Aleah Brubaker, MD

Abstract

Combined heart-liver transplant is an emerging option for patients with indications for heart transplantation and otherwise prohibitive hepatic dysfunction. Heart-liver transplantation is particularly relevant for patients with single ventricle physiology who often develop Fontan-associated liver disease and fibrosis. While only performed at a limited number of centers, several approaches to combined heart-liver transplantation have been described. The en bloc technique offers several potential advantages over the traditional sequential technique. Specifically, en bloc heart-liver transplantation may allow improved hemodynamics, decreased bleeding, reduced liver allograft ischemic time, and may result in reduced rates of graft dysfunction. Here we describe our center's en bloc heart-liver procurement technique in detail, with the aim of allowing broader use and standardization of this technique. Supplemental Visual Abstract; http://links.lww.com/TP/C147.

View details for DOI 10.1097/TP.0000000000003697

View details for PubMedID 33606485

View details for Web of Science ID 000574027003241

View details for Web of Science ID 000618872101233

View details for Web of Science ID 000618872101227

View details for Web of Science ID 000618872101244

View details for Web of Science ID 000505634300148

Abstract

The data on the outcomes of solid organ transplant recipients who have contracted coronavirus disease 2019 (COVID-19) are still emerging. Kidney transplant recipients are commonly prescribed renin-angiotensin-aldosterone system (AAS) inhibitors given the prevalence of hypertension, diabetes, and cardiovascular disease. As the angiotensin-converting enzyme 2 (ACE2) facilitates the entry of coronaviruses into target cells, there have been hypotheses that preexisting use of Renin-Angiotensin-Aldosterone System (RAAS) inhibitors may increase the risk of developing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Given the common use of RAAS inhibitors among solid organ transplant recipients, we sought to review the RAAS cascade, the mechanism of SARS-CoV-2 entry, and pertinent data related to the effect of RAAS inhibitors on ACE2 to guide management of solid organ transplant recipients during the COVID-19 pandemic. At present there is no clear evidence to support the discontinuation of RAAS inhibitors in solid organ transplant recipients during the COVID-19 pandemic.

View details for DOI 10.1111/ctr.13991

View details for PubMedID 32446267

View details for Web of Science ID 000505634300187

View details for Web of Science ID 000485482200254

View details for DOI 10.1097/TP.0000000000002093

View details for Web of Science ID 000437463700036

View details for Web of Science ID 000392621100013

Abstract

Exacerbation of cutaneous wound infections and delayed wound closure are frequent complications seen in alcohol exposed subjects who sustain injuries. We previously reported that acute alcohol exposure alters the early dermal inflammatory phase of wound healing and also several parameters of the proliferative wound healing phase in wounds from ethanol (EtOH)-treated mice for several days or weeks after EtOH exposure. Hence, it is likely that the cumulative defects arising in the early phases of the wound healing process directly contribute to the increased complications observed in intoxicated patients at the time of injury.C57BL/6 mice were given intraperitoneal EtOH (2.2 g/kg body weight) or vehicle (saline) EtOH using our episodic binge EtOH exposure protocol (3 days EtOH, 4 days off, 3 days EtOH) to yield a blood alcohol concentration (BAC) of 300 mg/dl at the time of wounding. Mice were subjected to six 3 mm full-thickness dorsal wounds and immediately treated topically with 10 l of sterile saline (control) or diluted Staphylococcus aureus corresponding to 1 10(4) CFU/wound. Wounds were harvested at 24 hours post injury to evaluate wound area, neutrophil and macrophage accumulation, and the protein levels of cytokines, interleukin-6 (IL-6), IL-1, and IL-10, and chemokines, macrophage inflammatory protein-2 (MIP-2) and MIP-1, monocyte chemotactic protein-1 (MCP-1), and keratinocyte-derived chemokine (KC). The abundance and localization of cathelicidin-related antimicrobial peptide (CRAMP) and the kallikrein epidermal proteases (KLK5 and KLK7) were also determined.Compared to control mice, EtOH-treated mice exhibited delayed wound closure, decreased macrophage accumulation, and impaired production of MIP-1. Furthermore, skin from EtOH-treated mice demonstrated a reduction in the abundance of epidermal CRAMP and KLK7.These findings suggest that EtOH exposure hinders several distinct components of the innate immune response, including phagocyte recruitment and chemokine/cytokine and AMP production. Together, these effects likely contribute to delayed wound closure and enhanced infection severity observed in intoxicated patients.

View details for DOI 10.1111/acer.12369

View details for Web of Science ID 000334657200020

View details for PubMedID 24689549

View details for PubMedCentralID PMC4001884

Abstract

T-helper (Th)-17 lymphocytes play a crucial role in maintenance and regulation of gut immunity. Our laboratory has demonstrated that acute ethanol (EtOH) exposure before burn injury results in intestinal T cell suppression and enhanced bacterial translocation.To extend these studies, we examined the effects of EtOH exposure and burn injury on Th17 responses within intestinal lymphoid Peyer's patches (PP). We further investigated whether restitution of interleukin (IL)-23 enhances PP cell IL-17 and IL-22 after EtOH and burn injury.Male mice, approximately 25 g, were gavaged with EtOH (2.9 mg/kg) before receiving an approximately 12.5% total body surface area full thickness burn. One day postinjury, PP mixed cells were cultured in the presence of plate-bound anti-CD3/soluble anti-CD28 in the presence or absence of IL-23 for 48 hours. Supernatants were harvested for IL-17 and IL-22 levels.When combined with EtOH intoxication, burn injury significantly decreased IL-17 and IL-22, as compared with sham injury. IL-23 treatment successfully increased levels of IL-22 but not IL-17. This restoration was prevented when PP cells were treated with CH-223191, an aryl hydrocarbon receptor inhibitor. To further delineate the mechanism of differential IL-17 and IL-22 suppression, PP cells were treated with phorbol 12-myristate 13-acetate (PMA) and ionomycin, which signal via protein kinase C (PKC) and calcium flux. Treatment with PMA and ionomycin significantly prevented the decrease in IL-17 but not IL-22 after EtOH exposure and burn injury.These findings suggest that IL-23-mediated restoration of IL-22 is aryl hydrocarbon receptor dependent, whereas IL-17 requires activation of protein kinase C and intracellular calcium signaling.

View details for DOI 10.1097/SLA.0b013e3182a626f2

View details for Web of Science ID 000336248000042

View details for PubMedID 23989051

View details for PubMedCentralID PMC3925750

Abstract

There are many age-associated changes in the respiratory and pulmonary immune system. These changes include decreases in the volume of the thoracic cavity, reduced lung volumes, and alterations in the muscles that aid respiration. Muscle function on a cellular level in the aging population is less efficient. The elderly population has less pulmonary reserve, and cough strength is decreased in the elderly population due to anatomic changes and muscle atrophy. Clearance of particles from the lung through the mucociliary elevator is decreased and associated with ciliary dysfunction. Many complex changes in immunity with aging contribute to increased susceptibility to infections including a less robust immune response from both the innate and adaptive immune systems. Considering all of these age-related changes to the lungs, pulmonary disease has significant consequences for the aging population. Chronic lower respiratory tract disease is the third leading cause of death in people aged 65 years and older. With a large and growing aging population, it is critical to understand how the body changes with age and how this impacts the entire respiratory system. Understanding the aging process in the lung is necessary in order to provide optimal care to our aging population. This review focuses on the nonpathologic aging process in the lung, including structural changes, changes in muscle function, and pulmonary immunologic function, with special consideration of obstructive lung disease in the elderly.

View details for DOI 10.2147/CIA.S51152

View details for PubMedID 24235821

View details for PubMedCentralID PMC3825547

View details for DOI 10.1016/j.jamcollsurg.2012.06.073

View details for Web of Science ID 000308909600024

Abstract

We have previously demonstrated that aging is associated with prolonged pulmonary inflammation in a murine model of thermal injury. To further investigate these observations, we examined lung congestion, markers of neutrophil chemotaxis and adhesion, and lung endothelia responses in young and aged mice following burn injury. Analysis of lung tissue and bronchoalveolar lavage fluid 24 hours after injury revealed that more neutrophils accumulated in the lungs of aged mice (p<0.05), but did not migrate into the alveoli. We then sought to determine if accumulation of neutrophils in the lungs of aged mice was due to differences in the peripheral neutrophil pool or local changes within the lung. Following burn injury, aged mice developed a pronounced peripheral blood neutrophilia (p<0.05) in comparison to their younger counterparts. In aged animals, there was a reduced frequency and mean fluorescent intensity of neutrophil CXCR2 expression (p<0.05). Interestingly, in uninjured aged mice, peripheral blood neutrophils demonstrated elevated chemokinesis, or hyperchemokinesis, (p<0.05), but showed a minimal chemotatic response to KC. To determine if age impacts neutrophil adhesion molecules, we assessed CD62L and CD11b expression on peripheral blood neutrophils. No age-dependent difference in the frequency or mean fluorescent intensity of CD62L or CD11b was observed post-burn trauma. Examination of pulmonary vasculature adhesion molecules which interact with neutrophil selectins and integrins revealed that intracellular adhesion molecule-1 (ICAM-1) was elevated in aged mice at 24 hours after burn as compared to young mice (p<0.05). Overall, our data suggests that age-associated pulmonary congestion observed following burn injury may be due to differences in lung endothelial adhesion responses that are compounded by elevated numbers of hyperchemokinetic circulating neutrophils in aged mice.

View details for PubMedID 22724082

View details for PubMedCentralID PMC3375080

View details for Web of Science ID 000304659701189

Abstract

The relationship between advanced age and immunologic deficits is becoming an area of rapidly advancing research. Many of the clinical hurdles in the elderly population result from dysregulation of the immune system leading to the inability of the elderly to swiftly combat infection and to the increased incidence of chronic disease states and autoimmune conditions. Herein, we address the crucial alterations in the innate immune system that occur with advancing age. Specifically, we discuss how the effects of advanced age may lead to functional changes in the neutrophil, macrophage, dendritic cell, natural killer cell, and natural killer T cell populations in human and murine models that translate into aberrant innate immune responses. Furthermore, we elucidate how these changes may contribute to documented deficits in adaptive immunity as well as the pathological conditions and the increased morbidity and mortality seen in the elderly population.

View details for PubMedID 21461315

View details for Web of Science ID 000208675500189

View details for Web of Science ID 000208467802136

Abstract

Low-molecular-weight heparins (LMWHs) are polypharmacologic drugs used to treat thrombotic and cardiovascular disorders. These drugs are manufactured using different chemical and enzymatic methods, resulting in products with distinct chemical and pharmacologic profiles. Generic LMWHs have been introduced in Asia and South America, and several generic suppliers are seeking regulatory approval in the United States and the European Union. For simple small-molecule drugs, generic drugs have the same chemical structure, potency, and bioavailability as the innovator drug. Applying this definition to complex biological products such as the LMWHs has proved difficult. One major issue is defining appropriate criteria to demonstrate bioequivalence; pharmacopoeial specifications alone appear to be inadequate. Whereas available generic versions of LMWHs exhibit similar molecular and pharmacopoeial profiles, marked differences in their biological and pharmacologic behavior have been noted. Preliminary studies have demonstrated differences in terms of anti-Xa activity and tissue factor pathway inhibitor release after subcutaneous administration, as well as antiplatelet and profibrinolytic effects. The current data emphasize the need to consider multiple functional parameters when defining bioequivalence of biologic drugs with complex structures and activities and also underscore the importance of further pharmacologic studies involving animal models and human clinical trials. The U.S. Food and Drug Administration and the European Medicine Evaluation Agency are currently developing guidelines for the acceptance of biosimilar agents including LMWHs. Until such guidelines are complete, generic interchange may not be feasible.

View details for DOI 10.1055/s-2008-1066026

View details for Web of Science ID 000255122700007

View details for PubMedID 18393144

View details for Web of Science ID 000251100802391