[Organ Bath Experiments on Human Pulmonary Vessels: Assessment of Drug Efficacy for Treatment of Pulmonary Arterial Hypertension]. / Organbadversuche an humanen Pulmonalgefäßen: Beurteilung der Medikamentenwirkung zur Behandlung der pulmonalarteriellen Hypertonie.

Various vasodilator medications are used in the treatment of pulmonary arterial hypertension (PAH), such as endothelin receptor antagonists (ERA) or phosphodiesterase-5-(PDE-5-)inhibitors. In a human ex vivo model, we investigated whether the combination of two substance classes could achieve a higher effect or - without loss of vasodilatation - a lower dosage of the individual substances might be sufficient. We established an ex vivo organ bath model to evaluate the dose-dependent effects of ERA and PDE-5-inhibitors on pulmonary vessels harvested from patients who underwent surgery (lung resection/transplantation). We compared the combined use of both substance classes with administration of one class of drugs alone. Due to the limitations of the experimental design, it is not possible to extrapolate our results to the conditions in vivo. Nevertheless, organ bath proved to be helpful in evaluating the dose-dependent effects of ERA and PDE-5 inhibitors, which is not practical in everyday clinical practice. In this setting, the effectiveness of the combination therapy and the potential for dose reduction depended on the concentrations used and on the influence of previous illnesses on blood vessel function. This article describes the most important results of our experimental investigations and suggestions for future projects.

Evaluation of the combination of endothelin receptor antagonists (ERA) and phosphodiesterase-5 inhibitors for the treatment of pulmonary arterial hypertension (PAH) in pathologic human pulmonary arteries in an ex-vivo organ bath model.

PURPOSE: Medical combination therapy of pulmonary arterial hypertension (PAH) may alleviate the drawbacks of monotherapy by avoiding drug tolerance and by increasing effectiveness, as shown by the combination of ambrisentan and tadalafil (AMBITION trial). The present ex-vivo study evaluated the combination of the endothelin receptor antagonists (ERA) macitentan and bosentan with the phosphodiesterase-5 (PDE-5) inhibitor vardenafil in pulmonary arteries from patients suffering from terminal lung disease as a model of PAH. METHODS: Segments of the pulmonary vessels were excised from resected lungs of patients requiring lung transplantation (LTX). Contraction of pulmonary arteries (PA) was elicited by consecutive dose-response curves of endothelin-1 (ET-1) followed by norepinephrine (NE) to allow inhibition by different pathways. Forces were measured isometrically in an organ bath in the presence and absence of ERA and PDE-5 inhibitors and their combination. RESULTS: PA of 38 patients were examined between October 2016 and November 2019. Bosentan (1E-7 M) and macitentan (1E-8 M, 3E-8 M, 1E-7 M) inhibited ET-1 induced contractions, whereas vardenafil (1E-6 M, 3E-6 M, 1E-5 M) inhibited only the NE induced part of the contractions. Vardenafil enhanced bosentan-induced inhibition of vasoconstriction in a dose-dependent fashion. Combination effects exceeded single bosentan at 3E-6 M and 1E-5 M vardenafil, and they exceeded single vardenafil at the lower vardenafil concentrations. Macitentan showed a more pronounced inhibition than bosentan regardless of the lower concentrations. Accordingly, combination effects with vardenafil resembled those of macitentan alone. CONCLUSIONS: Macitentan and bosentan were potent antagonists of vasoconstriction in PA of LTX patients. The benefit of drug combinations was demonstrated at selected concentrations only owing to a narrow therapeutic range of vardenafil in this ex-vivo model. These results suggest the utility of drug combinations other than the established pair of ambrisentan and tadalafil in PAH treatment but also make a case for a further assessment of vasodilator properties of drugs complementing ERA.

Development of the Fibromyalgia Burden Assessment: measuring the multifaceted burden of fibromyalgia.

OBJECTIVES: To develop a questionnaire assessing the burden of fibromyalgia's impacts on patients' lives. METHODS: A literature review was conducted to identify impacts of fibromyalgia and their consequences on patients' lives. Exploratory interviews were performed with 15 fibromyalgia patients in France, Germany and Spain. Using patients' wording, items were generated simultaneously in French, German, Spanish, and UK English. Relevance and comprehension of the resulting questionnaire versions were tested with 21 additional fibromyalgia patients; questionnaires were revised accordingly. RESULTS: Three domains, Burden associated with the impacts of fibromyalgia, Symptoms and Influencing factors, were identified from the literature review. Following patient interviews, the burden domain was further divided based on the nature of the impact: Pain, Physical impact (including tiredness, sleep problems and other symptoms), Activities of Daily Living impact (including autonomy and coping), Social and Family Life impact, Work, Studies and Personal Finances impact, Psychological impact (including cognitive impact), and Relationship to Medicine and Disease. The resulting test versions of the questionnaire contained 79 items. Comprehension tests identified problematic items and cultural differences and suggested deletions or rewording. After revision and linguistic harmonization, the pilot version of the questionnaire contained 62 items divided into 7 sections, and was named Fibromyalgia Burden Assessment (FMBA©). CONCLUSIONS: The FMBA is a self-reported questionnaire allowing the assessment and a better understanding of the impacts of fibromyalgia and the burden associated with these on patients' daily lives. It is available in UK English, French, German and Spanish. Its scoring and validation remain to be undertaken.

Predicting laser-induced bulk damage and conditioning for deuterated potassium dihydrogen phosphate crystals using an absorption distribution model.

We present an empirical model that describes the experimentally observed laser-induced bulk damage and conditioning behavior in deuterated potassium dihydrogen phosphate (DKDP) crystals. The model expands on an existing nanoabsorber precursor model and the multistep absorption mechanism to include two populations of absorbing defects, one with linear absorption and another with nonlinear absorption. We show that this model connects previously uncorrelated small-beam damage initiation probability data to large-beam damage density measurements over a range of nanosecond pulse widths. In addition, this work predicts the damage behavior of laser-conditioned DKDP.

Demonstration of high-energy 2 omega (526.5 nm) operation on the National Ignition Facility Laser System.

A single beamline of the National Ignition Facility (NIF) has been operated at a wavelength of 526.5 nm (2 omega) by frequency converting the fundamental 1053 nm (1 omega) wavelength with an 18.2 mm thick type-I potassium dihydrogen phosphate (KDP) second-harmonic generator (SHG) crystal. Second-harmonic energies of up to 17.9 kJ were measured at the final optics focal plane with a conversion efficiency of 82%. For a similarly configured 192-beam NIF, this scales to a total 2 omega energy of 3.4 MJ full NIF equivalent (FNE).

National Ignition Facility laser performance status.

The National Ignition Facility (NIF) is the world's largest laser system. It contains a 192 beam neodymium glass laser that is designed to deliver 1.8 MJ at 500 TW at 351 nm in order to achieve energy gain (ignition) in a deuterium-tritium nuclear fusion target. To meet this goal, laser design criteria include the ability to generate pulses of up to 1.8 MJ total energy, with peak power of 500 TW and temporal pulse shapes spanning 2 orders of magnitude at the third harmonic (351 nm or 3omega) of the laser wavelength. The focal-spot fluence distribution of these pulses is carefully controlled, through a combination of special optics in the 1omega (1053 nm) portion of the laser (continuous phase plates), smoothing by spectral dispersion, and the overlapping of multiple beams with orthogonal polarization (polarization smoothing). We report performance qualification tests of the first eight beams of the NIF laser. Measurements are reported at both 1omega and 3omega, both with and without focal-spot conditioning. When scaled to full 192 beam operation, these results demonstrate, to the best of our knowledge for the first time, that the NIF will meet its laser performance design criteria, and that the NIF can simultaneously meet the temporal pulse shaping, focal-spot conditioning, and peak power requirements for two candidate indirect drive ignition designs.

Prediction of response to IVIg treatment in patients with lower motor neurone disorders.

The distinction between multifocal motor neuropathy, treatable by intravenous immunoglobulins (IVIg), and degenerative motor neurone disorders is often difficult. To find predictive factors for the response to IVIg treatment, 40 consecutive patients with pure lower motor neurone disorders (LMND) were prospectively examined. They all received at least two times IVIg (2 g/kg bodyweight). Prior to the first and before all the following treatments a standardized evaluation was performed including clinical examination, neurophysiological and laboratory evaluation. According to changes in the neurological examination and the Neuromuscular Symptom Score, the patients were divided into responders and non-responders after the second course of treatment. In our study, no single clinical, neurophysiological, or laboratory parameter was sensitive enough to predict response. The only single parameter that highly correlated with a positive response to treatment was an elevated GM1 antibody titre. Lack of response to IVIg treatment is likely in patients with generalization of electromyographic signs of denervation beyond the clinically involved site, proximal localization of the weakness, and an elevated level of the creatinekinase. Conduction blocks do not distinguish between both groups. We propose a scoring system combining clinical, serological and neurophysiological data in order to decide which patients with LMND may receive IVIg.

The T102C polymorphism of the 5-HT2A-receptor gene in fibromyalgia.

Based on a possible involvement of serotonergic dysfunction in the pathophysiology of fibromyalgia (FM) and on preliminary reports of a possible genetically driven vulnerability for this disorder we investigated the silent T102C polymorphism of the 5-HT2A-receptor gene in 168 FM patients and 115 healthy controls. Our results showed a significantly different genotype distribution in FM patients with a decrease in T/T and an increase in both T/C and C/C genotypes as compared to the control population (Fisher's Exact test, two-sided, P = 0.008). However, the increase in allele-C102 frequency felt short of significance (P = 0.07). Correlation of genotypes to clinical parameters revealed no influences on age of onset, duration of disease or psychopathological symptoms, measured with the Beck Depression Inventory and the symptom checklist SCL-90-R. In contrast to that the pain score, being a self reported information on pain severity, was significantly higher in patients of the T/T genotype (Mann-Whitney U test, P = 0.028). This suggests that the T102-allele might be involved in the complex circuits of nociception. However, the T102C polymorphism is not directly involved in the aetiology of FM but might be in linkage dysequilibrium with the true functional variant, which has to be unravelled.

Very long lasers.

The properties and oscillation characteristics of very long cw xenon lasers are discussed and pertinent long laser experiments described. High-gain 3.508-microm xenon laser amplifiers were used in these experiments. Laser cavity lengths of up to 30 km were studied. Spectrum analyses revealed complex oscillation spectra exhibiting the characteristics of both homogeneous and inhomogeneous laser mode structures. Long laser Doppler experiments, Q-switching studies, and modulation experiments were performed. Applications to atmospheric pollution detection are discussed.