Chimerism-Based Experimental Models for Tolerance Induction in Vascularized Composite Allografts: Cleveland Clinic Research Experience

The preclinical experimental models of vascularized composite allografts (VCAs) have been rapidly developed for the assessment of immunomodulatory protocols for clinical application. Recently, researchers have focused on immunomodulatory protocols which overcome the immunologic barrier between the allogeneic donor and recipient and may lead to tolerance induction. In order to test the feasibility of chimerism induction, experimental VCAs have been performed in different models including rodents, large animals, and nonhuman primates. These models differ in the complexity of transplanted tissue and in their responses to immunomodulatory protocols. In most applications, VCA contains multiple-tissue components; however, each individual component of CTA possesses unique immunologic characteristics that ultimately contribute to the chimerism induction and successful outcome of the VCA. Heterogenic character and complexity of tissue components in different VCA models determine the quality and robustness of donor-specific chimerism. As introduced in experimental studies, variable immunomodulatory options have been studied to achieve tolerance to VCA in rodents and large animal models allowing for widespread application in clinic. In this paper, based on our own experience, we have analyzed the current knowledge of tolerance-inducing strategies via chimerism induction in VCA experimental models in the context of immunomodulatory protocols and VCA complexity and their relevance and applicability to clinical practice

Chimerism-Based Experimental Models for Tolerance Induction in Vascularized Composite Allografts: Cleveland Clinic Research Experience

The preclinical experimental models of vascularized composite allografts (VCAs) have been rapidly developed for the assessment of immunomodulatory protocols for clinical application. Recently, researchers have focused on immunomodulatory protocols which overcome the immunologic barrier between the allogeneic donor and recipient and may lead to tolerance induction. In order to test the feasibility of chimerism induction, experimental VCAs have been performed in different models including rodents, large animals, and nonhuman primates. These models differ in the complexity of transplanted tissue and in their responses to immunomodulatory protocols. In most applications, VCA contains multiple-tissue components; however, each individual component of CTA possesses unique immunologic characteristics that ultimately contribute to the chimerism induction and successful outcome of the VCA. Heterogenic character and complexity of tissue components in different VCA models determine the quality and robustness of donor-specific chimerism. As introduced in experimental studies, variable immunomodulatory options have been studied to achieve tolerance to VCA in rodents and large animal models allowing for widespread application in clinic. In this paper, based on our own experience, we have analyzed the current knowledge of tolerance-inducing strategies via chimerism induction in VCA experimental models in the context of immunomodulatory protocols and VCA complexity and their relevance and applicability to clinical practice

Modafinil. Armodafinil. The use of eugeroics in assisting the treatment of depression, bipolar disorder, and schizophrenia. Benefits, drawbacks, and adverse effects

Modafinil is used to treat narcolepsy with cataplexy and is also being extensively studied to find new therapeutic uses. In recent years, there have been reports suggesting the potential benefits of modafinil in the treatment of psychiatric illnesses such as depression and bipolar depression. In the case of depression, modafinil can be used as an adjuvant or as monotherapy in patients who do not respond sufficiently to antidepressants. Studies have shown that modafinil improves symptoms of depression, reduces fatigue and improves cognitive function. There are also reports of a beneficial effect of modafinil in the treatment of seasonal depression. For bipolar depression, modafinil can be used as an adjunct therapy during the depressive phase, particularly in patients experiencing slowness, lethargy and loss of pleasure. Studies suggest that modafinil may improve depressive symptoms without inducing manic episodes. There are also data indicating modafinil's potential efficacy in treating negative symptoms and improving cognitive function in patients with schizophrenia. In conclusion, modafinil appears to be a promising drug in aiding the treatment of various psychiatric illnesses

Zatorowość płucna — czy infekcja SARS CoV-2 wpływa na przebieg kliniczny i rokowanie?

Introduction. Coronavirus disease 2019 (COVID-19) is a disease associated with an increased risk of thromboembolic complications up to 5 months after infection. The study aimed to assess the effect of active or recent (defined as within the past 3 months) COVID-19 on the clinical course of pulmonary embolism (PE) and patients’ survival as compared to patients with pulmonary embolism without a history or active COVID-19. Material and methods. Eighty-seven patients diagnosed with pulmonary embolism, and hospitalized from March 2020 to July 2021 were qualified for the study. The patients were divided into two groups: 1. COVID (+): patients with an active severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection confirmed by the polymerase chain reaction (PCR) or antigen test in the period no longer than 3 months before the diagnosis of PE (n = 38); 2. COVID (–): patients tested negative for SARS-CoV-2 and without typical history of infection (n = 49). The following data were analysed: clinical data, results of computed tomography, transthoracic echocardiography, ultrasound of deep veins of lower limbs, and results of laboratory tests (D-dimer, N-termina pro-B-type natriuretic peptide, cardiac troponin I, C-reactive protein [CRP]). For statistical analysis, Statistica version 13 was used. Results. Significant differences between the COVID (+) and COVID (–) groups were observed in the incidence of complete respiratory failure in 39.5% and 6.12% of patients respectively, p = 0.001 and higher in-hospital mortality 26.3% vs. 4.08%; p = 0.003. The Cox regression did not reveal any factor significantly associated with in-hospital mortality besides the previous diagnosis of neoplasm (hazard ratio 3.23; 95% confidence interval: 0.81; 12.95; p = 0.09). The COVID (+) group was characterized by significantly higher levels ​​of CRP (9.43/52.50/113.23 [mg/L] vs. 6.40/24.70/47.40 [mg/L]; p = 0.04). Conclusions. Patients with COVID-19 and PE present higher mortality than patients without concurrent or recent SARS-CoV-2 infection. Further studies are warranted to identify specific factors associated with the observed higher mortality in this population.Wstęp. Choroba koronawirusowa 2019 (COVID-19) jest związana ze zwiększonym ryzykiem powikłań zakrzepowo-zatorowych do 5 miesięcy po zakażeniu. Celem niniejszej pracy była ocena wpływu czynnego lub przebytego niedawno (w ciągu ostatnich 3 miesięcy) COVID-19 na przebieg kliniczny zatorowości płucnej (PE) i przeżycie pacjentów w porównaniu z pacjentami z zatorowością płucną bez wywiadu lub aktywnej COVID-19. Materiały i metody. Do badania zakwalifikowano 87 pacjentów z rozpoznaniem PE, hospitalizowanych od marca 2020 do lipca 2021 roku. Pacjentów podzielono na dwie grupy: 1. COVID (+): pacjenci z czynną infekcją SARS-CoV-2 potwierdzoną łańcuchową reakcją polimerazy (PCR) lub testem antygenowym w okresie nie dłuższym niż 3 miesiące przed rozpoznaniem PE, (n = 38); 2. COVID (–): pacjenci z ujemnym wynikiem testu na SARS-CoV-2 i bez typowej historii infekcji (n = 49). Analizie poddano dane kliniczne, wyniki tomografii komputerowej, echokardiografii przezklatkowej, USG żył głębokich kończyn dolnych, wyniki badań laboratoryjnych (D-dimer, N-końcowy fragment propeptydu natriuretycznego typu B, troponinę sercową I, białko C-reaktywne). Do analizy statystycznej wykorzystano program Statistica w wersji 13. Wyniki. Zaobserwowano istotne różnice między grupami z COVID (+) i COVID (–) w częstości występowania całkowitej niewydolności oddechowej odpowiednio u 39,5%; 6,12% pacjentów, p = 0,001 i wyższej śmiertelności wewnątrzszpitalnej (26,3% vs. 4,08%; p = 0,003). Regresja Coxa nie ujawniła żadnego czynnika istotnie związanego ze śmiertelnością wewnątrzszpitalną poza wcześniejszym rozpoznaniem nowotworu (współczynnik ryzyka 3,23; 95-procentowy przedział ufności: 0,81; 12,95; p = 0,09). Grupa COVID (+) charakteryzowała się istotnie wyższymi stężeniami białka C-reaktywnego (9,43/52,50/113,23 [mg/l] vs. 6,40/24,70/47,40 [mg/l]; p = 0,04). Wnioski. Wśród pacjentów z COVID-19 i PE wykazano wyższą śmiertelność niż u osób bez jednoczesnego lub niedawnego zakażenia SARS-CoV-2. Uzasadnione są dalsze badania w celu zidentyfikowania specyficznych czynników związanych z obserwowaną wyższą śmiertelnością w tej populacji

Mesenchymal Stem/Progenitor Cells and Their Derivates in Tissue Regeneration

Mesenchymal stem/stromal cells (MSC) have been extensively studied over the last 30 years in the context of their regenerative and immunomodulatory activities for potential application in regenerative medicine [...

Mesenchymal Stromal Cells and Tissue-Specific Progenitor Cells: Their Role in Tissue Homeostasis

Multipotent mesenchymal stromal/stem cells (MSCs) reside in many human organs and comprise heterogeneous population of cells with self-renewal ability. These cells can be isolated from different tissues, and their morphology, immunophenotype, and differentiation potential are dependent on their tissue of origin. Each organ contains specific population of stromal cells which maintain regeneration process of the tissue where they reside, but some of them have much more wide plasticity and differentiate into multiple cells lineage. MSCs isolated from adult human tissues are ideal candidates for tissue regeneration and tissue engineering. However, MSCs do not only contribute to structurally tissue repair but also MSC possess strong immunomodulatory and anti-inflammatory properties and may influence in tissue repair by modulation of local environment. This paper is presenting an overview of the current knowledge of biology of tissue-resident mesenchymal stromal and progenitor cells (originated from bone marrow, liver, skeletal muscle, skin, heart, and lung) associated with tissue regeneration and tissue homeostasis

Immune Responses in Transplantation: Application to Composite Tissue Allograft

After announcements of successful hand, larynx, knee, muscle, nerve, and, most recently, face transplantation, composite tissue allografts (CTAs) have been introduced into the armamentarium of plastic and reconstructive surgery. Because the microsurgical techniques required to perform CTA transplants are well established and used in daily practice by plastic surgeons, the immunologic aspects of transplantation remain of great interest to plastic surgeons. CTAs offer a unique potential for coverage of large multitissue defects; however, compared with the relatively homogenous tissue of solid organ transplants, the heterogenicity of tissue components of CTA may generate high immunologic responses. Although modern immunosuppressive agents significantly improve successful allograft acceptance, chronic allograft rejection as well as immunosuppressive drug toxicity remain major problems in the clinical practice of transplantation. The major goal of transplantation immunology is to develop tolerance to allograft transplants and long-term drug-free survival. Several experimental protocols have been designed to develop tolerance; however, none of them have been proved to induce tolerance in clinical transplantation. This review outlines the mechanisms of allograft acceptance and rejection and describes the barriers to transplantation tolerance based on our current knowledge as it applies to solid organs and CTA transplants. The review also describes innovative immunosuppressive protocols