A new approach to quantify visceral fat via bioelectrical impedance analysis and ultrasound compared to MRI.

BACKGROUND: Visceral adipose tissue (VAT) has been linked to systemic proinflammatory characteristics, and measuring it accurately usually requires sophisticated instruments. This study aimed to estimate VAT applying a simpler method that uses total subcutaneous fat and total body fat (BF) measurements. METHOD: As part of our experimental approach, the subcutaneous fat mass (SFT) was measured via US (SFTtotal), and VAT was quantified by assessing MRI data. Both parameters were added to obtain total body fat (BFcalc). Those results were then compared to values obtained from a bioelectrical impedance analysis (BFBIA). Multiple regression analyses were employed to develop a simplified sex-specific equation for SFT, which was subsequently used in conjunction with BFBIA to determine VAT (VATEq). RESULT: We observed excellent reliability between BFBIA and BFcalc, with no significant difference in body fat values (20.98 ± 8.36 kg vs. 21.08 ± 8.81 kg, p = 0.798, ICC 0.948). VATEq_female/male revealed excellent reliability when compared to VATMRI, and no significant difference appeared (women: 0.03 ± 0.66 kg with a 95% CI ranging from -1.26 kg to 1.32 kg, p = 0.815, ICC: 0.955.; men: -0.01 ± 0.85 kg with a 95% CI ranging from -1.69 kg to 1.66 kg, p = 0.925, ICC: 0.952). CONCLUSION: Taking an experimental approach, VAT can be determined without MRI.

Outcomes following cardiac sympathetic denervation in patients with structural heart disease and refractory ventricular arrhythmia.

AIM: Cardiac sympathetic denervation (CSD) has been introduced as a bailout therapy in patients with structural heart disease and refractory ventricular arrhythmias (VAs), but available data are scarce. Purpose of this study was to estimate immediate results, complications, and mid-term outcomes of CSD following recurrent VA after catheter ablation. METHODS AND RESULTS: Adult patients who underwent CSD in the Heart Center Leipzig from March 2017 to February 2021 were retrospectively analysed. Follow-up (FU) was executed via implantable cardioverter defibrillator (ICD) interrogation, telephone interviews, and reviewing medical records. Twenty-one patients (age 63.7 ± 14.4 years, all men, 71.4% non-ischaemic cardiomyopathy, left ventricular ejection fraction 31.6 ± 12.6%) received CSD via video-assisted thoracoscopic surgery (90.5% bilateral, 9.5% left-sided only). Indication for CSD was monomorphic ventricular tachycardia in 76.2% and ventricular fibrillation in 23.8 with 71.4% of patients presenting with electrical storm before index hospitalization. Procedure-related major complications occurred in 9.5% of patients. In-hospital adverse events not related to surgery were common (28.6%) and two patients died during the index hospital stay. During FU (mean duration 9.1 ± 6.5 months), five more patients died. Of the remaining patients, 38.5 and 76.9% were free from any VA or ICD shocks, respectively. CONCLUSIONS: The CSD showed additional moderate efficacy to suppress VAs, when performed as a bailout therapy after previously unsuccessful catheter ablation. At 9 months, it was associated with freedom of ICD shocks in two-thirds of patients. In a population with many comorbidities, the rate of CSD-related complications was acceptable, although there was an overall high risk of procedure unrelated adverse events and death.

Decreased exercise capacity in young athletes using self-adapted mouthguards.

PURPOSE: There is evidence of both the preventive effects and poor acceptance of mouthguards. There are various effects on performance depending on the type of mouthguard model. Hemodynamic responses to wearing a mouthguard have not been described. The aim of this study was to investigate the effects of self-adapted mouthguards with breathing channels (SAMGvent). METHODS: In this randomized crossover study, 17 healthy, active subjects (age 25.12 ± 2.19 years) underwent body plethysmography and performed two incremental exertion tests wearing a (SAMGvent) and not wearing (CON) a mouthguard. Blood lactate, spirometrics, and thoracic impedance were measured during these maximum exercise tests. RESULTS: The mean values using a SAMGvent revealed significantly greater airway resistance compared to CON (0.53 ± 0.16 kPa·L-1 vs. 0.35 ± 0.10 kPa·L-1, respectively; p = < 0.01). At maximum load, ventilation with SAMGvent was less than CON (118.4 ± 28.17 L min-1 vs. 128.2 ± 32.16 L min-1, respectively; p = < 0.01). At submaximal loads, blood lactate responses with SAMGvent were higher than CON (8.68 ± 2.20 mmol·L-1 vs. 7.89 ± 1.65 mmol·L-1, respectively; p < 0.01). Maximum performance with a SAMGvent was 265.9 ± 59.9 W, and without a mouthguard was 272.9 ± 60.8 W (p < 0.01). Maximum stroke volume was higher using a SAMGvent than without using a mouthguard (138.4 ± 29.9 mL vs. 130.2 ± 21.2 mL, respectively; p < 0.01). CONCLUSION: Use of a self-adapted mouthguard led to increased metabolic effort and a significant reduction in ventilation parameters. Unchanged oxygen uptake may be the result of cardiopulmonary compensation and increased breathing efforts, which slightly affects performance. These results and the obvious preventive effects of mouthguards support their use in sports.

Effects of Custom-made Mouthguards on Cardiopulmonary Exercise Capacity.

The importance of using mouthguards as well as their low acceptance rate have been demonstrated. The aim of this study was to investigate the influence of customized mouthguards on hemodynamics.. This randomized crossover study used data from 13 subjects (23.5±1.4 years). The cardiopulmonary and metabolic parameters were observed during ergometer tests without mouthguard (control) in comparison to two types of mouthguards (with and normal without breathing channels). Maximum ventilation was significantly decreased with the normal mouthguard (113.3±30.00 l ∙ min-1) in contrast to the mouthguard with breathing channels (122.5±22.9 l ∙ min-1) and control (121.9±30.8 l ∙ min-1). Also the inspiration time was longer when using the normal mouthguard (0.70±0.11 s) compared to the mouthguard with breathing channels (0.63±0.11 s) and control (Co 0.64±0.10 s). Lactate was also increased under the influence of the mouthguard with breathing channels (10.72±1.4 mmol ∙ l-1) compared to the control (9.40±1.77 mmol ∙ l-1) and the normal mouthguard (9.02±1.67 mmol ∙ l-1). In addition, stroke volume kinetics (p=0.048) and maximum heart rates (p=0.01) show changes. Despite equal levels of oxygen uptake and performances under all three conditions, the use of mouthguards showed differences in cardiopulmonary parameters. The use of mouthguards during exercise does not affect physical performance and can be recommended for injury prevention.

Intra-Aortic Balloon Pump Malposition Reduces Visceral Artery Perfusion in an Acute Animal Model.

Visceral artery perfusion can be potentially affected by intra-aortic balloon pump (IABP) catheters. We utilized an animal model to quantify the acute impact of a low balloon position on mesenteric artery perfusion. In six pigs (78 ± 7 kg), a 30-cc IABP was placed in the descending aorta in a transfemoral procedure. The celiac artery (CA) and the cranial mesenteric artery (CMA) were surgically dissected. Transit time blood flow was measured for (i) baseline, (ii) 1:1 augmentation with the balloon proximal to the visceral arteries, and (iii) 1:1 augmentation with the balloon covering the visceral arteries. Blood flow in the CMA and CA was reduced by 17 and 24%, respectively, when the balloon compromised visceral arteries compared with a position above the visceral arteries (flow in mL/min: CMA: (i) 1281 ± 512, (ii) 1389 ± 287, (iii) 1064 ± 276, P < 0.05 for 3 vs. 1 and 3 vs. 2; CA: (i) 885 ± 370, (ii) 819 ± 297, (iii) 673 ± 315; P < 0.05 for 3 vs. 1). The covering of visceral arteries by an IABP balloon causes a significant reduction of visceral artery perfusion; thus, the positioning of this device during implantation is critical for obtaining a satisfactory outcome.

[Primary care medicine in Germany at the crossroads]. / Primärmedizinische Versorgung in Deutschland am Scheideweg.

In addition to the existing social law options for primary care under medical responsibility for those with statutory health insurance, there are several projects to supplement the service structures: healthcare kiosks, primary care centers and community health nursing as well as general practitioner outpatient clinics in hospitals. These new projects amount to an institutionalization of services that were previously based at outpatient offices and partially to the transfer of medical services that were previously the responsibility of doctors to the responsibility of non-physician healthcare professionals, with additional financial outlay but without creating new care capacities. The constructs considered do not appear to be suitable for making a relevant contribution to compensating for the gap in doctors specialized in general or internal medicine and in other medical professionals in a demographically induced capacity phasing out process that is forecast to last until around 2036. The further development of German social law on primary care should instead focus on increasing the efficiency of resources which are becoming scarcer through guided and graduated access to doctors according to medical criteria.

Amino acid derived quinazolines as Rock/PKA inhibitors.

SAR and lead optimization studies for Rock inhibitors based on amino acid-derived quinazolines are described. Studies demonstrated that these amino acid derived quinazolinones were mainly pan-Rock (I & II) inhibitors. While selectivity against other kinases could be achieved, selectivity for most of these compounds against PKA was not achieved. This is distinct from Rock inhibitors based on non-amino acid derived quinazolinones, where high selectivity against PKA could be obtained.(22) The inhibitors presented here in some cases possessed sub-nanomolar inhibition of Rock, nanomolar potency in ppMLC cell based assays, low to fair cytochrome P-450 inhibition, and good human microsomal stability.

Outcome and incidence of re-intervention after surgical repair of tetralogy of fallot.

OBJECTIVES: Timing of primary repair of tetralogy of Fallot (TOF) remains controversial. We evaluated the long-term outcome of early primary treatment strategy in a patient cohort with TOF less than eight months of age. METHODS: A group of 120 patients with TOF less than eight months of age (5 ± 2.4 months) underwent early primary repair of TOF between October 1998 and August 2009. Sixty-one patients received a transanular (TAN) repair, and 59 patients received a right ventricular outflow tract (RVOT) + main pulmonary artery (MPA) double patch repair with concomitant pulmonary valve reconstruction. RESULT: There was no early or late mortality. The follow-up was 100% completed. There were eight reoperations and eight patients underwent catheter intervention for severe pulmonary valve insufficiency or stenosis, obstruction of right ventricular outflow tract, and stenosis of pulmonary arteries. Actuarial survival was 100% at ten years. At latest follow-up 80 patients were in NYHA Class I without any antiarrhythmic medications. On latest echocardiography, 90 (75%) patients had mild to moderate pulmonary regurgitation, and 10 had a right ventricular outflow tract gradient more than 40 mmHg. CONCLUSIONS: These data strongly support the concept of early primary repair of TOF in patients with well developed pulmonary arteries. Early primary repair is associated with an excellent early and late outcomes, an acceptable risk of reoperation and re-intervention, and a low incidence of significant right ventricular dysfunction.

C-kitpos cells in the human left atrial appendage.

Background: Subpopulations of myocardial c-kitpos cells have the ability to stimulate regeneration in ischemic heart disease by paracrine effects. The left atrial appendage (LAA), which is easy accessible during cardiac surgery, may represent a perfect source for c-kitpos cell extraction for autologous cell therapies in the living human. So far, frequency and distribution of c-kitpos cells in LAA are unknown. Methods: LAAs of patients who underwent cardiac surgery due to coronary artery disease (coronary artery bypass graft, CABG), valvular heart disease or both and of two body donors were examined. Tissue was fixed in 4 % paraformaldehyde, embedded in paraffin, dissected in consecutive sections and stained for c-kitpos cells. In parallel, grade of fibrosis, amount of fat per section and cells positive for mast cell tryptase were examined. Results: We collected 27 LAAs (37.0 % female, mean left ventricular ejection fraction 50.4 %, 63.0 % persistent atrial fibrillation (AF)). Most of the patients underwent combined CABG and valve surgery (51.9 %). C-kitpos cells were detected in 3 different regions: A) Attached to the epicardial fat layer, B) close to vascular structures and C) between cardiomyocytes. C-kitpos cells ranged from 0.05 c-kitpos cells per mm2 to 67.5 c-kitpos cells per mm2. We found no association between number of c-kitpos cells and type of AF, amount of fibrosis or amount of fat. Up to 72 % of c-kitpos cells also showed a positive staining for mast cell tryptase. Conclusion: C-kitpos cells are frequent in LAAs of cardiovascular patients with a rather homogenous distribution throughout the LAA. The LAA can therefore be considered as a source for extraction of a reasonable quantity of autologous cardiac progenitor cells in the living human patient.

Measurement of subcutaneous fat tissue: reliability and comparison of caliper and ultrasound via systematic body mapping.

Caliper and ultrasound (US) are used to measure subcutaneous fat tissue depth (SFT) and then to calculate total body fat. There is no evidence-based recommendation as to whether caliper or US are equally accurate. The aim of this paper was therefore to compare reliability of both methods. In this methodical study, 54 participants (BMI: 24.8 ± 3.5 kg/m2; Age: 43.2 ± 21.7 years) were included. Using systematic body mapping, the SFT of 56 areas was measured. We also analyzed 4 body sites via MRI. A comparison between caliper and US detected clear differences in mean SFT of all areas (0.83 ± 0.33 cm vs. 1.14 ± 0.54 cm; p < 0.001) showing moderate reliability (ICC 0.669, 95%CI: 0.625-0.712). US and MRI revealed in the abdominal area a SFT twice as thick as caliper (2.43 ± 1.36 cm vs. 2.26 ± 1.32 cm vs. 1.15 ± 0.66 cm; respectively). Caliper and US revealed excellent intrarater (ICC caliper: 0.944, 95%CI: 0.926-0.963; US: 0.934, 95%CI: 0.924-0.944) and good interrater reliability (ICC caliper: 0.794, 95%CI: 0.754-0.835; US: 0.825, 95%CI: 0.794-0.857). Despite the high reliability in measuring SFT that caliper and US show, our comparison of the two methods yielded clear differences in SFT, particularly in the abdominal area. In accuracy terms, US is preferable for most mapping areas.

Discovery and optimization of indoles and 7-azaindoles as Rho kinase (ROCK) inhibitors (part-I).

Rho kinase (ROCK) inhibitors are potential therapeutic agents to treat disorders such as hypertension, multiple sclerosis, cancers, and glaucoma. Here, we disclose the synthesis, optimization, biological evaluation of potent indole and 7-azaindole based ROCK inhibitors that have high potency on ROCK (IC(50)=1 nM) with 740-fold selectivity over PKA (47). Moreover, 47 showed very good DMPK properties making it a good candidate for further development. Finally, docking studies with a homology model of ROCK-II were performed to rationalize the binding mode of these compounds and showed the compounds bound in both orientations to take advantage to H-bonds with Lys-121 of ROCK-II.

Discovery and optimization of indole and 7-azaindoles as Rho kinase (ROCK) inhibitors (part-II).

Therapeutic interventions with Rho kinase (ROCK) inhibitors may effectively treat several disorders such as hypertension, stroke, cancer, and glaucoma. Herein we disclose the optimization and biological evaluation of potent novel ROCK inhibitors based on substituted indole and 7-azaindole core scaffolds. Substitutions on the indole C3 position and on the indole NH and/or amide NH positions all yielded potent and selective ROCK inhibitors (25, 42, and 50). Improvement of aqueous solubility and tailoring of in vitro and in vivo DMPK properties could be achieved through these substitutions.

Synthesis and biological evaluation of 4-quinazolinones as Rho kinase inhibitors.

Rho kinase (ROCK) is an attractive therapeutic target for various diseases including glaucoma, hypertension, and spinal cord injury. Herein, we report the development of a series of ROCK-II inhibitors based on 4-quinazolinone and quinazoline scaffolds. SAR studies at three positions of the quinazoline core led to the identification of analogs with high potency against ROCK-II and good selectivity over protein kinase A (PKA).

The development of benzimidazoles as selective rho kinase inhibitors.

Rho Kinase (ROCK) is a serine/threonine kinase whose inhibition could prove beneficial in numerous therapeutic areas. We have developed a promising class of ATP-competitive inhibitors based upon a benzimidazole scaffold, which show excellent potency toward ROCK (IC(50)<10nM). This report details the optimization of selectivity for ROCK over other related kinases such as Protein kinase A (PKA).

Benzothiazoles as Rho-associated kinase (ROCK-II) inhibitors.

A series of benzothiazole derivatives as ROCK inhibitors have been discovered. Compounds with good biochemical and cellular potency, and sufficient kinase selectivity have been identified.

[Verbesserung der Lebensqualität durch integrative onkologische Rehabilitation]. / Sustained Improvement of Quality of Life following Integrative Oncological Rehabilitation.

Hintergrund: Die onkologische Rehabilitation ist integraler Bestandteil der Versorgung krebskranker Menschen. Nach einer dreiwöchigen stationären Rehabilitation mit multimodalem und integrativem Ansatz wurden die Effekte auf Belastungen und Lebensqualität der Patienten überprüft. Patienten und Methoden: 74 Krebspatienten erhielten ein komplexes Therapieprogramm, das Therapien zur Verbesserung der funktionalen Gesundheit, zur Reduktion psychosozialer Belastungen und komplementäre Massnahmen beinhaltete. Der Erfolg der Therapie wurde mit validierten Fragebögen am Abschluss der Rehabilitation (T2) und 3 Monate danach (T3) bestimmt. Ergebnisse: Es zeigte sich eine signifikante Besserung von Distress, Angst, Depression, Fatigue und Lebensqualitätsfunktionsskalen zum Zeitpunkt T2 und T3. Von T2 nach T3 war der Therapieeffekt rückläufig, ohne die Werte von T1 zu erreichen. Schlussfolgerungen: Eine multimodale, integrative onkologische Rehabilitation führt zu einer über 3 Monate anhaltenden Besserung des subjektiven Befindens der Patienten. Dieses Therapiekonzept sollte in einer Folgestudie mit einer Standardrehabilitation verglichen werden. BACKGROUND: Oncological rehabilitation is an integral part in the care of cancer patients. Following an inpatient rehabilitation of 3 weeks' duration with multidimensional and integrative components, the effects on distress and quality of life were measured. PATIENTS AND METHODS: 74 cancer patients received a complex treatment program, including treatments for improvement of functional health, reduction of psychosocial distress and complementary therapies. The treatment outcome was evaluated with validated questionnaires at the end of the rehabilitation (T2) and 3 months thereafter (T3). RESULTS: We observed significant improvement of distress, anxiety, depression, fatigue and quality of life at T2 and T3. In the interval from T2 to T3, the treatment effect was declining, without reaching the values of T1. CONCLUSIONS: A multidimensional integrative oncological rehabilitation improves the subjective condition of the patients over a 3-month period. This treatment concept should be tested in a comparative study against standard rehabilitation.

Detection of myosin light chain phosphorylation--a cell-based assay for screening Rho-kinase inhibitors.

Here, we describe the first example of a cell-based myosin light chain phosphorylation assay in 96-well format that allows for the rapid screening of novel Rho-kinase inhibitors. We obtained IC(50) values for the prototypic Rho-kinase inhibitors Y-27632 (1.2+/-0.05microM) and Fasudil (3.7+/-1.2microM) that were similar to those previously published utilizing electrophoresis-based methodologies. H-1152P, a Fasudil analog showed an IC(50) value of 77+/-30nM. Data derived from a set of 21 novel Rho-kinase inhibitors correlate with those generated by a well-established cell-based phenotypic Rho-kinase inhibition assay (R(2)=0.744). These results show that imaging technology measuring changes in myosin light chain phosphorylation can be used to rapidly generate quantitative IC(50) values and to screen a larger set of small molecule Rho-kinase inhibitors and suggests that this approach can be broadly applied to other cell lines and signaling pathways.

Comparison of miniaturized time-resolved fluorescence resonance energy transfer and enzyme-coupled luciferase high-throughput screening assays to discover inhibitors of Rho-kinase II (ROCK-II).

Kinases are important drug discovery targets for a wide variety of therapeutic indications; consequently, the measurement of kinase activity remains a common high-throughput screening (HTS) application. Recently, enzyme-coupled luciferase-kinase (LK) format assays have been introduced. This format measures luminescence resulting from metabolism of adenosine triphosphate (ATP) via a luciferin/luciferase-coupled reaction. In the research presented here, 1536-well format time-resolved fluorescence resonance energy transfer (TR-FRET) and LK assays were created to identify novel Rho-associated kinase II (ROCK-II) inhibitors. HTS campaigns for both assays were conducted in this miniaturized format. It was found that both assays were able to consistently reproduce the expected pharmacology of inhibitors known to be specific to ROCK-II (fasudil IC50: 283 +/- 27 nM and 336 +/- 54 nM for TR-FRET and LK assays, respectively; Y-27632 IC50: 133 +/- 7.8 nM and 150 +/- 22 nM for TR-FRET and LK assays, respectively). In addition, both assays proved robust for HTS efforts, demonstrating excellent plate Z' values during the HTS campaign (0.84 +/- 0.03; 0.72 +/- 0.05 for LK and TR-FRET campaigns, respectively). Both formats identified scaffolds of known and novel ROCK-II inhibitors with similar sensitivity. A comparison of the performance of these 2 assay formats in an HTS campaign was enabled by the existence of a subset of 25,000 compounds found in both our institutional and the Molecular Library Screening Center Network screening files. Analysis of the HTS campaign results based on this subset of common compounds showed that both formats had comparable total hit rates, hit distributions, amount of hit clusters, and format-specific artifact. It can be concluded that both assay formats are suitable for the discovery of ROCK-II inhibitors, and the choice of assay format depends on reagents and/or screening technology available.

Benzimidazole- and benzoxazole-based inhibitors of Rho kinase.

Inhibitors of Rho kinase have been developed based on two distinct scaffolds, benzimidazoles, and benzoxazoles. SAR studies and efforts to optimize the initial lead compounds are described. Novel selective inhibitors of ROCK-II with excellent potency in both enzyme and cell-based assays were obtained. These inhibitors possess good microsomal stability, low cytochrome P-450 inhibitions and good oral bioavailability.