Enriched stable 204Pb as tracer at ultra-low levels in clinical investigations.

The potential of enriched Pb (204Pb) was assessed to monitor pathways of trace levels of Pb in the pg range within the human body via isotope pattern variation in situations where natural lead cannot be used as a tracer due to regulatory limitations. Isotope ratio measurements were accomplished by means of (multi-collector) inductively coupled plasma mass spectrometry including a comparison of single and multi-collector ICP-MS for low-level 204Pb assessment. Isotopic pattern results from a blend of a large quantity of the element with a natural isotopic composition and an enriched stable isotope at orders of magnitude lower levels pose a nontrivial analytical problem. Isotope pattern deconvolution was successfully applied as mathematical tool based on multiple linear regressions. The method allowed for deconvolving the isotope pattern from measured isotope ratios without knowing the quantities of different isotope sources incorporated and mixed into the sample at levels of < 1 pg 204Pb/g blood. The objective of this manuscript is to evaluate and summarize the analytical aspects for Pb isotope pattern deconvolution based on the results of a clinical trial, where a 204Pb-enriched isotope tracer was applied to investigate the bioavailability of orally applied Pb along with purified clinoptilolite tuff as potential supplement. This unique approach allows to reduce tracer amounts to harmless levels to human health, which are in accordance with the legal regulative to study enrichment levels of < 0.01% in human blood.

Topically administered purified clinoptilolite-tuff for the treatment of cutaneous wounds: A prospective, randomised phase I clinical trial.

In an ageing society, chronic ulcers pose an increasingly relevant healthcare issue associated with significant morbidity and an increasing financial burden. Hence, there is an unmet medical need for novel, cost-effective therapies that improve healing of chronic cutaneous wounds. This prospective, randomised, open-label, phase I trial investigated the safety and tolerability of topically administered purified clinoptilolite-tuff (PCT), mainly consisting of the naturally occurring zeolite-mineral clinoptilolite, in artificial wounds in healthy male volunteers compared to the standard of care (SoC). We found that topically administered PCT was safe for therapeutic application in acute wounds in healthy male volunteers. No significant differences in wound healing or wound conditions were observed compared to SoC-treated wounds. However, we found a significantly higher proportion of CD68-positive cells and a significantly lower proportion of α-smooth muscle actin-positive cells in PCT-treated wounds. Scanning electron microscopy revealed PCT particles in the restored dermis in some cases. However, these did not impede wound healing or clinical symptoms. Hence, purified PCT could represent an attractive, cost-effective wound treatment promoting the process of healing.

Cardiovascular risk and mortality in patients with hyperuricemia treated with febuxostat or allopurinol: a retrospective nation-wide cohort study in Austria 2014-2017.

Patients with hyperuricemia and gout are at an increased risk for cardiovascular (CV) disease. Inhibition of the xanthine oxidase with allopurinol or febuxostat have become the mainstay for urate lowering therapy. However, it has been suggested that febuxostat increases the risk for CV mortality as compared to allopurinol. The aim of this retrospective cohort study was to assess the CV risk among patients with febuxostat or allopurinol therapy. Patients who initiated urate lowering therapy with febuxostat or allopurinol between 2014 and 2017 were selected from the drug reimbursement database of the Austrian health insurances funds. The primary CV endpoint was a composite of angina pectoris, nonfatal myocardial infarction, nonfatal subarachnoid or cerebral hemorrhage, nonfatal ischemic stroke, or death from any cause. In total, 28.068 patients (62.1% male) with a mean age of 71 years were included. 7.767 initiated febuxostat treatment and 20.301 received allopurinol. The incidence rate per 100 patient-years of the composite primary endpoint was 448 (febuxostat) and 356 (allopurinol) with a corresponding adjusted hazard ratio (HR) of 0.58 (95% CI 0.53-0.63) for allopurinol vs. febuxostat initiators. Similar HR were found for secondary endpoints including all-cause mortality [0.61 (95% CI 0.55-0.68)] and separate analyses of cardiac events [0.48 (95% CI 0.38-0.61)] and ischemic stroke [0.47 (95% CI 0.36-0.61)]. Data from this Austrian population-based study suggests that febuxostat initiators are at an increased risk for nonfatal CV events or death from any cause as compared to those with allopurinol. This is consistent with CV concerns of other trials, which limited the broad therapeutic use of febuxostat.

Antibiotic prescription after tooth extraction in adults: a retrospective cohort study in Austria.

BACKGROUND: Broad spectrum antibiotics are often used for the prophylaxis of infectious endocarditis and treatment of odontogenic infections, but there are limited data related to antibiotic use and adherence to prescription guidelines.  METHODS: Data from patients with tooth extraction between 2014 and 2018 were selected from a database of a regional health insurance fund. We created three data sets, one based on all tooth extractions, one on multiple teeth extractions, and one including only single tooth extraction. After data collection, descriptive analysis was carried out. The differences in prescription pattern of antibiotic medicine were tested by χ2 test, Student´s t-test or ANOVA. RESULTS: From 43,863 patients with tooth extraction, 53% were female, and 3,983 patients (9.1%) filled a prescription for antibiotic medicine. From 43,863 patients, 157 patients (0.4%) had endocarditis risk, but only 8 patients of these (5.1%) filled an antibiotic prescription. In total, 9,234 patients had multiple and 34,437 patients had only one tooth extraction. Patients with more than one tooth extraction received more often antibiotic treatment (10.7%) compared to those with single tooth extractions (χ2 = 36; p < 0,001). Patients with more than one tooth extraction were older, however, younger patients received antibiotics more frequently (t = 28,774, p = 0.001). There was no relationship with endocarditis risk status. Clindamycin and amoxicillin/clavulanic acid were the most frequently prescribed antibiotic medicines. CONCLUSIONS: In this retrospective cohort study, dentists did not discriminate prophylactic antibiotic prescription with regard to endocarditis risk status. A factor influencing prescribing behaviour of antibiotic medicines was the number of extracted teeth.

Serum antibody response to BNT162b2 after natural SARS-CoV-2 infection.

BACKGROUND: There is preliminary evidence that individuals with previous SARS-CoV-2 infections exhibit a more pronounced antibody response. However, these assumptions have not yet been supported by data obtained through various CE-marked tests. This study aimed to close this gap. METHODS: Sixty-nine seronegatives and 12 individuals post-SARS-CoV-2 infection (tested by CE-labelled Roche NC immunoassay or PCR-confirmed assay) were included 21 ± 1 days after receiving the first dose of the Pfizer/BioNTech BNT162b2 vaccine. Antibody response to viral spike protein (S) was assessed by CE-labelled Roche S and DiaSorin S1/S2 assays and by a surrogate virus neutralization test (sVNT). RESULTS: After a single dose of BNT162b2, individuals after natural SARS-CoV-2 infection presented with markedly higher anti-S levels than naïve individuals (Roche S: 9078.5 BAU/mL [5267.0-24 298.5] vs 79.6 [24.7-142.3]; and DiaSorin S1/S2: 1465.0 AU/mL [631.0-5365.0] vs 63.7 [47.8-87.5]) and showed all the maximum observed inhibition activity in the sVNT (98%), without overlaps between groups. There was a trend for higher responses in those with a more distant infection, although not statistically significant. The relative antibody increase after dose 2 was significantly higher among naïve individuals (25-fold), but antibody levels remained below that of seropositives. CONCLUSIONS: Compared with naïve individuals, seropositives after natural SARS-CoV-2 infection presented with a substantially higher antibody response already after dose 1 of BNT162b2, as measured by two CE-marked in vitro diagnostic tests and a sVNT. These results should stimulate discussion and research on whether individuals after previous SARS-CoV-2 infection would benefit from a two-part vaccination schedule or whether these currently much-needed second doses could be saved.

Oral anticoagulant therapy and outcome in patients with stroke. A retrospective nation-wide cohort study in Austria 2012-2017.

PURPOSE: Patients with stroke are at high risk of recurrence of vascular events. Non-vitamin K oral anticoagulant (NOAC) and vitamin K antagonists (VKA) are used as secondary prophylaxis. The aim of this study was to evaluate the utilization of NOAC and VKA, and their impact on re-stroke or death in Austria. METHODS: We analyzed retrospective data between 2012 and 2017 from medical services covered by the health insurance funds, which provides health care for all residents in Austria. Patients without anticoagulant medication 3 months preceding the index event were eligible. RESULTS: 76 354 patients were discharged with a hospital diagnosis of stroke. From these, 16 436 patients with a median age of 78 years received VKA or NOAC. After adjustment, the recurrence of stroke was less frequent in patients with NOAC compared to those with VKA (HR 0.87; 95%CI 0.77-0.97). However, there was no difference in mortality rate after adjustment for age, sex, and co-morbidities for patients with NOAC (HR 1.0; 95%CI 0.92-1.08). Diabetes (HR 1.25, 95%CI 1.08-1.45; HR 1.25, 95% CI 1.13-1.38) and cardiovascular disease (HR 1.43, 95%CI 1.24-1.65; HR 1.27, 95%CI 1.16-1.39) were significantly associated with re-stroke or death. Younger age (p = 0.0028; HR 0.99, 95%CI 0.99-0.99) was significantly associated with re-stroke, and advanced age (p < 0.0001; HR 1.09, 95%CI 1.08-1.09) with death. CONCLUSION: NOAC prescription is related with a reduced risk of re-stroke but increased mortality compared to patients with VKA. The event risk is associated with diabetes, cardiovascular disease and age.

Utilization of potentially inappropriate medication and risk of adverse drug events among older adults with chronic renal insufficiency: a population-wide cohort study.

BACKGROUND: The use of potentially inappropriate medication (PIM) in population of older adults may result in adverse drug events (ADE) already after short term exposure, especially when it is prescribed to patients with chronic kidney disease (CKD). In order to limit ADE in the treatment of older adults PIM lists have been constructed as a source of information for healthcare professionals. The aim of this study was to estimate the utilization of PIM and incidence of ADE in older adults (≥70 years) with CKD. METHODS: We conducted a retrospective population-wide cohort study including patients from Lower Austria who were 70 years or older and diagnosed with CKD in the period from 2008 to 2011. Utilization of PIM was estimated from prescriptions filled by target population. We estimated risks of hospitalization due to ADE within 30 days after incident PIM prescription and compared them to a PIM-free control group by using marginal structural models (MSM). RESULTS: We identified 11,547 patients (women: 50.6%, median age in 2008: 78 years) who fulfilled the inclusion criteria. In total 24.7 and 8.1% of all prescriptions from that period contained a medication with a substance listed in the EU (7)-PIM and AT-PIM list, respectively. Proton pump inhibitors and Ginkgo biloba were the most often prescribed PIMs in this population. 94.6 and 79.3% patients filled at least one EU(7)-PIM and AT-PIM prescription, respectively. Despite the relatively high utilization of PIM there was only a low incidence of clinically relevant ADE. No event type exceeded the threshold level of 1% in the analysis of risks of ADE after filling a prescription for PIM. Nevertheless, MSM analysis showed an increased risk for 11 drugs and reduced risk for 4 drugs. CONCLUSIONS: PIM prescription was common among older adults with CKD, however, only a small number of these drugs eventually led to hospitalization due to ADE within 30 days after incident PIM was filled. In the absence of a clinically important PIM-related increase in risk, an assessment of potential ADE severity to a PIM list by using a warning score system seems prudent.

Effect of hydroxypropyl-ß-cyclodextrin in fluid and semi-solid submicron emulsions on physiological skin parameters during regular in vivo application.

OBJECTIVE: The aim of the present study was to evaluate the effect of hydroxypropyl-ß-cyclodextrin (HP-ß-CD) in cosmetic submicron emulsions and submicron emulsion gels on physiological skin parameters during regular application in a clinical set-up. METHODS: Formulation morphology was investigated using cryo-transmission electron microscopy. Stability of the employed formulations was determined by photon correlation spectroscopy, measurement of pH and rheological properties. Effect on physiological skin parameters was evaluated during regular application over four weeks in a parallel group study (n = 15, healthy forearm skin) with a Corneometer, Sebumeter, skin-pH-Meter, Aquaflux and an Epsilon sensor. Confocal Raman spectroscopy was employed to monitor urea and NMF levels. RESULTS: Both submicron emulsions and gels showed satisfying storage stability irrespective of cyclodextrin incorporation. No statistically significant effects on skin barrier function and any of the observed parameters were obtained, indicating good skin tolerability of all tested formulations. CONCLUSION: Results suggest good skin tolerability of the developed cosmetic submicron emulsions and gels with HP-ß-CD.

OBJECTIF: Le but de la présente étude était d'évaluer l'effet de l'hydroxypropyl-ß-cyclodextrine (HP-ß-CD) dans les émulsions cosmétiques submicroniques et les gels d'émulsion submicronique sur les paramètres physiologiques de la peau lors d'une application régulière dans une configuration clinique. MÉTHODES: La morphologie de la formulation a été étudiée en utilisant la microscopie électronique à transmission cryo. La stabilité des formulations employées a été déterminée par spectroscopie de corrélation de photons, mesure du pH et des propriétés rhéologiques. L'effet sur les paramètres physiologiques de la peau a été évalué lors d'une application régulière pendant quatre semaines dans une étude de groupe parallèle (n = 15, peau d'avant-bras saine) avec un cornéomètre, un sébumètre, un pH-mètre cutané, un Aquaflux et un capteur Epsilon. La spectroscopie Raman confocale a été utilisée pour surveiller les niveaux d'urée et de NMF. RÉSULTATS: Les émulsions et les gels submicroniques ont montré une stabilité de stockage satisfaisante indépendamment de l'incorporation de cyclodextrine. Aucun effet statistiquement significatif sur la fonction de barrière cutanée et aucun des paramètres observés n'a été obtenu, indiquant une bonne tolérance cutanée de toutes les formulations testées. CONCLUSION: Les résultats suggèrent une bonne tolérance cutanée des émulsions et des gels cosmétiques submicroniques développés avec HP-ß-CD.

Interleaved 31 P MRS/1 H ASL for analysis of metabolic and functional heterogeneity along human lower leg muscles at 7T.

PURPOSE: MR offers the unique possibility to noninvasively investigate cellular energy metabolism via 31P MRS, while blood perfusion, which provides oxygen and substrates to the tissue, is accessible by arterial spin labeling (ASL) 1H MRI. Because metabolic and hemodynamic parameters are linked, it would be desirable to study them simultaneously. A 3D-resolved method is presented that allows such measurements with high spatiotemporal resolution and has the potential to discern differences along an exercising muscle. METHODS: Multi-voxel localized 31 P MRS was temporally interleaved with multi-slice pASL 1H MRI. Phosphorus spectra were collected from two adjacent positions in gastrocnemius medialis (GM) during rest, submaximal plantar flexion exercise and recovery, while perfusion and T2* -weighted axial images were acquired at the same time. Seventeen healthy volunteers (9 f / 8 m) were studied at 7 T. RESULTS: An increase of postexercise perfusion and T2* -weighted signal in GM positively correlated with end-exercise PCr depletion and pH drop. At proximal positions functional and metabolic activity was higher than distally, that is, perfusion increase and peak T2* -weighted signal, end-exercise PCr depletion, end-exercise pH, and PCr recovery time constant were significantly different. An NOE-induced SNR increase of approximately 20 % (P < .001), at rest, was found in interleaved 31 P spectra, when comparing to 31 P-only acquisitions. CONCLUSIONS: A technique for fast, simultaneous imaging of muscle functional heterogeneity in ASL, T2* and acquisition of time-resolved 31 P  MRS data is presented. These single exercise recovery experiments can be used to investigate local variations during disease progression in patients suffering from vascular or muscular diseases.

Dose-dependent naloxone-induced morphine withdrawal symptoms in opioid-dependent males-a double-blinded, randomized study.

AIMS: Oral opioid preparations combined with naloxone are intended to induce a transient acute withdrawal syndrome to avoid intravenous misuse. This trial aimed to establish an appropriate morphine-naloxone dose ratio for an abuse-deterrent oral opioid formulation. METHODS: In a randomized, double-blinded, 2 × 2 cross-over trial, 43 patients with opioid use disorder were challenged with intravenous morphine HCl Ph.Eur. (75 mg; [morphine mono]) or morphine HCl Ph.Eur. and naloxone HCl Ph.Eur. at ratios of 100:1 (75 mg: 0.75 mg; [morphine-naloxone 100:1]) or 200:1 (75 mg: 0.375 mg; [morphine-naloxone 200:1]). Acute naloxone-induced opioid withdrawal was evaluated using subjective (Short Opiate Withdrawal Scale-German [SOWS-G]) and observer-rated (Objective Opiate Withdrawal Scale [OOWS], Wang scale) questionnaires, and physiological parameters. For statistical analysis, the area under the curve between baseline and 20 minutes after drug administration of the outcome variables was calculated. RESULTS: Intravenous morphine-naloxone caused rapid withdrawal symptoms. Coadministration of naloxone dose-dependently (morphine-naloxone 100:1 > morphine-naloxone 200:1) increased SOWS-G, OOWS and Wang Scale area under the curve when compared to morphine mono, respectively (all P < .0001). A similar response was detectable for changes of pupil diameter. Blood pressure and respiratory rate changed heterogeneously, and heart rate was unaltered by morphine without or with naloxone. CONCLUSION: Morphine-naloxone 100:1 effectively suppresses the pleasurable effects of intravenous morphine and results in an aversive withdrawal reaction. A lower naloxone concentration as used in morphine-naloxone 200:1 does not appear to be appropriate to prevent intravenous morphine misuse.

ADMA and NT pro-BNP are associated with overall mortality in elderly.

BACKGROUND: Increased asymmetrical dimethylarginine (ADMA) and NT pro-BNP concentrations have been associated with mortality in patients with cardiovascular (CV) disease and the general population. The use of these prognostic markers in an older population is not established yet. The aim of the present study was to investigate the prognostic value of age, sex, BMI, co-medication and CV laboratory risk markers in geriatric care patients. MATERIALS AND METHODS: In this prospective observational single-centre cohort study data of long-term geriatric care patients were collected. Blood samples were collected between 14.09.2009 and 16.12.2009, and mortality was recorded up to 90 months. ADMA, its symmetric isomer SDMA, L-arginine, NT pro-BNP and CRP were determined at study entry. Simple associations of risk factors for survival period were explored by Spearman correlation coefficient. Significant univariate predictors for survival period were used in the Cox proportional hazard model. RESULTS: A total of 481 patients were screened, and data from 449 patients were analysed. A total of 381 patients died during the observation period. Full data sets from 344 patients were used for Cox regression analysis. Male sex, older age, lower BMI, use of neuroleptic medicine, peripheral artery disease, and elevated plasma concentrations of ADMA, NT pro-BNP, and CRP were significant predictors of mortality. CONCLUSION: The concentration of ADMA and NT pro-BNP may be used as an early risk marker for overall mortality in geriatric care. Neuroleptic medicine is associated with increased mortality in this population.

Intravenous Heme Arginate Induces HO-1 (Heme Oxygenase-1) in the Human Heart.

Objective- HO-1 (heme oxygenase-1) induction may prevent or reduce ischemia-reperfusion injury. We previously evaluated its in vivo induction after a single systemic administration of heme arginate in peripheral blood mononuclear cells. The current trial was designed to assess the pharmacological tissue induction of HO-1 in the human heart with heme arginate in vivo. Approach and Results- Patients planned for conventional aortic valve replacement received placebo (n=8), 1 mg/kg (n=7) or 3 mg/kg (n=9) heme arginate infused intravenously 24 hours before surgery. A biopsy of the right ventricle was performed directly before aortic cross-clamping and after cross-clamp release. In addition, the right atrial appendage was partially removed for analysis. HO-1 protein and mRNA concentrations were measured in tissue samples and in peripheral blood mononuclear cells before to and up to 72 hours after surgery. No study medication-related adverse events occurred. A strong, dose-dependent effect on myocardial HO-1 mRNA levels was observed (right ventricle: 7.9±5.0 versus 88.6±49.1 versus 203.6±148.7; P=0.002 and right atrium: 10.8±8.8 versus 229.8±173.1 versus 392.7±195.7; P=0.001). This was paralleled by a profound increase of HO-1 protein concentration in atrial tissue (8401±3889 versus 28 585±10 692 versus 29 022±8583; P<0.001). Surgery and heme arginate infusion significantly increased HO-1 mRNA concentration in peripheral blood mononuclear cells ( P<0.001). HO-1 induction led to a significant increase of postoperative carboxyhemoglobin (1.7% versus 1.4%; P=0.041). No effect on plasma HO-1 protein levels could be detected. Conclusions- Myocardial HO-1 mRNA and protein can be dose-dependently induced by heme arginate. Protective effects of this therapeutic strategy should be evaluated in upcoming clinical trials. Clinical Trial Registration- URL: http://www.clinicaltrials.gov . Unique identifier: NCT02314780.

Open-Label Two-Dose Pilot Study of Landiolol for the Treatment of Atrial Fibrillation/Atrial Flutter in Caucasian Patients.

BACKGROUND: We investigated for the first time the suitability of landiolol, an ultra-short-acting ß1-specific ß-blocker, for the treatment of atrial fibrillation/atrial flutter (AF/AFL) in Caucasian patients.Methods and Results:The 20 study patients received landiolol as a continuous infusion (starting dose 40 µg/kg/min) with (B+CI) or without (CI) a preceding bolus dose (100 µg/kg/min administered over 1 min) in a prospective open-label study. The primary endpoint was the proportion of patients with sustained heart rate (HR) reduction ≥20% or to <90 beats/min within 16 min of starting the CI. Secondary endpoints were the pharmacodynamics, pharmacokinetics, AF/AFL symptoms, safety and tolerability of landiolol. At 16 min, HR was reduced in all patients treated with landiolol. The primary endpoint was met by 60% of patients in the CI group and 40% in the B+CI group without a significant group difference. Overall reduction of AF/AFL symptoms at 16 min was 72%. Safety and local tolerability of landiolol were excellent, and no serious adverse events occurred. CONCLUSIONS: Continuous infusion of landiolol with a starting dose of 40 µg/kg/min is suitable for the acute treatment of tachycardic AF/AFL in Caucasian patients. Administration of a preceding bolus seems unnecessary.

SSRI co-medication with NOAC or VKA does not increase hospitalisation for bleeding: A retrospective nationwide cohort study in Austria 2010-2015.

OBJECTIVES: Non-vitamin K oral anticoagulants (NOACs) or vitamin K antagonists (VKAs) are used for the prophylaxis and treatment of thromboembolic events. A potential drug-drug interaction and increased bleeding events have been reported with co-medication of selective serotonin receptor inhibitors (SSRIs) and VKA. The aim of this study was to investigate the bleeding risk of a coprescription of NOAC or VKA with SSRI. METHODS: Patients with prescription of NOAC or VKA and an antidepressant drug therapy (ADTx) were selected from the drug reimbursement database of 13 Austrian health insurance funds. For this cohort, hospital discharge diagnoses for gastrointestinal bleeding, cerebral haemorrhage, and bleeding anaemia between 2010 and 2015 were analysed. RESULTS: Data were available from 50 196 female and 31 308 male patients. Among these, 892 patients had 987 hospitalisations with bleeding events. The most frequent bleeding cases were gastrointestinal bleedings with 588 events (59.6%), followed by cerebral haemorrhage with 344 (34.8%), and bleeding anaemia with 55 events (5.6%), respectively. The risk of bleeding events was similar between SSRI and other ADTx, when combined with oral anticoagulants (p = 0.51). Concomitant treatment of patients with SSRI or other ADTx and NOAC was associated with an increased bleeding risk compared with cotreatment with VKA (1.21, 95% CI: 1.05-1.40; p = 0.0097). CONCLUSION: Co-medication of SSRI with VKA or NOAC has little if any impact on hospital discharge diagnoses for bleeding events compared with cotreatment of those anticoagulants with other antidepressant medications.

Dynamic multivoxel-localized 31 P MRS during plantar flexion exercise with variable knee angle.

Exercise studies investigating the metabolic response of calf muscles using 31 P MRS are usually performed with a single knee angle. However, during natural movement, the distribution of workload between the main contributors to force, gastrocnemius and soleus is influenced by the knee angle. Hence, it is of interest to measure the respective metabolic response of these muscles to exercise as a function of knee angle using localized spectroscopy. Time-resolved multivoxel 31 P MRS at 7 T was performed simultaneously in gastrocnemius medialis and soleus during rest, plantar flexion exercise and recovery in 12 healthy volunteers. This experiment was conducted with four different knee angles. PCr depletions correlated negatively with knee angle in gastrocnemius medialis, decreasing from 79±14 % (extended leg) to 35±23 %(∼40°), and positively in soleus, increasing from 20±21 % to 36±25 %; differences were significant. Linear correlations were found between knee angle and end-exercise PCr depletions in gastrocnemius medialis (R2 =0.8) and soleus (R2 =0.53). PCr recovery times and end-exercise pH changes that correlated with PCr depletion were consistent with the literature in gastrocnemius medialis and differences between knee angles were significant. These effects were less pronounced in soleus and not significant for comparable PCr depletions. Maximum oxidative capacity calculated for all knee angles was in excellent agreement with the literature and showed no significant changes between different knee angles. In conclusion, these findings confirm that plantar flexion exercise with a straight leg is a suitable paradigm, when data are acquired from gastrocnemius only (using either localized MRS or small surface coils), and that activation of soleus requires the knee to be flexed. The present study comprises a systematic investigation of the effects of the knee angle on metabolic parameters, measured with dynamic multivoxel 31 P MRS during muscle exercise and recovery, and the findings should be used in future study design.

Cardiovascular Effects of Stress During Acutely Increased Free Fatty Acids in a Randomized, Double-Blind, Cross-Over Study in Humans.

Increased free fatty acids stimulate sympathetic nervous system activity, impair endothelium-dependent vasodilation, and increase regional blood flow. The aim of this study was to assess if fatty acids acutely elevated by infusion of intralipid/heparin affect cardiovascular reactivity employing two stressors eliciting either a cardiac (Stroop test) or vascular (Cold Face test) dominated pressor response. Two stress tasks were performed in 20 healthy subjects (10 women, 10 men) before and during a 180-min intralipid/heparin or saline infusion as placebo on alternate trial days in a randomized crossover study design. Blood pressure, heart rate, cardiac index, and total peripheral resistance index were measured. At baseline, the Stroop test did not affect hemodynamic parameters, and the Cold Face test had an impact on hemodynamic parameters except for heart rate. Plasma fatty acids concentrations increased to 810% (t=11.0, p<0.001) of baseline and C-peptide increased by 17% (t=4.66, p<0.001) during intralipid/heparin infusion. This was paralleled by increased cardiac index (F=9.98; p<0.005 vs. saline) and reduced total peripheral resistance index (F=4.46; p<0.05 vs saline). There was no effect of intralipid/heparin or saline infusion on Stroop test or Cold Face test reactivity of hemodynamic parameters. An acute increase in free fatty acids does not affect the magnitude or pattern of stress response in healthy volunteers, but primarily alter the underlying cardiovascular tone by decreasing total peripheral resistance index and increasing cardiac index to maintain a constant blood pressure.

Landiolol: pharmacology and its use for rate control in atrial fibrillation in an emergency setting.

This article provides new insight on landiolol, an ultra-short acting injectable betablocker, recently approved in Europe, with regard to its pharmacokinetic and pharmacodynamic profile, along with its first experience in Caucasian healthy volunteers and patients with atrial fibrillation. Landiolol as iv formulation exhibited in an emergency setting rapid rate reduction in patients with tachycardic atrial fibrillation without pronounced blood pressure drop both in caucasian and asian populations in similar manner.

Interleaved multivoxel 31 P MR spectroscopy.

PURPOSE: Separate measurements are required when investigating multiple exercising muscles with singlevoxel-localized dynamic 31 P-MRS. With multivoxel spectroscopy, 31 P-MRS time-series spectra are acquired from multiple independent regions during one exercise-recovery experiment with the same time resolution as for singlevoxel measurements. METHODS: Multiple independently selected volumes were localized using temporally interleaved semi-LASER excitations at 7T. Signal loss caused by mutual saturation from shared excitation or refocusing slices was quantified at partial and full overlap, and potential contamination was investigated in phantom measurements. During an exercise-recovery experiment both gastrocnemius medialis and soleus of two healthy volunteers were measured using multivoxel acquisitions with a total TR of 6 s, while avoiding overlap of excitation slices. RESULTS: Signal reduction by shared adiabatic refocusing slices selected 1 s after the preceding voxel was between 10% (full overlap) and 20% (half overlap), in a phantom measurement. In vivo data were acquired from both muscles within the same exercise experiment, with 13-18% signal reduction. Spectra show phosphocreatine, inorganic phosphate, adenosine-triposphate, phosphomonoesters, and phosphodiesters. CONCLUSION: Signal decrease was relatively low compared to the 2-fold increase in information. The approach could help to improve the understanding in metabolic research and is applicable to other organs and nuclei. Magn Reson Med 77:921-927, 2017. © 2016 The Authors Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Ticagrelor mitigates ischaemia-reperfusion induced vascular endothelial dysfunction in healthy young males - a randomized, single-blinded study.

AIMS: Animal data suggest that ticagrelor but not clopidogrel protects against tissue injury. It is unclear if this effect of ticagrelor is also detectable in humans. We studied the effect of ticagrelor and clopidogrel at standard clinical doses on endothelial dysfunction in an experimental model of forearm vascular ischaemia-reperfusion (IR) injury. METHODS: In a randomized, single-blinded trial, 24 subjects underwent forearm blood flow (FBF) measurements in response to the endothelium-dependent vasodilator acetylcholine (ACh) and to glyceryltrinitrate (GTN; endothelium-independent) before and after a 20 min forearm ischaemia. FBF reactivity was assessed after an oral loading dose of ticagrelor or clopidogrel and after 14 days of regular intake of maintenance doses of the study medicines. In addition, the effect on platelet inhibition was evaluated using multiple electrode aggregometry. RESULTS: ACh-induced vasodilation was impaired during reperfusion and not completely normalized by acute or chronic treatment with ticagrelor or clopidogrel (post- vs. pre-ischaemia). However, ticagrelor mitigated endothelial dysfunction compared to clopidogrel after loading (FBF AChAUC ratio post- vs. pre-ischaemia: 0.83 [0.70; 0.96] vs. 0.64 [0.56; 0.72]; P = 0.024) and after chronic administration (FBF AChAUC ratio: 0.86 [0.71; 1.00] vs. 0.66 [0.55; 0.77]; P = 0.027). As expected, GTN-induced vasodilation was not affected by ischaemia. Ticagrelor or clopidogrel treatment inhibited platelet activation to a similar degree. CONCLUSION: Our data indicate that ticagrelor treatment exerts a greater vascular salutary effect than clopidogrel during reperfusion after an acute vascular occlusion. IR-induced vascular injury cannot be prevented completely by administration of these antiplatelet agents at standard clinical doses.

The recipient's heme oxygenase-1 promoter region polymorphism is associated with cardiac allograft vasculopathy.

Heme oxygenase-1 (HO-1) catalyses the degradation of heme to biliverdin, free iron, and carbon monoxide. The promoter region contains a highly polymorphic (GT)n repeat, where shorter (GT)n repeat sequences are linked to higher transcriptional activity, which was shown to correlate with a cytoprotective effect. Higher HO-1 levels may protect from cardiac allograft vasculopathy. Cardiac allograft recipients transplanted between 1988 and 2012 were analyzed for the HO-1 (GT)n repeat polymorphism using PCR and DNA fragment analysis with capillary electrophoresis. A relation to cardiac allograft vasculopathy (CAV) was analyzed using Cox regression including common risk factors for CAV and the occurrence of rejection episodes as explanatory variables. A total of 344 patients were analyzed, of which 127 patients were positive for CAV (36.9%). In our multivariable Cox regression analysis, the short homozygous HO-1 (GT)n genotype with <27 repeats (S/S) revealed a higher risk for CAV (P = 0.032). Donor age (P = 0.001) and donor weight (P = 0.005) were significant predictors for CAV. A potential risk for CAV was associated with rejection episodes (P = 0.058) and history of smoking (P = 0.06). The recipient HO-1 (GT)n genotype may contribute to CAV development. This finding has to be evaluated in larger series including studies targeting the underlying disease mechanism.