Development Of Neurological Dysfunction Research Articles

Neurological involvement in hematopoietic stem cell transplantation-associated thrombotic microangiopathy.

Transplantation-associated thrombotic microangiopathy (TA-TMA) is a well-recognized serious complication of hematopoietic stem cell transplantation (HSCT). The understanding of TA-TMA pathophysiology has expanded in recent years. Dysregulation of the complement system is thought to cause endothelial injury and, consequently, microvascular thrombosis and tissue damage. TA-TMA can affect multiple organs, and each organ exhibits specific features of injury. Central nervous system (CNS) manifestations of TA-TMA include posterior reversible encephalopathy syndrome, seizures, and encephalopathy. The development of neurological dysfunction is associated with a significantly lower overall survival in patients with TA-TMA. However, there are currently no established histopathological or radiological criteria for the diagnosis of CNS TMA. Patients who receive total body irradiation (TBI), calcineurin inhibitors (CNI), and severe acute and chronic graft-versus-host disease (GVHD) are at a high risk of experiencing neurological complications related to TA-TMA and should be considered for directed TA-TMA therapy. However, the incidence and clinical manifestations of TA-TMA neurotoxicity remain unclear. Studies specifically examining the involvement of CNS in TMA syndromes are limited. In this review, we discuss clinical manifestations and imaging abnormalities in patients with nervous system involvement in TA-TMA. We summarize the mechanisms underlying TA-TMA and its neurological complications, including endothelial injury, evidence of complement activation, and treatment options for TA-TMA.

E3 ubiquitin ligase Triad1 promotes neuronal apoptosis by regulating the p53-caspase3 pathway after spinal cord injury

Purpose Spinal cord injury entails a high risk of major disability, but there is still no effective treatment for this condition. This study aims to explore the neuronal apoptosis after spinal cord injury, which is a key component of secondary injury processes, and plays a critical role in the development of neurological dysfunction. Materials and Methods We studied the expression of the E3 ubiquitin ligase Triad1 and its interaction with p53 in the spinal cord after a spinal cord contusion injury in rats. We explored the regulation function of Triad1 to the neuronal apoptosis through p53-caspase3 pathway in primary neurons. Results Triad1 was markedly up-regulated in the grey matter one day after injury, and the distribution and time point of Triad1 expression correlated with the presence of apoptotic neurons. Co-immunoprecipitation experiments further demonstrated that Triad1 interacted with p53 after spinal cord injury. Specific siRNA and overexpression plasmids for Triad1 were transfected into primary neurons, and the expression of both p53 and caspase3 was altered following the change of Triad1. Conclusions These findings indicate that Triad1 is involved in regulating the pathological process of neuronal apoptosis mediated by p53-caspase3 pathway after spinal cord injury.

Novel Role of HAX-1 in Neurons Protection After Spinal Cord Injury Involvement of IRE-1.

Spinal cord injury (SCI) is one of the diseases with high probability of causing disability in human beings, and there is no reliable treatment at present. Neuronal apoptosis is a vital component of secondary injury and plays a critical role in the development of neurological dysfunction after spinal cord injury. In this study, we found that the expression and distribution of HAX-1 in neurons increased 1day after SCI. PC12 cells overexpressing HAX-1 showed decreased apoptosis and PC12 cells are more likely to undergo apoptosis after down-regulating HAX-1, which was confirmed via TUNEL experiments. We found GRP94 showed the same trend as HAX-1 in expression and interacted with HAX-1 and IRE-1 in both spinal cord tissue and PC12 cells, and this interaction seems to be enhanced after SCI. When the expression of HAX-1 was up-regulated, GRP94 also increased, but IRE-1 did not change at all. Further studies showed that overexpression of HAX-1 decreased the expression of pIRE-1, rather than IRE-1, and downstream proteins of the IRE signaling pathway (Caspase12, pJNK and CHOP) were significantly reduced, and vice versa. In animals treated with HAX-1 expressing adenovirus there are more neuronal cells remaining in the damaged spinal cord tissue, and hindlimb motor function of rats was significantly improved. So, we speculate that HAX-1 might play a role in protecting neurons from apoptosis after SCI by regulating the IRE-1 signaling pathway via promoting the dissociation of GRP94 from IRE-1. This may provide a theoretical basis and a potential therapeutic target for clinical improvement of neural function recovery after SCI.

Acyl‐CoA Synthetase 6 Mediates Brain Docosahexaenoic Acid (DHA) Enrichment and Neuroprotection

The omega‐3 fatty acid, docosahexaenoic acid (DHA), is enriched in the central nervous system and thought to protect against neurological dysfunction. Yet, studying the role of brain DHA metabolism in the development of neurological dysfunction has remained limited because the biochemical mechanisms regulating DHA enrichment in the brain remain unclear. To define a critical regulatory node in brain DHA biochemistry we targeted long chain acyl‐CoA synthetase 6 (Acsl6) because this enzyme initiates cellular fatty acid metabolism, is enriched in the brain and prefers DHA as its substrate. Genetically deleting Acsl6 in mice resulted in large and specific reductions (35–72%) in DHA‐containing phospholipids across tissues that highly express Acsl6 (i.e. the central nervous system). Acsl6−/− mice develop age‐related deleterious neurological pathology characterized by increased astrogliosis and microglia. Surprisingly, this pathology develops in the absence of alterations in pro‐ and anti‐inflammatory lipid mediators, suggesting alternative mechanisms mediating neuroinflammation in Acsl6‐induced DHA deficiency. Together our findings demonstrate a novel central nervous system DHA‐deficient model susceptible to aging‐induced neuroinflammatory pathology.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Neuroinflammatory mechanisms of blood-brain barrier damage in ischemic stroke.

As part of the neurovascular unit, the blood-brain barrier (BBB) is a unique, dynamic regulatory boundary that limits and regulates the exchange of molecules, ions, and cells between the blood and the central nervous system. Disruption of the BBB plays an important role in the development of neurological dysfunction in ischemic stroke. Blood-borne substances and cells have restricted access to the brain due to the presence of tight junctions between the endothelial cells of the BBB. Following stroke, there is loss of BBB tight junction integrity, leading to increased paracellular permeability, which results in vasogenic edema, hemorrhagic transformation, and increased mortality. Thus, understanding principal mediators and molecular mechanisms involved in BBB disruption is critical for the development of novel therapeutics to treat ischemic stroke. This review discusses the current knowledge of how neuroinflammation contributes to BBB damage in ischemic stroke. Specifically, we provide an updated overview of the role of cytokines, chemokines, oxidative and nitrosative stress, adhesion molecules, matrix metalloproteinases, and vascular endothelial growth factor as well as the role of different cell types in the regulation of BBB permeability in ischemic stroke.

DISTURBANCE OF THE PROGESTERONE AND ITS METABOLITES SYNTHESIS IN THE DEVELOPMENT OF NEUROLOGICAL DISORDERS IN CHILDREN AFTER CYTOMEGALOVIRUS INFECTION DURING PREGNANCY

Cytomegalovirus (CMV) infection is one of the causes of congenital neurological disorders and the virus itself is the most common viral agent causing an imbalance in the production of placenta progesterone and its neuroactive metabolites – allopregnenolone and 5α-dihydroprogesterone. The aim was to evaluate the concentration of progesterone and its metabolites – 5α-dihydroprogesterone and allopregnenolone – in placenta during exacerbation of CMV infection in the first trimester of pregnancy, and the impact of these disturbances on the development of neurological disorders in children. We examined 30 pregnant women with exacerbation of CMV infection in the first trimester of pregnancy and 30 pregnant women with latent disease; and later their newborns. The enzyme immunoassay was used to determine concentration of progesterone in placenta; the histochemical method – to determine 5α-dihydroprogesterone and allopregnenolone. Newborns underwent neurosonography studies. Exacerbation of CMV infection in the first trimester of pregnancy decreased progesterone in placenta by 1.3 times, 5α-dihydroprogesterone – by 1.73 times and allopregnenolone – by 2 times. Ultrasound examination of the brain showed ventriculomegaly, periventricular ischemia, and pseudocysts in newborns up to one year from mothers with exacerbation of CMV during pregnancy. Later, minimal brain dysfunctions were manifested by motor disorders, increased general, vegetative excitability, and a tendency to digestive and sleep disorders. The data obtained indicate that the exacerbation of CMV infection in the first trimester of pregnancy is interrelated with a decrease in the concentration of progesterone and its metabolites (5α-dihydroprogesterone, allopregnenolone) in the placenta and development of neurological dysfunction in newborns.

Methionine synthase reductase deficiency (CblE): A report of two patients and a novel mutation

Importance: Functional methionine synthase reductase deficiency, also known as cobalamin E disorder, is a rare autosomal recessive inherited disease that results in an impaired remethylation of homocysteine to methionine. It presents with macrocytic anemia, hyperhomocysteinemia, and hypomethioninemia, and may also be accompanied with neurological impairment.Clinical presentation: We describe two new cases of unrelated girls with megaloblastic anemia misclassified at first as congenital dyserythropoietic anemia with development of neurologic dysfunction in one of them.Intervention: The posterior finding of biochemical features (hyperhomocysteinemia and hypomethioninemia) focused the diagnosis on the inborn errors of intracellular vitamin B12. Subsequent molecular analysis of the methionine synthase reductase (MTRR) gene revealed compound heterozygosity for a transition c.1361C > T (p.Ser454Leu) and another, not yet described in literature, c.1677–1G > A (p.Glu560fs) in one patient, and a single homozygosis mutation, c.1361C > T (p.Ser545Leu) in the other one. These mutations confirmed the diagnosis of cobalamin E deficiency.Conclusion: Treatment with hydroxocobalamin in combination with betaine appears to be useful for hematological improvement and prevention of brain disabilities in CblE-affected patients. Our study widens the clinical, molecular, metabolic, and cytological knowledge of deficiency MTRR enzyme.

Blood–Brain Barrier Breakdown in Acute and Chronic Cerebrovascular Disease

Disruptions of the blood-brain barrier (BBB) and edema formation both play key roles in the development of neurological dysfunction in acute and chronic cerebral ischemia. Animal studies have revealed the molecular cascades that are initiated with hypoxia/ischemia in the cells forming the neurovascular unit and that contribute to cell death. Matrix metalloproteinases cause reversible degradation of tight junction proteins early after the onset of ischemia, and a delayed secondary opening during a neuroinflammatory response occurring from 24 to 72 hours after. Cyclooxygenases are important in the delayed opening as the neuroinflammatory response progresses. An early opening of the BBB within the 3-hour therapeutic window for tissue-type plasminogen activator can allow it to enter the brain and increase the risk of hemorrhage. Chronic hypoxic hypoperfusion opens the BBB, which contributes to the cognitive changes seen with lacunar strokes and white matter injury in subcortical ischemic vascular disease. This review will describe the molecular and cellular events associated with BBB disruption and potential therapies directed toward restoring the integrity of the neurovascular unit.

The effects of Tanshinone IIA on blood–brain barrier and brain edema after transient middle cerebral artery occlusion in rats

Disruption of blood-brain barrier (BBB) and edema formation play a key role in the development of neurological dysfunction after cerebral ischemia. In this study, the effects of Tanshinone IIA (Tan IIA), one of the active ingredients of Salvia miltiorrhiza root, on the BBB and brain edema after transient middle cerebral artery occlusion in rats were examined. Our study demonstrated that Tan IIA reduced brain infarct area, water content in the ischemic hemisphere. Furthermore, Tan IIA significantly decreased BBB permeability to Evans blue, suppressed the expression of intercellular adhesion molecule-1 (ICAM-1), matrix metalloproteinase-9 (MMP-9), inhibited the degradation of tight junction proteins zonula occludens-1 (ZO-1) and Occludin. These results demonstrated that Tan IIA was effective for attenuating the extent of brain edema formation in response to ischemia injury in rats, partly by Tan IIA's protective effect on the BBB. Our results may have implications in the treatment of brain edema in cerebral ischemia.

Spontaneous Hematomyelia in a Child With Hemophilia A

Hemorrhagic complications in patients with hemophilia have been occasionally reported in the spinal column and the spinal cord. Treatment is based on prompt replacement therapy as the occurrence and development of neurologic dysfunction are related to the length of time between the onset of symptoms and the factor replacement. We report case of a 7-year-old hemophilic boy who presented with flaccid paraparesis resulting from thoracic hematomyelia. The patient showed gradual improvement on medical management with cryoprecipitate infusions. This case calls attention to the need for prompt diagnosis of rarely reported spinal hematomyelia based on clinical manifestations and radiologic features and highlights its management options in patients with hemophilia.

Living Related Liver Transplantation in Crigler-Najjar Syndrome Type 1

Four children underwent living related liver transplantation because of Crigler-Najjar syndrome type 1. Three were infants aged 2, 8(1/2), and 15 months, and weighed 5, 8, and 10 kg, respectively. Pretransplantation unconjugated bilirubin concentration was 22 to 30 mg/dL despite 12 to 14 hours of phototherapy daily. Patient 1, the 2-month-old infant, with unconjugated bilirubin concentration of 30 mg/dL, had a high-pitched cry, suggestive of bilirubin encephalopathy; results of neurologic examination were normal. Plasmapheresis and urgent liver transplantation were performed. Patient 4, a 13-year-old girl, had learning difficulties at school and attended a special class. Three patients received left lateral liver segments, and 1 patient received a left lobe. Biliary reconstruction was completed with duct-to-duct anastomosis. Bile leakage developed at the anastomosis in 2 patients, which was treated successfully with cholangioplasty. In all patients, the unconjugated bilirubin concentration normalized by day 1 posttransplantation, and no phototherapy was necessary. After transplantation, the 2-month-old infant with suspected encephalopathy exhibited hypotonia, spasticity of the lower extremities, and lack of head control. He died after vomitus aspiration during sleep at 10 months posttransplantation. The other 3 patients are alive with normal neurodevelopmental milestones. Irreversible brain damage may occur early in the course of Crigler-Najjar syndrome type 1. Urgent treatment including plasmapheresis, exchange transfusion, phototherapy, and liver transplantation may not reverse brain damage. Young infants must be evaluated carefully for subtle signs and symptoms of bilirubin encephalopathy. Liver transplantation is curative if performed before development of neurologic dysfunction.

Cervical spine involvement in rheumatoid arthritis: correlation between neurological manifestations and magnetic resonance imaging findings

To evaluate the correlation between neurological deficits indicative of compressive myelopathy and MRI findings in a series of patients with RA and symptomatic involvement of the cervical spine. Forty-one consecutive patients with RA were studied using cervical spine MRI. Unconditional logistic regression analysis was used to identify MRI parameters of cervical spine involvement associated with the development of neurological dysfunction. The mean age of the 41 patients (33 women and 8 men) was 59 yrs (range 23-82 yrs), while the median disease duration was 18 +/- 9 yrs (range 4-40 yrs). According to Ranawat's classification, 17 (42%) patients were in Class I, 21 (51%) in Class II and 3 (7%) in Class III. Thus, patients with clinical manifestations of compressive myelopathy (Ranawat's Class II + III) represented 58% (24/41) of all cases. Among the different MRI parameters of cervical spine involvement analysed, only the presence of atlantoaxial spinal canal stenosis [odds ratio (OR) 4.55; 95% CI 1.14-18.15], atlantoaxial cervical cord compression (OR 9.6; 95% CI 1.08-85.16) and subaxial myelopathy changes (OR 11.43; 95% CI 1.3-100.81) were associated with a significantly increased risk for neurological dysfunction (Ranawat's Class II or III). In RA patients with symptomatic cervical spine involvement, there is a strong correlation between the development of neurological dysfunction and MRI identification of atlantoaxial spinal canal stenosis, especially in those cases with evidence of upper cervical cord or brainstem compression and subaxial myelopathy changes.

A Study of Potential Interactive Genetic Factors in Huntington’s Disease

Aim: To assess the role of genetic factors, other than the CAG repeat length, on the development of Huntington’s disease (HD) in an isolated Caucasian population in the south-west of Western Australia. Methods: 114 patients with symptomatic HD according to the Unified HD Rating Scale research criteria were examined along with 51 control patients. The length of the CAG repeat sequence in the IT15 gene and the adjacent CCG and Δ2642 polymorphisms were determined by polymerase chain reaction along with common genotypes of the angiotensin-converting enzyme (ACE) and apolipoprotein E (APOE) genes. Results: The CAG expansion was associated with age of onset and the development of neurological dysfunction. We found no effect of the expanded CCG allele on age of onset, neurological dysfunction or the size of the CAG expansion. We observed a twofold increase in the Δ2642 polymorphism and the risk of developing symptomatic HD which was not significant (OR 2.06; 95% CI 0.60–7.07). The presence of an APOE Ε4 allele was associated with an increased risk of HD which was not significant either (OR 1.04–1.73; 95% CI 0.10–10.68). ACE genotypes showed no association with risk factors for the disease. Conclusion: In our study of a geographically isolated Caucasian HD population in the south-west of Western Australia we have not observed that the expanded CCG allele, the Δ2642 polymorphism, the APOE Ε4 allele and ACE genotypes are associated with an increased risk for the development of symptomatic HD.

Intrathecal administration of morphine, but not small dose, induced spastic paraparesis after a noninjurious interval of aortic occlusion in rats.

We sought to investigate the dose-response relationship for the effect of intrathecal morphine on the transient spastic paraparesis after short-lasting spinal ischemia in rats. Spinal ischemia was induced by aortic occlusion for 6 min with a balloon catheter in rats previously implanted with an intrathecal catheter for drug delivery. After ischemia, the animals were allowed to recover, and 3, 10, or 30 microg of morphine or saline was injected intrathecally at 30 min after reperfusion. In a separate group, the quantal bioassay for the effect of intrathecal morphine on neurological function after ischemia was performed to calculate 50% effective dose values for inducing paraparesis at 2 h of reperfusion. Subsequently, histopathology of the spinal cord was assessed at 48 h of reperfusion. Intrathecal injection of 30 or 10 micro g of morphine, but 3 micro g of neither morphine nor saline, caused a progressive development of hindlimb spasticity. The 50% effective dose values for inducing paraparesis were 16.1 +/- 1.5 microg in assessing behavioral analysis at 2 h after intrathecal morphine. Histopathological analysis of spinal cords in the 30- microg group revealed the presence of dark-staining alpha-motoneurons in lumbosacral segments. We conclude that spinal administration of a large dose of morphine after transient aortic occlusion may be associated with a potential risk of paraparesis and the corresponding development of neurological dysfunction. Careful attention should be paid when intrathecal morphine is used for pain control after thoracoabdominal aortic aneurysm repair. Spinal administration of large-dose morphine after transient aortic occlusion may be associated with a potential risk of irreversible spinal neuronal degeneration and the corresponding development of neurological dysfunction.

Pro: Prevention of neurologic dysfunction associated with cardiac surgery requires pharmacologic brain protection

C ARDIAC SURGERY has become the most commonly performed major surgery in the United States over the past four decades. In large part, this has been attributed to success in decreasing mortality rates and improvements in cardiac, hematologic, and other morbidity rates. In contrast to these improvements, the incidence of neurologic dysfunction has not diminished, with cerebral injury accounting for an increased proportion of deaths after cardiac surgery. 1 These complications consume a tremendous amount of resources, both during as well as after hospitalization, and may have profound impact on the lives of patients and their families. 2 Although prevention of neurologic dysfunction has proven to be an elusive goal, recent scientific advances provide a basis for hope. Although the best-studied type of surgery is coronary artery bypass grafting (CABG), neurologic complications also occur frequently with valve replacement and other types of openchamber heart surgery as well as with repair of congenital heart disease. The preponderance of evidence suggests most neurologic dysfunction associated with cardiac surgery results from cerebral embolization. Sources of emboli include atheromatous debris from the aorta, thrombus, air, valvular debris, and emboli from the cardiopulmonary bypass circuit. However, global ischemia or watershed-type injuries may also result from circulatory arrest or severe hemodynamic instability. Clearly, the cascade of events leading to neurologic injury associated with cardiac surgery may be interrupted at several points. The argument has been advanced that neurologic dysfunction continues to occur with a disturbingly high incidence because of the increasing age of the patient population and the presence of other comorbid conditions. Indeed, numerous studies have identified several preoperative risk factors for adverse neurologic outcomes, including advanced age, previous stroke or transient ischemic attacks, hypertension, diabetes mellitus, carotid atherosclerosis, and pulmonary disease. 2,3 Identification of these risk factors has allowed the development of preoperative stroke risk indices that quantitate a patient's relative risk of sustaining a perioperative stroke) ,4 Therefore, the simplest, although probably least acceptable, strategy would be not to operate on patients at high risk. Although this approach would undoubtedly decrease the incidence of cerebral injury, it would also deprive many patients of a chance of prolonging and improving the quality of their lives. Clinicians should discuss the risk-to-benefit ratio very frankly with these patients, because the benefit of prolonged survival may be offset by the likelihood of substantial postoperative disability. These may also be the patients most likely to benefit from therapeutic interventions, and future interventional trials should be focused on this subset of patients presenting for cardiac surgery. It must also be emphasized that the clinician's ability to predict these complications remains limited, and even low-risk patients may sustain neurological injury after cardiac surgery. Another potential method of decreasing neurologic dysfunction associated with cardiac surgery is alteration of surgical techniques to decrease the incidence of cerebral embolization. Currently, much attention has been focused on the role of proximal aortic atherosclerosis in the development of neurologic dysfunction after surgery. 1,2,s,6 Although patients with diseased aortae are clearly at increased risk for sustaining neurological insults, it is much less clear which, if any, therapeutic maneuvers may lessen the chance for such an insult. Techniques that have been touted to decrease neurologic injury in these patients include alterations in the aortic cross-clamping site, changes in the site of the proximal anastomoses, use of only arterial grafts, performing all grafts with a single crossclamp, and even graft replacement of the diseased portion of the aorta using hypothermic circulatory arrest. 5,6 Unfortunately, these nonrandomized studies have potential for selection bias and have insufficient power to permit drawing conclusions. It is critical that such trials examine all sources of morbidity and long-term outcomes, especially for aggressive interventions that may carry significant morbidity of their own. Management of cardiopulmonary bypass may also decrease cerebral embolization. Pugsley et al7 showed use of an arterial filter decreases the number of emboli, and membrane oxygenators have also been associated with decreased rates of embolization. Again, no trial has demonstrated neurologic benefit associated with these techniques. One exception is the use of c~-stat blood gas management that has been shown to decrease neuropsychological dysfunction, but not neurologic dysfunction in patients undergoing CABG. 8 Whether this translates into

Elevated central nervous system prostaglandins in human immunodeficiency virus-associated dementia.

The dementia associated with human immunodeficiency virus (HIV) is poorly understood. Dementia is accompanied by infection and activation of macrophage lineage cells in the brain and production of toxic products by these cells has been postulated to play a role in the pathogenesis of dementia. Eicosanoids are potential products of activated macrophages that can mediate cell injury. We measured the levels of prostaglandin E2 in the cerebrospinal fluid of HIV-positive individuals with dementia and/or myelopathy and compared these levels with those of HIV-negative patients with other neurological diseases and HIV-positive patients without dementia. Cerebrospinal fluid prostaglandin E2 levels were increased in dementia. This increase was associated with severity of dementia and correlated with cerebrospinal fluid levels of neopterin and beta 2-microglobulin. Prostaglandins F2 alpha and thromboxane B2, additional products of the cyclooxygenase pathway of arachidonic acid metabolism, were also elevated in dementia, but leukotriene C4, a product of the lipoxygenase pathway was not. Since synthesis of prostaglandins is regulated in part by the levels of inducible forms of cyclooxygenase, we measured the levels of cyclooxygenase-1 and 2 mRNAs in the brains of HIV-positive individuals with and without dementia by reverse transcriptase polymerase chain reaction. Levels of intact cyclooxygenase-1 mRNA were higher in the brains of demented individuals, but this did not reach statistical significance. These data demonstrate that prostaglandins are increased in the central nervous system in HIV-associated dementia and may play a role in the development of neurological dysfunction.

Monitoring of neurotransmitter amino acids by means of an indwelling cisterna magna catheter: A comparison of two rodent models of fulminant liver failure

Alterations of brain and cerebrospinal fluid amino acids have consistently been described in human and experimental fulminant liver failure. To evaluate the significance of such changes in the pathogenesis of hepatic encephalopathy in fulminant liver failure, brain and cerebrospinal fluid amino acids (glutamate, aspartate, GABA, glycine, taurine) were measured at various stages during the development of neurological dysfunction in rats after hepatic devascularization or thioacetamide treatment to induce acute liver failure. To facilitate repetitive removal of cerebrospinal fluid, a technique employing long-term implantation of cisterna magna catheters in conscious, freely moving rats was developed. Brain but not cerebrospinal fluid concentrations of the excitatory amino acids glutamate and aspartate were reduced in both animal models of fulminant liver failure in parallel with deterioration of neurological status. Brain and cerebrospinal fluid GABA levels were not significantly altered. Cerebrospinal fluid glycine levels were increased two to three times in parallel with increasing brain glycine content in the devascularized rat but were unchanged in thioacetamide-induced liver failure, suggesting distinct pathophysiological mechanisms in these two experimental situations. On the other hand, onset of coma in both animal models of fulminant liver failure was accompanied by significantly increased cerebrospinal fluid taurine levels. We suggest that such changes result from taurine release from astrocytes in brain into the extracellular fluid; this is consistent with taurine's role in the regulation of intracellular osmolarity in brain. Sequential measurements of amino acids in the cerebrospinal fluid of small rodents with indwelling cisterna magna catheters adds a useful new approach for exploring the neurobiology of hepatic encephalopathy in fulminant liver failure.

Copper and neurological function.

The role of copper in maintaining normal neurological function has been examined in animals copper-deficient by dietary means, and in the genetic disorders of copper homeostasis -- Menkes' kinky-hair disease in humans and the mottled (Mo) mutants in the mouse. With the exception of the disorder in Mo mice, reduced myelination is a constant feature of these copper diseases but there is otherwise a lack of conformity in the structural defects produced in different species. Dietary copper-deficient animals show a reduction in noradrenaline and dopamine concentrations, together with a depressed tyrosine 3-monooxygenase activity (EC 1.14.16.2). Noradrenaline concentrations are also reduced in brain tissue of Mo mice and this reduction is associated with a decrease in the vivo activity of the copper metalloenzyme, dopamine beta-monooxygenase (EC 1.14.17.1). Many tissues contain potent inhibitors of dopamine beta-monooxygenase activity, and assays of this enzyme have utilized cupric ions to inactivate these inhibitors. The elevated in vitro activities of dopamine beta-monooxygenase obtained for both Mo brain and adrenal tissue may therefore reflect either a reduced inactivation of these endogenous inhibitors in the intact animal or the activation in vitro of apoenzyme. Concentrations of dopamine and tyrosine 3-monooxygenase are unchanged in Mo mice. The reduction in dopamine and tyrosine 3-monooxygenase activity in dietary copper-deficient animals may therefore reflect neuronal loss rather than reduced catalytic activity of the catecholamine biosynthetic pathway. The possible effects of depressed activities of cytochrome c oxidase (EC 1.9.3.1) and superoxide dismutase (EC 1.15.1.1) in the development of neurological dysfunction are also discussed, and attention is drawn to the possible significance of the elevated uptake of neutral amino acids, especially tyrosine and tryptophan, by Mo brain tissue.