[Autonomy and welfare in intensive care medicine : Practical approach in difficult situations]. / Autonomie und Fürsorge in der Intensivmedizin : Praktisches Vorgehen in schwierigen Situationen.

In intensive care units far-reaching decisions are often made at short notice that require the consent of the informed patient. If this is not possible due to the patient's condition, physicians and legal representatives must ascertain the previously expressed or presumed will of the patient and act accordingly. The legal principles are specified in the Patient Advance Directives Act and the Patient Rights Act. Any indications for medical treatment need a clearly defined aim of the therapy, which can be questioned during the progress of the disease. To avoid conflicts between patient autonomy and medical treatment, the aims of therapy must be regularly discussed with the patient, representatives or relatives and documented in a written form. Checklists can be useful for structured consultations, to promote transparency and to avoid misunderstandings. Ethics consultations can help to deescalate critical situations.

[The effect of peridural analgesia on long-term survival after surgery in patients with colorectal cancer : A systematic meta-analysis]. / Effekt einer perioperativen Periduralanalgesie auf das Langzeitüberleben von Patienten nach Resektion eines kolorektalen Karzinoms : Eine systematische Metaanalyse.

BACKGROUND: The results of recent clinical studies suggest a potential benefit of peridural analgesia (PDA) during general anesthesia on long-term survival in patients after surgery for colorectal cancer. In order to test the hypothesis a meta-analysis was performed. OBJECTIVES: To determine the prognostic impact of perioperative PDA on long-term survival in patients with colorectal cancer who underwent surgical resection. MATERIAL AND METHODS: By searching the relevant literature (up to May 2014) a total of 5 studies were identified from a total of 608 publications and a meta-analysis was carried out. Adjusted hazard ratios (HR) with 95 % confidence intervals (CI) were used to assess the strength of associations. The random effects model was used to analyze the data and a modified forest plot was applied. Additionally, a potential publication bias was visually examined in a funnel plot. RESULTS: A positive association between PDA and improved long-term survival was observed in patients who underwent surgery for colorectal cancer without metastases (HR = 0.81, 95 % CI 0.68-0.96, p = 0.055). CONCLUSION: Despite a publication bias the use of PDA in patients who underwent surgery for colorectal cancer without metastases seemed to be advantageous. Randomized controlled trials are warranted to confirm the positive effects of additional PDA. The exact mechanisms of tumor suppressive effects of PDA have not yet been elucidated.

[Delirium in the intensive care unit]. / Delir auf der Intensivstation.

In recent years delirium in the intensive care unit (ICU) has internationally become a matter of rising concern for intensive care physicians. Due to the design of highly sophisticated ventilators the practice of deep sedation is nowadays mostly obsolete. To assess a ventilated ICU patient for delirium easy to handle bedside tests have been developed which permit a psychiatric scoring. The significance of ICU delirium is equivalent to organ failure and has been proven to be an independent prognostic factor for mortality and length of ICU and hospital stay. The pathophysiology and risk factors of ICU delirium are still insufficiently understood in detail. A certain constellation of pre-existing patient-related conditions, the current diagnosis and surgical procedure and administered medication entail a higher risk for the occurrence of ICU delirium. A favored hypothesis is that an imbalance of the neurotransmitters acetylcholine and dopamine serotonin results in an unpredictable neurotransmission. Currently, the administration of neuroleptics, enforced physiotherapy, re-orientation measures and appropriate pain treatment are the basis of the therapeutic approach.

Maternal separation during a specific postnatal time window prevents reinforcement of hippocampal long-term potentiation in adolescent rats.

In an attempt to develop an animal model to study the etiology of brain dysfunction in relation to early life experience, we tested the hypothesis that early-life stress during specific postnatal time windows affects long-term potentiation (LTP) reinforcement in adolescence. Male Wistar rat pups were stressed by separation from their dams for 24 h at postnatal day (PND) 4, 9, or 18. The animals were tested for reinforcement of LTP at adolescence (9 weeks old) by exposing them to a 2-min swim-stress. Here, we show that maternal separation during (at PND9) but not at the beginning (at PND4) or after (at PND18) the stress-hyporesponsive-period of the hypothalamic-pituitary-adrenal-axis impairs emotional LTP-reinforcement in adolescent animals. Thus, this in vivo model allows the investigation of physiological and pathophysiological emotional information processing at the cellular level in freely behaving adolescent animals.

Endocrine and behavioural plasticity in response to juvenile stress in the semi-precocial rodent Octodon degus.

The present study in the South American rodent Octodon degus shows for the first time that the postnatal development of hypothalamic-pituitary-adrenal axis function in this semi-precocial species differs from that of altricial rodents, i.e. rats or mice, in several aspects. Our experiments revealed a particular pattern of hypothalamic-pituitary-adrenal axis activity during the first 3 weeks of life characterized by (i) a period of low plasma glucocorticoid concentrations, during which (ii) brief stress exposure (1 h parental separation) is able to elevate glucocorticoids significantly. In addition, (iii) repeated stress exposure (1 h parental separation daily) during the first 3 weeks of life resulted in females, but not in males, in an attenuated separation-induced increase of glucocorticoids, and a higher behavioural activity in both sexes at postnatal day 21. These data indicate that parental separation early in life acts as a 'strong' stressor in this species, which on the long run can alter endocrine stress response at the time of weaning in a sex-specific manner. These findings support the role of the hypothalamic-pituitary-adrenal axis as one of the key factors mediating the effects of early life stress on the neuronal network and behaviour in O. degus.

Opiate modulation of monoamines in the chick forebrain: possible role in emotional regulation?

Numerous studies have shown that the opiate system is crucially involved in emotionally guided behavior. In the present study, we focussed on the medio-rostral neostriatum/hyperstriatum ventrale (MNH) of the chick forebrain. This avian prefrontal cortex analogue is critically involved in auditory filial imprinting, a well-characterized juvenile emotional learning event. The high density of mu-opiate receptors expressed in the MNH led to the hypothesis that mu-opiate receptor-mediated processes may modulate the glutamatergic, dopaminergic, and/or serotonergic neurotransmission within the MNH and thereby have a critical impact on filial imprinting. Using microdialysis and pharmaco-behavioral approaches in young chicks, we demonstrated that: the systemic application of the mu-opiate receptor antagonist naloxone (5, 50 mg/kg) significantly increased extracellular levels of 5-HIAA and HVA; the systemic application of the specific mu-opiate receptor agonist DAGO (5 mg/kg) increased the levels of HVA and taurine, an effect that was antagonized by simultaneously applied naloxone (5 mg/kg); the local application of DAGO (1 mM) had no effects on 5-HIAA, HVA, glutamate, and taurine, however, the effects of systemically injected naloxone (5 mg/kg) were abolished by simultaneously applied DAGO (1 mM); the systemic application of naloxone (5 mg/kg) increased distress behavior (measured as the duration of distress vocalization during separation from the peer group). These results are in line with our hypothesis that the mu-opiate receptor-mediated modulation of serotonergic and dopaminergic neurotransmission alters the emotional and motivational status of the animal and thereby may play a modulatory role during filial imprinting in the newborn animal.

Hypoxic increase in nitric oxide generation of rat sensory neurons requires activation of mitochondrial complex II and voltage-gated calcium channels.

Recently, we have demonstrated that sensory neurons of rat lumbar dorsal root ganglia (DRG) respond to hypoxia with an activation of endothelial nitric oxide (NO) synthase (eNOS) resulting in enhanced NO production associated with mitochondria which contributes to resistance against hypoxia. Extracellular calcium is essential to this effect. In the present study on rat DRG slices, we set out to determine what types of calcium channels operate under hypoxia, and which upstream events contribute to their activation, thereby focusing upon mitochondrial complex II. Both the metallic ions Cd2+ and Ni2+, known to inhibit voltage-gated calcium channels and T-type channels, respectively, and verapamil and nifedipine, typical blocker of L-type calcium channels completely prevented the hypoxic neuronal NO generation. Inhibition of complex II by thenoyltrifluoroacetone at the ubiquinon binding site or by 3-nitropropionic acid at the substrate binding site largely diminished hypoxic-induced NO production while having an opposite effect under normoxia. An additional blockade of voltage-gated calcium channels entirely abolished the hypoxic response. The complex II inhibitor malonate inhibited both normoxic and hypoxic NO generation. These data show that complex II activity is required for increased hypoxic NO production. Since succinate dehydrogenase activity of complex II decreased at hypoxia, as measured by histochemistry and densitometry, we propose a hypoxia-induced functional switch of complex II from succinate dehydrogenase to fumarate reductase, which subsequently leads to activation of voltage-gated calcium channels resulting in increased NO production by eNOS.

Haloperidol impairs auditory filial imprinting and modulates monoaminergic neurotransmission in an imprinting-relevant forebrain area of the domestic chick.

In vivo microdialysis and behavioural studies in the domestic chick have shown that glutamatergic as well as monoaminergic neurotransmission in the medio-rostral neostriatum/hyperstriatum ventrale (MNH) is altered after auditory filial imprinting. In the present study, using pharmaco-behavioural and in vivo microdialysis approaches, the role of dopaminergic neurotransmission in this juvenile learning event was further evaluated. The results revealed that: (i) the systemic application of the potent dopamine receptor antagonist haloperidol (7.5 mg/kg) strongly impairs auditory filial imprinting; (ii) systemic haloperidol induces a tetrodotoxin-sensitive increase of extracellular levels of the dopamine metabolite, homovanillic acid, in the MNH, whereas the levels of glutamate, taurine and the serotonin metabolite, 5-hydroxyindole-3-acetic acid, remain unchanged; (iii) haloperidol (0.01, 0.1, 1 mm) infused locally into the MNH increases glutamate, taurine and 5- hydroxyindole-3-acetic acid levels in a dose-dependent manner, whereas homovanillic acid levels remain unchanged; (iv) systemic haloperidol infusion reinforces the N-methyl-d-aspartate receptor-mediated inhibitory modulation of the dopaminergic neurotransmission within the MNH. These results indicate that the modulation of dopaminergic function and its interaction with other neurotransmitter systems in a higher associative forebrain region of the juvenile avian brain displays similar neurochemical characteristics as the adult mammalian prefrontal cortex. Furthermore, we were able to show that the pharmacological manipulation of monoaminergic regulatory mechanisms interferes with learning and memory formation, events which in a similar fashion might occur in young or adult mammals.

Ethanol reduces excitability in a subgroup of primary sensory neurons by activation of BK(Ca) channels.

Ethanol effects on the central nervous system have been well investigated and described in recent years; modulations, by ethanol, of several ligand-gated and voltage-gated ion channels have been found. In this paper, we describe a shortening of action potential duration (APD) by ethanol in approximately equal to 40% of small diameter neurons in rat dorsal root ganglia (DRG). In these neurons, designated as group A neurons, we observed an ethanol-induced increase in whole-cell outward-current. As iberiotoxin, a specific blocker of large-conductance calcium-activated K+ channels (BK(Ca) channels), blocks the effects of ethanol, we investigated the interaction between these channels and ethanol in outside-out patches. Open probability of BK(Ca) channels was increased 2-6 x depending on the concentration (40-80 mM approximately equal to 2-4 per thousand v/v) of ethanol. Functional consequences were a prolongation of the refractory period, which was reversible after addition of iberiotoxin, and reduced firing frequency during ethanol application. In contrast, another type of neuron (group B) showed a prolonged APD during application of ethanol which was irreversible in most cases. In 90% of cases, neurons of group A showed a positive staining for isolectin B4 (I-B4), a marker for nociceptive neurons. We suggest that the activation of BK(Ca) channels induced by clinically relevant concentrations of ethanol, the resulting modulations of APD and refractory period of DRG neurons, might contribute to clinically well-known ethanol-induced analgesia and paresthesia.

Alterations of amino acids and monoamine metabolism in male Fmr1 knockout mice: a putative animal model of the human fragile X mental retardation syndrome.

The Fragile X syndrome, a common form of mental retardation in humans, is caused by silencing the fragile X mental retardation (FMR1) gene leading to the absence of the encoded fragile X mental retardation protein 1 (FMRP). We describe morphological and behavioral abnormalities for both affected humans and Fmr1 knockout mice, a putative animal model for the human Fragile X syndrome. The aim of the present study was to identify possible neurochemical abnormalities in Fmr1 knockout mice, with particular focus on neurotransmission. Significant region-specific differences of basal neurotransmitter and metabolite levels were found between wildtype and Fmr1 knockout animals, predominantly in juveniles (post-natal days 28 to 31). Adults (postnatal days 209 to 221) showed only few abnormalities as compared with the wildtype. In juvenile knockout mice, aspartate and taurine were especially increased in cortical regions, striatum, hippocampus, cerebellum, and brainstem. In addition, juveniles showed an altered balance between excitatory and inhibitory amino acids in the caudal cortex, hippocampus, and brainstem. We detected very few differences in monoamine turnover in both age stages. The results presented here provide the first evidence that lack of FMRP expression in FMRP knockout mice is accompanied by age-dependent, region-specific alterations in neurotransmission.

N-methyl-D-aspartate receptor-mediated modulation of monoaminergic metabolites and amino acids in the chick forebrain: an in vivo microdialysis and electrophysiology study.

The associative avian forebrain region medio-rostral neostriatum/hyperstriatum ventrale (MNH) is involved in auditory filial imprinting and may be considered the avian analogue of the mammalian prefrontal cortex. In search of the neurochemical and physiological mechanisms which play a role in this learning process, we introduced microdialysis and a combined microdialysis/electrophysiological approach in domestic chicks a few days old. With this technique, we were able to follow changes of the extracellular levels of glutamate, taurine, 5-hydroxyindoleacetic acid (5-HIAA), a metabolite of serotonin, and homovanillic acid (HVA), a metabolite of dopamine, and neuronal activity simultaneously in freely moving animals. We obtained first evidence of a modulatory interaction between glutamatergic and monoaminergic neurotransmission mediated by N-methyl-D-aspartate (NMDA) receptors. During local intracerebral infusion of 300 microM NMDA via reverse microdialysis, an increase of taurine and a decrease of 5-HIAA and HVA were detected, accompanied by enhanced extracellular spike rates. Glutamate was increased only during consecutive infusion of increasing NMDA concentrations, when higher (1 mM) NMDA concentrations were infused. The effects of NMDA were antagonized by D, L-2-amino-5-phosphonovaleric acid (1 mM). Infusion of high potassium induced similar changes in taurine, 5-HIAA, and HVA, as found during infusion of NMDA, but decreased extracellular spike rates, which indicates that different cellular mechanisms may underlie the observed neurochemical changes. Neither urethane anesthesia nor different delays between probe implantation and experiment influenced the neurochemical and electrophysiological results; however, changes of taurine were observed only in chronically implanted, awake animals. In summary, microdialysis in combination with electrophysiology provides a powerful tool to detect changes of neuronal activity and transmitter release in the avian brain, with which the role of transmitter interactions can be followed during and after different learning events.

Properties and functions of calcium-activated K+ channels in small neurones of rat dorsal root ganglion studied in a thin slice preparation.

1. Properties, kinetics and functions of large conductance calcium-activated K+ channels (BKCa) were investigated by the patch-clamp technique in small neurones (Adelta- and C-type) of a dorsal root ganglion (DRG) thin slice preparation without enzymatic treatment. 2. Unitary conductance of BKCa channels measured in symmetrical high K+ solutions (155 mM) was 200 pS for inward currents, and chord conductance in control solution was 72 pS. Potentials of half-maximum activation (V ) of the channels were linearly shifted by 43 mV per log10 [Ca2+]i unit (pCa) in the range of -28 mV (pCa 4) to +100 mV (pCa 7). Open probabilities increased e-times per 15-32 mV depolarization of potential. 3. In mean open probability, fast changes with time were mainly observed at pCa > 6 and at potentials > +20 mV, without obvious changes in the experimental conditions. 4. BKCa channels were half-maximally blocked by 0.4 mM TEA, measured by apparent amplitude reductions. They were completely blocked by 100 nM charybdotoxin and 50 nM iberiotoxin by reduction of open probability. 5. Two subtypes of small DRG neurones could be distinguished by the presence (type I) or absence (type II) of BKCa channels. In addition, less than 10 % of small neurones showed fast (approximately 135 V s-1) and short ( approximately 0.8 ms) action potentials (AP). 6. The main functions of BKCa channels were found to be shortening of AP duration, increasing of the speed of repolarization and contribution to the fast after-hyperpolarization. As a consequence, BKCa channels may reduce the amount of calcium entering a neurone during an AP. 7. BKCa channel currents suppressed a subsequent AP and prolonged the refractory period, which might lead to a reduced repetitive activity. We suggest that the BKCa current is a possible mechanism of the reported conduction failure during repetitive stimulation in DRG neurones.

Passive avoidance training and recall are associated with increased glutamate levels in the intermediate medial hyperstriatum ventrale of the day-old chick.

In the young chick, the intermediate medial hyperstriatum ventrale is involved in learning paradigms, including imprinting and passive avoidance learning. Biochemical changes in the intermediate medial hyperstriatum ventrale following learning include an up-regulation of amino-acid transmitter levels and receptor activity. To follow the changes of extracellular amino acid levels during passive avoidance training, we used an in vivo microdialysis technique. Probes were implanted in chicks before training the animals, either on a methylanthranylate- or water-coated bead. One hour later, recall was tested in both groups by presenting a similar bead. An increase of extracellular glutamate levels accompanied training and testing in both groups; during training, glutamate release was higher in methylanthranylate-trained than in water-trained chicks. When compared with the methylanthranylate-trained chicks during testing, the water-trained chicks showed enhanced extra-cellular glutamate levels. No other amino acid examined showed significant changes. After testing, the chicks were anesthetized and release-stimulated with an infusion of 50 mM potassium. Extracellular glutamate and taurine levels were significantly increased in both methylanthranylate- and water-trained chicks. The presentation of methylanthranylate as an olfactory stimulus significantly enhanced glutamate levels, especially in methylanthranylate-trained chicks. The results suggest that such changes in extracellular glutamate levels in the intermediate medial hyperstriatum ventrale accompany pecking at either the water- or the methylanthranylate-bead. The taste of the aversant may be responsible for the greater increases found in methylanthranylate-trained birds.

Distinct activation of monoaminergic pathways in chick brain in relation to auditory imprinting and stressful situations: a microdialysis study.

In the forebrain of the domestic chick (Gallus gallus domesticus), an area termed the mediorostral neostriatum/hyperstriatum ventrale is strongly involved in emotional learning paradigms such as acoustic filial imprinting. Furthermore, the involvement of the mediorostral neostriatum/hyperstriatum ventrale in stressful situations, such as social separation, has been demonstrated in 2-deoxyglucose studies. The aim of the present study was to examine whether quantitative changes of dopamine, serotonin and their metabolites occur during auditory filial imprinting and during social separation. Using in vivo microdialysis in tone-imprinted and in naive, control chicks, we compared the extracellular levels of homovanillic acid, a metabolite of dopamine, and 5-hydroxyindoleacetic acid, a metabolite of serotonin, during the presentation of the imprinting tone. A small, but statistically significant, decrease of extracellular homovanillic acid levels was found in the mediorostral neostriatum/hyperstriatum ventrale of imprinted chicks compared to control animals, whereas changes of 5-hydroxyindoleacetic acid were not detected. In a second experiment, we investigated the levels of homovanillic acid and 5-hydroxyindoleacetic acid in the mediorostral neostriatum/hyperstriatum ventrale of socially reared chicks during different stress situations, such as handling or separation from their cage mates. Handling induced a significant increase of homovanillic acid and 5-hydroxyindoleacetic acid, while social separation resulted in a significant increase of 5-hydroxyindoleacetic acid and only a slight increase of homovanillic acid. Despite considerable inter-individual variability, the increase of distress vocalizations (duration of distress calls) after social separation displayed a good correlation to the increased 5-hydroxyindoleacetic acid levels in all animals analysed. These results provide the first evidence that the physiological response of the mediorostral neostriatum/hyperstriatum ventrale related to different emotional conditions after acoustic imprinting and during stressful situations is, at least in part, mediated by dopaminergic and/or serotonergic pathways. Furthermore, the results from the present study indicate a distinct activation of dopaminergic and serotonergic pathways in relation to the behavioural situation and the associated changes of emotional status.

Stimulus-evoked increase of glutamate in the mediorostral neostriatum/hyperstriatum ventrale of domestic chick after auditory filial imprinting: an in vivo microdialysis study.

Imprinting in chicks is a form of juvenile learning that has been used to study the basic cellular mechanisms of learning and memory. The forebrain area mediorostral neostriatum/hyperstriatum ventrale (MNH) is a center for acoustic imprinting. Electrophysiological and pharmacological behavioral studies in the MNH have demonstrated that the glutamatergic system and the associated receptors are critically involved in auditory filial imprinting. Accordingly, we investigated the hypothesis that stimulus-evoked glutamate release may be altered after this learning process. Using an in vivo microdialysis technique, we observed a significantly higher increase of extracellular glutamate level in tone-imprinted chicks during exposure to the previously imprinted tone than in socially imprinted control chicks. In a further series of experiments, where we exposed animals from both experimental groups to handling distress, glutamate levels in MNH showed only a slight increase, whereas we observed a pronounced increase of extracellular glutamate in the lobus parolfactorius (LPO), the avian analogue of the basal ganglia. No difference of distress-evoked glutamate release was found in MNH and LPO between tone-imprinted and socially imprinted chicks. The tone-evoked enhanced glutamate response in tone-imprinted chicks suggests that during auditory imprinting glutamatergic synapses develop the potential to increase transmitter release in response to the imprinting stimulus.

[Management of unstable pertrochanteric and per- to subtrochanteric femoral fractures with the dynamic hip screw]. / Die Versorgung instabiler pertrochantärer und per- bis subtrochantärer Oberschenkelbrüche mit der dynamischen Hüftschraube (DHS).

The operative treatment of fractures of the proximal end of femur with the dynamic hip screw (DHS) permits a weight-bearing stable osteosynthesis. In 5.2 years between 1985 and 1990 531 patients were treated with a DHS. The average age was 75 years. This method of osteosynthesis was also performed in 59 patients with unstable per- or per-subtrochanteric fractures. Complications such as pseudarthrosis, necrosis or penetration of the head of femur, implant bending or breaking were not observed. The dynamic hip screw is a valid procedure for an early and weight-bearing treatment also for unstable pertrochanteric fractures of the femur with special benefits for the elderly.