Combination Therapy Reverses Hyperglycemia in NOD Mice With Established Type 1 Diabetes

An increasing number of therapies have proven effective at reversing hyperglycemia in the nonobese diabetic (NOD) mouse model of type 1 diabetes (T1D), yet situations of successful translation to human T1D are limited. This may be partly due to evaluating the effect of treating immediately at diagnosis in mice, which may not be reflective of the advanced disease state in humans at disease onset. In this study, we treated NOD mice with new-onset as well as established disease using various combinations of four drugs: antithymocyte globulin (ATG), granulocyte-colony stimulating factor (G-CSF), a dipeptidyl peptidase IV inhibitor (DPP-4i), and a proton pump inhibitor (PPI). Therapy with all four drugs induced remission in 83% of new-onset mice and, remarkably, in 50% of NOD mice with established disease. Also noteworthy, disease remission occurred irrespective of initial blood glucose values and mechanistically was characterized by enhanced immunoregulation involving alterations in CD4⁺ T cells, CD8⁺ T cells, and natural killer cells. This combination therapy also allowed for effective treatment at reduced drug doses (compared with effective monotherapy), thereby minimizing potential adverse effects while retaining efficacy. This combination of approved drugs demonstrates a novel ability to reverse T1D, thereby warranting translational consideration.     

Dose‐Intensified Granulocyte‐Monocyte Apheresis in Therapy Refractory Ulcerative Colitis

Granulocyte‐monocyte apheresis (GMA) is an emerging therapeutic option in active course of ulcerative colitis (UC). Appropriate GMA dose, including total number, frequency, and duration of the individual GMA session, is a matter of debate. It was the aim of the present study to evaluate the efficacy of a dose‐intensified GMA regimen in patients with moderately to severely active UC. A prospective open‐label, single‐center study was performed in 10 patients with active UC (Rachmilewitz Clinical Activity Index [CAI] ≥ 8 points; Rachmilewitz Endoscopic Index ≥ 7 points). Patients had failed to improve after treatment with steroids and/or immunomodulators. GMA was performed twice weekly for 2 h to a maximum of 10 sessions. In each GMA session, the adsorber was changed after 1 h of treatment time. Four patients achieved remission with a CAI ≤ 4 points. Three patients had a response with an improvement of CAI of ≥3 points. Three patients showed no benefit from GMA. The quality of life score determined by the inflammatory bowel disease questionnaire‐Deutschland increased by 26 points in median. First and second filters had similar efficiency in granulocyte and monocyte adsorption. No major adverse effects were observed. Dose‐intensified GMA as reported in this study provided an encouraging short‐term response rate of 70% in patients with moderately to severely active UC not responding to standard steroid or immunomodulator therapy. Although all patients relapsed not later than 16 weeks, GMA might be useful to reduce steroid and immunomodulator usage, or to delay surgery in this patient group.     

Renale Denervierung und Hypertonie

Catheter-based renal nerve ablation can lower blood pressure (BP) in hypertensive patients. The concept is based on solid physiological studies suggesting that efferent and afferent renal nerves contribute to arterial hypertension. The preliminary results on the efficacy and safety of catheter-based renal nerve ablation on BP control in resistant hypertension have been encouraging; however, these studies were uncontrolled. In several small studies it was observed early that most patients can be controlled by pharmaceutical treatment and only a few patients respond to ablation therapy. A large prospective trial with a control group (sham treatment) was therefore necessary. The Simplicity-3 trial fulfilled these criteria. More than 600 patients were successfully studied and in March 2014 the results were published. No significant differences between the two groups were observed, one treated with renal nerve ablation and the other group controlled only by medication. These results are in contrast to the previous (uncontrolled) studies and observations from a worldwide registry. Several explanations have been put forward to explain these results. Important are (1) compliance, i.e. patients taking their medication during the study and also (2) inexperience with the method in small centers. Simplicity-3 has put a halt on using renal denervation in most countries. It is now important to find out why the method only works in some patients, what the criteria to use it are and to define a patient group where renal denervation is useful as a therapeutic method to treat patients with hypertension.