Patients with inflammatory bowel disease have increased risk of autoimmune and inflammatory diseases.

AIM: To investigate whether immune mediated diseases (IMD) are more frequent in patients with inflammatory bowel disease (IBD). METHODS: In this population based registry study, a total of 47325 patients with IBD were alive and registered in the Danish National Patient Registry on December 16, 2013. Controls were randomly selected from the Danish Civil Registration System (CRS) and matched for sex, age, and municipality. We used ICD 10 codes to identify the diagnoses of the included patients. The IBD population was divided into three subgroups: Ulcerative colitis (UC), Crohn's disease (CD) and Both the latter referring to those registered with both diagnoses. Subsequently, odds-ratios (OR) and 95%CI were obtained separately for each group and their respective controls. The use of Bonferoni post-test correction adjusted the significance level to P < 0.00125. P-values were estimated using Fisher's exact test. RESULTS: There were significantly more women than men in the registry, and a greater percentage of comorbidity in the IBD groups (P < 0.05). Twenty different IMDs were all significantly more frequent in the IBD group. Sixteen were associated with UC versus twelve with CD. In both UC and CD ORs were significantly increased (P < 0.00125) for primary sclerosing cholangitis (PSC), celiac disease, type 1 diabetes (T1D), sarcoidosis, asthma, iridocyclitis, psoriasis, pyoderma gangrenosum, rheumatoid arthritis, and ankylosing spondylitis. Restricted to UC (P < 0.00125) were autoimmune hepatitis, primary biliary cholangitis, Grave's disease, polymyalgia rheumatica, temporal arteritis , and atrophic gastritis. Restricted to CD (P < 0.00125) were psoriatic arthritis and episcleritis. Restricted to women with UC (P < 0.00125) were atrophic gastritis, rheumatoid arthritis, temporal arteritis, and polymyalgia rheumatica. Restricted to women with CD were episcleritis, rheumatoid arthritis, and psoriatic arthritis. The only disease restricted to men (P < 0.00125) was sarcoidosis. CONCLUSION: Immune mediated diseases were significantly more frequent in patients with IBD. Our results strengthen the hypothesis that some IMDs and IBD may have overlapping pathogenic pathways.

High expression of KCa3.1 in patients with clear cell renal carcinoma predicts high metastatic risk and poor survival.

BACKGROUND: Ca2+-activated K+ channels have been implicated in cancer cell growth, metastasis, and tumor angiogenesis. Here we hypothesized that high mRNA and protein expression of the intermediate-conductance Ca2+-activated K+ channel, KCa3.1, is a molecular marker of clear cell Renal Cell Carcinoma (ccRCC) and metastatic potential and survival. METHODOLOGY/PRINCIPAL FINDINGS: We analyzed channel expression by qRT-PCR, immunohistochemistry, and patch-clamp in ccRCC and benign oncocytoma specimens, in primary ccRCC and oncocytoma cell lines, as well as in two ccRCC cell lines (Caki-1 and Caki-2). CcRCC specimens contained 12-fold higher mRNA levels of KCa3.1 than oncocytoma specimens. The large-conductance channel, KCa1.1, was 3-fold more highly expressed in ccRCC than in oncocytoma. KCa3.1 mRNA expression in ccRCC was 2-fold higher than in the healthy cortex of the same kidney. Disease specific survival trended towards reduction in the subgroup of high-KCa3.1-expressing tumors (p<0.08 vs. low-KCa3.1-expressing tumors). Progression-free survival (time to metastasis/recurrence) was reduced significantly in the subgroup of high-KCa3.1-expressing tumors (p<0.02, vs. low-KCa3.1-expressing tumors). Immunohistochemistry revealed high protein expression of KCa3.1 in tumor vessels of ccRCC and oncocytoma and in a subset of ccRCC cells. Oncocytoma cells were devoid of KCa3.1 protein. In a primary ccRCC cell line and Caki-1/2-ccRCC cells, we found KCa3.1-protein as well as TRAM-34-sensitive KCa3.1-currents in a subset of cells. Furthermore, Caki-1/2-ccRCC cells displayed functional Paxilline-sensitive KCa1.1 currents. Neither KCa3.1 nor KCa1.1 were found in a primary oncocytoma cell line. Yet KCa-blockers, like TRAM-34 (KCa3.1) and Paxilline (KCa1.1), had no appreciable effects on Caki-1 proliferation in-vitro. CONCLUSIONS/SIGNIFICANCE: Our study demonstrated expression of KCa3.1 in ccRCC but not in benign oncocytoma. Moreover, high KCa3.1-mRNA expression levels were indicative of low disease specific survival of ccRCC patients, short progression-free survival, and a high metastatic potential. Therefore, KCa3.1 is of prognostic value in ccRCC.

[Severe interstitial lung disease due to treatment with infliximab and azathioprine].

A 41-year-old man developed severe interstitial lung disease (ILD) after treatment with infliximab (IFX) and azathioprine (AZA). A relapse of ulcerative colitis was treated with corticosteroids (CS) and IFX as rescue therapy. Following remission AZA was given as prophylaxis. AZA was initiated the same day as the third infusion of IFX (week 6). Within a few days he developed signs of lung involvement progressing into severe ILD. A high resolution computed tomography showed subacute hypersensitive pneumonitis. He was treated with oxygen and high dose CS. After three months his state of health had returned to normal.

The role of T cell potassium channels, KV1.3 and KCa3.1, in the inflammatory cascade in ulcerative colitis.

Ulcerative Colitis (UC) is a chronic inflammatory bowel disease located in the mucosa of the large bowel. UC often affects young adults between 15 and 40 years of age with no pre-dominant sex. Over time, incidence rates are steadily increasing and the cause of the disease remains unknown. Symptoms are general discomfort and bloody diarrhea. UC is diagnosed by endoscopic examination of the large bowel, where different hallmarks are found. It is of great importance that attacks/relapses are treated medically, as flares may cause death due to inflammatory destruction of the mucosa and perforation of the colon leading to extreme infection of the abdominal cavity. UC often affects the social life of the patients, as they feel that they must be in the immediate vicinity of toilets. Therefore, many patients prefer to stay at home during active disease. For society, UC is a costly disease due to patients reporting in sick and expensive medications. When medical treatment fails, UC patients must undergo surgery and have their colon removed (colectomy). This PhD project focused on the immune system of the body. Specifically, we looked into T cells (the chairmen of the immune system) that we believe play an important role in disease activity. When T cells are activated in inflammatory diseases, they produce several signaling substances (cytokines) that attract and activate the other parts of the immune system. T cells regulate their effector functions through calcium regulation. Upon activation, calcium is released from intracellular stores, which causes calcium channels to be embedded in the cell membrane (CRAC channels). As long as the T cells are stimulated, the two potassium channels KV1.3 and KCa3.1 maintain the driving force for calcium influx, thus keeping the T cells activated. Our aims were to investigate whether the two potassium channels KV1.3 and KCa3.1 were upregulated in mucosal biopsies from patients with active UC and whether there were correlations between the expression of the channels and the disease severity assessed by endoscopic and histological evaluation. Moreover, we used a rat colitis model (dextran sodium sulphate-induced) to examine the effect of pharmacological inhibition of KV1.3 and KCa3.1 on inflammation. We found that the expression of T cell potassium channel, KV1.3, was increased in active UC and a higher expression correlated well with both the endoscopic and the histological degree of inflammation. This suggests KV1.3 to be involved in the inflammatory process of UC. We did not find an increase of the other potassium channel, KCa3.1, at the gene expression level, but the channels were definitely present in the infiltrating T cells as examined by immunostaining. Preliminary gene expression data showed similar changes of gene expression in biopsies from Crohns disease (CD) patients. In addition, we conducted first pilot studies investigating whether pharmacological blockade of the channels ameliorates colitis in the rat DSS-model. We found a tendency towards less endoscopic inflammation in the acute phase (at day 7 and 10). However, at study termination, the improvement of inflammation failed to reach a significant level, presumably because of insufficient compound absorption from the intestine (based on low plasma concentration and previously reported amelioration of colitis by inhibiting KCa3.1). Based on these findings in our target identification study, it is suggested that both KV1.3 and KCa3.1 play a role in the inflammation of UC and possibly of CD and represent new pharmacological targets.

[Atypical manifestation of infective endocarditis]. / Atypisk manifestation ved infektiøs endokarditis.

Infective endocarditis is a serious disease associated with a high mortality. The initial presentation may be non-specific and misleading, thus delaying correct diagnosis. In this case report, we describe a 46-year-old woman, who presented with symptoms suggestive of systemic lupus erythematosus, including malar rash, arthritis, acute renal failure and thrombocytopenia, but she was subsequently proven to have infective endocarditis involving the mitral valve. Her rheumatological symptoms diminished after antibiotic therapy and mitral valve surgery.

Defibrillator charging before rhythm analysis significantly reduces hands-off time during resuscitation: a simulation study.

BACKGROUND: Our objective was to reduce hands-off time during cardiopulmonary resuscitation as increased hands-off time leads to higher mortality. METHODS: The European Resuscitation Council (ERC) 2005 and ERC 2010 guidelines were compared with an alternative sequence (ALT). Pulseless ventricular tachycardia and asystole were presented randomly to all participants in a simulation setting. A manikin (Resusci Anne; Laerdal Scandinavia A/S, Stavanger, Norway) and a defibrillator (LIFEPACK 12; Physio-Control, Inc, Redmond, WA, USA) were used. In ALT, chest compressions were only interrupted for postcharging rhythm analysis and immediate shock delivery. Comparing ALT to ERC 2005 and ERC 2010 shock delivery was done using paddles and pads, respectively. RESULTS: Sample sizes were calculated with α of .05 and 90% power. Hence, we needed 4 and 12 participants, respectively. In ERC 2005 vs ALT, 10 physicians were included. All had prior experience in advanced life support. Chest compressions were shorter interrupted using ALT (mean, 6.7 vs 13.0 seconds). Analyzing data for ventricular tachycardia scenarios only, hands-off time was shorter using ALT (mean, 7.1 vs 18.2 seconds). In ERC 2010 vs ALT, 12 physicians were included. Two physicians had not prior experience in advanced life support. Hands-off time was reduced using ALT (mean, 3.9 vs 5.6 seconds). Looking solely at ventricular tachycardia scenarios, hands-off time was shortened using ALT (mean, 4.5 vs 7.6 seconds). No significant reduction was observed in either of the asystole scenarios. CONCLUSION: In a simulation setting, we demonstrated that charging of the defibrillator before rhythm analysis significantly reduced hands-off time compared with the ERC 2005 and ERC 2010 guidelines.