Accumulation of amyloid-ß in the brain of mouse models of Alzheimer's disease is modified by altered gene expression in the presence of human apoE isoforms during aging.

Apolipoprotein E4 (apoE4) is a risk factor for Alzheimer's disease (AD). Here, we investigated brain amyloid-ß (Aß) accumulation throughout the aging process in an amyloid precursor protein (APP) knock-in (KI) mouse model of AD that expresses human APPNL-G-F with or without human apoE4 or apoE3. Brain Aß42 levels were significantly lower in 9-month-old mice that express human isoforms of apoE than in age-matched APP-KI control mice. Linear accumulation of Aß42 began in 5-month-old apoE4 mice, and a strong increase in Aß42 levels was observed in 21-month-old apoE3 mice. Aß42 levels in cerebroventricular fluid were higher in apoE3 than in apoE4 mice at 6-7 months of age, suggesting that apoE3 is more efficient at clearing Aß42 than apoE4 at these ages. However, apoE3 protein levels were lower than apoE4 protein levels in the brains of 21-month-old apoE3 and apoE4 mice, respectively, which may explain the rapid increase in brain Aß42 burden in apoE3 mice. We identified genes that were downregulated in a human apoE-dependent (apoE4 > apoE3) and age-dependent (apoE3 = apoE4) manner, which may regulate brain Aß burden and/or AD progression. Analysis of gene expression in AD mouse models helps identify molecular mechanisms of pleiotropy by the human APOE gene during aging.

Primary biliary cirrhosis-autoimmune hepatitis overlap syndrome concomitant with systemic sclerosis, immune thrombocytopenic purpura.

A 58-year-old Japanese woman presented with chronic fluctuating liver dysfunction with purpura. Raynaud's phenomenon had been diagnosed 4 years previously. At the initial examination, skin biopsy showed limited cutaneous systemic sclerosis (SSc). Laboratory investigations revealed liver dysfunction. Anti-nuclear antibodies, anti-mitochondria M2 antibody, anti-thyroglobulin antibody, and platelet-associated IgG were positive. Primary biliary cirrhosis (PBC) and autoimmune hepatitis (AIH) were diagnosed serologically, clinically and histologically. Immune thrombocytopenic purpura (ITP) was diagnosed by bone marrow puncture, clinical and laboratory findings, and Helicobacter pylori IgG was positive. She was treated with prednisolone 30 mg/day, ursodeoxycholic acid 600 mg/day, and a 7-day course of lansoprazole plus amoxicillin and clarithromycin. Thrombocytes increased rapidly and transaminase improved at day 7. We report a rare case of PBC-AIH overlap syndrome with concurrent ITP and SSc which suggest the presence of shared genetic susceptibility factors in multiple autoimmune conditions including PBC, AIH, ITP and SSc.

Hepatic granulomas as primary presentation of Mycobacterium avium infection in an HIV-negative, nonimmunosuppressed patient.

Nontuberculous hepatic granuloma in patients not infected by human immunodeficiency virus (HIV) is rare. We report an 89-year-old woman who presented with hepatic granuloma without lung involvement. Ultrasonography and computed tomography (CT) of the abdomen showed low-density lesions in the liver. Histopathological examination of a liver biopsy revealed florid, caseating granulomatous reaction with aggregates of epithelioid histiocytes and Langerhans-type giant cells in a predominantly portal and periportal distribution. Gastric juice cultures were positive for Mycobacterium avium. The patient was treated with antimycobacterial therapy. Her clinical condition improved dramatically within 1 month of starting therapy, with marked reduction in hepatomegaly together with normalization of liver biochemistry and CT findings.