Selected abbreviations and acronyms 5-HT serotonin DSM Diagnostic and Statistical Manual of Mental Disorders EEG electroencephalogram HDRS Hamilton

Depression Rating Scale LDAEP loudness dependence of auditory evoked potentials MAOI monoamine oxidase inhibitor MDD Major Depressive Disorder SSRI selective serotonin reuptake inhibitor STAR*D Sequenced Alternatives to Relieve Depression TCA tricyclic antidepressant
Depressive Inhibitors,research,lifescience,medical disorders constitute a major public health issue, and are estimated to rank in second position among all diseases by the year 2010, thus contributing heavily to the global burden of diseases in man, according to Murray and Lopez, who conducted a study for the World Health Inhibitors,research,lifescience,medical Organization (WHO).1 Therefore, the effort to alleviate depressive symptoms in the general

population is a major public health issue. The concept of clinical remission in the treatment of major depressive disorders has gained growing attention in the last few years. The reasons for this relatively recent interest, are manifold. Depressed patients, as well as patient organizations, are not totally Inhibitors,research,lifescience,medical satisfied with the current effectiveness and tolerance of available antidepressant Inhibitors,research,lifescience,medical medications. Despite the obvious benefits of antidepressants, many depressed patients are still suffering from ABT-737 price incapacitating residual symptoms. Furthermore, follow-up investigations have demonstrated that depressed patients who do not reach full remission after antidepressant therapy, that is, patients who are still presenting a number of residual symptoms, are at. a higher risk of relapse or recurrence than patients achieving full remission after treatment.2-4 Conversely, depressed patients who Inhibitors,research,lifescience,medical reach full remission after treatment have a better level of functioning5

and have an improved prognosis6 compared these with patients who are nonremitters. Adequate clinical remission is therefore of great, functional importance for the patient, because it seems to be a predictor of long-term stability and a rather good indicator of better psychosocial functioning, which is of utmost, importance for assessing quality of life in our depressed patients.7“9 For the above reasons, it becomes of great, interest, to the scientific community and to our patients to report, in future clinical trials, not only rates of responders but also remission rates, in order to assess the real clinical efficacy of antidepressants and to position new treatments in outcome studies.

This pattern is consistent with the dense innervations (stronger than cortex) observed for both the hippocampus and amygdala, two regions with simplified cytoarchitecture (ie, pattern of laminar structure). Given its overall connectivity pattern, the magnocellular basal forebrain system is in a favorable position to influence cortical sites across the brain, including sensory cortex, and thus to influence the flow of information processing. These distributed effects result in increased vigilance, alertness, and attention, Inhibitors,research,lifescience,medical and more generally have the potential for widespread impact on cognitive function

both in health and mental illness.6,7 As with other neurotransmitter systems in the brain, the effects of the magnocellular system are at times described as relatively global, or at least unspecific. However, specific effects have also been documented.

Inhibitors,research,lifescience,medical For instance, visual responses that are conveyed to prefrontal cortex engage the basal forebrain in a polysynaptic way, which then further enhances visual responding.8 Direct stimulation of the basal forebrain also enhances the cortical coding of natural scenes in visual cortex Inhibitors,research,lifescience,medical by markedly improving the reliability of cell responses.9 Whereas the magnocellular system projects in a widespread, distributed fashion to cortical and subcortical regions, it is noteworthy that afferent fibers originate from a much more circumscribed set of regions. Cortically, inputs originate largely from nonisocortical areas.5,10

Given that these are exactly the regions that receive the densest inputs from the basal forebrain, potent basal forebrain-cortical Inhibitors,research,lifescience,medical circuits can be established. Amygdala A remarkable property of the primate amygdala is its massive interconnection with cortex. Based on the available data at Inhibitors,research,lifescience,medical the time, analysis of amygdala connectivity revealed that this structure was connected to all but eight of the cortical areas included in the study11 (see also refs 12,13). These connections involved multiple region clusters, suggesting that the amygdala14 is not only one of the most highly connected regions of the brain, but that its connectivity topology is consistent with that of a “connector” hub15 (where a hub is a region with a high degree of connectivity) PD184352 (CI-1040) that links multiple “provincial” hubs15 – where the latter refers to regions of dense connectivity more closely associated with a specific Cell Cycle inhibitor functional group, such as area V4 in visual cortex.16 In this manner, the amygdala has strong potential for integrating cognitive and emotional information.17 When whole-brain connectivity data are analyzed, prefrontal areas are among those most distant from the sensory periphery – based on the average number of connections.11 Thus, on average, the prefrontal cortex receives highly processed and integrated sensory information.

34,35 Increases in SWS have now been demonstrated in depressed

patients,36 and the receptor profile of this new antidepressant should help sleep onset, cause a phase advance in #selleck chemical randurls[1|1|,|CHEM1|]# patients with circadian phase delays,37 and synchronize biological rhythms.38-41 The drug is also weight-neutral, and putativcly does not, involve the sexual dysfunction common to most, selective selective serotonin uptake inhibitors (SSRIs). Thus, Inhibitors,research,lifescience,medical the novel norepinephrine and dopamine disinhibition (NDDI), combined with melatonin receptor agonism and circadian phase realignment, offer potential therapeutic approaches to bipolar depression. Altered glutamatergic mechanisms: the potential for acute onset of antidepressant effects While most of our efficacious antidepressant Inhibitors,research,lifescience,medical treatments have typically required 2 to 4 weeks or longer for maximal therapeutic effectiveness, many different procedures indicate that results can be achieved much more rapidly.

In the approximate 50% of responders to one night of sleep deprivation, therapeutic effects are apparent (literally) overnight. The critical issue is maintaining efficacy, and several attempts have shown to be effective including cotreatment with lithium,42 light,43 and sleepphase Inhibitors,research,lifescience,medical alterations.44 As noted above, the antidepressant effects of TRH are also rapid in onset, but the brief duration again limits current, utility. Intravenous administration of the glutamate antagonist ketamine also appears capable of inducing rapid onset, of antidepressant effects and in this case, improvement can last, some 3 to 5 days or longer.45 How to capture Inhibitors,research,lifescience,medical the acute onset, of effects in the long term remains a therapeutic conundrum. One approach to this being explored is to follow ketamine administration with another Inhibitors,research,lifescience,medical glutamate-active agent, riluzole, which has shown promise in the treatment of

unipolar and bipolar depressed patients.46 This glutamate-active agent is approved for neural protection in amyotrophic lateral sclerosis, and both the acute effects of ketamine and longer-term responses to riluzole demonstrate the potential therapeutic utility of altering glutamatergic tone as a. novel approach to therapeutics. In an initial series of three highly treatment-refractory depressed patients, Charney et al47 reported remarkable and sustained effects of acute ketamine no achieved by an additional three intermittent ketamine infusions. These data suggest, a shift in therapeutic approaches toward exploring new ways of maintaining the acute onset of antidepressants induced by ketamine and related agents. For example, Preskorn et al48 reported rapid onset of antidepressant effects with a specific antagonist of glutamate GluR 2B subunits. The aminergic systems have proven to be effective targets of delayed onset, of maximum antidepressant effects, and y-aminobutyric acid (GABA)ergic mechanisms have been intimately implicated in anxiolytic, if not. antidepressant, efficacy.

Acknowledgments This paper was written with support from the following grants MHCRC: Neurobiology and Phenomenology of the Major Psychoses (MH43271); Phenomenology and the Classification of Schizophrenia (5R01MH031593); MR Imaging in the Major Psychoses (5R01 MH040856); Training in the Neurobiology of Schizophrenia and evaluation with DTI (Magnotta K award); and BRAINS Torin 1 chemical structure Morphology

Inhibitors,research,lifescience,medical and Image Analysis (5R01 NS050568). The author has no conflict of interest to disclose that is relevant to the subject of this manuscript.
The introduction of magnetic resonance imaging (MRI) into neuroscience has instigated a revolution in the magnitude and type of research relating brain function to behavior. Functional MRI (fMRI) has been at the forefront of this effort for several reasons. Before MRI, functional neuroimaging was only feasible with radioisotopic tracers such as oxygen-15 labeled water or fluorine-18 Inhibitors,research,lifescience,medical labeled deoxy glucose, and the temporal resolution was in minutes. Such a time resolution precludes detailed mapping of cognitive operations that take place over much shorter epochs. In

Inhibitors,research,lifescience,medical addition to improved temporal resolution down to about 2 to 16 seconds (duration of the “hemodynamic response”), fMRI has provided several other advantages relevant to its use in neuroscience: higher spatial resolution, noninvasiveness, lack of ionizing radiation, direct correlation with anatomical imaging, greater repeatability (without limitations of radiation exposure), feasibility in children, and affordability The relative disadvantages are: loud background noise generated by the gradients, need to adapt stimulus Inhibitors,research,lifescience,medical presentation and recording of performance to the magnet bore setting, Inhibitors,research,lifescience,medical low signal-to-noise ratio, lack of quantitation in physiologic units for the most abundant

methods, and the need to exclude individuals with metal in their bodies or who have claustrophobia. With the increased utilization of the method, many of these disadvantages have been addressed through the use of specialized equipment compatible with the MRI environment. As a result, there has been an explosion of studies of fMRI across the neurosciences, both in healthy people and in patients with brain disorders. Blood oxygenation level-dependent many (BOLD) fMRI This method is the most widely applied in fMRI studies. The technique relies on magnetic susceptibility effects of deoxyhemoglobin, which cause regional signal changes in imaging sequences that are sensitive to susceptibility (eg, echoplanar or routine gradient echo sequences). When the brain is activated by task demands, a net increase in signal intensity is observed in regions activated by the task. This is attributed to a greater increase in regional oxygenated blood flow that exceeds regional oxygen consumption. A variety of pulse sequences can be applied to obtain BOLD measures.

Previous studies had shown two particular SNPs of the CRHR1 gene, namely rs1876831 and rs242938, were associated with binge drinking specifically, and amount of alcohol intake in general, in both adolescent and adult populations (( Treutlein et al., 2006), except see ( Dahl et al., 2005)). This group more recently reported that stressful life events occurring between

either 12–15 years of age ( Blomeyer et al., 2008) or between 15-19 years of age ( Schmid et al., 2010) resulted in heavier and earlier initiation of alcohol use in subjects that had either the Epigenetics inhibitor rs1876831 or rs242938 SNP in the CRHR1 gene. Though it is currently unknown what functional implications the rs242938 SNP has on CRHR1, the rs1876831 SNP has been implicated in Libraries elevated transcriptional activation of CRHR1 ( Treutlein et al., 2006). It is important to note that experiments using genetically selected rats with a high alcohol preference show increased Crhr1 expression levels in the AZD9291 in vitro brain compared to unselected rats with little alcohol preference ( Hansson et al., 2006). These human and non-human

animal data suggest that adolescent stress and variations in CRH receptor activity can lead to alcohol abuse vulnerability. From a resilience perspective, unfortunately not much is known regarding G × E interactions on adolescent alcohol use patterns. However, there has been recent research conducted on the H2 haplotype at chromosome 17q21.31 and protection against stress-induced alcohol dependence (Nelson et al., 2010). The CRHR1 gene is located in this chromosomal region ( Koolen et al., 2008) and the H2 haplotype has been noted to influence recombination at this site, modifying the risk of various neurological disorders such as mental retardation and progressive supranuclear palsy ( Stefansson et al., 2005 and Pastor PDK4 et al., 2004). It was found that carriers of the H2 haplotype appeared to be protected from alcohol dependence in adulthood when exposed

to early life adversity in the form childhood sexual abuse. Whether this H2 haplotype would be protective against significant life stressors experienced during adolescence is currently unknown. Given the involvement of CRHR1 genetic alterations in stress-related vulnerabilities to alcohol use and abuse during adolescence, this would be an interesting association for future experiments to explore. Regardless, these G × E interaction studies are making it increasingly clear that it will be informative to take genetic background into consideration when addressing why some adolescents are more resistant they others to stressful life events. As research moves forward and we continue to elucidate the mechanisms through which adolescents show heightened susceptibility to stress-induced dysfunctions, it will be equally important to appreciate the mechanisms that confer resilience to these stress-induced vulnerabilities.

2.1. Interstitial Fluid Transport 2.1.1. Mass Conservation Equation This is described by ∂ρ∂t+∇·(ρv)=(Fv−Fly)ρ, (1) where ρ and v are the density and velocity of the interstitial

fluid, respectively. Fv is the interstitial fluid loss from the blood vessels per unit volume of tumour tissue, and Fly is the fluid absorption rate by the lymphatics per unit volume of tumour tissue. Fv and Fly are given by Starling’s law Fv=KvSV[pv−pi−σT(πv−πi)], (2) where Kv is the hydraulic conductivity of the microvascular wall, S/V is the surface area of blood vessels per unit volume of tumour tissue, pv and pi are the vascular and interstitial fluid pressures, respectively, σT Inhibitors,research,lifescience,medical represents the average osmotic reflection coefficient for plasma protein, πv is the osmotic pressure of the plasma, and πi is that of interstitial Inhibitors,research,lifescience,medical fluid. The lymphatic drainage, Fly, is related to the pressure difference between the interstitial fluid and lymphatics: Fly=KlySlyV(pi−ply), (3) where Kly is the hydraulic conductivity of the lymphatic wall, Sly/V is the surface area of lymphatic vessels per unit volume of tumour tissue, and ply is the intralymphatic

pressure. 2.1.2. Momentum Conservation Equation Since the intercapillary distance (33–98μm [19, 20]) is usually 2-3 orders of magnitude smaller than the length scale for Inhibitors,research,lifescience,medical Inhibitors,research,lifescience,medical drug transport (approximately 70mm in this study), it is reasonable to treat the tumour and its surrounding tissues as porous media, for which the Navier-Stokes equations are applicable. By ignoring the gravitational effect, the momentum equation is expressed as ∂(ρv)∂t+∇·(ρvv)=−∇pi+∇·τ+F, (4)

where τ is the stress tensor which is given by τ=μ[∇v+(∇v)T]−23μ(∇·v)I, (5) where I is the unit tensor. The last term in (4), F, represents the Darcian GPCR Compound Library clinical trial resistance to fluid flow through Inhibitors,research,lifescience,medical porous media and is given by F=Wμv+12Cρ|v|v, (6) and W is a diagonal matrix with all diagonal elements calculated as W=κ−1, (7) where μ is the dynamic viscosity of interstitial fluid, C is the prescribed matrix of the inertial loss term, and κ is the permeability of the interstitial Adenosine triphosphate space. Since the velocity of interstitial fluid is very slow (|v | 1) [15], the inertial loss term can be neglected when compared to the Darcian resistance. In addition, the interstitial fluid is treated as incompressible with a constant viscosity. Hence, (6) can be reduced to F=Wμv. (8) 2.2. Drug Transport Drug transport is described by equations for the free and bound drug concentrations in the interstitial fluid and the intracellular concentration. 2.2.1. Free Doxorubicin Concentration in the Interstitial Fluid (Cfe) This is described by ∂Cfe∂t+∇·(Cfev)=Dfe∇2Cfe+Si, (9) where Dfe is the diffusion coefficient of free doxorubicin.

While this might have made sense prior to pregnancy, this plan would actually increase the exposures for the baby. First, the baby has already been exposed to the newer antidepressant, and switching to a second medication would be another exposure. In addition, the likelihood that

the patient could relapse while switching is high, thus exposure to the mood disorder would be a third exposure for the Inhibitors,research,lifescience,medical child; (iii) Consider whether the mother plans to breastfeed and discuss whether the medication can be safely used during breastfeeding and what the plan would be for monitoring the medication during breastfeeding; (iv) Discuss psychotherapy treatment options. Table I. Practical guidelines for treating depression during pregnancy and postpartum Inhibitors,research,lifescience,medical Conclusions Perinatal depression is often debilitating to the woman experiencing it and to her family. Screening must be a routine part of postpartum care as there are effective treatments Inhibitors,research,lifescience,medical available that can prevent needless suffering. Although the etiology of perinatal depression remains unclear, headway is

being made toward a better understanding of the complicated interplay of reproductive steroids (estrogen and progesterone) with the HPA axis and other neuroregulatory systems implicated in depressive illness. Further study of the alterations in the HPA axis during the transition from pregnancy to the postpartum period may provide new insights into the pathophysiology

of perinatal mood disturbances. Animal studies have been used successfully to model perinatal maternal behavior and to study the Inhibitors,research,lifescience,medical pathogenesis of perinatal anxiety, stress, and depression. In addition, the rapidly growing field of behavioral epigenetics offers an intriguing area Inhibitors,research,lifescience,medical of study that may provide new insights into the nature of gene-environment interactions during development. Future research will help to disentangle the complex genetic, environmental, and epigenetic mechanisms that mediate maternal mental illness during the perinatal period including the subsequent influence on maternal behavior and infant outcomes. Regarding treatment of depression during pregnancy, antidepressant use in pregnant women is often necessary in order to prevent to maternal psychiatric illness. Recent collaborative consensus statements by the American Psychiatric Association and the American College of Obstetricians and Gynecologists provide a useful framework for the interpretation of data about the safety of psychotropic medications during pregnancy and lactation. Therefore, individualized recommendations based on the patient’s past www.selleckchem.com/products/pci-32765.html history should ideally be implemented prior to pregnancy with a goal of minimizing exposures.

The opposite has to be expected, when ON-1910 release channels close again, and the Ca2+ pumping rate exceeds the release rate. 2.3. From Chemical Potentials to Mechanical Force Generation In striated muscle cells like ventricular muscle cells (VMs) or skeletal muscle

fibers (SMFs), force generation as well as shortening is brought about by the cyclic action of cross bridges. It is a known fact that this process is powered by ATP splitting. The underlying mechanism of the energy transduction process, however, is not completely understood. Here, a thermodynamic description of Inhibitors,research,lifescience,medical the cycle is derived using a formalism recently published [1]. It takes into account the basic energetics of enzyme-catalysed reactions, which states that the overall affinity of the catalysed and non-catalysed processes must be equal. For an enzyme-catalysed reaction like: (S = substrate, E = enzyme, ES = enzyme-substrate complex, P = product), this means that Inhibitors,research,lifescience,medical at steady state the sum of the affinities of substrate binding, transition, and product release must yield the affinity of the non-catalysed reaction, which is given by the reaction affinity of all involved

compounds in the bulk solution: (7a) or, after contraction of the first two terms: (7b) yielding, (7c) With K’r = K’B Inhibitors,research,lifescience,medical × K’T × K’R(k’B, k’T, and k’R are equilibrium constants of the binding, transition, and release reaction, respectively, whereas k’r denotes that of the non-catalysed reaction). An analogous reaction sequence is used here to describe the cross-bridge cycle. The following cycle is given in chemical notation, i.e., the charges of involved species are taken into account. The cycle begins with the splitting reaction of the de-energised actomyosin complex (A-M) by MgATP2- in the diffusional space of myofibrils: R1 This Inhibitors,research,lifescience,medical first reaction yields dissociated

actomyosin with MgATP2- bound to myosin (the bold point denotes binding to myosin). Two negative charges develop on the dissociated actin, Inhibitors,research,lifescience,medical which are neutralised by potassium ions, K+, stemming from free MgATP2−, which is now bound to myosin heads. On the dissociated myosin heads, it neutralises both emerging positive charges. This first actomyosin dissociation and binding of MgATP2− to myosin is followed by ATP Sodium butyrate splitting on the myosin heads. This transition reaction is described by R2 It is coupled to the formation of energised myosin (), which is characterised by a tilting of the myosin head from a more bent arms position by an angle of about 60° towards the respective Z disc, so that now the myosin head builds a right angle with the opposing actin filament. contains free energy from reaction R2 as conformational energy. The force generating stroke of the myosin head is triggered by the association reaction to form the energised actomyosin complex (cross-bridge): R3 Because of uncompensated charges, the resulting intermediate in curly brackets lacks firmness.

Major depression affects 5% to 10% of older adults who visit a primary care provider46-48 and has negative implications for the prognosis of almost all co-occurring medical illnesses with which such patients may present. Treatment of child and adolescent depression Drug treatment for children or adolescents with depression is primarily dependent on SSRIs as first-line

acute treatment. Efficacy Inhibitors,research,lifescience,medical trials have been conducted with fluoxetine, paroxetine, and citalopram.49-51 The recommended practice is to start at half the usual dose of an SSRI (eg, 10 mg/day fluoxetine, paroxetine, or citalopram) for 1 week for adjustment purposes and then increase the dose to the equivalent of 20 mg/day Nutlin-3a clinical trial fluoxetine for another 3 weeks.45 It takes up to 4 weeks at steady state to determine whether a given dose will be helpful Thus, further increases should be made at 4-week intervals. Because children and adolescents metabolize SSRI more rapidly than adults, they often require Inhibitors,research,lifescience,medical doses above the equivalent of 20 mg fluoxetine to attain a clinical response.52 The large National Institute

of Mental Health (NIMH) multicenter contract, Treatment for Adolescents With Depression Study (TADS),53 Inhibitors,research,lifescience,medical for the treatment of depression in adolescents has been recently completed, and perhaps will provide more definitive data for this population. In a sample of 439 adolescents (aged 12 to 17 years) with major depression, four randomly assigned interventions were utilized: fluoxetine (10 to 40 mg/day) with cognitive behavioral therapy (CBT); fluoxetine alone; Inhibitors,research,lifescience,medical CBT alone; and placebo. As noted in Table VI, 71% responded to the combined treatment, with 60.6% to fluoxetine alone, 43.2% to CBT alone, and 34.8% to placebo. A clinically useful manner to review these findings is to calculate number needed to treat (NNT; calculated as 1/risk difference). NNT represents the number of subjects Inhibitors,research,lifescience,medical who would have to be treated with active

treatment to obtain one success that would not be obtained with the control treatment. Referring to Table VI, NNT for the combination treatment is 3, fluoxetine alone 4, and CBT alone 12, suggesting a medium effect size for the combination treatment and for fluoxetine alone. In addition, clinically significant suicidal thinking present in 29% of the sample at baseline improved significantly. Seven (1.6%) of ever 439 patients attempted suicide, but there were no completed suicides. Table VI. Treatment for Adolescents with Depression Study (TADS) randomized controlled trial.53 NNT, number needed to treat; CBT, cognitive behavioral therapy. Treatment of geriatric depression In a similar fashion, SSRIs have now largely replaced TCAs and MAOIs as first-line acute treatments for latelife depression.54 SSRIs are administered in older patients with initial dosing at half the usual effective dose and doubled after 1 week.

Labor progresses rapidly (see Fig. 1) and 25 min after arrival at the hospital she fells an initial urge to push. Another 10 min later the water breaks; it is meconium-stained,

and the cervix is now dilated to 9 cm. The fetal head is now 1 cm above the ischial spines. CTG is applied again and due to the patient record it reveals minor FHR Modulators decelerations that return to normal baseline. She receives an oxygen mask. At 1.05 am the midwife encourages click here her to push. The head is described as just below the spines. The descent of the head of the baby progresses normally during pushes, but it retracts between contractions. After 20 min of pushing there is still no sign of further fetal decent and the woman is asked to gasp. Due to the lack of progression an obstetrician is called and arrives at 1.35 am. The fetal head is still just below the spines. The obstetrician orders

Syntocinon® (generic name oxytocin) 10 I.E. in a 1000 ml NaCl-solution. Due to the already frequent contractions the drip is started cautiously 6 ml/h that is half the standard dose. At 1.50 am the woman is again encouraged to push. It is noted in the hospital record that ‘the drip is slowly increased to 24 ml/h’. Suddenly at 2.06 am there Galunisertib cost is fetal bradycardia to 75–80 beats per minute and the fetal head detracts resulting in a loss of fetal station. Simultaneously the woman starts to complain about unremitting abdominal pain and she turns pail. As the uterus

is palpated uterine defense is noted and an emergent cesarean section is ordered. A girl is born 14 min later, Apgar 1/1, 5/10 min and pH 6.68, SBE − 19 and weight 4800 g. The baby is transferred to an intensive care unit in another hospital. She receives 72 h of hypothermal treatment. At age 3 the girl is diagnosed with cerebral palsy. The uterus is severely damaged. There is a full, posterior rupture extending from the fundus down, and there is almost a complete separation between the uterus and the vagina. The uterine scar is sewed continuously but with numerous insertions due to uncontrollable bleeding. The uterus is restored, but she bleeds 5500 ml during the operation. Two hours after the termination of the operation she is bleeding heavily again, and Sodium butyrate is re-operated. The bleeding is located at the lower part of the uterine rare side and in the left side of cervix and after several insertions hemostasis is obtained. However there is still diffuse bleeding from the fundal part. A double B-lynch suture is applied. In the patient record it is estimated that the total blood loss was 10 l. She receives 27 product with 245 ml erythrocytes, 18 product with 270 ml plasma and 9 products with 350 ml thrombocytes. She also received approximately 2.4 l NaCl solution which indicates that her blood loss might have been underestimated (total amount of IV products = 14.6 l + 2.4 l NaCl). After the second operation she is sedated for approximately 14 h.