Effects of mesenchymal stem cell therapy on alopecia areata in cellular and hair follicle organ culture models.

Mesenchymal stem cell therapy (MSCT) has been suggested as a new therapeutic strategy for immunological disorders. There have been only a few attempts to treat alopecia areata (AA) with MSCT. MSCT efficacy and mechanism of action in treating AA are not known. We sought to investigate the effect of human hematopoietic mesenchymal stem cells (hHMSCs) on an in vitro model of AA and to explore relevant mechanisms that regulate efficacy. An AA-like environment was induced by pretreatment of human dermal papilla cells (hDPCs) with interferon gamma (IFN-γ). hHMSCs were administered to the hDPCs, and cell viability was determined. Similar studies were also conducted with human hair follicles (HFs) in culture. The change in expression of the Wnt/ß-catenin pathway and JAK/STAT pathway-related molecules and growth factors in hHMSC-treated hDPCs was also examined by reverse transcription-PCR, Western blot assay and growth factor array. Immune privilege-related molecules were examined by immunohistochemistry in HF culture models. hHMSCs enhanced the cell viability of the hDPCs. hHMSCs activated several molecules in the Wnt/ß-catenin signalling pathway, including ß-catenin and phosphorylated GSK3b, and decreased IFN-γ-induced expression of DKK1 in hDPCs. hHMSCs suppressed IFN-γ-induced expression of caspase-1, caspase-3 and IFN-γ receptor. hHMSCs induced the phosphorylation of STAT1 and STAT3 compared to controls and IFN-γ-pretreated hDPCs. hHMSC-treated HFs enhanced several growth factor mRNAs. hHMSC pretreatment modulated IFN-γ-induced expression of molecules related to HF immune privilege on HFs in organ culture. These data suggest MSCT may be a new potential therapeutic option in treating AA.

Prevalence of Ocular Hypertension and Glaucoma as Well as Associated Factors in Graves' Orbitopathy.

PURPOSE: The purpose of this study was to determine the prevalence of ocular hypertension (OHT) and open-angle glaucoma (OAG) in patients with Graves' orbitopathy (GO) and to investigate the associations between clinical features of the disease and the prevalence of OHT and OAG. METHODS: A cross-sectional analytic study was conducted among a total of 1128 patients with GO. A complete ophthalmic examination was performed, including intraocular pressure, optic disc photography, visual field testing using a Humphrey visual field analyzer, and retinal nerve fiber layer thickness measured by optical coherence tomography. The results were analyzed by univariate and multivariate logistic regression. RESULTS: A 6.8% prevalence of OHT (77/1128) and a 1.6% prevalence of OAG (18/1128) were observed. When considering only patients older than 40 years, the prevalence of OHT and OAG was 9.5% and 3.4%, respectively. Twenty-nine of the 1128 patients (2.6%) developed compressive optic neuropathy. Of the factors evaluated, male sex [odds ratio (OR), 1.83; 95% confidence interval (CI), 1.08-3.10], duration of GO (6 to 24 mo; OR, 2.08; 95% CI, 1.17-3.71; 24 to 60 mo; OR, 3.45; 95% CI, 1.66-7.18), clinical activity score ≥3 (OR, 1.76; 95% CI, 1.03-3.01), extraocular muscle involvement (OR, 4.65; 95% CI, 2.54-8.50), and lid retraction (OR, 2.17; 95% CI, 1.19-3.96) were associated with the prevalence of OHT in GO. The prevalence of OAG was associated with male sex (OR, 4.29; 95% CI, 1.60-11.51) and duration of GO (≥60 mo; OR, 4.28; 95% CI, 1.11-16.47). CONCLUSIONS: The prevalence of OHT in patients with GO was higher and the prevalence of OAG was similar to that in the general population.

Serum CYR61 Is Associated with Disease Activity in Graves' Orbitopathy.

PURPOSE: To investigate the clinical implications of cysteine-rich angiogenic inducer 61 (CYR61) in Graves' orbitopathy (GO). METHODS: Sera from 52 GO patients, 23 Graves' disease (GD) patients, and 20 healthy controls, and orbital fat tissue samples from 12 of 52 GO patients and 8 control subjects were included for analysis. Concentrations of CYR61 were measured from sera with an enzyme-linked immunosorbent assay, and CYR61 mRNA expression levels were evaluated from orbital fat tissue with polymerase chain reaction. RESULTS: Serum CYR61 levels were higher in GO patients than in controls (p = 0.001). Patients with active GO showed higher CYR61 levels than those with inactive GO (p < 0.001) or GD (p = 0.004). Expression of CYR61 mRNA was 7.4-fold higher in patients with GO than in healthy controls (p < 0.001). CONCLUSIONS: CYR61 could be an adjuvant biomarker associated with the inflammatory activity of GO.

Meibomian Gland Dysfunction Associated With Periocular Radiotherapy.

PURPOSE: To investigate the influence of periocular radiotherapy on meibomian glands. METHODS: We evaluated 28 patients (40 eyes) who received radiotherapy (RT group) for conjunctival or orbital lymphoma and 30 age-matched control subjects (60 eyes). Subjects underwent slit-lamp examination of the eyelids, Schirmer test, meibography, and evaluation of tear film breakup time (TBUT), Ocular Surface Disease Index (OSDI) scores, meibomian glands evaluation (meiboscore, meibum expressibility, and lid margin abnormality scores), and tear film lipid layer thickness using an ocular surface interferometer. These parameters were compared between subjects in the RT and control groups. RESULTS: Meiboscores as well as meibum expressibility and OSDI scores in the RT group were significantly higher compared with those in the control group (1.6 ± 0.9 vs. 0.4 ± 0.6, 1.6 ± 1.0 vs. 0.2 ± 0.4, and 48.1 ± 21.4 vs. 6.2 ± 4.4, respectively, P < 0.001, all), whereas the Schirmer value (9.2 ± 5.1 vs. 12.3 ± 5.2, P = 0.004), TBUT (4.2 ± 2.5 vs. 6.4 ± 2.6, P = 0.001), and lipid layer thickness (61.0 ± 29.3 vs. 85.2 ± 20.0, P < 0.001) in the RT group were lower compared with those in the control group. The percentage of meibomian gland dropout was significantly correlated with age (P = 0.025) and total radiation dose (P = 0.012), regardless of the target location of irradiation. Even low-dose irradiated eyes (<30 Gy) exhibited significantly higher meiboscores (P < 0.001) and shorter TBUT (P = 0.005) compared with control eyes. CONCLUSIONS: Eyes that received periocular radiotherapy exhibited relatively high tear film instability induced by meibomian gland dysfunction, contributing to the high severity of dry eye symptoms.

Orbital Lymphangioma: Characteristics and Treatment Outcomes of 12 Cases.

PURPOSE: To report the patient characteristics and treatment outcomes in 12 cases of orbital lymphangioma. METHODS: In this study, orbital lymphangioma was diagnosed based on clinical, radiologic (computed tomography, magnetic resonance imaging), and histologic findings when possible. Patients whose vision was not compromised by orbital lymphangioma, or that did not have increased intraocular pressure (IOP), received oral corticosteroids. Orbital lymphangioma that affected vision or increased IOP was treated by surgery, which included aspiration of blood or partial resection with or without injection of a sclerosant. RESULTS: Four patients without compromised vision responded well to oral corticosteroids. Eight patients with compromised vision underwent some form of surgery. Bleeding recurred in three patients after aspiration of blood and in two after partial resection and intralesional injection of a sclerosant. Overall, five patients were treated successfully by aspiration of blood, intralesional injection of a sclerosant, and application of continuous negative pressure by appropriate drainage. Partial resection was successful in two patients with organized hematoma. CONCLUSIONS: Orbital lymphangioma that does not compromise vision can be treated medically using oral corticosteroids. Patients with threatened vision or elevated IOP due to acute hemorrhage should be treated by aspiration of blood, intralesional injection of a sclerosant, and application of continuous negative pressure. Partial resection may be effective only in patients with organized hematoma.

Changes in pupillary distance after fat versus bony orbital decompression in Graves' orbitopathy.

OBJECTIVE: To report changes in pupillary distance (PD) after orbital decompression in patients with Graves' orbitopathy (GO). DESIGN: Retrospective comparative case series. PARTICIPANTS: A total of 59 cases who underwent the same type of orbital decompression on both eyes. METHODS: The medical records of 111 patients who underwent orbital decompression were reviewed retrospectively. Fifty-nine patients without restrictive myopathy who underwent the same procedure on both eyes were included. Patients were divided into the following 3 groups by procedure: only fat decompression (group 1, n = 18), fat and medial wall decompression (group 2, n = 11), and fat, medial, and inferior wall decompression (group 3, n = 30). Preoperative and postoperative PD and proptosis were measured. RESULTS: PD shortened by 2.9 mm in group 1 (p < 0.001), 2.4 mm in group 2 (p < 0.001), and 3.5 mm in group 3 (p < 0.001). Proptosis improved by 3.5 mm in group 1 (p < 0.001), 3.5 mm in group 2 (p < 0.001), and 4.6 mm in group 3 (p < 0.001). PD changes were not significantly different between the groups (p = 0.328). The change in PD was significantly correlated with the mean amount of proptosis reduction (r = 0.374, p = 0.003). CONCLUSIONS: PD shortened after orbital decompression in patients with fat proliferative GO. The change in PD was not related to the type of orbital decompression, but rather to the amount of proptosis reduction. Postoperative changes in PD should be considered when performing orbital decompression.

Surgical Outcomes of Porcine Acellular Dermis Graft in Anophthalmic Socket: Comparison with Oral Mucosa Graft.

PURPOSE: We describe our experience with the Permacol graft in anophthalmic socket reconstruction, and compare it to the autologous buccal mucosal graft, emphasizing the postoperative vascularization and contraction of each graft. METHODS: This was a retrospective comparative study. We measured the time necessary for the graft surface to be completely vascularized, as well as the fornix depth of the conjunctival sac in anophthalmic patients. RESULTS: Ten patients underwent Permacol graft reconstruction, with 44 undergoing buccal mucosal graft reconstruction. Seven eyelids (70%) in the Permacol group had a good outcome, with improvement in lower eyelid position and prosthesis retention. Nine out of 10 eyelids (90%) in this group showed complete vascularization of the graft at 2.6 ± 1.9 months postoperatively, while the grafted buccal mucosa was fully vascularized at 1.1 ± 0.3 months postoperatively (p < 0.01). Postoperative fornix depth in the Permacol group was 9.1 ± 2.2 mm, compared to 14.9 ± 4.5 mm in the buccal mucosal graft group (p < 0.01). Mean increases in fornix depth were 33.1% and 67.9% of the mean vertical length of the implanted graft. CONCLUSIONS: The Permacol graft can be useful as spacer graft material in anophthalmic socket patients. It takes longer to vascularize, and undergoes greater graft shrinkage with time, compared to the buccal mucosal graft.

Correction of Lower Eyelid Retraction Using Acellular Human Dermis During Orbital Decompression.

PURPOSE: To investigate the surgical outcome of grafting acellular human dermis compared with concurrent lower eyelid retractor recession during swinging eyelid orbital decompression for correction of lower eyelid retraction in patients with Graves' orbitopathy. METHODS: Institutional Review Board-approved retrospective nonrandomized study of 54 Graves' orbitopathy patients (95 eyes) from 2008 to 2012. Patients who received decompression were divided into 3 groups: Group 1 with conjunctival lengthening using 0.3-mm thickness AlloDerm (36 eyes), Group 2 with inferior retractor recession (33 eyes), and Group 3 with decompression only (26 eyes). Outcome measures included lower eyelid height, inferior sclera show, cosmetic appearance, and complications. RESULTS: Baseline clinical characteristics and the degree of improvement of exophthalmos were not different between groups. Preoperative MRD2 was higher in group 1 (8.0 mm) than in groups 2 (6.9 mm, p < 0.001) and 3 (6.6 mm, p < 0.001). Mean improvement of MRD2 as well as postoperative improvement of inferior scleral show at postoperative 4 to 6 months were significantly higher in group 1 (2.7 mm) than in groups 2 (1.8 mm, p < 0.001) and 3 (1.2 mm, p < 0.001). CONCLUSION: Simultaneous correction of lower eyelid retraction using thin AlloDerm during swinging eyelid orbital decompression maximizes improvement of lower eyelid retraction compared with concurrent inferior retractor recession.

Clinical implications of serum IgG4 levels in patients with IgG4-related ophthalmic disease.

AIMS: The present study aimed to investigate the clinical implications of serum IgG4 levels in patients with IgG4-related ophthalmic disease (ROD). METHODS: The medical records of 31 patients who met the diagnostic criteria for IgG4-ROD were retrospectively reviewed. Twenty-five patients whose serum IgG4 levels could be identified were included. Clinical manifestations and serum IgG4 levels before and after corticosteroid treatment were obtained. Factors associated with relapse were evaluated by comparing the features of patients with disease relapse with those of patients without relapse. RESULTS: Twenty-four patients were 'definite' and one was 'probable' for IgG4-ROD according to the diagnostic criteria. Serum IgG4 levels were higher in patients with systemic involvement (p=0.046). All patients improved clinically after corticosteroid treatment. Serum IgG4 levels decreased after steroid treatment (p=0.005) and normalised in nine patients. In cases of relapse, serum IgG4 levels increased along with the aggravation of symptoms (p=0.047). Serum IgG4 levels that were still elevated (≥135 mg/dL) after steroid treatment (p=0.034) and cessation of steroid treatment during disease remission (p=0.043) were predictive factors for IgG4-ROD relapse. CONCLUSIONS: Serum IgG4 level can be considered an adjunctive marker for treatment response in IgG4-ROD. Patients with serum IgG4 levels that remain elevated after steroid treatment should be carefully observed for relapse. A continuing maintenance dose of oral steroid is recommended to prevent relapse, even when clinical remission is achieved.

Kawasaki Disease with Fever and Cervical Lymphadenopathy as the Sole Initial Presentation

BACKGROUND AND OBJECTIVES: Some patients with Kawasaki disease (KD) present with fever and cervical lymphadenopathy alone. The purpose of this study was to characterize the clinical features of these unusual KD patients and determine whether this is a severe form of KD associated with increased risks of intravenous immunoglobulin (IVIG) resistance and coronary artery lesions (CALs). SUBJECTS AND METHODS: A total of 146 children with KD were reviewed retrospectively, and classified into two groups according to initial clinical features. Those presenting with only fever and cervical lymphadenopathy (LKD) were classified as LKD patients. Other-KD patients included all except the LKD patients. RESULTS: Among 146 KD patients, 13 (8.9%) were classified as LKD patients. The LKD patients were significantly older and admitted earlier. The duration between fever onset and KD diagnosis was significantly longer in the LKD patients (5.9 days vs. 4.9 days, p=0.023). The frequency of IVIG resistance was not different between the two groups., In the LKD patients, the incidence of CALs was significantly higher in the acute phase, and without significant difference in the convalescent phase. The percentage of neutrophils and C-reactive protein, albumin, and total bilirubin levels were significantly higher in LKD patients. CONCLUSION: Even though LKD patients were older, admitted earlier, and had higher inflammatory marker levels, they did not have a greater risk of CALs or IVIG resistance. However, echocardiography may be helpful in the acute stage if patients have only fever and cervical lymphadenopathy and are unresponsive to empirical antibiotics.

Repeated Microneedle Stimulation Induces Enhanced Hair Growth in a Murine Model.

BACKGROUND: Microneedle is a method that creates transdermal microchannels across the stratum corneum barrier layer of skin. No previous study showed a therapeutic effect of microneedle itself on hair growth by wounding. OBJECTIVE: The aim of this study is to investigate the effect of repeated microwound formed by microneedle on hair growth and hair growth-related genes in a murine model. METHODS: A disk microneedle roller was applied to each group of mice five times a week for three weeks. First, to identify the optimal length and cycle, microneedles of lengths of 0.15 mm, 0.25 mm, 0.5 mm, and 1 mm and cycles of 3, 6, 10, and 13 cycles were applied. Second, the effect of hair growth and hair-growth-related genes such as Wnt3a, ß-catenin, vascular endothelial growth factor (VEGF), and Wnt10b was observed using optimized microneedle. Outcomes were observed using visual inspection, real-time polymerase chain reaction, and immunohistochemistry. RESULTS: We found that the optimal length and cycle of microneedle treatment on hair growth was 0.25 mm/10 cycles and 0.5 mm/10 cycles. Repeated microneedle stimulation promoted hair growth, and it also induced the enhanced expression of Wnt3a, ß-catenin, VEGF, and Wnt10b. CONCLUSION: Our study provides evidence that microneedle stimulation can induce hair growth via activation of the Wnt/ß-catenin pathway and VEGF. Combined with the drug delivery effect, we believe that microneedle stimulation could lead to new approaches for alopecia.

Is modified clinical activity score an accurate indicator of diplopia progression in Graves' orbitopathy patients?

The aim of this study is to describe characteristics of Graves' orbitopathy (GO) patients with progressive diplopia and to consider whether modified clinical activity score (CAS) is a useful indicator for prediction of diplopia progression. Medical records and images of GO patients with progressive diplopia were retrospectively reviewed. Clinical parameters (e.g., modified CAS, modified NOSPECS score, exophthalmometry results, score of diplopia, and prevalence of optic neuropathy) were evaluated. Thyroid stimulating hormone receptor autoantibody (TRAb) values were determined. Maximum recti muscle diameters and extraocular muscle (EOM) indices were evaluated. Sixty-three of the 435 GO patients had progressive diplopia; 44.4% (28/63) of these patients had a low CAS (<3). The subgroup analysis (by modified CAS, group 1: CAS<3, group 2: CAS≥3) revealed that the mean modified NOSPECS score and exophthalmos value were significantly higher in group 2 (7.2, 19.1 mm) compared with group 1 patients (5.5, 17.7 mm) (p<0.001, p=0.037, respectively). Score of diplopia, prevalence of optic neuropathy and the positive rate and level of TRAb were not significantly different between groups. There were no differences in maximum recti muscle diameters or EOM indices between the two groups. Diplopia may progress even in patients with a low modified CAS. CAS may not reflect the inflammatory activity of myopathy, especially in mild to moderate GO with low NOSPECS and exophthalmos values. Careful patient follow-up using subjective and objective measures for diplopia should be performed.

The Effect of Systemic Steroids and Orbital Radiation for Active Graves Orbitopathy on Postdecompression Extraocular Muscle Volume.

PURPOSE: To evaluate the effect of orbital radiation prior to surgery on the clinical course and extraocular muscle (EOM) radiologic volume changes after decompression in Graves orbitopathy (GO). DESIGN: Retrospective, interventional case series. METHODS: The medical records of patients treated with orbital decompression for GO and who underwent postoperative orbital computed tomography were reviewed. Only patients who underwent rehabilitative decompression in the inactive phase and who received systemic corticosteroids alone (ST group) or combined orbital radiation and systemic corticosteroids (SRT group) in the active inflammatory phase of the disease were selected. The main outcome measure was the comparison of preoperative and postoperative EOM volumes. Secondary outcome measures were changes in proptosis and diplopia after decompression. RESULTS: Thirty-seven of 114 patients were selected for this study. There were no differences between the ST group (n = 22, 42 eyes) and SRT group (n = 15, 30 eyes) in terms of demographics or predecompression characteristics. After decompression surgery, the total EOM volume significantly increased by 15% in the ST group, but radiated EOMs in the SRT group did not expand, resulting in decreased induction of postoperative diplopia. The percentages of patients showing increased diplopia after decompression differed significantly between the groups (ST group, 40.9% vs SRT group, 13.3%, P = .04). However, there was no difference in exophthalmos reduction after decompression between the 2 groups. CONCLUSIONS: Orbital radiation prior to orbital decompression can reduce both the postoperative increase in EOM volume and deterioration in diplopia.

A Randomized Clinical Trial to Evaluate the Efficacy and Safety of Lidocaine-Containing Monophasic Hyaluronic Acid Filler for Nasolabial Folds.

BACKGROUND: Hyaluronic acid dermal fillers are most frequently used for unwanted wrinkles. Recently, lidocaine has been incorporated into hyaluronic acid fillers to reduce injection discomfort. METHODS: A randomized, multicenter, double-blind, intraindividual trial was designed to compare a new lidocaine-containing monophasic hyaluronic acid filler (Neuramis Deep Lidocaine) with a lidocaine-containing biphasic hyaluronic acid filler (Restylane Perlane-L) in moderate to severe nasolabial folds. Fifty-eight patients with moderate to severe nasolabial folds were randomized to an injection of Neuramis or Perlane-L in the left or right side of the face. Clinical efficacy and safety were assessed by blinded investigators, independent expert panels, and patients based on the Wrinkle Severity Rating Scale and the Global Aesthetic Improvement Scale at weeks 8, 16, and 24 after the injection. RESULTS: Wrinkle Severity Rating Scale improvement from baseline with Neuramis (1.64 ± 0.74) was significantly greater than with Perlane-L (1.45 ± 0.54) at week 24 (p < 0.05). The mean Global Aesthetic Improvement Scale score at week 24 was 2.36 ± 0.55 for Neuramis and 2.00 ± 0.50 for Perlane-L (p < 0.05). However, the difference in pain reduction between Neuramis- and Perlane-L-treated sides was not statistically significant. CONCLUSIONS: The efficacy and safety of Neuramis are comparable to those of Perlane-L in Wrinkle Severity Rating Scale and Global Aesthetic Improvement Scale improvement for the management of nasolabial folds. Furthermore, the difference in pain reduction between the two fillers was not clinically significant. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, I.

A Clinicoimmunohistopathologic Study of Anetoderma: Is Protruding Type More Advanced in Stage Than Indented Type?

Background. The clinical and histopathologic classification of anetoderma are not well characterized. Objective. We aimed to investigate the clinical and histopathologic characteristics of anetoderma and to correlate clinical phenotypes with immunohistopathologic findings. Methods. We retrospectively reviewed the medical records of 30 patients with anetoderma and performed immunohistochemistry for elastin, fibrillin-1, metalloproteinase- (MMP-) 2, MMP-7, MMP-9, and MMP-12, and tissue inhibitor of metalloproteinase- (TIMP-) 1 and TIMP-2. Results. Protruding type (n = 17) had a longer disease duration and more severe loss of elastin, without changes in fibrillin, than indented type (n = 13). MMP-2 and MMP-9 showed significantly higher expressions in the dermis compared with controls (p < 0.05). MMP-7 and MMP-12 showed little expressions in both anetoderma and control tissue. TIMP-1 was highly expressed in anetoderma lesions and controls. TIMP-2 expression was variable. Conclusions. Our findings suggest that protruding type anetoderma may represent a more advanced stage and that MMP-2 and MMP-9 could be responsible for elastic fiber degradation in anetoderma.