Publications by authors named "Bernd Walter"

25 Publications

  • Page 1 of 1

Multimodal pathophysiological dataset of gradual cerebral ischemia in a cohort of juvenile pigs.

Sci Data 2021 01 7;8(1). Epub 2021 Jan 7.

Institute of Molecular Cell Biology, Jena University Hospital, Jena, Germany.

Ischemic brain injuries are frequent and difficult to detect reliably or early. We present the multi-modal data set containing cardiovascular (blood pressure, blood flow, electrocardiogram) and brain electrical activities to derive electroencephalogram (EEG) biomarkers of corticothalamic communication under normal, sedation, and hypoxic/ischemic conditions with ensuing recovery. We provide technical validation using EEGLAB. We also delineate the corresponding changes in the electrocardiogram (ECG)-derived heart rate variability (HRV) with the potential for future in-depth analyses of joint EEG-ECG dynamics. We review an open-source methodology to derive signatures of coupling between the ECoG and electrothalamogram (EThG) signals contained in the presented data set to better characterize the dynamics of thalamocortical communication during these clinically relevant states. The data set is presented in full band sampled at 2000 Hz, so the additional potential exists for insights from the full-band EEG and high-frequency oscillations under the bespoke experimental conditions. Future studies on the dataset may contribute to the development of new brain monitoring technologies, which will facilitate the prevention of neurological injuries.
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http://dx.doi.org/10.1038/s41597-020-00781-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7791136PMC
January 2021

Early increase of cannabinoid receptor density after experimental traumatic brain injury in the newborn piglet.

Acta Neurobiol Exp (Wars) 2014 ;74(2):197-210

Department of Neuroradiopharmaceuticals, Institute of Radiopharmaceutical Cancer Research, Research Site Leipzig, Helmholtz-Zentrum Dresden-Rossendorf, Leipzig, Germany,

Paediatric traumatic brain injury (TBI) is a leading cause of death and disability. Previous studies showed neuroprotection after TBI by (endo)cannabinoid mechanisms, suggesting involvement of cannabinoid receptors (CBR). We therefore determined CBR densities and expression of the translocator protein 18 kDA (TSPO) in newborn piglets after experimental TBI. Newborn female piglets were subjected to sham operation (n=6) or fluid-percussion (FP) injury (n=7) under controlled physiological conditions. After six hours, brains were frozen, sagittally cut and incubated with radioligands for CBR ([3HCP-55,940, [3H]SR141716A) and TSPO ([3H]PK11195), an indicator of gliosis/brain injury. Early after injury, FP-TBI elicited a significant ICP increase at a temporary reduced cerebral perfusion pressure; however, CBF and CMRO2 remained within physiological range. At 6 hours post injury, we found a statistically significant increase in binding of the non-selective agonist [3H]CP-55,940 in 15 of the 24 investigated brain regions of injured animals. By contrast, no significant changes in binding of the CB1R-selective antagonist [3H]SR141716A were observed. A non-significant trend towards increased binding of [3H]PK11195 was observed, suggesting an incipient microglial activation. We therefore conclude that in this model and time span after injury, the increase in [3H]CP-55,940 binding reflects changes in CB2R density, while CB1R density is not affected. The results may provide explanation for the neuroprotective properties of cannabinoid ligands and future therapeutic strategies of TBI.
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April 2015

Resistance of brain glucose metabolism to thiopental-induced CNS depression in newborn piglets.

Int J Dev Neurosci 2013 May 7;31(3):157-64. Epub 2013 Jan 7.

Institute of Molecular Cell Biology, Jena University Hospital, Friedrich Schiller University, Jena, Germany.

The transition from mild sedation to deep anaesthesia is marked by the phenomenon of burst suppression (BS). FDG-PET studies show that the cerebral metabolic rate for glucose (CMRglc) declines dramatically with onset of BS in the adult brain. Global CMRglc increases substantially in the post-natal period and achieves its maximum in preadolescence. However, the impact of post-natal brain development on the vulnerability of CMRglc to the onset of BS has not been documented. Therefore, cerebral blood flow and metabolism were measured using a variant of the Kety-Schmidt method, in conjunction with quantitative regional estimation of brain glucose uptake by FDG-PET in groups of neonate and juvenile pigs, under a condition of light sedation or after induction of deep anaesthesia with thiopental. Quantification of simultaneous ECoG recordings was used to establish the correlation between anaesthesia-related changes in brain electrical activity and the observed cerebrometabolic changes. In the condition of light sedation the magnitude of CMRglc was approximately 20% higher in the older pigs, with the greatest developmental increase evident in the cerebral cortex and basal ganglia (P<0.05). Onset of BS was associated with 20-40% declines in CMRglc. Subtraction of the mean parametric maps for CMRglc showed the absolute reductions in CMRglc evoked by thiopental anaesthesia to be two-fold greater in the pre-adolescent pigs than in the neonates (P<0.05). Thus, the lesser suppression of brain energy demand of neonate brain during deep anaesthesia represents a reduced part of thiopental suppressing brain metabolism in neonates.
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http://dx.doi.org/10.1016/j.ijdevneu.2012.12.008DOI Listing
May 2013

Isoflurane/nitrous oxide anesthesia and stress-induced procedures enhance neuroapoptosis in intrauterine growth-restricted piglets.

Intensive Care Med 2012 Jul 11;38(7):1205-14. Epub 2012 May 11.

Institute of Laboratory Animal Science and Welfare, Jena University Hospital, Friedrich Schiller University, Jena, Germany.

Purpose: There is compelling evidence that interference of various anesthetics with synaptic functions and stress-provoking procedures during critical periods of brain maturation results in increased neuroapoptotic cell death. The hypothesis is that adverse intrauterine environmental conditions leading to intrauterine growth restriction (IUGR) with altered brain development may result in enhanced susceptibility to developmental anesthetic neurotoxicity.

Methods: This was a prospective, randomized, blinded animal study performed in a university laboratory involving 20 normal-weight (NW) and 19 IUGR newborn piglets. General inhalation anesthesia with isoflurane and nitrous oxide at clinically comparable dosages were administered for about 10 h. Surgical and monitoring procedures were accompanied by appropriate stage of general anesthesia. Resulting effects on developmental anesthetic and stress-induced neurotoxicity were assessed by estimation of apoptotic rates in untreated piglets and piglets after 10-h general anesthesia with MAC 1.0 isoflurane in 70 % nitrous oxide and 30 % oxygen.

Results: IUGR piglets exposed to different levels of isoflurane inhalation exhibited a significant increased apoptosis rate (TUNEL-positive neuronal cells) compared to NW animals of similar condition (P < 0.05). Cardiovascular and metabolic monitorings revealed similar effects of general anesthesia together with similar effects on brain electrical activity and broadly a similar dose-dependent gradual restriction in brain oxidative metabolism in NW and IUGR piglets.

Conclusions: There is no indication that the increased rate in neuroapoptosis in IUGR piglets is confounded by additional adverse systemic or organ-specific impairments resulting from administered mixed inhalation anesthesia. Developmental anesthetic and stress-induced neuroapoptosis presumably originated in response to fetal adaptations to adverse conditions during prenatal life and should be considered in clinical interventions on infants having suffered from fetal growth restriction.
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http://dx.doi.org/10.1007/s00134-012-2576-2DOI Listing
July 2012

Quantification of compensatory processes of postnatal hypoxia in newborn piglets applying short-term nonlinear dynamics analysis.

Biomed Eng Online 2011 Oct 3;10:88. Epub 2011 Oct 3.

Department of Medical Engineering and Biotechnology, University of Applied Sciences, Jena, Germany.

Background: Newborn mammals suffering from moderate hypoxia during or after birth are able to compensate a transitory lack of oxygen by adapting their vital functions. Exposure to hypoxia leads to an increase in the sympathetic tone causing cardio-respiratory response, peripheral vasoconstriction and vasodilatation in privileged organs like the heart and brain. However, there is only limited information available about the time and intensity changes of the underlying complex processes controlled by the autonomic nervous system.

Methods: In this study an animal model involving seven piglets was used to examine an induced state of circulatory redistribution caused by moderate oxygen deficit. In addition to the main focus on the complex dynamics occurring during sustained normocapnic hypoxia, the development of autonomic regulation after induced reoxygenation had been analysed. For this purpose, we first introduced a new algorithm to prove stationary conditions in short-term time series. Then we investigated a multitude of indices from heart rate and blood pressure variability and from bivariate interactions, also analysing respiration signals, to quantify the complexity of vegetative oscillations influenced by hypoxia.

Results: The results demonstrated that normocapnic hypoxia causes an initial increase in cardiovascular complexity and variability, which decreases during moderate hypoxia lasting one hour (p < 0.004). After reoxygenation, cardiovascular complexity parameters returned to pre-hypoxic values (p < 0.003), however not respiratory-related complexity parameters.

Conclusions: In conclusion, indices from linear and nonlinear dynamics reflect considerable temporal changes of complexity in autonomous cardio-respiratory regulation due to normocapnic hypoxia shortly after birth. These findings might be suitable for non-invasive clinical monitoring of hypoxia-induced changes of autonomic regulation in newborn humans.
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http://dx.doi.org/10.1186/1475-925X-10-88DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3224473PMC
October 2011

Traumatic brain injury elicits similar alterations in α7 nicotinic receptor density in two different experimental models.

Neuromolecular Med 2011 Mar 21;13(1):44-53. Epub 2010 Sep 21.

Institute of Radiopharmacy, Research Site Leipzig, Research Center Dresden-Rossendorf, Permoserstraße 15, 04318, Leipzig, Germany.

Traumatic brain injury (TBI) is a major cause of death and disability worldwide, especially in children and young adults. Previous studies have shown alterations in the central cholinergic neurotransmission after TBI. We therefore determined α7 nicotinic acetylcholine receptor (nAChR) densities in newborn piglets and adult rats after experimental TBI. Thirteen newborn piglets (post-TBI survival time: 6 h) underwent fluid percussion (FP) injury (n = 7) or sham operation (n = 6). Furthermore, adult rats randomized into three groups of post-TBI survival times (2, 24, 72 h) received controlled cortical impact injury (CCI, n = 8) or sham operation (n = 8). Brains were frozen, sagittally cut and incubated with the α7-specific radioligand [(125)I]α-bungarotoxin for autoradiography. In injured newborn piglets, decreased α7 receptor densities were observed in the hippocampus (-38%), the hippocampus CA1 (-40%), thalamus (-30%) and colliculus superior (-30%). In adult rats, CCI decreased the receptor densities (between -16 and -47%) in almost any brain region within 2 and 24 h. In conclusion, widespread and significantly lowered α7 nAChR densities were demonstrated in both TBI models. Our results suggest that a nearly similar TBI-induced decrease in the α7 density in the brain of immature and adult animals is found, even with the differences in species, age and experimental procedures. The alterations make the α7 nAChR a suitable target for drug development and neuroimaging after TBI.
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http://dx.doi.org/10.1007/s12017-010-8136-4DOI Listing
March 2011

Age-dependent effects of gradual decreases in cerebral perfusion pressure on the neurochemical response in swine.

Intensive Care Med 2010 Jun 16;36(6):1067-75. Epub 2010 Mar 16.

Institute of Molecular Cell Biology, Universitätsklinikum Jena, Friedrich Schiller University, 07745, Jena, Germany.

Objective: There is still a lack of knowledge on the age-dependent relation between a reduction in cerebral perfusion pressure (CPP) and compromised brain perfusion leading to excessive transmitter release and brain damage cascades. The hypothesis is that an age-dependent lower threshold of cerebral blood flow (CBF) autoregulation determines the amount and time course of transmitter accumulation.

Design And Setting: This was a prospective randomized, blinded animal study performed in a university laboratory involving eight newborn and 11 juvenile anesthetized pigs.

Intervention: Striatal dopamine, glutamate, glucose, and lactate were monitored by microdialysis. For CPP manipulation, the cisterna magna was infused with artificial cerebrospinal fluid to control intracranial pressure at the maintained arterial blood pressure (stepwise CPP decrease in 15-min stages to 50, 40, 30, and finally 0 mmHg).

Measurements And Main Results: Juvenile pigs showed a gradual decrease in CBF between 50 mmHg CPP (CPP-50) and 30 mmHg CPP (CPP-30), but a significant CBF reduction did not occur in newborn piglets until CPP-30 (P < 0.05). At CPP-30, brain oxidative metabolism was reduced only in juveniles, concomitantly with elevations in dopamine and glutamate levels (P < 0.05). In contrast, newborn piglets exhibited a delayed and blunted accumulated of transmitters and metabolites (P < 0.05).

Conclusions: The lower limit of CBF autoregulation was associated with modifications in neurochemical parameters that clearly occurred before brain oxidative metabolism was compromised. Early indicators for mild to moderate hypoperfusion are elevated levels of lactate and dopamine, but elevated levels of glutamate appear to be an indicator of brain ischemia. The shift to the left of the lower autoregulatory threshold is mainly responsible for the postponed neurochemical response to decrements in the CPP in the immature brain.
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http://dx.doi.org/10.1007/s00134-010-1846-0DOI Listing
June 2010

Effects of lateral fluid percussion injury on cholinergic markers in the newborn piglet brain.

Int J Dev Neurosci 2010 Feb 12;28(1):31-8. Epub 2009 Oct 12.

Institute of Interdisciplinary Isotope Research, Leipzig, Germany.

Traumatic brain injury is a leading cause of death and disability in children. Studies using adult animal models showed alterations of the central cholinergic neurotransmission as a result of trauma. However, there is a lack of knowledge about consequences of brain trauma on cholinergic function in the immature brain. It is hypothesized that trauma affects the relative acetylcholine esterase activity and causes a loss of cholinergic neurons in the immature brain. Severe fluid percussion trauma (FP-TBI, 3.8+/-0.3atm) was induced in 15 female newborn piglets, monitored for 6h and compared with 12 control animals. The hemispheres ipsilateral to FP-TBI obtained from seven piglets were used for acetylcholine esterase histochemistry on frozen sagittal slices, while regional cerebral blood flow and oxygen availability was determined in the remaining eight FP-TBI animals. Post-fixed slices were immunohistochemically labelled for choline acetyltransferase as well as for low-affinity neurotrophin receptor in order to characterize cholinergic neurons in the basal forebrain. Regional cerebral blood flow and brain oxygen availability were reduced during the first 2h after FP-TBI (P<0.05). In addition, acetylcholine esterase activity was significantly increased in the neocortex, basal forebrain, hypothalamus and medulla after trauma (P<0.05), whereas the number of choline acetyltransferase and low-affinity neurotrophin receptor positive cells in the basal forebrain were unaffected by the injury. Thus, traumatic brain injury evoked an increased relative activity of the acetylcholine esterase in the immature brain early after injury, without loss of cholinergic neurons in the basal forebrain. These changes may contribute to developmental impairments after immature traumatic brain injury.
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http://dx.doi.org/10.1016/j.ijdevneu.2009.10.001DOI Listing
February 2010

Intrauterine growth restriction improves cerebral O2 utilization during hypercapnic hypoxia in newborn piglets.

J Physiol 2007 Oct 23;584(Pt 2):693-704. Epub 2007 Aug 23.

Institute of Molecular Cell Biology, Center for Molecular Biomedicine, and Department of Neuropaediatrics, Children's Hospital, Friedrich Schiller University, D-07740 Jena, Germany.

Data are scant regarding the capacity of cerebrovascular regulation during asphyxia for prevention of brain oxygen deficit in intrauterine growth-restricted (IUGR) newborns. We tested the hypothesis that IUGR improves the ability of neonates to withstand critical periods of severe asphyxia by optimizing brain oxygen supply. Studies were conducted to examine the effects of IUGR on cerebral blood flow (CBF) regulation and oxygen consumption (cerebral metabolic rate for oxygen, CMRO(2)) at different stages of asphyxia (hypercapnic hypoxaemia) in comparison to pure hypoxia (normocapnic hypoxaemia). We used 1-day-old anaesthetized and ventilated piglets. Animals were divided into normal weight (NW) piglets (n = 47; aged 11-26 h, body weight 1481 +/- 121 g) and IUGR piglets (n = 48; aged 13-28 h, body weight 806 +/- 42 g) according to their birth weight. Different stages of hypoxaemia were induced for 1 h by appropriate lowering of the inspired fraction of oxygen (moderate hypoxia: = 31-34 mmHg; severe hypoxia: = 20-22 mmHg). Fourteen NW and 16 IUGR piglets received additionally 9% CO(2) in the breathing gas, so that a of 74-80 mmHg resulted (hypoxia/hypercapnia groups). Eight NW and nine IUGR animals served as untreated controls. Furthermore, affinity of haemoglobin for oxygen was measured under hypoxic and asphyxic conditions. During asphyxia cerebral oxygen extraction was markedly increased in IUGR animals (P < 0.05). This resulted in a significantly diminished CMRO(2)-related increase of CBF at gradually reduced arterial oxygen content (P < 0.05). Therefore, an enhanced effectivity in oxygen availability appeared in newborn IUGR piglets under graded asphyxia by improved cerebral oxygen utilization (P < 0.05). This was not supported by related O(2) affinity of haemoglobin. Thus, IUGR newborns are more capable to ensure brain O(2) demand during asphyxia (hypercapnic hypoxia) than NW neonates.
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http://dx.doi.org/10.1113/jphysiol.2007.142778DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2277152PMC
October 2007

Detecting the signature of reticulothalamocortical communication in cerebrocortical electrical activity.

Clin Neurophysiol 2007 Sep 28;118(9):1969-79. Epub 2007 Jun 28.

Department of Obstetrics and Gynaecology, Lawson Health Research Institute, The University of Western Ontario, London, Ont., Canada N6A 4V2.

Objective: Reticulothalamocortical (RTC) and cortico-cortical (CC) communications underlie multiple fundamental neurophysiological processes. Detecting changes in RTC versus CC communication from the EEG alone remains an unsolved problem. RTC communication shows complex (linear and nonlinear) properties in EEG. Aiming to detect changes in complexity of RTC communication from EEG, we applied a novel concept to analyze the complexity of information flow in RTC communication on different time scales of neuronal oscillations with mutual information function (MIF).

Methods: We studied information flow in RTC and CC communication in a previously established model of moderate and deep propofol/fentanyl anesthesia in six juvenile pigs. We recorded the electrothalamogram (EThG) of the reticular thalamic nucleus (RTN) and the electrocorticogram (ECoG) of five ipsilateral regions and characterized their linear (spectral power, coherence) and complexity (MIF) properties.

Results: During deep anesthesia, ECoG complexity over the temporoparietal region decreased on the time scale of beta frequency band. The spectral power in the beta frequency band decreased over others, but not over the temporoparietal region. Coherence decreased predominantly in the alpha band in both CC and RTC communication while information flow complexity decreased specifically in RTC, but not in CC, communication, suggesting higher information flow in RTC communication during deep anesthesia.

Conclusions: Information flow complexity changes in ECoG specifically reflect changes in RTC communication.

Significance: RTC communication can be quantified from cerebrocortical activity alone by assessing information flow complexity of CC communication.
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http://dx.doi.org/10.1016/j.clinph.2007.05.071DOI Listing
September 2007

Muscle growth and fiber type composition in hind limb muscles during postnatal development in pigs.

Cells Tissues Organs 2006 ;182(3-4):171-81

Institute of Sports and Sports Science, Eberhard Karls University, Tubingen, Germany.

Rapid postnatal development in pigs is reflected by differentiation in skeletal muscle. This process depends on muscle function and demands, but a comprehensive overview of individual developmental characteristics of quickly growing leg muscles in pigs is still missing. This study focused on the development of 10 hind limb muscles in pigs. To determine these changes in mass, fiber type patterns and fiber diameters were analyzed 0, 2, 4, 7, 14, 28, 42, 56 and 400 days after birth. Generally, the proportion of slow fibers increased from birth to 8 weeks. Thereafter, only minor changes in muscle fiber type composition were observed. The majority of the muscles contained less then 10% slow-twitch fibers at birth, increasing to between 12 (Musculus vastus lateralis) and 38% (M. gastrocnemius medialis) in adult pigs. By contrast, postural muscles already had 20-30% slow fibers at birth, and this contribution increased up to 65% in adults (i.e. M. vastus intermedius). From birth to the 2nd week, only in slow fibers could activity of oxidative enzymes be detected. A differentiation of fast-twitch fibers into subtypes with high (comparable to type IIA) and low oxidative metabolism (equivalent to type IIB) occurred between the 2nd and 4th week of life. The ratio between type II fibers with high and low oxidative enzyme activity did not change markedly through development in any muscle, although there was a trend towards an increasing proportion of type IIA fibers in the soleus. In the majority of the muscles investigated, the fast-twitch fibers with low oxidative metabolism (IIB) obtained the largest cross-sectional area. In contrast, at birth no remarkable differences in the diameter of fast and slow fibers were found. The rapid increase in muscle mass compared to body mass reflects the high performance in meat production of the cross pig investigated.
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http://dx.doi.org/10.1159/000093966DOI Listing
September 2006

Renal Angiotensin receptor type 1 and 2 upregulation in intrauterine growth restriction of newborn piglets.

Cells Tissues Organs 2006 ;182(2):106-14

Department of Internal Medicine III, Universitatsklinikum Jena, Friedrich Schiller University, Germany.

Epidemiological and experimental studies suggest that intrauterine growth restriction (IUGR) is associated with abnormalities in kidney development which is thought to be linked with alterations causing adult cardiovascular diseases. The renin-angiotensin system (RAS) plays an important role in the development of renal vascular and tubular structures, and is known to be altered by experimentally induced IUGR. These experimental models of IGUR have been criticized because they may have a more severe impact on intrauterine development than that which is normally encountered in humans. Therefore, we asked whether naturally occurring small-for-gestational-age newborn piglets exhibit features of altered RAS activity. We investigated the regional renal expression of angiotensin II type 1 (AT1) and AT2 receptors in normal-weight and IUGR piglets. The AT1 receptor mRNA expression was markedly enhanced in IUGR piglets, in the renal cortex by 64% and in the renal medulla by 52% (p < 0.05, compared with normal littermates). In contrast, mRNA expression for the AT2 receptor was similar in both the normal-weight and IUGR piglets. A significantly higher AT1 receptor protein expression was found in the IUGR piglets (p < 0.05) in the glomeruli, in the proximal and distal tubules, as well as in the collecting ducts by immunohistochemistry. Furthermore, AT2 receptor protein expression was significantly higher in the IUGR piglets (p < 0.05) in the subcapsular nephrogenic zone and in the distal tubules and collecting ducts. Thus, IUGR is accompanied by an upregulation of angiotensin II receptor expression in the kidneys of newborn piglets. This may indicate an alteration of the RAS in newborns suffering from naturally occurring IUGR.
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http://dx.doi.org/10.1159/000093065DOI Listing
August 2006

Stereotactic approach and electrophysiological characterization of thalamic reticular and dorsolateral nuclei of the juvenile pig.

Acta Neurobiol Exp (Wars) 2006 ;66(1):43-54

Institute for Molecular Cell Biology, Pathophysiology Laboratory, Universitätsklinikum Jena, Friedrich Schiller University, D-07740 Jena, Germany.

Few reports exist on complex functions of pig's central nervous system. A direct access to thalamic structures enables a deeper understanding of neuronal networks. Here we present an easy to implement stereotactic approach to reach both reticular and dorsolateral thalamic nuclei (RTN and LD). In thirteen pigs (7 weeks old) the correct electrode position was confirmed for 22 out of 26 thalamic electrodes (RTN: A+2, L9, V24 and LD: A-2, L5, V20, with bregma A 0, L 0). Quantitative effects of isoflurane/nitrous oxide (State 1) and fentanyl sedation (State 2) were determined by brain hemodynamics and metabolism. Neurophysiologic features were performed by spectral power, coherence and SEP analysis. Brain blood flow (by 21 +/- 13%) and oxidative brain metabolism (CMRO, by 26 +/- 12%, CMRGlucose by 26 +/- 22%) were markedly reduced during State 1 (P<0.05). Regional thalamic blood flow exhibited similar alterations, but side-differences did not occur. State 1 induced quite similar brain activity in cortical as well as thalamic regions investigated. During State 2 electrocortical activity of low frequency ranges was markedly reduced, whereas spectral band power of high frequency ranges was additionally decreased in RTN (P<0.05). Thus, we used a convenient approach for targeted deep electrode implementation and characterized electrophysiological features in RTN and LD.
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June 2006

Intrauterine growth restriction induces increased capillary density and accelerated type I fiber maturation in newborn pig skeletal muscles.

J Perinat Med 2006 ;34(3):235-42

Institute for Molecular Cell Biology, Pathophysiology Lab, Friedrich Schiller University, Jena, Germany.

Aims: Humans with low birth weight exhibit evidences of vascular dysfunction. Recent findings indicate a microvascular rarefaction in skeletal muscles soon after postnatal development in rats suffered by intrauterine protein restriction.

Methods: To examine the effects of intrauterine growth restriction on capillary density, muscle fiber distribution and accompanying muscular and systemic circulation immediately after birth, studies were conducted on 1-day-old anesthetized normal weight (n = 7) and intrauterine growth restricted (n = 6) piglets. Cardiac output and hind limb muscle blood flow were measured by colored microspheres. Counting of type I fibers and skeletal capillary numbers was done by immunohistochemical staining.

Results: Increased proportion of type I fibers and capillary density was found in the flexor digitalis superficialis and gastrocnemius medialis (P < 0.05) in newborn IUGR piglets. Furthermore, a marked correlation was shown between capillary density and type I fiber fraction for all flexor muscles studied (P < 0.05). Moreover, cardiac output and muscular blood flow were markedly increased in IUGR piglets (P < 0.05). Correspondingly, total peripheral resistance, as well as vascular resistance, of hind limb flexors appeared significantly decreased (P < 0.05).

Conclusions: Compromised intrauterine environmental conditions leading to fetal growth restriction provokes coordinated structural and functional adaptation of skeletal muscles.
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http://dx.doi.org/10.1515/JPM.2006.042DOI Listing
October 2006

A pig model with secondary increase of intracranial pressure after severe traumatic brain injury and temporary blood loss.

J Neurotrauma 2005 Jul;22(7):807-21

Department for Anesthesiology and Intensive Care Medicine and Matha-Maria Hospital, Halle, Germany.

There is a lack of animal models of traumatic brain injury (TBI) that adequately simulate the longterm changes in intracranial pressure (ICP) increase following clinical TBI. We therefore reproduced the clinical scenario in an animal model of TBI and studied long-term postinjury changes in ICP and indices of brain injury. After induction of anesthesia, juvenile piglets were randomly traumatized using fluid-percussion injury (FPI) to induce either moderate (mTBI = 6 pigs: 3.2 +/- 0.6 atm) or severe (sTBI = 7 pigs: 4.1 +/- 1.0 atm) TBI. Injury was followed by a 30% withdrawal of blood volume. ICP and systemic hemodynamic were monitored continuously. Repeated measurements of global cerebral blood flow (CBF) and cerebral metabolic rate of oxygen (CMRO2) were performed at baseline, at the end of blood withdrawal, after volume replacement, and at 8 and 24 h postinjury. Histological and immunocytochemical studies have also performed. ICP peaked immediately following FPI (mTBI: 33 +/- 16 mm Hg; sTBI: 47 +/- 14 mm Hg, p < 0.05) in both groups. In the sTBI group, we noted a second peak at 5 +/- 1.5 h postinjury. This second ICP peak was accompanied by a 50% reduction in CBF (44 +/- 31 mL . min . 100 g(-1)) and CMRO(2) (2.5 +/- 2.0 mL . min . 100 g(1)). Moderate TBI typically resulted in focal pathological change whereas sTBI caused more diffuse change, particularly in terms of the ensuing axonal damage. We thus describe an animal model of severe TBI with a reproducible secondary ICP increase accompanied by patterns of diffuse brain damage. This model may be helpful in the study of pathogenetic relevance of concomitant affections and verify new therapeutic approaches in severe TBI.
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http://dx.doi.org/10.1089/neu.2005.22.807DOI Listing
July 2005

Canadian law and the legal process.

Authors:
Bernd Walter

J Am Acad Psychiatry Law 2005 ;33(1):135-6; author reply 136

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August 2005

The effect of mild hypothermia on plasma fentanyl concentration and biotransformation in juvenile pigs.

Anesth Analg 2005 Apr;100(4):996-1002

Department of Anesthesiology and Intensive Care Medicine, Institute for Pathophysiology and Pathobiochemistry, Friedrich-Schiller-University, Jena, Germany.

Therapeutic hypothermia may alter the required dosage of analgesics and sedatives, but no data are available on the effects of mild hypothermia on plasma fentanyl concentration during continuous, long-term administration. We therefore assessed in a porcine model the effect of prolonged hypothermia on plasma fentanyl concentration during 33 h of continuous fentanyl administration. Seven female piglets (weight: 11.8 +/- 1.1 kg) were anesthetized by IV fentanyl (15 microg . kg(-1) . h(-1)) and midazolam (1.0 mg . kg(-1) . h(-1)). After preparation and stabilization (12 h), the animals were cooled to a core temperature of 31.6 degrees +/- 0.2 degrees C for 6 h and were then rewarmed and kept normothermic at 37.7 degrees +/- 0.3 degrees C for 6 more hours. Plasma fentanyl concentrations were measured by radioimmunoassay, cardiac index by thermodilution, and blood flows of the kidney, spleen, pancreas, stomach, gut, and hepatic artery by a colored microspheres technique. Furthermore, in an additional 4 pigs, temperature dependency of hepatic microsomal cytochrome P450 3A4 (CYP3A4) was determined in vitro by ethylmorphine N-demethylation. Plasma fentanyl concentration increased by 25% +/- 11% (P < 0.05) during hypothermia and remained increased for at least 6 h after rewarming. Hypothermia reduced the cardiac index (41% +/- 15%, P < 0.05), as well as all organ blood flows except the hepatic artery. A strong temperature dependency of CYP3A4 was found (P < 0.01). Mild hypothermia induced a distribution and/or elimination-dependent increase in plasma fentanyl concentration which remained increased for several hours after rewarming. Consequently, a prolonged increase of the plasma fentanyl concentration should be anticipated for appropriate control of the analgesia/sedatives during and early after therapeutic hypothermia.
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http://dx.doi.org/10.1213/01.ANE.0000146517.17910.54DOI Listing
April 2005

Effect of moderate hypercapnic hypoxia on cerebral dopaminergic activity and brain O2 uptake in intrauterine growth-restricted newborn piglets.

Pediatr Res 2005 Mar 20;57(3):363-70. Epub 2004 Dec 20.

Institute of Pathophysiology and Pathobiochemistry, Universitätsklinikum Jena, Friedrich Schiller University, D-07740 Jena, Germany.

There is evidence that intrauterine growth restriction (IUGR) is associated with altered dopaminergic function in the immature brain. Compelling evidence exists that in the newborn brain, specific structures are especially vulnerable to O2 deprivation. The dopaminergic system is shown to be sensitive to O2 deprivation in the immature brain. However, the respective enzyme activities have not been measured in the living neonatal brain after IUGR under hypercapnic hypoxia (H/H). Therefore, 18F-labeled 6-fluoro-L-3,4-dihydroxyphenylalanine (FDOPA) together with positron emission tomography was used to estimate the aromatic amino acid decarboxylase activity of the brain of seven normal weight (body weight 2078 +/- 434 g) and seven IUGR newborn piglets (body weight 893 +/- 109 g). Two positron emission tomography scans were performed in each piglet. All animals underwent a period of normoxia and moderate H/H. Simultaneously, cerebral blood flow was measured with colored microspheres and cerebral metabolic rate of O2 was determined. In newborn normal-weight piglets, the rate constant for FDOPA decarboxylation was markedly increased in mesostriatal regions during H/H, whereas brain oxidative metabolism remained unaltered. In contrast, moderate H/H induced in IUGR piglets a marked reduction of clearance rates for FDOPA metabolites (p <0.05), which was accompanied by a tendency of lowering the rate constant for FDOPA conversion. Furthermore, IUGR piglets maintained cerebral O2 uptake in the early period of H/H, but during the late period of H/H, a significantly reduced cerebral metabolic rate of O2 occurred (p <0.05). Thus, IUGR is accompanied by a missing activation of dopaminergic activity and attenuated brain oxidative metabolism during moderate H/H. This may indicate endogenous brain protection against O2 deprivation.
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http://dx.doi.org/10.1203/01.PDR.0000150800.19956.F0DOI Listing
March 2005

The influx of neutral amino acids into the porcine brain during development: a positron emission tomography study.

Brain Res Dev Brain Res 2004 Sep;152(2):241-53

Institute of Interdisciplinary Isotope Research Leipzig, Permoserstrasse 15, D-04318 Leipzig, Germany.

Pigs of three different age groups (newborns, 1 week old, 6 weeks old) were used to study the transport of the large neutral amino acids 6-[18F]fluoro-L-DOPA ([18F]FDOPA) and 3-O-methyl-6-[18F]fluoro-L-DOPA ([18F]OMFD) across the blood-brain barrier (BBB) with positron emission tomography (PET). Compartmental modeling of PET data was used to calculate the blood-brain clearance (K1) and the rate constant for the brain-blood transfer (k2) of [18F]FDOPA and [18F]OMFD after i.v. injection. A 40-70% decrease of K1(OMFD), K1(FDOPA) and k2(OMFD) from newborns to juvenile pigs was found whereas k2(FDOPA) did not change. Generally, K1(OMFD) and k2(OMFD) are lower than K1(FDOPA) and k2(FDOPA) in all regions and age groups. The changes cannot be explained by differences in brain perfusion because the measured regional cerebral blood flow did not show major changes during the first 6 weeks after birth. In addition, alterations in plasma amino acids cannot account for the described transport changes. In newborn and juvenile pigs, HPLC measurements were performed. Despite significant changes of single amino acids (decrease: Met, Val, Leu; increase: Tyr), the sum of large neutral amino acids transported by LAT1 remained unchanged. Furthermore, treatment with a selective inhibitor of the LAT1 transporter (BCH) reduced the blood-brain transport of [18F]FDOPA and [18F]OMFD by 35% and 32%, respectively. Additional in-vitro studies using human LAT1 reveal a much lower affinity of FDOPA compared to OMFD or L-DOPA. The data indicate that the transport system(s) for neutral amino acids underlie(s) developmental changes after birth causing a decrease of the blood-brain barrier permeability for those amino acids during brain development. It is suggested that there is no tight coupling between brain amino acid supply and the demands of protein synthesis in the brain tissue.
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http://dx.doi.org/10.1016/j.devbrainres.2004.07.002DOI Listing
September 2004

Age-dependent effects of severe traumatic brain injury on cerebral dopaminergic activity in newborn and juvenile pigs.

J Neurotrauma 2004 Aug;21(8):1076-89

Department of Neurosurgery, Friedrich Schiller University Jena, Germany.

There is evidence that the dopaminergic system is sensitive to traumatic brain injury (TBI). However, the age-dependency of this sensitivity has not been studied together with brain oxidative metabolism. We postulate that the acute effects of severe TBI on brain dopamine turnover are age-dependent. Therefore 18F-labelled 6-fluoro-L-3,4-dihydroxyphenylalanine (FDOPA) together with Positron-Emission-Tomography (PET) was used to estimate the activity of the aromatic amino acid decarboxylase (AADC) in the brain of 11 newborn piglets (7-10 days old) and nine juvenile pigs (6-7 weeks old). Six newborn and five juvenile animals were subjected to a severe fluid-percussion (FP) induced TBI. The remaining animals were used as sham operated untreated control groups. Simultaneously, the regional cerebral blood flow (CBF) was measured with colored microspheres and the cerebral metabolic rates of oxygen and glucose were determined. At 1 h after FP-TBI, [18F]FDOPA was infused and PET scanning was performed for 2 h. At 2 h after FP-TBI administration, a second series of measurements of physiological values including CBF and brain oxidative metabolism data had been obtained. Severe FP-TBI elicited a marked increase in the rate constant for fluorodopamine production (k3FDOPA) in all brain regions of newborn piglets studied by between 97% (mesencephalon) and 143% (frontal cortex) (p < 0.05). In contrast, brain hemodynamics and cerebral oxidative metabolism remained unaltered after TBI. Furthermore, the permeability-surface area product of FDOPA (PSFDOPA) was unchanged. In addition, regional blood flow differences between corresponding ipsi- and contralateral brain regions did not occur after TBI. Thus, it is suggested that severe FP-TBI induces an upregulation of AADC activity of newborn piglets that is not related to alterations in brain oxidative metabolism.
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http://dx.doi.org/10.1089/0897715041651024DOI Listing
August 2004

Intrauterine growth restriction ameliorates the effects of gradual hemorrhagic hypotension on regional cerebral blood flow and brain oxygen uptake in newborn piglets.

Pediatr Res 2004 Oct 4;56(4):639-46. Epub 2004 Aug 4.

Institute for Pathophysiology, Friedrich Schiller University, D-07740 Jena, Germany.

Data are scant regarding the development of cerebrovascular autoregulation in intrauterine growth-restricted (IUGR) newborns. We tested the hypothesis that IUGR improves the ability of neonates to withstand critical periods of gradual hemorrhagic hypotension by optimizing cerebrovascular autoregulation. Studies were conducted on 1-d-old anesthetized piglets divided into groups of normal weight (NW, n = 14, body weight = 1518 +/- 122 g) and IUGR (n = 14, body weight = 829 +/- 50 g) animals. Physiologic parameters, including regional cerebral blood flow (CBF) and cerebral metabolic rate of oxygen (CMRO(2)), were similar in NW and IUGR piglets under baseline conditions. Controlled arterial blood loss [hemorrhagic hypotension (HH)] induced a stepwise reduction of the mean arterial blood pressure of 49 +/- 3 mm Hg (mild HH), 39 +/- 3 mm Hg (moderate HH), and 30 +/- 3 mm Hg (severe HH) in seven NW and seven IUGR piglets (p < 0.05). In NW piglets, cortical CBF and CMRO(2) was reduced already at moderate HH (p < 0.05). A similar CMRO(2) reduction occurred during severe HH in NW and IUGR piglets (p < 0.05). In addition, during mild and moderate HH, primarily in IUGR piglets, an increase in regional CBF of brainstem, cerebellum, and thalamus was shown compared with baseline values (p < 0.05). Furthermore, under these conditions, cerebral cortex blood flow was maintained in newborn IUGR animals. In contrast, NW piglets exhibited a significant reduction in CBF (p < 0.05) during moderate HH. Thus, IUGR resulted in an improved ability to withstand critical periods of gradual oxygen deficit as shown by improved cerebrovascular autoregulation during hemorrhagic hypotension.
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http://dx.doi.org/10.1203/01.PDR.0000139425.94975.77DOI Listing
October 2004

Developmental changes in the activities of aromatic amino acid decarboxylase and catechol-O-methyl transferase in the porcine brain: a positron emission tomography study.

Neurosci Lett 2004 Jul;364(3):159-63

Institut für Interdisziplinäre Isotopenforschung, Permoserstrasse 15, D-04318 Leipzig, Germany.

Newborn (7-10 days old) and young (6-8 weeks old) pigs were used to study the metabolism of 6-[18F]fluoro-L-DOPA (FDOPA) in various brain regions with positron emission tomography (PET). Compartmental modeling of PET data was used to calculate the rate constants for the decarboxylation of FDOPA (k3) and for the metabolism of the resulting [18F]fluoro-dopamine (kcl). Whereas general physiological parameters such as cerebral blood flow, cerebral oxygen uptake, arterial blood gases and glucose concentration remained unchanged in young pigs as compared to newborns, a 50-200% increase of k3 in frontal cortex, striatum and mesencephalon was found. Also a 60% enhancement of kcl in the frontal cortex was measured, which is related to changes of the catechol-O-methyl-transferase (COMT) activity and implies a special function of this enzyme in the development of this brain region. In addition, measurement of plasma metabolites of FDOPA with HPLC was performed. The metabolism of FDOPA in young pigs was significantly faster than in newborns. Calculation of the rate constant for O-methylation of FDOPA by COMT revealed a significant elevation of this enzyme activity in young pigs compared to newborns. The increase of AADC and COMT activity with brain development is considered to be associated with special stages of neuronal maturation and tissue differentiation.
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http://dx.doi.org/10.1016/j.neulet.2004.04.041DOI Listing
July 2004

Marked reduction of brainstem blood flow in artificially ventilated newborn piglets during normoxia and normocapnic hypoxia.

Intensive Care Med 2003 Dec 16;29(12):2277-2284. Epub 2003 Oct 16.

Institute of Pathophysiology, Friedrich Schiller University, 07740 , Jena, Germany.

Objective: To estimate the effect of artificial ventilation on regional cerebral blood flow, cardiovascular regulation, and cerebral oxidative metabolism in newborns.

Design And Subjects: Comparison of three randomized treatment groups of newborn piglets: Group 1 (artificially ventilated sham-operated group; n =7); group 2 (artificially ventilated group with normoxia and moderate normocapnic hypoxia; n =7); group 3 (spontaneously breathing group with normoxia and moderate normocapnic hypoxia; n =6).

Measurements And Results: Animals were anesthetized with 0.5% isoflurane in 70% nitrous oxide and 30% oxygen. Groups 1 and 2 were artificially ventilated. Animals in group 3 breathed spontaneously. Moderate normocapnic hypoxia was induced in groups 2 and 3 for 1 h by lowering the inspiratory oxygen fraction from 0.35 to 0.11. Mode of ventilation induced at most marginal effects on global cerebrovascular response, cardiovascular regulation, and cerebral oxidative metabolism. However, under normoxic conditions, regional cerebral blood flow of the medulla oblongata, pons, mesencephalon, thalamus, and cerebellum were markedly reduced in artificially ventilated piglets ( P <0.05). Moderate normocapnic hypoxia led to a marked increase in regional cerebral blood flow, which was significantly lower in the medulla oblongata, pons, mesencephalon, thalamus, and cerebellum of artificially ventilated piglets ( P <0.05).

Conclusion: Artificial ventilation clearly induces reduced neuronal activity in the brain stem and cerebellum of newborn piglets. This is suggested by a considerably reduced blood flow in these regions under normoxia and moderate normocapnic hypoxia. However, there is no relevant detrimental effect on cardiovascular regulation and brain oxidative metabolism.
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http://dx.doi.org/10.1007/s00134-003-2007-5DOI Listing
December 2003

Impact of asymmetric intrauterine growth restriction on organ function in newborn piglets.

Eur J Obstet Gynecol Reprod Biol 2003 Sep;110 Suppl 1:S40-9

Institute for Pathophysiology, Friedrich Schiller University, D-07740 Jena, Germany.

Fetal malnutrition may induce asymmetric intrauterine growth restriction (aIUGR) with long-lasting consequences. Understanding the organ-specific structural and functional effects aIUGR may have on the newborn, and understanding the potential impact on the neonatal response to compromising conditions, appears to be essential for adequate treatment. Therefore, a survey is given of some organ-specific alterations in newborns, which have suffered from aIUGR. We studied these effects in a model of asymmetric intrauterine growth restriction based on the spontaneous occurrence of runting in pigs. We wish to demonstrate that experimental studies in animal models are necessary and helpful to elucidate pathogenetic mechanisms. aIUGR seems to have both beneficial and detrimental effects on the newborn. The development of skeletal muscles (conversion to oxidative type I fibers) and of their vascular supply as well as of the brain dopaminergic activity is accelerated. Also, aIUGR apparently improves the ability to withstand critical periods of gradual oxygen deficit as shown by the maintenance of renal blood flow during severe systemic hypoxia, and by improved cerebrovascular autoregulation in hemorrhagic hypotension. On the other hand, aIUGR leads to the reduction of the number of nephrons and to impaired renal excretory functions with arterial hypertension and chronic renal failure.
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http://dx.doi.org/10.1016/s0301-2115(03)00171-4DOI Listing
September 2003

Effect of hypoxia/hypercapnia on metabolism of 6-[(18)F]fluoro-L-DOPA in newborn piglets.

Brain Res 2002 Apr;934(1):23-33

Institute of Pathophysiology, Friedrich Schiller University, D-07740 Jena, Germany.

There is evidence that the dopaminergic system is sensitive to altered p(O(2)) in the immature brain. However, the respective enzyme activities have not been measured in the living neonatal brain together with brain oxidative metabolism. Therefore 18F-labelled 6-fluoro-L-3,4-dihydroxyphenylalanine (FDOPA) together with positron emission tomography (PET) was used to estimate the activity of the aromatic amino acid decarboxylase (AADC) in the brain of fifteen newborn piglets (2-5 days old). Two PET scans were performed in each piglet. Eleven animals underwent a period of normoxia and moderate hypoxia/hypercapnia (H/H). The remaining four animals were used as an untreated control group. Simultaneously, the brain tissue p(O(2)) was recorded, the regional cerebral blood flow (CBF) was measured with colored microspheres and the cerebral metabolic rate of oxygen (CMRO(2)) was determined. In addition, in four untreated and six H/H treated piglets the relative amounts of fluorodopamine and the respective metabolites were determined in brain tissue samples using HPLC analysis. H/H conditions were induced by lowering the inspired fraction of oxygen from 0.35 to 0.10 and adding CO(2) to the inspired gas resulting in an arterial p(CO(2)) between 74 and 79 mmHg. H/H elicited a more than 3-fold increase of the CBF (P<0.05) so that the CMRO(2) remained unchanged throughout the H/H period. Despite this, the brain tissue p(O(2)) was reduced from 19+/-4 to 6+/-3 mmHg (P<0.05). The permeability-surface area product of FDOPA (PS(FDOPA)) was unchanged. However, the transfer rate of FDOPA (k(3)(FDOPA)) of the nigrostriatal dopaminergic system and the relative amounts of fluorodopamine and the respective metabolites were significantly increased (P<0.05). It is suggested that H/H induces an increase of AADC activity. However, an H/H-induced CBF increase maintains bulk O(2) delivery and preserves CMRO(2).
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http://dx.doi.org/10.1016/s0006-8993(02)02315-6DOI Listing
April 2002