Right ventricular function in pulmonary (arterial) hypertension.

The right ventricle (RV) is the main determinant of prognosis in pulmonary hypertension. Adaptation and maladaptation of the RV are of crucial importance. In the course of disease, RV contractility increases through changes in muscle properties and muscle hypertrophy. At a certain point, the point of "uncoupling," the afterload exceeds contractility, and maladaptation as well as dilation occurs to maintain stroke volume (SV). To understand the adaptational processes and to further develop targeted medication directly affecting load-independent contractility, an accurate and precise assessment of contractility and RV-pulmonary artery (PA) coupling should be performed. In this review, we shed light on existing methods to assess RV function, including the gold standard measurement of contractility and RV-PA coupling, and we evaluate existing surrogates of RV-PA coupling.

[Pulmonary hypertension : What is new in therapy?]. / Pulmonale Hypertonie : Was ist neu in der Therapie?

Pulmonary hypertension (PH) comprises a group of pulmonary vascular diseases that are characterized by progressive exertional dyspnea and right heart insufficiency ultimately resulting in right heart decompensation. The classification is into five clinical subgroups that form the absolutely essential basis for decisions on the indications for different pharmacological and non-pharmacological forms of treatment. The guidelines were updated in 2015 and in addition to the hitherto existing pharmacological treatment options of phosphodiesterase type 5 inhibitors, endothelin receptor antagonists and prostacyclins, the soluble guanylate cyclase stimulator riociguat has now been incorporated for treatment of certain forms of PH. This article provides an overview of the new treatment recommendations in the current guidelines, e. g. for PH patients who are in intensive care units due to surgical interventions or progressive right heart insufficiency.

[Tachycardia and pulmonary arterial hypertension]. / Tachykardien bei pulmonalarterieller Hypertonie.

Pulmonary hypertension is newly defined as an elevation of the mean pulmonary arterial pressure >20 mmHg and a pulmonary vascular resistance ≥3 Wood units. Arrhythmias are an increasing problem in patients with pulmonary hypertension. Pathophysiological aspects leading to supraventricular arrhythmias are atrial fibrosis caused by increased right atrial pressure and dilation. An increased sympathetic tone leads to prolongation of action potential and delayed polarisations causing arrhythmias. Therapy of arrhythmias includes drugs (preferred amiodarone) and electrophysiological therapy like electric cardioversion and ablation, which is safe in patients with pulmonary hypertension.

Corrigendum: A multiply-add engine with monolithically integrated 3D memristor crossbar/CMOS hybrid circuit.

This corrects the article DOI: 10.1038/srep42429.

A multiply-add engine with monolithically integrated 3D memristor crossbar/CMOS hybrid circuit.

Silicon (Si) based complementary metal-oxide semiconductor (CMOS) technology has been the driving force of the information-technology revolution. However, scaling of CMOS technology as per Moore's law has reached a serious bottleneck. Among the emerging technologies memristive devices can be promising for both memory as well as computing applications. Hybrid CMOS/memristor circuits with CMOL (CMOS + "Molecular") architecture have been proposed to combine the extremely high density of the memristive devices with the robustness of CMOS technology, leading to terabit-scale memory and extremely efficient computing paradigm. In this work, we demonstrate a hybrid 3D CMOL circuit with 2 layers of memristive crossbars monolithically integrated on a pre-fabricated CMOS substrate. The integrated crossbars can be fully operated through the underlying CMOS circuitry. The memristive devices in both layers exhibit analog switching behavior with controlled tunability and stable multi-level operation. We perform dot-product operations with the 2D and 3D memristive crossbars to demonstrate the applicability of such 3D CMOL hybrid circuits as a multiply-add engine. To the best of our knowledge this is the first demonstration of a functional 3D CMOL hybrid circuit.

The immunogenicity of glycerol-preserved donor skin.

Previous clinical observations have suggested that the application of glycerol-preserved donor skin as a temporary wound dressing provokes a weaker rejection reaction than fresh, vital donor skin. Like others, we frequently observed that considerable parts of the allodermis not only remained on the wound for an extended period of time, but even became re-epithelialized in some cases. In order to quantify this effect, we applied the mixed lymphocyte culture (MLC) test in a rat model, using the two highly inbred, histoincompatible rat strains DA and Lewis as donor and recipient respectively. Using the methodology of the Euro Skin Bank, Beverwijk, The Netherlands, split thickness skin, excised from the back of the rats, was equilibrated in 98 per cent glycerol. The immunological reaction after grafting vital DA-skin, glycerolized DA-skin onto Lewis rats, and vital as well as glycerolized Lewis-skin onto Lewis rats was compared. The results of these experiments do not support the clinical observations that the glycerolization procedure results in decreased immunogenicity of donor skin.

The distally pedicled peroneus brevis muscle flap: a new flap for the lower leg.

Defects of the skin and soft tissue in the region of the lateral malleolus of the ankle and the Achilles tendon, resulting in exposed bone, tendons, or osteosynthetic material, cannot be covered with free skin transplants. Local or free flaps must be employed. The authors present the construction of a peroneus brevis muscle flap with a distal pedicle as a useful alternative. Between 1993 and 1999, distal pedicled peroneus brevis muscle flaps were used in 19 patients with various types of defects. During construction of the flap, both the long peroneal muscle and the peroneal artery remained intact. In the region of the distal third of the fibula, consistently arranged branches run from the artery into the muscle, and these form the distal pedicle. The proximal portion of the muscle can be transposed distally and easily extends to the tip of the fibula and the attachment of the Achilles tendon to the calcaneus. Primary healing occurred in 16 patients undergoing flap construction. Donor-site morbidity was mostly limited to the donor-site scar. The distally pedicled peroneus brevis muscle flap is a reliable means for covering defects in the lower leg. This form of muscle flap has not yet been described in the known literature. In the authors' opinion, this flap constitutes a logical and valuable extension of local flap procedures for plastic surgery in the distal leg region.

The influence of systemic growth hormone administration on the healing time of skin graft donor sites in a pig model.

A more rapid healing of skin graft donor sites has often been observed during ultimoratio therapies with growth hormone in adults who have suffered extremely severe burns. The purpose of this animal experimental study was to examine the influence of systemic growth hormone administration on the healing time of skin graft donor sites under standardized conditions in pigs. The animals were 14 (7 experimental and 7 control) male, sexually mature, German domestic pigs, in which 30 skin graft donor sites 8 cm x 4 cm and 0.6 mm deep were created. Fifteen each of the skin graft donor sites were bandaged with the same material [hydrocolloid bandage (Varihaesive E) and PVP-iodine gauze (Braunovidon Gaze)]. The test period was 15 days for each pig, whereby recombinant growth hormone (0.5 IU/kg body weight per day) was applied subcutaneously in the experimental group. The bandages were changed under brief narcosis every 2 days, during which one skin-punch biopsy was taken per skin graft donor site, and blood samples were drawn for determination of the serum IGF-1 values. Photographic documentation was also recorded. The biopsies were examined histologically (hematoxylin and eosin stain) and immunohistochemically (collagen IV and VII, and laminin), whereby histologically the start of keratinization was assessed as a healing criterion. The serum IGF-1 values in the growth hormone group were statistically significantly higher than in the control group. Immunohistochemically, a complete basal membrane was observed in both the experimental and the control group after the 7th or 8th day. A clearly elevated serum IGF-1 level correlated in the growth hormone group with the skin graft donor sites healing. It could thus be demonstrated both clinically and histologically that systemic application of growth hormone results in a statistically significantly more rapid healing of the skin graft donor sites by 2 days earlier than in the control group.

Burden of pulmonary arterial hypertension in Germany.

This study aimed to describe health care provision, resource consumption and related costs, as well as treatment patterns and quality of life in adult patients with pulmonary arterial hypertension (PAH) in Germany. Data for this retrospective and prospective cost-of-illness-study were derived from hospitals, general practitioners and patients. Costs were evaluated from the perspective of third party payer and patient. Quality of life data were collected by using three validated instruments. A total of 167 patients were enrolled at 10 hospitals. Time period from first occurrence of symptoms to confirmed diagnosis of PAH was 2.3 years on average. Mean number of GP visits was 1.5 per patient per month, and within 15 months, inpatient stays were reported for 50% of patients. The ratio of combination therapy to single-drug therapy for endothelin receptor antagonists, phosphodiesterase-5-inhibitor and prostacyclin analogues increased significantly during 15 months. Treatment costs were, on average, euro47,400 per patient per year, arising mainly from drugs. Compared to the general population, quality of life of PAH patients was considerably impaired. This is the first study which evaluated aspects of the medical and economic consequences of PAH based on a large cohort of PAH patients in Germany.

[A role for combination therapy in pulmonary arterial hypertension]. / Kombinationstherapie der Pulmonal-Arteriellen Hypertonie (PAH) -- Ergebnisse eines Experten-Workshops.

For patients with pulmonary arterial hypertension (PAH) two first line therapies - iloprost inhalation (Ventavis) and bosentan (Tracleer) -- are available in Germany. A third substance, sildenafil, is already approved in the US and will be approved for this indication in the European Union soon. Patients with PAH can be stabilized or improved with a specific mono-therapy for a limited period of time only. Therefore, the question arises when and how to initiate treatment escalation. The available data from controlled clinical trials are insufficient to give a definite answer to these questions. Moreover, it is still unclear which combination of the above mentioned substances may be superior in the treatment of PAH. On the other hand, combination therapy is already reality in clinical practice. Based on this background experts from specialized centers dealing with PAH discussed the scientific basis of the role of combination therapy in PAH patients during a workshop held on April 22/23. 2005 in Wiesbaden. The goal of this workshop was to formulate a common position with regard to combination therapy of PAH on the basis of the available scientific data and clinical experience.

[Therapy of pulmonary arterial hypertension]. / Medikamentöse Therapie der pulmonalen Hypertonie.

New drugs for pulmonary arterial hypertension have shown efficacy in randomized controlled trials. Endothelin receptor antagonists (ERA) and prostanoids are most important for clinical practice. Bosentan represents the first approved orally active therapy for PAH. Besides its hepatotoxicity it is mostly well tolerated. The first approved prostanoid, epoprostenol, is currently first choice only for decompensated right heart failure in PAH. It has to be delivered continuously intravenously and is prone to complications, side effects and very high costs. Alternatively, subcutaneous treprostinil can be applied. It is less risky and expensive but may cause local pain at the infusion site. Inhaled iloprost combines the features of a prostanoid with pulmonary and intrapulmonary selectivity. Alternatively, iloprost is being used as continuous intravenous infusion. The phosphodiesterase-5 inhibitor sildenafil was effective in two randomized controlled trials but has not been approved for PAH therapy.

Aerosolized prostacyclin and iloprost in severe pulmonary hypertension.

OBJECTIVE: To compare the effects of aerosolization of prostacyclin and its stable analog iloprost with those of nasal oxygen, inhaled nitric oxide, and intravenous prostacyclin on hemodynamics and gas exchange in patients with severe pulmonary hypertension. DESIGN: Open uncontrolled trial. SETTING: Justus-Liebig-University, Giessen Germany. PATIENTS: 4 patients with primary pulmonary hypertension and 2 patients with severe pulmonary hypertension associated with calcinosis, the Raynaud phenomenon, esophageal dysfunction, sclerodactyly, and telangiectasia (the CREST syndrome). All were classified as New York Heart Association class III or class IV. INTERVENTION: Short-term applications of O2, inhaled nitric oxide, intravenous prostacyclin, aerosolized prostacyclin, and aerosolized iloprost during repeated catheter investigation of the right side of the heart within a 1-month period. One patient had long-term therapy with inhaled iloprost. RESULTS: Aerosolized prostacyclin decreased pulmonary artery pressure in 6 patients from (mean +/- SE) 62.3 +/- 4.1 mm Hg to 50.8 +/- 5.5 mm Hg and reduced pulmonary vascular resistance from 1721 +/- 253 dyne/s cm-5 to 1019 +/- 203 dyne/s cm-5, and it increased cardiac output from 2.75 +/- 0.21 L/min to 4.11 +/- 0.54 L/min, mixed venous oxygen saturation from 51.1% +/- 3/4% to 66.3% +/- 4.1% and arterial oxygen saturation from 90.6% +/- 2.7% to 93.8% +/- 23% (P<0.05 for all changes). Mean systemic arterial pressure was only slightly affected. The responses lasted for 10 to 30 minutes after inhalation was terminated. Aerosolized iloprost had an identical efficacy profile but was associated with a longer duration of the pulmonary vasodilatory effect (60 min to 120 min). In comparison, intravenous prostacyclin reduced pulmonary vascular resistance with corresponding efficacy but produced a more pronounced decline in systemic artery pressure and no clinically significant decrease in pulmonary artery pressure. Nitric oxide and O2 were less potent pulmonary vasodilators in these patients. In one patient, 1 year of therapy with aerosolized iloprost (100 microgram/d in six aerosol doses) resulted in sustained efficacy of the inhaled vasodilator regimen and clinical improvement. CONCLUSION: Aerosolization of prostacyclin or its stable analog iloprost causes selective pulmonary vasodilatation, increases cardiac output, and improves venous and arterial oxygenation in patients with severe pulmonary hypertension. Thus, it may offer a new strategy for treatment of this disease.

Combination anesthesia with ketamine and pentobarbital: a long-term porcine model.

Anesthesia of the pig poses great problems for experimental animal-based research and particularly in shock research. In this study, five mechanically ventilated domestic pigs were given long-term anesthesia with a combination of ketamine plus pentobarbital. Circulatory parameters were recorded every 2 h via an arterial catheter placed in the right common carotid artery, a Swan-Gans thermodilution catheter (7F), that was placed in the pulmonary artery of the right middle-lobe in a wedge position through the external jugular vein, and another catheter in the internal jugular vein for measuring central venous pressure. Moreover, body weight, blood gases, pH, blood cells, electrolytes and serum enzymes were measured. Further serum traits as total protein and glucose and pathological alterations in different organs were recorded. The animals were observed for a period of 96 h and then killed painlessly. It was shown that pigs can survive 96-h anesthesia with the combination of ketamine and pentobarbital. Optimum, carefully controlled anesthesia did not impair the integrity of the regulatory mechanisms of circulation.