Essentials Risk-stratification often fails to predict clinical deterioration in pulmonary embolism (PE). First-ever high-throughput metabolomics analysis of risk-stratified PE patients. Changes in circulating metabolites reflect a compromised energy metabolism in PE. Metabolites play a key role in the pathophysiology and risk stratification of PE.
Background Patients with acute pulmonary embolism (PE) exhibit wide variation in clinical presentation and outcomes. Our understanding of the pathophysiologic mechanisms differentiating low-risk and high-risk PE is limited, so current risk-stratification efforts often fail to predict clinical deterioration and are insufficient to guide management. Objectives To improve our understanding of the physiology differentiating low-risk from high-risk PE, we conducted the first-ever high-throughput metabolomics analysis (843 named metabolites) comparing PE patients across risk strata within a nested case-control study. Patients/methods We enrolled 92 patients diagnosed with acute PE and collected plasma within 24 h of PE diagnosis. We used linear regression and pathway analysis to identify metabolites and pathways associated with PE risk-strata. Results When we compared 46 low-risk with 46 intermediate/high-risk PEs, 50 metabolites were significantly different after multiple testing correction. These metabolites were enriched in the following pathways: tricarboxylic acid (TCA) cycle, fatty acid metabolism (acyl carnitine) and purine metabolism, (hypo)xanthine/inosine containing. Additionally, energy, nucleotide and amino acid pathways were downregulated in intermediate/high-risk PE patients. When we compared 28 intermediate-risk with 18 high-risk PE patients, 41 metabolites differed at a nominal P-value level. These metabolites were enriched in fatty acid metabolism (acyl cholines), and hemoglobin and porphyrin metabolism. Conclusion Our results suggest that high-throughput metabolomics can provide insight into the pathophysiology of PE. Specifically, changes in circulating metabolites reflect compromised energy metabolism in intermediate/high-risk PE patients. These findings demonstrate the important role metabolites play in the pathophysiology of PE and highlight metabolomics as a potential tool for risk stratification of PE.

The attainment of new function by a protein is achieved through convergent/divergent evolution. In present work, the sequence analysis of a 34kDa protein from Putranjiva roxburghii, earlier reported as a potent trypsin inhibitor, showed resemblance to some of the wound inducible and vegetative storage proteins. A detailed sequence analysis revealed that these proteins belong to PNP-UDP family. In case of P. roxburghii protein, an approximately 46 residue insert disrupts the PNP domain. Similar disruption of PNP domain is observed in related plant proteins. The characterization of recombinant full length and truncated (without 46 residue insert) forms of P. roxburghii PNP family protein (PRpnp) unraveled that trypsin inhibitory active site is located within the insert. The truncated form containing uninterrupted PNP domain showed strong PNP enzymatic activity where it hydrolyzed the N-glycosidic bond of inosine and guanosine. The full length protein, however, showed weak PNP enzyme activity which may be due to presence of the insert. These results indicate towards the neofunctionalization of PRpnp to a potent trypsin inhibitor through an insert containing inhibitory residue to cater to the needs of plant defense. The similar wound inducible and vegetative storage proteins may have also evolved due to evolutionary needs.

The structural properties and ultrafast electronic deactivation dynamics of the inosine dimer in CHCl3 have been investigated by two-dimensional (1)H NMR and static FTIR spectroscopy and by femtosecond time-resolved transient absorption spectroscopy, respectively. The (1)H NMR and IR spectra show the formation of a well-defined, symmetric dimer with an association equilibrium constant of KI·I = 690 ± 100 M(-1). The excited-state dynamics after photoexcitation at λpump = 260 nm monitored by ultrafast absorption spectroscopy show great similarity with those of the monomer inosine in an aqueous solution and are governed by a decay time of τ = 90 ± 10 fs, which is one of the shortest electronic lifetimes of all nucleobases and nucleobase dimers studied so far. On the basis of these observations, the inosine dimer is expected to follow a similar relaxation pathway as the monomer, involving an out-of-plane deformation of the six-membered ring. The importance of the C(2) position for the electronic deactivation of hypoxanthine and guanine is discussed. The obtained well-determined structure and straightforward dynamics qualify the inosine dimer as an excellent reference case for more complicated systems such as the G·G dimer and the G·C and A·T Watson-Crick pairs.

The injection of HgCl2 to Wistar rats results in the affection of the excretory renal function, the development of immunosuppressive properties of red blood cells and the depression of immunological functions. The exposure to heat in combination with the injection of thiamin and inosin caused normalization of the immunological parameters of the intoxicated animals. The exposure to cold aggravates the severity of the immunological abnormalities induced by the injection of HgCl2. Thiamin in combination with inosin and carnitin with biotin significantly weaken the immunological disorders caused by intoxication and cooling.

The urinary excretion of six methylated ribonucleosides was measured in a case of anorexia nervosa during the first eight weeks of therapy. Four phases can be distinguished. Highly elevated values are found in a clearly catabolic situation. Immediately after onset of therapy when catabolism is stopped but nutrition still inadequate the excretion of RNA-catabolites is lowered markedly. As soon as normocaloric nutrition is reached after two weeks, a short but clearcut peak-excretion can be observed. Finally, the excretion of methylated RNA-catabolites is stabilized on an intermediate level after three to six weeks, when nutrition is constantly normocaloric and weight continues to increase linearly.

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Deficiency of purine nucleoside phosphorylase (PNP) was detected in a 3-yr-old boy who was admitted for investigation of a behavior disorder and spastic diplegia. The urinary excretion of purines, analyzed by high-performance liquid chromatography, showed the presence of large amounts of (deoxy)inosine and (deoxy)guanosine and low uric acid levels. Analysis of the (deoxy)nucleotide pools of erythrocytes showed elevated levels of deoxyguanine nucleotides and NAD and decreased guanine nucleotides. PNP activity in red blood cells was 0.1-0.5% of normal on two occasions and undetectable on four later measurements. Furthermore no immunoreactive material could be detected in his red cell lysate using an anti-PNP antiserum. PNP activities in the red cells of the patient\'s parents were 35 and 50% of normal. The presence of (minor) residual PNP activity in the patient enabled the investigation of some enzyme properties after partial purification. No abnormalities could be detected in substrate affinity for inosine, heat stability, and electrophoretic properties. In the heterozygous parents no signs of a mutant enzyme could be found. The molecular specific activities of the parental enzymes were also normal, indicating that no immunoreactive material attributable to inactive-mutant enzyme subunits was present. A striking feature of the patient is the prevailing neurologic abnormalities presumably caused by the metabolic disorder. A severe lymphopenia exists; however, clinical symptoms of an immune deficiency did not become apparent until the age of 4 yr.

An unsuccessful treatment with recombinant alpha-2 interferon and isoprinosine in a patient with AIDS and Kaposi\'s sarcoma is reported.

A long-term study of isoprinosine, with temporary discontinuation of the treatment, in a 25-year-old man with subacute sclerosing panencephalitis is presented. Isoprinosine appears to have mainly an effect on the mental disturbances in stage I. EEG and CFS changes correlate well with the clinical course and the influence of isoprinosine.