[Show abstract][Hide abstract] ABSTRACT: Atrial fibrillation and obstructive sleep apnea are responsible for significant morbidity and mortality in the industrialized world. There is a high medical need for novel drugs against both diseases, and here, Kv1.5 channels have emerged as promising drug targets. In humans, TASK-1 has an atrium-specific expression and TASK-1 is also abundantly expressed in the hypoglossal motor nucleus. We asked whether known Kv1.5 channel blockers, effective against atrial fibrillation and/or obstructive sleep apnea, modulate TASK-1 channels. Therefore, we tested Kv1.5 blockers with different chemical structures for their TASK-1 affinity, utilizing two-electrode voltage clamp (TEVC) recordings in Xenopus oocytes. Despite the low structural conservation of Kv1.5 and TASK-1 channels, we found all Kv1.5 blockers analyzed to be even more effective on TASK-1 than on Kv1.5. For instance, the half-maximal inhibitory concentration (IC50) values of AVE0118 and AVE1231 (A293) were 10- and 43-fold lower on TASK-1. Also for MSD-D, ICAGEN-4, S20951 (A1899), and S9947, the IC50 values were 1.4- to 70-fold lower than for Kv1.5. To describe this phenomenon on a molecular level, we used in silico models and identified unexpected structural similarities between the two drug binding sites. Kv1.5 blockers, like AVE0118 and AVE1231, which are promising drugs against atrial fibrillation or obstructive sleep apnea, are in fact potent TASK-1 blockers. Accordingly, block of TASK-1 channels by these compounds might contribute to the clinical effectiveness of these drugs. The higher affinity of these blockers for TASK-1 channels suggests that TASK-1 might be an unrecognized molecular target of Kv1.5 blockers effective in atrial fibrillation or obstructive sleep apnea.
Pflügers Archiv - European Journal of Physiology 12/2014; 467(5). DOI:10.1007/s00424-014-1665-1 · 3.07 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The current kinetics of two-pore domain potassium (K2P) channels resemble those of the steady-state K(+) currents being active during the plateau phase of cardiac action potentials. Recent studies support that K2P channels contribute to these cardiac currents and thereby influence action potential duration in the heart. Ten of the 15 K2P channels present in the human genome are sensitive to variations of the extracellular and/or intracellular pH value. This review focuses on a set of K2P channels which are inhibited by extracellular protons, including the subgroup of tandem of P domains in a weak inward-rectifying K(+) (TWIK)-related acid-sensitive potassium (TASK) and TWIK-related alkaline-activated K(+) (TALK) channels. The role of TWIK-1 in the heart is also discussed since, after successful expression, an extracellular pH dependence, similar to that of TASK-1, was described as a hallmark of TWIK-1. The expression profile in cardiac tissue of different species and the functional data in the heart are summarized. The distinct role of the different acid-sensitive K2P channels in cardiac electrophysiology, inherited forms of arrhythmias and pharmacology, and their role as drug targets is currently emerging and is the subject of this review.
Pflügers Archiv - European Journal of Physiology 11/2014; 467(5). DOI:10.1007/s00424-014-1637-5 · 3.07 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Urosepsis is defined as sepsis caused by a urogenital tract infection. Urosepsis in adults comprises approximately 25% of all sepsis cases, and is in most cases due to complicated urinary tract infections. The urinary tract is the infection site of severe sepsis or septic shock in approximately 10-30% of cases. Severe sepsis and septic shock is a critical situation, with a reported mortality rate nowadays still ranging from 30% to 40%. Urosepsis is mainly a result of obstructed uropathy of the upper urinary tract, with ureterolithiasis being the most common cause. The complex pathogenesis of sepsis is initiated when pathogen or damage-associated molecular patterns recognized by pattern recognition receptors of the host innate immune system generate pro-inflammatory cytokines. A transition from the innate to the adaptive immune system follows until a TH 2 anti-inflammatory response takes over, leading to immunosuppression. Treatment of urosepsis comprises four major aspects: (i) early diagnosis; (ii) early goal-directed therapy including optimal pharmacodynamic exposure to antimicrobials both in the plasma and in the urinary tract; (iii) identification and control of the complicating factor in the urinary tract; and (iv) specific sepsis therapy. Early adequate tissue oxygenation, adequate initial antibiotic therapy, and rapid identification and control of the septic focus in the urinary tract are critical steps in the successful management of a patient with urosepsis, which includes early imaging, and an optimal interdisciplinary approach encompassing emergency unit, urological and intensive-care medicine specialists.
International Journal of Urology 05/2013; 20(10). DOI:10.1111/iju.12200 · 1.80 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: This study aimed to evaluate the outcome of patients with abdominal, thoracic or vascular operations and long-term intensive care unit (ICU) treatment.
The present retrospective observational cohort study was performed at the authors' surgical ICU at the Marburg University Medical Centre. All patients who stayed at the ICU longer than 48 h and underwent visceral, thoracic or vascular surgery between January 2005 and December 2006 were retrospectively analysed. Patients with an ICU stay of 20 or more days were defined as the long-term study group. Clinical variables were tested for prognostic value.
In 2 years, 852 patients were treated at the intensive care unit. Follow-up was available in 502 patients, with 219 patients treated for two and more days and a median of 16.4 days. Sixty-seven long-term patients were compared to 152 (69.4 %) patients treated between 2 and 20 days. Overall survival after 12 months was 50.2 % (110/219), while 65.8 % (144/219) were discharged from ICU. Older age, longer treatment at the ICU and increased simplified acute physiology score (SAPS) at admission were associated with decreased 12-month survival, while no statistical differences were observed for the underlying and malignant disease by univariate analysis. The risk of death was 29, 56 and 61 % for patients treated 2-4, 5-19 and ≥20 days at the ICU. Decreased survival of patients treated for 5-19 and ≥20 days were confirmed by logrank test (p = 0.001).
Patients with long-term ICU stay showed decreased survival than patients who are treated less than 5 days but similar survival as patients which stayed between 5 and 19 days. Malignant disease is not associated with an unfavourable 12-month survival while older age, higher SAPS index at discharge and longer stay at ICU are. Long-term ICU survivors have no increased risk to succumb after discharge from ICU.
Langenbeck s Archives of Surgery 06/2012; 397(6):995-9. DOI:10.1007/s00423-012-0966-0 · 2.16 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A 69-year-old woman reported that underwent endonasal frontal sinus surgery under general anesthesia. In her medical history the patient reports a multiple occurrence of angina pectoris attacks, especially in stressful situations. Coronary heart disease has so far been excluded. At preoperative presentation of this patient was in good general and nutritional state. Intraoperative hypotension had to be treated with norepinephrine. In the recovery room, the patient developed angina pectoris symptoms and the ECG showed T negativity. The patient was admitted on an ICU. Coronary angiography showed left ventricular apical ballooning with a transient akinesia typical of the left ventricle, as is seen in a Tako-Tsubo syndrome. The symptoms are similar to acute coronary artery disease, but without stenosis of coronary arteries. Physical or emotional stress is known to trigger Tako-Tsubo Syndrome, but the exact etiology or pathophysiology remains somewhat unclear.
[Show abstract][Hide abstract] ABSTRACT: Atrial fibrillation is the most common arrhythmia in the elderly, and potassium channels with atrium-specific expression have been discussed as targets to treat atrial fibrillation. Our aim was to characterize TASK-1 channels in human heart and to functionally describe the role of the atrial whole cell current I(TASK-1).
Using quantitative PCR, we show that TASK-1 is predominantly expressed in the atria, auricles and atrio-ventricular node of the human heart. Single channel recordings show the functional expression of TASK-1 in right human auricles. In addition, we describe for the first time the whole cell current carried by TASK-1 channels (I(TASK-1)) in human atrial tissue. We show that I(TASK-1) contributes to the sustained outward current I(Ksus) and that I(TASK-1) is a major component of the background conductance in human atrial cardiomyocytes. Using patch clamp recordings and mathematical modeling of action potentials, we demonstrate that modulation of I(TASK-1) can alter human atrial action potential duration.
Due to the lack of ventricular expression and the ability to alter human atrial action potential duration, TASK-1 might be a drug target for the treatment of atrial fibrillation.
[Show abstract][Hide abstract] ABSTRACT: Invasive infections through to sepsis caused by fungi in intensive care units have increased markedly in the past few years. In the mean time almost every tenth case of sepsis in the intensive care unit is the result of an invasive fungal infection. Not only hemato-oncological or organ-transplanted patients are affected but increasingly also those patients who have been under intensive care for a considerable time and who exhibit particular risk factors. The lethality among the afflicted patients is high. The diagnosis of fungal infections is still difficult; unambiguous, highly sensitive and specific test procedures are still lacking. The decision for therapy must often be made empirically and as early as possible. In the past few years newly developed antimycotic agents have opened up new options for therapy.
[Show abstract][Hide abstract] ABSTRACT: The "Acute Respiratory Distress Syndrome" (ARDS) is a life threatening disease and is associated with a high mortality, mainly due to multi-organ failure. Invasive mechanical ventilation can worsen multi-organ failure which must be avoided. A tidal volume of 6 ml/kg bodyweight should be the aim. Extracorporeal lung assist devices like ECMO or iLA can contribute to lung-protective mechanical ventilation.
[Show abstract][Hide abstract] ABSTRACT: Cervical plexus blocks have been established as safe and feasible procedures for carotid endarterectomy. Comparable perioperative complication rates have been reported for plexus techniques and general anaesthesia. The results of the GALA trial support the theory that the indication for insertion of intraluminal shunts was significantly reduced by regional procedures (14 % vs. 43 %) in consequence of the more reliable diagnosis of neurological complications. However, it has not been identified yet which technique (superficial, deep or a combination) offers the highest effectiveness.
[Show abstract][Hide abstract] ABSTRACT: The decision for an anticoagulant for renal replacement therapy (RRT) in patients with acute renal failure and heparin-induced thrombocytopenia (HIT) has to be made carefully. Based on results from the literature argatroban is favoured in patients without hepatic dysfunction, referring to its short halftime and easy feasable monitoring. In the case of coexsisting hepatic disorder, danaparoid provides a safe alternative therapy. However, long halftime and the difficult elimination of the substance are unfavourable. Lepirudin represents another possible anticoagulant therapy. Bleeding complications and monitoring of the ecarin clotting time imposes limitations. Experiences with bivalirudin, fondaparinux and prostaglandines are limited and future trials will have to determine the significance of their application in RRT in HIT patients. Furthermore it has to be proven whether the combination of alternative anticoagulants with citrate prolongates circuit halftime of CVVH.