Hyperoxia: Effects on the vascularization of the developing central nervous system

Summary Litters of experimental and control hamsters were killed on postnatal days 3, 4, 7, 14, 21, and 28 following 7 days of exposure to 85% oxygen at normabaric pressure. Using analysis of variance (ANOVA), light microscopy quantitation of the number of blood vessel profiles per unit area in the region of the frontal cerebral cortex demonstrated that the combined effect of treatment and age on the animals produced a highly statistically significant difference (P<0.001) in the numbers of blood vessel profiles. The statistically separated treatment effect was also found to be significant (P<0.05). The data are summarized in Table 1. Ultrastructural analysis of animals exposed to oxygen only, i.e., killed without being returned to the normal air environment, demonstrated severe signs of vaso-obliteration. Animals which were returned to a normal atmosphere following 7 days in oxygen showed a progressive decrease in the signs of vaso-obliteration. This present study demonstrated the marked similarity between the effects of hyperoxia on the CNS and on the neuro-retina.This study was supported by The Alberta Heart Foundation     

Cytokines and the central nervous system

Cytokines are involved both in the immune response and in controlling various events in the central nervous system, that is, they are equally immunoregulators and modulators of neural functions and neuronal survival. On the other hand, cytokine production is under the tonic control of the peripheral and the central nervous system and the cytokine balance can be modulated by the action of neurotransmitters released from nonsynaptic varicosities [131]. The neuroimmune interactions are therefore bidirectional-cytokines and other products of the immune cells can modulate the action, differentiation, and survival of neuronal cells, while the neurotransmitter and neuropeptide release play a pivotal role in influencing the immune response. Cytokines and their receptors are constitutively expressed by and act on neurons in the central nervous system, in both its normal and its pathological state, but cytokine overexpression in the brain is an important factor in the pathogenesis of neurotoxic and neurodegenerative disorders. Accordingly, it can be accepted that the peripheral and central cytokine compartments appear to be integrated, and their effects might synergize or inhibit each other; however, it should always be taken into account that they are spatiotemporally differentially regulated. New concepts are reviewed in the regulation of relations between cytokine balance and neurodegeneration, including intracellular receptor-receptor, cell-cell, and systemic neuroimmune interactions that promote the further elucidation of the complexities and cascade of the possible interactions between cytokines and the central nervous system.     

The effects of protein malnutrition on the developing central nervous system in the rat

We have carried out a multi-disciplinary study of the effects of prenatal protein malnutrition on the developing rat brain. These experiments, involving anatomical, physiological, biochemical, and behavioral approaches, have revealed that malnutrition induced prenatally can affect various parameters of brain growth and development. Some of these effects can be reversed depending on when dietary restitutions are carried out. However, if protein malnutrition is maintained during the brain growth spurt or critical growth periods there are many permanent sequelae that cannot be reversed by subsequent restitution of high protein diets. We have reviewed the concept of critical periods of brain growth relative to the various aspects of neural morphogenesis in the rat, that is, the birth of neurons, migration of neurons, differentiation of neurons, and synapse formation. We have also discussed the rapid phases of brain growth in the rat as compared to similar phases in other species as a basis for determining whether the rat model can provide time-tables for brain growth in other species, including man. Different components of the brain, both morphological and chemical, have their own cycles of rapid development so that insults to the brain at particular periods affect particular aspects of brain chemistry and neuronal systems. Development of chemical circuits in the brain, such as the aminergic neurons, and their eventual adequate functioning, depends on development of the neurotransmitters themselves. These latter are markedly affected by protein malnutrition. Major physiological-behavioral states, such as the sleep-waking continuum, are markedly affected by protein malnutrition as are many behaviors. Some of these latter are merely late or retarded in development but others remain permanently altered. By approaching the problem of protein malnutrition from multiple points of view we have been able to pinpoint several brain areas showing the most drastic residua of early protein malnutrition and are beginning, by use of morphometric, electro-ontogenetic, biochemical development and behavioral studies, to define brain locales and basic mechanisms by which these insults produce their effects.     

Bilirubin toxicity in the developing nervous system

Bilirubin toxicity remains a significant problem despite recent advances in the care of jaundiced (hyperbilirubinemic) neonates. A recent surge in reported cases of classical kernicterus, due in part to earlier hospital discharge and relaxation of treatment criteria for hyperbilirubinemia, and new reports of hyperbilirubinemia-induced auditory dysfunction using evoked potential based infant testing and hearing screening, underscore the need to better understand how hyperbilirubinemia causes brain damage in some infants, especially because the damage is preventable. Recent progress in understanding bilirubin binding and neurotoxicity resulting from unbound or “free” unconjugated bilirubin, how bilirubin affects the central nervous system in vivo and in vitro, and the use of new clinical tools in neonates, for example magnetic resonance imaging revealing bilateral lesions in globus pallidus and subthalamus, and abnormal brainstem auditory evoked potentials with normal inner ear function, may lead to improved detection and prevention of neurologic dysfunction and damage from bilirubin. Finally, the concern is raised that partial or isolated neurologic sequelae, for example auditory neuropathy and other central auditory processing disorders, may result from excessive amount and duration of exposure to free, unconjugated bilirubin at different stages of neurodevelopment.     

Comparative effects of alcohol and thiamine deficiency on the developing central nervous system

The present study addresses the still unresolved issue of the character of alcohol-thiamine metabolic interferences in the developing central nervous system (CNS). Investigations compare developmental neurotoxicity evoked by three patterns of maternal thiamine deficiency (pre, peri and postnatal), with two patterns of maternal chronic alcohol intake (alcohol alone and alcohol + thiamine cotreatment), on seven neurodevelopmental abilities in the offspring. The three patterns of thiamine deficiency, pair-compared with controls, highlight four sequences of development: (1) embryonic-perinatal sequence; (2) perinatal-postnatal sequence; (3) “ontogeny in ontogeny out” sequence; (4) “off and on” developing sequence. The results suggest a temporally- and regionally emergence of structures and centers underlying functional maturation during CNS ontogenesis. Furthermore, both developmental thiamine deficiencies and ethanol exposure produce two waves of neurofunctional alterations, peaking at P15 (postnatal day 15) and P25, respectively. The first peak of vulnerability is a prenatal event; it may interfere with the periods of intense cellular proliferation and migration. The second peak represents both perinatal and postnatal events; it may interfere with the periods of cellular differentiation, synaptogenesis, axonogenesis and myelinogenesis. Alcohol + thiamine cotreatment fails to reduce the first peak, but neutralizes essentially the second peak. The results suggest that alcohol interferes with thiamine during cellular differentiation and membrane developmental processes mainly. Indeed, among the three conditions of thiamine-deficient diet, only perinatal thiamine deficiency exhibits a closer relationship with developmental alcohol exposure. Together, these observations suggest that the critical period for alcohol-thiamine antagonism occurs perinatally and affects primarily cellular differentiation.     

Neurotoxicity ofN-methyl-d-aspartate is markedly enhanced in developing rat central nervous system

The neurotoxic lesion produced by direct injection of 25 nmol ofN-methyl-d-aspartate (NMDA) into the corpus striatum of 7-day-old rats was compared to the effects of injecting 75 nmol into the striatum or hippocampus of adults. The area of histopathology in the immature striatum was 21 × larger than the striatal lesions in adults. Damage from NMDA injected into the immature striatum also extended into the dorsal hippocampus and produced an area of destruction which was 16 × larger than observed after direct injection into the adult hippocampus. Several studies have implicated excessiveN-methyl-d-aspartate receptor activation in the pathogenesis of hypopoxic-ischemic and hypoglycemic injury and our results suggest that this neurotoxic mechanism is extremely active in the immature brain.     

Spectra of central nervous system melioidosis

Burkholderia pseudomallei infection of the central nervous system (CNS) is rare with less than 50 cases reported over the last 30 years. The retrospective melioidosis study at University Malaya Medical Centre has documented three cases of CNS melioidosis out of more than 160 cases of melioidosis since 1978. There were two patients with brain abscess and one with spinal epidural abscess. The predisposing factors were: one patient was an aboriginal farmer and the other two were diabetic. Their age ranged from 17 to 45 years. Prominent neurological features were limb weakness, cranial nerve palsy (6th and 7th) and visual disturbance. CT brain scan and MRI spine showed abscess formation, subdural collection, and spinal epidural collection, osteomyelitis of vertebra and occipital bone and also sagital sinus thrombosis. All these patients underwent surgical drainage leading to bacteriological diagnosis as well as appropriate long-term antibiotic therapy. All had good recovery at 6 months after completion of treatment.     

Liposome toxicity in the mouse central nervous system

This study has shown that while some liposomes are highly toxic to the central nervous system, others, of different composition, are tolerated well in the dosage used (0.02–0.05 ml ≡ 4–12 mg of lipid/inoculum). Those composed of lecithin-cholesterol-dicetyl phosphate or lecithin-cholesterol-stearylamine produced generalised epileptic seizures and some deaths due to respiratory failure immediately after injection, and a subsequent widespread tissue necrosis. However liposomes composed of lecithin-cholesterol-phosphatidic acid, or dipalmitoyl lecithin only, produced minimal morphological changes and by the sixth day post-injection the pathology was limited to the mechanical trauma caused by the injection. It is concluded that liposomes of appropriate composition may be sufficiently benign to use as carriers of therapeutic agents into the CNS.     

Selective vulnerability in the developing central nervous system

Selective patterns of cerebral injury are observed after a variety of insults at different ages during development. Distinct populations of cells demonstrate selective vulnerability during these specific developmental stages, which may account for the observed patterns of injury. We review the evidence that injury to preoligodendrocytes and subplate neurons contributes to periventricular white matter injury in preterm infants, whereas thalamic neuronal cell vulnerability and neuronal nitric oxide synthase-expressing striatal interneurons resistance result in deep gray nuclei damage in the term infant. The unique roles of particular mechanisms including oxidative stress, glutamatergic neurotransmission, and programmed cell death are discussed in the context of this selective vulnerability.     

D-serine in the developing human central nervous system

To elucidate the role of D-serine in human central nervous system, we analyzed D-serine, L-serine, and glycine concentrations in cerebrospinal fluid of healthy children and children with a defective L-serine biosynthesis (3-phosphoglycerate dehydrogenase deficiency). Healthy children showed high D-serine concentrations immediately after birth, both absolutely and relative to glycine and L-serine, declining to low values at infancy. D-Serine concentrations were almost undetectable in untreated 3-phosphoglycerate dehydrogenase-deficient patients. In one patient treated prenatally, D-serine concentration was nearly normal at birth and the clinical phenotype was normal. These observations suggest a pivotal role for D-serine in normal and aberrant human brain development.     

Primary rhabdomyosarcoma of the central nervous system

Summary A case of primary rhabdomyosarcoma in the brain stem is described in an 8 year old girl. The clinical data showed a right side hemiplegia then a total paralysis of the left sixth cranial nerve and a paraplegia which became lethal in 3 months. The necrospy revealed a tumoral nodule in the left medulla oblongata and pons with diffuse subarachnoidal extension from the cranial nerves to the cauda equine roots. Histologically the tumor appeared to be polymorph with numerous rhabdomyoblasts which had a clear cross striation and which were sometimes less differentiated without any neuronal or glial elements. Perivascular tumoral cells and blood vessels were closely linked, the Virchow-Robin spaces were clearly involved. The electron microscopic study confirmed that the less differentiated cells were of a rhabdomyoblastic nature. A review of the litterature indicates that these malignant neoplasias are highly exceptional, and can be classified within the group of primary tumors of the neuraxis with muscular elements. The histogenetic origin of these tumors appears to be the ectomesenchyme of neural creats.Our special thanks to Miss Chantal Mariotte who took care of the translation.Department of Neurology (Pr. Ag. J. Perret)     

Adriamycin-induced, TNF-alpha-mediated central nervous system toxicity

The clinical effectiveness of adriamycin (ADR), a potent chemotherapeutic, is known to be limited by severe cardiotoxic side effects. However, the effect of ADR on brain tissue is not well understood. It is generally thought that ADR is not toxic to the brain because ADR does not pass the blood-brain barrier. The present study demonstrates that ADR autofluorescence was detected only in areas of the brain located outside the blood-brain barrier, but a strong tumor necrosis factor (TNF) alpha immunoreactivity was detected in the cortex and hippocampus of ADR-treated mice. Systemic injection of ADR led to a decline in brain mitochondrial respiration via complex I substrate shortly after ADR treatment (P < 0.05). Cytochrome c release, increased caspase 3 activity, and TUNEL-positive cell death all were suggestive of apoptosis in brain following systemic ADR treatment. The levels of the known pro-apoptotic proteins, p53 and Bax, were increased in brain mitochondria at 3 h following ADR treatment and declined by 48 h. In contrast, the anti-apoptotic protein, Bcl-xL, was increased later at 6 h post-ADR treatment and was sustained throughout 72 h. Furthermore, p53 migrated to mitochondria and interacted with Bcl-xL, supporting the hypothesis that mitochondria are targets of ADR-induced CNS injury. Neutralizing antibodies against circulating TNF completely abolished both the increased TNF in the brain and the observed mitochondrial injury in brain tissues. These results are consistent with the notion that TNF is an important mediator by which ADR induces central nervous system (CNS) injury. This study, the first to provide direct biochemical evidence of ADR toxicity to the brain, revealed novel mechanisms of ADR-induced CNS injury and suggests a potential therapeutic intervention against circulating TNF-induced CNS effects.     

Rhabdoid tumors of the central nervous system

Rhabdoid tumors of the central nervous system are rare malignancies with a still almost uniformly fatal outcome. There is still no proven curative therapy available. We report our experience with nine patients with central nervous system rhabdoid tumors. Gross complete surgical removal of the tumor was achieved in six patients. Seven patients received intensive chemotherapy. Four of these were treated in addition with both neuroaxis radiotherapy and a local boost directed to the tumor region, while two patients received local radiotherapy only. The therapy was reasonably well tolerated in most cases. Despite the aggressive therapy, eight of the nine patients died from progressive tumor disease, and one patient died from hemorrhagic brain stem lesions of unknown etiology. The mean survival time was 10 months after diagnosis. Conventional treatment, although aggressive, cannot change the fatal prognosis of central nervous system rhabdoid tumors. As these neoplasms are so rare, a coordinated register would probably be a good idea, offering a means of learning more about the tumor’s biology and possible strategies of treatment. Received: 7 September 1999     

Chromatolytic changes in the central nervous system of patients with the toxic oil syndrome

Summary Five patients died of a severe neuromyopathy months after the ingestion of adulterated rapessed oil. These patients were selected for this study due to the presence of striking chromatolytic lesions in symmetric and scattered nuclei of the brain stem, including the locus coeruleus, midline raphe, lateral reticular nuclei of the medulla and cuneate nuclei. Two of the five cases, in addition to these topographic levels of involvement, had remarkable chromatolysis, vacuolar degeneration and heavy silver impregnation of the swollen perykarya and proximal dendrites in the nuclei of the basis pontis. In this paper we analyze the features of the chromatolytic lesion and suggest that the neuronal pathology observed in these cases is an example of irreversible chromatolysis involving vacuolization and filamentous proliferation as final events of the chromatolytic process. The cause of the cell degeneration in the toxic oil syndrome (TOS) is yet undetermined. Chromatolysis in this disease may be the result of a neurotoxic action of the toxic factor in the adulterated oil.Supported by the Plan Nacional para el Síndrome Tóxico     

Neurotraumatology: Ultrasonic evaluation of the central nervous system

Abstract

In this study we describe the technique of intraoperative ultrasound imaging of brain and spinal cord in trauma patients. The images are shown and their interpretation is discussed. This intraoperative imaging allows for localization of hematomas, bone fragments and indriven foreign bodies (j.e., pieces of plastic, glass, metal, etc.). DISC matenal and bone fragments deep to the spinal cord can be localized with this technique. Real-time ultrasound can be used to guide instruments within the brain and, thereby, provide dynamic guidance for removal of bone fragments and foreign bodies dynamically. In summary, Intraoperative real-time ultrasonic Imaging is of use to the neurosurgeon in the treatment of the neurotrauma patient. [Neural Res 1997; 19: 317–322]

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Primary Hodgkin lymphoma of the central nervous system

Primary involvement of the central nervous system by Hodgkin lymphoma is rare; most cases represent metastases. We report a primary Hodgkin lymphoma presenting in the cerebellum of a 77-year-old man and review the literature on primary Hodgkin lymphoma of the central nervous system.     

Peripheral neuropathy and neurosteroid formation in the central nervous system

Neurons and glial cells are capable of synthesizing bioactive steroids also called neurosteroids which modulate the nervous system activity. Neurosteroids act via autocrine or paracrine mechanisms. Therefore, before neurosteroids can be considered as endogenous modulators of a specific neurophysiologic function, it is compulsory that the process of neurosteroidogenesis occurs in neural pathways controlling this function. Based on pharmacological observations, various studies suggested the involvement of endogenous neurosteroids in the modulation of a variety of neurobiological processes. However, the direct link between these processes and endogenous production of neurosteroids in the nervous system remains unknown. The present review recapitulates a series of results showing the existence of interactions between peripheral nerve injury and neurosteroid biosynthesis in the central nervous system (CNS). In particular, the paper discusses the impact of sciatic nerve ligature on genomic and biochemical components of neurosteroidogenesis in the spinal cord and brainstem areas including the parabrachial, raphe magnus and dorsal raphe nuclei which control nociception. It appears that peripheral nerve injuries evoke changes in the gene expression and biological activity of cytochrome P450side-chain-cleavage, the key enzyme catalyzing the onset of neurosteroidogenesis in the CNS. Owing to neurosteroid involvement in the control of various neurobiological functions, these data suggest that neurosteroidogenesis is an endogenous mechanism activated in the CNS for adaptation of the body to chronic peripheral neuropathies. Therefore, strategies based on selective targeting of neurosteroidogenic pathways may constitute interesting approaches to develop novel therapy against disorders provoked by central and peripheral neuropathies.