Umbilical Cord-derived Mesenchymal Stem Cells for COVID-19 Patients with Acute Respiratory Distress Syndrome (ARDS).

The coronavirus SARS-CoV-2 is cause of a global pandemic of a pneumonia-like disease termed Coronavirus Disease 2019 (COVID-19). COVID-19 presents a high mortality rate, estimated at 3.4%. More than 1 out of 4 hospitalized COVID-19 patients require admission to an Intensive Care Unit (ICU) for respiratory support, and a large proportion of these ICU-COVID-19 patients, between 17% and 46%, have died. In these patients COVID-19 infection causes an inflammatory response in the lungs that can progress to inflammation with cytokine storm, Acute Lung Injury (ALI), Acute Respiratory Distress Syndrome (ARDS), thromboembolic events, disseminated intravascular coagulation, organ failure, and death. Mesenchymal Stem Cells (MSCs) are potent immunomodulatory cells that recognize sites of injury, limit effector T cell reactions, and positively modulate regulatory cell populations. MSCs also stimulate local tissue regeneration via paracrine effects inducing angiogenic, anti-fibrotic and remodeling responses. MSCs can be derived in large number from the Umbilical Cord (UC). UC-MSCs, utilized in the allogeneic setting, have demonstrated safety and efficacy in clinical trials for a number of disease conditions including inflammatory and immune-based diseases. UC-MSCs have been shown to inhibit inflammation and fibrosis in the lungs and have been utilized to treat patients with severe COVID-19 in pilot, uncontrolled clinical trials, that reported promising results. UC-MSCs processed at our facility have been authorized by the FDA for clinical trials in patients with an Alzheimer's Disease, and in patients with Type 1 Diabetes (T1D). We hypothesize that UC-MSC will also exert beneficial therapeutic effects in COVID-19 patients with cytokine storm and ARDS. We propose an early phase controlled, randomized clinical trial in COVID-19 patients with ALI/ARDS. Subjects in the treatment group will be treated with two doses of UC-MSC (l00 × 106 cells). The first dose will be infused within 24 hours following study enrollment. A second dose will be administered 72 ± 6 hours after the first infusion. Subject in the control group will receive infusion of vehicle (DPBS supplemented with 1% HSA and 70 U/kg unfractionated Heparin, delivered IV) following the same timeline. Subjects will be evaluated daily during the first 6 days, then at 14, 28, 60, and 90 days following enrollment (see Schedule of Assessment for time window details). Safety will be determined by adverse events (AEs) and serious adverse events (SAEs) during the follow-up period. Efficacy will be defined by clinical outcomes, as well as a variety of pulmonary, biochemical and immunological tests. Success of the current study will provide a framework for larger controlled, randomized clinical trials and a means of accelerating a possible solution for this urgent but unmet medical need. The proposed early phase clinical trial will be performed at the University of Miami (UM), in the facilities of the Diabetes Research Institute (DRI), UHealth Intensive Care Unit (ICU) and the Clinical Translational Research Site (CTRS) at the University of Miami Miller School of Medicine and at the Jackson Memorial Hospital (JMH).

Johnson square procedure for lentigo maligna and lentigo maligna melanoma.

BACKGROUND: Lentigo maligna (LM) and lentigo maligna melanoma (LMM) can be difficult to manage surgically. Predetermined margins can be inadequate because of subclinical spread, or can affect function when margins are adjacent to the eye or mouth. AIM: To describe our 5-year experience in Nottingham of using the staged square procedure (Johnson square) in excising difficult facial LM and LMM. METHODS: The square procedure is a staged technique useful for ill-defined lesions and for lesions that have a high recurrence rate due to subclinical spread. It uses paraffin wax-embedded peripheral vertical sections for margin control, ensuring complete clearance as the surgical margins are usually examined at distances of 2-5 mm from the periphery of the lesion. RESULTS: We treated 21 patients with LM or LMM with the staged square procedure over a 5-year period. Of the 21 patients, 10 needed only one stage of surgery, 6 needed two stages, 3 needed three stages and 2 needed four stages. To date, there has been only one recurrence, which was of an extensive lesion that crossed the medial canthus, making margin control impossible because of the anatomical limitations. CONCLUSIONS: The staged square procedure is an effective treatment for LM and LMM. It attempts to conserve tissue while ensuring a higher clearance rate. This offers favourable cosmetic outcomes and better prognosis, especially for facial LM and LMM.

Review of the 92nd Annual Meeting of the British Association of Dermatologists, 3-5 July 2012, Birmingham, U.K.

This is a synopsis of the main research and clinical findings presented at the 92nd Annual Meeting of the British Association of Dermatologists, held on 3-5 July 2012 in Birmingham, U.K. The conference highlighted the biological, epidemiological and therapeutic advances that have been made recently in the field of dermatology. This synopsis is a selection of the major findings from the meeting; it is not intended to be a substitute for reading the conference proceedings and related references quoted in this article.

Primary cutaneous B-cell lymphoma in Nottinghamshire U.K.: prognosis of subtypes defined in the WHO-EORTC classification.

BACKGROUND: Primary cutaneous B-cell lymphomas (PCBCL), with the exception of large B-cell lymphoma of leg type and intravascular large B-cell lymphoma, are associated with an excellent prognosis. These lymphomas have become much better understood in recent years leading to the publication in 2005 of the World Health Organization-European Organisation for Research and Treatment of Cancer classification. OBJECTIVES: To determine the relative frequency of occurrence of subtypes of PCBCL in a defined population, and the survival of patients with these subtypes. METHODS: During the period 1987-2009, 61 consecutive patients with PCBCL were identified from the Nottingham Lymphoma Registry (population 1·1 million). After histological review, the number of patients with each subtype was as follows: marginal zone, 18; follicle centre, 14; diffuse large B cell, leg type, 16; diffuse large B cell, other sites, 12; and intravascular large B cell, one. RESULTS: The 5- and 10-year lymphoma-specific survival for patients with marginal zone lymphoma was 100%. The only patient with intravascular large B-cell lymphoma died from widespread disease in spite of chemotherapy. The 4-year lymphoma-specific survival for follicle centre cell lymphoma was 90%. Patients with the other subtypes had the following 5-year lymphoma-specific survival rates: diffuse large B cell, leg type, 61% and diffuse large B cell, other, 40%. The median age at diagnosis for patients with diffuse large B-cell lymphoma, leg type was 82 years and as a consequence the 5-year overall survival was only 15%. There was a 3·4-fold increase in the incidence of PCBCL from the period 1987-1997 to the period 1998-2009. CONCLUSIONS: PCBCL is a rare disease (incidence around three per million population per year). It is, in our view, essential that it is diagnosed by a pathologist with an interest in cutaneous lymphoma and that the very different prognosis of the individual subtypes is appreciated by the treating clinician.

Acral histiocytic nodules: a possible new variant of non-X histiocytosis.

Many types of histiocytoses have been described. We present a case of a 56-year-old woman who presented with multiple nodules on the hands. On histological examination of an excision biopsy, a mainly dermal lesion was seen, with scattered mononuclear inflammatory cells and occasional multinucleated cells in the background. The tumour was composed of short spindle-shaped histiocyte-like cells with vesicular nuclei and small nucleoli. These cells were positive for CD68 and focally positive for smooth-muscle actin. There was no lipid or haemosiderin pigment, and no cholesterol clefts. Further investigations did not find evidence of bony or systemic involvement. The non-Langerhans cell histiocytoses, also known as non-X histiocytoses, are rare and of unknown aetiology. Clinicopathologically, this case does not seem to fit with any of the recognized subtypes, and we propose that it may represent a previously undescribed variant of the disease.

A randomized trial of methotrexate vs. azathioprine for severe atopic eczema: a critical appraisal.

AIM: Schram et al. aimed to compare the efficacy and safety of methotrexate vs. azathioprine in adults with severe atopic eczema. SETTING AND DESIGN: This single-blind, parallel-group (ratio 1 : 1), randomized controlled trial was conducted in a secondary care setting in the Netherlands between July 2009 and December 2010. STUDY EXPOSURE: Patients with severe atopic eczema were randomly assigned in a 1 : 1 ratio to receive either methotrexate (10-22·5 mg weekly) or azathioprine (1·5-2·5 mg kg(-1) daily) for 12 weeks, followed by a 12-week follow-up period. OUTCOMES: The outcome measures comprised various eczema severity measures including: SCORing of Atopic Dermatitis index (SCORAD); Investigator Global Assessment (IGA); Patient Global Assessment (PGA); Eczema Area and Severity Index (EASI); and Patient-Oriented Eczema Measurement (POEM). Further outcomes included a visual analogue scale of itch and sleeplessness; Skindex-17; serum levels of thymus and activation-regulated chemokine; quantity of topical corticosteroids used; and the number of courses of rescue medication (oral prednisolone) used. PRIMARY OUTCOME MEASURE: The primary outcome was the mean change in SCORAD after 12 weeks of treatment. RESULTS: Forty-five patients were screened and 42 of these were included in the trial. At week 12, patients in the methotrexate group had a mean ± SD relative reduction in SCORAD of 42 ± 18% compared with 39 ± 25% in the azathioprine group (P = 0·52). Proportions of patients achieving at least mild disease and reductions in impact on quality of life and symptoms were similar in both groups at weeks 12 and 24. No statistically significant differences were found in the number and severity of adverse events. Abnormalities in blood count were more common in the azathioprine group but no serious adverse events occurred in either group. CONCLUSIONS: Schram et al. conclude that both methotrexate and azathioprine achieved clinically relevant improvement and were safe in the short term. They also conclude that both treatments are appropriate treatment options for severe atopic eczema in adult populations.

Outstanding survival and regeneration process by the use of intelligent acellular dermal matrices and mesenchymal stem cells in a burn pig model.

A pig model with a deep large burn was used to study the regeneration process induced by mesenchymal stem cells (MSCs) and acellular pig dermal matrices, made intelligent by the combination with biodegradable nanofibers loaded with growth factors (granulocyte-macrophage colony-stimulating factor and epidermal growth factor) and coated with the anti-CD44 monoclonal antibody (intelligent acellular dermal matrices, IADMs). These IADMs are specially designed to integrate in the wound bed as new biological scaffolds as well as to specifically recruit and attach circulating and/or externally applied MSCs through the anti-CD44 antibody while delivering precise amounts of growth factors. In this way, the reparative process as well as the aesthetic and functional results were enhanced in our burn model. The animal survived, the wound was completely closed, and total regeneration of the skin was obtained without much scarring. Surprisingly, hair follicles and other skin appendages developed despite the severity and deepness of the burn. Even burned muscles and ribs seemed to have undergone a regenerative process by the end of the study. Based on these findings, we have proposed the use of IADMs and autologous, allogeneic or xenogeneic MSCs, as a new paradigm for the future treatment of large burns and probably other dermatological and cosmetic human conditions.

Circulating endothelial progenitor cells and erectile dysfunction: possibility of nutritional intervention?

To provide an overview of molecular and cellular processes involved in erectile dysfunction (ED) with emphasis on circulating endothelial progenitor cells (EPC) and discuss possible nutraceutical means of intervention. A review of literature on Pubmed related to EPC and ED was conducted. Patients with ED appear to possess a reduced number of circulating EPC, which is associated with poor endothelial function possibly as a result of underlying low-grade inflammation. Several studies support the possibility of improving erectile function by inhibition of inflammation as well as administration of various stem cell types. One particularly interesting approach is nutraceutical supplementation to increase circulating EPC, as demonstrated in the product Stem-Kine. Interventions aimed at increasing circulating EPC may have potential in treatment of vascular ED.

Clinical benefits of continuous leukocyte filtration during cardiopulmonary bypass in patients undergoing valvular repair or replacement.

Valve operations in the form of repair or replacement make up a significant population of patients undergoing surgical procedures in the USA annually with the use of cardiopulmonary bypass. These patients experience a wide range of complications that are considered to be mediated by activation of complement and leukocytes. The extracorporeal perfusion circuit consists of multiple synthetic artificial surfaces. The biocompatibility of the blood contact surfaces is a variable that predisposes patients to an increased risk of complement mediation and activation. This can result in an inflammatory process, causing leukocytes to proliferate and sequester in the major organ systems. The purpose of this study was to determine whether filtration of activated leukocytes improved clinical outcomes following surgical intervention for valve repair or replacement. In this paper, we report a retrospective matched cohort study of 700 patients who underwent valve procedures from June 1999 to December 2002. The control group (CG) consisted of patients who had a conventional arterial line filter. In the study group (SG), patients had a conventional arterial line filter and a leukocyte arterial line filter (Pall Medical, NY). In the SG, blood diverted to the cardioplegia system was also leukocyte depleted to enhance myocardial preservation by adapting this device to the outflow port on the filter. Patient characteristics were similar for the SG and the CG, including 228 males and 122 females, mean age (62.4 versus 64.2 years), cardiopulmonary bypass time (127+/-64 versus 116+/-53 min), and aortic crossclamp time (84+/-23 versus 81+/-23 min). Our results demonstrate that the SG achieved statistically significant reduction in the time to extubation (p =0.03) and the number of patients with prolonged intubation in excess of 24 hours (p <0.04), in addition to improved postoperative oxygenation (p=0.01), and decreased length of hospital stay (p =0.03). We believe that leukocyte filters are clinically beneficial, as demonstrated by the results presented in this study.