Intramyocardial hemorrhage drives fatty degeneration of infarcted myocardium.

Sudden blockage of arteries supplying the heart muscle contributes to millions of heart attacks (myocardial infarction, MI) around the world. Although re-opening these arteries (reperfusion) saves MI patients from immediate death, approximately 50% of these patients go on to develop chronic heart failure (CHF) and die within a 5-year period; however, why some patients accelerate towards CHF while others do not remains unclear. Here we show, using large animal models of reperfused MI, that intramyocardial hemorrhage - the most damaging form of reperfusion injury (evident in nearly 40% of reperfused ST-elevation MI patients) - drives delayed infarct healing and is centrally responsible for continuous fatty degeneration of the infarcted myocardium contributing to adverse remodeling of the heart. Specifically, we show that the fatty degeneration of the hemorrhagic MI zone stems from iron-induced macrophage activation, lipid peroxidation, foam cell formation, ceroid production, foam cell apoptosis and iron recycling. We also demonstrate that timely reduction of iron within the hemorrhagic MI zone reduces fatty infiltration and directs the heart towards favorable remodeling. Collectively, our findings elucidate why some, but not all, MIs are destined to CHF and help define a potential therapeutic strategy to mitigate post-MI CHF independent of MI size.

Lasers, lights, and compounds for hair loss in aesthetics.

Hair loss is a common complaint that is often stressful for patients and a challenge for practitioners to treat. Fortunately, innovations in the field have contributed to growing evidence for several promising topical, oral, and light and energy-based therapies. We have reviewed the current literature about the efficacy of these treatments, including topical agents (finasteride, latanoprost, spironolactone, caffeine, and metformin), oral minoxidil, nutraceuticals, platelet-rich plasma, low-level laser therapy, fractional lasers, and laser-assisted drug delivery. In addition, several debates related to these treatments have been discussed, including post-finasteride syndrome, effects of biotin supplementation on laboratory testing, standardization of platelet-rich plasma and low-level laser therapy, and combination treatment to enhance hair transplantation.

Intramyocardial Hemorrhage and the "Wave Front" of Reperfusion Injury Compromising Myocardial Salvage.

BACKGROUND: Reperfusion therapy for acute myocardial infarction (MI) is lifesaving. However, the benefit of reperfusion therapy can be paradoxically diminished by reperfusion injury, which can increase MI size. OBJECTIVES: Hemorrhage is known to occur in reperfused MIs, but whether hemorrhage plays a role in reperfusion-mediated MI expansion is not known. METHODS: We studied cardiac troponin kinetics (cTn) of ST-segment elevation MI patients (n = 70) classified by cardiovascular magnetic resonance to be hemorrhagic (70%) or nonhemorrhagic following primary percutaneous coronary intervention. To isolate the effects of hemorrhage from ischemic burden, we performed controlled canine studies (n = 25), and serially followed both cTn and MI size with time-lapse imaging. RESULTS: CTn was not different before reperfusion; however, an increase in cTn following primary percutaneous coronary intervention peaked earlier (12 hours vs 24 hours; P < 0.05) and was significantly higher in patients with hemorrhage (P < 0.01). In hemorrhagic animals, reperfusion led to rapid expansion of myocardial necrosis culminating in epicardial involvement, which was not present in nonhemorrhagic cases (P < 0.001). MI size and salvage were not different at 1 hour postreperfusion in animals with and without hemorrhage (P = 0.65). However, within 72 hours of reperfusion, a 4-fold greater loss in salvageable myocardium was evident in hemorrhagic MIs (P < 0.001). This paralleled observations in patients with larger MIs occurring in hemorrhagic cases (P < 0.01). CONCLUSIONS: Myocardial hemorrhage is a determinant of MI size. It drives MI expansion after reperfusion and compromises myocardial salvage. This introduces a clinical role of hemorrhage in acute care management, risk assessment, and future therapeutics.

The erythema Q-score, an imaging biomarker for redness in skin inflammation.

Physician rating of cutaneous erythema is central to clinical dermatological assessment as well as quantification of outcome measures in clinical trials in a number of dermatologic conditions. However, issues with inter-rater reliability and variability in the setting of higher Fitzpatrick skin types make visual erythema assessment unreliable. We developed and validated a computer-assisted image-processing algorithm (EQscore) to reliably quantify erythema (across a range of skin types) in the dermatology clinical setting. Our image processing algorithm evaluated erythema based upon green light suppression differentials between affected and unaffected skin. A group of four dermatologists used a 4-point Likert scale as a human evaluation of similar erythematous patch tests. The algorithm and dermatologist scores were compared across 164 positive patch test reactions. The intra-class correlation coefficient of groups and the correlation coefficient between groups were calculated. The EQscore was validated on and independent image set of psoriasis, minimal erythema dose testing and steroid-induced blanching images. The reliability of the erythema quantification method produced an intra-class correlation coefficient of 0.84 for the algorithm and 0.67 for dermatologists. The correlation coefficient between groups was 0.85. The EQscore demonstrated high agreement with clinical scoring and superior reliability compared with clinical scoring, avoiding the pitfalls of erythema underrating in the setting of pigmentation. The EQscore is easily accessible (http://lab.rockefeller.edu/krueger/EQscore), user-friendly, and may allow dermatologists to more readily and accurately rate the severity of dermatological conditions and the response to therapeutic treatments.

Hair Transplantation Controversies.

BACKGROUND: Hair transplant surgery creates consistently natural appearing transplanted hair for men. It is increasingly popular procedure to restore natural growing hair for men with hair loss. OBJECTIVE: To review some current controversies in hair transplant surgery. MATERIALS AND METHODS: Review of the English PubMed literature and specialty literature in hair transplant surgery. RESULTS: Some of the controversies in hair transplant surgery include appropriate donor harvesting technique including elliptical donor harvesting versus follicular unit extraction whether manual versus robotic, the role of platelet-rich plasma and low-level light surgery in hair transplant surgery. CONCLUSION: Hair transplant surgery creates consistently natural appearing hair. As with all techniques, there are controversies regarding the optimal method for performing the procedure. Some of the current controversies in hair transplant surgery include optimal donor harvesting techniques, elliptical donor harvesting versus follicular unit extraction, the role of low-level light therapy and the platelet-rich plasma therapy in the procedure. Future studies will further clarify their role in the procedure.

Efficacy and safety of ustekinumab treatment in adults with moderate-to-severe atopic dermatitis.

Atopic dermatitis (AD) is the most common inflammatory skin disease, but treatment options for moderate-to-severe disease are limited. Ustekinumab is an IL-12/IL-23p40 antagonist that suppresses Th1, Th17 and Th22 activation, commonly used for psoriasis patients. We sought to assess efficacy and safety of ustekinumab in patients with moderate-to-severe AD. In this phase II, double-blind, placebo-controlled study, 33 patients with moderate-to-severe AD were randomly assigned to either ustekinumab (n=16) or placebo (n=17), with subsequent crossover at 16 weeks, and last dose at 32 weeks. Background therapy with mild topical steroids was allowed to promote retention. Study endpoints included clinical (SCORAD50) and biopsy-based measures of tissue structure and inflammation, using protein and gene expression studies. The ustekinumab group achieved higher SCORAD50 responses at 12, 16 (the primary endpoint) and 20 weeks compared to placebo, but the difference between groups was not significant. The AD molecular profile/transcriptome showed early robust gene modulation, with sustained further improvements until 32 weeks in the initial ustekinumab group. Distinct and more robust modulation of Th1, Th17 and Th22 but also Th2-related AD genes was seen after 4 weeks of ustekinumab treatment (i.e. MMP12, IL-22, IL-13, IFN-γ, elafin/PI3, CXCL1 and CCL17; P<.05). Epidermal responses (K16, terminal differentiation) showed faster (4 weeks) and long-term regulation (32 weeks) from baseline in the ustekinumab group. No severe adverse events were observed. Ustekinumab had clear clinical and molecular effects, but clinical outcomes might have been obscured by a profound "placebo" effect, most likely due to background topical glucocorticosteroids and possibly insufficient dosing for AD.

Two-Stage Growth of Polymer Nanoparticles at the Liquid-Vapor Interface by Vapor-Phase Polymerization.

In this article, we study the growth of polymer nanoparticles that are formed on the surface of silicone oils via initiated chemical vapor deposition. The average radius of the particles can be increased by decreasing the silicone oil viscosity, increasing the deposition time, or increasing the deposition rate. The time series data indicates that there are two stages for particle growth. Particle nucleation occurs in the first stage and the particle size is dependent on the liquid viscosity and deposition rate. Particle growth occurs in the second stage, during which the particle size is dependent only on the amount of deposited polymer. This two-step process allows us to make core-shell particles by sequentially depositing different polymers. The benefits of our nanoparticle synthesis process are that solvents and surfactants are not required and the size of the nanoparticles can be controlled over a wide range of radii with a relatively narrow distribution.

A mild topical steroid leads to progressive anti-inflammatory effects in the skin of patients with moderate-to-severe atopic dermatitis.

BACKGROUND: Topical glucocorticosteroids are considered an efficient treatment option for atopic dermatitis (AD), but a global assessment of glucocorticosteroid responses on key disease circuits upon weeks to months of treatment is currently lacking. OBJECTIVE: We sought to assess short (4 weeks) and long-term (16 weeks) application of topical glucocorticosteroids on AD skin and define response biomarkers. METHODS: The effects of triamcinolone acetonide cream 0.025% were assessed based on gene expression and immunohistochemistry studies at baseline, 4 weeks, and 16 weeks in biopsy specimens from 15 patients with moderate-to-severe AD. RESULTS: At 16 weeks, only 3 patients were clinical responders (by using SCORAD50 criteria), but 6 patients qualified as responders based on histologic criteria. Baseline characteristics indicated more severe disease in nonresponders. While 3 of 15 patients experienced only transient benefit after 4 weeks, others showed progressive improvements toward 16 weeks. Topical glucocorticosteroid use in patients with AD resulted in improvements of the AD genomic signature of 25.6% at 4 weeks and 71.8% at 16 weeks, respectively, and even 123.9% in the histologic responder group. Cytokines (IL-12p40, IL-13, IL-22, CCL17, CCL18, peptidase inhibitor 3 [PI3]/elafin, and S100As) showed consistent decreases from baseline toward 16 weeks with corresponding improvements in epidermal disease hallmarks (keratin 16 and loricrin) in lesional skin from responders (P < .05). Nonresponders largely showed lesser/nonsignificant reductions in key inflammatory and barrier markers (keratin 16, IL-13, IL-22, CCL17, CCL18, PI3/elafin, S100As, and loricrin). The combination of IL-21 and IFN-γ baseline expression closely predicted individual clinical glucocorticosteroid responses at 16 weeks of treatment. CONCLUSION: Our study indicates that even low-potency glucocorticosteroids can broadly affect immune and barrier responses in patients with moderate-to-severe AD, associating higher baseline severity with increased steroid resistance in patients with AD.

Petrolatum: Barrier repair and antimicrobial responses underlying this "inert" moisturizer.

BACKGROUND: Petrolatum is a common moisturizer often used in the prevention of skin infections after ambulatory surgeries and as a maintenance therapy of atopic dermatitis (AD). However, the molecular responses induced by petrolatum in the skin have never been assessed. OBJECTIVE: We sought to define the cutaneous molecular and structural effects induced by petrolatum. METHODS: Thirty-six healthy subjects and 13 patients with moderate AD (mean SCORAD score, 39) were studied by using RT-PCR, gene arrays, immunohistochemistry, and immunofluorescence performed on control skin, petrolatum-occluded skin, and skin occluded with a Finn chamber only. RESULTS: Significant upregulations of antimicrobial peptides (S100A8/fold change [FCH], 13.04; S100A9/FCH, 11.28; CCL20/FCH, 8.36; PI3 [elafin]/FCH, 15.40; lipocalin 2/FCH, 6.94, human ß-defensin 2 [DEFB4A]/FCH, 4.96; P < .001 for all) and innate immune genes (IL6, IL8, and IL1B; P < .01) were observed in petrolatum-occluded skin compared with expression in both control and occluded-only skin. Application of petrolatum also induced expression of key barrier differentiation markers (filaggrin and loricrin), increased stratum corneum thickness, and significantly reduced T-cell infiltrates in the setting of "normal-appearing" or nonlesional AD skin, which is known to harbor barrier and immune defects. CONCLUSIONS: Petrolatum robustly modulates antimicrobials and epidermal differentiation barrier measures. These data shed light on the beneficial molecular responses of petrolatum in barrier-defective states, such as AD and postoperative wound care.

Port wine stain treated with a combination of pulsed dye laser and topical rapamycin ointment.

BACKGROUND AND OBJECTIVE: A port wine stain (PWS) is a type of capillary vascular malformation composed of malformed, dilated blood vessels within the papillary and reticular dermis. Currently, pulsed dye laser (PDL) is considered the therapeutic gold standard, although greater than 90% of lesions may be refractory to treatment. Studies have shown that a delay in treatment results in a higher proportion of patients who develop hypertrophy and nodularity within lesions that become more resistant to therapy. Therapeutic resistance is multifactorial, but is believed to be largely due to revascularization after laser treatment. Oral sirolimus and topical imiquimod have shown promise as adjunctive therapies to minimize post-laser revascularization, but both have significant side effects. We wish to demonstrate the utility of adjunct topical sirolimus to reduce revascularization after PDL treatment. STUDY DESIGN/PATIENTS AND METHODS: This is a single patient case report of a 56-year-old male patient with an extensive PWS. After seeing initial improvement with PDL alone, he began to experience thickening and nodularity of his PWS necessitating surgical debulking. Since this procedure, topical sirolimus 0.5% ointment has been added to his treatment regimen as an adjunct to PDL. The patient is being treated with PDL (Vbeam Perfecta, Candela/Syneron, Wayland, MA) every 4-6 weeks at varied settings with the following laser parameters: fluence 9-11 J/cm(2), pulse duration 0.45-1.5 ms, focal spot size 7 mm, cooling 30/20. Sirolimus 0.5% ointment is applied to the area twice daily. RESULTS: The patient showed significant improvement in color and texture of his PWS. Compared to the initial therapy of PDL alone, topical sirolimus ointment in conjunction with PDL demonstrated greater improvement and maintenance of therapeutic results with fewer overall laser treatments. CONCLUSION: Topical sirolimus 0.5% ointment is a safe and effective adjunct to PDL in the treatment of PWS.

Non-ablative fractional resurfacing in the treatment of scar contracture.

BACKGROUND AND OBJECTIVES: A 28-year-old female presented with extensive scarring after a traumatic injury to her right lower extremity. She had been hit by a vehicle one year prior to presentation and had several open fractures with extensive overlying cutaneous damage, which required multiple surgeries and skin grafts. She had limited range of motion of the affected limb secondary to scar contracture. STUDY DESIGN/MATERIALS AND METHODS: The patient received 6 treatments with a non-ablative fractional resurfacing (NAFR) device with two wavelengths (Fraxel DUAL, Solta Medical, Hayward, CA) spaced 4-8 weeks apart. The patient received two treatments with the 1927 nm NAFR thulium laser (10 mJ, 30% density, 8 passes) and two treatments with the 1550 nm NAFR laser (40 mJ, 17-26% density, 8 passes). Before and after treatment photographs were taken, as well as range of motion measurements with respect to her right ankle. RESULTS: The patient had 50-75% improvement in the texture and discoloration. There was both subjective and objective improvement in the range of motion of her right lower extremity. The patient experienced mild erythema and edema, both of which resolved after 7-10 days. CONCLUSION: Recent studies have shown great functional improvement in scar contractures with ablative fractional laser treatments; however, these treatments are accompanied by significant downtime along with risk of further scarring and infection. NAFR is an accessible treatment with a low side effect profile and to our knowledge has not been reported as efficacious in the treatment of scar contracture. This case report is novel in its demonstration of the utility of a dual wavelength NAFR in the treatment of scar contracture and functional impairment.

Fabricating Polymer Canopies onto Structured Surfaces Using Liquid Scaffolds.

In this work, we study the use of initiated chemical vapor deposition in conjunction with liquid scaffolds to deposit polymer canopies onto structured surfaces. Liquid is applied to micropillar and microstructure surfaces to act as a scaffolding template such that the deposited polymer films take the shape of the liquid surface. Two methods for directing the location of the scaffolding liquid were examined. In the first method, high surface tension liquids rest in a Cassie-Baxter state over the structured surfaces, allowing for control over the canopy location and size by varying the position and volume of the liquid. In the second method, the structured surfaces are inverted onto a thin layer of low surface tension liquid, allowing the coverage and height of the canopy to be controlled by varying the area and thickness of the liquid layer. Although the canopies demonstrated in this study were fabricated using initiated chemical vapor deposition, the generality of our scaffolding method can easily be translated to other vapor deposition processes.

Patients with atopic dermatitis have attenuated and distinct contact hypersensitivity responses to common allergens in skin.

BACKGROUND: Atopic dermatitis (AD) is the most common inflammatory disease. The prevalence of allergic contact dermatitis to allergens (eg, fragrance) is higher in patients with AD, despite a trend toward weaker clinical allergic contact dermatitis reactions. The role of the AD skin phenotype in modulating allergic sensitization to common sensitizers has not been evaluated. OBJECTIVE: We sought to investigate whether patients with AD have altered tissue immune responses on allergen challenge. METHODS: Gene expression and immunohistochemistry studies were performed on biopsy specimens from 10 patients with AD and 14 patients without AD patch tested with common contact allergens (nickel, fragrance, and rubber). RESULTS: Although 1085 differentially expressed genes (DEGs) were commonly modulated in patch-tested skin from patients with AD and patients without AD versus control skin, 1185 DEGs were uniquely altered in skin from patients without AD, and only 246 DEGs were altered in skin from patients with AD. Although many inflammatory products (ie, matrix metalloproteinase 12/matrix metalloproteinase 1/S100A9) were upregulated in both groups, higher-magnitude changes and upregulation of interferon responses were evident only in the non-AD group. Stratification by allergen showed decreased expression of immune, TH1-subset, and TH2-subset genes in nickel-related AD responses, with increased TH17/IL-23 skewing. Rubber/fragrance showed similar trends of lesser magnitude. Negative regulators showed higher expression in patients with AD. CONCLUSIONS: Through contact sensitization, our study offers new insights into AD. Allergic immune reactions were globally attenuated and differentially polarized in patients with AD, with significant decreases in levels of TH1 products, some increases in levels of TH17 products, and inconsistent upregulation in levels of TH2 products. The overall hyporesponsiveness in skin from patients with background AD might be explained by baseline immune abnormalities, such as increased TH2, TH17, and negative regulator levels compared with those seen in non-AD skin.

Cyclosporine in patients with atopic dermatitis modulates activated inflammatory pathways and reverses epidermal pathology.

BACKGROUND: Atopic dermatitis (AD) is the most common inflammatory disease. Evolving disease models link changes in epidermal growth and differentiation to T(H)2/T(H)22 cytokine activation. However, these models have not been tested by in vivo suppression of T-cell cytokines. Cyclosporine (CsA) is an immunosuppressant that is highly effective for severe disease, but its mechanism in AD skin lesions has not been studied. OBJECTIVE: We sought to establish the ability of a systemic immunosuppressant to modulate immune and epidermal alterations that form the pathogenic disease phenotype and to correlate changes with clinical improvement. METHODS: CsA's effects on AD skin pathology were evaluated by using gene expression and immunohistochemistry studies in baseline, week 2, and week 12 lesional and nonlesional biopsy specimens from 19 patients treated with 5 mg/kg/d CsA for 12 weeks. RESULTS: After 2 and 12 weeks of treatment, we observed significant reductions of 51% and 72%, respectively, in SCORAD scores. Clinical improvements were associated with significant gene expression changes in lesional but also nonlesional skin, particularly reductions in levels of T(H)2-, T(H)22-, and some T(H)17-related molecules (ie, IL-13, IL-22, CCL17, S100As, and elafin/peptidase inhibitor 3), and modulation of epidermal hyperplasia and differentiation measures. CONCLUSIONS: This is the first study that establishes a relationship between cytokine activation and molecular epidermal alterations, as well as correlations between disease biomarkers in the skin and clinical improvement. The reversal of the molecular phenotype with CsA and the associated biomarkers can serve as a reference for the successful modulation of tissue inflammation with specific immune antagonists in future studies, contributing to the understanding of the specific cytokines involved in epidermal pathology.

Molecular profiling of contact dermatitis skin identifies allergen-dependent differences in immune response.

BACKGROUND: Allergic contact dermatitis (ACD) is the most common occupational disease. Although murine contact hypersensitivity provides a framework for understanding ACD, it carries important differences from its human counterpart. Unlike the contact hypersensitivity model, which is induced by potent sensitizers (ie, dinitrofluorobenzene), human ACD is induced by weak-to-moderate sensitizers (ie, nickel), which cannot induce reactions in mice. Distinct hapten-specific immune-polarizing responses to potent inducers were suggested in mice, with unclear relevance to human ACD. OBJECTIVE: We explored the possibility of distinct T-cell polarization responses in skin to common clinically relevant ACD allergens. METHODS: Gene-expression and cellular studies were performed on common allergens (ie, nickel, fragrance, and rubber) compared with petrolatum-occluded skin, using RT-PCR, gene arrays, and immunohistochemistry. RESULTS: Despite similar clinical reactions in all allergen groups, distinct immune polarizations characterized different allergens. Although the common ACD transcriptome consisted of 149 differentially expressed genes across all allergens versus petrolatum, a much larger gene set was uniquely altered by individual allergens. Nickel demonstrated the highest immune activation, with potent inductions of innate immunity, TH1/TH17 and a TH22 component. Fragrance, and to a lesser extent rubber, demonstrated a strong TH2 bias, some TH22 polarization, and smaller TH1/TH17 contributions. CONCLUSIONS: Our study offers new insights into the pathogenesis of ACD, expanding the understanding of T-cell activation and associated cytokines in allergen-reactive tissues. It is the first study that defines the common transcriptome of clinically relevant sensitizers in human skin and identifies unique pathways preferentially activated by different allergens, suggesting that ACD cannot be considered a single entity.