Functional characterization of the biogenic amine transporters on human macrophages.

Monocyte-derived macrophages (MDMs) are key players in tissue homeostasis and diseases regulated by a variety of signaling molecules. Recent literature has highlighted the ability for biogenic amines to regulate macrophage functions, but the mechanisms governing biogenic amine signaling in and around immune cells remain nebulous. In the CNS, biogenic amine transporters are regarded as the master regulators of neurotransmitter signaling. While we and others have shown that macrophages express these transporters, relatively little is known of their function in these cells. To address these knowledge gaps, we investigated the function of norepinephrine transporter (NET) and dopamine transporter (DAT) on human MDMs. We found that both NET and DAT are present and can uptake substrate from the extracellular space at baseline. Not only was DAT expressed in cultured MDMs, but it was also detected in a subset of intestinal macrophages in situ. Surprisingly, we discovered a NET-independent, DAT-mediated immunomodulatory mechanism in response to LPS. LPS induced reverse transport of dopamine through DAT, engaging an autocrine/paracrine signaling loop that regulated the macrophage response. Removing this signaling loop enhanced the proinflammatory response to LPS. Our data introduce a potential role for DAT in the regulation of innate immunity.

Long-term results of percutaneous transhepatic cholangiographic drainage for palliation of malignant biliary obstruction.

INTRODUCTION: Percutaneous stenting is established in the palliation of malignant biliary obstruction. We examined the indications, success rate, complications, and long-term postoperative course of patients undergoing this procedure. METHODS: All patients undergoing percutaneous transhepatic cholangiography (PTC) and metal stenting over a 12-month period in a tertiary referral center were studied. Data regarding diagnosis, number and type of procedures, complications, and survival were collected from multidisciplinary case notes and general practitioner records. RESULTS: There were 21 patients of median age 70 (mean, 71; range, 54-93), 56.5% (11) had pancreatic cancer and 33% (7) cholangiocarcinoma. The mean number of PTC procedures was 2.43 and mean length of stay in hospital 20.66 days (range, 3-99). Serum bilirubin fell post drainage from 397 to 226 (µmol/L; p < 0.001) on discharge, however, in 19% (4) there was no significant reduction. Complications included cholangitis (19%) and acute pancreatitis (10%). Mortality was high and 9 patients (43%) died within 30 days, of whom 2 died in the hospital (1 from ascending cholangitis and another from pneumonia). The median time between discharge and death was 25 days (mean, 59.1 days) and no patient was alive after 193 days. CONCLUSIONS: The prognosis following PTC stenting of malignant biliary obstruction is extremely poor despite adequate drainage. The procedure can lead to significant morbidity and a lengthy hospital stay. Patient selection is therefore of paramount importance and an expedient treatment protocol and early return home recommended.