Entecavir and tenofovir on renal function in patients with hepatitis B virus‐related hepatocellular carcinoma

The use of tenofovir disoproxil fumarate (TDF) is associated with a risk of renal dysfunction. We investigated whether TDF is associated with the deterioration of renal function in patients with hepatitis B virus (HBV)‐related hepatocellular carcinoma (HCC) requiring frequent computed tomography (CT) evaluations and transarterial chemoembolization (TACE) sessions, when compared to entecavir (ETV). Between 2007 and 2017, 493 patients with HBV‐related HCC were enrolled. The number of CT evaluations and TACE sessions were collected through 3 years of follow‐up. The median age of the study population (373 men and 120 women; 325 with ETV and 168 with TDF) was 56.5 years. TDF was significantly associated with a serum creatinine increase (≥25% from the baseline; unadjusted hazard ratio [uHR] = 1.620) and an estimated glomerular filtration rate (eGFR) reduction (<20% from the baseline) (uHR = 1.950) (all P < .05), when compared to ETV. In addition, CT evaluations ≥4 times/year were significantly associated with a serum creatinine increase (uHR = 2.709), eGFR reduction (uHR = 3.274) and chronic kidney disease (CKD) progression (≥1 CKD stage from the baseline) (uHR = 1.980) (all P < .05). In contrast, TACE was not associated with all renal dysfunction parameters (all P > .05). After adjustment, TDF use was independently associated with the increased risk of eGFR reduction (adjusted HR [aHR] = 1.945; P = .023), whereas CT evaluation ≥4 times/year was independently associated with the increased risk of serum creatinine increase (aHR = 2.898), eGFR reduction (aHR = 3.484) and CKD progression (aHR = 1.984) (all P < .01). In conclusion, patients with HBV‐related HCC treated with TDF and frequent CT evaluations should be closely monitored for the detection of associated renal dysfunction.     

Continuous illumination through larval development suppresses dopamine synthesis in the suprachiasmatic nucleus, causing activation of α-MSH synthesis in the pituitary and abnormal metamorphic skin pigmentation in flounder

In order to better understand the endocrine aberrations related to abnormal metamorphic pigmentation that appear in flounder larvae reared in tanks, this study examined the effects of continuous 24-h illumination (LL) through larval development on the expression of tyrosine hydroxylase-1 (th1), proopiomelanocortin (pomc), α-melanophore-stimulating hormone (α-MSH) and melanin concentrating hormone (MCH), which are known to participate in the control of background adaptation of body color. We observed two conspicuous deviations in the endocrine system under LL when compared with natural light conditions (LD). First, LL severely suppressed th1 expression in the dopaminergic neurons in the anterior diencephalon, including the suprachiasmatic nucleus (SCN). Second, pomc and α-MSH expression in the pars intermedia melanotrophs was enhanced by LL. Skin color was paler under LL than LD before metamorphic pigmentation, and abnormal metamorphic pigmentation occurred at a higher ratio in LL. We therefore hypothesize that continuous LL inhibited dopamine synthesis in the SCN, which resulted in up-regulation of pomc mRNA expression in the melanotrophs. In spite of the up-regulation of pomc in the melanotrophs, larval skin was adjusted to be pale by MCH which was not affected by LL. Accumulation of α-MSH in the melanotrophs is caused by uncoupling of α-MSH synthesis and secretion due to inhibitory role of MCH on α-MSH secretion, which results in abnormal metamorphic pigmentation by affecting differentiation of adult-type melanophores. Our data demonstrate that continuous illumination at the post-embryonic stage has negative effects on the neuroendocrine system and pituitary in flounder.     

A case of adenocarcinoma in situ of the distal common bile duct diagnosed by percutaneous transhepatic cholangioscopy

Extrahepatic cholangiocarcinoma is often clinically challenging to diagnose. Even multidisciplinary approaches which include computed tomography, magnetic resonance imaging, and endoscopic retrograde cholangiography are unsatisfactory in some cases, especially with biliary stricture. Percutaneous transhepatic cholangioscopy (PTCS) with its direct visualization for biopsy appears to be a promising technique for detecting cholangiocarcinoma at an early stage. We report a case of adenocarcinoma in situ of the distal common bile duct (CBD) that was confirmed by PTCS. This case suggests the useful role of PTCS in the differential diagnosis of a distal CBD obstruction, particularly when other diagnostic modalities do not provide definitive information.     

Adipose Tissue Macrophages Function As Antigen-Presenting Cells and Regulate Adipose Tissue CD4+ T Cells in Mice

The proinflammatory activation of leukocytes in adipose tissue contributes to metabolic disease. How crosstalk between immune cells initiates and sustains adipose tissue inflammation remains an unresolved question. We have examined the hypothesis that adipose tissue macrophages (ATMs) interact with and regulate the function of T cells. Dietary obesity was shown to activate the proliferation of effector memory CD4⁺ T cells in adipose tissue. Our studies further demonstrate that ATMs are functional antigen-presenting cells that promote the proliferation of interferon-γ–producing CD4⁺ T cells in adipose tissue. ATMs from lean and obese visceral fat process and present major histocompatibility complex (MHC) class II–restricted antigens. ATMs were sufficient to promote proliferation and interferon-γ production from antigen-specific CD4⁺ T cells in vitro and in vivo. Diet-induced obesity increased the expression of MHC II and T-cell costimulatory molecules on ATMs in visceral fat, which correlated with an induction of T-cell proliferation in that depot. Collectively, these data indicate that ATMs provide a functional link between the innate and adaptive immune systems within visceral fat in mice.Obesity-induced inflammation contributes to the development of type 2 diabetes, metabolic syndrome, and cardiovascular disease (1–3). Accumulation of activated leukocytes in metabolic tissues is a driving force for obesity-associated metabolic inflammation (metainflammation) and insulin resistance (3,4). In adipose tissue, a vast array of leukocytes have been identified and reported to contribute to obesity-induced metainflammation. How adipose tissue leukocytes interact to shape the inflammatory environment within fat is an important unresolved gap in our current understanding of metabolic disease.In humans and rodent models, F4/80⁺ adipose tissue macrophages (ATMs) are the predominant leukocyte found in metabolically healthy and insulin-resistant fat (5). Resident (type 2) ATMs are distributed between adipocytes in healthy adipose tissue throughout development, express anti-inflammatory markers typical of “alternatively activated” or M2 polarized macrophages, and promote tissue homeostasis (6,7). Disruption of macrophage M2 polarization increases the susceptibility to insulin resistance induced by a high-fat diet (HFD) (8–10). Obesity triggers the accumulation of F4/80⁺ ATMs that coexpress the dendritic cell (DC) marker CD11c as well as genes typically expressed by “classically activated” or proinflammatory M1 polarized macrophages (11–13). M1 ATMs form multicellular lipid-laden clusters, known as crown-like structures (CLS), around dead adipocytes in obese fat (6,14,15) and produce inflammatory cytokines (e.g., interleukin [IL]-1β, IL-6, and tumor necrosis factor-α [TNF-α]) that can impair insulin action in adipocytes (16,17). Current models suggest that obesity promotes metainflammation in part by altering the balance between type 2 and type 1 ATMs in visceral fat (13,18).In addition to ATMs, adipose tissue contains lymphocytes (e.g., natural killer T cells [NKTs], conventional CD4⁺ T cells [Tconvs], regulatory CD4⁺ T cells [Tregs], cytotoxic CD8⁺ T cells, and B cells) that are also regulated by metabolic status (19–24). Treg content in visceral fat is inversely correlated with measures of insulin resistance and inflammation (19,25,26), suggesting that Tregs are anti-inflammatory. In contrast, T helper 1 (Th1) CD4⁺ T cells and CD8⁺ adipose tissue T cells (ATTs) accumulate in fat during obesity, promoting IFN-γ and TNF-α production and insulin resistance (20,21,27). Thus, analogous to ATMs, the imbalance between anti-inflammatory Tregs and proinflammatory CD4⁺/CD8⁺ ATTs contributes to metainflammation.The mechanisms that regulate ATTs in adipose tissue are largely unknown. Spectratyping experiments suggest that CD4⁺ ATTs (but not CD8⁺ ATTs) undergo monoclonal expansion within fat and have an effector-memory (CD44^High CD62L^Low) phenotype (19,21,28). This implies that ATT activation and expansion may be an adaptive immune response to an obesity-induced antigen. T-cell activation depends on an intricate relationship between T cells and antigen-presenting cells (APCs) (29). Classically, APCs (specifically, macrophages and DCs) shape CD4⁺ T-cell activation by three signals: 1) presentation of peptide antigens on major histocompatibility complex (MHC) class II (MHC II) molecules (signal 1), 2) expression of T-cell costimulatory molecules (e.g., CD40, CD80, and CD86) (signal 2), and 3) production of cytokines (e.g., transforming growth factor-β, IL-10, or IL-12) (signal 3). These three signals shape the differentiation of naïve CD4⁺ T cells into effector T-cell subsets (e.g., Th1, Th2, Th17, Treg).The APCs that interact with ATTs in fat have not been well characterized but could include ATMs, adipose tissue DCs, adipose tissue B cells, mast cells, and neutrophils (24,30–34). Quantitative changes in ATTs can precede the accumulation of type 1 CD11c⁺ ATMs in visceral fat in obese mice, suggesting that APCs present in lean and obese fat could trigger an adaptive immune response. Because ATMs are the predominant leukocyte population in lean and obese fat and ATMs from obese mice and humans express MHC II molecules (35–37), we tested the hypothesis that ATMs (CD11b⁺ F4/80⁺) are capable of functioning as APCs to regulate CD4⁺ ATT activation and proliferation. We report that ATMs within visceral fat from mice phagocytose and process antigens for presentation, express costimulatory molecules, and induce antigen-specific CD4⁺ T-cell proliferation in vitro and in situ. Furthermore, we found proliferating ATTs localized with ATMs in fat-associated lymphoid clusters (FALCs) where antigen-specific T-cell activation and proliferation may be initiated. Our data indicate that ATMs meet the functional definition of APCs and suggest that MHC II-restricted antigens presented by ATMs in visceral fat regulate Tregs and Tconvs CD4⁺ ATTs in mice.