incidence of upper eyelid retraction was significantly higher in eyes with SLK than in those without SLK at the 4-week follow-up (P = .021). The severity of rose bengal staining and fluorescein staining improved significantly after treatment (P < .001). Although the Schirmer test results remained constant before and after the treatment (P = .212), tear film break-up time increased significantly in the posttherapeutic state (P = .009). No serious adverse events were reported. CONCLUSIONS: Topical rebamipide improved SLK in patients with thyroid eye disease, suggesting a first-line treatment in such patients.

Reconstruction of a congenital upper eyelid coloboma using a lamellar-based technique.

A 17-year-old woman presented with a left upper eyelid coloboma from birth, extending from the lateral side of the punctum to the center of the eyelid as much as 10 mm in width. The posterior lamella (tarsus) was lost completely in this area, but an anterior lamella defect was limited to 1 to 2 mm in height. The area was devoid of eyelashes. Part of the medial tarsal plate was spared. The anterior and posterior lamellae of this eyelid were separately reconstructed with an anterior skin crease incision and posterior wedge excision with a good cosmetic outcome.

Anatomy of deep lateral and medial orbital walls: implications in orbital decompression surgery.

BACKGROUND: Isolated deep lateral and combined medial orbital wall decompressions (balanced decompression) are well accepted for treatment of disfiguring proptosis and compressive optic neuropathy in patients with Graves' orbitopathy. However, cerebrospinal fluid leakage and/or optic nerve injury occasionally occur during these operations. PURPOSE: To describe the anatomy of the deep lateral and medial orbital walls and its surgical implications in orbital decompression. METHODS: We reviewed literature on the anatomy of the deep lateral and medical orbital walls. In addition, we performed cadaver dissection and computed tomographics studies to illustrate the anatomy. RESULTS: We provided an anatomical overview and elucidated the detailed surgical anatomy of the posterior and superior borders of the deep lateral orbital wall, the posterior and accessory ethmoidal foramina, and the frontoethmoidal suture. CONCLUSIONS: The anatomy of the deep lateral and medical orbital walls presented here will warrant safe and confident performance of orbital decompression surgery.

Tightly regulated and homogeneous transgene expression in human adipose-derived mesenchymal stem cells by lentivirus with tet-off system.

Genetic modification of human adipose tissue-derived multilineage progenitor cells (hADMPCs) is highly valuable for their exploitation in therapeutic applications. Here, we have developed a novel single tet-off lentiviral vector platform. This vector combines (1) a modified tetracycline (tet)-response element composite promoter, (2) a multi-cistronic strategy to express an improved version of the tet-controlled transactivator and the blasticidin resistance gene under the control of a ubiquitous promoter, and (3) acceptor sites for easy recombination cloning of the gene of interest. In the present study, we used the cytomegalovirus (CMV) or the elongation factor 1 α (EF-1α) promoter as the ubiquitous promoter, and EGFP was introduced as the gene of interest. hADMPCs transduced with a lentiviral vector carrying either the CMV promoter or the EF-1α promoter were effectively selected by blasticidin without affecting their stem cell properties, and EGFP expression was strictly regulated by doxycycline (Dox) treatment in these cells. However, the single tet-off lentiviral vector carrying the EF-1α promoter provided more homogenous expression of EGFP in hADMPCs. Intriguingly, differentiated cells from these Dox-responsive cell lines constitutively expressed EGFP only in the absence of Dox. This single tet-off lentiviral vector thus provides an important tool for applied research on hADMPCs.

Inferior oblique muscle origin: horizontal location in relation to ala nasi and its gender difference.

We studied the horizontal location of the inferior oblique muscle (IOM) origin in relation to the ipsilateral ala nasi and compared the results between genders in 76 orbits of 38 Japanese cadavers. Consequently, the IOM origin was located 1.2 mm laterally to the vertical line through the lateral margin of the ipsilateral ala nasi. No significant difference was noted between genders (males, 1.3 mm; females, 0.9 mm; P = 0.257, Student t test) or between sides (right, 1.1 mm; left, 1.3 mm; P = 0.570, Student t test). In contrast, the mean interalae-nasi distance was 39.8 mm and was significantly greater in males than that in females (males, 40.8 mm; females, 38.6 mm; P = 0.049, Student t test). The ala nasi can be used as a reference point irrespective of gender or side for identifying the IOM origin during oculoplastic surgery.

Preaponeurotic fat advancement for prevention of unexpected higher eyelid crease in upper eyelid-lengthening surgery.

PURPOSE: To present a modified technique based on preaponeurotic fat advancement for preventing higher eyelid crease in upper eyelid-lengthening surgery. METHODS: Outcomes of Japanese patients with Graves' orbitopathy-related upper eyelid retraction who underwent transcutaneous upper eyelid-lengthening surgery were reviewed. The minimum follow-up period was 6 months. A total of 17 upper eyelids in 11 patients (average age, 38.4 years) were included. After confirming appropriate upper eyelid lowering with good contour, preaponeurotic fat was fully exposed and fixed on the upper tarsal plate 1 mm superior to the planned eyelid crease with 5 sutures. Skin-tarsus-skin sutures were placed to create an eyelid crease and close the skin. Simple suture tarsorrhaphy was performed with 2 sutures. RESULTS: No upper eyelids demonstrated higher eyelid crease postsurgically. Upper eyelid fullness caused by the advanced preaponeurotic fat was not conspicuous. CONCLUSIONS: Our technique is a countermeasure against higher eyelid crease in upper eyelid-lengthening surgery.

Human adipose tissue-derived multilineage progenitor cells exposed to oxidative stress induce neurite outgrowth in PC12 cells through p38 MAPK signaling.

BACKGROUND: Adipose tissues contain populations of pluripotent mesenchymal stem cells that also secrete various cytokines and growth factors to support repair of damaged tissues. In this study, we examined the role of oxidative stress on human adipose-derived multilineage progenitor cells (hADMPCs) in neurite outgrowth in cells of the rat pheochromocytoma cell line (PC12). RESULTS: We found that glutathione depletion in hADMPCs, caused by treatment with buthionine sulfoximine (BSO), resulted in the promotion of neurite outgrowth in PC12 cells through upregulation of bone morphogenetic protein 2 (BMP2) and fibroblast growth factor 2 (FGF2) transcription in, and secretion from, hADMPCs. Addition of N-acetylcysteine, a precursor of the intracellular antioxidant glutathione, suppressed the BSO-mediated upregulation of BMP2 and FGF2. Moreover, BSO treatment caused phosphorylation of p38 MAPK in hADMPCs. Inhibition of p38 MAPK was sufficient to suppress BMP2 and FGF2 expression, while this expression was significantly upregulated by overexpression of a constitutively active form of MKK6, which is an upstream molecule from p38 MAPK. CONCLUSIONS: Our results clearly suggest that glutathione depletion, followed by accumulation of reactive oxygen species, stimulates the activation of p38 MAPK and subsequent expression of BMP2 and FGF2 in hADMPCs. Thus, transplantation of hADMPCs into neurodegenerative lesions such as stroke and Parkinson's disease, in which the transplanted hADMPCs are exposed to oxidative stress, can be the basis for simple and safe therapies.

Intracoronary artery transplantation of cardiomyoblast-like cells from human adipose tissue-derived multi-lineage progenitor cells improve left ventricular dysfunction and survival in a swine model of chronic myocardial infarction.

Transplantation of human cardiomyoblast-like cells (hCLCs) from human adipose tissue-derived multi-lineage progenitor cells improved left ventricular function and survival of rats with myocardial infarction. Here we examined the effect of intracoronary artery transplantation of human CLCs in a swine model of chronic heart failure. Twenty-four pigs underwent balloon-occlusion of the first diagonal branch followed by reperfusion, with a second balloon-occlusion of the left ascending coronary artery 1 week later followed by reperfusion. Four weeks after the second occlusion/reperfusion, 17 of the 18 surviving animals with severe chronic MI (ejection fraction <35% by echocardiography) were immunosuppressed then randomly assigned to receive either intracoronary artery transplantation of hCLCs hADMPCs or placebo lactic Ringer's solution with heparin. Intracoronary artery transplantation was followed by the distribution of DiI-stained hCLCs into the scarred myocardial milieu. Echocardiography at post-transplant days 4 and 8 weeks showed rescue and maintenance of cardiac function in the hCLCs transplanted group, but not in the control animals, indicating myocardial functional recovery by hCLCs intracoronary transplantation. At 8 week post-transplantation, 7 of 8 hCLCs transplanted animals were still alive compared with only 1 of the 5 control (p=0.0147). Histological studies at week 12 post-transplantation demonstrated engraftment of the pre DiI-stained hCLCs into the scarred myocardium and their expression of human specific alpha-cardiac actin. Human alpha cardiac actin-positive cells also expressed cardiac nuclear factors; nkx2.5 and GATA-4. Our results suggest that intracoronary artery transplantation of hCLCs is a potentially effective therapeutic strategy for future cardiac tissue regeneration.