Local carbachol application induces oral microvascular recruitment and improves gastric tissue oxygenation during hemorrhagic shock in dogs.

Introduction: Hemorrhagic shock is characterized by derangements of the gastrointestinal microcirculation. Topical therapy with nitroglycerine or iloprost improves gastric tissue oxygenation but not regional perfusion, probably due to precapillary adrenergic innervation. Therefore, this study was designed to investigate the local effect of the parasympathomimetic carbachol alone and in combination with either nitroglycerine or iloprost on gastric and oral microcirculation during hemorrhagic shock. Methods: In a cross-over design five female foxhounds were repeatedly randomized into six experimental groups. Carbachol, or carbachol in combination with either nitroglycerine or iloprost were applied topically to the oral and gastric mucosa. Saline, nitroglycerine, or iloprost application alone served as control groups. Then, a fixed-volume hemorrhage was induced by arterial blood withdrawal followed by blood retransfusion after 1h of shock. Gastric and oral microcirculation was determined using reflectance spectrophotometry and laser Doppler flowmetry. Oral microcirculation was visualized with videomicroscopy. Statistics: 2-way-ANOVA for repeated measurements and Bonferroni post-hoc analysis (mean ± SEM; p < 0.05). Results: The induction of hemorrhage led to a decrease of gastric and oral tissue oxygenation, that was ameliorated by local carbachol and nitroglycerine application at the gastric mucosa. The sole use of local iloprost did not improve gastric tissue oxygenation but could be supplemented by local carbachol treatment. Adding carbachol to nitroglycerine did not further increase gastric tissue oxygenation. Gastric microvascular blood flow remained unchanged in all experimental groups. Oral microvascular blood flow, microvascular flow index and total vessel density decreased during shock. Local carbachol supply improved oral vessel density during shock and oral microvascular flow index in the late course of hemorrhage. Conclusion: The specific effect of shifting the autonomous balance by local carbachol treatment on microcirculatory variables varies between parts of the gastrointestinal tract. Contrary to our expectations, the improvement of gastric tissue oxygenation by local carbachol or nitroglycerine application was not related to increased microvascular perfusion. When carbachol is used in combination with local vasodilators, the additional effect on gastric tissue oxygenation depends on the specific drug combination. Therefore, modulation of tissue oxygen consumption, mitochondrial function or alterations in regional blood flow distribution should be investigated.

High-spatial resolution functional chemistry of nitrogen compounds in the observed UK meteorite fall Winchcombe.

Organic matter in extraterrestrial samples is a complex material that might have played an important role in the delivery of prebiotic molecules to the early Earth. We report here on the identification of nitrogen-containing compounds such as amino acids and N-heterocycles within the recent observed meteorite fall Winchcombe by high-spatial resolution spectroscopy techniques. Although nitrogen contents of Winchcombe organic matter are low (N/C ~ 1-3%), we were able to detect the presence of these compounds using a low-noise direct electron detector. These biologically relevant molecules have therefore been tentatively found within a fresh, minimally processed meteorite sample by high spatial resolution techniques conserving the overall petrographic context. Carbon functional chemistry investigations show that sizes of aromatic domains are small and that abundances of carboxylic functional groups are low. Our observations demonstrate that Winchcombe represents an important addition to the collection of carbonaceous chondrites and still preserves pristine extraterrestrial organic matter.

Prevalence and prognostic value of neurological affections in hospitalized patients with moderate to severe COVID-19 based on objective assessments.

Neurological manifestations of coronavirus disease 2019 (COVID-19) have been frequently described. In this prospective study of hospitalized COVID-19 patients without a history of neurological conditions, we aimed to analyze their prevalence and prognostic value based on established, standardized and objective methods. Patients were investigated using a multimodal electrophysiological approach, accompanied by neuropsychological and neurological examinations. Prevalence rates of central (CNS) and peripheral (PNS) nervous system affections were calculated and the relationship between neurological affections and mortality was analyzed using Firth logistic regression models. 184 patients without a history of neurological diseases could be enrolled. High rates of PNS affections were observed (66% of 138 patients receiving electrophysiological PNS examination). CNS affections were less common but still highly prevalent (33% of 139 examined patients). 63% of patients who underwent neuropsychological testing (n = 155) presented cognitive impairment. Logistic regression models revealed pathology in somatosensory evoked potentials as an independent risk factor of mortality (Odds Ratio: 6.10 [1.01-65.13], p = 0.049). We conclude that hospitalized patients with moderate to severe COVID-19 display high rates of PNS and CNS affection, which can be objectively assessed by electrophysiological examination. Electrophysiological assessment may have a prognostic value and could thus be helpful to identify patients at risk for deterioration.

Blood pH Analysis in Combination with Molecular Medical Tools in Relation to COVID-19 Symptoms.

The global outbreak of SARS-CoV-2/COVID-19 provided the stage to accumulate an enormous biomedical data set and an opportunity as well as a challenge to test new concepts and strategies to combat the pandemic. New research and molecular medical protocols may be deployed in different scientific fields, e.g., glycobiology, nanopharmacology, or nanomedicine. We correlated clinical biomedical data derived from patients in intensive care units with structural biology and biophysical data from NMR and/or CAMM (computer-aided molecular modeling). Consequently, new diagnostic and therapeutic approaches against SARS-CoV-2 were evaluated. Specifically, we tested the suitability of incretin mimetics with one or two pH-sensitive amino acid residues as potential drugs to prevent or cure long-COVID symptoms. Blood pH values in correlation with temperature alterations in patient bodies were of clinical importance. The effects of biophysical parameters such as temperature and pH value variation in relation to physical-chemical membrane properties (e.g., glycosylation state, affinity of certain amino acid sequences to sialic acids as well as other carbohydrate residues and lipid structures) provided helpful hints in identifying a potential Achilles heel against long COVID. In silico CAMM methods and in vitro NMR experiments (including 31P NMR measurements) were applied to analyze the structural behavior of incretin mimetics and SARS-CoV fusion peptides interacting with dodecylphosphocholine (DPC) micelles. These supramolecular complexes were analyzed under physiological conditions by 1H and 31P NMR techniques. We were able to observe characteristic interaction states of incretin mimetics, SARS-CoV fusion peptides and DPC membranes. Novel interaction profiles (indicated, e.g., by 31P NMR signal splitting) were detected. Furthermore, we evaluated GM1 gangliosides and sialic acid-coated silica nanoparticles in complex with DPC micelles in order to create a simple virus host cell membrane model. This is a first step in exploring the structure-function relationship between the SARS-CoV-2 spike protein and incretin mimetics with conserved pH-sensitive histidine residues in their carbohydrate recognition domains as found in galectins. The applied methods were effective in identifying peptide sequences as well as certain carbohydrate moieties with the potential to protect the blood-brain barrier (BBB). These clinically relevant observations on low blood pH values in fatal COVID-19 cases open routes for new therapeutic approaches, especially against long-COVID symptoms.

Pravastatin Improves Colonic and Hepatic Microcirculatory Oxygenation during Sepsis without Affecting Mitochondrial Function and ROS Production in Rats.

Microcirculatory and mitochondrial dysfunction are considered the main mechanisms of septic shock. Studies suggest that statins modulate inflammatory response, microcirculation, and mitochondrial function, possibly through their action on peroxisome proliferator-activated receptor alpha (PPAR-α). The aim of this study was to examine the effects of pravastatin on microcirculation and mitochondrial function in the liver and colon and the role of PPAR-α under septic conditions. This study was performed with the approval of the local animal care and use committee. Forty Wistar rats were randomly divided into 4 groups: sepsis (colon ascendens stent peritonitis, CASP) without treatment as control, sepsis + pravastatin, sepsis + PPAR-α-blocker GW6471, and sepsis + pravastatin + GW6471. Pravastatin (200 µg/kg s.c.) and GW6471 (1 mg/kg) were applied 18 h before CASP-operation. 24 h after initial surgery, a relaparotomy was performed, followed by a 90 min observation period for assessment of microcirculatory oxygenation (µHbO2) of the liver and colon. At the end of the experiments, animals were euthanized, and the colon and liver were harvested. Mitochondrial function was measured in tissue homogenates using oximetry. The ADP/O ratio and respiratory control index (RCI) for complexes I and II were calculated. Reactive oxygen species (ROS) production was assessed using the malondialdehyde (MDA)-Assay. Statistics: two-way analysis of variance (ANOVA) + Tukey's/Dunnett's post hoc test for microcirculatory data, Kruskal-Wallis test + Dunn's post hoc test for all other data. In control septic animals µHbO2 in liver and colon deteriorated over time (µHbO2: -9.8 ± 7.5%* and -7.6 ± 3.3%* vs. baseline, respectively), whereas after pravastatin and pravastatin + GW6471 treatment µHbO2 remained constant (liver: µHbO2 pravastatin: -4.21 ± 11.7%, pravastatin + GW6471: -0.08 ± 10.3%; colon: µHbO2 pravastatin: -0.13 ± 7.6%, pravastatin + GW6471: -3.00 ± 11.24%). In both organs, RCI and ADP/O were similar across all groups. The MDA concentration remained unchanged in all groups. Therefore, we conclude that under septic conditions pravastatin improves microcirculation in the colon and liver, and this seems independent of PPAR-α and without affecting mitochondrial function.

Chronotype, Time of Day, and Performance on Intelligence Tests in the School Setting.

Research suggests the existence of an association between chronotype and intellectual performance, but the nature of this link remains unclear. Studies conducted in a laboratory setting point to the synchrony effect (better performance at a person's preferred time of day) for fluid intelligence, but not for crystallized intelligence, whereas studies that have analyzed students' grades suggest that the effect exists for both. In the present study, we aimed to verify the synchrony effect by applying direct measures of crystallized intelligence, fluid intelligence, and subjective sleepiness-alertness in a sample of high school students during their morning or afternoon class. The results revealed a synchrony effect for crystallized, but not for fluid intelligence. During morning class, students with a morning chronotype performed better than evening chronotypes on a test of crystallized intelligence, whereas during afternoon class there was no difference between chronotypes. The association resulted from decreased performance during morning class in evening chronotypes that improved during afternoon class and constant performance in morning chronotypes. These effects were independent of sleepiness-alertness levels. The results suggest that individual differences between chronotypes may be important for tasks performed during morning classes, but not during afternoon ones, and that performance across school days may depend on time of day in evening chronotypes.

Gemfibrozil Improves Microcirculatory Oxygenation of Colon and Liver without Affecting Mitochondrial Function in a Model of Abdominal Sepsis in Rats.

Recent studies observed, despite an anti-hyperlipidaemic effect, a positive impact of fibrates on septic conditions. This study evaluates the effects of gemfibrozil on microcirculatory variables, mitochondrial function, and lipid peroxidation levels with regard to its potential role as an indicator for oxidative stress in the colon and liver under control and septic conditions and dependencies on PPARα-mediated mechanisms of action. With the approval of the local ethics committee, 120 Wistar rats were randomly divided into 12 groups. Sham and septic animals were treated with a vehicle, gemfibrozil (30 and 100 mg/kg BW), GW 6471 (1 mg/kg BW, PPARα inhibitor), or a combination of both drugs. Sepsis was induced via the colon ascendens stent peritonitis (CASP) model. Then, 24 h post sham or CASP surgery, a re-laparotomy was performed. Measures of vital parameters (heart rate (HR), mean arterial pressure (MAP), and microcirculation (µHbO2)) were recorded for 90 min. Mitochondrial respirometry and assessment of lipid peroxidation via a malondialdehyde (MDA) assay were performed on colon and liver tissues. In the untreated sham animals, microcirculation remained stable, while pre-treatment with gemfibrozil showed significant decreases in the microcirculatory oxygenation of the colon. In the CASP animals, µHbO2 levels in the colon and the liver were significantly decreased 90 min after laparotomy. Pre-treatment with gemfibrozil prevented the microcirculatory aberrations in both organs. Gemfibrozil did not affect mitochondrial function and lipid peroxidation levels in the sham or CASP animals. Gemfibrozil treatment influences microcirculation depending on the underlying condition. Gemfibrozil prevents sepsis-induced microcirculatory aberrances in the colon and liver PPARα-independently. In non-septic animals, gemfibrozil impairs the microcirculatory variables in the colon without affecting those in the liver.

COVID-19-lockdown delayed sleep timing in Tyrolean teachers.

Delayed school start times improve students' sleep, but little is known about its impact on teachers. The Austrian COVID-19 lockdown, enabling teachers to choose their working hours, created the unique opportunity to test the impact of a forced home office on Tyrolean teachers' sleep. From April to May 2020, a cross-sectional and complete online survey was implemented with 2,314 Tyrolean teachers participating. Bedtimes and wake times on workdays and on weekends were measured before the lockdown (retrospectively) and during the lockdown. Additional variables were calculated: time spent in bed on workdays/weekends, social jetlag, and sleep loss. During the lockdown, as compared to the period before it, the teachers reported later bedtimes and rise times, longer sleep duration on workdays, decreased workday sleep loss, and reduced social jetlag. These effects occurred predominantly due to a delay in rise times on workdays and were enhanced in younger teachers. Changing to a home office during lockdown induced a robust drift towards later hours on workdays, indicating that teachers benefit from delayed school start times by aligning their workday sleep habits to their biological sleep needs. In conclusion, not only adolescent students but also teachers benefit from a delayed school start.

Gender does not make the difference: interest in STEM by gender is fully mediated by technical socialization and degree program.

In Germany, there is a shortage of skilled workers in the fields of science, technology, engineering, and mathematics (STEM) and especially in technology with declining interest in technology and with supposedly fewer teachers in technology education in the next 20 years. The present study examined whether students' interest in STEM is dependent on their career choices (i.e., their degree program), their technical socialization, their personality, and gender. A survey in Germany, Baden-Wuerttemberg (N = 350) examined gender-specific differences in teacher training students with and without technology and engineering students via structural equation modelling with the mediators personality, technical socialization, and degree program. Results show that interest in STEM by gender is fully mediated by technical socialization and degree program. Solutions for the reduction of the staff shortage and gender gap in the technical domain are discussed and it is suggested that an integration of technology lessons in the school curriculum and a reduction of gender normatives may help.

Local Mucosal CO2 but Not O2 Insufflation Improves Gastric and Oral Microcirculatory Oxygenation in a Canine Model of Mild Hemorrhagic Shock.

Introduction: Acute hemorrhage results in perfusion deficit and regional hypoxia. Since failure of intestinal integrity seem to be the linking element between hemorrhage, delayed multi organ failure, and mortality, it is crucial to maintain intestinal microcirculation in acute hemorrhage. During critical bleeding physicians increase FiO2 to raise total blood oxygen content. Likewise, a systemic hypercapnia was reported to maintain microvascular oxygenation (µHbO2). Both, O2 and CO2, may have adverse effects when applied systemically that might be prevented by local application. Therefore, we investigated the effects of local hyperoxia and hypercapnia on the gastric and oral microcirculation. Methods: Six female foxhounds were anaesthetized, randomized into eight groups and tested in a cross-over design. The dogs received a local CO2-, O2-, or N2-administration to their oral and gastric mucosa. Hemorrhagic shock was induced through a withdrawal of 20% of estimated blood volume followed by retransfusion 60 min later. In control groups no shock was induced. Reflectance spectrophotometry and laser Doppler were performed at the gastric and oral surface. Oral microcirculation was visualized by incident dark field imaging. Systemic hemodynamic parameters were recorded continuously. Statistics were performed using a two-way-ANOVA for repeated measurements and post hoc analysis was conducted by Bonferroni testing (p < 0.05). Results: The gastric µHbO2 decreased from 76 ± 3% to 38 ± 4% during hemorrhage in normocapnic animals. Local hypercapnia ameliorated the decrease of µHbO2 from 78 ± 4% to 51 ± 8%. Similarly, the oral µHbO2 decreased from 81 ± 1% to 36 ± 4% under hemorrhagic conditions and was diminished by local hypercapnia (54 ± 4%). The oral microvascular flow quality but not the total microvascular blood flow was significantly improved by local hypercapnia. Local O2-application failed to change microvascular oxygenation, perfusion or flow quality. Neither CO2 nor O2 changed microcirculatory parameters and macrocirculatory hemodynamics under physiological conditions. Discussion: Local hypercapnia improved microvascular oxygenation and was associated with a continuous blood flow in hypercapnic individuals undergoing hemorrhagic shock. Local O2 application did not change microvascular oxygenation, perfusion and blood flow profiles in hemorrhage. Local gas application and change of microcirculation has no side effects on macrocirculatory parameters.

Natural Fe-bearing aluminous bridgmanite in the Katol L6 chondrite.

Bridgmanite, the most abundant mineral of the Earth's lower mantle, has been reported in only a few shocked chondritic meteorites; however, the compositions of these instances differ from that expected in the terrestrial bridgmanite. Here, we report the first natural occurrence of Fe-bearing aluminous bridgmanite in shock-induced melt veins within the Katol L6 chondrite with a composition that closely matches those synthesized in high-pressure and temperature experiments over the last three decades. The Katol bridgmanite coexists with majorite and metal-sulfide intergrowths. We found that the natural Fe-bearing aluminous bridgmanite in the Katol L6 chondrite has a significantly higher Fe3+/ΣFe ratio (0.69 ± 0.08) than coexisting majorite (0.37 ± 0.10), which agrees with experimental studies. The Katol bridgmanite is arguably the closest natural analog for the bridgmanite composition expected to be present in the Earth's lower mantle. Textural observations and comparison with laboratory experiments suggest that the Katol bridgmanite formed at pressures of ∼23 to 25 gigapascals directly from the chondritic melt generated by the shock event. Thus, the Katol L6 sample may also serve as a unique analog for crystallization of bridgmanite during the final stages of magma ocean crystallization during Earth's formation.

Sub-therapeutic vasopressin but not therapeutic vasopressin improves gastrointestinal microcirculation in septic rats: A randomized, placebo-controlled, blinded trial.

INTRODUCTION: Sepsis impairs gastrointestinal microcirculation and it is hypothesized that this might increase patient's mortality. Sub-therapeutic vasopressin improves gastric microcirculation under physiologic conditions whereas a therapeutic dosing regimen seems to be rather detrimental. However, the effects of sub-therapeutic vasopressin on gastrointestinal microcirculation in sepsis are largely unknown. Therefore, we conducted this trial to investigate the effect of sub-therapeutic as well as therapeutic vasopressin on gastrointestinal microcirculation in sepsis. METHODS: 40 male Wistar rats were randomized into 4 groups. Colon ascendens stent peritonitis (CASP)-surgery was performed to establish mild or moderate sepsis. 24 hours after surgery, animals received either vasopressin with increasing dosages every 30 min (6.75, 13.5 (sub-therapeutic), 27 mU · kg-1 · h-1 (therapeutic)) or vehicle. Microcirculatory oxygenation (µHBO2) of the colon was recorded for 90 min using tissue reflectance spectrophotometry. Intestinal microcirculatory perfusion (total vessel density (TVD; mm/mm2) and perfused vessel density (PVD; mm/mm2)) were measured using incident dark field-Imaging at baseline and after 60 min. RESULTS: In mild as well as in moderate septic animals with vehicle-infusion intestinal µHbO2, TVD and PVD remained constant. In contrast, in moderate sepsis, sub-therapeutic vasopressin with 13.5 mU · kg-1 · h-1 elevated intestinal µHBO2 (+ 6.1 ± 5.3%; p < 0.05 vs. baseline) and TVD (+ 5.2 ± 3.0 mm/mm2; p < 0.05 vs. baseline). µHBO2, TVD and PVD were significantly increased compared to moderate sepsis alone. However, therapeutic vasopressin did not change intestinal microcirculation. In mild septic animals sub-therapeutic as well as therapeutic vasopressin had no relevant effect on gastrointestinal microcirculation. Systemic blood pressure remained constant in all groups. CONCLUSION: Sub-therapeutic vasopressin improves gastrointestinal microcirculatory oxygenation in moderate sepsis without altering systemic blood pressure. This protective effect seems to be mediated by an enhanced microcirculatory perfusion and thereby increased oxygen supply. In contrast, therapeutic vasopressin did not show this beneficial effect.

Animal Welfare Attitudes: Effects of Gender and Diet in University Samples from 22 Countries.

Animal Welfare Attitudes (AWA) are defined as human attitudes towards the welfare of animals in different dimensions and settings. Demographic factors, such as age and gender are associated with AWA. The aim of this study was to assess gender differences among university students in a large convenience sample from twenty-two nations in AWA. A total of 7914 people participated in the study (5155 women, 2711 men, 48 diverse). Participants completed a questionnaire that collected demographic data, typical diet and responses to the Composite Respect for Animals Scale Short version (CRAS-S). In addition, we used a measure of gender empowerment from the Human Development Report. The largest variance in AWA was explained by diet, followed by country and gender. In terms of diet, 6385 participants reported to be omnivores, 296 as pescatarian, 637 ate a vegetarian diet and 434 were vegans (n = 162 without answer). Diet was related with CRAS-S scores; people with a vegan diet scored higher in AWA than omnivores. Women scored significantly higher on AWA than men. Furthermore, gender differences in AWA increased as gender inequality decreased.

Sodium Thiosulfate Improves Intestinal and Hepatic Microcirculation Without Affecting Mitochondrial Function in Experimental Sepsis.

Introduction: In the immunology of sepsis microcirculatory and mitochondrial dysfunction in the gastrointestinal system are important contributors to mortality. Hydrogen sulfide (H2S) optimizes gastrointestinal oxygen supply and mitochondrial respiration predominantly via K(ATP)-channels. Therefore, we tested the hypothesis that sodium thiosulfate (STS), an inducer of endogenous H2S, improves intestinal and hepatic microcirculation and mitochondrial function via K(ATP)-channels in sepsis. Methods: In 40 male Wistar rats colon ascendens stent peritonitis (CASP) surgery was performed to establish sepsis. Animals were randomized into 4 groups (1: STS 1 g â€¢ kg-1 i.p., 2: glibenclamide (GL) 5 mg • kg-1 i.p., 3: STS + GL, 4: vehicle (VE) i.p.). Treatment was given directly after CASP-surgery and 24 hours later. Microcirculatory oxygenation (µHBO2) and flow (µflow) of the colon and the liver were continuously recorded over 90 min using tissue reflectance spectrophotometry. Mitochondrial oxygen consumption in tissue homogenates was determined with respirometry. Statistic: two-way ANOVA + Dunnett´s and Tukey post - hoc test (microcirculation) and Kruskal-Wallis test + Dunn's multiple comparison test (mitochondria). p < 0.05 was considered significant. Results: STS increased µHbO2 (colon: 90 min: + 10.4 ± 18.3%; liver: 90 min: + 5.8 ± 9.1%; p < 0.05 vs. baseline). Furthermore, STS ameliorated µflow (colon: 60 min: + 51.9 ± 71.1 aU; liver: 90 min: + 22.5 ± 20.0 aU; p < 0.05 vs. baseline). In both organs, µHbO2 and µflow were significantly higher after STS compared to VE. The combination of STS and GL increased colonic µHbO2 and µflow (µHbO2 90 min: + 8.7 ± 11.5%; µflow: 90 min: + 41.8 ± 63.3 aU; p < 0.05 vs. baseline), with significantly higher values compared to VE. Liver µHbO2 and µflow did not change after STS and GL. GL alone did not change colonic or hepatic µHbO2 or µflow. Mitochondrial oxygen consumption and macrohemodynamic remained unaltered. Conclusion: The beneficial effect of STS on intestinal and hepatic microcirculatory oxygenation in sepsis seems to be mediated by an increased microcirculatory perfusion and not by mitochondrial respiratory or macrohemodynamic changes. Furthermore, the effect of STS on hepatic but not on intestinal microcirculation seems to be K(ATP)-channel-dependent.

Prolonged Neuropsychological Deficits, Central Nervous System Involvement, and Brain Stem Affection After COVID-19-A Case Series.

Objective: The affection of both the peripheral (PNS) and central nervous system (CNS) by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been assumed to play a direct role in the respiratory failure of patients with Corona virus disease 2019 (COVID-19) through affection of medullary cardiorespiratory centers resulting in neurological complications and sequelae. Methods: We used a multimodal electrophysiological approach combined with neuropsychological investigations to study functional alteration of both the PNS and CNS in four patients with severe COVID-19. Results: We found electrophysiological evidence for affection of both the PNS and CNS, and particularly affection of brain stem function. Furthermore, our neuropsychological investigations provide evidence of marked impairment of cognition independent of delirium, and outlasting the duration of acute infection with SARS-CoV-2. Conclusion: This case series provides first direct electrophysiological evidence for functional brain stem involvement in COVID-19 patients without evident morphological changes supporting the notion of the brain stem contributing to respiratory failure and thus promoting severe courses of the disease. Moreover, sustained neuropsychological sequelae in these patients may be of particular psychosocial and possibly also economic relevance for society.

A primordial 15N-depleted organic component detected within the carbonaceous chondrite Maribo.

We report on the detection of primordial organic matter within the carbonaceous chondrite Maribo that is distinct from the majority of organics found in extraterrestrial samples. We have applied high-spatial resolution techniques to obtain C-N isotopic compositions, chemical, and structural information of this material. The organic matter is depleted in 15N relative to the terrestrial value at around δ15N ~ -200‰, close to compositions in the local interstellar medium. Morphological investigations by electron microscopy revealed that the material consists of µm- to sub-µm-sized diffuse particles dispersed within the meteorite matrix. Electron energy loss and synchrotron X-ray absorption near-edge structure spectroscopies show that the carbon functional chemistry is dominated by aromatic and C=O bonding environments similar to primordial organics from other carbonaceous chondrites. The nitrogen functional chemistry is characterized by C-N double and triple bonding environments distinct from what is usually found in 15N-enriched organics from aqueously altered carbonaceous chondrites. Our investigations demonstrate that Maribo represents one of the least altered CM chondrite breccias found to date and contains primordial organic matter, probably originating in the interstellar medium.

Topical Melatonin Improves Gastric Microcirculatory Oxygenation During Hemorrhagic Shock in Dogs but Does Not Alter Barrier Integrity of Caco-2 Monolayers.

Systemic administration of melatonin exerts tissue protective effects in the context of hemorrhagic shock. Intravenous application of melatonin prior to hemorrhage improves gastric microcirculatory perfusion and maintains intestinal barrier function in dogs. The aim of the present study was to analyze the effects of a topical mucosal melatonin application on gastric microcirculation during hemorrhagic shock in vivo and on mucosal barrier function in vitro. In a randomized cross-over study, six anesthetized female foxhounds received 3.3 mg melatonin or the vehicle as a bolus to the gastric and oral mucosa during physiological and hemorrhagic (-20% blood volume) conditions. Microcirculation was analyzed with reflectance spectrometry and laser doppler flowmetry. Systemic hemodynamic variables were measured with transpulmonary thermodilution. For analysis of intestinal mucosal barrier function in vitro Caco-2 monolayers were used. The transepithelial electrical resistance (TEER) and the passage of Lucifer Yellow (LY) from the apical to the basolateral compartment of Transwell chambers were measured. Potential barrier protective effects of melatonin against oxidative stress were investigated in the presence of the oxidant H2O2. During physiologic conditions topical application of melatonin had no effect on gastric and oral microcirculation in vivo. During hemorrhagic shock, gastric microcirculatory oxygenation (µHbO2) was decreased from 81 ± 8% to 50 ± 15%. Topical treatment with melatonin led to a significant increase in µHbO2 to 60 ± 13%. Topical melatonin treatment had no effect on gastric microcirculatory perfusion, oral microcirculation or systemic hemodynamics. Incubation of H2O2 stressed Caco-2 monolayers with melatonin did neither influence transepithelial electrical resistance nor LY translocation. Topical treatment of the gastric mucosa with melatonin attenuates the shock induced decrease in microcirculatory oxygenation. As no effects on local microcirculatory and systemic perfusion were recorded, the improved µHbO2 is most likely caused by a modulation of local oxygen consumption. In vitro melatonin treatment did not improve intestinal barrier integrity in the context of oxidative stress. These results extend the current knowledge on melatonin's protective effects during hemorrhage in vivo. Topical application of melatonin exerts differential effects on local microcirculation compared to systemic pretreatment and might be suitable as an adjunct for resuscitation of hemorrhagic shock.

Indomethacin Increases the Efficacy of Oxygen Utilization of Colonic Mitochondria and Uncouples Hepatic Mitochondria in Tissue Homogenates From Healthy Rats.

Background: Studies suggest that indomethacin (Indo) exhibits detrimental changes in the small intestine (microvascular disorder, villus shortening, and epithelial disruption), mainly due to mitochondrial uncoupling. The effects of Indo on colon and liver tissue are unclear. The aim of this study was to determine the effects of Indo on mitochondrial respiration in colonic and hepatic tissue. Methods: Mitochondrial oxygen consumption was assessed in colon and liver homogenates from healthy rats. Homogenates were incubated without drug (control) or Indo (colon: 0.36, 1, 30, 179, 300, 1,000, 3,000 µM; liver: 0.36, 1, 3, 10, 30, 100, 179 µM; n = 6). State 2 (substrate-dependent) and state 3 (ADP-dependent respiration) were evaluated with respirometry. The respiratory control index (RCI) was derived and the ADP/O ratio was calculated. Statistics: Data presented as % of control, min/median/max, Kruskal-Wallis+Dunn's correction, * p < 0.05 vs. control. Results: Indo had no effect on RCI of colonic mitochondria. ADP/O ratio increased in complex I at concentrations of 1,000 and 3,000 µM (Indo 1,000 µM: 113.9/158.9/166.9%*; Indo 3,000 µM: 151.5/183.0/361.5%*) and in complex II at concentrations of 179 and 3,000 µM vs. control (179 µM: 111.3/73.1/74.9%*; 3,000 µM: 132.4/175.0/339.4%*). In hepatic mitochondria RCI decreased at 179 µM for both complexes vs. control (complex I: 25.6/40.7/62.9%*, complex II: 57.0/73.1/74.9%*). The ADP/O ratio was only altered in complex I at a concentration of 179 µM Indo vs. control (Indo 179 µM: 589.9/993.7/1195.0 %*). Conclusion: Indo affected parameters of mitochondrial function in an organ-specific and concentration-dependent manner. In colonic tissue, RCI remained unaltered whereas the ADP/O ratio increased. Indo at the highest concentration decreased the RCI for both complexes in hepatic mitochondria. The large increase in ADP/O ratio in complex I at the highest concentration likely reflects terminal uncoupling.

Effect of Pravastatin Pretreatment and Hypercapnia on Intestinal Microvascular Oxygenation and Blood Flow During Sepsis.

INTRODUCTION: In septic patients, adequate microvascular oxygenation (µHBO2) of the intestine is vital for their outcome. Recent studies suggest that statins can ameliorate septic microcirculation in a variety of tissues. However, the effect on intestinal microvascular oxygenation and blood flow is largely unknown. Furthermore, there are indications that statin therapy might not be beneficial in the presence of hypercapnia, as observed in septic acute respiratory distress syndrome (ARDS) patients. Therefore, the present study explores the effect of pravastatin with and without additional moderate acute hypercapnia on intestinal microvascular oxygenation and blood flow in experimental sepsis. METHODS: Forty male Wistar rats were randomized into four groups. Half of the animals received 0.2 mg • kg pravastatin s.c., the other half received the same volume as vehicle (NaCl 0.9%). After 18 h, colon ascendens stent peritonitis surgery was conducted in all animals to induce sepsis. Twenty-four hours after surgery, baseline was established and the animals were subjected to either 120 min of normocapnic (pCO2 40 ±â€Š6 mm Hg) or moderate hypercapnic (pCO2 72 ±â€Š10 mm Hg) ventilation. Microcirculatory oxygenation (µHBO2) and perfusion (µflow) of the colon were continuously recorded using tissue reflectance spectrophotometry and laser Doppler, respectively. RESULTS: In normocapnic septic animals µHBO2 decreased over time (-8.4 ±â€Š8.7%; P < 0.05 vs. baseline), whereas after pravastatin pretreatment µHBO2 remained constant (-1.9 ±â€Š5.7% vs. baseline). However, in hypercapnic septic animals pretreated with pravastatin µHBO2 declined significantly over time (-8.9 ±â€Š11.8%; P < 0.05 vs. baseline) and was significantly lower compared with normocapnic pravastatin-pretreated animals. µflow did not change over time in any group. CONCLUSION: Pravastatin pretreatment ameliorates the intestinal microvascular oxygenation in sepsis and thus seems to prevent intestinal hypoxia. Furthermore, we demonstrated that additional hypercapnia abolishes this effect, indicating why septic ARDS patients might not benefit from pravastatin therapy.

Regional hypothermia improves gastric microcirculatory oxygenation during hemorrhage in dogs.

Mild systemic hypothermia increases gastric mucosal oxygenation (µHbO2) during hemorrhagic shock in dogs. In the context of critical blood loss hypothermia might be fatal due to adverse side effects. Selective regional hypothermia might overcome these limitations. The aim of our study was to analyze the effects of regional gastric and oral mucosal hypothermia on µHbO2 and perfusion (µflow). In a cross-over study six anesthetized dogs were subjected to local oral and gastric mucosal hypothermia (34°C), or maintenance of local normothermia during normovolemia and hemorrhage (-20% blood volume). Macro- and microcirculatory variables were recorded continuously. During normovolemia, local hypothermia increased gastric microcirculatory flow (µflow) without affecting oxygenation (µHbO2) or oral microcirculation. During mild hemorrhagic shock gastric µHbO2 decreased from 72±2% to 38±3% in the normothermic group. This was attenuated by local hypothermia, where µHbO2 was reduced from 74±3% to 52±4%. Local perfusion, oral microcirculation and macrocirculatory variables were not affected. Selective local hypothermia improves gastric µHbO2 during hemorrhagic shock without relevant side effects. In contrast to systemic hypothermia, regional mucosal hypothermia did not affect perfusion and oxygen supply during hemorrhage. Thus, the increased µHbO2 during local hypothermia rather indicates reduced mucosal oxygen demand.