Conjugated bilirubin triggers anemia by inducing erythrocyte death.

UNLABELLED: Hepatic failure is commonly associated with anemia, which may result from gastrointestinal bleeding, vitamin deficiency, or liver-damaging diseases, such as infection and alcohol intoxication. At least in theory, anemia during hepatic failure may result from accelerated clearance of circulating erythrocytes. Here we show that bile duct ligation (BDL) in mice leads to severe anemia despite increased reticulocyte numbers. Bilirubin stimulated suicidal death of human erythrocytes. Mechanistically, bilirubin triggered rapid Ca(2+) influx, sphingomyelinase activation, formation of ceramide, and subsequent translocation of phosphatidylserine to the erythrocyte surface. Consistent with our in vitro and in vivo findings, incubation of erythrocytes in serum from patients with liver disease induced suicidal death of erythrocytes in relation to their plasma bilirubin concentration. Consistently, patients with hyperbilirubinemia had significantly lower erythrocyte and significantly higher reticulocyte counts compared to patients with low bilirubin levels. CONCLUSION: Bilirubin triggers suicidal erythrocyte death, thus contributing to anemia during liver disease.

Ustekinumab Is Rapid-Acting and Is an Effective Long-Term Treatment for Patients with Active Psoriatic Arthritis: Real-World Evidence from the Non-interventional SUSTAIN Study.

INTRODUCTION: Psoriatic arthritis (PsA) is a chronic, progressive disease that places a significant burden on patients and healthcare systems. The SUSTAIN study collected real-world evidence on long-term effectiveness, impact on quality of life, and safety of ustekinumab treatment for PsA. METHODS: SUSTAIN was a prospective, non-interventional study conducted in Germany. Patients with active PsA received ustekinumab for 160 weeks in routine clinical care, with assessments at baseline, week 4, and every 12 weeks thereafter. This analysis focuses on patients who remained in SUSTAIN until week 160. RESULTS: Of 337 patients enrolled, 129 were documented at week 160, of which 123 (95.3%) had received previous PsA medication, including biologics. Decreases from baseline to week 4 were observed for tender joint count (TJC, 8.0 to 5.8) and swollen joint count (SJC, 4.5 to 3.1); these decreases continued to week 28 and were maintained to week 160 (1.0 and 0.4, respectively). Similarly, skin assessments in patients with PsA and psoriasis revealed improvement at week 4, which continued to week 28, with a sustained effect until week 160. Similar patterns of response were observed for patient-assessed pain, sleep quality, and health scores. Improvements in TJC, SJC, Psoriasis Area and Severity Index, and affected body surface area were observed irrespective of the number of prior biologic therapies used. Minimal disease activity was achieved by 36 (31.9%) patients at week 28, and by 38 (33.6%) at week 52. Ustekinumab-related adverse events (AEs) and serious AEs were reported in 61 (47.3%) and 4 (3.1%) patients, respectively. At week 160, 100% of patients assessed ustekinumab tolerability as good or very good. CONCLUSIONS: In a real-world setting, patients with active PsA who received ustekinumab until 160 weeks (3 years), including those who received prior biologic therapies, had a rapid onset of effect and sustained response to treatment, with high tolerability. TRIAL REGISTRATION: PEI NIS No. 290.

Physicians in the pharmaceutical industry: their roles, motivations, and perspectives.

Although physicians occupy a significant number of key positions in the pharmaceutical industry, practicing clinicians are often unaware of the variety of career paths within this industry, or of the structure of a pharmaceutical company. Here, we address questions that practicing clinicians frequently ask their colleagues in the pharmaceutical industry. In addition to providing an overview of the common roles occupied by physicians in pharma, we also describe the various motivations for transitioning into the industry and discuss different scenarios regarding the timing of the career change. Furthermore, we outline the characteristics and skills that enable physicians to have a successful career in pharma.

Arginase-1 overexpression induces cationic amino acid transporter-1 in psoriasis.

Regulated uptake of extracellular l-arginine by cationic amino acid transporters (CATs) is required for inducible nitric oxide synthase and arginase activity. Both enzymes were recently recognized as important in the pathophysiology of psoriasis because of their contribution to epidermal hyperproliferation. We here characterize the expression pattern of CATs in psoriatic skin compared to healthy skin. CAT-1 mRNA expression was strongly upregulated in lesional and nonlesional areas of psoriatic skin compared to healthy skin, whereas expression of CAT-2A and the inducible isoform CAT-2B was unaltered in psoriatic skin. Furthermore, we tested the hypothesis that arginase-1 overexpression regulates CAT expression via intracellular l-arginine concentration. In in vitro experiments with arginase-1 overexpressing HaCaT cells, CAT-1 mRNA expression was increased. Likewise, this occurs in l-arginine-starved HaCaT cells. Both CAT-2 isoforms were not affected. Arginase-1 overexpression limits the synthesis of NO at physiological, but not supraphysiological, l-arginine levels. Plasma l-arginine concentration was diminished in psoriasis patients and the arginase product l-ornithine was significantly increased compared to healthy controls. In summary, arginase-1 overexpression leads to upregulated CAT-1 expression in psoriatic skin, which is due to lowered intracellular l-arginine levels and limits NO synthesis at physiological l-arginine concentrations.

Cocoa-related flavonoids inhibit CFTR-mediated chloride transport across T84 human colon epithelia.

Cocoa beans have historically been used as a treatment for diarrhea, leading us to hypothesize that polyphenols contained in cocoa inhibit intestinal Cl- secretion. In this study, the dose-dependent effects of flavonoid compounds present in cocoa, or molecularly closely related compounds, were tested on forskolin-stimulated cystic fibrosis transmembrane conductance regulator (CFTR)-mediated Cl- secretion across T84 colonic epithelia in Ussing chambers. Addition of cocoa extract or cocoa flavanols to the mucosal side of tissues caused partial inhibition following Michaelis-Menten kinetics and resulted in a rank order of maximum blocker effects as follows: epicatechin > catechin > or = standardized cocoa preparation > or = procyanidin B2. Half-maximal blocker concentrations (Ki) were not substantially different between the tested preparations and were in the range of 100 micromol/L. For comparison, the structurally related flavonoids, quercetin and luteolin, caused a total block of Cl- currents with Ki values similar to the cocoa flavanols tested. Morin and baicalein were less effective blockers. Effects of test compounds on mucosal redox potential did not correlate with blocker activity. These data indicate that cocoa flavanols target intestinal CFTR Cl- transport and may serve as mild inhibitors of cAMP-stimulated Cl- secretion in the intestine.