A novel open channel blocker of GABA-A receptors

GABA-A receptors are chloride ion channels composed of five subunits, mediating fast synaptic and tonic inhibition in the mammalian brain. 19 different subunit isoforms have been identified, with the major receptor type in mammalian adult brain consisting of α1, β2, and γ2 subunits. GABA-A receptors are the target of numerous sedating and anxiolytic drugs such as benzodiazepines. The currently known endogenous ligands are GABA, neurosteroids and the endocannabinoid 2- arachidonoyl glycerol (2-AG). The pharmacological properties of this chloride ion channel strictly depend on receptor subunit composition and arrangement. GABA-A receptors bind and are inhibited by epileptogenic agents such as picrotoxin, and cyclodiene insecticides such as dieldrin. We screened aromatic monovalent anions with five-fold symmetry for inhibition of GABA-A receptors. One of the anions, PCCPinhibited currents elicited by GABA with comparable potency as picrotoxin. This inhibition showed all characteristics of an open channel block. The GABA-A receptor ion channel is lined by residues from the M2 membrane-spanning segment. To identify important residues of the pore involved in the interaction with the blocking molecules PCCP-, a mutation scan was performed in combination with subsequent analysis of the expressed mutant proteins using electrophysiological techniques. In a second project we characterised a light-switchable modulator of GABA-A receptors based on propofol. It was my responsibility to investigate the switching kinetics in patch clamp experiments. After its discovery in 1980, propofol has become the most widely used intravenous general anaesthetic. It is commonly accepted that the anaesthesia induced by this unusually lipophilic drug mostly results from potentiation of GABA induced currents. While GABA-A receptors respond to a variety of ligands, they are normally not sensitive towards light. This light sensitivity could be indirectly achieved by using modulators that can be optically switched between an active and an inactive form. We tested an azobenzene derivative of propofol where an aryldiazene unit is directly coupled to the pharmacophore. This molecule was termed azopropofol (AP2). The effect of AP2 on Cl- currents was investigated with electrophysiological techniques using α1β2γ2 GABA-A receptors expressed in Xenopus oocytes and HEK-cells. In the third project we wanted to investigate the functional role of GABA-A receptors in the liver, and their possible involvement in cell proliferation. GABA-A receptors are also found in a wide range of peripheral tissues, including parts of the peripheral nervous system and non-neural tissues such as smooth muscle, the female reproductive system, liver and several cancer tissues. However their precise function in non neuronal or cancerous cells is still unknown. For this purpose we investigated expression, localization and function of the hepatocytes GABA-A receptors in model cell lines and healthy and cancerous hepatocytes.

Real-time simulation of large open quantum spin systems driven by dissipation

We consider a large quantum system with spins 12 whose dynamics is driven entirely by measurements of the total spin of spin pairs. This gives rise to a dissipative coupling to the environment. When one averages over the measurement results, the corresponding real-time path integral does not suffer from a sign problem. Using an efficient cluster algorithm, we study the real-time evolution from an initial antiferromagnetic state of the two-dimensional Heisenberg model, which is driven to a disordered phase, not by a Hamiltonian, but by sporadic measurements or by continuous Lindblad evolution.

Novel radiotherapy techniques for involved-field and involved-node treatment of mediastinal Hodgkin lymphoma: when should they be considered and which questions remain open?

PURPOSE Hodgkin lymphoma (HL) is a highly curable disease. Reducing late complications and second malignancies has become increasingly important. Radiotherapy target paradigms are currently changing and radiotherapy techniques are evolving rapidly. DESIGN This overview reports to what extent target volume reduction in involved-node (IN) and advanced radiotherapy techniques, such as intensity-modulated radiotherapy (IMRT) and proton therapy-compared with involved-field (IF) and 3D radiotherapy (3D-RT)- can reduce high doses to organs at risk (OAR) and examines the issues that still remain open. RESULTS Although no comparison of all available techniques on identical patient datasets exists, clear patterns emerge. Advanced dose-calculation algorithms (e.g., convolution-superposition/Monte Carlo) should be used in mediastinal HL. INRT consistently reduces treated volumes when compared with IFRT with the exact amount depending on the INRT definition. The number of patients that might significantly benefit from highly conformal techniques such as IMRT over 3D-RT regarding high-dose exposure to organs at risk (OAR) is smaller with INRT. The impact of larger volumes treated with low doses in advanced techniques is unclear. The type of IMRT used (static/rotational) is of minor importance. All advanced photon techniques result in similar potential benefits and disadvantages, therefore only the degree-of-modulation should be chosen based on individual treatment goals. Treatment in deep inspiration breath hold is being evaluated. Protons theoretically provide both excellent high-dose conformality and reduced integral dose. CONCLUSION Further reduction of treated volumes most effectively reduces OAR dose, most likely without disadvantages if the excellent control rates achieved currently are maintained. For both IFRT and INRT, the benefits of advanced radiotherapy techniques depend on the individual patient/target geometry. Their use should therefore be decided case by case with comparative treatment planning.

Psychological interventions for acute pain after open heart surgery

BACKGROUND Acute postoperative pain is one of the most disturbing complaints in open heart surgery, and is associated with a risk of negative consequences. Several trials investigated the effects of psychological interventions to reduce acute postoperative pain and improve the course of physical and psychological recovery of participants undergoing open heart surgery. OBJECTIVES To compare the efficacy of psychological interventions as an adjunct to standard care versus standard care alone or standard care plus attention in adults undergoing open heart surgery on pain, pain medication, mental distress, mobility, and time to extubation. SEARCH METHODS We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2013, Issue 8), MEDLINE (1946 to September 2013), EMBASE (1980 to September 2013), Web of Science (all years to September 2013), and PsycINFO (all years to September 2013) for eligible studies. We used the 'related articles' and 'cited by' options of eligible studies to identify additional relevant studies. We also checked lists of references of relevant articles and previous reviews. We also searched the ProQuest Dissertations and Theses Full Text Database (all years to September 2013) and contacted the authors of primary studies to identify any unpublished material. SELECTION CRITERIA Randomised controlled trials comparing psychological interventions as an adjunct to standard care versus standard care alone or standard care plus attention in adults undergoing open heart surgery. DATA COLLECTION AND ANALYSIS Two review authors (SK and JR) independently assessed trials for eligibility, estimated the risk of bias and extracted all data. We calculated effect sizes for each comparison (Hedges' g) and meta-analysed data using a random-effects model. MAIN RESULTS Nineteen trials were included (2164 participants).No study reported data on the number of participants with pain intensity reduction of at least 50% from baseline. Only one study reported data on the number of participants below 30/100 mm on the Visual Analogue Scale (VAS) in pain intensity. Psychological interventions have no beneficial effects in reducing pain intensity measured with continuous scales in the medium-term interval (g -0.02, 95% CI -0.24 to 0.20, 4 studies, 413 participants, moderate quality evidence) nor in the long-term interval (g 0.12, 95% CI -0.09 to 0.33, 3 studies, 280 participants, low quality evidence).No study reported data on median time to remedication or on number of participants remedicated. Only one study provided data on postoperative analgesic use. Studies reporting data on mental distress in the medium-term interval revealed a small beneficial effect of psychological interventions (g 0.36, 95% CI 0.10 to 0.62, 12 studies, 1144 participants, low quality evidence). Likewise, a small beneficial effect of psychological interventions on mental distress was obtained in the long-term interval (g 0.28, 95% CI 0.05 to 0.51, 11 studies, 1320 participants, low quality evidence). There were no beneficial effects of psychological interventions on mobility in the medium-term interval (g 0.23, 95% CI -0.22 to 0.67, 3 studies, 444 participants, low quality evidence) nor in the long-term interval (g 0.29, 95% CI -0.14 to 0.71, 4 studies, 423 participants, low quality evidence). Only one study reported data on time to extubation. AUTHORS' CONCLUSIONS For the majority of outcomes (two-thirds) we could not perform a meta-analysis since outcomes were not measured, or data were provided by one trial only. Psychological interventions have no beneficial effects on reducing postoperative pain intensity or enhancing mobility. There is low quality evidence that psychological interventions reduce postoperative mental distress. Due to limitations in methodological quality, a small number of studies, and large heterogeneity, we rated the quality of the body of evidence as low. Future trials should measure crucial outcomes (e.g. number of participants with pain intensity reduction of at least 50% from baseline) and should focus to enhance the quality of the body of evidence in general. Altogether, the current evidence does not clearly support the use of psychological interventions to reduce pain in participants undergoing open heart surgery.

Open issues in transcatheter aortic valve implantation. Part 2: procedural issues and outcomes after transcatheter aortic valve implantation.

This article provides an overview on procedure-related issues and uncertainties in outcomes after transcatheter aortic valve implantation (TAVI). The different access sites and how to select them in an individual patient are discussed. Also, the occurrence and potential predictors of aortic regurgitation (AR) after TAVI are addressed. The different methods to quantify AR are reviewed, and it appears that accurate and reproducible quantification is suboptimal. Complications such as prosthesis-patient mismatch and conduction abnormalities (and need for permanent pacemaker) are discussed, as well as cerebrovascular events, which emphasize the development of optimal anti-coagulative strategies. Finally, recent registries have shown the adoption of TAVI in the real world, but longer follow-up studies are needed to evaluate the outcome (but also prosthesis durability). Additionally, future studies are briefly discussed, which will address the use of TAVI in pure AR and lower-risk patients.

Open issues in transcatheter aortic valve implantation. Part 1: patient selection and treatment strategy for transcatheter aortic valve implantation.

An exponential increase in the use of transcatheter aortic valve implantation (TAVI) in patients with severe aortic stenosis has been witnessed over the recent years. The current article reviews different areas of uncertainty related to patient selection. The use and limitations of risk scores are addressed, followed by an extensive discussion on the value of three-dimensional imaging for prosthesis sizing and the assessment of complex valve anatomy such as degenerated bicuspid valves. The uncertainty about valvular stenosis severity in patients with a mismatch between the transvalvular gradient and the aortic valve area, and how integrated use of echocardiography and computed tomographic imaging may help, is also addressed. Finally, patients referred for TAVI may have concomitant mitral regurgitation and/or coronary artery disease and the management of these patients is discussed.

Outcomes after endovascular or open repair for degenerative descending thoracic aortic aneurysm using linked hospital data.

BACKGROUND The population-based effectiveness of thoracic endovascular aortic repair (TEVAR) versus open surgery for descending thoracic aortic aneurysm remains in doubt. METHODS Patients aged over 50 years, without a history of aortic dissection, undergoing repair of a thoracic aortic aneurysm between 2006 and 2011 were assessed using mortality-linked individual patient data from Hospital Episode Statistics (England). The principal outcomes were 30-day operative mortality, long-term survival (5 years) and aortic-related reinterventions. TEVAR and open repair were compared using crude and multivariable models that adjusted for age and sex. RESULTS Overall, 759 patients underwent thoracic aortic aneurysm repair, mainly for intact aneurysms (618, 81·4 per cent). Median ages of TEVAR and open cohorts were 73 and 71 years respectively (P < 0·001), with more men undergoing TEVAR (P = 0·004). For intact aneurysms, the operative mortality rate was similar for TEVAR and open repair (6·5 versus 7·6 per cent; odds ratio 0·79, 95 per cent confidence interval (c.i.) 0·41 to 1·49), but the 5-year survival rate was significantly worse after TEVAR (54·2 versus 65·6 per cent; adjusted hazard ratio 1·45, 95 per cent c.i. 1·08 to 1·94). After 5 years, aortic-related mortality was similar in the two groups, but cardiopulmonary mortality was higher after TEVAR. TEVAR was associated with more aortic-related reinterventions (23·1 versus 14·3 per cent; adjusted HR 1·70, 95 per cent c.i. 1·11 to 2·60). There were 141 procedures for ruptured thoracic aneurysm (97 TEVAR, 44 open), with TEVAR showing no significant advantage in terms of operative mortality. CONCLUSION In England, operative mortality for degenerative descending thoracic aneurysm was similar after either TEVAR or open repair. Patients who had TEVAR appeared to have a higher reintervention rate and worse long-term survival, possibly owing to cardiopulmonary morbidity and other selection bias.

The impact of pelvic venous pressure on blood loss during open radical cystectomy and urinary diversion: Results from a secondary analysis of a randomized clinical trial

PURPOSE Blood loss and blood substitution are associated with higher morbidity after major abdominal surgery. During major liver resection, low local venous pressure, has been shown to reduce blood loss. Ambiguity persists concerning the impact of local venous pressure on blood loss during open radical cystectomy. We aimed to determine the association between intraoperative blood loss and pelvic venous pressure (PVP) and determine factors affecting PVP. MATERIAL AND METHODS In the frame of a single-center, double-blind, randomized trial, PVP was measured in 82 patients from a norepinephrine/low-volume group and in 81 from a control group with liberal hydration. For this secondary analysis, patients from each arm were stratified into subgroups with PVP <5 mmHg or ≥5 mmHg measured after cystectomy (optimal cut-off value for discrimination of patients with relevant blood loss according to the Youden's index). RESULTS Median blood loss was 800 ml [range: 300-1600] in 55/163 patients (34%) with PVP <5 mmHg and 1200 ml [400-3000] in 108/163 patients (66%) with PVP ≥5 mmHg; (P<0.0001). A PVP <5 mmHg was measured in 42/82 patients (51%) in the norepinephrine/low-volume group and 13/81 (16%) in the control group (P<0.0001). PVP dropped significantly after removal of abdominal packing and abdominal lifting in both groups at all time points (at begin and end of pelvic lymph node dissection, end of cystectomy) (P<0.0001). No correlation between PVP and central venous pressure could be detected. CONCLUSIONS Blood loss was significantly reduced in patients with low PVP. Factors affecting PVP were fluid management and abdominal packing.

Perioperative use of crystalloids in patients undergoing open radical cystectomy: balanced Ringer's maleate versus a glucose 5%/potassium-based balanced solution: study protocol for a randomized controlled trial

BACKGROUND The optimal crystalloid solution to use perioperatively in patients undergoing open radical cystectomy remains unclear. Many of the fluids used for intravenous hydration contain supraphysiologic concentrations of chloride, which can induce hyperchloremia and metabolic acidosis, resulting in renal vasoconstriction and decreased renal function. In addition, patients receiving less fluid and less sodium show faster recovery of gastrointestinal (GI) function after colonic surgery. METHODS AND DESIGN This is an investigator-initiated, single-center, randomized, controlled, parallel group trial with assessor-blinded outcome assessment, in the Department of Urology, University Hospital Bern, Switzerland. The study will involve 44 patients with bladder cancer scheduled for radical cystectomy and urinary diversion. The primary outcome is the duration between the end of surgery and the return of the GI function (first defecation). Secondary outcomes are fluid balance (body weight difference postoperatively versus preoperatively) and the incidence of kidney function disorders according to the Risk-Injury-Failure-Loss-End Stage Renal Disease (RIFLE classification). An equal number of patients are allocated to receive Ringerfundin® solution or a glucose/potassium-based balanced crystalloid solution as baseline infusion during the entire time that intravenous administration of fluid is necessary during the perioperative period. The randomized crystalloid solution is infused at a rate of 1 ml/kg/h until the bladder has been removed, followed by 3 ml/kg/h until the end of surgery. Postoperative hydration is identical in both groups and consists of 1,500 ml of the randomized crystalloid solution per 24 hours. Postoperative patient care is identical in both groups; patients are allowed to drink clear fluids immediately after surgery, and liquid diet is started on postoperative day 1, as well as active mobilization and the use of chewing gum. Body weight is measured daily in the morning. Time of first flatus and first defecation are recorded. DISCUSSION This trial assesses the benefits and harms of two different balanced crystalloid solutions for perioperative fluid management in patients undergoing open radical cystectomy with urinary diversion, with regard to return of GI function and effects on postoperative renal function. TRIAL REGISTRATION Current Controlled Trials ISRCTN32976792 (registered on November 21 2013).

Comparative effects of teriparatide and ibandronate on spine bone mineral density (BMD) and microarchitecture (TBS) in postmenopausal women with osteoporosis: a 2-year open-label study

UNLABELLED Treatment effects over 2 years of teriparatide vs. ibandronate in postmenopausal women with osteoporosis were compared using lumbar spine bone mineral density (BMD) and trabecular bone score (TBS). Teriparatide induced larger increases in BMD and TBS compared to ibandronate, suggesting a more pronounced effect on bone microarchitecture of the bone anabolic drug. INTRODUCTION The trabecular bone score (TBS) is an index of bone microarchitecture, independent of bone mineral density (BMD), calculated from anteroposterior spine dual X-ray absorptiometry (DXA) scans. The potential role of TBS for monitoring treatment response with bone-active substances is not established. The aim of this study was to compare the effects of recombinant human 1-34 parathyroid hormone (teriparatide) and the bisphosphonate ibandronate (IBN), on lumbar spine (LS) BMD and TBS in postmenopausal women with osteoporosis. METHODS Two patient groups with matched age, body mass index (BMI), and baseline LS BMD, treated with either daily subcutaneous teriparatide (N = 65) or quarterly intravenous IBN (N = 122) during 2 years and with available LS BMD measurements at baseline and 2 years after treatment initiation were compared. RESULTS Baseline characteristics (overall mean ± SD) were similar between groups in terms of age 67.9 ± 7.4 years, body mass index 23.8 ± 3.8 kg/m(2), BMD L1-L4 0.741 ± 0.100 g/cm(2), and TBS 1.208 ± 0.100. Over 24 months, teriparatide induced a significantly larger increase in LS BMD and TBS than IBN (+7.6 % ± 6.3 vs. +2.9 % ± 3.3 and +4.3 % ± 6.6 vs. +0.3 % ± 4.1, respectively; P < 0.0001 for both). LS BMD and TBS were only weakly correlated at baseline (r (2) = 0.04) with no correlation between the changes in BMD and TBS over 24 months. CONCLUSIONS In postmenopausal women with osteoporosis, a 2-year treatment with teriparatide led to a significantly larger increase in LS BMD and TBS than IBN, suggesting that teriparatide had more pronounced effects on bone microarchitecture than IBN.

A pentasymmetric open channel blocker for Cys-loop receptor channels.

γ-Aminobutyric acid type A receptors (GABAA receptors) are chloride ion channels composed of five subunits, mediating fast synaptic and tonic inhibition in the mammalian brain. These receptors show near five-fold symmetry that is most pronounced in the second trans-membrane domain M2 lining the Cl- ion channel. To take advantage of this inherent symmetry, we screened a variety of aromatic anions with matched symmetry and found an inhibitor, pentacyanocyclopentdienyl anion (PCCP-) that exhibited all characteristics of an open channel blocker. Inhibition was strongly dependent on the membrane potential. Through mutagenesis and covalent modification, we identified the region α1V256-α1T261 in the rat recombinant GABAA receptor to be important for PCCP- action. Introduction of positive charges into M2 increased the affinity for PCCP- while PCCP- prevented the access of a positively charged molecule into M2. Interestingly, other anion selective cys-loop receptors were also inhibited by PCCP-, among them the Drosophila RDL GABAA receptor carrying an insecticide resistance mutation, suggesting that PCCP- could serve as an insecticide.

Transdiaphragmatic Resuscitative Open Cardiac Massage: Description of the Technique and a First Case-Series of an Alternative Approach to the Heart

Abstract BACKGROUND: The purpose of this paper is to describe the transdiaphragmatic approach to the heart for open CPR in patients that arrest at laparotomy and to present a first case series of patients that have undergone this procedure. METHODS: All patients who had undergone intraperitoneal transdiaphragmatic open CPR between January 1, 2002 and December 31, 2012 were retrieved from the operation registry at Bern University Hospital, Switzerland. Transdiaphragmatic access to the heart is initiated with a 10-cm-long anterocaudal incision in the central tendon of the diaphragm--approximately at 2 o'clock. Internal cardiac compression through the diaphragmatic incision can be performed from both sides of the patient. From the right side of the patient, cardiac massage is performed with the right hand and vice versa. RESULTS: A total of six patients were identified that suffered cardiac arrest during laparotomy with open CPR performed through the transdiaphragmatic approach. Four patients suffered cardiac arrest during orthotopic liver transplantation and two trauma patients suffered cardiac arrest during damage control laparotomy. In three patients, cardiac activity was never reestablished. However, three patients regained a perfusion heart rhythm and two of these survived to the ICU. One patient ultimately survived to discharge. CONCLUSIONS: In patients suffering cardiac arrest during laparotomy, the transdiaphragmatic approach allows for a rapid, technically easy, and almost atraumatic access to the heart, with excellent CPR performance. After this potentially life-saving procedure, pulmonary or surgical site complications are expected to occur much less compared with the conventionally performed emergency department left-sided thoracotomy.

Laparoscopic versus open end colostomy closure: a single-center experience

The aim of this study was to review our experience with laparoscopic end colostomy closure. A retrospective review of a prospectively entered database was performed. Proportions and continuous variables were compared using the Fisher's exact and the Mann-Whitney U tests, respectively. Within the study period, 53 patients underwent closure of end colostomies. The main reasons for the colonic resections were perforated diverticulitis (52.7%) and neoplasms (20.8%). In 28 patients (53%), laparoscopic closure (LC) was attempted. Demographics did not differ between the attempted LC and the primary open closure (OC) group. The conversion rate from an LC to an OC was 50 per cent (14 of 28), mostly as a result of adhesions (71.4%). Hospital length of stay (HLOS) was significantly longer for the OC than with the attempted LC group (15.4 ± 11.9 days vs 11.3 ± 8.5 days, P = 0.046). The overall complication rate was not different between the completed LC and the OC groups (43 vs 56%, P = 0.634). The majority of complications detected (91.1%) were minor and could be treated conservatively. The role of laparoscopy to close end colostomies is questionable, because the conversion rate is high. However, a shorter HLOS can be expected when laparoscopy is successful. To reduce morbidity resulting from prolonged operation times, it is crucial to convert early and pre-emptively if hostile adhesions are found.