Lipids join the post-genomic era.
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Genes, Developmental↗
Biomedical subjects
Reinhard Bauer
Publications and source records attributed to Reinhard Bauer.
Gene silencing in a human organotypic skin model.
Here we present a simple and highly reproducible method which allows the study of the effects of a single gene knockdown in an organotypic skin model. Human keratinocytes (KC) were transfected with backbone-modified short interfering RNAs (siRNAs) specific for vascular endothelial growth factor (VEGF) and matriptase-1. Twenty-four hours later the transfected cells were seeded onto fibroblast collagen suspensions and allowed to build up a multilayered epidermis by culture at the air/medium interface for 7 days. Protein expression of both targeted genes remained down-regulated by more than 80% up to 8 days after transfection. As expected, VEGF knockdown by siRNA did not alter epidermis formation in our organotypic skin model. By contrast ablation of matriptase-1 led to aberrant KC differentiation and impaired filaggrin processing and resulted in an epidermal phenotype closely resembling that of matriptase-1 deficient mouse skin. Our results suggest that siRNA-mediated gene silencing is highly efficient in an organotypic skin model and readily allows the assessment of the roles of individual genes during terminal KC differentiation.
Animals↗
Heteromerization of innexin gap junction proteins regulates epithelial tissue organization in Drosophila.
Gap junctions consist of clusters of intercellular channels, which enable direct cell-to-cell communication and adhesion in animals. Whereas deuterostomes, including all vertebrates, use members of the connexin and pannexin multiprotein families to assemble gap junction channels, protostomes such as Drosophila and Caenorhabditis elegans use members of the innexin protein family. The molecular composition of innexin-containing gap junctions and the functional significance of innexin oligomerization for development are largely unknown. Here, we report that heteromerization of Drosophila innexins 2 and 3 is crucial for epithelial organization and polarity of the embryonic epidermis. Both innexins colocalize in epithelial cell membranes. Innexin3 is mislocalized to the cytoplasm in innexin2 mutants and is recruited into ectopic expression domains defined by innexin2 misexpression. Conversely, RNA interference (RNAi) knockdown of innexin3 causes mislocalization of innexin2 and of DE-cadherin, causing cell polarity defects in the epidermis. Biochemical interaction studies, surface plasmon resonance analysis, transgenesis, and biochemical fractionation experiments demonstrate that both innexins interact via their C-terminal cytoplasmic domains during the assembly of heteromeric channels. Our data provide the first molecular and functional demonstration that innexin heteromerization occurs in vivo and reveal insight into a molecular mechanism by which innexins may oligomerize into heteromeric gap junction channels.
Amino Acid Sequence↗
Renal Angiotensin receptor type 1 and 2 upregulation in intrauterine growth restriction of newborn piglets.
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.
Angiotensin I↗
Muscle growth and fiber type composition in hind limb muscles during postnatal development in pigs.
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.
Animals↗
Intrauterine growth restriction induces increased capillary density and accelerated type I fiber maturation in newborn pig skeletal muscles.
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.
Animals↗
Stereotactic approach and electrophysiological characterization of thalamic reticular and dorsolateral nuclei of the juvenile pig.
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.
Anesthetics↗
Neuroprotective effects of topiramate after hypoxia-ischemia in newborn piglets.
BACKGROUND: Perinatal hypoxia-ischemia (HI) is associated with delayed cerebral damage, which involves receptor-mediated excitotoxicity. Until now, successful interventions to reduce excitotoxicity early after HI in experimental settings failed to transform into clinical applications owing to negative side effects. A promising new approach using the anticonvulsant Topiramate (TPM) has shown to be effective to reduce brain damage after early HI in a rodent model of combined TPM-hypothermia. Here, we used TPM solely administered 1 h after HI in a neonatal piglet model in order to verify possible neuroprotection. METHODS: Newborn piglets were subjected to HI by transient occlusion of carotid arteries and hypotension (62-65% of baseline). Fifteen minutes later, an additional reduction of the inspired oxygen fraction to 0.06 was performed for 13 min. One cohort (VEHICLE, n = 8) received saline solution i.v. 1 h after HI and then twice a day. Two further cohorts were treated at same times with TPM (HI-TPM10, n = 8, loading dose 20 mg/kg; maintenance dose 10 mg/kg/day; HI-TPM20, n = 8, loading dose 50 mg/kg; maintenance dose 20 mg/kg/day). Untreated animals (CONTROL, n = 8) received all experimental procedures except HI. Animals were monitored 3 days after HI concerning occurrence of seizures as well as neurological and behavioral functions. After 72 h, the brains were perfused and processed to assess neuronal loss and DNA-fragments (TUNEL staining). RESULTS: There was a significant reduction of neuronal cell loss in HI-TPM20 animals. However, apoptosis was increased in the frontal white matter of HI-TPM20 animals. CONCLUSIONS: Exclusive TPM treatment shows neuroprotection in newborn piglets after HI.
Animals↗
Intercellular communication: the Drosophila innexin multiprotein family of gap junction proteins.
Gap junctions belong to the most conserved cellular structures in multicellular organisms, from Hydra to man. They contain tightly packed clusters of hydrophilic membrane channels connecting the cytoplasms of adjacent cells, thus allowing direct communication of cells and tissues through the diffusion of ions, metabolites, and cyclic nucleotides. Recent evidence suggests that gap junctions are constructed by three different families of four transmembrane proteins: the Connexins and the Innexins found in vertebrates and in invertebrates, respectively, and the Innexin-like Pannexins, which were recently discovered in humans. This article focuses on the Drosophila Innexin multiprotein family, which is comprised of eight members. We highlight common structural features and discuss recent findings that suggest close similarities in cellular distribution, function, and regulation of Drosophila Innexins and vertebrate gap junction proteins.
Adherens Junctions↗
A pig model with secondary increase of intracranial pressure after severe traumatic brain injury and temporary blood loss.
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.
Animals↗
The effect of mild hypothermia on plasma fentanyl concentration and biotransformation in juvenile pigs.
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.
Analgesics, Opioid↗
Effect of moderate hypercapnic hypoxia on cerebral dopaminergic activity and brain O2 uptake in intrauterine growth-restricted newborn piglets.
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.
Animals↗
Stretched poly(dimethylsiloxane) gels as NMR alignment media for apolar and weakly polar organic solvents: an ideal tool for measuring RDCs at low molecular concentrations.
The measurement of residual dipolar couplings (RDCs), meanwhile a standard method for obtaining structural information in biomolecular NMR, requires partial alignment of the sample. Special demands on alignment media so far limit the applicability of this approach to small molecules in organic solvents. Major limitations are the free scalability of alignment and the suppression of residual signals of the alignment medium to allow effective measurement of low-concentration samples. Here, we present stretched poly(dimethylsiloxane) (PDMS) cross-linked by beta-rays as an alignment medium with no visible impurities in 1H NMR spectra but a single signal at approximately 0.1 ppm that can easily be removed by slightly modified water suppression methods. Besides the free scalability, its applicability to the measurement of RDCs in small molecules at low concentration is demonstrated on a approximately 12 mM sample of spiroindene. The induced alignment tensor in this case can be predicted reasonably well by a simplified model on the basis of steric interactions only.
Dimethylpolysiloxanes↗
The influx of neutral amino acids into the porcine brain during development: a positron emission tomography study.
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.
Aging↗
Intrauterine growth restriction ameliorates the effects of gradual hemorrhagic hypotension on regional cerebral blood flow and brain oxygen uptake in newborn piglets.
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.
Adaptation, Physiological↗
Developmental changes in the activities of aromatic amino acid decarboxylase and catechol-O-methyl transferase in the porcine brain: a positron emission tomography study.
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.
Age Factors↗
Gap junction channel protein innexin 2 is essential for epithelial morphogenesis in the Drosophila embryo.
Direct communication of neighboring cells by gap junction channels is essential for the development of tissues and organs in the body. Whereas vertebrate gap junctions are composed of members of the connexin family of transmembrane proteins, in invertebrates gap junctions consist of Innexin channel proteins. Innexins display very low sequence homology to connexins. In addition, very little is known about their cellular role during developmental processes. In this report, we examined the function and the distribution of Drosophila Innexin 2 protein in embryonic epithelia. Both loss-of-function and gain-of-function innexin 2 mutants display severe developmental defects due to cell death and a failure of proper epithelial morphogenesis. Furthermore, immunohistochemical analyses using antibodies against the Innexins 1 and 2 indicate that the distribution of Innexin gap junction proteins to specific membrane domains is regulated by tissue specific factors. Finally, biochemical interaction studies together with genetic loss- and gain-of-function experiments provide evidence that Innexin 2 interacts with core proteins of adherens and septate junctions. This is the first study, to our knowledge, of cellular distribution and protein-protein interactions of an Innexin gap junctional channel protein in the developing epithelia of Drosophila.
Animals↗
Traumatic injury in the developing brain--effects of hypothermia.
Little is known about the underlying mechanisms of head trauma in the developing brains, despite considerable social and economic impact following such injuries. Age has been shown to substantially influence morbidity and mortality. Children younger than 4 years of age had worse cognitive, motor, and brain atrophy outcomes than children 6 years of age and older. Younger children tend to more frequently suffer from diffuse cerebral swelling compared to adults. Typical autoptic findings also include axonal injury and ischemic neurodegeneration. These differences impact not only the primary response of the brain to injury but the secondary response as well. The complexity of damaging mechanisms in traumatic brain injury contributes to the problem of determining effective therapy. As an alternative/ adjunct to pharmacological approaches, hypothermia has been shown to be cerebroprotective in traumatized adult brains. Although a large number of animal studies have shown protective effects of hypothermia in a variety of damaging mechanisms after TBI, little data exist for young, developing brains. The injury mechanisms of TBI in the immature, effects of hypothermia following resuscitation on adult and immature traumatized brains, and some possible mechanisms of action of hypothermia in the immature traumatized brain are discussed in this review.
Age Factors↗