ABSTRACT
BACKGROUND & AIMS: Interferon-associated depression is a frequent side effect of antiviral therapy for chronic hepatitis C. The aim of the present study was to investigate the correlation between platelet serotonin (5-hydroxytryptamine, 5-HT) concentrations and IFN-induced depression. METHODS: The study represents a secondary analysis of a previously published trial on the efficacy of SSRI medication in HCV patients on IFN therapy. Ninety-three patients were longitudinally assessed for depression and platelet serotonin. Evaluation time points were: prior to IFN therapy, at weeks 4, 12, and 24 of IFN treatment, and 4 weeks after antiviral treatment. Depression was assessed using the Hospital Anxiety and Depression Scale (HADS). Platelet serotonin concentrations were measured by ELISA. RESULTS: Platelet serotonin concentrations were significantly decreased during interferon therapy (p=0.001) in 74 of the 93 patients (79.6%). Clinically relevant depression occurred in 33.3% of patients - however, IFN-induced depression was not significantly linked to either baseline 5-HT concentrations or kinetics. In the subgroup of patients with IFN-induced depression who received the selective serotonin reuptake inhibitor (SSRI) citalopram (20 mg daily, n=17), serotonin levels declined further during anti-depressant medication, becoming statistically significant within the first 2 weeks (p<0.001) of SSRI treatment. CONCLUSIONS: We demonstrate a significant impact of IFN and SSRI intake on platelet serotonin levels, suggesting a biochemical analogy between 5-HT metabolism in blood platelets and the CNS. Platelet 5-HT levels might serve as a surrogate marker for patient adherence to antiviral and anti-depressant medication. For the prediction of IFN-induced depression, however, platelet 5-HT measurements are not suitable.
Subject(s)
Antiviral Agents/adverse effects , Antiviral Agents/therapeutic use , Depression/chemically induced , Hepatitis C, Chronic/drug therapy , Interferon-alpha/adverse effects , Interferon-alpha/therapeutic use , Polyethylene Glycols/adverse effects , Polyethylene Glycols/therapeutic use , Serotonin/blood , Adolescent , Adult , Aged , Biomarkers/blood , Blood Platelets/metabolism , Citalopram/adverse effects , Citalopram/therapeutic use , Depression/drug therapy , Depression/epidemiology , Drug Therapy, Combination , Female , Hepatitis C, Chronic/psychology , Humans , Incidence , Interferon alpha-2 , Male , Middle Aged , Recombinant Proteins , Retrospective Studies , Ribavirin/therapeutic use , Risk Factors , Selective Serotonin Reuptake Inhibitors/adverse effects , Selective Serotonin Reuptake Inhibitors/therapeutic use , Time Factors , Young AdultABSTRACT
BACKGROUND & AIMS: Acute pancreatitis constitutes a life-threatening condition in which pancreatic acinar cells undergo massive cell death. We investigated the incidence of apoptosis, autophagy, and necrosis affecting acinar cells in the early onset of acute pancreatitis induced by chronic alcohol feeding and acute endotoxemia. METHODS: Rats were fed either an ethanol-containing or a control diet over 14 weeks and killed 3 or 24 hours after a single lipopolysaccharide injection. Apoptosis, necrosis, and autophagy of pancreatic acinar cells were assessed by histology, electron microscopy, immunofluorescence, and biochemical methods. RESULTS: The combination of alcohol exposure and endotoxemia resulted in the depletion of several lysosomal proteins including lysosomal-associated membrane protein-2 (Lamp-2), a protein that is required for the proper fusion of autophagosomes with lysosomes. Accordingly, Lamp-2 depletion correlated with the accumulation of autophagosomes and a relative paucity of autolysosomes, reduced adenosine-5'-triphosphate levels, and a switch from apoptotic to necrotic cell death. This switch to necrosis was accompanied by reduced caspase activation and the nuclear release of the proinflammatory factor high mobility group box 1. Importantly, human patients with alcoholic pancreatitis also exhibited local Lamp-2 depletion, which points to a crucial role for Lamp-2 and autophagy in pancreatic acinar cell death. CONCLUSIONS: Our data suggest that acinar cell vacuolization in pancreatitis is mediated by an endotoxemia-induced inhibition of the late stage of autophagy. The combination of alcohol and endotoxemia attenuated apoptosis response yet enhanced acinar cell necrosis. The depletion of lysosomal proteins plays a critical role in the early onset of acute pancreatitis.
Subject(s)
Apoptosis , Autophagy , Lysosomal Membrane Proteins/metabolism , Lysosomal-Associated Membrane Protein 2/metabolism , Lysosomes/metabolism , Pancreas/metabolism , Pancreatitis, Alcoholic/metabolism , Pancreatitis/metabolism , Acute Disease , Adenosine Triphosphate/metabolism , Animals , Caspase 3/metabolism , Caspase 9/metabolism , Cathepsin B/metabolism , Cell Line , Disease Models, Animal , Down-Regulation , Endotoxemia/chemically induced , Endotoxemia/complications , Endotoxemia/metabolism , Endotoxemia/pathology , Ethanol , HMGB1 Protein/metabolism , Humans , Lipopolysaccharides , Lysosomal-Associated Membrane Protein 2/genetics , Lysosomes/enzymology , Male , Necrosis , Pancreas/enzymology , Pancreas/pathology , Pancreatitis/etiology , Pancreatitis/pathology , Pancreatitis, Alcoholic/etiology , Pancreatitis, Alcoholic/pathology , RNA Interference , Rats , Rats, Sprague-Dawley , Time Factors , Transfection , Trypsin/metabolismABSTRACT
Coronary calcification is a potent predictor of cardiac events. In patients with chronic renal disease, both prevalence and intensity of coronary calcification are increased. It has remained uncertain whether it is the intima of the coronaries or the media that is calcified and whether the morphologic details of calcified plaques differ between renal and nonrenal patients. Autopsy samples of coronaries were obtained from standard sites in 23 renal and 23 age- and gender-matched nonuremic patients. Specimens were examined using light and electron microscopy, immunohistochemistry, backscatter imaging, and x-ray analysis. In coronaries, calcified plaques occupied a similar proportion of the intima area in renal versus nonrenal patients (17.3 +/- 11.9 versus 18.1 +/- 11.9%) but occupied a significantly higher proportion of the media (16.6 +/- 10.6 versus 3.8 +/- 2.31%). Expression of the proteins osteocalcin, C-reactive protein, TGF-beta, and collagen IV was significantly more intensive around coronary plaques of renal compared with nonrenal patients. The non-plaque-bearing intima of renal patients showed minimal staining for fetuin, but fetuin staining was seen surrounding calcified plaques. In addition, more pronounced deposition of C5b-9 was found around coronary plaques of renal patients, and glycophorin deposition pointed to more past intraplaque hemorrhage in renal patients. Calcification by electron backscatter analysis is more intense in the coronary media, but not if the intima is more intense in renal compared with nonrenal patients. A more marked inflammatory response in renal patients is suggested by more frequent presence and greater intensity of markers of inflammation.