Synthesis of 1H-isoindolin-1-ones via a simple photodecarboxylative addition of carboxylates to phthalimides and evaluation of their antibiotic activity.

A variety of 3-hydroxy-isoindolin-1-one derivatives were synthesized using the photodecarboxylative addition of carboxylates to phthalimide derivatives in aqueous media. Subsequent acid-catalyzed dehydration furnished 3-(alkyl and aryl)methyleneisoindolin-1-ones with variable E-diastereoselectivity in good to excellent overall yields. Noteworthy, the parent 3-phenylmethyleneisoindolin-1-one underwent isomerization and oxidative decomposition when exposed to light and air. Selected 3-hydroxy-isoindolin-1-one and 3-(alkyl and aryl)methyleneisoindolin-1-one derivatives showed moderate antibacterial activity that justifies future elaboration and study of these important bioactive scaffolds.

Performance of a chirped-pulse Fourier transform millimeter wave spectrometer in the range of 75-110 GHz.

We present a home-built chirped-pulse Fourier transform millimeter wave (CP-FTMMW) spectrometer. The setup is devoted to the sensitive recording of high-resolution molecular spectroscopy in the W band between 75 and 110 GHz. We describe the experimental setup in detail, including a characterization of the chirp excitation source, the optical beam path, and the receiver. The receiver is a further development of our 100 GHz emission spectrometer. The spectrometer is equipped with a pulsed jet expansion and a DC discharge. Spectra of methyl cyanide as well as hydrogen cyanide (HCN) and hydrogen isocyanide (HNC) products from the DC discharge of this molecule are recorded to characterize the performance of the CP-FTMMW instrument. The formation of the HCN isomer is favored by a factor of 63 with respect to HNC. Hot/cold calibration measurements enable a direct comparison of the signal and noise levels of the CP-FTMMW spectra to those of the emission spectrometer. For the CP-FTMMW instrument, we find many orders of magnitude of signal enhancement and a much stronger noise reduction due to the coherent detection scheme.

Sex-Specific Relationship Between Parathyroid Hormone and Platelet Indices in Phenotypes of Heart Failure-Results From the MyoVasc Study.

Background: Heart failure (HF) is a multifactorial syndrome with pathophysiological complexities still not fully understood. Higher mean platelet volume (MPV), a potential marker of platelet activation, and high concentrations of parathyroid hormone (PTH) have been implicated in the pathogenesis of HF. Aim: This study aims to investigate sex-specifically the association between PTH concentrations and platelet indices in phenotypes of HF. Methods and Results: PTH and platelet indices (MPV and platelet count) were available in 1,896 participants from the MyoVasc study in Mainz, Germany. Multivariable linear regression models, adjusted for age, sex, season, vitamin D status, cardiovascular risk factors, comorbidities, estimated glomerular filtration rate, and medication, were used to assess the associations between platelet indices and PTH. The results showed distinct sex-specific associations between PTH and platelet indices. A positive association between PTH and MPV was found in females with symptomatic HF with reduced ejection fraction (HFrEF) only [ß = 0.60 (0.19; 1.00)]. Platelet count was inversely associated with PTH in male HFrEF individuals [ß = -7.6 (-15; -0.30)] and in both males and females with HF with preserved ejection fraction (HFpEF). Conclusion: This study reports differential, sex-specific relationships between PTH and platelet indices in HF individuals independent of vitamin D status and clinical profile. Particularly in phenotypes of symptomatic HF, distinct associations were observed, suggesting a sex-specific mechanism involved in the interaction between PTH and platelets.

A prospective cohort study to identify and evaluate endotypes of venous thromboembolism: Rationale and design of the Genotyping and Molecular Phenotyping in Venous ThromboEmbolism project (GMP-VTE).

Several clinical, genetic and acquired risk factors for venous thromboembolism (VTE) have been identified. However, the molecular pathophysiology and mechanisms of disease progression remain poorly understood. This is reflected by uncertainties regarding the primary and secondary prevention of VTE and the optimal duration of antithrombotic therapy. A growing body of literature points to clinically relevant differences between VTE phenotypes (e.g. deep vein thrombosis (DVT) versus pulmonary embolism (PE), unprovoked versus provoked VTE). Extensive links to cardiovascular, inflammatory and immune-related morbidities are testament to the complexity of the disease. The GMP-VTE project is a prospective, multi-center cohort study on individuals with objectively confirmed VTE. Sequential data sampling was performed at the time of the acute event and during serial follow-up investigations. Various data levels (e.g. clinical, genetic, proteomic and platelet data) are available for multi-dimensional data analyses by means of advanced statistical, bioinformatic and machine learning methods. The GMP-VTE project comprises n = 663 individuals with acute VTE (mean age: 60.3 ±â€¯15.9 years; female sex: 42.8%). In detail, 28.4% individuals (n = 188) had acute isolated DVT, whereas 71.6% subjects (n = 475) had PE with or without concomitant DVT. In the study sample, 28.9% (n = 129) of individuals with PE and 30.1% (n = 55) of individuals with isolated DVT had a recurrent VTE event at the time of study enrolment. The systems-oriented approach for the comprehensive dataset of the GMP-VTE project may generate new biological insights into the pathophysiology of VTE and refine our current understanding and management of VTE.

In Vitro Entero-Capillary Barrier Exhibits Altered Inflammatory and Exosomal Communication Pattern after Exposure to Silica Nanoparticles.

The intestinal microvasculature (iMV) plays multiple pathogenic roles during chronic inflammatory bowel disease (IBD). The iMV acts as a second line of defense and is, among other factors, crucial for the innate immunity in the gut. It is also the therapeutic location in IBD targeting aggravated leukocyte adhesion processes involving ICAM-1 and E-selectin. Specific targeting is stressed via nanoparticulate drug vehicles. Evaluating the iMV in enterocyte barrier models in vitro could shed light on inflammation and barrier-integrity processes during IBD. Therefore, we generated a barrier model by combining the enterocyte cell line Caco-2 with the microvascular endothelial cell line ISO-HAS-1 on opposite sides of a transwell filter-membrane under culture conditions which mimicked the physiological and inflamed conditions of IBD. The IBD model achieved a significant barrier-disruption, demonstrated via transepithelial-electrical resistance (TER), permeability-coefficient (Papp) and increase of sICAM sE-selectin and IL-8. In addition, the impact of a prospective model drug-vehicle (silica nanoparticles, aSNP) on ongoing inflammation was examined. A decrease of sICAM/sE-selectin was observed after aSNP-exposure to the inflamed endothelium. These findings correlated with a decreased secretion of ICAM/E-selectin bearing exosomes/microvesicles, as evaluated via ELISA. Our findings indicate that aSNP treatment of the inflamed endothelium during IBD may hamper exosomal/microvesicular systemic communication.

Resonant inelastic x-ray incarnation of Young's double-slit experiment.

Young's archetypal double-slit experiment forms the basis for modern diffraction techniques: The elastic scattering of waves yields an interference pattern that captures the real-space structure. Here, we report on an inelastic incarnation of Young's experiment and demonstrate that resonant inelastic x-ray scattering (RIXS) measures interference patterns, which reveal the symmetry and character of electronic excited states in the same way as elastic scattering does for the ground state. A prototypical example is provided by the quasi-molecular electronic structure of insulating Ba3CeIr2O9 with structural Ir dimers and strong spin-orbit coupling. The double "slits" in this resonant experiment are the highly localized core levels of the two Ir atoms within a dimer. The clear double-slit-type sinusoidal interference patterns that we observe allow us to characterize the electronic excitations, demonstrating the power of RIXS interferometry to unravel the electronic structure of solids containing, e.g., dimers, trimers, ladders, or other superstructures.

Coagulation and inflammation in long-term cancer survivors: results from the adult population.

Essentials The increase of cancer survival remains curtailed by cardiovascular mortality. We studied a large range of inflammatory and coagulation biomarkers in long-term cancer survivors. Cancer history has an important impact on mortality independent of cardiovascular risk factors. Fibrinogen and von Willebrand factor are potential biomarkers in survivors of increased mortality. SUMMARY: Background The advances in cancer treatment and detection of early cancer have resulted in a steady increase in the number of of cancer survivors over the years. However, because of the long-term toxic effects of chemotherapy and radiotherapy, the incidence of cardiovascular disease (CVD) is increasing in survivors. Objectives To investigate traditional cardiovascular risk factors (CVRFs), inflammation and the coagulation profile in long-term cancer survivors (cancer diagnosis ≥ 5 years) from a large adult population-based study sample. Methods The presence of cardiovascular risk factors (CVRFs) and laboratory markers were compared in individuals with (n = 723) and without (n = 13626) a long-term history of cancer from the Gutenberg Health Study. Data on coagulation factors, D-dimer and von Willebrand factor (VWF) activity were available for 4974 individuals (n = 244 cancer survivors). Results In multivariable regression models, a history of cancer was, independently of CVRFs and CVD, associated with higher fibrinogen levels (ß 6.99, 95% confidence interval [CI] 1.16-12.8), VWF activity (ß 5.08, 95% CI 0.02-10.1), and antithrombin activity (ß 1.85, 95% CI 0.44-3.27). Cancer survivors with CVD showed notably higher VWF activity than individuals with CVD without a history of cancer, with a difference in the means of 23.0 (7.9-38.1). Multivariate Cox regression analysis, adjusted for CVRFs, confirmed that a long-term history of cancer is associated with a 72% higher mortality. Increased mortality in cancer survivors was dependent on fibrinogen level and VWF activity level. Conclusion Cancer survivors showed a worse inflammation and coagulation profile than individuals without a history of cancer. Overall mortality in long-term cancer survivors was increased independently of traditional CVRFs. These results underline the need to further investigate plasma biomarkers as complementary cardiovascular risk predictors in cancer survivors.

Mean Platelet Volume and Arterial Stiffness - Clinical Relationship and Common Genetic Variability.

Vessel wall stiffening is an important clinical parameter, but it is unknown whether platelets, key elements in the pathogenesis of arterial thrombosis, are associated with arterial stiffness. The present studies sought to determine whether mean platelet volume (MPV), a potential marker of platelet activation, is linked to vascular elasticity as assessed by the augmentation index (AIx), in 15,010 individuals from the population-based Gutenberg Health Study. Multivariable analysis showed that MPV in both males (ß 0.776; 95thCI [0.250;1.16]; p = 0.0024) and females (ß 0.881[0.328;1.43]; p = 0.0018) is strongly associated with AIx. Individuals with MPV and AIx above the sex-specific medians had worse survival. Association analysis between MPV-related genetic variants and arterial stiffness identified four genetic variants in males and one in females related with AIx. Cox regression analysis for mortality identified one of these joint genetic variants close to ring finger protein 145 gene (RNF145, rs10076782) linked with increased mortality (hazard ratio 2.02; 95thCI [1.35;3.02]; p = 0.00061). Thus, these population-based data demonstrate a close relation between platelet volume as a potential marker of platelet activation and arterial stiffness in both sexes. Further research is warranted to further elucidate the mechanisms underlying larger platelets' role in arterial stiffening including the role of shared common genetics.

Sex-specific differences in genetic and nongenetic determinants of mean platelet volume: results from the Gutenberg Health Study.

Mean platelet volume (MPV), a measure of platelet size, is a potential biological marker of platelet function. To date, a comprehensive analysis including known genetic and nongenetic factors that determine MPV is still lacking. MPV has been evaluated in 15 010 individuals from the population-based Gutenberg Health Study. Genetic information was available for 4175 individuals. Our results showed that age (ß, 0.0346; 95% confidence interval [CI], 0.0255 to 0.0436), cardiovascular risk factors (CVRFs) such as smoking (ß, 0.178; 95% CI, 0.128 to 0.229), hypertension (ß, 0.05; 95% CI, 0.00289 to .0981), and high glucose level (ß, 0.00179; 95% CI, 0.0006 to 0.00299) were linked with higher MPV in males only. Intake of oral contraceptives (ß, 0.150; 95% CI, 0.0649 to 0.236) and menstruation (ß, 0.123; 95% CI, 0.0231 to 0.224) were strongly associated with higher MPV in females. Seven single nucleotide polymorphisms (SNPs) for females and 4 SNPs for males were associated with higher MPV. The full model, including age, CVRFs, laboratory parameters, medications, and genetic variation, explained 20.4% of the MPV variance in females and 18.6% in males. The curves of cumulative mortality, stratified for sex, showed worse survival for males only with MPV > 9.96 fL vs MPV ≤ 9.96 fL (P < .0001). This study provides evidence for heterogeneity in the profile of determinants for MPV between sexes. The observed interactions between genetic variability, CVRFs, and MPV and its association with the development of cardiovascular disease or thrombotic risk need to be further investigated.

Weyl spin liquids.

The fractionalization of quantum numbers in interacting quantum many-body systems is a central motif in condensed-matter physics with prominent examples including the fractionalization of the electron in quantum Hall liquids or the emergence of magnetic monopoles in spin-ice materials. Here, we discuss the fractionalization of magnetic moments in three-dimensional Kitaev models into Majorana fermions (and a Z_{2} gauge field) and their emergent collective behavior. We analytically demonstrate that the Majorana fermions form a Weyl superconductor for the Kitaev model on the recently synthesized hyperhoneycomb structure of ß-Li_{2}IrO_{3} when applying a magnetic field. We characterize the topologically protected bulk and surface features of this state, which we dub a Weyl spin liquid, including thermodynamic and transport signatures.

Distribution, genetic and cardiovascular determinants of FVIII:c - Data from the population-based Gutenberg Health Study.

BACKGROUND: Elevated levels of FVIII: c are associated with risk for both venous and arterial thromboembolism. However, no population-based study on the sex-specific distribution and reference ranges of plasma FVIII: c and its cardiovascular determinants is available. FVIII: c was analyzed in a randomly selected sample of 2533 males and 2440 females from the Gutenberg Health Study in Germany. Multivariable regression analyses for FVIII: c were performed under adjustment for genetic determinants, cardiovascular risk factors and cardiovascular disease. RESULTS AND CONCLUSIONS: Females (126.6% (95% CI: 125.2/128)) showed higher FVIII: c levels than males (121.2% (119.8/122.7)). FVIII: c levels increased with age in both sexes (ß per decade: 5.67% (4.22/7.13) male, 6.15% (4.72/7.57) female; p<0.001). Sex-specific reference limits and categories indicating the grade of deviation from the reference were calculated, and nomograms for FVIII: c were created. FVIII: c was approximately 25% higher in individuals with non-O blood type. Adjusted for sex and age, ABO-blood group accounted for 18.3% of FVIII: c variation. In multivariable analysis, FVIII: c was notably positively associated with diabetes mellitus, obesity, hypertension and dyslipidemia and negatively with current smoking. In a fully adjusted multivariable model, the strongest associations observed were of elevated FVIII: c with diabetes and peripheral artery disease in both sexes and with obesity in males. Effects of SNPs in the vWF, STAB2 and SCARA5 gene were stronger in females than in males. The use of nomograms for valuation of FVIII: c might be useful to identify high-risk cohorts for thromboembolism. Additionally, the prospective evaluation of FVIII: c as a risk predictor becomes feasible.

LPS-induced effects on angiotensin I-converting enzyme expression and shedding in human pulmonary microvascular endothelial cells.

Angiotensin I-converting enzyme (kininase II, ACE, and CD143) availability is a determinant of local angiotensin and kinin concentrations and their physiological actions. Until now, it is unclear whether the decrease of pulmonary ACE activity in sepsis-described in clinical studies-is due to an enzyme compensatory downregulation (reduced ACE-mRNA expression) to shedding of ACE or endothelial damage. To address these questions, ACE distribution under septic conditions was studied in vitro by treating pulmonary microvascular endothelial cells (HPMEC) and human umbilical vein endothelial cells (HUVEC) with lipopolysaccharide from Escherichia coli (LPS). Primary isolated HUVEC and HPMEC were compared by detecting ACE activity, membrane-bound ACE, as well as shedding and mRNA production of ACE with and without LPS (1 ng/ml-1 µg/ml). ACE mRNA expression was detected by real-time PCR, and shedded ACE was measured in cell culture supernatant by ELISA. Additionally, membrane-bound protein expression was investigated by immunohistochemistry in situ. In septic ARDS, the distribution of ACE protein was significantly reduced in all lung endothelial cells (p<0.001). After stimulation with LPS, cultivated HPMEC showed more markedly than HUVEC, a concentration-dependent reduction of ACE protein expression compared to the respective untreated controls. Real-time PCR demonstrated a reduced ACE mRNA expression after LPS stimulation, predominantly in HPMEC. Specifically, in HPMEC, a concentration-dependent increase of shedded ACE was shown 24 h after LPS treatment. HPMEC cultures are an apt model for the investigation of pulmonary ACE expression in sepsis. This study suggests that reduced pulmonary microvascular endothelial ACE expression in septic ARDS is caused by two processes: (initial) increased shedding of ACE accompanied by a compensatory downregulation of ACE-mRNA and membrane-bound protein expression.

Vascular endothelial cadherin expression in lung specimens of patients with sepsis-induced acute respiratory distress syndrome and endothelial cell cultures.

AIMS: Vascular endothelial (VE) cadherin is a cell adhesion molecule localized at endothelial cell (EC) junctions. As a major component of endothelial adherens junctions, its main function is the maintenance and regulation of EC integrity. In the acute respiratory distress syndrome (ARDS), increased vascular permeability is a major mechanism in pulmonary edema and lung dysfunction. In this study, VE-cadherin expression was investigated in ARDS lungs and control tissue as well as in an ARDS cell culture model. METHODS: Lung specimens of patients with ARDS due to Gram-negative sepsis (n = 20; control lung tissue: n = 41) and cell cultures of human pulmonary microvascular ECs and human umbilical vein ECs stimulated with LPS, TNF-α and IFN-γ were stained with a VE-cadherin antibody. Staining intensity was semiquantitatively evaluated by conventional light and immunofluorescence microscopy. RESULTS: VE-cadherin expression was statistically significantly reduced in the endothelium of all vessel types in ARDS lungs compared to control tissue. Cell cultures showing disrupted cellular borders confirmed these results. CONCLUSION: Reduced expression of VE-cadherin has to be considered as a major mechanism of increased vessel permeability in ARDS. The previously described vessel-type-specific expression pattern of VE-cadherin in the human lung is not influenced by ARDS.

Quality management in the prophylaxis of venous thrombembolism--results of a survey including 464 medical and surgical patients.

BACKGROUND: We surveyed the quality of risk stratification politics and monitored the rate of entries to our company-wide protocol for venous thrombembolism (VTE) prophylaxis in order to identify safety concerns. PATIENTS AND METHODS: Audit in 464 medical and surgical patients to evaluate quality of VTE prophylaxis. RESULTS: Patients were classified as low 146 (31 %), medium 101 (22 %), and high risk cases 217 (47 %). Of these 262 (56.5 %) were treated according to their risk status and in accordance with our protocol, while 9 more patients were treated according to their risk status but off-protocol. Overtreatment was identified in 73 (15.7 %), undertreatment in 120 (25,9 %) of all patients. The rate of incorrect prophylaxis was significantly different between the risk categories, with more patients of the high-risk group receiving inadequate medical prophylaxis (data not shown; p = 0.038). Renal function was analyzed in 392 (84.5 %) patients. In those patients with known renal function 26 (6.6 %) received improper medical prophylaxis. If cases were added in whom prophylaxis was started without previous creatinine control, renal function was not correctly taken into account in 49 (10.6 %) of all patients. Moreover, deterioration of renal function was not excluded within one week in 78 patients (16.8 %) and blood count was not re-checked in 45 (9.7 %) of all patients after one week. There were more overtreatments in surgical (n = 53/278) and more undertreatments in medical patients (n = 54/186) (p = 0.04). Surgeons neglected renal function and blood controls significantly more often than medical doctors (p-values for both < 0.05). CONCLUSIONS: We found a low adherence with our protocol and substantial over- and undertreatment in VTE prophylaxis. Besides, we identified disregarding of renal function and safety laboratory examinations as additional safety concerns. To identify safety problems associated with medical VTE prophylaxis and "hot spots" quality management-audits proved to be valuable instruments.

Condensing non-Abelian quasiparticles.

A most interesting feature of certain fractional quantum Hall states is that their quasiparticles obey non-Abelian fractional statistics. So far, candidate non-Abelian wave functions have been constructed from conformal blocks in cleverly chosen conformal field theories. In this work we present a hierarchy scheme by which we can construct daughter states by condensing non-Abelian quasiparticles (as opposed to quasiholes) in a parent state, and show that the daughters have a non-Abelian statistics that differs from the parent. In particular, we discuss the daughter of the bosonic, spin-polarized Moore-Read state at nu=4/3 as an explicit example.

Hyperbranched PEG by random copolymerization of ethylene oxide and glycidol.

The synthesis of hyperbranched poly(ethylene glycol) (hbPEG) in one step was realized by random copolymerization of ethylene oxide and glycidol, leading to a biocompatible, amorphous material with multiple hydroxyl functionalities. A series of copolymers with moderate polydispersity ($\overline {M} _{{\rm w}} /\overline {M} _{{\rm n}} $ < 1.8) was obtained with varying glycidol content (3-40 mol-%) and molecular weights up to 49 800 g mol(-1) . The randomly branched structure of the copolymers was confirmed by (1) H and (13) C NMR spectroscopy and thermal analysis (differential scanning calorimetry). MTS assay demonstrated low cell toxicity of the hyperbranched PEG, comparable to the highly established linear PEG.

Acute cytotoxicity and apoptotic effects after l-Pam exposure in different cocultures of the proximal and distal respiratory system.

Sulphur and nitrogen mustard are strong alkylating agents which can cause after inhalation acute lung injury in the larynx, trachea and large bronchi and can lead to alveolar edema. In our study we tested the N-Lost l-Phenylalanine Mustard (l-Pam). Therefore we seeded the alveolar type II cell line NCI H441 on the upper membrane of a Transwell filter plate and the endothelial cell line ISO-Has-1 on the lower side of the membrane for the alveolar model and combined the human bronchial explant-outgrowth cells and fibroblasts in the bronchial model and exposed both models with various concentrations of l-Pam. Treatment with l-Pam led to a concentration-dependent decrease of the transepithelial electrical resistance and therefore impairment of barrier function in both models. Changes in morphology could be observed. In the bronchial model damaged cell organelles whereas in the alveolar model a widening of intercellular spaces could be seen. Loss of cell-matrix adhesion as well as apoptotic and necrotic cell death could be demonstrated. In conclusion, treatment with the nitrogen mustard in the coculture models showed comparable results to sulphur mustard treatment and thus this model could be useful to explore similarities and differences in signal transduction pathways after treatment with both sulphur and nitrogen mustard.

Acute morphological and toxicological effects in a human bronchial coculture model after sulfur mustard exposure.

Sulfur mustard (SM) is a strong alkylating agent. Inhalation of SM causes acute lung injury accompanied by severe disruption of the airway barrier. In our study, we tested the acute effects after mustard exposure in an in vitro coculture bronchial model of the proximal barrier. To achieve this, we seeded normal human bronchial epithelial explant-outgrowth cells (HBEC) together with lung fibroblasts as a bilayer on filter plates and exposed the bronchial model after 31 days of differentiation to various concentrations of SM (30, 100, 300, and 500 microM). The HBEC formed confluent layers, expressing functional tight junctions as measured by transepithelial electrical resistance (TER). Mucus production and cilia formation reappeared in the coculture model. TER was measured after 2 and 24 h following treatment. Depending on the different concentrations, TER decreased in the first 2 h up to 55% of the control at the highest concentration. After 24 h, TER seemed to recover because at concentrations up to 300 microM values were equal to the control. SM induced a widening of intercellular spaces and a loss in cell-matrix adhesion. Mucus production increased with the result that cilia ceased to beat. Changes in the proinflammatory cytokines interleukin (IL)-6 and IL-8 were also observed. Apoptotic markers such as cytochrome c, p53, Fas-associated protein with death domain, and procaspase-3 were significantly induced at concentrations of less than 100 microM. In summary, SM induces morphological and biochemical changes that reflect pathological effects of SM injury in vivo. It is hoped to use this coculture model to understand further the pathogenesis of SM-induced barrier injury and to search for novel approaches in SM therapy.