BackgroundIn rodent models of Parkinson’s disease (PD), dopamine neuron loss is accompanied by increased expression of angiotensin II (AngII), its type 1 receptor (AT1), and NADPH oxidase (Nox) in the nigral dopamine neurons and microglia. AT1 blockers (ARBs) stymie such oxidative damage and neuron loss. Whether changes in the AngII/AT1/Nox4 axis contribute to Parkinson neuropathogenesis is unknown. Here, we studied the distribution of AT1 and Nox4 in dopamine neurons in two nigral subregions: the less affected calbindin-rich matrix and the first-affected calbindin-poor nigrosome 1 of three patients, who were clinically asymptomatic, but had nigral dopamine cell loss and Braak stages consistent with a neuropathological diagnosis of PD (prePD). For comparison, five clinically- and neuropathologically-confirmed PD patients and seven age-matched control patients (AMC) were examined.ResultsAT1 and Nox4 immunoreactivity was noted in dopamine neurons in both the matrix and the nigrosome 1. The total cellular levels of AT1 in surviving dopamine neurons in the matrix and nigrosome 1 declined from AMC>prePD>PD, suggesting that an AngII/AT1/Nox4 axis orders neurodegenerative progression. In this vein, the loss of dopamine neurons was paralleled by a decline in total AT1 per surviving dopamine neuron. Similarly, AT1 in the nuclei of surviving neurons in the nigral matrix declined with disease progression, i.e., AMC>prePD>PD. In contrast, in nigrosome 1, the expression of nuclear AT1 was unaffected and similar in all groups. The ratio of nuclear AT1 to total AT1 (nuclear + cytoplasmic + membrane) in dopamine neurons increased stepwise from AMC to prePD to PD. The proportional increase in nuclear AT1 in dopamine neurons in nigrosome 1 of prePD and PD patients was accompanied by elevated nuclear expression of Nox4, oxidative damage to DNA, and caspase-3-mediated cell loss.ConclusionsOur observations are consistent with the idea that AngII/AT1/Nox4 axis-mediated oxidative stress gives rise to the dopamine neuron dysfunction and loss characteristic of the neuropathological and clinical manifestations of PD and suggest that the chance for a neuron to survive increases in association with lower total as well as nuclear AT1 expression. Our results support the need for further evaluation of ARBs as disease-modifying agents in PD.

INTRODUCTION: Liver biopsy (LB) is a known risk factor for tumor seeding and hepatocellular carcinoma (HCC) recurrence. The time from LB to confirmed needle tract seeding (NTS) varies from 3 months to 4 years. We present case of recurrent HCC due to NTS 13 years after LB who presented with a right intercostal wall mass. CASE DESCRIPTION/METHODS: A 32-year-old Caucasian male presented to his primary care provider (PCP) in 2004 with recurrent right upper abdominal pain. A CT abdomen & pelvis showed 15 × 12 × 12 cm lesion in the right lobe of the liver with central hypodensity and 1-2 cm solid peripheral rim. His PCP requested CT guided percutaneous needle biopsy. Cytologic analysis was negative for malignant cells. After referral to our institution he underwent posterior right hepatectomy. A 14 × 12 × 7 cm well circumscribed tumor was removed with histopathology confirming well-differentiated HCC with negative margins (Figure 1A). In 2007, new hepatic lesions were noted during HCC surveillance for which he underwent orthotopic liver transplantation (OLT). He continued HCC surveillance which included CT abdomen, pelvis and thorax every 1- and 3-years, whole body bone scintigraphy every 3 years and abdominal US every 6-month intervals; which were negative for HCC recurrence. In 2017 (13 years post OLT), he returned with six months of right intercostal pain and swelling. CT chest & abdomen showed a large mass involving the right 10th rib, soft tissue, and lung nodules (Figure 2). Biopsy of the mass showed well-differentiated HCC, suspicious for vascular invasion (Figures 1B and 3). He was initially started sorafenib however could not tolerate it. He could not receive nivolumab due to risk of rejection and is currently on cabozatinib. He received palliative radiation for pain related to metastasis. DISCUSSION: This case highlights NTS from the LB resulting in HCC recurrence and potentially compromising curative therapies such as hepatectomy and OLT. NTC in HCC is rare with a reported incidence from 1 to 5% and could potential implant 1,000 to 100,000 malignant cells along the needle tract. Due to the risk of NTS, percutaneous biopsy is avoided in indeterminate nodules and should be used only in selected cases. Prompt referral to an experienced hepatologist is imperative. LB should be reserved for lesions in which no definitive surgical intervention is planned, and pathological confirmation is necessary for non-surgical therapy.

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INTRODUCTION: Epstein-Barr virus (EBV) usually causes asymptomatic infections in adults. In rare cases, infected individuals develop Chronic Active EBV (CAEBV), a systemic disorder characterized by elevated EBV DNA in blood and lymphocytes in tissues. We present a rare case of CAEBV in a 24-year-old woman with serology suggestive of autoimmune hepatitis (AIH). CASE DESCRIPTION/METHODS: A 24-year-old Guatemalan woman presented with RUQ abdominal pain, nausea, vomiting and subjective chills for two weeks. Labs were significant for AST 1,167 U/L, ALT 1,049 U/L, total bilirubin 2.8 mg/dL, INR 1.2, ALP 1,118 U/L, GGT 123 U/L, EBV PCR > 1,000,000 copies, EBV IgM positive, positive ANA, serum IgG 3,690 mg/dL (normal 700 – 1,600), weakly positive smooth muscle antibody (SMA) titers 1:40 (negative < 1:20), and F-actin antibodies 42 units (positive ≥ 31 units). Mild scleral icterus and RUQ abdominal tenderness noted on physical exam. CT abdomen & pelvis showed hepatosplenomegaly. Liver biopsy (LB) showed panlobular hepatitis with focal parenchymal necrosis and a prominent sinusoidal T-lymphocyte dominant infiltrate, many of which were positive for EBV-encoded small RNAs (EBER) on in situ hybridization (Figure 1). Bone marrow biopsy (BMB) showed mildly hypocellular bone marrow without evidence of lymphoproliferative disorder. She left against medical advice (AMA) 6 days later and did not follow up in clinic. Five months later, she returned with similar complaints with pancytopenia and febrile neutropenia. A repeat BMB showed a hypercellular bone marrow with findings suggestive of CAEBV of T-cell type. She left AMA shortly after initiating steroids. A referral to the National Institute of Health for stem cell transplant (SCT) was unsuccessful as she was lost to follow up. DISCUSSION: Hepatic manifestations of CAEBV include acute hepatitis in 47% of patients in the United States with a mixed hepatocellular-cholestatic pattern and hepatomegaly. Her labs were suggestive of AIH such as elevated IgG, positive ANA, weakly positive SMA titers & elevated F-actin antibodies. Several cases report false positive serology suggestive of AIH in patients with active EBV. Inappropriate and possibly dangerous treatment could result if one is unaware of this association. Allogenic hematopoietic SCT is the only known curative therapy to date and without treatment, the average time to death after disease onset is 6.2 years. Given the high mortality associated with delay in treatment, prompt recognition and diagnosis of CAEBV is imperative.