Search

Turkish expresses adverbial subordination predominantly by means of converb clauses. These are headed by nonfinite verbs, i.e. converbs, which have a converb suffix attached to the stem. The different converbs express different aspectual relations between the subordinate and the superordinate clause, and they can be modifying or non-modifying. We analyse data from speakers of Turkish as a heritage language in Germany and the U.S. as well as monolingual speakers of Turkish in Turkey. The data come from two age groups: adults and adolescents. We show that unlike in canonical Turkish, converbs in heritage Turkish can be multifunctional, meaning that they can express both simultaneity and causality, for example. Furthermore, we show that converbs in heritage Turkish can be both modifying and non-modifying. As possible factors which might be responsible for such variation, we discuss language contact, sociolinguistic differences between the speaker communities (Germany vs. the U.S.) and age of the speakers.

Turkish is a language described as relying predominantly on non-finite subordination in the domain of clause combining. However, there are also strategies of finite subordination, as well as means of syndetic and asyndetic paratactic clause combining, especially in the informal settings. Clause combining is and has been one of the focal points of research on heritage Turkish (h-Turkish). One point is particularly clear: In comparison with the monolingual setting, finite means of clause combining are more frequent in h-Turkish in Germany, the U.S., and the Netherlands, while non-finite means of clause combining are less frequent. Overall, our results confirm the findings of earlier studies: heritage speakers in Germany and the U.S. prefer paratactic means of clause combining using connectors, as opposed to monolingual speakers. Our results also reveal that age (adolescents vs. adults) and register (informal vs. formal) significantly modulate the use of connectors. Moreover, we find that the shift in preferences in means of clause combining triggers an expansion in the system of connectors and leads to the development of new narrative connectors, such as o zaman and derken. The system of syndetic paratactic clause combining is expanding in heritage Turkish. This expansion calls for multifaceted modeling of change in heritage languages, which integrates language-internal factors (register), dynamics of convergence with the contact languages, and extra-linguistic factors (age and language use).

Summary L3 acquisition has begun to attract the attention of many scholars in recent years. Heritage contexts are especially fruitful areas to understand how linguistic and nonlinguistic mechanisms interact with one another. The current study focuses on L3 English acquisition of object pronouns with L1 Turkish, L2 German speakers. We seek to find out whether the speakers could produce object pronouns accurately, whether L3 English proficiency has any effects on their acquisition, and finally, whether all object pronouns are acquired in the same way. Data for this study come from a corpus consisting of written and oral productions of 167 participants, who were students in four distinct grades, namely 5th, 7th, 10th and 12th graders at different schools in Berlin, Germany. The results reveal that participants were highly meticulous in their object pronoun use. Also, no clear L1 effect was observed, while L2 impact is implied. Lastly, proficiency and linguistic features are noted as significant factors that have an impact on L3 acquisition.

This article presents an empirical study on selected aspects of the orthographic performance of mono- and bilingual students in German. Particular attention is paid to the question whether a connection can be drawn between the orthographic performance of the bilingual students in German and their first language. For this purpose, a corpus is analyzed with data from approx. 800 test students. One group is monolingual in German, one is bilingual German–Turkish and one is bilingual German–Russian. A highly significant influence of Russian resp. Turkish on the performance to differentiate between tense and lax vowels is found. This corresponds to expectations insofar as in opposition to German, neither in Turkish nor in Russian, tense and lax vowels are distinguished phonologically. In other areas of orthography, this influence of the first language is not measurable or not to the same extent.

Reporting of new or unexpected adverse drug reactions of medicines that are subject to additional monitoring (“black triangle” label), such as the antipsychotic drug cariprazine, is of paramount importance to improve pharmacotherapy safety.

Prior studies suggest an association between Vitamin K antagonists (VKA) and cerebral microbleeds (CMBs); less is known about nonvitamin K oral anticoagulants (NOACs). In this observational study we describe CMB profiles in a multicenter cohort of 89 anticoagulation‐related intracerebral hemorrhage (ICH) patients. CMB prevalence was 51% (52% in VKA‐ICH, 48% in NOAC‐ICH). NOAC‐ICH patients had lower median CMB count [2(IQR:1–3) vs. 7(4–11); P

BACKGROUND AND PURPOSE Progressive multifocal leukoencephalopathy (PML), an opportunistic infection of the central nervous system from the John Cunningham virus (JCV), is a side effect of natalizumab (NTZ) treatment for relapsing-remitting multiple sclerosis (RRMS), potentially leading to a substantial increase of physical and mental disability. Nevertheless, data of neuropsychological impairment during the NTZ-PML disease course are missing. Our objective was to evaluate the neuropsychological disease course of NTZ-PML patients and to compare neuropsychological deficits of NTZ-PML patients with two different non-PML multiple sclerosis (MS) cohorts. METHODS Neuropsychological examinations of 28 NTZ-PML patients performed during different phases of the disease ([i] at PML diagnosis, [ii] during immune reconstitution inflammatory syndrome [IRIS], and [iii] post-IRIS/PML) were retrospectively analyzed and compared to those of NTZ-treated RRMS or secondary progressive MS patients with and without immunotherapy. RESULTS Compared to controls, NTZ-PML patients performed worse in neuropsychological examinations during all stages of disease, mainly affecting visuospatial ability and working memory. Furthermore, failure to eliminate the JCV from the central nervous system was associated with a progredient decline of cognition, especially working memory. CONCLUSIONS Working memory and visuospatial abilities are the core neuropsychological deficits of NTZ-PML patients in long-term follow-up. Our findings should be implemented in neurorehabilitation strategies.

Introduction: With more widespread anticoagulant use, anticoagulation-associated intracerebral hemorrhage (ICH) represents an increasing proportion of all ICH. We hypothesized that c ombining ischemic and hemorrhagic stroke risk estimation can guide treatment decisions, with more precision than ischemic risk estimation alone. Methods: We enrolled consecutive patients with anticoagulation-associated ICH in 15 centers in USA, Europe and Asia from 2015-2017. Each patient was assigned annual baseline ischemic stroke and hemorrhage risk based on their CHA 2 DS 2 -VASc and HAS-BLED scores without and with index ICH taken into account. We computed a net risk by subtracting the hemorrhagic from the ischemic risk. If the sum was positive the patient was assigned a “Favorable” indication for anticoagulation; if negative an “Unfavorable”. We compared clinical and neuroimaging characteristics between the two groups. Results: Our cohort comprised 357 patients (59% male, median age 76 [68-82] years). 69% used vitamin-K antagonists (VKA), 31 % Non vitamin K antagonist (NOAC). 191 (53.5%) of patients had a favorable indication for anticoagulation prior to their ICH event; the rest 166 (46.5%) had an unfavorable indication. Those with an unfavorable indication were younger (72[66-80] vs 78[73-84] years, p=0.001, had a lower CHA 2 DS 2 -VASc score (3[3-4] vs 5[4-6], p Conclusions: In this anticoagulation-associated ICH cohort, baseline hemorrhage risk exceeded ischemic risk in ~50% of patients. This finding highlights the need for careful consideration of risk/benefit ratio prior to anticoagulation decisions. The remaining ~ 50% suffered an ICH although their baseline risk of ischemia exceeded that of hemorrhage which stresses the need for imaging, serum or other biomarkers to allow more precise estimation of hemorrhagic complication risk.

ObjectiveTo determine the prevalence of antibodies to Epstein-Barr virus (EBV) in a large cohort of patients with early multiple sclerosis (MS).MethodsSerum samples were collected from 901 patients with a clinically isolated syndrome (CIS) or early relapsing–remitting multiple sclerosis (RRMS) participating in the German National MS cohort, a prospective cohort of patients with early MS with stringent inclusion criteria. Epstein-Barr nuclear antigen (EBNA)-1 and viral capsid antigen (VCA) antibodies were measured in diluted sera by chemiluminescence immunoassays (CLIAs). Sera of EBNA-1 and VCA antibody-negative patients were retested undiluted by an EBV IgG immunoblot. For comparison, we retrospectively analysed the EBV seroprevalence across different age cohorts, ranging from 0 to >80 years, in a large hospital population (N=16 163) from Berlin/Northern Germany.ResultsEBNA-1 antibodies were detected by CLIA in 839 of 901 patients with CIS/RRMS. Of the 62 patients without EBNA-1 antibodies, 45 had antibodies to VCA as detected by CLIA. In all of the remaining 17 patients, antibodies to EBV were detected by immunoblot. Altogether, 901 of 901 (100%) patients with CIS/RRMS were EBV-seropositive. EBV seropositivity increased with age in the hospital population but did not reach 100% in any of the investigated age cohorts.ConclusionThe complete EBV seropositivity in this large cohort of patients with early MS strengthens the evidence for a role of EBV in MS. It also suggests that a negative EBV serology in patients with suspected inflammatory central nervous system disease should alert clinicians to consider diagnoses other than MS.

Background and Purpose— The aim of this study was to prospectively validate our prior findings of smaller hematoma volume and lesser neurological deficit in nonvitamin K oral anticoagulant (NOAC) compared with Vitamin K antagonist (VKA)-related intracerebral hemorrhage (ICH). Methods— Prospective 12-month observational study in 15 tertiary stroke centers in the United States, Europe, and Asia. Consecutive patients with premorbid modified Rankin Scale score of 33%] increase), neurological severity measured by National Institutes of Health Stroke Scale score, 90-day mortality, and functional status (modified Rankin Scale score). Results— Our cohort comprised 196 patients, 62 NOAC related (mean age, 75.0±11.4 years; 54.8% men) and 134 VKA related (mean age, 72.3±10.5; 73.1% men). There were no differences in vascular comorbidities, antiplatelet, and statin use; NOAC-related ICH patients had lower median baseline hematoma volume (13.8 [2.5–37.6] versus 19.5 [6.6–52.0] mL; P =0.026) and were less likely to have severe neurological deficits (National Institutes of Health Stroke Scale score of >10 points) on admission (37% versus 55.3%, P =0.025). VKA-ICH were more likely to have significant hematoma expansion (37.4% versus 17%, P =0.008). NOAC pretreatment was independently associated with smaller baseline hematoma volume (standardized linear regression coefficient:−0.415 [95% CI, −0.780 to −0.051]) resulting in lower likelihood of severe neurological deficit (odds ratio, 0.44; 95% CI, 0.22−0.85) in multivariable-adjusted models. Conclusions— Patients with NOAC-related ICH have smaller baseline hematoma volumes and lower odds of severe neurological deficit compared with VKA-related ICH. These findings are important for practicing clinicians making anticoagulation choices.

Background and purpose To date, normal values for optic nerve diameter (OND) and optic nerve sheath diameter (ONSD) for transorbital sonography (TOS) have only been reported by individual small-scale studies, exposing a great variability in the measurement of the OND and ONSD. Methods We performed a systematic review and metanalysis of available to date studies on TOS evaluation of adults without elevated intracranial pressure to provide an overview of the published literature, measuring methods and further specify normal values for OND and ONSD. Results In total, we included 39 studies with 2,927 healthy volunteers (mean age 36.1 years, 44.4% female), so that a total of 5,854 eyes were examined. All pooled analyses were based on random effect models. Mean values for OND were provided in 13 studies. Calculated mean pooled OND value was 3.08 mm (95% confidence interval [CI], 2.9-3.25), with low heterogeneity across studies (I2 = 12.7%). Thirty-four studies provided mean values for ONSD measurement. The pool of mean ONSD measurements was 4.78 mm (95% CI, 4.63-4.94), with evidence of substantial heterogeneity between estimates ONSD (I2 = 50.6%). There were no significant differences (P = .139) in the subsequent subgroup analysis for the different geographic continents. Also, no significant differences could be recorded for the effect of age (P = .824) or gender (P = .093). Conclusions TOS is a frequently described and widely used method. We provide reference values of OND and ONSD that are based on metanalytical analysis. Different measuring methods of ONSD result in higher heterogeneity. Subgroup analysis revealed no significant correlation between ONSD and age, gender, or geographic origin.

ObjectiveTo investigate if patients with neuromyelitis optica spectrum disorder (NMOSD) develop subclinical visual pathway impairment independent of acute attacks.MethodsA total of 548 longitudinally assessed full-field visual evoked potentials (VEP) of 167 patients with NMOSD from 16 centers were retrospectively evaluated for changes of P100 latencies and P100-N140 amplitudes. Rates of change in latencies (RCL) and amplitudes (RCA) over time were analyzed for each individual eye using linear regression and compared using generalized estimating equation models.ResultsThe rates of change in the absence of optic neuritis (ON) for minimal VEP intervals of ≥3 months between baseline and last follow-up were +1.951 ms/y (n = 101 eyes; SD = 6.274; p = 0.012) for the P100 latencies and −2.149 µV/y (n = 64 eyes; SD = 5.013; p = 0.005) for the P100-N140 amplitudes. For minimal VEP intervals of ≥12 months, the RCL was +1.768 ms/y (n = 59 eyes; SD = 4.558; p = 0.024) and the RCA was −0.527 µV/y (n = 44 eyes; SD = 2.123; p = 0.111). The history of a previous ON >6 months before baseline VEP had no influence on RCL and RCA. ONs during the observational period led to mean RCL and RCA of +11.689 ms/y (n = 16 eyes; SD = 17.593; p = 0.003) and −1.238 µV/y (n = 11 eyes; SD = 3.708; p = 0.308), respectively.ConclusionThis first longitudinal VEP study of patients with NMOSD provides evidence of progressive VEP latency delay occurring independently of acute ON. Prospective longitudinal studies are needed to corroborate these findings and help to interpret the clinical relevance.

Congenital diaphragmatic hernia (CDH) occurs in similar to 1:2,000 pregnancies and is associated with substantial morbidity and mortality. Fetal tracheal occlusion (TO) is an emerging therapy that improves lung growth and reduces mortality, although substantial respiratory compromise persists in survivors. In this study, we used tracheal fluid in a fetal sheep model of CDH with TO for proteomic analysis with subsequent validation of findings in sheep lung tissue. We found that the proteomic profiles of CDH tracheal fluid was most similar to control lung and CDH/TO lung most similar to TO lung. Among 118 proteins altered in CDH, only 11 were reciprocally regulated in CDH/TO. The most significantly altered pathways and processes were cell proliferation, phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin signaling, inflammation, and microtubule dynamics. CDH suppressed and TO promoted cell proliferation and AKT-related signaling cascades. By Western blot analysis and immunohistochemistry, epithelial PCNA and phosphorylated AKT were decreased in CDH and increased in TO and CDH/TO lungs. The Wnt target Axin2 was decreased threefold in CDH lung compared with control without a significant increase in CDH/TO lung. Cilia-related pathways were among the most dysregulated with CDH lung having a nearly twofold increase in acetylated alpha-tubulin and a relative increase in the number of ciliated cells. While TO improves lung growth and patient survival in CDH, the procedure substantially alters many processes important in lung development and cell differentiation. Further elucidation of these changes will be critical to improving lung health in infants with CDH treated with TO., National Heart, Lung, and Blood Institute; Spanish Health Institute Carlos III Economy and Development Ministry; Parker B. Francis Fellowship Award; Cincinnati Children’s Hospital Research Foundation Procter Award

The hyperechogenicity of the substania nigra (SN) has been established as a valid finding in patients with Parkinson&acute, s disease (PD), probably caused by an increased tissue iron concentration in the SN. The application of transcranial sonography (TCS) has been investigated for further echogenic basal ganglia alterations in patients with extrapyramidal movement disorders. Compared to PD, a hyperechogenic nucleus lentiformis (LN) has been reported to appear more frequently in atypical parkinsonian syndromes (aPS) such as the parkinsonian phenotype of multiple system atrophy (MSA-P) or the progressive supranuclear palsy (PSP). As the evidence providing study sizes are small, we conduct the first meta-analysis of the prevalence of LN hyperechogenicity in PD and aPS. We search for available studies providing prevalence of LN hyperechogenicity in patients with PD and aPS (MSA-P and PSP) detected by TCS in MEDLINE and SCOPUS databases. We calculate the prevalence rates of LN hyperechogenicity detection in patients with clinical diagnosis of PD vs. aPS under the random-effects model. We include a total of 1330 patients, 1091 PD and 239 aPS (MSA-P and PSP). We find a significantly higher prevalence of LN hyperechogenicity in aPS (76%, 95% CI: 0.62-0.88) compared to PD (16%, 95% CI: 0.10-0.23). After proving a higher prevalence of LN hyperechogenicity in aPS compared to PD, its histopathological cause needs to be investigated. Furthermore, its full diagnostic accuracy and the qualification to serve as a risk factor for MSA-P and PSP should also be questioned in future studies.

Publicado em: Schroeder, Christoph. Zum Sprachverstandnis in der Migrationsdebattein Deutschland. In: Ekinci, Yuksel; Montanari, Elke; Selmani, Lirim (Hrsg.). Grammatik und Variation. Festschrift fur Ludger Hoffmann zum 65. Geburtstag. Heidelberg: Synchron, 2017. p. 361-367.

What really is refractory or resistant hypertension? Twenty years ago, Setaro and Black defined the condition as blood pressure >140/90 mm Hg, no evidence of secondary hypertension, maximal doses of at least 2 appropriate antihypertensive agents, and sufficient treatment duration to allow the treatments to be effective.1 Today, we would probably expand the definition to at least 3 agents2 or patients who do not respond to 3 agents, including a thiazide diuretic plus mineralocorticoid-receptor inhibition. Thirty years ago, Swales et al performed a trial of regimens for such patients.3 One of the following 4 regimens was used: oral diazoxide, minoxidil, captopril, or quadruple therapy (diuretic+β-adrenoceptor blocker+hydralazine+prazosin). Despite the severity of hypertension, blood pressure could be controlled in almost all these patients. Since then, sleep apnea has come under scrutiny as a common unappreciated cause. Ruttanaumpawan et al found that about half of their 42 therapy-resistant patients with hypertension were suffering from obstructive sleep apnea.4 Of course, there is always the lingering possibility that the patients are just not ingesting their medicines, and novel strategies have been developed to deal with that issue.5 The advent of device-related treatments has pretty well laid the issue of refractory hypertension to rest. Typing the condition into search engines invariably leads the searcher to articles on catheter-based renal denervation.6 We present a case that we believe is an example for truly resistant hypertension, and we like to coin in the term device-resistant hypertension into the debate about uncontrollable hypertension. Our patient, who kindly provided written consent for this report, is a slender (body mass index, 17.4 kg/m2) 51-year-old woman, who was normotensive until age 36 years. By that time, she had had 4 uneventful pregnancies without complications. Her mother was hypertensive, and her father also had elevated blood pressure …

Several studies have identified circulating biomarkers to be associated with the presence and severity of pulmonary arterial hypertension (PAH). Recent evidence supports a role for galectin-3 (Gal-3) and the mineralcorticoid aldosterone in left ventricular failure. However, studies on aldosterone together with Gal-3 in PAH are lacking.We investigated a novel Aldosterone-galectin-3 (Gal-3) tandem and several other potential PAH biomarkers and their association with the disease severity.A total of 57 patients, 41 with idiopathic PAH. (IPAH) and 16 with PAH associated with connective tissue disease (CTD), and 8 age-matched, non-relative controls were studied. Gal-3, aldosterone and other potential protein plasma concentrations were measured by single ELISA and multi-array MSD (Meso Scale Discovery) technology.Gal-3 values were increased in both patients with IPAH (12.2±0.6 ng/mL; p0.05) and with PAH-CTD (14.1±1.6 ng/mL; p0.05) versus control (8.5±0.9 ng/mL), while aldosterone was significantly elevated in IPAH only (248.5±38.8 pg/mL vs control 71.9±18.2 pg/mL; p0.05). In addition, aldosterone, Gal-3, and N-terminal pro-brain natriuretic peptide (NT-proBNP) values were all higher in patients in WHO functional class II-III versus PAH functional class I or controls. The vascular injury marker intercellular adhesion molecule 1 (ICAM-1) was increased in IPAH and PAH-CTD versus controls (559.5±18.2 pg/mL and 734.1±59.4 pg/mL vs controls 394.8±39.3 pg/mL, p0.05, p0.0001, respectively), whereas vascular cell adhesion molecule 1 (VCAM-1) and proinflammatory, anti-angiogenic interleukin-12 (IL-12) were elevated in PAH-CTD only (879.5±110.0 pg/mL and 391.2±70.3 pg/mL vs controls 489.8±44.6 pg/mL, p0.01, and 102.1±15.2 pg/mL, p0.01, respectively).Heightened Gal-3 and aldosterone plasma concentrations in PAH patients indicate a role for Gal-3 signalling in the pathobiology of IPAH and PAH-CTD, and may serve as biomarkers for functional status and progression of disease.

Background Sympathetic and parasympathetic influences on heart rate (HR), which are governed by baroreflex mechanisms, are integrated at the cardiac sinus node through hyperpolarization‐activated cyclic nucleotide–gated channels (HCN4). We hypothesized that HCN4 blockade with ivabradine selectively attenuates HR and baroreflex HR regulation, leaving baroreflex control of muscle sympathetic nerve activity intact. Methods and Results We treated 21 healthy men with 2×7.5 mg ivabradine or placebo in a randomized crossover fashion. We recorded electrocardiogram, blood pressure, and muscle sympathetic nerve activity at rest and during pharmacological baroreflex testing. Ivabradine reduced normalized HR from 65.9±8.1 to 58.4±6.2 beats per minute ( P Conclusions HCN4 blockade with ivabradine reduced HR, leaving physiological regulation of HR and muscle sympathetic nerve activity as well as baroreflex blood pressure buffering intact. Ivabradine could aggravate bradycardia during parasympathetic activation. Clinical Trial Registration URL: http://www.clinicaltrials.gov . Unique identifier: NCT00865917.

Gender differences in human cardiovascular norepinephrine transporter function may be mediated through female sex hormones. We studied 16 healthy eumenorrheic women (25±1 years) during the early follicular phase (day 5±0) and midluteal phase (day 22±0) of the menstrual cycle. In a randomized, crossover, double-blind fashion, subjects ingested 8 mg of the selective norepinephrine transporter inhibitor reboxetine or placebo. We monitored heart rate, blood pressure, and thoracic bioimpedance at rest and during standard autonomic function tests, including head-up tilt. Venous estradiol and progesterone concentrations were higher in the luteal than in the follicular phase but did not differ between placebo and norepinephrine transporter inhibition testing days. On placebo, hemodynamics at rest and in response to different stressors were mostly identical between cycle phases. In the supine position, norepinephrine transporter inhibition increased blood pressure and stroke volume to a greater extent during the follicular than during the luteal phase. Conversely, the increase in heart rate and cardiac output with norepinephrine transporter inhibition was augmented in the luteal compared with the follicular phase. During head-up tilt with norepinephrine transporter inhibition, blood pressure and stroke volume decreased to a greater extent in the follicular than in the luteal phase. The tachycardic response to head-up tilt with norepinephrine transporter inhibition was augmented in the follicular phase. Our study suggests that sex hormones alter the hemodynamic response to norepinephrine transporter inhibition in women. The phenomenon may be explained by an effect of female sex hormones on norepinephrine transporter function, on compensatory cardiovascular responses, or both.

ObjectivesWe tested the hypothesis that pharmacological norepinephrine reuptake transporter (NET) inhibition delays the onset of head-up tilt-induced presyncope in healthy subjects.BackgroundTreatment of neurally mediated syncope is unsatisfactory. In a previous study in a small number of healthy subjects, pharmacologic NET inhibition delayed the onset of head-up tilt-induced pre-syncope.MethodsWe combined data sets from 3 substudies comprising 51 healthy subjects without a history of syncope. In a double-blind, randomized, cross-over fashion, subjects underwent 2 head-up tilt tests, once with placebo and once with a NET inhibitor (sibutramine or reboxetine). Tilt testing was prematurely ended when pre-syncopal symptoms such as dizziness, nausea, or visual disturbances occurred together with a decrease in blood pressure and/or heart rate.ResultsThe mean tolerated tilt test duration was 29 ± 2 min with placebo and 35 ± 1 min with NET inhibition (p = 0.001). The odds ratio for premature abortion of head-up tilt testing was 0.22 (95% confidence interval 0.09 to 0.55, p < 0.001) in favor of NET inhibition. Norepinephrine reuptake transporter inhibition elicited a pressor response and increased upright heart rate.ConclusionsIn healthy subjects, NET inhibition prevents tilt-induced neurally mediated (pre)syncope. Therefore, NET inhibition may be a worthwhile target of drug intervention for larger trials in highly symptomatic patients with neurally mediated syncope.

Previous studies suggest that neuronal norepinephrine transporter function may regulate the distribution of sympathetic activity among blood vessels, heart, and kidney; we tested the functional relevance in humans. Sixteen healthy men (26±1 years) ingested 8 mg of the selective norepinephrine reuptake transporter inhibitor reboxetine or a matching placebo on 2 separate days in a double-blind, randomized, crossover fashion. We monitored heart rate, thoracic bioimpedance, blood pressure, glomerular filtration rate, and renal blood flow. Ninety minutes after ingestion of the test medication, subjects were tilted to a 45° head-up position, where they remained for an additional 30 minutes. Reboxetine increased supine systolic blood pressure through an increase in cardiac output whereas systemic vascular resistance decreased. Furthermore, reboxetine increased heart rate, particularly with a head-up tilt. Supine plasma renin activity was 0.71±0.15 ng angiotensin (Ang)/L per mL/h with placebo and 0.36±0.07 ngAng/L per mL/h with reboxetine ( P

Background— Norepinephrine transporter (NET) inhibition increases the responsiveness to vasoactive medications and attenuates the response to sympathetic stimuli. The phenomenon may be a result of impaired regulation of sympathetic vasomotor tone. Methods and Results— We studied the effects of the selective NET blocker reboxetine and placebo on baroreflex control of heart rate (HR) and sympathetic traffic in a randomized, double-blind, crossover manner in healthy subjects. Subjects ingested 8 mg reboxetine or placebo 12 hours and 1 hour before testing. ECGs were measured for HR, brachial and finger blood pressure (BP), and muscle sympathetic nerve activity (MSNA). Sympathetic and parasympathetic baroreflex slopes were determined by use of incremental phenylephrine and nitroprusside infusions. The dose to reach BP changes of 12.5 mm Hg was significantly lower during NET inhibition (0.25 versus 0.64 μg · kg −1 · min −1 phenylephrine and 0.40 versus 1.10 μg · kg −1 · min −1 nitroprusside, P Conclusions— NET inhibition profoundly and selectively reduces baroreflex control of sympathetic vasomotor tone and attenuates the responsiveness to sympathetic stimuli. The reduction in baroreflex buffering increases the sensitivity to vasoactive medications. Therefore, our findings represent a novel mechanism for drug interactions.

Background— Sibutramine, a serotonin and norepinephrine transporter blocker, is widely used as an adjunctive obesity treatment. Norepinephrine reuptake inhibition with sibutramine conceivably could exacerbate arterial hypertension and promote cardiovascular disease. Methods and Results— In 11 healthy subjects (7 men, age 27±2 years, body mass index 23.1±0.7 kg/m 2 ), we compared the effect of sibutramine or matching placebo (ingested 26, 14, and 2 hours before testing) on cardiovascular responses to autonomic reflex tests and to a graded head-up tilt test. In addition, we tested sibutramine in combination with metoprolol. Testing was conducted in a double-blind and crossover fashion. Supine systolic blood pressure was 113±3 mm Hg with placebo, 121±3 mm Hg with sibutramine ( P Conclusions— The cardiovascular effect of the antiobesity drug sibutramine results from a complex interaction of peripheral and central nervous system effects. The inhibitory clonidine-like action of sibutramine on the central nervous system attenuates the peripheral stimulatory effect. Our findings strongly suggest that current concepts regarding the action of sibutramine on the sympathetic nervous system should be reconsidered.

Background — Observations in patients with functional mutations of the norepinephrine transporter (NET) gene suggest that impaired norepinephrine uptake may contribute to idiopathic orthostatic intolerance. Methods and Results — We studied the effect of the selective NET blocker reboxetine and placebo in a randomized, double-blind, crossover fashion on cardiovascular responses to cold pressor testing, handgrip testing, and a graded head-up tilt test (HUT) in 18 healthy subjects. In a subset, we determined isoproterenol and phenylephrine sensitivities. Subjects ingested 8 mg reboxetine or placebo 12 hours and 1 hour before testing. In the supine position, heart rate was 65±2 bpm with placebo and 71±3 bpm with reboxetine. At 75° HUT, heart rate was 84±3 and 119±4 bpm with placebo and with reboxetine ( P P Conclusions — Selective NET blockade creates a phenotype that resembles idiopathic orthostatic intolerance. This observation supports the hypothesis that disordered norepinephrine uptake mechanisms can contribute to human cardiovascular disease. Our study also suggests that NET inhibition might be useful in preventing vasovagal reactions.

Objective:To report a rare case of incipient granulomatous hypophysitis presenting by atypical trigemino-autonomic cephalalgia (TAC) and Horner syndrome.Methods:The patient was investigated with repeated brain MRI, CSF examination, thoracic CT, Doppler and duplex ultrasound of the cerebral arteries, and extensive serologic screening for endocrine and autoimmune markers. Written informed consent was obtained from the patient for access to clinical files for research purposes and for publication.Results:We present a middle-aged woman with a history of an autoimmune pancreatitis type 2 who had therapy-refractory TAC with Horner syndrome. Initial cerebral MRI showed only indistinct and unspecific signs of a pathologic process. A biopsy revealed a granulomatous hypophysitis. The symptoms disappeared after transsphenoidal subtotal resection of the pituitary mass and anti-inflammatory therapy.Conclusions:This case elucidates that inflammatory pituitary diseases must be taken into account in case of atypical and refractory TAC, especially in patients with a history of autoimmune diseases. To our knowledge, the association between TAC accompanied by Horner syndrome and hypophysitis has not yet been described before.

Item does not contain fulltext Hyperpolarization-activated, cyclic nucleotide-gated 4 (HCN4) channels comprise the final pathway for autonomic heart rate (HR) regulation. We hypothesized that HCN4 inhibition could reverse autonomic imbalance in a human model of cardiac sympathetic activation. Nineteen healthy men ingested oral metoprolol+reboxetine, ivabradine+reboxetine, or placebo+reboxetine in a double-blind, randomized, crossover fashion. We assessed HR, blood pressure (BP), stroke volume, and cardiac output during rest and profound orthostatic stress. HR variability, BP variability, and baroreflex sensitivity were analyzed. Metoprolol, but not ivabradine, decreased resting HR and BP. Ivabradine attenuated the HR increase to orthostatic stress, albeit to a lesser extent than metoprolol. Stroke volume and cardiac output at a given HR were significantly lower with metoprolol. Unlike metoprolol, ivabradine did not affect HR variability, BP variability, or baroreflex sensitivity. Ivabradine attenuates sympathetic influences on HR at the sinus node level, leaving myocardial sympathetic activation unopposed. Reversal of parasympathetic dysfunction by ivabradine appears limited.

Fiscal rules have become popular to limit deficits and high debt burdens in industrialized countries. A growing literature examines their impact based on aggregate fiscal performance. So far, no evidence exists on how fiscal rules influence deficit expectations of fiscal policy makers. In the context of the German debt brake, we study this expectation dimension. In a first step, we introduce a simple dynamic model in an environment characterized by the lagged implementation of a new rule. Lagged implementation characterizes the setup of the German debt brake and raises credibility issues. In a second step, we analyze a unique survey of members of all 16 German state parliaments and show that the debt brake’s credibility is far from perfect. The heterogeneity of compliance expectations in the survey closely corresponds to our theoretical predictions regarding states’ initial fiscal conditions, specific state fiscal rules and bailout perceptions. In addition, there is a robust asymmetry in compliance expectations between insiders and outsiders (both for in-state vs out-of-state politicians and the government vs opposition dimension), which we attribute to overconfidence rather than noisy information. These results suggest that national fiscal rules can be strengthened through nobailout rules, sustainable initial fiscal conditions and complementary sub-national rules.

Experimental studies suggested that statins attenuate vascular AT1 receptor responsiveness. Moreover, the augmented excessive pressor response to systemic angiotensin II infusions in hypercholesterolemic patients was normalized with statin treatment. In 12 hypercholesterolemic patients, we tested the hypothesis that statin treatment attenuates angiotensin II-mediated vasoconstriction in hand veins assessed by a linear variable differential transducer. Subjects ingested daily doses of either atorvastatin (40 mg) or positive control irbesartan (150 mg) for 30 days in a randomized and cross-over fashion. Ang II–induced venoconstriction at minute 4 averaged 59%±10% before and 28%±9% after irbesartan (mean ± SEM; P

Central β-adrenoreceptors may augment sympathetic outflow. We tested the hypothesis that β-blockade attenuates central sympathetic outflow by inhibiting central adrenoreceptors. We studied 18 healthy controls (4 female, 14 male; age, 26±6 years, body mass index, 23±3 kg/m 2 ). ECG, brachial, and finger arterial blood pressure, muscle sympathetic nerve activity, and respiration were measured continuously before and during complete β-blockade. Subjects received a total intravenous dose of 0.21 mg/kg of propranolol in 15 minutes. Spontaneous baroreflex slopes were calculated using the sequence technique (BRSup, BRSdown). The sympathetic baroreflex slope was determined at baseline using phenylephrine and sodium nitroprusside infusions. The subjects underwent cold pressor testing before and during β-blockade. The R-R interval increased from 861±119 ms at baseline to 952±141 ms during β-blockade ( P P =NS). β-Blockade did not affect baroreflex sensitivity (BRSup: 21±10 versus 28±11 ms/mmHg, P P =NS). Muscle sympathetic nerve activity increased significantly during β-blockade (number of bursts/100 beats: 32±9 versus 40±14, P

The urokinase receptor (uPAR) is highly expressed in the human promyelocytic cell line U937 and contributes to transmembrane signalling. However, the signalling mechanisms are poorly understood. We used the patch-clamp technique to demonstrate that urokinase (uPA) binds to uPAR and thereby stimulates Ca(2+)-activated K+ channels in U937 cells. uPA transiently increased K+ currents within 30 s. The K+ currents were pertussis toxin-sensitive and were also observed in Ca(2+)-free solution. However, when cells were dialysed with EGTA, uPA did not affect K+ currents. The intracellular Ca2+ response to uPA was independent of extracellular Ca2+, was pertussis toxin-sensitive, and was blocked by both thapsigargin and the phospholipase C inhibitor U-73122. The uPA-induced increase in intracellular Ca2+ was independent of uPA proteolytic activity. Furthermore, uPA initiated a rapid formation of inositol 1,4, 5-trisphosphate [Ins(1,4,5)P3]. The amino-terminal uPA fragment and uPA inactivated with diisopropyl fluorophosphate or with inhibitory antibody, elicited the same Ca2+ signal. On the other hand, Ca2+ signalling required the intact uPAR because the effects were abrogated by PtdIns-specific phospholipase C, which removes the uPAR from the cell surface. The prevention of glycosyl phosphatidylinositol moiety synthesis and interference with uPAR anchoring to the cell surface using mannosamine also abolished Ca2+ signals. Taken together, our findings indicate that uPA binds to uPAR and stimulates the production of Ins(1,4,5)P3 via a G-protein- and phospholipase C-dependent mechanism. Ins(1,4,5)P3 in turn liberates Ca2+ from intracellular stores, which leads to the stimulation of Ca(2+)-activated K+ channels.

Fiscal federalism in Germany is characterized by lacking sub-national tax autonomy and intensive fiscal equalization. Due to a sunset clause, the current equalization system has to be renegotiated by the year 2019. Against this backdrop, this contribution studies the reform preferences of members of state parliaments. The study makes use of a self-conducted survey among the members of all 16 German state parliaments. It tests to which extent the preferences of these veto players for tax autonomy and fiscal equalization are driven by states’ self-interest, party ideology and individual characteristics. The results are helpful to understand the political-economic constraints of federal reforms. They indicate that besides the individual ideological position higher state wealth and lower debt levels are linked to larger reform support. Therefore, a promising new reform would have to address budgetary legacies like high pre-existing debt.

Approximately 80–90% of the norepinephrine released in the brain or in peripheral tissues is taken up again through the neuronal norepinephrine transporter (NET). Pharmacological studies with NET inhibitors showed that NET has opposing effects on cardiovascular sympathetic regulation in the brain and in the periphery. Furthermore, NET is involved in the distribution of sympathetic activity between vasculature, heart, and kidney. Genetic NET dysfunction is a rare cause of the postural tachycardia syndrome. The condition is characterized by excessive adrenergic stimulation of the heart, particularly with standing. Conversely, NET inhibition may be beneficial in hypoadrenergic states, such as central autonomic failure or neurally mediated syncope, which results from acute sympathetic withdrawal. Biochemical studies suggested reduced NET function in some patients with essential hypertension. Furthermore, cardiac NET function appears to be reduced in common heart diseases, such as congestive heart failure, ischemic heart disease, and stress-induced cardiomyopathy. Whether NET dysfunction is a consequence or cause of progressive heart disease in human subjects requires further study. However, studies with the nonselective NET inhibitor sibutramine suggest that reduced NET function could have an adverse effect on the cardiovascular system. Given the widespread use of medications inhibiting NET, the issue deserves more attention.

Background Acute kidney allograft rejection is a major cause for declining graft function and has a negative impact on the long-term graft survival. The majority (90%) of acute rejections are T-cell mediated and, therefore, the anti-rejection therapy targets T-cell-mediated mechanisms of the rejection process. However, there is increasing evidence that intragraft B-cells are also important in the T-cell-mediated rejections. First, a significant proportion of patients with acute T-cell-mediated rejection have B-cells present in the infiltrates. Second, the outcome of these patients is inferior, which has been related to an inferior response to the conventional anti-rejection therapy. Third, treatment of these patients with an anti-CD20 antibody (rituximab) improves the allograft outcome as reported in single case observations and in one small study. Despite the promise of these observations, solid evidence is required before incorporating this treatment option into a general treatment recommendation. Methods/Design The RIACT study is designed as a randomized, double-blind, placebo-controlled, parallel group multicenter Phase III study. The study examines whether rituximab, in addition to the standard treatment with steroid-boli, leads to an improved one-year kidney allograft function, compared to the standard treatment alone in patients with acute T-cell mediated tubulointerstitial rejection and significant B-cell infiltrates in their biopsies. A total of 180 patients will be recruited. Discussion It is important to clarify the relevance of anti-B cell targeting in T-cell mediated rejection and answer the question whether this novel concept should be incorporated in the conventional anti-rejection therapy. Trial registration Clinical trials gov. number: NCT01117662

Cytochrome P450 (CYP)-dependent metabolites of arachidonic acid (AA; 20:4 n-6) regulate vascular, renal, and cardiac function. However, the same CYP isoforms that metabolize AA also accept eicosapentaenoic acid (EPA; 20:5 n-3) and docosahexaenoic acid (DHA; 22:6 n-3) as alternative substrates, suggesting that the profile of physiologically active CYP-eicosanoids can be modulated in vivo by changing the dietary fatty acid composition. After we proved this hypothesis in rodents, we now expanded our studies to humans. The trial included 10 healthy men and 10 women aged 18 to 45 years (EudraCT: 2009-013458-33). They ingested 1 Omacor® capsule (480 mg EPA + 360 mg DHA) daily for the first 4 weeks, and two capsules daily in the subsequent 4 weeks, followed by 8 weeks of wash-out. Fatty acids and CYP-dependent metabolites were determined in blood and urine samples by gas chromatography and LC-MS/MS, respectively. The Omega-3 Index (% EPA + DHA of total fatty acids in red blood cells) increased from 4.98±0.80 to 8.03±1.06 at week 8 (p ® , and returned to baseline (1.38±0.75) after cessation of supplementation. Among the individual regioisomeric epoxymetabolites, AA-derived 14,15-EET predominated at baseline but was clearly exceeded by the EPA-derived 17,18-EEQ after EPA/DHA supplementation (3.24±0.26 vs.1.88±0.22 at week 0 and 2.96±0.24 vs. 6.15±0.43 ng/ml plasma at week 8). The plasma level of DHA-derived 19,20-EDP increased from 1.23±0.11 at week 0 to 2.52±0.19 at week 8. These results demonstrate that the human CYP-eicosanoid profile is highly susceptible to changes in dietary fatty acids. In particular, EPA/DHA supplementation promotes the formation of 17,18-EEQ that we previously identified as a candidate for mediating vasodilatory and antiarrhythmic effects of omega-3 fatty acids.

To the Editor: Agonistic autoantibodies directed against G protein–coupled receptors are implicated in the pathogenesis of various human cardiovascular disorders. A patient subset with idiopathic dilated cardiomyopathy features agonistic antibodies directed against β-1 adrenoreceptors. Subsequently, immunization against β-adrenoreceptors in rats, as well as transfer of serum to nonimmunized animals, induces left ventricular dilation and dysfunction.1 Agonistic antibodies against the angiotensin II subtype 1 receptor may contribute to preeclampsia and humorally mediated kidney transplant rejection. More recent studies identified agonistic antibodies against the α-1 adrenoreceptor in 51% of treatment-resistant hypertension patients.2 In vitro, patient and rabbit α-1 adrenoreceptor antibodies activated protein kinase C-α and transient extracellular-related kinase phosphorylation and induced mesentery artery segment contraction.2 Finally, 5 patients in whom agonistic α-1 adrenoreceptor antibodies were removed through immunoabsorption showed favorable blood pressure responses.2 Another study arrived at similar conclusions after infused antibodies rapidly raised blood pressure in anesthetized rats; prazosin abolished the response.3 However, how agonistic …

BACKGROUND: Due to lack of efficacy in recent trials, current guidelines for the treatment of neurally-mediated (vasovagal) syncope do not promote cardiac pacemaker implantation. However, the finding of asystole during head-up tilt -induced (pre)syncope may lead to excessive cardioinhibitory syncope diagnosis and treatment with cardiac pacemakers as blood pressure is often discontinuously measured. Furthermore, physicians may be more inclined to implant cardiac pacemakers in older patients. We hypothesized that true cardioinhibitory syncope in which the decrease in heart rate precedes the fall in blood pressure is a very rare finding which might explain the lack of efficacy of pacemakers in neurally-mediated syncope. METHODS: We studied 173 consecutive patients referred for unexplained syncope (114 women, 59 men, 42 ± 1 years, 17 ± 2 syncopal episodes). All had experienced (pre)syncope during head-up tilt testing followed by additional lower body negative suction. We classified hemodynamic responses according to the modified Vasovagal Syncope International Study (VASIS) classification as mixed response (VASIS I), cardioinhibitory without (VASIS IIa) or with asystole (VASIS IIb), and vasodepressor (VASIS III). Then, we defined the exact temporal relationship between hypotension and bradycardia to identify patients with true cardioinhibitory syncope. RESULTS: Of the (pre)syncopal events during tilt testing, 63% were classified as VASIS I, 6% as VASIS IIb, 2% as VASIS IIa, and 29% as VASIS III. Cardioinhibitory responses (VASIS class II) progressively decreased from the youngest to the oldest age quartile. With more detailed temporal analysis, blood pressure reduction preceded the heart-rate decrease in all but six individuals (97%) overall and in 10 out of 11 patients with asystole (VASIS IIb). CONCLUSIONS: Hypotension precedes bradycardia onset during head-up tilt-induced (pre)syncope in the vast majority of patients, even in those classified as cardioinhibitory syncope according to the modified VASIS classification. Furthermore, cardioinhibitory syncope becomes less frequent with increasing age.