Hans Michael Steffen

Longitudinal Analysis of Distribution and Function of Plasmacytoid Dendritic Cells in Peripheral Blood and Gut Mucosa of HIV infected patients

Aberrant activation of plasmacytoid dendritic cells (pDCs) with excessive production of interferon alpha (IFNα) represents one of the hallmarks of immune activation during chronic phase of human immunodeficiency virus (HIV) infection. A number of studies have shown that disruption of mucosal integrity in the gut is a cause of persistent immune activation. However, little is known about the role that pDCs play in this process, and our current understanding comes from the simian immunodeficiency virus macaque model. Thus, in the present study we sought to investigate the frequency and function of pDCs in peripheral blood and gut samples from HIV-infected individuals before and 6 months after initiation of antiretroviral therapy (ART). We show that circulating pDCs were depleted in ART-naive HIV+ patients, and upregulated the gut-homing receptor CD103 compared with uninfected controls. By converse, pDCs accumulated in the terminal ileum of ART-naive HIV individuals compared with controls. Baseline levels of IFNα production and markers of immune activation in gut samples of ART-naive HIV subjects were elevated. All these parameters declined after 6 months of ART. Our results suggest that in chronic HIV infection, pDCs migrate from peripheral blood to the gut-associated lymphatic tissue, where they may contribute to immune activation.

Control of mitogenic and motogenic pathways by miR-198, diminishing hepatoma cell growth and migration

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer deaths, worldwide. MicroRNAs, inhibiting gene expression by targeting various transcripts, are involved in genomic dysregulation during hepatocellular tumorigenesis. In previous studies, microRNA-198 (miR-198) was shown to be significantly downregulated in HCV-positive hepatocellular carcinoma (HCC). Herein, the function of miR-198 in hepatocellular carcinoma cell growth and gene expression was studied. In hepatoma cell-types with low levels of liver-specific transcription factor HNF1α indicating a low differentiation grade, miR-198 expression was most downregulated. However, miR-198 treatment did not restore the expression of the liver-specific transcription factors HNF1α or HNF4α. Importantly, overexpression of miR-198 in Pop10 hepatoma cells markedly reduced cell growth. In agreement, comprehensive gene expression profiling by microarray hybridisation and real-time quantification revealed that central signal transducers of proliferation pathways were downregulated by miR-198. In contrast, genes mediating cellular adherence were highly upregulated by miR-198. Thus, the low expression of E-cadherin and claudin-1, involved in cell adhesion and cell-cell contacts, was abolished in hepatoma cells after miR-198 overexpression. This definite induction of both proteins by miR-198 was shown to be accompanied by a significantly impaired migration activity of hepatoma Pop10 cells. In conclusion, miR-198 acts as a tumor suppressor by repression of mitogenic and motogenic pathways diminishing cell growth and migration.

Reduced lymphocyte β2‐adrenoceptor density and impaired diastolic left ventricular function in patients with glucocorticoid deficiency

OBJECTIVE Patients with adrenal crisis are at risk of severe hypotension not responding to administration of catecholamines. As glucocorticoids may be a prerequisite for intact β‐adrenoceptor function, impaired adrenoceptor activity may explain the hypotension and reduced cardiac performance in adrenal insufficiency. The aim of our study was, therefore, to further elucidate the permissive action of glucocorticoids on adrenergic function and cardiac performance.

Changes in plasma norepinephrine concentration and thrombocyte α2-adrenoceptor density during long-term antihypertensive therapy with nitrendipine and captopril

Summary Antihypertensive drugs influence the sympathetic nervous system in different ways that may cause adverse or beneficial effects. We treated 48 hypertensive patients with either nitrendipine (10–20 mg twice daily, b.i.d.) or captopril (25–50 mg b.i.d.) for 16 weeks to evaluate changes in plasma catecholamines, platelet α2- and lymphocyte β2-adrenoceptors. Blood pressure (BP) decreased from 153/95 to 135/87 mm Hg with captopril and from 155/99 to 137/89 mm Hg with nitrendipine. Treatment with nitrendipine significantly stimulated plasma norepinephrine (NE) from 327 ± 37 to 446 ± 50 pg/ml, and treatment with captopril resulted in a significant reduction in platelet α2-adrenoceptor density from 265 ± 39 to 171 ± 26 fmol/mg protein. Despite having equal BP-lowering properties, captopril and nitrendipine have different effects on the sympathetic nervous system. Stimulation of plasma NE during long-term treatment with nitrendipine may contribute to possible adverse effects, whereas reduction in α2-adrenoceptors induced by captopril may contribute to the vasodilating effect of angiotensin-converting enzyme (ACE) inhibition.

Expression of Angiotensin II Receptor Type 1 Is Reduced in Advanced Rat Liver Fibrosis

In this study, we assessed the hypothesis that the expression of angiotensin II receptor type 1 (AGTR1) in liver tissue changes with increasing fibrosis, which would influence the antifibrotic efficacy of AGTR1 blockers. Rats were treated with candesartancilexetil (CAN) initiated 8 or 15 days after bile duct occlusion (BDO). Four weeks after BDO, AGTR1 mRNA and protein were decreased compared to those in sham-operated animals depending on the amount of fibrosis. Starting CAN early, but not late, reduced mRNA of profibrotic TGF-β, MMP2, and Smad2. However, CAN had no significant effect on collagen I, fibrosis, or intrahepatic resistance. In conclusion, progression of liver fibrosis reduces AGTR1 expression. Therefore, in our model, antifibrotic effects of CAN are insufficient to improve fibrosis or intrahepatic resistance. However, if AGTR1 blockade is started early, a decrease in essential profibrotic molecules is achieved. Hence, early initiation of therapy with AGTR1 blockers may be crucial for the prevention of cirrhosis.

Plasma Catecholamines, Thrombocyte Alpha 2- and Lymphocyte Beta 2-Adrenoceptor Densities in Hypertensive Patients with Low or Normal Plasma Renin Concentrations

The sympathetic nervous system is unique in the regulation of plasma renin, for it can stimulate or suppress renin release by activation of either renal beta- or alpha2-adreno ceptors. The authors studied plasma renin concentration (PRC), noradrenalin and adrenalin levels in plasma, and the densities of lymphocyte beta2-adrenoceptors and thrombocyte alpha2-adrenoceptors in 25 hypertensive patients with either normal (11-40 mU/L; n=9) or low PRC (0-10 mU/L; n=14). There were no differences in plasma cate cholamine levels and adrenoceptor densities between the two patient groups. A positive correlation (r=0.66; P < 0.005) between beta2-adrenoceptor density and PRC in the patient group with low PRC, and a negative correlation (r=-0.72; P < 0.01) between alpha2-adrenoceptor density and plasma renin in patients with normal PRC were found. They conclude that adrenoceptor densities on blood elements and plasma catecholamines do not differ in low and normal renin hypertension. The significant correlations between adrenoceptor densities and PRCs may indicate that adrenoceptors on blood elements mirror adrenoceptor densities in the kidney and that tonic suppression of renin release through alpha2-adrenoceptors is preserved in hypertensive patients with normal plasma renin levels.

Serrated polyposis syndrome may go undiagnosed even in structured colorectal cancer screening programmes performed by endoscopists with otherwise good quality indices

We have read the article by Ijspeert et al with great interest as it comprises the largest series of colonoscopies concerning the serrated polyposis syndrome (SPS) published so far.1 SPS is characterised by multiple serrated polyps (SP) throughout the colon and it is associated with an increased risk of colorectal cancer (CRC).2 A 5-year cumulative incidence of CRC during surveillance after clearing of all relevant polyps of 1.5% has been reported.2 Recently published guidelines recommend resection of all clinically relevant lesions and starting annual colonoscopy surveillance thereafter.3 Therefore, early recognition and treatment of SPS is important to achieve low long-term risk of CRC.4 We retrospectively analysed 4161 primary screening colonoscopies of average-risk individuals aged ≥50 years performed by 15 different experienced gastroenterologists (≥300 colonoscopies of all indications per year during the …