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Background The Pipeline embolization device (PED) has expanded the range of aneurysms amenable to endovascular treatment, including some that were previously untreatable. The PED contains several metals, including nickel, cobalt, chromium, platinum, and tungsten. The safety of PED implantation in patients with cutaneous metal allergy is unknown. The aim of this study was to assess clinical and angiographic outcomes of PED treatment in patients with cutaneous metal allergy. Methods A single-institution neurointerventional database was retrospectively reviewed for patients with documented cutaneous metal allergy who were treated with the PED. Patient, aneurysm, and procedural data were collected, including perioperative and delayed complications. Posttreatment angiograms were reviewed for in-Pipeline stenosis and aneurysm occlusion. Results Twenty patients with metal allergy underwent 23 PED treatments for 26 aneurysms. The cohort was 95% (19/20) female; mean age was 55.7 years. Aneurysms were primarily anterior circulation (92%, 24/26) and saccular (92%; 24/26); mean size was 8.8 mm (range, 2–32 mm). One PED was implanted in 70% (14/20) of patients, 25% (5/20) had 2 devices placed, and 1 patient had 3 devices. One major procedural complication occurred (4.3%, 1/23) in which a stroke was caused by perioperative PED thrombosis. Angiographic follow-up was available for all patients (mean duration 15.7 months; range, 6–64 months), which demonstrated a complete aneurysm occlusion rate of 88% (23/26). Asymptomatic in-Pipeline stenosis occurred in 2 cases, resulting in 65% and 50% parent artery stenosis, respectively. Conclusions Preliminary results suggest that PED implantation in patients with cutaneous metal allergy is safe and effective.

Studies concerning quantities of microplastics (MP) including tire wear particles (TWP) contamination in air samples are scarce. Spider webs have been suggested as a cheap and easily accessible biomonitor particularly for inorganic contaminates. Here, we emphasize the potential of spider webs to gain insights in the spatial and temporal trends of MP in urban air. The samples, collected in a mid-sized German city, were processed with Fentons reagent and measured using pyrolysis-gas chromatography-mass spectrometry for specific, polymer related indicator compounds. All samples contained TWP and other MP. The latter are detected and quantified as pyrolysis products of a polymer backbone. The results were expressed as clusters (prefix "C"). Determined polymer contaminations ranged from 11.4 μg/mg to 108 μg/mg spider web sample. The dominant polymer was C-PET (Ø 36.0% of total MP) derived most likely from textile fibers. Additionally, there was evidence for traffic-related contaminations. In particular car tire tread (Ø 40.8% of total MP) and

Microplastics (MP) are ubiquitous throughout the environment as a result of an ongoing, increasing, but also lavish use, of plastics over time and its inherent persistence. In contrast, there are almost no data that allow drawing conclusions about the evolution of plastic pollution in the environment over the past decades. This study investigates the MP load in blue mussels from the North and Baltic Sea archived by the German Environmental Specimen Bank in a time series covering almost 30 years. Samples were enzymatically and chemically oxidative digested for MP extraction and subsequent analyzed mass-quantitatively for nine common polymer clusters by pyrolysis gas chromatography-mass spectrometry. Seven polymer clusters were detected in mussel tissue. Summed MP levels were at ppm levels (

The Scepter XC balloon catheter can be used for balloon-assisted coiling (BAC) of cerebral aneurysms but also accommodates delivery of a low-profile visible intraluminal stent (LVIS Jr.). We assessed the safety and effectiveness of BAC using the Scepter XC, with LVIS Jr. stent-assisted coiling (SAC) as a bailout option.A single-institution prospectively maintained neurointerventional database was reviewed for wide-necked (neck width ≥4 mm or dome/neck ratio2) saccular aneurysms treated using the Scepter XC. Complication and angiographic occlusion rates of BAC and SAC procedures were compared. Multivariate logistic regression was used to identify variables predictive of complete aneurysm occlusion.The cohort included 141 wide-necked saccular intracranial aneurysms treated in 135 procedures. SAC was used to treat 30% of aneurysms by deploying the LVIS Jr. through the Scepter XC. The overall procedural complication rate was 8.9%, including a 1.5% rate of symptomatic thromboembolic events and 3.0% rate of hemorrhagic complications, with no significant differences in complications between BAC and SAC procedures (P = 0.27). The overall complete or near-complete aneurysm occlusion rate was 96%, with trends toward higher complete aneurysm occlusion and lower retreatment rates with SAC (78 vs. 57%; P = 0.13; 0 vs. 8.4%, P = 0.13). Multivariate logistic regression identified aneurysm size, procedure technique (BAC or SAC), and duration of follow-up as independent predictors of complete aneurysm occlusion.Use of the Scepter XC for BAC, with LVIS Jr. SAC as a bailout option, shows acceptable angiographic and clinical results.

Microplastics (MP) have been recorded in various environments around the globe. For a better understanding of distribution patterns and for providing a basis for risk assessments, detailed data on MP concentrations and polymer compositions are required. This study investigated the effluents of two German wastewater treatment plants (WWTP) monthly over one year, in order to better understand their temporal input of MP into the receiving river systems. MP item data down to 11 μm were obtained by means of Fourier Transform Infrared (FTIR) spectroscopy under the application of an improved polymer database. Complementary mass data were obtained by pyrolysis gas chromatography-mass spectrometry (Py-GC/MS) (for one WWTP). Both FTIR and Py-GC/MS analysis revealed a homogeneous polymer composition over the year, with a general dominance of polyolefins. Elevated MP item and mass concentrations (maximum: 3 × 10

The aim of this study was to evaluate the possibility of predicting boar taint in live pigs non-invasively. For this, different magnetic resonance imaging based body composition traits (including testis volume) were compared with androstenone, skatole, and indole levels (ng/g fat) of the carcass` fat tissue after slaughtering. Additionally, in order to find traits which could help in predicting boar taint, the related sensory test results were included in the analysis. A number of 34 entire boars (EB) and 34 immunocastrated boars (IB; first injection at an age of 77 ± 1 days and second injection at an age of 137 ± 1 days) were scanned two times during growth (at 60 and 90 kg live body weight) using magnetic resonance imaging (MRI). Three body regions (shoulder, loin, and ham) were examined. Additionally the testes volume was calculated. After slaughtering, boar taint samples were taken for olfactory testing and stable isotope dilution assays. These data were compared with selected body composition traits in order to analyze the relationship between MRI traits and boar taint. The results showed that IB tend to have greater subcutaneous fat layers (belly fat, shoulder fat, back fat) than EB. Within EB, larger testis volumes and a higher amount of body fat (especially belly fat) are associated with a higher level of androstenone.

A B S T R A C T Purpose: The dynamic intraligamentary stabilization (DIS) technique is based on a different treatment approach than ACL reconstruction in that it intends to promote self-healing of the ligament. It is only recommended for acute injuries (

Tire wear particles (TWP) are assumed to be the most dominant source of environmental microplastics (MP). Besides rubber components around 60% of tires are additives such as filling material and various chemicals added for vulcanization. The inevitably released TWP in daily traffic are therefore considered a threat to the ecosystem. Nevertheless, published studies on MP mass loads often exclude elastomers. Data concerning composition and concentrations of TWP compared to prominent “traditional” MP polymers, such as polyethylene, polypropylene, poly(ethylene terephthalate) and poly(vinyl chloride), are missing. Identification and quantification of TWP was implemented in an existing pyrolysis-gas chromatography–mass spectrometry (Py-GC/MS) method for MP determination. An approach to differentiate between car and truck tire wear and to quantify their respective mass loads is presented. Complex environmental samples such as road dust, fresh water and marine sediments, blue mussels, and marine salts were partly retrospectively analyzed using Py-GC/MS. The results showed ratios of car to truck tire wear up to 16 to 1 and underline the dominance of car compared to truck tire wear mass loads in all analyzed samples. Even though some retrospective data sets might be affected by suboptimal density separation conditions (NaBr, ρ = 1.5 g/cm3), TWP concentrations in road dust clearly exceeded those of “traditional” MP (O 5 g TWP vs 0.3 g MP per kg road dust (dry weight). Samples included in this study, which were archived further away from TWP sources such as roads, reflected decreasing TWP concentrations (O 24 μg TWP vs. 107 μg MP per kg sediment (dry weight); O 126 μg TWP vs. 378 μg MP per kg marine salt) or were no longer present (blue mussels), while “traditional” polymers were still ubiquitously distributed.

Anaerobic biodegradation of hydrocarbons mainly related to petroleum can be observed in numerous natural and anthropogenically overprinted environments. While microbiological and chemical tracers are used to study the development of such habitats, not much is known about the impact of particular bacteria on the system. Therefore, we used Aromatoleum sp. HxN1, an n-alkane-utilizing betaproteobacterium capable of degrading crude oil constituents under strictly anoxic conditions, as a model organism to examine its potential to release carboxylic acid metabolites into the surrounding environment. We conducted cultivation experiments with pure substrates, as well as with crude oil, and demonstrated that intermediates of catabolic pathways were highly abundant in the exometabolome. Strikingly, the metabolites found in highest concentrations in the cell-free culture supernatant of strain HxN1 grown with crude oil were associated with the transformation of potentially toxic aromatic hydrocarbons, which do not support growth of this particular bacterium. Additionally, a deficiency in coenzyme A caused by a highly productive substrate transformation may induce the excretion of a surplus of metabolites in order to regain coenzyme A. Under natural conditions, i.e., in the presence of mixed communities, such transformation products may be further degraded by other organisms, ultimately leading to mineralization.

Keratinocytes are central to the barrier functions of surface epithelia, such as the gingiva and epidermis. RIPK4 is a key regulator of keratinocyte differentiation; however, the signalling pathways in which it functions remain poorly defined. In this study, we identified a regulatory relationship between RIPK4 and ELF3, an ETS family transcription factor. RIPK4 was shown to be important for the upregulation of ELF3 gene expression by the PKC agonist PMA in both oral and epidermal keratinocytes. RIPK4 promotes keratinocyte differentiation in part by phosphorylating and thereby activating the IRF6 transcription factor. Significantly, silencing of IRF6 inhibited the PMA-inducible expression of ELF3. A role for the GRHL3 transcription factor, a downstream target gene of IRF6, in the regulation of ELF3 expression was similarly demonstrated. ELF3 has previously been shown to regulate the expression of SPPR1A and SPRR1B, small proline-rich proteins that contribute to the cornification of keratinocytes. Consistently, RIPK4 and IRF6 were important for the PMA-inducible expression of SPRR1A and SPRR1B. They were also important for the upregulation of TGM1, a transglutaminase that catalyses the cross-linking of proteins, including small proline-rich proteins, during keratinocyte cornification. RIPK4 was also shown to upregulate the expression of TGM2 independently of IRF6. Collectively, our findings position RIPK4 upstream of a hierarchal IRF6-GRHL3-ELF3 transcription factor pathway in keratinocytes, as well as provide insight into a potential role for RIPK4 in the regulation of keratinocyte cornification.

Keratinocytes of the oral mucosa and epidermis play key roles in host defense. In addition to functioning as a physical barrier, they also produce cytokines to elicit inflammation in response to infection or injury. We recently established that receptor-interacting protein kinase 4 (RIPK4) and interferon regulatory factor 6 (IRF6) function as a cell-intrinsic signaling axis to regulate keratinocyte differentiation. In this study, we have demonstrated a functional relationship between RIPK4 and IRF6 in the control of proinflammatory cytokine expression in keratinocytes. The overexpression of RIPK4 by oral keratinocytes induced the strong expression of CCL5 and CXCL11. In contrast, the expression of other cytokines (e.g. IL8 and TNF) was largely unaffected, thus demonstrating specificity in the induction of proinflammatory cytokine expression by RIPK4. CCL5 and CXCL11 expression were also induced in response to the activation of the PKC pathway, and gene silencing experiments indicated that their inducible expression was dependent on RIPK4 and IRF6. Moreover, gene reporter assays suggested that RIPK4 induces CCL5 and CXCL11 expression by stimulating the transactivation of their promoters by IRF6. Accordingly, our findings suggest that the RIPK4-IRF6 signaling axis plays a multifaceted role in barrier epithelial homeostasis through its regulation of both keratinocyte inflammation and differentiation.

Background The pathophysiology of delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage (aSAH) may include platelet activation and microthrombi formation. Antiplatelet therapy may reduce the incidence of DCI and improve clinical outcomes after aSAH. This study compared outcomes among aSAH patients receiving aspirin monotherapy versus dual antiplatelet therapy (DAPT). Methods Aneurysmal subarachnoid hemorrhage patients treated at a single institution between November 2011 and December 2017 were divided according to whether they received aspirin monotherapy or DAPT after endovascular treatment. Baseline characteristics and outcomes of the groups were compared, including incidences of delayed cerebral ischemia, bleeding complications, symptomatic vasospasm, in-hospital mortality, and functional status 6 months after discharge. Results During the study period, 142 patients met study inclusion criteria, of which 123 were treated with aspirin monotherapy (87 %) and 19 were treated with DAPT (13 %). There was no statistically significant difference between the aspirin monotherapy and DAPT groups with respect to incidences of delayed cerebral ischemia (4.9 vs 10.5 %; p = 0.32), symptomatic vasospasm (13.0 vs 15.8 %; p = 0.74), or good clinical outcome at 6-month follow up (73.3 vs 66.7 %; p = 0.56). The DAPT group experienced a higher incidence of in-hospital mortality (21 vs 5.7 %; p = 0.02), but DAPT did not remain independently predictive of this outcome on regression analysis. There was a trend toward a higher bleeding complication rate in the DAPT group (0.8 vs 5.3 %; p = 0.13). Conclusions DAPT does not reduce the incidence of DCI or improve outcomes in aSAH patients, and may increase the risk of clinically significant bleeding complications.

Four common consumer plastic samples (polyethylene, polystyrene, polyethylene terephthalate, polyvinylchloride) were studied to investigate the impact of physical parameters such as turbulence, salinity and UV irradiance on leaching behavior of selected plastic components. Polymers were exposed to two different salinities (i.e. 0 and 35 g/kg), UV radiation and turbulence. Additives (e.g. bisphenol A, phthalates, citrates, and Irgafos® 168 phosphate) and oligomers were detected in initial plastics and aqueous extracts. Identification and quantification was performed by GC-FID/MS. Bisphenol A and citrate based additives are leached easier compared to phthalates. The print highly contributed to the chemical burden of the analyzed polyethylene bag. The study underlines a positive relationship between turbulence and magnitude of leaching. Salinity had a minor impact that differs for each analyte. Global annual release of additives from assessed plastics into marine environments is estimated to be between 35 and 917 tons, of which most are derived from plasticized polyvinylchloride.

Ultrahigh spectral brightness femtosecond XUV and X-ray sources like free electron lasers (FEL) and table-top high harmonics sources (HHG) offer fascinating experimental possibilities for analysis of transient states and ultrafast electron dynamics. For electron spectroscopy experiments using illumination from such sources, the ultrashort high-charge electron bunches experience strong space–charge interactions. The Coulomb interactions between emitted electrons results in large energy shifts and severe broadening of photoemission signals. We propose a method for a substantial reduction of the effect by exploiting the deterministic nature of space–charge interaction. The interaction of a given electron with the average charge density of all surrounding electrons leads to a rotation of the electron distribution in 6D phase space. Momentum microscopy gives direct access to the three momentum coordinates, opening a path for a correction of an essential part of space–charge interaction. In a first experiment with a time-of-flight momentum microscope using synchrotron radiation at BESSY, the rotation in phase space became directly visible. In a separate experiment conducted at FLASH (DESY), the energy shift and broadening of the photoemission signals were quantified. Finally, simulations of a realistic photoemission experiment including space–charge interaction reveals that a gain of an order of magnitude in resolution is possible using the correction technique presented here.

The objective of this study was to investigate non-invasive imaging methods to update the used regression equation for stationary tested boars. A total of 94 boars were examined. 20 boars were dissected to provide the reference LMP. Performance data (PD) from right carcasses were available from all groups. The left carcasses were studied by MRI & DXA. Based on the reference LMP and the MRI & DXA data, regression equations for LMP were developed. The estimates for LMP based on MRI & DXA data were used to calculate new regression equations for entire male carcass halves based on linear PD. Further 33 PD sets served as independent sample, which was included in a Monte Carlo simulation for imputing the missing reference LMPs (n=74) and discussing the accuracy of the results. The LMP regression equation based on the combined MRI & DXA data is as accurate as the former regression equation, but needs only three instead of seven variables.

Background Although a relationship between elevated triglycerides (TG) and cardiovascular diseases is generally accepted, its extent is still discussed. This retrospective study analyzed the incidence of cardiovascular events (CVE) and pancreatitis as well as the therapeutic regimen in patients being treated for hypertriglyceridemia (HTG) at an outpatient department. Methods The cohort included 183 patients with mild and 49 patients with severe HTG; subgroups were formed and compared according to gender, presence of metabolic vascular syndrome (MVS) and lipid values. Results Patients in this study seem to have had CVE at younger age than reported event rates in the general population. TG levels, rates of CVE and pancreatitis were reduced in all groups during therapy, which could be linked to use of omega-3 fatty acids and fibrates. Patients with persisting severe HTG as a result of incompliance showed massive risk for pancreatitis. Conclusion Although no significant association between TG levels and CVE could be established, the combination of HTG and other cardiovascular risk factors such as MVS seems to be especially dangerous. The lipid-lowering drug therapy appeared to be effective with respect to CVE and pancreatitis incidence.

Objective: To determine whether functional capacity evaluation (FCE) tests predict future work capacity (WC) of patients with whiplash-associated disorders (WADs) grades I and II who did not regain full WC 6 to 12 weeks after injury.Design: Prospective cohort study.Setting: Rehabilitation center.Participants: Workers (N=267) listed on workers' compensation with grade I or El WADs 6 to 12 weeks after injury.Interventions: Patients performed 8 work-related FCE tests.Main Outcome Measures: WC (0-100%) measured at baseline and 1, 3, 6, and 12 months after testing. Correlation coefficients between FCE tests and WC were calculated. A linear mixed-model analysis was used to assess the association between FCE and future WC.Results: Mean +/- SD WC increased over time from 20.8%+/- 27.6% at baseline to 32.3%+/- 38.4%, 51.3%+/- 42.8%, 65.6%+/- 42.2%, and 83.2%+/- 35.0% at the 1-, 3-, 6-, and 12-month follow-ups, respectively. Correlation coefficients between FCE tests and WC ranged from r=.06 (lifting low at 12-mo follow-up) to r=.39 (walking speed at 3mo). Strength of the correlations decreased over time. FCE tests did not predict WC at follow-up. The predictors of WC were ln (time) (beta=23.74), mother language (beta=5.49), WC at baseline (beta=1.01), and self-reported disability (beta=-.20). Two interaction terms, ln (time) x WC (beta=-.19) and ln (time) x self-reported disability (beta=-.21), were significant predictors of WC.Conclusions: FCE tests performed within 6 to 12 weeks after WADs injury grades I and II are associated with WC at baseline but do not predict future WC, whereas time course, mother language, WC at baseline, and self-reported disability do predict future WC. Additionally, the interaction between time course WC at baseline and self-reported disability predicted future WC. (C) 2014 by the American Congress of Rehabilitation Medicine

Plastic waste is continuously introduced not only into marine, but also freshwater environments, where it fragments into microplastics. Organisms may be affected by the particles themselves due to ingestion and indirectly via incorporated additives such as plasticizers, since these substances have the ability to leach out of the polymer matrix. Although it has been indicated that the likelihood of additives leaching out into the gut lumen of organisms exposed to microplastics is low, studies distinguishing between the effects of the synthetic polymer itself and incorporated additives of the same polymer are scarce. Since this is obligatory for risk assessment, we analyzed the chronic effects of flexible polyvinylchloride (PVC), a widely used polymer, containing the plasticizer diisononylphthalate (DiNP) on morphology and life history of the freshwater crustacean Daphnia magna and compared these effects with the effects of rigid PVC, lacking DiNP, as well as a glass bead control. After up to 31 days of exposure, rigid PVC and glass beads did not affect body length and relative tail spine length of D. magna, whereas flexible PVC led to an increased body length and a reduced number of offspring. None of the treatments increased the mortality significantly. We were able to show that 2.67μg/L DiNP leached out of the flexible PVC into the surrounding medium using GC-MS. Yet, we were not able to measure leachate inside the gut lumen of D. magna. The effects emerged towards the end of the experiment, due to the time dependent process of leaching. Therefore, the results highlight the relevance of long-term chronic exposure experiments, especially as leaching of additives takes time. Further, our study shows the importance to distinguish between microplastics containing leachable additives and the raw polymer in ecotoxicological testing.

Microplastics (MP) are an omnipresent marine contaminant. Mass related MP data facilitate interregional and/or temporal comparisons of MP loads in various environmental compartments. Pyrolysis-gas chromatography-mass spectrometry (Py-GC/MS) provided mass and type classification of MP for nine environmentally common polymers at trace levels. Applied to 17 commercial Atlantic and Mediterranean marine salt samples all targeted polymers were detected at least once. Polypropylene and poly(ethylene terephthalate) (both in 16 of the 17 samples), polyethylene (15/17), polystyrene (13/17) and poly(vinyl chloride) (7/17) were those most frequently found. Total MP content of Fleur de Sel (FdS) (138–1993 μg/kg) exceeded that of sea salt (14–60 μg/kg) considerably, due to different harvesting conditions. Disposable packaging and textile fibers are supposed to be the most prominent sources. Regional patterns of MP compositions are distinguished and enable mapping for further targeted source related studies. MP in FdS reflects the MP mass load of corresponding coastal waters and provides its temporal/spatial investigation.

Background. Acute cardiogenic shock is associated with high mortality rates. Mechanical circulatory devices have been increasingly used in this setting for hemodynamic support. The Impella device (Abiomed Inc, Danvers, MA) is a microaxial left ventricular assist device that can be inserted using a less invasive technique. This study was conducted to determine the outcome of patients who have undergone placement of the Impella device for acute cardiogenic shock in our institution. Methods. A retrospective record review of 47 patients who underwent placement of the Impella device was performed from January 1, 2006, to December 31, 2011. Records were evaluated for demographics, operative details, and postoperative outcomes. Operative mortality was defined as death within 30 days of the operation. Results. The patients (33 male) were an average age of 60.23 ±13 years. The indication for placement of the Impella device included cardiogenic shock in 15 patients (32%) and postcardiotomy cardiogenic shock in 32 (68%). Of the 47 patients, 38 (80%) received the Impella 5.0 and the rest the 2.5 device. Ventricular function recovered in 34 of 47 patients (72%), and the device was removed, with 4 patients (8%) transitioned to long-term ventricular assist devices. The 30-day mortality was 25% (12 of 47 patients). Complications occurred in 14 patients (30%), consisting of device malfunction, high purge pressures, tube fracture, and groin hematoma. Conclusions. This is one of the largest series of patients undergoing placement of the Impella device for acute cardiogenicshock.Ouroutcomesshowed improved results compared with historical data. Myocardial recovery was accomplished in most patients. Finally, the 30-day mortality and complication rate was acceptable in these critical patients. These benefits were all achieved with the Impella device in a less invasive method.

The drug ‘‘mumia vera’’ has a long tradition in ancient medicine. It was considered an omnipotent panacea for a broad spectrum of diseases based on virtue associated with asphalt and other bituminous substances combined with the belief in the magic healing power of death. This made it a precious ingredient of medication and it represents a particular facet of medicinal cannibalism. ‘‘Mumia’’ was a common, and much sought after, component of pharmacists’ stock in trade, particularly in the Middle Ages. A shortage of sources for authentic mummies from Egypt resulted in the production of fakes, including dried human bodies. A rare tiny residue in a historic 18th century pharmaceutical vessel labelled MUMIA was microscopically subsampled and analysed with Curie point pyrolysis–gas chromatography–mass spectrometry (CP-py-GC–MS) and GC–MS. From the data (e.g. fatty acids, terpenes, triterpenoids, n-alkanes, n-alkenes, wax esters) there is strong evidence that the vessel contained authentic mummy material. All subsamples could be put into a logical context of the mummification process and its product, i.e. fibres from bandages, wrappings or filling material, conifer wood fibres as a possible part of cover material, ‘‘used’’ embalming material in the form of a mixture of cedrium, pistachia resin (possibly Chios turpentine) and beeswax, (hydrolysed) fat (evidently including human sebum, possibly adipocere), mummified skin or tissue (possibly treated with polyunsaturated plant oil, highly oxidised by the time of analysis) and Dead Sea asphalt with a possible admixture of some asphalt from a different source.

Two successive degradation steps involving Na 2 Cr 2 O 7 /AcOH and RuO 4 were carried out on a Type II-S kerogen from the Miocene Monterey Formation (California) after pre-saponification of the ester bonds by KOH/MeOH treatment. Detailed gas chromatography (GC) and gas chromatography–mass spectrometry (GC–MS) analysis of the soluble acids revealed significant qualitative and quantitative variation of the various types of products obtained from the two different degradation steps. Maleimides (lH-pyrrole-2,5-diones), dominated by Me,Et-maleimide, were the major degradation products released by Na 2 Cr 2 O 7 /AcOH oxidation indicating that their precursors, probably tetrapyrrole pigments, occur ether- as well as sulfur-bound in the kerogen. On the other hand, a scarcely reported homologous series of 2-methyl- n -alkanoic acids (C 8 –C 27 ) was identified as the most prominent series of carboxylic acids obtained after RuO 4 oxidation. The results support the high specificity of the RuO 4 oxidation method in revealing information on the nature of the alkyl chains substituting the aromatic moieties in the kerogen structure and point to the presence of aryl–alkyl ether groups in the kerogen. The significance of the lipid composition of the kerogen is further discussed in terms of biomarker information and their original attachment to the macromolecular structure.

Colony stimulating factor-1 (CSF-1) mediates its pleiotropic effects on macrophages through the CSF-1 receptor (CSF-1R), a receptor tyrosine kinase. Current models of CSF-1 signalling imply that the CSF-1R activates signalling pathways exclusively at the plasma membrane and the subsequent internalisation of the CSF-1R simply facilitates its lysosomal degradation in order to prevent on-going signalling. Here, we sought to establish if the CSF-1R may in fact continue to signal following its internalisation. Erk1/2, Akt and Stat3 activation were abrogated when the internalisation of the CSF-1R was impaired, with the effects on Stat3 distinct from those for Erk1/2 and Akt. Pharmacologic inhibition of the CSF-1R following its internalisation resulted in less sustained Erk1/2 and Akt activity, whereas Stat3 activity was unaffected. Significantly, the suppressive effects of the CSF-1R inhibitor on the up-regulation of gene expression by CSF-1 (e.g. cyclin D1 and Bcl-xL gene expression) were comparable irrespective of whether the inhibitor was added prior to CSF-1 stimulation or following the internalisation of the CSF-1R. Similarly, pharmacologic inhibition of Erk1/2 (or Akt) activity either prior to CSF-1 stimulation or subsequent to CSF-1R internalisation had comparable effects on the regulation of gene expression by CSF-1. Together, our data argue that key signalling responses to CSF-1 depend on the ability of the CSF-1R to signal from endosomes following its internalisation, thus adding an important spatiotemporal aspect to CSF-1R signalling.

Ruthenium tetroxide oxidation was applied to sulfur-rich kerogens from the Nordlinger Ries, southern Germany, to provide complementary structural information about the nature of alkyl substituents attached to aromatic moieties. The oxidation products contained series of straight-chain monocarboxylic acids (C8–C29), α,ω-dicarboxylic acids (C7–C26), isoprenoid acids (C14–C21, except C18), non-isoprenoid branched acids (mainly iso and anteiso C11–C18 acids), 3β-carboxysteroids (C28–C31) and steroid ketones (C27–C30). Furthermore, 4-hydroxy-4,8,12,16-tetramethylheptadecanoic acid γ-lactone, 6,10,14-trimethylpentadecan-2-one, and 10-oxo-n-octadecanoic acid were identified. The oxidation products are discussed in terms of their original contribution to the macromolecular structure. The results support previous suggestions that alkyl–aryl ether groups are present in the kerogen, probably as a result of O-alkylation between phenols and aliphatic precursors. Of particular interest, however, is the identification of a predominant homologous series of 2-methyl n-alkanoic acid methyl esters (C9–C28) in one of the samples. The release of this scarcely reported series of branched acids points toward the specificity of RuO4 oxidation revealing structural information on the alkyl chains substituting the aromatic moieties in the kerogen structure, and implies that some of the bound lipids were contributed by sulfate-reducing bacteria.

Thevetia cardiac glycosides can lead to intoxication, thus they are important indicators for forensic and pharmacologic surveys. Six thevetia cardiac glycosides, including two with unknown structures, were isolated from the seeds of the Yellow Oleander (Thevetia peruviana (Pers.) K. Shum., Apocynaceae). LC-ESI⁺-MS(/MS) analysis under high-resolution conditions used as a qualitative survey of the primary glycosides did not lead to fragmentation of the aglycones. Acid hydrolysis of the polar and non-volatile thevetia glycosides under severe conditions yielded the aglycones of the thevetia glycosides and made them amenable to GC-MS analysis. Comparison of mass spectral fragmentation patterns of the aglycones, as well as high-resolution mass spectrometric and NMR data of four of the primary thevetia glycosides including the two unknowns, revealed the structures of the complete set of six thevetia glycosides. The identified compounds are termed thevetin C and acetylthevetin C and differ by an 18,20-oxido-20,22-dihydro functionality from thevetin B and acetylthevetin B, respectively. The absence of an unsaturated lactone ring renders the glycosides cardio-inactive. The procedures developed in this study and the sets of analytical data obtained will be useful for screening and structure assessment of other, particularly polar, cardiac glycosides.

The improvement of carcass quality is one of the main breeding goals in pig production. To select appropriate breeding animals, it is of major concern to exactly and reliably analyze the body composition in vivo . Therefore, the objective of the study was to examine whether the combination of dual-energy X-ray absorptiometry (DXA) and magnetic resonance imaging (MRI) offers the opportunity to reliably analyze quantitative and qualitative body composition characteristics of different pig breeding groups in vivo . In this study, a total of 77 pigs were studied by DXA and MRI at an average age of 154 days. The pigs originated from different autochthonous or conventional breeds or crossbreeds and were grouped into six breed types: Cerdo Iberico (Ib); Duroc × Ib (Du_Ib); White Sow Lines (WSL, including German Landrace and German Large White); Hampshire/Pietrain (Pi_Ha, including Hampshire, Pietrain × Hampshire (PiHa) and Pietrain × PiHa); Pietrain/Duroc (Pi_Du, including Pietrain × Duroc (PiDu) and Pietrain × PiDu); crossbred WSL (PiDu_WSL, including Pietrain × WSL and PiDu × WSL). A whole-body scan was performed by DXA with a GE Lunar DPX-IQ in order to measure the amount and percentage of fat tissue (FM; %FM), lean tissue (LM; %LM) and bone mineral, whereas a Siemens Magnetom Open with a large body coil was used for MRI in the thorax region between 13th and 14th vertebrae in order to measure the area of the loin (LA) and the above back fat area (FA) of both body sides. A GLM procedure using SAS 9.2 was used to analyze the data. As expected, the native breed Ib followed by Du_Ib crossbreeds showed the highest %FM (27.2%, 25.0%) combined with the smallest LA (46.2 cm 2 , 73.6 cm 2 ), whereas Ib had the lowest BW at an average age of 154 days. Pigs with Pi_Ha origin presented the least %FM (12.4%) and largest LA (99.5 cm 2 ). The WSL and PiDu_WSL showed an intermediate body composition. Therefore, it could be concluded that DXA and MRI and especially their combination are very suitable methods to reliably identify differences in body composition and carcass traits among different pig lines in vivo .

The neutron diagnostics in tokamaks like Joint European Torus (JET) are essential in estimating fusion power. The neutron activation method, supported by neutron transport calculations, is particularly useful for the evaluation of the total neutron yield from a single plasma discharge. This paper presents the results of activation experiments and calculations carried out for JET plasmas, from the selection of the activation materials to their irradiations in the neutron field of JET discharges. Neutron transport calculations were performed, leading to activation coefficients for new materials. The results of the calculations were used to design new composite samples to obtain information on both the yield and the neutron spectrum. The neutron measurements using these new activation materials were performed during the last JET experimental campaigns. The results are compared with neutron transport calculations. Additionally, application of the cadmium difference method allows revelation of the part of thermal neutrons near the tokamak first wall. The advantages of new activation materials and benchmarking the activation method against neutron transport calculations are also discussed.

Mangroves are the dominant type of vegetation along many tropical coasts. Organic matter (OM) derived from mangrove leaf litter and root material is stored in sediments and is a major contributor to the amount and chemical composition of sedimentary OM. A set of organic biomarkers in sediments was applied as a palaeo-indicator for the Holocene dynamics of a mangrove Estuary (Rio Caeté, Pará, Brazil). Six sediment cores were collected perpendicular to the present coast line and analysed for triterpenols and sitosterol. The influence of microbial biomarker degradation was implemented from a previous study. Biomarker profiles were validated with pollen data and multivariate statistics to test whether these compounds were suitable indicators for the palaeo-vegetation. Sediments deposited up to 2 Ma BP showed biomarker assemblages similar to those of recent surface sediment. In two cores, the biomarker composition revealed a transition from marsh to mangrove vegetation. Taraxerol, germanicol and b-amyrin provided the most significant chemotaxonomical information and, especially in combination, served as reliable proxies for OM from Rhizophora mangle in northern Brazil. The maximum age of the mangrove system ranged between 1000 and 5100 yr depending on the topographic elevation of the drilling location. Fil: Koch, Boris Peter. Alfred Wegener Institute for Polar and Marine Research; Alemania. University of Applied Sciences; Alemania Fil: Souza Filho, Pedro. Federal University of Pará; Brasil Fil: Behling, Hermann. University of Göttingen; Alemania Fil: Cohen, Marcelo C. L.. University of Pará; Brasil Fil: Kattner, Gerhard. Alfred Wegener Institute for Polar and Marine Research; Alemania Fil: Rullkötter, Jürgen. Carl von Ossietzky University of Oldenburg; Alemania Fil: Scholz Böttcher, Barbara. Carl von Ossietzky University of Oldenburg; Alemania Fil: Lara, Ruben Jose. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto Argentino de Oceanografía. Universidad Nacional del Sur. Instituto Argentino de Oceanografía; Argentina. Center for Tropical Marine Ecology; Alemania

Purpose: To present the first direct experimental in vitro comparison of the biological effectiveness of rangeequivalent protons and carbon ion beams for Chinese hamsterovary cells exposed in a three-dimensional phantom using a pencil beam scanning technique and to compare the experimental data with a novel biophysical model. Methodsand Materials:Cell survivalwasmeasuredinthe phantomafter irradiation withtwo opposingfields,thus mimicking the typical patient treatment scenario. The novel biophysical model represents a substantial extension of the local effect model, previously used for treatment planning in carbon ion therapy for more than 400 patients, and potentially can be used to predict effectiveness of all ion species relevant for radiotherapy. A key feature of the new approach is the more sophisticated consideration of spatially correlated damage induced by ion irradiation. Results: The experimental data obtained for Chinese hamster ovary cells clearly demonstrate that higher cell killing is achieved in the target region with carbon ions as compared with protons when the effects in the entrance channel are comparable. The model predictions demonstrate agreement with these experimental data and with data obtained with helium ions under similar conditions. Good agreement is also achieved with relative biological effectiveness values reported in the literature for other cell lines for monoenergetic proton, helium, and carbon ions. Conclusion: Both the experimental data and the new modeling approach are supportive of the advantages of carbon ions as compared with protons for treatment-like field configurations. Because the model predicts the effectiveness for several ion species with similar accuracy, it represents a powerful tool for further optimization and utilization of the potential of ion beams in tumor therapy. 2010 Elsevier Inc. Ion beam therapy, Relative biological effectiveness (RBE), Biophysical model, Treatment planning.

Osteochondrosis (OC) or leg weakness is an economically important disease of young fast growing pigs and is a concern of animal welfare. The etiology and pathogenesis of osteochondrosis is not fully understood yet, but any abnormalities in the formation of hypertrophic chondrocytes and disrupted blood supply to the growth cartilage are very important predisposing factors. Matrix gla protein (MGP) as a potential calcification inhibitor of extracellular matrix might contribute to the development of OC. Molecular characterization, polymorphisms analysis, methylation at promoter region and expression of MGP gene and protein were performed in both healthy and OC cartilage collected from a Duroc x Pietrain resource population. The porcine MGP gene consists of 4 exons and 3 introns. The full-length MGP cDNA isolated from articular cartilage consists of 606 bp with a 69-bp 5' UTR, a 312-bp open reading frame with a start codon, a 225-bp 3' UTR. Three single-nucleotide polymorphisms (SNP) were detected in the intron 1 (A-115G, C-1073T and C-1135A) and one in the 3'UTR (C-3767T). The relative abundance of MGP mRNA was lower (P

Both natriuretic peptides and nitric oxide may be protective in cardiac hypertrophy, although their functional effects are diminished in hypertrophy. Hypoxia inducible factor-1 (HIF-1) may also protect in cardiac hypertrophy. We hypothesized that upregulation of HIF-1 would protect the functional effects of cyclic GMP (cGMP) signaling in hypertrophied ventricular myocytes.A cardiac hypertrophy model was created in mice by transverse aorta constriction. HIF-1 was increased by deferoxamine (150 mg/kg for 2 days). HIF-1alpha protein levels were examined. Functional parameters were measured (edge detector) on freshly isolated myocytes at baseline and after BNP (brain natriuretic peptide, 10(-8)-10(-7)M) or CNP (C-type natriuretic peptide, 10(-8)-10(-7)M) or SNAP (S-nitroso-N-acetyl-penicillamine, a nitric oxide donor, 10(-6)-10(-5)M) followed by KT5823 (a cyclic GMP-dependent protein kinase (PKG) inhibitor, 10(-6)M). We also determined PKG expression levels and kinase activity.We found that under control conditions, BNP (-24%), CNP (-22%) and SNAP (-23%) reduced myocyte shortening, while KT5823 partially restored function. Deferoxamine treated control myocytes responded similarly. Baseline function was reduced in the myocytes from hypertrophied heart. BNP, CNP, SNAP and KT5823 also had no significant effects on function in these myocytes. Deferoxamine restored the negative functional effects of BNP (-22%), CNP (-18%) and SNAP (-19%) in hypertrophic cardiac myocytes and KT5823 partially reversed this effect. Additionally, deferoxamine maintained PKG expression levels and activity in hypertrophied heart.Our results indicated that the HIF-1 protected the functional effects of cGMP signaling in cardiac hypertrophy through preservation of PKG.

The tensile strength of sapphire fibres coated with NiAl containing a V 2 AlC interlayer was investigated. The effect of the deposition processes as well as the influence of temperature experienced during diffusion bonding onto the tensile strength was analysed. Strength degradation mechanisms were identified by chemical and morphological analysis. The investigated material systems show significant strength degradation at room temperature. This may be due to thermal stress induced twin formation as well as formation of fracture mirrors. Thermal stresses arise upon cooling after the deposition and the consolidation process, respectively. With the introduction of a V 2 AlC interlayer chemical reactions between fibre and matrix could be prevented and the population of morphological features on the fibre surface due to Al 2 O 3 surface diffusion acting as stress concentration sites could be reduced. The extensive reduction in fibre strength can be understood based on thermal stress induced twinning and fracture mirror formation.

Objective In clinical practice, reperfusion of ischemic myocardium usually occurs under high arterial oxygen levels. However, this might aggravate cardiac ischemia–reperfusion injury caused by excessive oxidative stress. In an experimental in vivo study, the cardioprotective role of hypoxic reoxygenation during initial reperfusion was assessed. Methods Twenty-one adult pigs were started on cardiopulmonary bypass with aortic crossclamping (90 minutes) and cardioplegic arrest. During initial reperfusion, 10 pigs underwent standard hypoxic reoxygenation (Pao 2 , 250–350 mm Hg), whereas gradual reoxygenation (Pao 2 , 40–90 mm Hg) was performed in 11 pigs. Cardiac function was analyzed by means of the thermodilution method and conductance catheter technique. Results In both groups cardiac index was decreased 10 minutes after cardiopulmonary bypass compared with preoperative values. Sixty minutes after cardiopulmonary bypass, cardiac index improved significantly after gradual reoxygenation compared with that after hypoxic reoxygenation (3.2 ± 0.6 vs 2.5 ± 0.5 L · min −1 · m −2 , P = .04). Correspondingly, end-systolic pressure–volume relationship and peak left ventricular pressure increase were significantly less decreased in the gradual reoxygenation group. During and after reperfusion, malondialdehyde and troponin T values within the coronary sinus were significantly lower after gradual reoxygenation (60 minutes after declamping: malondialdehyde, 7.6 ± 0.8 vs 4.6 ± 0.5 μmol/L [ P = .007]; troponin, 0.12 ± 0.02 vs 0.41 ± 0.12 ng/mL [ P = .02]). Conclusion Hypoxic reoxygenation at the onset of reperfusion attenuates myocardial ischemia–reperfusion injury and helps to preserve cardiac performance after myocardial ischemia in a pig model.

Macrophages are important mediators of the immune response to infection by virtue of, amongst other things, their ability to secrete cytokines (e.g. TNF) that trigger inflammation. However, excessive systemic release of inflammatory cytokines can cause septic shock and ultimately death. Tolerance is an adaptive mechanism that prevents macrophage activation and inflammatory cytokine production. The activation of macrophages by pathogens is largely mediated by Toll-like receptors (TLRs). IRAK-4 and IRAK-1 are proximal protein kinases in TLR signalling pathways; IRAK-1 is activated via its phosphorylation by IRAK-4. The rapid degradation of IRAK-1 following its TLR-induced activation has been proposed to represent a major mechanism for tolerance. Here, we established that IRAK-1 degradation is insufficient to cause tolerance; in the absence of IRAK-1, IRAK-4 likely activates downstream signalling proteins (e.g. NF-kappaB) via IRAK-2. Significantly, tolerance coincided with IRAK-4 down-regulation, which occurred at the protein level via proteolytic degradation as well as at the mRNA level. Gene silencing experiments confirmed the importance of IRAK-4 for the regulation of TNF expression. The different kinetics of IRAK-4 and IRAK-1 down-regulation may result in both quantitative and qualitative differences in TLR signalling and potentially allow macrophages to temporally modify their inflammatory responses. Furthermore, differences in the kinetics and extent of IRAK-4 down-regulation by TLR ligands may provide a mechanism whereby macrophages can tailor their inflammatory response according to the location and/or type of pathogen detected.

Surface sediments from the shelf area of the Campeche Sound (Gulf of Mexico) and the adjacent abyssal plain were sampled in the course of environmental monitoring for petroleum pollution as a result of industrial activity in the largest oil field in Mexico. Offshore oil production, refinery activities and heavy ship traffic, as well as natural petroleum seeps, are potential sources of pollution of water and sediment in the area. Gas chromatography–mass spectrometry (GC–MS) analysis of the nonaromatic hydrocarbon fractions of the sediment extracts revealed overlapping hydrocarbon assemblages indicating multiple sources. Samples taken close to known asphalt seeps exhibit biomarker patterns virtually identical to those of reference crude oils, so the asphalts have apparently escaped from petroleum reservoirs with fractured cap rocks. Other sediments, with distributions superimposed on mature fossil hydrocarbons, contain biomarkers typical of neither fossil fuels nor immature organic matter (OM) in marine surface sediments. They obviously derive from drill cuttings recovered during penetration of Tertiary to Cretaceous deposits and disposed of into the shallow sea, as indicated by the comparative analysis of drill cuttings from several wells in the area.

Purpose To analyze the accuracy of relative biologic effectiveness (RBE) values for treatment planning in carbon ion radiotherapy based on the local effect model (LEM) and to discuss the implications on the clinically relevant depth dose profiles. Methods and Materials Predictions of the LEM are compared with a broad panel of experimental data in vitro and to the tolerance of the rat spinal cord in vivo. To improve the accuracy of the LEM, the description of track structure is modified by taking into account a velocity-dependent extension of the inner part of the track. Results The original version of the LEM (LEM I) underestimates the therapeutic ratio of carbon ions (i.e., the ratio of RBE in the Bragg peak region as compared with the RBE in the entrance channel). Although significantly reduced, the cluster extension of the LEM (LEM II) still shows the same tendency. Implementation of the modified track structure (LEM III) almost completely compensates these systematic deviations, and predictions of RBE by LEM III for high and low energetic carbon ions show good agreement for a wide panel of different cell lines, as well as for the tolerance of the rat spinal cord. As a consequence, the expected RBE in the normal tissue surrounding the tumor becomes significantly lower than estimated with the LEM in its original version (LEM I). Conclusions The modified track structure description represents an empiric approach to improve the accuracy of the LEM for treatment planning. This will be particularly useful for further optimization of carbon ion therapy in general and with respect to comparison with other treatment modalities, such as protons or intensity-modulated radiotherapy.

A high-performance liquid chromatographic method with indirect fluorescence detection has been developed for quantification of dipicolinic acid, a major constituent of bacterial endospores. After separation on a reversed-phase column, a post-column reagent of sodium acetate at 1 mol l(-1) with 50 micromol l(-1) terbium chloride was added for complexation of dipicolinic acid. Terbium monodipicolinate complexes formed were quantified by measuring the fluorescence emission maximum at 548 nm after excitation with UV light at 270 nm wavelength. Parameters of post-column complexation were optimized to achieve a detection limit of 0.5 nmol DPA l(-1), corresponding to about 10(3) Desulfosporosinus orientis endospores per ml. The method was applied to the analysis of spore contamination in tuna and for estimating the endospore numbers in marine sediments.

Exposure to nitrates causes tachyphylaxis to nitric oxide (NO), which reduces the effects of the second messenger cyclic guanosine-3′,-5′-monophosphate (cyclic GMP). We tested the hypothesis that prolonged exposure to NO would also blunt the effects of natriuretic peptides. Cardiac myocytes were isolated from control ( N = 7) and chronic nitroglycerin (patched, N = 7) rabbits. Patched animals received a transdermal nitroglycerin patch (0.3 mg/h for 5 days). Myocyte function was determined at baseline, after C-type natriuretic peptide (CNP, 10 −8 and 10 −7 M) or brain natriuretic peptide (BNP, 10 −8 and 10 −7 M) or S -nitroso- N -acetyl-penicilliamine (SNAP, a NO donor, 10 −6 and 10 −5 M) followed by KT5823 (a cyclic GMP protein kinase inhibitor, 10 −6 M). Soluble and particulate guanylyl cyclase activities were measured in vitro and phosphoprotein analysis was performed. In control animals, CNP 10 −8 M (5.14 ± 0.5%) and 10 −7 M (4.4 ± 0.7%) significantly reduced percentage shortening from baseline (6.1 ± 1.6%). KT5823 restored percentage shortening to 4.9 ± 0.8%. Similar data were obtained with BNP and SNAP. In patched animals, CNP, BNP, SNAP had no significant effects on percentage shortening. The data on maximal rate of shortening and relaxation were consistent with these results. Guanylyl cyclase activities were not different in the control and patched animals. The myocytes from control and patched animals had similar protein phosphorylation patterns. Our data suggested that in addition to NO, the responses to both natriuretic peptides were downregulated after chronic exposure to nitroglycerin, but these effects were not due to changes in either guanylyl cyclase or cyclic GMP protein kinase, suggesting an altered downstream pathway.

A study was conducted to compare swine body composition measurements (fat tissue, lean tissue and bone mineral) made by DXA in vivo and on the right carcass half using two GE Lunar DPX pencil beam instruments at two different locations. Pigs weighing between 60 and 105 kg were first scanned in vivo by DXA and after slaughter the right carcass half of each pig was scanned — 78 pigs at the USDA in Beltsville, MD using a GE Lunar DPX-L instrument and 62 pigs at the LVG in Oberschleissheim, Germany using a GE Lunar DPX-IQ instrument (an updated model of the DPX-L). In addition to a separate analysis, despite confounding effects likely caused by the different study locations and probe preparations (scan modes) the data were pooled. Based on linear regression analysis of the pooled data, the relationship between DXA carcass half (dependent variable) and in vivo measurements resulted in coefficients of determination (R 2 ) of 0.58 for fat percentage (√MSE=3.82%) and of 0.52 for lean percentage (√MSE=4.09%). The R 2 values were expectedly higher when the data sets were analyzed separately for each location: 0.79 (√MSE=2.38%) and 0.85 (√MSE=1.60%) for fat percentage and 0.79 (√MSE=2.41%) and 0.84 (√MSE=1.65%) for lean percentage at USDA and LVG, respectively. Regardless of the relatively close relationship among in vivo and carcass results for the pooled data, caution is advised in comparing measurements among GE Lunar DPX-L and DPX-IQ instruments, since the residuals (√MSE) for the regression analysis of DXA FAT% and DXA LEAN% measurements exceed 2.5%.

One major rationale for the application of heavy ion beams in tumor therapy is their increased relative biological effectiveness (RBE) in the Bragg peak region. For dose prescription, the increased effectiveness has to be taken into account in treatment planning. Hence, the complex dependencies of RBE on the dose level, biological endpoint, position in the field etc. require biophysical models, which have to fulfill two important criteria: simplicity and quantitative precision. Simplicity means that the number of free parameters should be kept at a minimum. Due to the lack of precise quantitative data, at least at present, this requirement is incompatible with approaches aiming at the molecular modeling of the whole chain of production, processing and repair of biological damages. Quantitative precision is required since steep gradients in the dose response curves are observed for most tumor and normal tissues; thus, even small uncertainties in the estimation of the biologically effective dose can transform into large uncertainties in the clinical outcome. The paper will give a general introduction into the field, followed by a description of a specific model, the so called ‘Local Effect Model’ (LEM). This model has been successfully applied within treatment planning in the GSI pilot project for carbon ion tumor therapy over almost 10 years now. The model is based on the knowledge of charged particle track structure in combination with the response of the cells or tissues under consideration to conventional photon radiation. The model is compared to other approaches developed for the calculation of the biological effects of high-LET radiation. Furthermore, recent improvements of the model are described. Due to the quantitative precision, besides applications in tumor therapy the LEM seems to be adequate for the calculation of stochastic radiation effects, i.e. in the framework of radiation protection. Examples for the calculation of cell transformation are presented.

The consequences of chronic nitric oxide synthase (NOS) blockade on the myocardial metabolic and guanylyl cyclase stimulatory effects of exogenous nitric oxide (NO) were determined. Thirty-three anesthetized open-chest rabbits were randomized into four groups: control, NO donor S -nitroso- N -acetyl-penicillamine (SNAP, 10 − 4 M), NOS blocking agent N G -nitro- l -arginine methyl ester ( l -NAME, 20 mg/kg/day) for 10 days followed by a 24 hour washout and l -NAME for 10 days followed by a 24 hour washout plus SNAP. Myocardial O 2 consumption was determined from coronary flow (microspheres) and O 2 extraction (microspectrophotometry). Cyclic GMP and guanylyl cyclase activity were determined by radioimmunoassay. There were no baseline metabolic, functional or hemodynamic differences between control and l -NAME treated rabbits. SNAP in controls caused a reduction in O 2 consumption (SNAP 5.9 ± 0.6 vs. control 8.4 ± 0.8 ml O 2 /min/100 g) and a rise in cyclic GMP (SNAP 18.3 ± 3.8 vs. control 10.4 ± 0.9 pmol/g). After chronic l -NAME treatment, SNAP caused no significant changes in O 2 consumption (SNAP 7.1 ± 0.8 vs. control 6.4 ± 0.7) or cyclic GMP (SNAP 14.2 ± 1.8 vs. control 12.1 ± 1.3). In controls, guanylyl cyclase activity was significantly stimulated by SNAP (216.7 ± 20.0 SNAP vs. 34.4 ± 2.5 pmol/mg/min base), while this increase was blunted after l -NAME (115.9 ± 24.5 SNAP vs. 24.9 ± 4.7 base). These results demonstrated that chronic NOS blockade followed by washout blunts the response to exogenous NO, with little effect on cyclic GMP or myocardial O 2 consumption. This was related to reduced guanylyl cyclase activity after chronic l -NAME. These results suggest that, unlike many receptor systems, the NO–cyclic GMP signal transduction system becomes downregulated upon chronic inhibition.

BACKGROUND We tested the hypothesis that the negative functional effects of cyclic GMP would be attenuated by cyclic AMP and this interaction would be reduced in pacing-induced failure of hypertrophic hearts. MATERIALS AND METHODS 8-Bromo-cGMP (2 microg/kg/min) was infused into a coronary artery in eight control, eight ventricular hypertrophy (HYP), and eight hypertrophic failure (HYP-FAIL) dogs. Then isoproterenol (0.1 microg/kg/min) was infused, followed by 8 Br-cGMP. Regional myocardial work (force*shortening/min), and O(2) consumption (VO(2)) (coronary blood flow*O(2) extraction) were measured. Cyclic GMP levels were determined by radioimmunoassay. RESULTS 8-Br-cGMP significantly decreased regional work from 3812 +/- 839 g*mm/min by 17% and VO(2) by 29% in control, but not in HYP (1073 +/- 182 by -10%, VO(2) by -16%) or HYP-FAIL (495 +/- 145 by -9%, VO(2) by 0%). Isoproterenol increased work by 43% and VO(2) by 48% in controls and in HYP (work by 54%, VO(2) by 39%), but not in HYP-FAIL (work by -28%, VO(2) by -5%). Subsequently, 8-Br-cGMP had no effect on work or VO(2) in control (-2%, -13%), HYP (-12%, -30%), or HYP-FAIL (+13%, +14%). Cyclic AMP levels were elevated by isoproterenol in control (381 +/- 115 versus 553 +/- 119 pmol/g) and HYP (313 +/- 55 versus 486 +/- 227), but not in HYP-FAIL (300 +/- 60 versus 284 +/- 126). After isoproterenol, 8-Br-cGMP further elevated cyclic AMP in control (687 +/- 122), but not in HYP or HYP-FAIL. CONCLUSIONS In controls, cyclic AMP attenuated cyclic GMPs negative functional and metabolic effects. The effects and the interaction were blunted in the HYP and HYP-FAIL groups.

We tested the hypothesis that the negative functional effects of cyclic GMP were mediated by ryanodine receptors, and that these effects would be reduced in thyroxine (thyroxine, 0.5 mg/kg/day, 16 days)-induced hypertrophic myocytes. Using rabbit ventricular myocytes from control (n = 9) and thyroxine (n = 9) hearts, percent cell shortening (%) and maximum rate of contraction and relaxation were determined using a video edge detector at baseline and after 10− 6, 10− 5 M 8-bromo-cyclic GMP. Dantrolene 10− 6 M, ryanodine receptor inhibitor, was added alone or after 8-Br-cGMP treatment. Changes in cytosolic Ca2+ concentration were assessed in fura-2-loaded control and thyroxine myocytes. 8-Br-cGMP caused a significant decrease in percent shortening, from 5.3 ± 0.9% to 3.9 ± 0.6% at 10− 5 M in control, and 3.4 ± 0.3% to 2.6 ± 0.4% in thyroxine myocytes. Dantrolene significantly decreased percent shortening from 4.5 ± 0.8% to 3.7 ± 0.1% in control and from 3.7 ± 0.1% to 2.8 ± 0.3% in thyroxine myocytes. In 8-Br-cGMP treated control myocytes, dantrolene did not significantly change myocyte contractility, which suggested that cyclic GMP acted on ryanodine receptors. However, in 8-Br-cGMP treated thyroxine myocytes, dantrolene further reduced myocyte contractility implying that the interaction of cyclic GMP and ryanodine receptors appeared to be interrupted in thyroxine myocytes. Maximum rate of contraction data were consistent with the percent cell shortening data and Ca2+ transients changed similarly to myocyte contractility. We conclude that effects of cyclic GMP on myocytes contractility were partially mediated though interaction with ryanodine receptors and the subsequent decrease in cytosolic calcium levels. This interaction was reduced in thyroxine hypertrophic myocytes.

In this study, we tested the hypothesis that the negative functional effects of cyclic GMP on cardiac myocytes would be affected by the actions of cyclic GMP on cyclic AMP phosphodiesterases. Ventricular myocytes from eight rabbits were used to determine the functional and cyclic AMP changes caused by 10(-7), 10(-6), 10(-5) M 8-Bromo-cGMP alone and after the administration of 10(-6) M milrinone (cyclic GMP-inhibited cyclic AMP phosphodiesterase inhibitor) or 10(-6) M erythro-9-(2-Hydroxy-3-3-nonyl)adenine (EHNA, cyclic GMP-stimulated cyclic AMP phosphodiesterase inhibitor). 8-Br-cGMP dose-dependently reduced %shortening by 35+/-4% of baseline at 10(-5) M. This effect was significantly blunted by EHNA at all doses. The maximum rate of shortening was reduced by 31+/-3% by 10(-5) M 8-Br-cGMP. This effect of 8-Br-cGMP was significantly enhanced (42+/-4%) in the milrinone group. A similar pattern was observed in the maximum rate of relaxation data. Cyclic AMP levels were significantly increased from a baseline level of 4.0+/-0.8 pmol/10(5) myocytes by milrinone (+60%), EHNA (+61%) and 8-Br-cGMP (+47%). The combination of EHNA plus 8-Br-cGMP increased cyclic AMP levels significantly more that the combination of milrinone plus 8-Br-cGMP. Exogenous cyclic GMP reduces myocyte function, while raising cyclic AMP possibly through cyclic GMP-inhibited cyclic AMP phosphodiesterase effects. Blocking cyclic GMP-inhibited cyclic AMP phosphodiesterase enhances the functional effects cyclic GMP, while blocking cyclic GMP-stimulated cyclic AMP phosphodiesterase reduced these effects. The study demonstrated a functional interaction between cyclic GMP and cyclic AMP related to the cyclic GMP affected cyclic AMP phosphodiesterases.