Central Nervous System Origin Research Articles

Propofol infusion syndrome

The clinical features of propofol infusion syndrome (PRIS) are acute refractory bradycardia leading to asystole, in the presence of one or more of the following: metabolic acidosis (base deficit > 10 mmol.l(-1)), rhabdomyolysis, hyperlipidaemia, and enlarged or fatty liver. There is an association between PRIS and propofol infusions at doses higher than 4 mg.kg(-1).h(-1) for greater than 48 h duration. Sixty-one patients with PRIS have been recorded in the literature, with deaths in 20 paediatric and 18 adult patients. Seven of these patients (four paediatric and three adult patients) developed PRIS during anaesthesia. It is proposed that the syndrome may be caused by either a direct mitochondrial respiratory chain inhibition or impaired mitochondrial fatty acid metabolism mediated by propofol. An early sign of cardiac instability associated with the syndrome is the development of right bundle branch block with convex-curved ('coved type') ST elevation in the right praecordial leads (V1 to V3) of the electrocardiogram. Predisposing factors include young age, severe critical illness of central nervous system or respiratory origin, exogenous catecholamine or glucocorticoid administration, inadequate carbohydrate intake and subclinical mitochondrial disease. Treatment options are limited. Haemodialysis or haemoperfusion with cardiorespiratory support has been the most successful treatment.

Proliferating Resident Microglia after Focal Cerebral Ischaemia in Mice

Cerebral ischaemia usually results in the rapid death of neurons within the immediate territory of the affected artery. Neuronal loss is accompanied by a sequence of events, including brain oedema, blood-brain barrier (BBB) breakdown, and neuroinflammation, all of which contribute to further neuronal death. Although the role of macrophages and mononuclear phagocytes in the expansion of ischaemic injury has been widely studied, the relative contribution of these cells, either of exogenous or intrinsic central nervous system (CNS) origin is still not entirely clear. The purpose of this study, therefore, was to use different durations of transient middle cerebral artery occlusion (tMCAo) in the mouse to investigate fully post-occlusion BBB permeability and cellular changes in the brain during the 72 h post-MCAo period. This was achieved using in vivo magnetic resonance imaging (MRI) and cell labelling techniques. Our results show that BBB breakdown and formation of the primary ischaemic damage after tMCAo is not associated with significant infiltration of neutrophils, although more are observed with longer periods of MCAo. In addition, we observe very few infiltrating exogenous macrophages over a 72 h period after 30 or 60 mins of occlusion, instead a profound increase in proliferating resident microglia cells was observed. Interestingly, the more severe injury associated with 60 mins of MCAo leads to a markedly reduced proliferation of resident microglial cells, suggesting that these cells may play a protective function, possibly through phagocytosis of infiltrating neutrophils. These data further support possible beneficial actions of microglial cells in the injured brain.

Comparison of Ataxia-Telangiectasia Mutated Protein Expression in Diffuse Large B-Cell Lymphomas of Primary Central Nervous System and Non–Central Nervous System Origin

The ataxia-telangiectasia mutated (ATM) gene encodes a nuclear 370-kd phosphoprotein known to be associated with chromosomal regions containing double-strand breaks. The mutations in the ATM gene may be involved in the development of some subtypes of sporadic lymphomas and leukemias. In primary central nervous system diffuse large B-cell lymphomas (PCNS DLBCLs), the pathogenetic role of ATM mutation has not been investigated. To investigate ATM protein expression in PCNS DLBCLs, in comparison with that in non-central nervous system (non-CNS) DLBCLs and to study the relationship of ATM protein loss with several clinicopathologic parameters. This study included 42 cases of PCNS DLBCL and 33 cases of non-CNS DLBCL from immunocompetent patients. The ATM protein loss was analyzed by immunohistochemical staining. For the subclassification of DLBCL and analysis of the relationship between ATM and other prognostic markers, we performed immunohistochemical evaluation to detect the following markers: Bcl-6, CD10, multiple myeloma-1, CD138, Bcl-2, Ki-67, and p53. The loss of ATM expression was statistically more frequent in PCNS DLBCLs (21/42 cases [50.0%]) than in non-CNS DLBCLs (0/33 cases [0.0%]; P < .001). The loss of ATM expression was not a prognostic marker in PCNS DLBCLs (P = .64). The loss of ATM expression had a strong correlation with the germinal center B-cell-like subtype (P = .01), a low Ki-67 labeling index (P = .03), and low Bcl-2 expression (P = .01) among several clinicopathologic parameters. Our results suggest that the ATM protein is more strongly correlated with PCNS DLBCL lymphomagenesis than with non-CNS DLBCLs, especially in germinal center B-cell-like subtypes demonstrating low Ki-67 labeling indexes and low Bcl-2 expression.

Comparison of Ataxia-Telangiectasia Mutated Protein Expression in Diffuse Large B-Cell Lymphomas of Primary Central Nervous System and Non–Central Nervous System Origin

Abstract Context.—The ataxia-telangiectasia mutated (ATM) gene encodes a nuclear 370-kd phosphoprotein known to be associated with chromosomal regions containing double-strand breaks. The mutations...

Ghrelin and the Growth Hormone Secretagogue Receptor Constitute a Novel Autocrine Pathway in Astrocytoma Motility

Originally thought of as a stomach-derived endocrine peptide acting via its receptors in the central nervous system to stimulate food intake and growth hormone expression, ghrelin and its receptor (growth hormone secretagogue receptor (GHS-R)) are widely expressed in a number of organ systems, including cancer cells. However, the direct functional role of ghrelin and its receptor in tumors of central nervous system origin remains to be defined. Here, we demonstrate that the human astrocytoma cell lines U-118, U-87, CCF-STTG1, and SW1088 express 6-, 11-, 15-, and 29-fold higher levels of GHS-R compared with primary normal human astrocytes. The ligation of GHS-R by ghrelin on these cells resulted in an increase in intracellular calcium mobilization, protein kinase C activation, actin polymerization, matrix metalloproteinase-2 activity, and astrocytoma motility. In addition, ghrelin led to actin polymerization and membrane ruffling on cells, with the specific co-localization of the small GTPase Rac1 with GHS-R on the leading edge of the astrocytoma cells and imparting the tumor cells with a motile phenotype. Disruption of the endogenous ghrelin/GHS-R pathway by RNA interference resulted in diminished motility, matrix metalloproteinase activity, and Rac expression, whereas tumor cells stably overexpressing GHS-R exhibited increased cell motility. The relevance of ghrelin and GHS-R expression was verified in clinically relevant tissues from 20 patients with oligodendrogliomas and grade II-IV astrocytomas. Analysis of a central nervous system tumor tissue microarray revealed that strong GHS-R and ghrelin expression was significantly more common in high grade tumors compared with low grade ones. Together, these findings suggest a novel role for the ghrelin/GHS-R axis in astrocytoma cell migration and invasiveness of cancers of central nervous system origin.

Comparison of the expression and prognostic significance of differentiation markers between diffuse large B-cell lymphoma of central nervous system origin and peripheral nodal origin.

Whether diffuse large B-cell lymphoma (DLBCL) of primary central nervous system origin (PCNSL) is biologically different from DLBCL of peripheral nodal origin (NL) remains unclear. The purpose of this study was to compare the expression frequencies and prognostic significance of a panel of cell differentiation markers between these two disease entities. This study included HIV-unrelated patients with PCNSL (n = 51) and NL (n = 72) treated at four hospitals in Taiwan for whom archival tumor tissue was available. Immunohistochemistry for CD10, BCL-6, MUM-1, vs38c, CD138, and BCL-2 was done. CD10, BCL-6, and MUM-1 expression results were used to classify all cases into the germinal center B-cell (GCB) or the non-GCB subgroup. The prognostic significances of clinical and immunophenotypic markers were evaluated. Nuclear MUM-1 expression was significantly higher in PCNSL than in NL (P < 0.001; 84% versus 53%). PCNSL tumors were more frequently classified into the non-GCB subgroup than NL tumors (P = 0.020; 78% versus 62%). For patients with PCNSL, univariate analysis showed that patients with BCL-6 expression had a trend towards longer survival (P = 0.073; median survival, 25.3 versus 7.3 months), and multivariate analysis showed BCL-6 was an independent prognostic factor (P = 0.026). For patients with NL, both of univariate (P = 0.003) and multivariate analyses (P = 0.002) showed that GCB was significantly associated with favorable survival. The higher frequency of non-GCB subclassification, which was mainly contributed by nuclear MUM-1 expression in PCNSL implies that it has a more differentiated cellular origin than NL. BCL-6 expression in patients with PCNSL and GCB subgroup in patients with NL were favorable prognostic factors.

Changes in acquired immunodeficiency syndrome‐related non‐Hodgkin lymphoma in the era of highly active antiretroviral therapy

The authors sought to determine whether the availability of highly active antiretroviral therapy (HAART) coincided with changes in the epidemiology of acquired immunodeficiency syndrome (AIDS)-related non-Hodgkin lymphoma (NHL). Cancer registry data from 1988-2000 were linked with AIDS registry data from 1981 to July 2003 for San Diego County to identify 537 AIDS-NHL patients. By using the total number of patients with AIDS who were alive as of July 1 annually as the AIDS population denominator, the average annual incidence of NHL was estimated among patients with AIDS for the pre-HAART period (1988-1995) and post-HAART period (1996-2000). The chi-square test was used to compare proportions, and a Cox proportional hazards model was used to compare survival between the pre-HAART and post-HAART periods. The incidence of NHL decreased from 29.6 per 1000 person-years pre-HAART to 6.5 per 1000 person-years post-HAART. The proportion of patients who had NHL of central nervous system (CNS) origin decreased from 28% pre-HAART to 17% post-HAART. Among patients with systemic NHL, 54% received chemotherapy pre-HAART, and 72% received chemotherapy post-HAART. The percentage of intermediate-grade NHL increased from 33% pre-HAART to 49% post-HAART, and the percentage of high-grade NHL decreased from 38% to 19%, respectively. A diagnosis of human immunodeficiency virus infection preceding the NHL diagnosis and Stage IV NHL were associated with worse survival, whereas a diagnosis of NHL in the post-HAART period and chemotherapy were associated with better survival. The median survival was 4 months pre-HAART and 9 months post-HAART. Since the introduction of HAART, there has been a decrease in the incidence of systemic and CNS NHL among patients with AIDS. Among patients with systemic, AIDS-related NHL, there has been decreased high-grade histology, increased use of chemotherapy, and improved survival.

The case for a central nervous system (CNS) origin for the Schwann cells that remyelinate CNS axons following concurrent loss of oligodendrocytes and astrocytes

In certain experimental and naturally occurring pathological situations in the central nervous system (CNS), demyelinated axons are remyelinated by Schwann cells. It has always been assumed that these Schwann cells are derived from Schwann cells associated with peripheral nerves. However, it has become apparent that CNS precursors can give rise to Schwann cells in vitro and following transplantation into astrocyte-free areas of demyelination in vivo. This paper compares the behaviour of remyelinating Schwann cells following transplantation of peripheral nerve derived Schwann cells over, and into, astrocyte-depleted areas of demyelination to that which follows transplantation of CNS cells and that seen in normally remyelinating ethidium bromide induced demyelinating lesions. It concludes that while the examination of normally remyelinating lesions can not resolve the origin of the remyelinating Schwann cells, the results from transplantation studies provide strong evidence that the Schwann cells that remyelinate CNS axons are most likely generated from CNS precursors. In addition these studies also indicate that the precursors that give rise to these Schwann cells are the same cells that give rise to remyelinating oligodendrocytes.

Truncated N-terminal mutants of SV40 large T antigen as minimal immortalizing agents for CNS cells

Immortalized central nervous system (CNS) cell lines are useful as in vitro models for innumerable purposes such as elucidating biochemical pathways, studies of effects of drugs, and ultimately, such cells may also be useful for neural transplantation. The SV40 large T (LT) oncoprotein, commonly used for immortalization, interacts with several cell cycle regulatory factors, including binding and inactivating p53 and retinoblastoma family cell-cycle regulators. In an attempt to define the minimal requirements of SV40 T antigen for immortalizing cells of CNS origin, we constructed T155c, encoding the N-terminal 155 amino acids of LT. The p53 binding region is known to reside in the C-terminal region of LT. An additional series of mutants was produced to further narrow the molecular targets for immortalization, and plasmid vectors were constructed for each. In a p53 temperature sensitive cell line model, T64-7B, expression of T155c and all constructs having mutations outside of the first 82 amino acids were capable of overriding cell-cycle block at the non-permissive growth temperature. Several cell lines were produced from fetal rat mesencephalic and cerebral cortical cultures using the T155c construct. The E107K construct contained a mutation in the Rb binding region, but was nonetheless capable of overcoming cell cycle block in T64-7B cell and immortalizing primary cultured cells. Cells immortalized with T155c were often highly dependent on the presence of bFGF for growth. Telomerase activity, telomere length, growth rates, and integrity of the p53 gene in cells immortalized with T155c did not change over 100 population doublings in culture, indicating that cells immortalized with T155c were generally stable during long periods of continuous culture.

Viruses and cancer: lessons from the human polyomavirus, JCV.

The possible role of eucaryotic viruses in the development of cancer has been the subject of intense investigation during the past 50 years. Thus far, a strong link between some RNA and DNA viruses and various cancers in humans has been established and the transforming activity of several of the viruses in cell culture and their oncogenecity in experimental animals has been well documented. Perhaps, one of the most common themes among the oncogenic viruses rests in the ability of one or more of the viral proteins to deregulate pathways involved in the control of cell proliferation. For example, inactivation of tumor suppressors through their association with viral transforming proteins, and/or impairment of signal transduction pathways upon viral infection and expression of viral proteins are among the key biological events that can either trigger and/or contribute to the process of cancer. In recent years, more attention has been paid to human polyomaviruses, particularly JC virus (JCV), which infects greater than 80% of the human population, due to the ability of this virus to induce a fatal demyelinating disease in the brain, its presence in various tumors of central nervous system (CNS) and non-CNS origin, and the oncogenic potential of this virus in several laboratory animal models. Here, we will focus our attention on JCV and describe several pathways employed by the virus to contribute to and/or accelerate cancer development.

Reduction in excess daytime sleepiness by modafinil in patients with myotonic dystrophy

Patients with myotonic dystrophy frequently suffer from excess daytime sleepiness, which can be a significant cause of disability. Previous studies have indicated that this excess daytime sleepiness is only occasionally due to obstructive sleep apnoea and may be principally of central nervous system origin. Modafinil has been successfully used to treat narcolepsy, a central disorder causing excess daytime sleepiness. We have investigated the use of this drug in myotonic dystrophy patients with excess daytime sleepiness. Patients were recruited from a clinic population on the basis of screening with the Epworth Sleepiness Scale. Patients scoring 10 and above were invited to participate in a randomized double-blind crossover trial of modafinil versus placebo, with four weeks in each arm of the study separated by a 2-week washout period. Patients were assessed by polysomnography at baseline. The primary outcome measures were change in both the Epworth Sleepiness Scale and a modified Maintenance of Wakefulness Test, which were measured at the start of each arm of the trial and in week 3 of each intervention period. In agreement with previous smaller studies, sleepiness is not correlated with CTG expansion size. Treatment with modafinil showed a non-significant reduction in median Epworth Sleepiness Scale. However, the median Maintenance of Wakefulness Test score was prolonged by treatment (31.7–40 min, P=0.006). There were no significant adverse cardiac effects of the drug in this group of patients (resting 12 lead and 24 h ECG monitoring). Selected patients with myotonic dystrophy and excess daytime sleepiness may benefit from modafinil. In this patient group the Epworth Sleepiness Scale may not be the most reliable measure of sleepiness. Despite the potential for cardiac disease in these patients, the drug was well tolerated with no adverse effects.

Neurovisceral integration in cardiac and emotional regulation.

The utility of heart-rate variability (HRV) to index important aspects of neural control of the heart has made it one of the most valuable tools for researchers interested in health and behavior. However, most of the literature and extant data on the central origins of HRV have been derived from animal models. As yet little is known about the central nervous system (CNS) origins and concomitants in humans. In the following we will briefly detail a set of neural structures that have been associated with important CNS functions including cardiac regulation and emotional regulation. We will briefly summarize recent data using pharmacological, neuroimaging, and psychophysiological techniques that have examined CNS concomitants of HRV especially during emotion. Based on these and other data will we report the results of a computational model that examined the interactions of several neural structures and their effect on emotion-related HRV.

Sympathetic nervous system and the kidney in hypertension

Long-term control of arterial pressure has been attributed to the kidney by virtue of its ability to couple the regulation of blood volume to the maintenance of sodium and water balance by the mechanisms of pressure natriuresis and diuresis. In the presence of a defect in renal excretory function, hypertension arises as the consequence of the need for an increase in arterial pressure to offset the abnormal pressure natriuresis and diuresis mechanisms, and to maintain sodium and water balance. There is growing evidence that an important cause of the defect in renal excretory function in hypertension is an increase in renal sympathetic nerve activity (RSNA). First, increased RSNA is found in animal models of hypertension and hypertensive humans. Second, renal denervation prevents or alleviates hypertension in virtually all animal models of hypertension. Finally, increased RSNA results in reduced renal excretory function by virtue of effects on the renal vasculature, the tubules, and the juxtaglomerular granular cells. The increase in RSNA is of central nervous system origin, with one of the stimuli being the action of angiotensin II, probably of central origin. By acting on brain stem nuclei that are important in the control of peripheral sympathetic vasomotor tone (e.g. rostral ventrolateral medulla), angiotensin II increases the basal level of RSNA and impairs its arterial baroreflex regulation. Therefore, the renal sympathetic nerves may serve as the link between central sympathetic nervous system regulatory sites and the kidney in contributing to the renal excretory defect in the development of hypertension.

Sympathetic nervous system and the kidney in hypertension.

Long-term control of arterial pressure has been attributed to the kidney by virtue of its ability to couple the regulation of blood volume to the maintenance of sodium and water balance by the mechanisms of pressure natriuresis and diuresis. In the presence of a defect in renal excretory function, hypertension arises as the consequence of the need for an increase in arterial pressure to offset the abnormal pressure natriuresis and diuresis mechanisms, and to maintain sodium and water balance. There is growing evidence that an important cause of the defect in renal excretory function in hypertension is an increase in renal sympathetic nerve activity (RSNA). First, increased RSNA is found in animal models of hypertension and hypertensive humans. Second, renal denervation prevents or alleviates hypertension in virtually all animal models of hypertension. Finally, increased RSNA results in reduced renal excretory function by virtue of effects on the renal vasculature, the tubules, and the juxtaglomerular granular cells. The increase in RSNA is of central nervous system origin, with one of the stimuli being the action of angiotensin II, probably of central origin. By acting on brain stem nuclei that are important in the control of peripheral sympathetic vasomotor tone (e.g. rostral ventrolateral medulla), angiotensin II increases the basal level of RSNA and impairs its arterial baroreflex regulation. Therefore, the renal sympathetic nerves may serve as the link between central sympathetic nervous system regulatory sites and the kidney in contributing to the renal excretory defect in the development of hypertension.

Pathophysiology of Parkinson's disease: from clinical neurology to basic neuroscience and back.

Parkinson's disease (PD) is characterized by motor and nonmotor (cognitive and limbic) deficits. The motor signs of PD include hypokinetic signs such as akinesia/bradykinesia, rigidity and loss of normal postural reflexes, and hyperkinetic signs such as tremor. Dopamine depletion in the striatum is the hallmark of PD and of its animal models, still the pathophysiology of the parkinsonian symptoms and especially of parkinsonian tremor are under debate. The most extreme hypotheses argue about peripheral versus central nervous system origin, intrinsic cellular oscillator versus network oscillators, and basal ganglia-based pathophysiology versus cerebellar-thalamic based pathophysiology. Recent studies support the view that parkinsonian symptoms are most likely due to abnormal synchronous oscillating neuronal activity within the basal ganglia. Peripheral factors do only play a minor role for the generation, maintenance, and modulation of PD tremor and other signs. The most likely candidates producing these neuronal oscillations are the weakly coupled neural networks of the basal ganglia-thalamo-cortical loops. However, the present evidence supports the view that the basal ganglia loops are influenced by other neuronal structures and systems and that the tuning of these loops by cerebello-thalamic mechanisms and by other modulator neurotransmitter systems entrain the abnormal synchronized oscillations. Neurosurgical procedures, such as lesions or high-frequency stimulation of different parts of the loop, might resume the normal unsynchronized activity of the basal ganglia circuitry, and, therefore, ameliorate the clinical symptoms of Parkinson's disease.

The interpretation of emotion from facial expressions for children with a visual sub‐type of dyslexia

Investigations of dyslexia have largely focussed on academic failure, but the development of social skills is being increasingly recognised as important. A number of studies have claimed that negative social skills identified in such people might relate to the inability to decode subtle social cues. In particular, facial expression has been identified as critical to the development of social responsiveness, with some studies finding that children with learning disabilities/dyslexia were less accurate in interpreting facial emotions. The majority of studies of interpretation of facial expression, however, viewed dyslexia as a unitary condition, and only made comparisons between this group and a group with no learning disabilities. There are almost certainly sub‐types, and a separate assessment of these is needed. In particular, people with visual processing disabilities which are sufficient to cause problems in identifying letters and words, may also have problems in interpreting subtle visual cues of facial emotion. This study investigated ability to interpret emotion in facial expression in a visual perceptual sub‐type called Irlen Syndrome (Scotopic Sensitivity Syndrome), which is claimed to have central nervous system origin, with a deficit in the magnocellular visual neurological pathway being implicated. A deficit in this pathway has also been proposed as a possible cause of visual processing problems leading to social misperception. The study assessed 38 children with Irlen Syndrome in comparison to 31 normally achieving peers aged between 8 and 12 years. Participants with Irlen Syndrome were as different from normal‐achieving peers in recognition of facial affect and recognition of faces as they were in word identification and word attack. Application of Irlen filters to the experimental group appeared to reduce the differences between groups on these tests.

CNS sympathetic outflow neurons to white fat that express MEL receptors may mediate seasonal adiposity.

Many animals show seasonal changes in adiposity that are triggered by changes in the photoperiod. For example, in short "winterlike" days, the nocturnal duration of pineal melatonin (MEL) secretion increases ultimately resulting in body fat decreases by Siberian hamsters. These decreases in body fat are mediated through increases in the sympathetic drive on white adipose tissue (WAT). The central nervous system (CNS) origins of the sympathetic outflow from brain to WAT include the suprachiasmatic nucleus (SCN), an area necessary for the reception of season-encoded MEL signals in Siberian hamsters. Therefore, we tested whether SCN neurons that are part of the sympathetic outflow to WAT also express MEL receptors (MEL(1a)). This was accomplished by labeling the sympathetic outflow from brain to WAT using a transsynaptic retrograde tract tracer, the pseudorabies virus (PRV), injected into inguinal WAT combined with labeling of brain MEL(1a) receptors using in situ hybridization. We found PRV-labeled neurons that also expressed MEL(1a)-receptor mRNA in several brain regions including the SCN. Thus the increased duration of MEL secretion in short days may increase MEL(1a)-receptor stimulation that, in turn, increases the sympathetic drive on WAT, thereby increasing lipolysis and decreasing adiposity.

Human neurotropic JC virus and its association with brain tumors.

JC virus (JCV) is a human polyomavirus known as the causative agent of the fatal demyelinating disease, Progressive Multifocal Leukoencephalopathy (PML). Further, in experimental animals this virus causes a broad range of tumors of central nervous system origin. Recent studies have suggested the association of JCV with several human tumors most notably malignant brain tumors of childhood, medulloblastoma. The development of tumors by JCV is most likely through mechanisms involving inactivation of tumor suppressors and de-regulation of signaling pathways such as Wnt by the viral early protein, T-antigen. The neurotropic nature of JCV along with the overwhelming evidence for its oncogenic potential in laboratory animals and its detection in significant numbers of human medulloblastomas invite the re-evaluation of the role for JCV in the development of human brain tumors.

The central opioid system in liver disease and its complications.

The best known example of an interaction between the liver and the brain is hepatic encephalopathy. In the 90s a central nervous system origin of the pruritus of cholestatic liver disease and more recently of fatigue of liver disease has been suggested. Hence, three important manifestations of liver disease may be of central origin. Evidence is accumulating that the central opioid system is involved in the development of these manifestations. This short review summarizes current knowledge on the role of the opioid system in development of these liver disease manifestations.

Leptin receptor-mediated regulation of cholinergic neurotransmitter phenotype in cells of central nervous system origin

Leptin receptor-mediated regulation of cholinergic neurotransmitter phenotype in cells of central nervous system origin