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Michael Kaiser,1 Rama Abdin,2 Simonetta I Gaumond,1 Naiem T Issa,3,4 Joaquin J Jimenez1 1Dr. Phillip Frost Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, FL, USA; 2Charles E. Schmidt College of Medicine, Florida Atlantic University, Boca Raton, FL, USA; 3Forefront Dermatology, Vienna, VA, USA; 4Issa Research and Consulting, LLC, Springfield, VA, USACorrespondence: Joaquin J Jimenez, Phillip Frost Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, FL, USA, Tel +1 305-243-6586, Email j.jimenez@med.miami.eduAbstract: Androgenetic alopecia (AGA) is the most common cause of hair loss in men and women. Traditionally, topical minoxidil and oral finasteride have been the standard of care yielding mixed results. New treatments such as Low-Level Laser Therapy (LLLT), microneedling, platelet-rich plasma (PRP), and others have been extensively studied in the literature, and the purpose of this review is to provide a comprehensive discussion of the latest treatment methods and their efficacy in treating AGA. Novel therapies such as oral minoxidil, topical finasteride, topical spironolactone, botulinum toxin, and stem cell therapy offer interesting alternatives to standard of care therapies for patients. In this review, we present data from recent studies on the clinical efficacy of these treatments. Furthermore, as new treatments have emerged, clinicians have tested combination therapies to assess whether there may be a synergistic relationship between multiple modalities. While there has been a great increase in the treatments available for AGA, the quality of evidence varies greatly and there is still a great need for randomized double blinded clinical trials to adequately assess the clinical efficacy of some treatments. While PRP and LLLT have demonstrated encouraging results, standardized treatment protocols are needed to adequately inform clinicians on how to use such therapies. Given the abundance of new therapeutic options, clinicians and patients must weigh the benefits and risks of each treatment option for AGA.Keywords: androgenetic alopecia, minoxidil, finasteride, platelet rich plasma, microneedling

Background/Aims: Literature regarding safe doses of carvedilol is limited, and safe doses across different Child classes of chronic liver disease are not clear. Patients and Methods: A total of 102 consecutive cirrhotic patients with significant portal hypertension were included in this study. Hepatic venous pressure gradient was measured at baseline and 3 months after dose optimization. Results: A total of 102 patients (63 males, 39 females) with a mean age of 58.3 ± 6.6 years were included. Among these patients, 42.2% had Child Class A, 31.9% had Class B, and 26.6% had Child Class C liver disease. The mean baseline hepatic venous pressure gradient was 16.75 ± 2.12 mmHg, and after dose optimization and reassessment of hepatic venous pressure gradient at 3 months, the mean reduction in the hepatic venous pressure gradient was 5.5 ± 1.7 mmHg and 2.8 ± 1.6 mmHg among responders and nonresponders respectively. The mean dose of carvedilol was higher in nonresponders (19.2 ± 5.7 mg) than responders (18.75 ± 5.1 mg). However, this difference was not statistically significant (P > 0.05). The univariate analysis determined that the absence of adverse events, the absence of ascites, and low baseline cardiac output were significantly associated with chronic response, whereas, the etiology, Child class, variceal size (large vs small), and gender were not. On multivariate analysis, the absence of any adverse event was determined to be an independent predictor of chronic response (OR 11.3, 95% CI; 1.9–67.8). Conclusion: The proper optimization of the dose of carvedilol, when administered chronically, may enable carvedilol treatment to achieve a greater response with minimum side effects among different Child classes of liver disease.

Alice L Yu,1 Michaela Kaiser,1 Markus Schaumberger,1 Elisabeth Messmer,1 Daniel Kook,1 Ulrich Welge-Lussen2 1Department of Ophthalmology, Ludwig-Maximilians-University, Munich, 2Department of Ophthalmology, Friedrich-Alexander-University, Erlangen, Germany Purpose: In this study, we assessed the outcome of penetrating keratoplasties using organ-cultured corneal tissues at the University Eye Hospital, Ludwig-Maximilians-University, Munich, Germany. The goal was to identify perioperative and postoperative risk factors that may affect graft survival.Patients and methods: The medical records of 377 patients who underwent a penetrating keratoplasty between 2001 and 2011 were reviewed. Organ-cultured corneal tissue was obtained from the eye bank of Ludwig-Maximilians-University. Perioperative and postoperative risk factors for graft failure were evaluated by univariate and multivariate analyses.Results: The 5-year overall survival rate of penetrating keratoplasties was 68%. Graft failure occurred in 26% of patients. High-risk keratoplasties, such as repeat penetrating keratoplasties and emergency penetrating keratoplasties, as well as postoperative conditions, such as glaucoma, retinal surgery, suture problems, persistent epithelial defect, infectious keratitis, and graft rejection, were significantly associated with graft failure in the multivariate analyses.Conclusion: This study showed a similar graft-survival rate as demonstrated in previous studies. In addition, a number of perioperative and postoperative risk factors were identified in this specific patient population. Keywords: penetrating keratoplasty, graft failure, risk factor, cornea bank

Renata V Contri,1 Luiza A Frank,2 Moacir Kaiser,1 Adriana R Pohlmann,1,3 Silvia S Guterres1,2 1Programa de Pós-Graduação em Ciências Farmacêuticas, 2Faculdade de Farmácia, 3Instituto de Química, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil Abstract: Capsaicin, a topical analgesic used in the treatment of chronic pain, has irritant properties that frequently interrupt its use. In this work, the effect of nanoencapsulation of the main capsaicinoids (capsaicin and dihydrocapsaicin) on skin irritation was tested in humans. Skin tolerance of a novel vehicle composed of chitosan hydrogel containing nonloaded nanocapsules (CH-NC) was also evaluated. The chitosan hydrogel containing nanoencapsulated capsaicinoids (CH-NC-CP) did not cause skin irritation, as measured by an erythema probe and on a visual scale, while a formulation containing free capsaicinoids (chitosan gel with hydroalcoholic solution [CH-ET-CP]) and a commercially available capsaicinoids formulation caused skin irritation. Thirty-one percent of volunteers reported slight irritation one hour after application of CH-NC-CP, while moderate (46% [CH-ET-CP] and 23% [commercial product]) and severe (8% [CH-ET-CP] and 69% [commercial product]) irritation were described for the formulations containing free capsaicinoids. When CH-NC was applied to the skin, erythema was not observed and only 8% of volunteers felt slight irritation, which demonstrates the utility of the novel vehicle. A complementary in vitro skin permeation study showed that permeation of capsaicinoids through an epidermal human membrane was reduced but not prevented by nanoencapsulation. Keywords: chitosan, nanocapsules, capsaicinoids, skin irritation, skin permeation

Airway hyperresponsiveness (AHR) is classically found in asthma, and persistent AHR is associated with poor asthma control. Although airway smooth muscle (ASM) cells play a critical pathophysiologic role in AHR, the paracrine contributions of surrounding cells such as fibroblasts to the contractile phenotype of ASM cells have not been examined fully. This study addresses the hypothesis that nicotine promotes a contractile ASM cell phenotype by stimulating fibroblasts to increase nerve growth factor (NGF) secretion into the environment.Primary lung fibroblasts isolated from wild type and α7 nicotinic acetylcholine receptor (α7 nAChR) deficient mice were treated with nicotine (50 µg/ml) in vitro for 72 hours. NGF levels were measured in culture media and in bronchoalveolar lavage (BAL) fluid from asthmatic, smoking and non-smoking subjects by ELISA. The role of the NFκB pathway in nicotine-induced NGF expression was investigated by measuring NFκB nuclear translocation, transcriptional activity, chromatin immunoprecipitation assays, and si-p65 NFκB knockdown. The ability of nicotine to stimulate a fibroblast-mediated, contractile ASM cell phenotype was confirmed by examining expression of contractile proteins in ASM cells cultured with fibroblast-conditioned media or BAL fluid.NGF levels were elevated in the bronchoalveolar lavage fluid of nicotine-exposed mice, current smokers, and asthmatic children. Nicotine increased NGF secretion in lung fibroblasts in vitro in a dose-dependent manner and stimulated NFκB nuclear translocation, p65 binding to the NGF promoter, and NFκB transcriptional activity. These responses were attenuated in α7 nAChR deficient fibroblasts and in wild type fibroblasts following NFκB inhibition. Nicotine-treated, fibroblast-conditioned media increased expression of contractile proteins in ASM cells.Nicotine stimulates NGF release by lung fibroblasts through α7 nAChR and NFκB dependent pathways. These novel findings suggest that the nicotine-α7 nAChR-NFκB- NGF axis may provide novel therapeutic targets to attenuate tobacco smoke-induced AHR.

Pulmonary hypertension (PH) is a serious disorder that causes significant morbidity and mortality. The pathogenesis of PH involves complex derangements in multiple pathways including reductions in peroxisome proliferator-activated receptor gamma (PPARγ). Hypoxia, a common PH stimulus, reduces PPARγ in experimental models. In contrast, activating PPARγ attenuates hypoxia-induced PH and endothelin 1 (ET-1) expression. To further explore mechanisms of hypoxia-induced PH and reductions in PPARγ, we examined the effects of hypoxia on selected microRNA (miRNA or miR) levels that might reduce PPARγ expression leading to increased ET-1 expression and PH. Our results demonstrate that exposure to hypoxia (10% O2) for 3-weeks increased levels of miR-27a and ET-1 in the lungs of C57BL/6 mice and reduced PPARγ levels. Hypoxia-induced increases in miR-27a were attenuated in mice treated with the PPARγ ligand, rosiglitazone (RSG, 10 mg/kg/d) by gavage for the final 10 d of exposure. In parallel studies, human pulmonary artery endothelial cells (HPAECs) were exposed to control (21% O2) or hypoxic (1% O2) conditions for 72 h. Hypoxia increased HPAEC proliferation, miR-27a and ET-1 expression, and reduced PPARγ expression. These alterations were attenuated by treatment with RSG (10 µM) during the last 24 h of hypoxia exposure. Overexpression of miR-27a or PPARγ knockdown increased HPAEC proliferation and ET-1 expression and decreased PPARγ levels, whereas these effects were reversed by miR-27a inhibition. Further, compared to lungs from littermate control mice, miR-27a levels were upregulated in lungs from endothelial-targeted PPARγ knockout (ePPARγ KO) mice. Knockdown of either SP1 or EGR1 was sufficient to significantly attenuate miR-27a expression in HPAECs. Collectively, these studies provide novel evidence that miR-27a and PPARγ mediate mutually repressive actions in hypoxic pulmonary vasculature and that targeting PPARγ may represent a novel therapeutic approach in PH to attenuate proliferative mediators that stimulate proliferation of pulmonary vascular cells.

The pathogenesis of acute lung injury (ALI) involves bidirectional cooperation and close interaction between inflammatory and coagulation pathways. A key molecule linking coagulation and inflammation is the procoagulant thrombin, a serine protease whose concentration is elevated in plasma and lavage fluids of patients with ALI and acute respiratory distress syndrome (ARDS). However, little is known about the mechanism by which thrombin contributes to lung inflammatory response. In this study, we developed a new mouse model that permits investigation of lung inflammation associated with intravascular coagulation. Using this mouse model and in vitro approaches, we addressed the role of non-muscle myosin light chain kinase (nmMLCK) in thrombin-induced endothelial cell (EC) inflammation and lung neutrophil (PMN) infiltration. Our in vitro experiments revealed a key role of nmMLCK in ICAM-1 expression by its ability to control nuclear translocation and transcriptional capacity of RelA/p65 in EC. When subjected to intraperitoneal thrombin challenge, wild type mice showed a marked increase in lung PMN infiltration via expression of ICAM-1. However, these responses were markedly attenuated in mice deficient in nmMLCK. These results provide mechanistic insight into lung inflammatory response associated with intravascular coagulation and identify nmMLCK as a critical target for modulation of lung inflammation.

The Borexino detector has convincingly shown its outstanding performances in the low energy, sub-MeV regime through its unprecedented accomplishments in the solar and geo-neutrinos detection. These performances make it the ideal tool to accomplish a state-of-the-art experiment able to test unambiguously the long-standing issue of the existence of a sterile neutrino, as suggested by the several anomalous results accumulated over the past two decades, i.e. the outputs of the LSND and Miniboone experiments, the results of the source calibration of the two Gallium solar neutrino experiments, and the recently hinted reactor anomaly. The SOX project will exploit two sources, based on Chromium and Cerium, respectively, which deployed under the experiment, in a location foreseen on purpose at the time of the construction of the detector, will emit two intense beams of neutrinos (Cr) and anti-neutrinos (Ce). Interacting in the active volume of the liquid scintillator, each beam would create an unmistakable spatial wave pattern in case of oscillation of the νe (or ν̅e) into the sterile state: such a pattern would be the smoking gun proving the existence of the new sterile member of the neutrino family. Otherwise, its absence will allow setting a very stringent limit on its existence.

The Borexino experiment located in the Gran Sasso National Laboratory, is an organic liquid scintillator detector conceived for the real time spectroscopy of low energy solar neutrinos. The phase-I of the data taking campaign (2007 – 2010) has allowed the first independent measurements of 7Be and pep solar neutrino fluxes as well as the first measurement of anti-neutrinos from the Earth. After a purification of the scintillator, Borexino is now in phase-II since 2011. Thanks to the unprecedented background levels, we have performed the first flux measurement of neutrinos from the fundamental pp reaction which powers the Sun. We review this breakthrough result and other recent results, including the latest review of our terrestrial neutrino analysis. We also discuss the upcoming measurements on middle energy solar neutrino spectral components (pep, CNO) and the new project SOX devoted to the study of sterile neutrinos via the use of a neutrino source placed in close proximity of the detector’s active material.