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Papers by Gary Levy

BackgroundNon-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are ... more BackgroundNon-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are highly prevalent conditions characterized by inflammation and fibrosis of the liver which can progress to cirrhosis and hepatocellular carcinoma if left untreated. Lifestyle disorders such as obesity, diabetes and dyslipidaemia predispose to and are associated with the disease progression. Conventional modalities are mainly symptomatic, with no definite solution. Beta glucan-based biological response modifiers are a potential strategy in lieu of their beneficial metabolic effects. Aureobasidium pullulans strains AFO-202 and N-163 beta glucans were evaluated for anti-fibrotic and anti-inflammatory hepatoprotective potentials in a NASH animal model in this study.MethodsIn the STAM™ murine model of NASH, five groups were studied for eight weeks— (1) vehicle (RO water), (2) AFO-202 beta glucan; (3) N-163 beta glucan, (4) AFO-202+N-163 beta glucan, and (5) telmisartan (standard pharmacologica...

Hepatology, 2007

Mouse hepatitis virus type 3 infection results in strain-dependent liver disease. The effects of ... more Mouse hepatitis virus type 3 infection results in strain-dependent liver disease. The effects of mouse hepatitis virus type 3 on the microcirculation of the liver in both fully susceptible (Balb/cJ) and fully resistant (A/& mice were studied. In Balb/cJ mice, 6 to 12 h r following infection, abnormalities in liver blood flow were observed which consisted of granular blood flow in both terminal hepatic and terminal portal venules. In addition, sinusoidal microthrombi were present predominantly in periportal areas. By 24 to 48 hr, liver cell edema and small focal lesions were prominent. At 48 hr, thrombi and hepatocellular necrosis were widespread, and blood was shunted from damaged areas into patent sinusoids. In sharp contrast to these abnormal findings, normal streamlined blood flow was present in the resistant A/J animals at all time points following infection. Since large amounts of virus were demonstrated by immunofluorescene in and by recovery and growth from livers of both resistant and susceptible strains, the presence of the virus per se cannot explain the abnormalities observed.

Ribavirin, a synthetic guanosine analogue, possesses a broad spectrum of activity against DNA and... more Ribavirin, a synthetic guanosine analogue, possesses a broad spectrum of activity against DNA and RNA viruses. It has been previously shown to attenuate the course of fulminant hepatitis in mice produced by murine hepatitis virus strain 3. We therefore studied the effects of ribavirin on murine hepatitis virus strain 3 replication, macrophage production of proinflammatory mediators including TNF, IL-1, and the procoagulant activity (PCA), fgl2 prothrombinase; and Th1/Th2 cytokine production. Although ribavirin had inhibitory effects on viral replication (<1 log), even at high concentrations complete eradication of the virus was not seen. In contrast, at physiologic concentrations (up to 500 g/ml), ribavirin markedly reduced viral-induced parameters of macrophage activation. With ribavirin treatment, the concentrations of PCA, TNF-␣ and IL-1␤ all decreased to basal concentrations: PCA from 941 ؎ 80 to 34 ؎ 11 mU/10 6 cells; TNF-␣ from 10.73 ؎ 2.15 to 2.74 ؎ 0.93 ng/ml; and IL-1␤ from 155.91 ؎ 22.62 to 5.74 ؎ 0.70 pg/ml. The inhibitory effects of ribavirin were at the level of gene transcription as evidenced by Northern analysis. Both in vitro and in vivo, ribavirin inhibited the production of IL-4 by Th2 cells, whereas it did not diminish the production of IFN-␥ in Th1 cells. In contrast, ribavirin had no inhibitory effect on TNF-␣ and IL-1␤ production in LPS-stimulated macrophages. These results suggest that the beneficial effects of ribavirin are mediated by inhibition of induction of macrophage proinflammatory cytokines and Th2 cytokines while preserving Th1 cytokines.

Military Medicine, 2020

Chromosomal translocations occur in 10 to 15% of men with azoospermia. Thirty distinct X-autosoma... more Chromosomal translocations occur in 10 to 15% of men with azoospermia. Thirty distinct X-autosomal balanced reciprocal translocations have been reported in the literature thus far. We present a novel case of azoospermia with a karyotype of 46,Y,t(X:16)(p22.1:p11.2). A 26-year-old, healthy, active duty male Solider presented with his dependent female partner for primary infertility. Female anatomical and endocrine evaluations were normal. Initial male evaluation revealed azoospermia on multiple semen analyses. Further evaluation with a detailed physical exam and laboratory tests were normal except for an abnormal karyotype with a reciprocal translocation at chromosomes X and 16. An open testicular biopsy demonstrated 75% late spermatid maturation arrest confirming reproductive potential although significantly reduced. Men who present with azoospermia should undergo a full endocrine and genetic evaluation with a thorough physical evaluation by an urologist. They can have limited but s...

Trends in Microbiology, 1995

NEWS AND COMMENT et ~1.'~ have genetically and biochemically characterized a dualspecificity phos... more NEWS AND COMMENT et ~1.'~ have genetically and biochemically characterized a dualspecificity phosphatase (IphP) in the cyanobacterium Nostoc commune. As N. commune is free living, IphP probably evolved directly from prokaryotic ancestry. In addition, a potential target for IphP has been found in N. commune, a rare example of protein tyrosine phosphorylation in a prokaryote. These results raise the possibility that tyrosine phosphorylation and its associated enzyme functions arose in evolution before the divergence of prokaryotes and eukaryotes. As eukaryotic organisms evolved and began to use protein tyrosine phosphorylation as a major mechanism to activate cellular responses in the immune system, microorganisms such as Yersinia seem to have acquired new genetic traits to subvert this process.

Seminars in liver disease, May 22, 2018

The authors assessed the incidence, management, and risk factors for postoperative complications ... more The authors assessed the incidence, management, and risk factors for postoperative complications after right lobe (RL) live donor hepatectomy in a high-volume center in North America. All donors undergoing an RL live donor hepatectomy between 2000 and 2017 at our institution were included. The primary outcome was the development of complications (both medical and surgical). Predictors of postoperative complications were determined by logistic regression. A total of 587 patients underwent RL live donor hepatectomy. Among those, 187 postoperative complications were diagnosed in 141 (24%) patients. One patient had >90-day morbidity, and there were no donor deaths. Overall complications were significantly higher in the first era, 2000 to 2008 (81 [57.4%]) versus the second era, 2009 to 2017 (60 [42.6%]) ( = 0.01). On multivariate analysis, the only predictor of postoperative complications was the center volume of RL live donor hepatectomy in the previous 12 months with an odds ratio ...

American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons, Jan 13, 2017

In a multicenter, open-label, study, 284 living-donor liver transplant patients were randomized a... more In a multicenter, open-label, study, 284 living-donor liver transplant patients were randomized at 30 ± 5 days posttransplant to start everolimus+reduced tacrolimus (EVR+rTAC) or continue standard tacrolimus (TAC Control). EVR+rTAC was non-inferior to TAC Control for the primary efficacy endpoint of treated BPAR, graft loss or death at 12 months posttransplant: difference -0.7% (90% CI -5.2%, 3.7%); P < .001 for non-inferiority. Treated BPAR occurred in 2.2% and 3.6% of patients, respectively. The key secondary endpoint, change in estimated glomerular filtration rate (eGFR) from randomization to month 12, achieved non-inferiority (P < .001 for non-inferiority), but not superiority and was similar between groups overall (mean -8.0 vs. -12.1 mL/min/1.73 m, P = .108), and in patients continuing randomized treatment (-8.0 vs. -13.3 mL/min/1.73 m, P = .046). In the EVR+rTAC and TAC control groups, study drug was discontinued in 15.5% and 17.6% of patients, adverse events with suspe...

Journal of visualized experiments : JoVE, Sep 15, 2016

Autoantibodies, which are antibodies against self-antigens, are present in many disease states an... more Autoantibodies, which are antibodies against self-antigens, are present in many disease states and can serve as markers for disease activity. The levels of autoantibodies to specific antigens are typically detected with the enzyme-linked immunosorbent assay (ELISA) technique. However, screening for multiple autoantibodies with ELISA can be time-consuming and requires a large quantity of patient sample. The antigen microarray technique is an alternative method that can be used to screen for autoantibodies in a multiplex fashion. In this technique, antigens are arrayed onto specially coated microscope slides with a robotic microarrayer. The slides are probed with patient serum samples and subsequently fluorescent-labeled secondary antibodies are added to detect binding of serum autoantibodies to the antigens. The autoantibody reactivities are revealed and quantified by scanning the slides with a scanner that can detect fluorescent signals. Here we describe methods to generate custom a...

PloS one, 2016

Autoantibodies directed against endogenous proteins including contractile proteins and endothelia... more Autoantibodies directed against endogenous proteins including contractile proteins and endothelial antigens are frequently detected in patients with heart failure and after heart transplantation. There is evidence that these autoantibodies contribute to cardiac dysfunction and correlate with clinical outcomes. Currently, autoantibodies are detected in patient sera using individual ELISA assays (one for each antigen). Thus, screening for many individual autoantibodies is laborious and consumes a large amount of patient sample. To better capture the broad-scale antibody reactivities that occur in heart failure and post-transplant, we developed a custom antigen microarray technique that can simultaneously measure IgM and IgG reactivities against 64 unique antigens using just five microliters of patient serum. We first demonstrated that our antigen microarray technique displayed enhanced sensitivity to detect autoantibodies compared to the traditional ELISA method. We then piloted this ...

Nature immunology, Jan 7, 2015

Resident macrophages densely populate the normal arterial wall, yet their origins and the mechani... more Resident macrophages densely populate the normal arterial wall, yet their origins and the mechanisms that sustain them are poorly understood. Here we use gene-expression profiling to show that arterial macrophages constitute a distinct population among macrophages. Using multiple fate-mapping approaches, we show that arterial macrophages arise embryonically from CX3CR1(+) precursors and postnatally from bone marrow-derived monocytes that colonize the tissue immediately after birth. In adulthood, proliferation (rather than monocyte recruitment) sustains arterial macrophages in the steady state and after severe depletion following sepsis. After infection, arterial macrophages return rapidly to functional homeostasis. Finally, survival of resident arterial macrophages depends on a CX3CR1-CX3CL1 axis within the vascular niche.

Journal of stem cells & regenerative medicine, 2011

Although transplantation is one of the major medical achievements of the last half century, the s... more Although transplantation is one of the major medical achievements of the last half century, the shortage of organs and need for long term immunosuppressive therapy limits its usefulness. Advances in stem cell therapy has the potential both to overcome the shortage of organs but also to provide novel ways of reintroducing a tolerogenic state in patients who require life saving transplantation therapy. Understanding mechanisms of rejection which involve both innate and adaptive immunity would allow for novel therapeutic approaches to eliminate or avoid the use of toxic immunosuppressive agents. The evolving era of functional genomics in organ transplantation has been supported by advances in gene profiling, sequencing, proteomics, antibody profiling and bioinformatics. Thus, heralding a new era of intelligent and personalized monitor and therapy. Molecular and cell based biomarkers and now emerging which may be useful to monitor the immune status of the patient and it is anticipated t...

Therapeutic Drug Monitoring, 2010

Springer Seminars in Immunopathology, 1981

Seminars in Immunology, 2011

The care of the transplant patient, from eligibility and evaluation to longterm follow-up present... more The care of the transplant patient, from eligibility and evaluation to longterm follow-up presents challenges to health care professionals. Issues such as organ rejection, infection and heart disease can be challenging to address. Faculty speakers will examine and discuss important patient care issues in kidney, pancreas and liver transplantation. Intended Audience This conference is intended for nephrologists, endocrinologists, gastroenterologists, hepatologists, internal medicine physicians, physician assistants, nurse practitioners and nurses with an interest in kidney, pancreas and/or liver transplantation. Elements of Competence This CME activity has been designed to change learner competence and focuses on the American Board of Medical Specialties areas of patient care and medical knowledge. Learning Objectives At the conclusion of this activity, participants will be able to: 1. Describe the history and current practice of kidney, pancreas and liver transplantation both nationally and at the University of Wisconsin. 2. Identify the indications and contraindications for transplantation in your clinical practice. 3. Explain the outcomes and current issues in the long-term follow-up care of the transplant patient. 4. Explain current research and discuss the future of organ transplantation and how it may impact your clinical practice.

Molecular Human Reproduction, 2004

Increased fgl2 prothrombinase activity in maternal decidua and fetal trophoblasts may trigger abo... more Increased fgl2 prothrombinase activity in maternal decidua and fetal trophoblasts may trigger abortions by proin¯ammatory cytokines induced by bacterial lipopolysaccharide (LPS) in mice and is implicated in human recurrent miscarriages and preeclampsia. De®ning the physiological and pathological role of the fgl2/®broleukin gene required an fgl2-knockout mouse and data on normal pattern of fgl2 expression during pregnancy. Expression of fgl2 protein was determined by immunostaining with speci®c antibody. Fgl2 knockout mice were generated and typed by PCR for presence of the altered gene. Immunostaining of timed CBAQDBA/2 mouse matings in a low-abortion-rate colony showed a distinct pattern of development of fgl2 protein expression in maternal decidua, and in embryonic tissues in early pregnancy. Outbred (mixed background) heterozygous fgl2 +/±Q+/± matings with a similar low abortion rate showed selective occult loss of both +/± and, to a greater extent, ±/± embryos prior to gestation day 11.5, in association with haemorrhage at the anti-mesometrial pole of fgl2-de®cient embryo. LPS injected on day 6.5 caused classical abortions at mid-pregnancy in fgl2 +/+Q+/+ matings, but not ±/±Q±/± matings. Physiological expression of fgl2 in fetal trophoblast may prevent occult loss in early pregnancy, along with other coagulation factors, but fgl2 expression is required for LPS to induce abortion pathology.

Liver Transplantation, 2004

Kidney International, 1990

Ancrod improves survival in murine systemic tupus erythematosus. The effect of ancrod, a defibrin... more Ancrod improves survival in murine systemic tupus erythematosus. The effect of ancrod, a defibrinating agent, on murine lupus glomerulonephritis in the male BXSB mouse was studied to determine the relationship between macrophage procoagulant activity (PCA), fibrin deposition and glomerulonephritis. Marked renal disease and fibrin deposition were noted by three months of age in control mice, whereas little or no disease was seen in ancrod treated mice until five months of age. Similar high titers of anti-DNA antibodies and renal deposition of IgG were seen in both groups of mice. PCA rose with age in both ancrod treated and untreated mice, although it was significantly higher in control animals than in the ancrod treated group. Furthermore, ancrod therapy resulted in a decrease in plasma PCA inducing activity (PIF) and a decrease in the effectiveness of PIF to induce PCA in peritoneal macrophages in vitro. No mortality was observed in the 20 ancrod treated mice, whereas 10 of 20 control animals died. We conclude that defibrination with ancrod delays the development of renal fibrin deposition and glomerulonephritis and improves survival in BXSB mice. This was associated with a decrease in plasma PCA inducing activity and with an inhibitory effect on PCA induction. These results suggest that PCA contributes to injury in murine lupus glomerulonephritis by promoting fibrin deposition. A number of investigators have shown that injury in glomerulonephritis (GN) is dependent upon activation of the coagulation system. Defibrination reduced the incidence of glomerular microthrombi [1], decreased fibrinogen deposition in the gbmeruli with a reduction in crescent formation [2], and protected against experimental nephrotoxic serum nephritis [3]. Pollak et a! found that treatment with ancrod improved renal function and reduced thrombi in patients with lupus GN [4]. Our previous studies have shown that induction of monocyte/macrophage (MO/MA) procoagulant activity (PCA) occurs in patients with active lupus nephritis, and also in the male BXSB mouse as GN develops with age [5, 6]. Studies by Holdsworth and Wiggins et al have also implicated PCA as being important in the induction of injury in other experimental models of GN [7-9]. The synthesis and secretion of PCA by MO/MA is now known to be an integral component of the host's immune response [10, 11]. PCA can be induced by a number of immu