Unimolecular and water reactions of oxygenated and unsaturated Criegee intermediates under atmospheric conditions.

Ozonolysis of unsaturated hydrocarbons (VOCs) is one of the main oxidation processes in the atmosphere. The stabilized Criegee intermediates (SCI) formed are highly reactive oxygenated species that potentially influence the HOx, NOx and SOx cycles, and affect aerosol formation by yielding low-volatility oxygenated compounds. The current knowledge spans mostly SCI formed from primary emitted VOCs, but little is known about the reactivity of oxygenated SCI. In this work we present a theoretical kinetic study of a large number of unsaturated and oxygenated SCI, covering CC, OH, OR, OOH, OOOH, COOH, COOR, and ONO2 functionalities at various stereo- and site-specific substitutions relative to the SCI carbonyl oxide moiety. Several novel reaction types are covered, the most important of which are fast intramolecular insertion reactions in OH, OOH and COOH groups, or secondary ozonide formation with a COOH group, forming cyclic oxygenated species; these reaction classes are reminiscent of the analogous bimolecular reactions. The reaction with H2O molecules was likewise studied, finding that these cyclisation reactions can be catalysed, with predicted rate coefficients nearing the collision limit. The theoretical data is used to extend the structure-activity relationships (SARs) proposed by Vereecken et al. (2017), predicting the dominant unimolecular reaction class and rate, and the rates for reaction with H2O and (H2O)2. The SARs cover over 300 SCI categories with over 40 substituent categories. The validation of these SARs is discussed, and an outlook is given for further improvement. The generally short lifetime of oxygenated SCI suggests that ozonolysis of secondary, oxygenated VOCs is unlikely to yield ambient concentrations of SCI exceeding 104 cm-3 but will contribute strongly to the in situ formation of oxygenated VOCs.

A structure activity relationship for ring closure reactions in unsaturated alkylperoxy radicals.

Terpenoids are an important class of multi-unsaturated volatile organic compounds emitted to the atmosphere. During their oxidation in the troposphere, unsaturated peroxy radicals are formed, which may undergo ring closure reactions by an addition of the radical oxygen atom on either of the carbons in the C[double bond, length as m-dash]C double bond. This study describes a quantum chemical and theoretical kinetic study of the rate of ring closure, finding that the reactions are comparatively fast with rates often exceeding 1 s-1 at room temperature, making these reactions competitive in low-NOx environments and allowing for continued autoxidation by ring closure. A structure-activity relationship (SAR) is presented for 5- to 8-membered ring closure in unsaturated RO2 radicals with aliphatic substituents, with some analysis of the impact of oxygenated substituents. H-migration in the cycloperoxide peroxy radicals formed after the ring closure was found to be comparatively slow for unsubstituted RO2 radicals. In the related cycloperoxide alkoxy radicals, migration of H-atoms implanted on the ring was similarly found to be slower than for non-cyclic alkoxy radicals and is typically not competitive against decomposition reactions that lead to cycloperoxide ring breaking. Ring closure reactions may constitute an important reaction channel in the atmospheric oxidation of terpenoids and could promote continued autoxidation, though the impact is likely to be strongly dependent on the specific molecular backbone.

Ubiquitous atmospheric production of organic acids mediated by cloud droplets.

Atmospheric acidity is increasingly determined by carbon dioxide and organic acids1-3. Among the latter, formic acid facilitates the nucleation of cloud droplets4 and contributes to the acidity of clouds and rainwater1,5. At present, chemistry-climate models greatly underestimate the atmospheric burden of formic acid, because key processes related to its sources and sinks remain poorly understood2,6-9. Here we present atmospheric chamber experiments that show that formaldehyde is efficiently converted to gaseous formic acid via a multiphase pathway that involves its hydrated form, methanediol. In warm cloud droplets, methanediol undergoes fast outgassing but slow dehydration. Using a chemistry-climate model, we estimate that the gas-phase oxidation of methanediol produces up to four times more formic acid than all other known chemical sources combined. Our findings reconcile model predictions and measurements of formic acid abundance. The additional formic acid burden increases atmospheric acidity by reducing the pH of clouds and rainwater by up to 0.3. The diol mechanism presented here probably applies to other aldehydes and may help to explain the high atmospheric levels of other organic acids that affect aerosol growth and cloud evolution.

Theoretical and experimental study of peroxy and alkoxy radicals in the NO3-initiated oxidation of isoprene.

The initial stages of the nitrate radical (NO3) initiated oxidation of isoprene, in particular the fate of the peroxy (RO2) and alkoxy (RO) radicals, are examined by an extensive set of quantum chemical and theoretical kinetic calculations. It is shown that the oxidation mechanism is highly complex, and bears similarities to its OH-initiated oxidation mechanism as studied intensively over the last decade. The nascent nitrated RO2 radicals can interconvert by successive O2 addition/elimination reactions, and potentially have access to a wide range of unimolecular reactions with rate coefficients as high as 35 s-1; the contribution of this chemistry could not be ascertained experimentally. The chemistry of the alkoxy radicals derived from these peroxy radicals is affected by the nitrate moiety, and can lead to the formation of nitrated epoxy peroxy radicals in competition with isomerisation and decomposition channels that terminate the organic radical chain by NO2 elimination. The theoretical predictions are implemented in the FZJ-NO3-isoprene mechanism for NO3-initiated atmospheric oxidation of isoprene. The model predictions are compared against peroxy radical (RO2) and methyl vinyl ketone (MVK) measurements in a set of experiments on the isoprene + NO3 reaction system performed in the SAPHIR environmental chamber (IsopNO3 campaign). It is shown that the formation of NO2 from the peroxy radicals can prevent a large fraction of the peroxy radicals from being measured by the laser-induced fluorescence (ROxLIF) technique that relies on a quantitative conversion of peroxy radicals to hydroxyl radicals. Accounting for the relative conversion efficiency of RO2 species in the experiments, the agreement between observations and the theory-based FZJ-NO3-isoprene model predictions improves significantly. In addition, MVK formation in the NO3-initiated oxidation was found to be suppressed by the epoxidation of the unsaturated RO radical intermediates, allowing the model-predicted MVK concentrations to be in good agreement with the measurements. The FZJ-NO3-isoprene mechanism is compared against the MCM v3.3.1 and Wennberg et al. (2018) mechanisms.

Experimental and theoretical study on the impact of a nitrate group on the chemistry of alkoxy radicals.

The chemistry of nitrated alkoxy radicals, and its impact on RO2 measurements using the laser induced fluorescence (LIF) technique, is examined by a combined theoretical and experimental study. Quantum chemical and theoretical kinetic calculations show that the decomposition of ß-nitrate-alkoxy radicals is much slower than ß-OH-substituted alkoxy radicals, and that the spontaneous fragmentation of the α-nitrate-alkyl radical product to a carbonyl product + NO2 prevents other ß-substituents from efficiently reducing the energy barrier. The systematic series of calculations is summarized as an update to the structure-activity relationship (SAR) by Vereecken and Peeters (2009), and shows increasing decomposition rates with higher degrees of substitution, as in the series ethene to 2,3-dimethyl-butene, and dominant H-migration for sufficiently large alkoxy radicals such as those formed from 1-pentene or longer alkenes. The slow decomposition allows other reactions to become competitive, including epoxidation in unsaturated nitrate-alkoxy radicals; the decomposition SAR is likewise updated for ß-epoxy substituents. A set of experiments investigating the NO3-initiated oxidation of ethene, propene, cis-2-butene, 2,3-dimethyl-butene, 1-pentene, and trans-2-hexene, were performed in the atmospheric simulation chamber SAPHIR with measurements of HO2 and RO2 radicals performed with a LIF instrument. Comparisons between modelled and measured HO2 radicals in all experiments, performed in excess of carbon monoxide to avoid OH radical chemistry, suggest that the reaction of HO2 with ß-nitrate alkylperoxy radicals has a channel forming OH and an alkoxy radical in yields of 15-65%, compatible with earlier literature data on nitrated isoprene and α-pinene radicals. Model concentrations of RO2 radicals when including the results of the theoretical calculations described here, agreed within 10% with the measured RO2 radicals for all species investigated when the alkene oxidation is dominated by NO3 radicals. The formation of NO2 in the decomposition of ß-nitrate alkoxy radicals prevents detection of the parent RO2 radical in a LIF instrument, as it relies on formation of HO2. The implications for measurements of RO2 in ambient and experimental conditions, such as for the NO3-dominated chemistry during nighttime, is discussed. The current results appear in disagreement with an earlier indirect experimental study by Yeh et al. on pentadecene.

Bispecific antibody-targeted phagocytosis of HER-2/neu expressing tumor cells by myeloid cells activated in vivo.

Studies from our laboratory and others have established that both mononuclear phagocytes and neutrophils mediate very efficient cytotoxicity when targeted through Fc receptors using a suitable monoclonal or bispecific antibody (BsAb). Cross-linking an Fc receptor for IgG (FcgammaR) triggers multiple anti-tumor activities including superoxide generation, cytokine and enzyme release, phagocytosis and antibody-dependent cellular cytotoxicity (ADCC). In this report, using unfractionated leukocytes and two color flow cytometric analysis, we describe the phagocytic capacity of peripheral blood polymorphonuclear cells (PMN) and monocytes isolated from patients enrolled in a phase I clinical trial of MDX-H210 given in combination with IFNgamma. MDX-H210 is a BsAb targeting the myeloid trigger molecule FcgammaRI and the HER-2/neu proto-oncogene product overexpressed on a variety of adenocarcinomas. In this trial, cohorts of patients received escalating doses of MDX-H210 3 times per week for 3 weeks. Interferon-gamma (IFNgamma) was given 24 h prior to each BsAb infusion. Our results demonstrate that monocytes from these patients were inherently capable of phagocytosing the HER-2/neu positive SK-BR-3 cell line and that addition of MDX-H210 into the assay significantly enhanced the number of targets phagocytosed. Two days after administration of an immunologically active dose of MDX-H210 (10 mg/m2), monocytes from these patients were able to phagocytose greater amounts of target cell material, indicating that these cells remained armed with functionally sufficient BsAb for at least 48 h. PMN from these patients very efficiently mediated phagocytosis through FcgammaRI after being treated with IFNgamma, but not before. We conclude that phagocytosis is not only an efficient mechanism of myeloid cell-mediated cytotoxicity, but may also be a mechanism by which antigens from phagocytosed cells can enter a professional antigen presenting cell for processing and presentation.

Human monocytes express CD163, which is upregulated by IL-10 and identical to p155.

CD163 is a glucocorticoid-inducible member of the scavenger receptor cysteine-rich family of proteins. Previous reports have indicated that CD163 is highly expressed on human macrophages, but found on less than 50% of peripheral blood monocytes. We now show that >99% of all CD14 positive monocytes express CD163 and that monocyte derived dendritic cells express low levels of CD163. We also show that IL-10, like glucocorticoids, induces high CD163 expression on cultured human monocytes. Glucocorticoid induced CD163 expression was not inhibited by anti-IL-10 and was additive with IL-10 treatment, suggesting that glucocorticoids increase CD163 expression by an IL-10 independent mechanism. Other anti-inflammatory cytokines (IL-4 and IL-13) did not increase CD163 expression. In addition, we show that p155 (a previously identified monocyte/macrophage marker of unknown function) shares identity with CD163. Western blots and flow cytometric analysis of HEK 293 cells transfected with the cDNA for CD163 were positive when probed with either mAb RM3/1 (which recognizes CD163) or Mac 2-48 (which defines p155).

The role of CD8+ CD40L+ T cells in the formation of germinal centers in rheumatoid synovitis.

In rheumatoid synovitis, lymphocytes can be arranged in follicular structures resembling secondary lymphoid follicles. To understand the organizing principles of this ectopic lymphoid tissue, the cellular components contributing to synovial follicles were examined. In 9 of 24 synovial tissue biopsies, lymphoid aggregates were found consisting of CD4+ T cells and CD20+ B cells. In four of the nine patients, the follicular centers were occupied by CD23+ CD21+ cellular networks representing follicular dendritic cells involved in germinal center reactions. In five patients, CD23+ cells were absent from the centers of the aggregates, suggesting that fully developed germinal centers are generated in only a subset of patients. To identify factors involved in the regulation of the synovial microarchitecture, cell populations contributing to the follicles were quantified by digital image analysis of immunostained tissue and by flow cytometry of tissue-derived lymphocytes. Proportions of CD4+, CD20+, and CD68+ cell subsets were surprisingly invariant, irrespective of the presence or absence of CD23+ follicular dendritic cells. Instead, tissue biopsies with CD23+ germinal center-like regions could be distinguished from those with CD23- T cell-B cell aggregates by a fourfold increase in the frequency of tissue-infiltrating CD8+ T cells, a fraction of which expressed CD40 ligand (CD40L). The data suggest a previously unsuspected role of CD8+ lymphocytes in modulating germinal center formation and raise the possibility that CD8+ CD40L+ T cells are involved in aggravating pathologic immune responses in rheumatoid synovitis.

[Schizophrenia and partial complex seizures--case report in diagnosis and differential diagnosis of psychoses and epilepsy]. / Schizophrenie und komplex-partielle Anfälle--Kasuistik zur Diagnose und Differentialdiagnose von Psychosen und Epilepsie.

We report on a 57 year-old patient with schizophrenia. After a 30 years course of the disease, he developed previous unknown psychopathological symptoms, and therapeutic interventions (neuroleptic drugs and electroconvulsive therapy) failed. Neurological examination and EEG revealed the diagnosis of complex partial epileptic seizures. MRI showed bitemporal localized cerebral lesions. Discussion focusses on generalization of microseizures in deep brain structures, and "kindling effect" of electroconvulsive therapy in a patient with pre-existing cerebral lesions.

[Differential diagnosis of malignant hyperthermia, febrile catatonia and neuroleptic malignant syndrome. A case comparison]. / Zur Differentialdiagnostik der malignen Hyperthermie, der febrilen Katatonie und des neuroleptischen malignen Syndroms. Ein kasuistischer Vergleich.

Malignant Hyperthermia (MH), Lethal Catatonia (LC), and Neuroleptic Malignant Syndrome (NMS) are known as rare potential lethal diseases. MH and NMS--both being drug-induced--have in common some main symptoms. LC and NMS, on the other hand, are hardly distinguishable by clinical means. After presentation of the case reports the differential diagnosis of the syndromes is discussed. While there is strong evidence for the MH to be drug-induced, the NMS cannot be explained sufficiently in this way. Clinically both can be differentiated. Lethal catatonia is a syndrome rather than a specific disease. Differential diagnosis for NMS is possible by the neuroleptic withdraw-trial.