Effects of the mixed phosphodiesterase III/IV inhibitor, zardaverine, on airway function in patients with chronic airflow obstruction

AbstractZardaverine is a selective inhibitor of phosphodiesterase (PDE) III and IV isozymes. It has been shown to exert potent bronchodilator effects in animals. In order to study the efficacy and safety in man, a phase II clinical trial in 10 patients with partially reversible chronic airflow obstruction was carried out. The trial was designed as a double-blind, randomized, five-period change-over study. Zardaverine (at single doses of 1·5 mg, 3·0 mg, or 6·0 mg), salbutamol (0·3 mg) and placebo were administered by metered dose inhaler on separate days. As evaluated by spirometry over a time period of 4 h, salbutamol induced a significant bronchodilatation. In contrast, zardaverine did not improve airway function in these patients. Unwanted effects of the study medication were not observed

Characterization of [3H][^3H]Phenobarbital Binding to Rat Brain Membranes

The binding of $[^3H]$phenobarbital to rat brain membranes was studied in order to determine its characteristics and specificity. The binding reaction was rapid and occurred at sites of low affinity. $(K_d = 700 μM)$ and very high density $(B_{max} = 2.7 nmoll/mg protein)$. It was unaffected by temperature changes from O°C to 95°C and was maximal at pH 5. Detergents in low concentrations markedly decreased the binding, apparently without solubilizing the binding sites. It is concluded that the binding of $[^3H]$ phenobarbital is a rather non-specific interaction with the plasma membrane

Appearance and Stability of Anomalously Fluctuating States in Shor's Factoring Algorithm

We analyze quantum computers which perform Shor's factoring algorithm, paying attention to asymptotic properties as the number L of qubits is increased. Using numerical simulations and a general theory of the stabilities of many-body quantum states, we show the following: Anomalously fluctuating states (AFSs), which have anomalously large fluctuations of additive operators, appear in various stages of the computation. For large L, they decohere at anomalously great rates by weak noises that simulate noises in real systems. Decoherence of some of the AFSs is fatal to the results of the computation, whereas decoherence of some of the other AFSs does not have strong influence on the results of the computation. When such a crucial AFS decoheres, the probability of getting the correct computational result is reduced approximately proportional to L^2. The reduction thus becomes anomalously large with increasing L, even when the coupling constant to the noise is rather small. Therefore, quantum computations should be improved in such a way that all AFSs appearing in the algorithms do not decohere at such great rates in the existing noises.Comment: 11 figures. A few discussions were added in verion 2. Version 3 is the SAME as version 2; only errors during the Web-upload were fixed. Version 4 is the publised version, in which several typos are fixed and the reference list is update

Positiver FDG-PET-Befund als Zeichen entzündlicher Aktivität bei langjähriger Lymphknotensilikose

Die diagnostische Differenzierung zwischen silikotischer Schwiele und tumoröser Raumforderung bereitet bei pulmonalen Raumforderungen von Quarzstaubexponierten häufig Probleme. Am Fallbeispiel wird der Stellenwert der 250 MBq F-18-Fluorodeoxyglucose-Positronenemissionstomographie (FDG-PET) zur Dignitätsbeurteilung pulmonaler Rundherde und suspekter Lymphknoten bei dieser Fragestellung dargestellt

Necessity of Superposition of Macroscopically Distinct States for Quantum Computational Speedup

For quantum computation, we investigate the conjecture that the superposition of macroscopically distinct states is necessary for a large quantum speedup. Although this conjecture was supported for a circuit-based quantum computer performing Shor's factoring algorithm [A. Ukena and A. Shimizu, Phys. Rev. A69 (2004) 022301], it needs to be generalized for it to be applicable to a large class of algorithms and/or other models such as measurement-based quantum computers. To treat such general cases, we first generalize the indices for the superposition of macroscopically distinct states. We then generalize the conjecture, using the generalized indices, in such a way that it is unambiguously applicable to general models if a quantum algorithm achieves exponential speedup. On the basis of this generalized conjecture, we further extend the conjecture to Grover's quantum search algorithm, whose speedup is large but quadratic. It is shown that this extended conjecture is also correct. Since Grover's algorithm is a representative algorithm for unstructured problems, the present result further supports the conjecture.Comment: 18 pages, 5 figures. Fixed typos throughout the manuscript. This version has been publishe

Therapeutic approaches in heart failure with preserved ejection fraction: past, present, and future

In contrast to the wealth of proven therapies for heart failure with reduced ejection fraction (HFrEF), therapeutic efforts in the past have failed to improve outcomes in heart failure with preserved ejection fraction (HFpEF). Moreover, to this day, diagnosis of HFpEF remains controversial. However, there is growing appreciation that HFpEF represents a heterogeneous syndrome with various phenotypes and comorbidities which are hardly to differentiate solely by LVEF and might benefit from individually tailored approaches. These hypotheses are supported by the recently presented PARAGON-HF trial. Although treatment with LCZ696 did not result in a significantly lower rate of total hospitalizations for heart failure and death from cardiovascular causes among HFpEF patients, subanalyses suggest beneficial effects in female patients and those with an LVEF between 45 and 57%. In the future, prospective randomized trials should focus on dedicated, well-defined subgroups based on various information such as clinical characteristics, biomarker levels, and imaging modalities. These could clarify the role of LCZ696 in selected individuals. Furthermore, sodium-glucose cotransporter-2 inhibitors have just proven efficient in HFrEF patients and are currently also studied in large prospective clinical trials enrolling HFpEF patients. In addition, several novel disease-modifying drugs that pursue different strategies such as targeting cardiac inflammation and fibrosis have delivered preliminary optimistic results and are subject of further research. Moreover, innovative device therapies may enhance management of HFpEF, but need prospective adequately powered clinical trials to confirm safety and efficacy regarding clinical outcomes. This review highlights the past, present, and future therapeutic approaches in HFpEF

Orexin receptors exert a neuroprotective effect in Alzheimer's disease (AD) via heterodimerization with GPR103

Orexins are neuropeptides that regulate the sleep-wake cycle and feeding behaviour. QRFP is a newly discovered neuropeptide which exerts similar orexigenic activity, thus playing an important role in energy homeostasis and regulation of appetite. The exact expression and signalling characteristics and physiological actions of QRFP and its receptor GPR103 are poorly understood. Alzheimerâ €™ s disease (AD) patients experience increased nocturnal activity, excessive daytime sleepiness, and weight loss. We hypothesised therefore that orexins and QRFP might be implicated in the pathophysiology of AD. We report that the down-regulation of hippocampal orexin receptors (OXRs) and GPR103 particularly in the cornu ammonis (CA) subfield from AD patients suffering from early onset familial AD (EOFAD) and late onset familial AD (LOAD). Using an in vitro model we demonstrate that this downregulation is due to to Aβ-plaque formation and tau hyper-phosphorylation. Transcriptomics revealed a neuroprotective role for both orexins and QRFP. Finally we provide conclusive evidence using BRET and FRET that OXRs and GPR103 form functional hetero-dimers to exert their effects involving activation of ERK 1/2. Pharmacological intervention directed at the orexigenic system may prove to be an attractive avenue towards the discovery of novel therapeutics for diseases such as AD and improving neuroprotective signalling pathways

Therapeutic approaches in heart failure with preserved ejection fraction: past, present, and future

In contrast to the wealth of proven therapies for heart failure with reduced ejection fraction (HFrEF), therapeutic efforts in the past have failed to improve outcomes in heart failure with preserved ejection fraction (HFpEF). Moreover, to this day, diagnosis of HFpEF remains controversial. However, there is growing appreciation that HFpEF represents a heterogeneous syndrome with various phenotypes and comorbidities which are hardly to differentiate solely by LVEF and might benefit from individually tailored approaches. These hypotheses are supported by the recently presented PARAGON-HF trial. Although treatment with LCZ696 did not result in a significantly lower rate of total hospitalizations for heart failure and death from cardiovascular causes among HFpEF patients, subanalyses suggest beneficial effects in female patients and those with an LVEF between 45 and 57%. In the future, prospective randomized trials should focus on dedicated, well-defined subgroups based on various information such as clinical characteristics, biomarker levels, and imaging modalities. These could clarify the role of LCZ696 in selected individuals. Furthermore, sodium-glucose cotransporter-2 inhibitors have just proven efficient in HFrEF patients and are currently also studied in large prospective clinical trials enrolling HFpEF patients. In addition, several novel disease-modifying drugs that pursue different strategies such as targeting cardiac inflammation and fibrosis have delivered preliminary optimistic results and are subject of further research. Moreover, innovative device therapies may enhance management of HFpEF, but need prospective adequately powered clinical trials to confirm safety and efficacy regarding clinical outcomes. This review highlights the past, present, and future therapeutic approaches in HFpEF