Subject(s)
Gabapentin , Pulmonary Disease, Chronic Obstructive , Humans , Pulmonary Disease, Chronic Obstructive/drug therapy , Gabapentin/therapeutic use , Gabapentin/adverse effects , gamma-Aminobutyric Acid/adverse effects , gamma-Aminobutyric Acid/therapeutic use , Amines/adverse effects , Amines/therapeutic use , Cyclohexanecarboxylic Acids/adverse effects , Cyclohexanecarboxylic Acids/therapeutic use , Pregabalin/therapeutic use , Pregabalin/adverse effectsABSTRACT
The direct and unambiguous detection and identification of individual metabolite molecules present in complex biological mixtures constitute a major challenge in (bio)analytical research. In this context, nuclear magnetic resonance (NMR) spectroscopy has proven to be particularly powerful owing to its ability to provide both qualitative and quantitative atomic-level information on multiple analytes simultaneously in a noninvasive manner. Nevertheless, NMR suffers from a low inherent sensitivity and, moreover, lacks selectivity regarding the number of individual analytes to be studied in a mixture of a myriad of structurally and chemically very different molecules, e.g., metabolites in a biofluid. Here, we describe a method that circumvents these shortcomings via performing selective, photochemically induced dynamic nuclear polarization (photo-CIDNP) enhanced NMR spectroscopy on unmodified complex biological mixtures, i.e., human urine and serum, which yields a single, background-free one-dimensional NMR spectrum. In doing this, we demonstrate that photo-CIDNP experiments on unmodified complex mixtures of biological origin are feasible, can be performed straightforwardly in the native aqueous medium at physiological metabolite concentrations, and act as a spectral filter, facilitating the analysis of NMR spectra of complex biofluids. Due to its noninvasive nature, the method is fully compatible with state-of-the-art metabolomic protocols providing direct spectroscopic information on a small, carefully selected subset of clinically relevant metabolites. We anticipate that this approach, which, in addition, can be combined with existing high-throughput/high-sensitivity NMR methodology, holds great promise for further in-depth studies and development for use in metabolomics and many other areas of analytical research.
Subject(s)
Magnetic Resonance Imaging , Metabolomics , Humans , Magnetic Resonance Spectroscopy/methods , Metabolomics/methodsABSTRACT
A 48-year-old-male presented with a five-week history of non-productive cough and exertional dyspnoea. A pulmonary function test showed a mild diffusion disorder. A CT scan revealed an atypical pneumonia with bipulmonary consolidations, which were accentuated in the right upper lobe. The transbronchial biopsy showed lipid-loaded macrophages. These findings confirmed the diagnosis of a lipoid pneumonia, which developed in the context of inhalation of substances containing menthol. After discontinuation of the causative agent and high-dose steroid administration the symptoms were reversible within a few weeks.
Subject(s)
Cough , Pneumonia, Lipid , Administration, Inhalation , Cough/diagnosis , Cough/drug therapy , Cough/etiology , Dyspnea/chemically induced , Dyspnea/diagnosis , Humans , Lung/pathology , Male , Middle Aged , Pneumonia, Lipid/chemically induced , Pneumonia, Lipid/diagnosisABSTRACT
Nivolumab was the first immune checkpoint inhibitor approved for use in advanced non-small cell lung cancer (NSCLC). This noninterventional, prospective cohort study investigates real-world effectiveness of nivolumab in pretreated NSCLC patients in Germany (Enlarge-Lung/CA209-580). Patients with squamous (SQ) or nonsquamous (NSQ) NSCLC previously treated for locally advanced or metastatic (stage IIIB/IV) disease received nivolumab according to the current Summary of Product Characteristics. Overall survival (OS) was the primary endpoint. Of 907 patients enrolled, 660 patients who were followed for at least 12 months across 79 study centers in Germany, were analyzed. Median OS was 11.2 months [95% confidence interval (CI), 9.1-12.9]; outcomes for the 418 patients with NSQ histology [13.1 mo (95% CI, 10.6-15.6)] were more favorable than outcomes for the 242 patients with SQ histology [8.9 mo (95% CI, 6.4-11.3)]. Patients' age, presence of distant or brain metastases, or line of therapy did not affect outcomes; however, patients with poor performance status (ECOG-PS ≥2, n=80) had shorter median OS [4.7 mo (95% CI, 3.1-5.4)]. This study represents one of the largest real-world cohorts providing outcomes of nivolumab in pretreated NSCLC. The results match well with the published evidence from pivotal clinical trials and demonstrate clinical effectiveness of nivolumab in advanced NSCLC.
Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Carcinoma, Non-Small-Cell Lung/pathology , Humans , Lung/pathology , Lung Neoplasms/diagnosis , Lung Neoplasms/drug therapy , Nivolumab/adverse effects , Prospective StudiesABSTRACT
Substrates containing 19 F can serve as background-free reporter molecules for NMR and MRI. However, inâ vivo applications are still limited due to the lower signal-to-noise ratio (SNR) when compared with 1 H NMR. Although hyperpolarization can increase the SNR, to date, only photo-chemically induced dynamic nuclear polarization (photo-CIDNP) allows for hyperpolarization without harmful metal catalysts. Photo-CIDNP was shown to significantly enhance 19 F NMR signals of 3-fluoro-DL-tyrosine in aqueous solution using flavins as photosensitizers. However, lasers were used for photoexcitation, which is expensive and requires appropriate protection procedures in a medical or lab environment. Herein, we report 19 F MR hyperpolarization at 4.7â T and 7â T with a biocompatible system using a low-cost and easy-to-handle LED-based set-up. First hyperpolarized 19 F MR images could be acquired, because photo-CIDNP enabled repetitive hyperpolarization without adding new substrates.
Subject(s)
Lasers , Magnetic Resonance Imaging , Magnetic Resonance Spectroscopy , Flavin Mononucleotide/chemistry , Flavins/chemistry , Fluorine/chemistry , Tyrosine/analogs & derivatives , Tyrosine/chemistryABSTRACT
Parahydrogen-induced polarization (PHIP) is a promising new tool for medical applications of MR, including MRI. The PHIP technique can be used to transfer high non-Boltzmann polarization, derived from parahydrogen, to isotopes with a low natural abundance or low gyromagnetic ratio (e.g. (13)C), thus improving the signal-to-noise ratio by several orders of magnitude. A few molecules acting as metabolic sensors have already been hyperpolarized with PHIP, but the direct hyperpolarization of drugs used to treat neurological disorders has not been accomplished until now. Here, we report on the first successful hyperpolarization of valproate (valproic acid, VPA), an important and commonly used antiepileptic drug. Hyperpolarization was confirmed by detecting the corresponding signal patterns in the (1)H NMR spectrum. To identify the optimal experimental conditions for the conversion of an appropriate VPA precursor, structurally related molecules with different side chains were analyzed in different solvents using various catalytic systems. The presented results include hyperpolarized (13)C NMR spectra and proton images of related systems, confirming their applicability for MR studies. PHIP-based polarization enhancement may provide a new MR technique to monitor the spatial distribution of valproate in brain tissue and to analyze metabolic pathways after valproate administration.
Subject(s)
Hydrogen/chemistry , Valproic Acid/chemistry , Catalysis , Fatty Acids, Unsaturated/chemistry , Magnetic Resonance Imaging , Pilot Projects , Proton Magnetic Resonance Spectroscopy , Signal Processing, Computer-AssistedABSTRACT
Fluorinated substances are important in chemistry, industry, and the life sciences. In a new approach, parahydrogen-induced polarization (PHIP) is applied to enhance (19)Fâ MR signals of (perfluoro-n-hexyl)ethene and (perfluoro-n-hexyl)ethane. Unexpectedly, the end-standing CF3 group exhibits the highest amount of polarization despite the negligible coupling to the added protons. To clarify this non-intuitive distribution of polarization, signal enhancements in deuterated chloroform and acetone were compared and (19)F-(19)Fâ NOESY spectra, as well as (19)F T1 values were measured by NMR spectroscopy. By using the well separated and enhanced signal of the CF3 group, first (19)Fâ MR images of hyperpolarized linear semifluorinated alkenes were recorded.
Subject(s)
Fluorocarbons/chemistry , Magnetic Resonance Spectroscopy/methods , Protons , Hydrogen/chemistry , Magnetic Resonance Imaging/methodsABSTRACT
Hyperpolarization (HP) techniques are increasingly important in magnetic resonance imaging (MRI) and spectroscopy (MRS). HP methods have the potential to overcome the fundamentally low sensitivity of magnetic resonance (MR). A breakthrough of HP-MR in life sciences and medical applications is still limited by the small number of accessible, physiologically relevant substrates. Our study presents a new approach to extend PHIP to substrates that primarily cannot be hyperpolarized due to a steady intramolecular re-arrangement, the so-called keto-enol tautomerism. To overcome this obstacle we exploited the fact that instead of the instable enol form the corresponding stable ester can be used as a precursor molecule. This strategy now enables the hydrogenation which is required to apply the standard PHIP procedure. As the final step a hydrolysis is necessary to release the hyperpolarized target molecule. Using this new approach ethanol was successfully hyperpolarized for the first time. It may therefore be assumed that the outlined multi-step procedure can be used for other keto-enol tautomerized substances thereby opening the application of PHIP to a multitude of molecules relevant to analyzing metabolic pathways.
Subject(s)
Ethanol/chemistry , Hydrogen/chemistry , Ketones/chemistry , Molecular Structure , StereoisomerismABSTRACT
The use of parahydrogen-induced polarization (PHIP) for signal enhancement in nuclear magnetic resonance spectroscopy (NMR) is well established. Recently, this method has been adopted to increase the sensitivity of magnetic resonance imaging (MRI). The transfer of non-thermal spin hyperpolarization--from parahydrogen to a heteronucleus--provides better contrast, thus enabling new imaging agents. The unique advantage of (19)F-MRI is that it provides non-invasive and background-free active marker signals in biomedical applications, such as monitoring drugs that contain (19)F. In former NMR spectroscopic experiments, hyperpolarized (19)F nuclei were efficiently generated by using low magnetic field (Earth's field) conditions. In order to apply the method to (19)F-hyperpolarized MRI, we chose an exploratory target molecule, for which a successful transfer of PHIP had already been attested. The transfer of hyperpolarization to (19)F was further optimized by adequate field manipulations below Earth's magnetic field. This technique, called field cycling, led to a signal enhancement of about 60. For the first time, hyperpolarized (19)F-MR images were received. Despite the low spin density of the sample (0.045 per thousand of the (1)H density in H(2)O), a sufficient signal-to-noise was obtained within a short acquisition time of 3.2 s.
Subject(s)
Hydrogen/chemistry , Magnetic Resonance Imaging/methods , Molecular ImagingABSTRACT
Significant (13)C NMR signal enhancement by a factor of 5000 of a barbituric acid derivative (5-methyl-5-propenyl-barbituric acid) via parahydrogen induced polarization is presented. This hyperpolarization is achieved by hydrogenating 5-methyl-5-propargyl-barbituric acid with 98% enriched para-H(2) under elevated temperature and pressure and transferring the initially created (1)H hyperpolarization with an INEPT-derived pulse sequence to (13)C. The polarization can be selectively transferred to different carbons in the barbituric acid derivative by applying different pulse delays in the INEPT pulse sequence. These results demonstrate the potential of using hyperpolarized barbituric acid derivatives as "active" contrast agents in MRI and visualizing their pharmacokinetics in vivo.
Subject(s)
Barbiturates/chemistry , Contrast Media/analysis , Contrast Media/chemical synthesis , Hydrogen/chemistry , Image Enhancement/methods , Magnetic Resonance Imaging/methods , Magnetic Resonance Spectroscopy/methods , Carbon Isotopes/chemistryABSTRACT
Homogeneous hydrogenation of barbituric acid derivatives with parahydrogen yields a substantial increase of the (1)H NMR signals of the reaction products. These physiologically relevant compounds were hydrogenated at both ambient and elevated temperatures and pressures using a standard cationic rhodium catalyst. The resulting nonthermal nuclear spin polarization (hyperpolarization) is limited by the spin-lattice relaxation time T(1) of the corresponding nuclei in the products, being shorter than the time constant of the hydrogenation. The signal-to-noise ratio of the NMR spectra could be further increased upon signal averaging the antiphase PHIP signals of 25 successive scans following 30 degrees pulse experiments and a delay of 10 s.
ABSTRACT
BACKGROUND: Bronchopulmonary disease due to inhalation of smoke from open woodfires represents a major health problem in developing countries. Due to increasing migration such patients also present to medical services in Europe. CASE REPORT AND DISCUSSION: An 84-year-old Afghan housewife who never smoked nor has a history of exposure to inorganic dusts, presents with chronic obstructive pulmonary disease (COPD) in association with bronchial anthracosis and stenosis of a bronchus. The complaints are found to be caused by chronic inhalation of smoke from an open woodfire which was used for cooking. The main complaints of "woodsmoke-associated lung disease" are cough und dyspnea with bronchial obstruction. Radiology and bronchoscopy usually reveal changes which are similar to pneumoconiosis of miners but without patients' relevant exposure. There is a frequent association of anthracotic bronchial stenosis and infection with tuberculosis. CONCLUSION: Since patients rarely recognize the risks of woodsmoke inhalation, they hardly report their exposure. Thus, the anamnesis is crucial to establish the right diagnosis and guide the patient to the appropriate diagnostic and therapeutic procedures.
Subject(s)
Anthracosilicosis/etiology , Bronchial Diseases/etiology , Charcoal/adverse effects , Cooking , Fires , Pulmonary Disease, Chronic Obstructive/etiology , Smoke Inhalation Injury/etiology , Afghanistan/ethnology , Aged, 80 and over , Anthracosilicosis/diagnosis , Anthracosilicosis/pathology , Biopsy , Bronchi/pathology , Bronchial Diseases/diagnosis , Bronchial Diseases/pathology , Diagnosis, Differential , Emigration and Immigration , Female , Germany , Humans , Lung/pathology , Pulmonary Disease, Chronic Obstructive/diagnosis , Pulmonary Disease, Chronic Obstructive/pathology , Respiratory Mucosa/pathology , Smoke Inhalation Injury/diagnosis , Smoke Inhalation Injury/pathology , Tomography, X-Ray ComputedABSTRACT
Triplet energies play a considerable role in optical spectroscopy, and can be determined from phosphorescence or the quenching thereof. Their role in spin chemistry may not be as obvious, but the triplet state has always had an important function or utility, namely of reaction intermediates such as radical pairs, their precursors, of carbenes, and of the final products. In situ NMR spectroscopy represents a useful tool to explore certain properties of the triplet state, especially in cases with no phosphorescence. The 'phase' of CIDNP resonances, i.e., emission or enhanced absorption, reflects the spin selectivity of electron transfer reactions. In radical ion pairs the spin selectivity is determined by the relation between the change of the standard free enthalpy DeltaG degrees during the electron back transfer and the triplet energies (E(T)) of the products. If triplet recombination is energetically feasible (DeltaG degrees > E(T)), it is typically the more efficient process in agreement with the Marcus theory.
ABSTRACT
BACKGROUND: PPARs exhibit anti-inflammatory capacities and are potential modulators of the inflammatory response. We hypothesized that their expression and/or function may be altered in cystic fibrosis (CF), a disorder characterized by an excessive host inflammatory response. METHODS: PPARalpha, beta and gamma mRNA levels were measured in peripheral blood cells of CF patients and healthy subjects via RT-PCR. PPARalpha protein expression and subcellular localization was determined via western blot and immunofluorescence, respectively. The activity of PPARalpha was analyzed by gel shift assay. RESULTS: In lymphocytes, the expression of PPARalpha mRNA, but not of PPARbeta, was reduced (-37%; p < 0.002) in CF patients compared with healthy persons and was therefore further analyzed. A similar reduction of PPARalpha was observed at protein level (-26%; p < 0.05). The transcription factor was mainly expressed in the cytosol of lymphocytes, with low expression in the nucleus. Moreover, DNA binding activity of the transcription factor was 36% less in lymphocytes of patients (p < 0.01). For PPARalpha and PPARbeta mRNA expression in monocytes and neutrophils, no significant differences were observed between CF patients and healthy persons. In all cells, PPARgamma mRNA levels were below the detection limit. CONCLUSION: Lymphocytes are important regulators of the inflammatory response by releasing cytokines and antibodies. The diminished lymphocytic expression and activity of PPARalpha may therefore contribute to the inflammatory processes that are observed in CF.