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European Heart Journal Advance Access published July 2, 2013
European Heart Journal CLINICAL RESEARCH Effect of nighttime aircraft noise exposure onendothelial function and stress hormone releasein healthy adults Frank P. Schmidt1, Mathias Basner2, Gunnar Kro ¨ ger1, Stefanie Weck1, Boris Schnorbus1, Axel Muttray3, Murat Sariyar4, Harald Binder4, Tommaso Gori1, Ascan Warnholtz1, andThomas Mu¨nzel1* 1Department of Medicine II, University Medical Center, Johannes Gutenberg University Mainz, Langenbeckstrasse 1, 55131 Mainz, Germany; 2Unit of Experimental Psychiatry, Division ofSleep and Chronobiology, Department of Psychiatry, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA; 3Institut fu¨r Arbeits-, Sozial- und Umweltmedizin,University of Mainz, Mainz, Germany; and 4Institute for Medical Biometry, Epidemiology and Informatics, University of Mainz, Mainz, Germany Received 31 January 2013; revised 6 June 2013; accepted 20 June 2013 Aircraft noise disturbs sleep, and long-term exposure has been shown to be associated with increases in the prevalence ofhypertension and an overall increased risk for myocardial infarction. The exact mechanisms responsible for these cardio-vascular effects remain unclear.
We performed a blinded field study in 75 healthy volunteers (mean age 26 years), who were exposed at home, in random order, to one control pattern (no noise) and two different noise scenarios [30 or 60 aircraft noise events per night with anaverage maximum sound pressure level (SPL) of 60 dB(A)] for one night each. We performed polygraphy during eachstudy night. Noise caused a worsening in sleep quality (P , 0.0001). Noise60, corresponding to equivalent continuous SPLs of 46.3 dB (Leq) and representing environmental noise levels associated with increased cardiovascular events,caused a blunting in FMD (P ¼ 0.016). As well, although a direct comparison among the FMD values in the noisegroups (control: 10.4 + 3.8%; Noise30: 9.7 + 4.1%; Noise60: 9.5 + 4.3%, P ¼ 0.052) did not reach significance, a mono-tone dose-dependent effect of noise level on FMD was shown (P ¼ 0.020). Finally, there was a priming effect of noise,i.e. the blunting in FMD was particularly evident when subjects were exposed first to 30 and then to 60 noiseevents (P ¼ 0.006). Noise-induced endothelial dysfunction (ED) was reversed by the administration of Vitamin C(P ¼ 0.0171). Morning adrenaline concentration increased from 28.3 + 10.9 to 33.2 + 16.6 and 34.1 + 19.3 ng/L(P ¼ 0.0099). Pulse transit time, reflecting arterial stiffness, was also shorter after exposure to noise (P ¼ 0.003).
In healthy adults, acute nighttime aircraft noise exposure dose-dependently impairs endothelial function and stimulatesadrenaline release. Noise-induced ED may be in part due to increased production in reactive oxygen species and may thusbe one mechanism contributing to the observed association of chronic noise exposure with cardiovascular disease.
Endothelial function † Aircraft noise † Cardiovascular risk Aircraft noise has been shown to be more annoying than road- and railway noise at the same equivalent noise level.Epidemiologic The WHO estimates that in high-income Western European coun- studies have demonstrated associations between long-term expos- tries (population 340 million) at least 1 million healthy life years ure to aircraft noise and an increased incidence of arterial hyperten- are lost every year due to environmental noise.The negative health sion and therefore cardiovascular The mechanisms outcomes of noise include annoyance,sleep disturbance,cardiovas- underlying these adverse cardiovascular effects of aircraft noise are cular diseaseand impairment of cognitive performance in children not fully understood. Nocturnal noise exposure seems to be more * Corresponding author. Tel: +49 6131 17 7250, Fax: +49 6131 17 6615, Email: & The Author 2013. Published by Oxford University Press on behalf of the European Society of Cardiology. This is an Open Access article distributed under the terms of the CreativeCommons Attribution Non-Commercial License (, which permits non-commercial re-use, distribution, and reproduction in any medium,provided the original work is properly cited. For commercial re-use, please contact [email protected] F.P. Schmidt et al.
relevant for the genesis of cardiovascular disease than daytime noise were persons with high nighttime traffic noise exposure at home as exposuprobably due to repeated autonomic arousals that have determined by noise maps available from municipal online resources been shown to habituate to a lesser degree to noise than, e.g. cortical (LA,eq,22-6h . 40 dB for aircraft noise and LA,eq,22-6h . 45 dB for road In general, the risk increases with exposure duration, and and rail traffic noise).
is higher in those who decide to sleep with open windows.
Undisturbed sleep of sufficient length is obligatory for the mainten- ance of daytime performance and health.The human organism The study enrolled 75 healthy non-smokers between 20 and 60 years of recognizes, evaluates, and reacts to environmental sounds even age. Before the study, audiometry was performed in all participants.
while These reactions are part of an integral activation Persons with an age-adjusted hearing loss of 20 dB or more on one or process of the organism that expresses itself, e.g. as changes in both ears were excluded from the study. Subjects with sleep disorders sleep structure or increases in blood pressure and heart rate.
[score .10 on the Pittsburgh Sleep Quality Index or psychi-atric disorders (assessed by M.I.NI. Screen interview) were also ineligible.
Environmental noise may decrease the restorative power of sleep Study participants were instructed to refrain from consumption of coffee, by means of repeatedly occurring activations (so-called sleep fragmen- tea, alcohol, sleep altering medications, and nicotine on the day prior to tation) that are associated with more awakenings/arousals, less deep the study night. Otherwise, they were told to continue their usual diet and sleep and rapid eye movement sleep, and early awakenings in the daily routines. Hormonal contraception was allowed but care was taken morning. Although healthy subjects have been shown to habituate to synchronize study nights with the hormonal status. Other hormonal to aircraft noise exposure to a certain degree,the habituation is therapies were excluded.
not complete, and noise-induced awakenings and, especially, activa-tions of the autonomic nervous system can still be observed in sub- jects that have been exposed to aircraft noise for several years.
After inclusion, participants returned to the laboratory for three visits.
Sleep disturbance and especially sleep restriction in turn have been During the night preceding each visit, subjects were exposed in a rando- shown to cause hormonal and metabolic – which mized order to one of three noise patterns. One night served as the could predispose to a future development of cardiovascular disease.
control night, and subjects were exposed to normal background noise.
Circadian changes related to altered sleep may also adversely During the other two nights, subjects were exposed to recording repro- affect the immune systemand may increase the responsiveness ducing different numbers of flights: Noise30 with playback of 30 aircraft of the heart to hypertrophic stimuli.Although plausible, the link noise events, and Noise60 with playback of 60 aircraft noise events.
between polysomnographic evidence of sleep disturbance during Study visits were prescheduled with at least three non-study nights aircraft noise exposure and cardiovascular outcomes is not well between two study nights and on the same weekday if possible. In preme-nopausal women, the visits were scheduled to occur in the same phase of established. It is largely unknown which changes or indices predict the hormonal cycle. Supplemental vitamins, alcohol, and caffeine contain- ing beverages were prohibited on the evening and night before the study.
Furthermore, polysomnography (i.e. the simultaneous measure- Participants were randomly given one of six different sequences of ment of the electroencephalogram, electrooculogram, and electro- noise and control nights according to the randomization plan (C-30-60, myogram) is a complex and cumbersome method, which is not C-60-30, 30-C-60, 30-60-C, 60-C-30, 60-30-C). At study onset, subjects very well suited for larger studies in the general populaThere- and investigators were both blinded to the noise pattern sequence. Par- fore, other methods, like actigraphy (a non-invasive technique to ticipants slept in their usual home environment and were asked to main- monitor human rest/activity cycles) and behaviourally confirmed tain their usual sleep – wake rhythm. They wore portable polygraphic awakenings, have been used in this context.
screening devices (SOMNOwatchTM plus, SOMNOmedics, Rander- In the case of aircraft noise, hypertension may be a consequence of sacker, Germany) during the night with continuous recording of ECG, the noise-induced release of stress hormones such as epi- and nor- SpO2, actimetry, light, and derived parameters as described in previousstudies.– epinephrine and/or the development of vascular (endothelial) dys- In the noise exposure nights, the same aircraft noise event was played function. Endothelial dysfunction (ED) is considered an early step back repeatedly. It was originally recorded in the bedroom of a resident in the development of atherosclerotic changes of the vasculature living in the vicinity of Du¨sseldorf airport (window tilted open), and was (for review ) and can be assessed non-invasively. Recent already used in previous studies on the effects of aircraft noise on studies indicate that in patients with coronary artery disease and sleep.Noise patterns were recorded as MP3 files and played back hypertension, ED assessment in the forearm may have prognostic on a standard portable audio system with a fixed speaker position relative to the head of the subject. The playback volume was levelled at each Based on these considerations, the primary aim of the present measurement site to guarantee similar SPLs at all study sites. During study was to test whether nocturnal exposure to aircraft noise may the night, the SPL was continuously recorded in the bedroom with induce ED. The morning plasma level of adrenaline was a secondary class-2 sound level meters (Datalogger DL-160S, Voltcraft, Germany; endpoint. In a subgroup of noise 60 subjects, we also tested whether Model 407764A Datalogger, Extech Instruments, USA) to assuresubject compliance. They were placed on the nightstand close to the par- acute vitamin C challenges may improve ED.
ticipants. All sound files were coded with a study number and were ofequal length and file size, making inadvertent unblinding less likely. All noise patterns started with a constant tone of 30 s duration to allowtesting of equipment function. The first aircraft noise event was played The study was approved by the ethics committee of University Medical back after 39.5 min to facilitate sleep onset. The last aircraft noise Center Mainz. All participants were volunteers and signed informed event was played back after 415 min. Each noise event lasted roughly consent. Anti-aircraft noise activists were excluded from the study as 45 s. Noise events followed a short – long – short pattern with time Effect of nighttime aircraft noise exposure Figure 1 Schematic representation of the noise events.
between events roughly 6:40 min and 16:40 min for Noise30 and which reproduces the increase in night noise previously shown to be 4:05 min and 6:40 min for Noise60 (Figure ).
associated with an increased incidence of cardiovascular events and After the study night, participants returned to the study centre in a prevalence of with the control visit. Further, a multi-factor fasting state for further testing. Flow-mediated dilatation of the brachial ANOVA [taking into account noise exposure, night of exposure, and artery was measured at the same time in the early morning and before subject id (for subject-related differences)] was performed. A test for a 10 a.m. by a technician using standardized techniques described previous- monotone effect of the exposure (dose of nighttime aircraft noise: 0, ly.Briefly, brachial artery diameter is measured with a linear ultra- 30, or 60) was performed by using exposure as a pseudo-continuous sound probe at rest and after a 5 min occlusion period with a pressure factor in the ANOVA. Further, a ( post hoc) multi-factor ANOVA was per- cuff. Changes in diameter are given in percent and reflect the endothelial formed with two additional factors: one for the comparison of FMD release of vasodilatory substances such as nitric oxide (NO). To address values after Noise60 in all subjects allocated to control – Noise30 – the role of reactive oxygen species in causing ED, FMD was also measured Noise60 or Noise30 – Noise60 – control to FMD values of all other in a subset of five subjects exposed to Noise60 before and after admin- patients, and the other for the same comparison after Noise30 in all sub- istration of vitamin C (2 g, p.o.) as previously described.After FMD jects exposed to Noise60 directly preceding Noise30. P-values ,0.05 measurement, blood samples were drawn and questionnaires were were considered significant. All tests were two-sided. P-values for sec- filled out. Blood samples were transported directly to a clinical laboratory ondary outcome variables are shown without adjustment for multiple for evaluation. Part of the blood was centrifuged, aliquoted, and frozen at testing. Based on the paper by Ghiadoni et ala difference between below 2628C for later testing. Global noise sensitivity was measured means of 2% could be expected (with SD of about 3%). With a sample size of 75 and a standard deviation of FMD differences between Horne-Ostberg Morningness-Eveningness Questionnaire (MEQ)was Noise60 and control of 3%, one may expect to detect a FMD difference used to assess individual chronotype. Pulse transit time (PTT, time of 0.98% with a power of 80% at the alpha-level 0.05.
between the R wave in the ECG and peak oxygen saturation measuredat the tip of the first finger of the right hand) and heart rate accelerations(number of accelerations .20 bpm and .2 s per h) were calculated.
Interleukin-6 and cortisol were measured in serum with chemilumines-cence immunoassay. Adrenaline was measured from NH4-heparine Study population and setting anticoagulated blood drawn 30 min after puncture and cooled during A total of 88 subjects were enrolled. Thirteen of them were excluded transport to the lab.
from the final analysis. Reasons for dropouts (3 study subjects beforeand 10 after the first study night) included the diagnosis of hyperthy- Statistical analysis roidism, relocation to noise-affected areas, protocol violations, and The primary endpoint of the study was the change in %FMD induced by inadequate data recording quality. The study subjects included in the different levels of noise. Secondary outcomes included the changes in the final analysis were on average 26 years (range 20 – 54 years) all variables measured (neurohormones, PTT, inflammatory markers, old, 61% were females. FMD data could not be analysed for one etc), the existence of a relationship between dose of noise and blunting visit in two subjects. The study population did not have relevant of FMD (dose – effect relationship), and whether Noise30 or Noise60 sleep disorders as assessed with the PSQI, and had a moderate had a priming effect on the blunting in FMD induced by, respectively, trend towards evening chronotype (characteristics shown in Noise60 or Noise30. A separate study was conducted to test theeffect of Vitamin C on FMD in subjects exposed to Noise60. Data are pre- Table None reported significant diseases.
sented as mean + standard deviation. The Kolmogorov – Smirnov test The average maximum SPL of aircraft noise events recorded in par- was used to assess whether the data were normally distributed. To ticipants' bedrooms is presented in Table . Overall nighttime SPLs address the primary endpoint, we first compared the effect of Noise60, had average peak levels of 49.6 dB(A) (control), 59.9 dB(A) F.P. Schmidt et al.
pseudo-continuous covariate in the AN(C)OVA in order to test Baseline characteristics of the study for a dose-dependency in the effect of noise on FMD, a linear relation- ship between FMD values and exposure was found (P ¼ 0.020), con-firming that the exposure to more severe noise causes more severe ED. Although a standard comparison among the three noise levels within the ANOVA, i.e. without assuming a monotone effect for dose as a pseudo-continuous covariate, did not reach statistical sig- nificance (control night: 10.4 + 3.8%; after 30 noise events: 9.7 + 4.1%; after 60 noise events: 9.5 + 4.3%, P ¼ 0.052, Figure A), the Baseline noise sensitivity, chronotype, sleep quality index introduction of the two additional factors described in the Methods section evidenced a priming effect of Noise30 nights on the blunting in FMD induced by Noise60 (P ¼ 0.006), i.e. Noise60 had the largest impact on FMD in the subjects who had already been exposed to Noise30. Finally, there was no effect of the random- Laboratory values ization sequence (means after each visit adjusted for the effect of Total cholesterol effect of noise: first visit: 9.8%, second visit: 10.0%, third visit: 9.4%, P ¼ 0.757).
Noise had no effect on blood flow and reactive hyperaemia (control: 855 + 357%; Noise30: 900 + 423%; Noise60: 900 + C-reactive protein 389%, P ¼ 0.55). As well, baseline arterial diameter did not signifi- cantly influence the effect of noise on FMD.
In order to study the mechanism of the blunting in FMD induced by Data are presented as mean + SD.
Noise60, we tested the impact of acute challenges with vitamin C in NoiSeQ, Dortmund Noise Sensitivity Questionnaire with three greatest noise five control subjects. In these subjects, 2 h after the administration of sensitivity; Horne-O ¨ stberg, Morningness-Eveningness Questionnaire; PSQI, Vitamin C, FMD was markedly improved (Figure B, P ¼ 0.0171). In Pittsburgh Sleep Quality Index.
contrast, in a separate control group of subjects exposed toNoise60 without Vitamin C, FMD did not change as an effect of (Noise30), and 60.9 dB(A) (Noise60) (both P , 0.0001 compared time (11.21 + 5.56%; FMD at 2 h: 11.47 + 5.80%; P ¼ 0.842).
with control). Corresponding equivalent continuous SPLs Leq(3) were 35.4 dB(A), 43.1 dB(A), and 46.3 dB(A), respectively. The Effects of night noise on neurohormones mean time between awakening and start of image acquisition for and markers of inflammation (Table ) FMD did not differ across visits (P . 0.5).
We found a marked increase in plasma adrenaline concentrations Control and noise exposure nights did not differ significantly with between control and Noise30 and 60 exposure nights, respectively regard to outside and body temperatures, total time in bed or sub- (control: 28.3 + 10.9 ng/L; Noise30: 33.2 + 16.6; Noise60: 34.1 + jective well being prior to the study night (data not shown). All 19.3 ng/L, P ¼ 0.0099, Figure In contrast, morning plasma levels data were normally distributed.
of cortisol did not increase with noise exposure. Likewise, inflamma-tory markers IL-6 and C-reactive protein were unaffected by noise Haemodynamic changes in response to night noiseAs a secondary predefined endpoint, we also found a dose-dependentdecrease in minimum PTT (Table ) after the noise nights, which was mirrored by the changes in systolic blood pressure (P ¼ 0.11 for the We demonstrate cardiovascular effects of nighttime aircraft noise in changes among visits, Table Automated heart rate analysis detected young and healthy individuals with low cardiovascular risk. Nighttime no significant change in mean and maximum heart rate. Heart rate ac- aircraft noise increased plasma epinephrine levels, worsened sleep celeration index as detected by the polygraphic device did not differ quality, and decreased pulse transit time, a parameter of arterial stiff- between noise exposure and control nights.
ness, which varies inversely to arterial blood pressure. A dose- With increasing number of noise events, study subjects reported dependent decrease in endothelial function after exposure to in- deteriorating sleep quality in the morning after the respective study creasing levels of noise was also observed. Acute Vitamin C chal- night (P ¼ 0.001).
lenges improved endothelial function in a separate group ofsubjects exposed to Noise60. We found no effect of aircraft noise ex- Effects of nocturnal noise on endothelial posure on nocturnal motility, heart rate or blood cortisol, neutro- phils, IL-6, or C-reactive protein.
The comparison of the FMD values measured after the control Interestingly, a priming effect of aircraft noise on ED was observed, visit and the Noise60 visit demonstrated a blunting in endothelial i.e. previous exposure to Noise30 caused Noise60 to have larger responses after noise (P ¼ 0.016). When all three levels of effects on endothelial function. These data demonstrate that aircraft noise were compared, and noise exposure (0, 30, 60) was used as a noise can affect endothelial function, and that rather than habituation, Effect of nighttime aircraft noise exposure Effects of nighttime noise on the quality of sleep, haemodynamic parameters, cortisol levels, and inflammation BPsys mean (mmHg) Pulse transit time (ms) Adrenaline (ng/L) C-reactive protein (mg/L) Data are presented as mean + SD.
Leq3 dB, long-term equivalent continuous sound level; PTT, pulse transit time; BP, blood pressure; HR accel, heart rate acceleration; IL-6, interleukin 6.
prior exposure to noise seems to amplify the negative effect of noise blood pressure by 6.2 and 7.4 mmHg, a phenomenon which, interest- on endothelial function. Although the mechanisms of these observa- ingly, was not necessarily associated with awakenings.
tions cannot be characterized at a molecular level in vivo in humans, it With regard to the pathophysiological mechanism behind the has been previously shown that other forms of mental stress lead to a changes in blood pressure and vascular function, we also report ele- decrease in endothelial – With regards to the molecular vated epinephrine levels after exposure to noise. It has been demon- mechanisms, previous studies indicate that noise leads to an strated that intermittent release of adrenaline may be implicated in up-regulation, rather than a downregulation, of the eNOS.Interest- the development of hypertension.Epinephrine is released as a re- ingly, such an increased eNOS activity does not necessarily result in sponse to different stressors such as and increases the release improved endothelial responses. For instance, in animal models of and the effects of norepinephrine.Interestingly, increased epineph- diabetes and/or hypertension, increased expression of an uncoupled rine levels have been found in patients with borderline hyperten- (superoxide-producing) eNOS is associated with impaired endothe- sion,suggesting a role in the early history of hypertension.
lial function (reviewed in). Since measurements of NO and/or Importantly, increased plasma catecholamines have also been superoxide production in the local vascular microenvironment are shown to correlate negatively with endothelial function as measured impossible to perform in humans, this question cannot be addressed by A recent study has linked autonomic sympathetic activa- at the present time. The improvement in FMD observed in our study tion to the development of hypertension in elderly patients inde- 2 h after application of the antioxidant vitamin C in subjects exposed pendent of the cause of activation of the autonomic nervous to Noise60 is compatible with this evidence, and it suggests that ex- posure to aircraft noise might lead to ED due to increased vascular Our results are congruent with the growing amount of data linking oxidative stress.
short sleep duration or sleep disturbances of various kinds to the de- We also demonstrate changes in PTT, a parameter that correlates velopment of cardiovascular disease. For example, shift work has inversely with changes in blood pressure. Briefly, PTT is measured as been shown to cause impaired endothelial function, sympathetic ac- the time it takes a pulse wave to travel between two arterial sites.
tivation, and metabolic changes.,Extensive evidence exists for the Rises in blood pressure cause vascular tone to increase, leading to relation between obstructive sleep apnoea, hypertension, ED, and increased arterial stiffness and a shorter PTT. As mentioned above, subsequently cardiovascular disease.Recently, the restless legs syn- these data are compatible with those of the HYENA project, in drome has been identified as another cause for sleep disruption, and which an increase prevalence of hypertension was reported in sub- it has been shown to increase the risk for myocardial infarction in jects exposed to nocturnal noise in the range of 50 dB (similar to women.There is ample evidence that nocturnal aircraft noise ex- our Noise60 condition; 46.3 dB).Similarly, acute noise events posure disturbs and fragments sleep, leads to changes in sleep struc- were associated in this study with increased systolic and diastolic ture, increases sleepiness during the following day, and leads to F.P. Schmidt et al.
Figure 3 Effects of Noise30 and Noise60 on plasma adrenaline levels. Nighttime noise exposure significantly increases circulatingcatecholamine levels. Data are mean + SD. P , 0.01, ANOVA.
sensitive individuals. Other environmental factors like air pollution,which has also been shown to influence endothelial function,mayinterfere with noise effects in epidemiological studies. Therefore,data from interventional studies may be helpful in judging the effectof nocturnal noise on cardiovascular health and disease.
Figure 2 (A) Effects of Noise30 and Noise60 on flow-mediated Limitations of the study dilation (FMD). Data are mean + SD; P ¼ 0.020 for a test using The protocol was designed as a field study with minimal sleep disrup- the level of noise a pseudo-continuous variable, demonstrating alinear relationship between FMD values and noise exposure.
tion due to environment and equipment, thus creating ecologically (B) Effects of Vitamin C (2 g, p.o.) in FMD of the brachial artery.
valid conditions. We avoided on purpose a pure laboratory environ- 2 h after Vitamin C administration, the antioxidant improved signifi- ment where ambient conditions, sound levels, and external stimuli cantly FMD in five control subjects exposed to Noise60. Date are can be controlled at the expense of creating artificial rather than fa- presented as mean + SD; P ¼ 0.0171 for the effect of Vitamin C miliar conditions. Sleep quality is very sensitive to changes in sur- on FMD, paired t-test.
roundings and study subjects usually show more pronouncedalterations of sleep in the laboratory than in the field.There wereno adaptation nights prior to study nights due to logistic constraintsand because, since subjects were not required to sleep in non-familiar impairments of cognitive performance.The results of our environments, our study design did not demand such adaptation. Re- study suggest that these changes in sleep structure negatively affect inforcing this, the analysis did not show a significant first-night effect the cardiovascular system, and that these changes, in the case of long- for our primary outcome,which supports the validity of our study term exposure, may predispose to the development of hypertension design and results. Study subjects were healthy, young, and with a and cardiovascular disease.
female majority and are therefore not representative of the whole The study by design eliminated noise adaptation processes, which population. In general, younger adults usually show less sleep pro- can often mask effects of environmental influences. Therefore, it is blems and disturbance than older persons when exposed to noise, unclear whether the negative cardiovascular effects observed in and the fact that noise had an impact also on such a low-risk popula- this study persist after weeks or months with continued noise expos- tion rather emphasizes the potential clinical relevance of the present ure. However, biologic adaptation is often incomplete and requires findings. Finally, endothelium-independent vasodilation was not sys- physiologic resources therefore also putting strain on the system as tematically measured and the data are not presented: nitroglycerin a whole. Effects of aircraft noise in population-based studies are responses were measured initially, but these measures were discon- likely to be mitigated by partial physiologic adaptation and avoidance tinued due to refusal by many study participants related to the side of residential areas with high levels of noise exposure by highly effects of the drug.
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Los Actos de Gobierno en el Derecho Peruano Los actos de Gobierno en el Derecho peruano Víctor Sebastián Baca Oneto* Sumario. 1. La teoría general de los actos políticos o de gobierno. 2. El Derecho Peruano y el régimen jurídico aplicable a los actos de Gobierno. 2.1. Unas palabras sobre el reconocimiento de la distinción subjetiva entre Gobierno y Administración en el ordenamiento peruano. 2.2. El régimen jurídico de los actos del Gobierno y su incidencia sobre la distinción material y subjetiva entre Gobierno y Administración. 2.2.a. Actos en ejercicio de la función legislativa. 2.2.b. Actos específicos del Gobierno. 2.3. Análisis de algunos casos típicos de actos de gobierno y de su relevancia para el establecimiento de una distinción entre Gobierno y Administración. 2.3.a. El mensaje anual del Presidente de la República y la exposición de la política general del Gobierno a cargo del Presidente del Consejo de Ministros. 2.3.b. Las iniciativas legislativas. 2.3.c. Disolución del Parlamento. 2.3.d. Declaratoria de Estados de excepción. 2.3.e. Gracia e indulto. 2.3.f. Aprobación y ratificación de tratados internacionales. 2.4. La distinción entre Gobierno y Administración en el ámbito local y regional. 2.4.a. El art. 39 LOM y las funciones de gobierno frente a las funciones administrativas. 2.4.b. Los medios jurídicos de actuación de las Municipalidades. 2.4.c. La función de gobierno de las Municipalidades. Conclusión. 2.4.d. La función de gobierno del Presidente regional. 3. El resultado del análisis del ordenamiento peruano: la inexistencia de una categoría autónoma de actos de gobierno.

Policies and Procedures Title: SUBCUTANEOUS THERAPY - INTERMITTENT AND CONTINUOUS I.D. Number: 1074 Date Revised: January 2015 [X] SHR Nursing Practice Committee Date Effective: January 2000 Scope: SHR & Affiliates Any PRINTED version of this document is only accurate up to the date of printing 24-Mar-15. Saskatoon Health Region (SHR)