Exercise-Induced Autophagy in Fatty Liver Disease.

Hepatic steatosis prevails each year. Autophagy is integral in mitochondrial quality control and lipid homeostasis in the liver. No pharmacological strategies are currently available to reduce hepatic steatosis, but exercise has been known to improve clinical outcomes of chronic liver disease, particularly nonalcoholic fatty liver disease (NAFLD). Recent studies suggest that exercise may improve NAFLD through enhancing autophagy.

Genitourinary resection at the time of cytoreductive surgery and heated intraperitoneal chemotherapy for peritoneal carcinomatosis is not associated with increased morbidity or worsened oncologic outcomes: a case-matched study.

BACKGROUND: Cytoreductive surgery (CRS) with heated intraperitoneal chemotherapy (HIPEC) has gained acceptance in the treatment of peritoneal carcinomatosis with reported morbidity and mortality rates of 27-56 and 0-11 %, respectively. The safety and oncologic outcome of genitourinary repair at the time of CRS and HIPEC remains unclear. METHODS: We identified 170 patients who underwent CRS-HIPEC at our institution between July 2007 and August 2011 with a minimum follow-up of 6 months. Thirty-four (20 %) underwent concomitant urologic reconstruction at the time of CRS-HIPEC and were matched by disease burden (intraoperative peritoneal cancer index [PCI]) and extent of surgery (ΔPCI) with a cohort of 38 (22.3 %) subjects without genitourinary involvement. The primary end points considered for this analysis included the development of major surgical (Clavien-Dindo Class III-V) complications and overall survival. RESULTS: Median follow-up was 9.4 months. The most commonly performed urologic interventions included partial cystectomy with primary repair in 23 (65.7 %) and segmental ureteral resection and repair in 11 (31.4 %). Patients with genitourinary reconstruction had more total organ involvement (6.5 vs. 4.3, p < 0.001) and more commonly underwent enteric anastomoses (82.4 vs. 57.9 %, p = 0.025). No significant differences were observed with regard to major morbidity, need for transfusion, operative time, intensive care unit admission, or length of stay. Among patients with appendiceal or colonic tumors (n = 46), overall survival was similar between genitourinary reconstruction and matched cohorts: 22.5 versus 15.1 months, respectively (p = 0.66). CONCLUSIONS: Genitourinary reconstruction at the time of CRS-HIPEC occurs more commonly in patients with extensive disease burden undergoing radical debulking, yet does not adversely influence surgical morbidity or survival.

Influenza Vaccination and Hospitalizations Among COVID-19 Infected Adults.

INTRODUCTION: To date, there are no effective treatments for decreasing hospitalizations in Coronavirus disease 2019 (COVID-19) infections. It has been suggested that the influenza vaccine might attenuate the severity of COVID-19. METHODS: This is a retrospective single-centered cohort review of a de-identified database of 2005 patients over the age of 18 within the University of Florida health care system who tested positive for COVID-19. Comorbidities and influenza vaccination status were examined. The primary outcome was severity of disease as reflected by hospitalization and intensive care unit (ICU) admission. Logistic regression was performed to examine the relationship between influenza status and hospitalization. RESULTS: COVID-19-positive patients who had not received the influenza vaccination within the last year had a 2.44 (95% CI, 1.68, 3.61) greater odds of hospitalization and a 3.29 (95% CI, 1.18, 13.77) greater odds of ICU admission when compared with those who were vaccinated. These results were controlled to account for age, race, gender, hypertension, diabetes, chronic obstructive pulmonary disease, obesity, coronary artery disease, and congestive heart failure. DISCUSSION: Our analysis suggests that the influenza vaccination is potentially protective of moderate and severe cases of COVID-19 infection. This protective effect holds regardless of comorbidity. The literature points to a potential mechanism via natural killer cell activation. Though our data potentially is limited by its generalizability and our vaccination rate is low, it holds significant relevance given the upcoming influenza season. Not only could simply encouraging influenza vaccination decrease morbidity and mortality from the flu, but it might help flatten the curve of the COVID-19 pandemic as well. We encourage further studies into this finding.

A rabbit ventricular action potential model replicating cardiac dynamics at rapid heart rates.

Mathematical modeling of the cardiac action potential has proven to be a powerful tool for illuminating various aspects of cardiac function, including cardiac arrhythmias. However, no currently available detailed action potential model accurately reproduces the dynamics of the cardiac action potential and intracellular calcium (Ca(i)) cycling at rapid heart rates relevant to ventricular tachycardia and fibrillation. The aim of this study was to develop such a model. Using an existing rabbit ventricular action potential model, we modified the L-type calcium (Ca) current (I(Ca,L)) and Ca(i) cycling formulations based on new experimental patch-clamp data obtained in isolated rabbit ventricular myocytes, using the perforated patch configuration at 35-37 degrees C. Incorporating a minimal seven-state Markovian model of I(Ca,L) that reproduced Ca- and voltage-dependent kinetics in combination with our previously published dynamic Ca(i) cycling model, the new model replicates experimentally observed action potential duration and Ca(i) transient alternans at rapid heart rates, and accurately reproduces experimental action potential duration restitution curves obtained by either dynamic or S1S2 pacing.

A case of extensive hepatic adenomatosis in a renal transplant patient.

Hepatic adenomatosis (HA) is a rare condition that is traditionally associated with oral contraceptive use, glycogen storage diseases or metabolic syndrome. Here we present a renal transplant recipient that was diagnosed with HA and has none of the traditional risk factors. We review the literature on diagnosing and managing HA.

Loss of sirtuin 1 and mitofusin 2 contributes to enhanced ischemia/reperfusion injury in aged livers.

Ischemia/reperfusion (I/R) injury is a causative factor contributing to morbidity and mortality during liver resection and transplantation. Livers from elderly patients have a poorer recovery from these surgeries, indicating reduced reparative capacity with aging. Mechanisms underlying this age-mediated hypersensitivity to I/R injury remain poorly understood. Here, we investigated how sirtuin 1 (SIRT1) and mitofusin 2 (MFN2) are affected by I/R in aged livers. Young (3 months) and old (23-26 months) male C57/BL6 mice were subjected to hepatic I/R in vivo. Primary hepatocytes isolated from each age group were also exposed to simulated in vitro I/R. Biochemical, genetic, and imaging analyses were performed to assess cell death, autophagy flux, mitophagy, and mitochondrial function. Compared to young mice, old livers showed accelerated liver injury following mild I/R. Reperfusion of old hepatocytes also showed necrosis, accompanied with defective autophagy, onset of the mitochondrial permeability transition, and mitochondrial dysfunction. Biochemical analysis indicated a near-complete loss of both SIRT1 and MFN2 after I/R in old hepatocytes, which did not occur in young cells. Overexpression of either SIRT1 or MFN2 alone in old hepatocytes failed to mitigate I/R injury, while co-overexpression of both proteins promoted autophagy and prevented mitochondrial dysfunction and cell death after reperfusion. Genetic approaches with deletion and point mutants revealed that SIRT1 deacetylated K655 and K662 residues in the C-terminus of MFN2, leading to autophagy activation. The SIRT1-MFN2 axis is pivotal during I/R recovery and may be a novel therapeutic target to reduce I/R injury in aged livers.

Magnetic Targeting of Stem Cell Derivatives Enhances Hepatic Engraftment into Structurally Normal Liver.

Attaining consistent robust engraftment in the structurally normal liver is an obstacle for cellular transplantation. Most experimental approaches to increase transplanted cells' engraftment involve recipient-centered deleterious methods such as partial hepatectomy or irradiation which may be unsuitable in the clinic. Here, we present a cell-based strategy that increases engraftment into the structurally normal liver using a combination of magnetic targeting and proliferative endoderm progenitor (EPs) cells. Magnetic labeling has little effect on cell viability and differentiation, but in the presence of magnetic targeting, it increases the initial dwell time of transplanted EPs into the undamaged liver parenchyma. Consequently, greater cell retention in the liver is observed concomitantly with fewer transplanted cells in the lungs. These highly proliferative cells then significantly increase their biomass over time in the liver parenchyma, approaching nearly 4% of total liver cells 30 d after transplant. Therefore, the cell-based mechanisms of increased initial dwell time through magnetic targeting combined with high rate of proliferation in situ yield significant engraftment in the undamaged liver.

Autophagy in Ischemic Livers: A Critical Role of Sirtuin 1/Mitofusin 2 Axis in Autophagy Induction.

No-flow ischemia occurs during cardiac arrest, hemorrhagic shock, liver resection and transplantation. Recovery of blood flow and normal physiological pH, however, irreversibly injures the liver and other tissues. Although the liver has the powerful machinery for mitochondrial quality control, a process called mitophagy, mitochondrial dysfunction and subsequent cell death occur after reperfusion. Growing evidence indicates that reperfusion impairs mitophagy, leading to mitochondrial dysfunction, defective oxidative phosphorylation, accumulation of toxic metabolites, energy loss and ultimately cell death. The importance of acetylation/deacetylation cycle in the mitochondria and mitophagy has recently gained attention. Emerging data suggest that sirtuins, enzymes deacetylating a variety of target proteins in cellular metabolism, survival and longevity, may also act as an autophagy modulator. This review highlights recent advances of our understanding of a mechanistic correlation between sirtuin 1, mitophagy and ischemic liver injury.

Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for peritoneal carcinomatosis: outcomes from a single tertiary institution.

BACKGROUND: Cytoreductive surgery (CRS) with heated intraperitoneal chemotherapy (HIPEC) is an effective but morbid procedure in the treatment of peritoneal carcinomatosis. We report our outcomes at a single tertiary institution. METHOD: A total of 170 consecutive patients underwent CRS-HIPEC for peritoneal carcinomatosis between July 2007 and August 2012. The peritoneal cancer index (1-39) was used for peritoneal carcinomatosis (PC) staging. Mitomycin C (88.8%) was administered intraperitoneally at 42 °C for 90 mins. Risk factors associated with major morbidities were analyzed. The Kaplan-Meier method was used for survival analyses. RESULTS: The mean age was 55.1 (±11.3) years, and the majority (77.1%) of patients had complete cytoreduction (CC0-1). Tumor types included colorectal (n = 51, 30.0%), appendiceal (n = 50, 29.4 %), pseudomyxoma peritonei (n = 16, 9.4%), and other (n = 53, 31.2%). Factors associated with major complications were estimated blood loss (>400 ml), length of stay (>1 week), intraoperative blood transfusion, operative time (>6 h), and bowel anastomosis. Intraoperative blood transfusion was the only independent prognostic factor on multivariate analysis (p = 0.031). Median follow-up was 15.7 months (±1.2). The recurrence rates for colorectal and appendiceal carcinoma at 1 and 3 years were 40%, 53.5% and 68%, 79.1%, respectively. The 1- and 3-year overall survival for colorectal and appendiceal carcinomatosis was 74.0%, 32.5% and 89.4%, 29.3%, respectively. Intraoperative peritoneal cancer index (PCI) score (>16) and need for blood transfusion were factors independently associated with poor survival (p < 0.05). CONCLUSION: Our single institution experience of CRS/HIPEC procedures for peritoneal carcinomatosis demonstrates acceptable perioperative outcome and long-term survival. Optimal cytoreduction was achieved in the majority of cases. Intraoperative PCI > 16 was associated with poor survival. This series supports the safety of CRS-HIPEC in selected patients.

Outcomes for cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in the elderly.

BACKGROUND: Cytoreductive surgery (CRS) with heated intraperitoneal chemotherapy (HIPEC) has gained acceptance in the treatment of peritoneal carcinomatosis (PC) with reported morbidity and mortality rates of 27-56% and 0-11% respectively. The safety and outcome of such major operation in the elderly remains unclear. We report our experience at a high volume tertiary center. METHOD: A total of 170 consecutive patients underwent CRS-HIPEC for peritoneal carcinomatosis between March 2007 and July 2012. Mitomycin C (88.8%) was administered intraperitoneally at 42 °C for 90 min. Patients were categorized into two groups according to the age at the time of surgery: Group 1 (≤65 years-old) and Group 2 (>65 years-old). Differences between the groups were analyzed. Univariate and multivariate analyses were performed to identify variables associated with major morbidity. RESULTS: Of the 170 patients, 35 were older than 65 years. The two most common tumor sites were colorectal and appendiceal cancer. The perioperative morbidity and mortality rates in the elderly were 18.8% and 8.6% respectively. Gender, tumor type, estimated blood loss >400 mL, intraoperative blood transfusion, operative time >6 h, bowel anastomosis, intraoperative PCI >16, and extent of cytoreduction (Δ PCI) were not associated with major morbidity in the older group (p > 0.05). At a median follow-up of 15.7 months (0.2-53.5 months), recurrence rate for colorectal/appendiceal PC at 1 year was 48.0% in Group 1 and 44.3% in Group 2 (p = NS). Median survival for the colorectal/appendiceal carcinomatosis patients in Group 1 (n = 81) was 29.79 (SE 4.7) months and in Group 2 (n = 20) was 21.2 (SE 3.0) months, (p = 0.06, NS). CONCLUSION: CRS-HIPEC procedures for peritoneal carcinomatosis in the elderly demonstrate comparable perioperative outcome in well-selected patients. Optimal cytoreduction was achieved in the majority of cases and survival was not significantly different from that of the younger group.

The pinwheel experiment revisited: effects of cellular electrophysiological properties on vulnerability to cardiac reentry.

In normal heart, ventricular fibrillation can be induced by a single properly timed strong electrical or mechanical stimulus. A mechanism first proposed by Winfree and coined the "pinwheel experiment" emphasizes the timing and strength of the stimulus in inducing figure-of-eight reentry. However, the effects of cellular electrophysiological properties on vulnerability to reentry in the pinwheel scenario have not been investigated. In this study, we extend Winfree's pinwheel experiment to show how the vulnerability to reentry is affected by the graded action potential responses induced by a strong premature stimulus, action potential duration (APD), and APD restitution in simulated monodomain homogeneous two-dimensional tissue. We find that a larger graded response, longer APD, or steeper APD restitution slope reduces the vulnerable window of reentry. Strong graded responses and long APD promote tip-tip interactions at long coupling intervals, causing the two initiated spiral wave tips to annihilate. Steep APD restitution promotes wave front-wave back interaction, causing conduction block in the central common pathway of figure-of-eight reentry. We derive an analytical treatment that shows good agreement with numerical simulation results.

Vulnerability to re-entry in simulated two-dimensional cardiac tissue: effects of electrical restitution and stimulation sequence.

Ventricular fibrillation is a lethal arrhythmia characterized by multiple wavelets usually starting from a single or figure-of-eight re-entrant circuit. Understanding the factors regulating vulnerability to the re-entry is essential for developing effective therapeutic strategies to prevent ventricular fibrillation. In this study, we investigated how pre-existing tissue heterogeneities and electrical restitution properties affect the initiation of re-entry by premature extrastimuli in two-dimensional cardiac tissue models. We studied two pacing protocols for inducing re-entry following the "sinus" rhythm (S1) beat: (1) a single premature (S2) extrastimulus in heterogeneous tissue; (2) two premature extrastimuli (S2 and S3) in homogeneous tissue. In the first case, the vulnerable window of re-entry is determined by the spatial dimension and extent of the heterogeneity, and is also affected by electrical restitution properties and the location of the premature stimulus. The vulnerable window first increases as the action potential duration (APD) difference between the inside and outside of the heterogeneous region increases, but then decreases as this difference increases further. Steeper APD restitution reduces the vulnerable window of re-entry. In the second case, electrical restitution plays an essential role. When APD restitution is flat, no re-entry can be induced. When APD restitution is steep, re-entry can be induced by an S3 over a range of S1S2 intervals, which is also affected by conduction velocity restitution. When APD restitution is even steeper, the vulnerable window is reduced due to collision of the spiral tips.

Short-term cardiac memory and mother rotor fibrillation.

Short-term cardiac memory refers to the effects of pacing history on action potential duration (APD). Although the ionic mechanisms for short-term memory occurring over many heartbeats (also called APD accommodation) are poorly understood, they may have important effects on reentry and fibrillation. To explore this issue, we incorporated a generic memory current into the Phase I Luo and Rudy action potential model, which lacks short-term memory. The properties of this current were matched to simulate quantitatively human ventricular monophasic action potential accommodation. We show that, theoretically, short-term memory can resolve the paradox of how mother rotor fibrillation is initiated in heterogeneous tissue by physiological pacing. In simulated heterogeneous two-dimensional tissue and three-dimensional ventricles containing an inward rectifier K(+) current gradient, short-term memory could spontaneously convert multiple wavelet fibrillation to mother rotor fibrillation or to a mixture of both fibrillation types. This was due to progressive acceleration and stabilization of rotors as accumulation of memory shortened APD and flattened APD restitution slope nonuniformly throughout the tissue.

Mechanism of shortened action potential duration in Na+-Ca2+ exchanger knockout mice.

In cardiac-specific Na(+)-Ca(2+) exchanger (NCX) knockout (KO) mice, the ventricular action potential (AP) is shortened. The shortening of the AP, as well as a decrease of the L-type Ca(2+) current (I(Ca)), provides a critical mechanism for the maintenance of Ca(2+) homeostasis and contractility in the absence of NCX (Pott C, Philipson KD, Goldhaber JI. Excitation-contraction coupling in Na(+)-Ca(2+) exchanger knockout mice: reduced transsarcolemmal Ca(2+) flux. Circ Res 97: 1288-1295, 2005). To investigate the mechanism that underlies the accelerated AP repolarization, we recorded the transient outward current (I(to)) in patch-clamped myocytes isolated from wild-type (WT) and NCX KO mice. Peak I(to) was increased by 78% and decay kinetics were slowed in KO vs. WT. Consistent with increased I(to), ECGs from KO mice exhibited shortened QT intervals. Expression of the I(to)-generating K(+) channel subunit Kv4.2 and the K(+) channel interacting protein was increased in KO. We used a computer model of the murine AP (Bondarenko VE, Szigeti GP, Bett GC, Kim SJ, and Rasmusson RL. Computer model of action potential of mouse ventricular myocytes. Am J Physiol Heart Circ Physiol 287: 1378-1403, 2004) to determine the relative contributions of increased I(to), reduced I(Ca), and reduced NCX current (I(NCX)) on the shape and kinetics of the AP. Reduction of I(Ca) and elimination of I(NCX) had relatively small effects on the duration of the AP in the computer model. In contrast, AP repolarization was substantially accelerated when I(to) was increased in the computer model. Thus, the increase in I(to), and not the reduction of I(Ca) or I(NCX), is likely to be the major mechanism of AP shortening in KO myocytes. The upregulation of I(to) may comprise an important regulatory mechanism to limit Ca(2+) influx via a reduction of AP duration, thus preventing Ca(2+) overload in situations of reduced myocyte Ca(2+) extrusion capacity.