Severe influenza resembling hemorrhagic shock and encephalopathy syndrome.

Influenza-associated encephalopathy is a clinically diverse syndrome and severe cases are not well documented outside Japan. Clinical, pathological and molecular aspects are described of two fatal cases presenting during 2004 and 2005 winter seasons in The Netherlands. Results showed that severe influenza can resemble hemorrhagic shock and encephalopathy syndrome, and proper testing for influenza virus should be considered in similar cases. The failure to detect viral replication in non-pulmonary organs including the brain would support the pathogenesis of this syndrome is based on proinflammatory cytokine responses.     

Investigation of Equine Influenza Cases Exhibiting Neurological Disease: Coincidence or Association?

Equine influenza is usually a transient and self-limiting disease. However, during an outbreak of equine influenza in the UK in 2003 there were reports of unusually severe clinical signs among unvaccinated animals. Two influenza-infected horses developed neurological signs, and one was subjected to euthanasia. Post-mortem examination of the brain revealed viral-type non-suppurative encephalitis, and influenza virus antigen was demonstrated by immunolabelling of sections of nasal mucosa. A syndrome known as influenza-associated encephalopathy has been described in man. Although not proved, the data suggest that similar disease mechanisms may operate in horses, and that equine influenza virus infection can result in encephalitis in the natural host, perhaps due to an aberrant host immune response.     

Examination and vaccination against influenza]

Influenza epidemics occur every winter with a large number of patients and deaths, causing serious public health problems in many countries. Recently, we have obtained several new measures against influenza, such as anti-influenza drugs and rapid detection kits for influenza virus antigens in patient specimens. In addition, it is noteworthy that the use of influenza vaccines has been re-evaluated in Japan, resulting in increased vaccination rates. As it is difficult to diagnose influenza by clinical symptoms alone, virological and serological examinations are important. Although there are many methods for the detection of influenza, virus isolation is the most sensitive and reliable. Moreover, antigenic characterization of the virus can be done only by virus isolation. In recent several years, rapid diagnosis has become important in connection with the use of anti-influenza drugs. The usefulness of the detection kits has been approved and the number of the kits used has increased considerably. The effectiveness of the influenza vaccine in elderly people has been demonstrated not only in other countries but also in Japan. However, there have been few reports describing the effectiveness of the vaccine in young children. Since influenza encephalopathy in infants is a serious problem in Japan, we have to investigate the usefulness of the vaccine in this age group.     

Two cases of cerebral salt wasting syndrome developing after cranial vault remodeling in craniosynostosis children

Hyponatremia has been recognized as an important postoperative metabolic complication after central nervous system (CNS) operations in children. If not appropriately treated, the postoperative hyponatremia can cause several types of CNS and circulatory disorders such as cerebral edema, increased intracranial pressure. The postoperative hyponatremia after CNS surgery has been considered as one of the underlying causes of the syndrome of inappropriate secretion of antidiuretic hormone (SIADH). In some cases, however, the cerebral salt wasting (CSW) syndrome has been detected. CSW syndrome is far less well-known than SIADH and also different from SIADH in diagnosis and treatment. It causes an increase in urine output and urine sodium after a trauma of CNS and dehydration symptoms. The appropriate treatment of CSW syndrome is opposite the usual treatment of hyponatremia caused by SIADH. The latter is treated with fluid restriction because of the increased level of free water and its dilutional effect causing hyponatremia, whereas the former is treated with fluid and sodium resuscitation because of the unusual loss of high urinary sodium. Early diagnosis and treatment of CSW syndrome after CNS surgery are, therefore, essential. We made a diagnosis of CSW syndrome in two craniosynostosis children manifesting postoperative hyponatremia and supplied them an appropriate amount of water and sodium via intravenous route. The hyponatremia or natricuresis of the children improved and neurologic and circulatory sequelae could be prevented.     

Lethal toxic encephalopathy due to childhood shigellosis or Ekiri syndrome

Lethal toxic encephalopathy due to shigellosis or Ekiri syndrome is a rare complication of shigellosis with a high fatality rate. Data are very limited on factors that can predict this encephalopathy, so we evaluated clinical and laboratory characteristics for these patients. In this study children with extreme toxicity and convulsions followed by rapid neurological deterioration resulting in brain edema and fatal outcome without sepsis and severe dehydration were selected as having lethal toxic encephalopathy. There were 1295 children with shigellosis during the 10 years of the study. Five children (0.4%) had lethal toxic encephalopathy due to shigellosis. Death occurred following rapid neurological detoriation resulting in brain edema despite intensive treatment. Evidence of brain edema may be a prediction factor for death. Early recognition of encephalopathy and measures to prevent brain edema may improve patient outcome.     

Influenza-associated acute encephalopathy in Japanese children in 1994-2002

We addressed the incidence of influenza-associated acute encephalopathy, which is distinct from Reye syndrome, in children in Japan. Eighty-nine children with a mean age of 3.8 years were reported to have developed this disease during eight influenza seasons (December 1994-April 2002) in Hokkaido, Japan. None of them had received aspirin. Most of the patients rapidly became comatose with or without convulsions with a mean interval of 1.7 days from the onset of fever to the onset of central nervous system symptoms. Thirty-three (37.1%) patients died and 17 (19.1%) patients had neurological sequelae. A total of 53 (59.6%) cases were proved to have an influenza virus infection. Interleukin-6 and tumor necrosis factor-alpha were markedly elevated in serum and cerebrospinal fluid samples from two patients who died after a rapid, fulminant course. A post-mortem examination of one fatal case revealed vasogenic brain edema with generalized vasculopathy, suggesting that the generalized impairment of vascular endothelial cells caused by highly activated cytokines plays a central role in the pathophysiology of this disease. We conclude that influenza-associated acute encephalopathy may be an underestimated syndrome and is another reason to promote vaccination against influenza in infants and younger children.     

Pathogenesis of Influenza A/H5N1 virus infection in ferrets differs between intranasal and intratracheal routes of inoculation

Most patients infected with highly pathogenic avian influenza A/H5N1 virus develop severe pneumonia resulting in acute respiratory distress syndrome, with extrarespiratory disease as an uncommon complication. Intranasal inoculation of ferrets with influenza A/H5N1 virus causes lesions in both the respiratory tract and extrarespiratory organs (primarily brain). However, the route of spread to extrarespiratory organs and the relative contribution of extrarespiratory disease to pathogenicity are largely unknown. In the present study, we characterized lesions in the respiratory tract and central nervous system (CNS) of ferrets (n = 8) inoculated intranasally with influenza virus A/Indonesia/5/2005 (H5N1). By 7 days after inoculation, only 3 of 8 ferrets had a mild or moderate bronchointerstitial pneumonia. In contrast, all 8 ferrets had moderate or severe CNS lesions, characterized by meningoencephalitis, choroiditis, and ependymitis, and centered on tissues adjoining the cerebrospinal fluid. These findings indicate that influenza A/H5N1 virus spread directly from nasal cavity to brain, and that CNS lesions contributed more than pulmonary lesions to the pathogenicity of influenza A/H5N1 virus infection in ferrets. In comparison, intratracheal inoculation of ferrets with the same virus reproducibly caused severe bronchointerstitial pneumonia. The method of virus inoculation requires careful consideration in the design of ferret experiments as a model for influenza A/H5N1 in humans.     

Multiple roles of chemokine CXCL12 in the central nervous system: a migration from immunology to neurobiology

Chemotactic cytokines (chemokines) have been traditionally defined as small (10-14kDa) secreted leukocyte chemoattractants. However, chemokines and their cognate receptors are constitutively expressed in the central nervous system (CNS) where immune activities are under stringent control. Why and how the CNS uses the chemokine system to carry out its complex physiological functions has intrigued neurobiologists. Here, we focus on chemokine CXCL12 and its receptor CXCR4 that have been widely characterized in peripheral tissues and delineate their main functions in the CNS. Extensive evidence supports CXCL12 as a key regulator for early development of the CNS. CXCR4 signaling is required for the migration of neuronal precursors, axon guidance/pathfinding and maintenance of neural progenitor cells (NPCs). In the mature CNS, CXCL12 modulates neurotransmission, neurotoxicity and neuroglial interactions. Thus, chemokines represent an inherent system that helps establish and maintain CNS homeostasis. In addition, growing evidence implicates altered expression of CXCL12 and CXCR4 in the pathogenesis of CNS disorders such as HIV-associated encephalopathy, brain tumor, stroke and multiple sclerosis (MS), making them the plausible targets for future pharmacological intervention.     

AIDS encephalopathy and tropism of HIV for brain monocytes/macrophages and microglial cells

HIV induces severe dementia in about 20% of adult AIDS patients. In children HIV-infected at birth, the incidence of specific neurological complications is still higher since severe encephalopathy occurs in almost all children who develop an early and severe immunosuppression. In all cases, the brain monocytes/macrophages and the microglial cells are the only cells which replicate HIV in the central nervous system (CNS) of these patients, and the appearance of neurological symptoms seems induced by an interaction between HIV-infected macrophages with neurons and glial cells. AIDS encephalopathy is related to two properties of HIV: to the viral tropism for monocytes/macrophages/microglial cells, which allow the brain infection, and to HIV tropism for CD4+ lymphocytes responsible for the appearance of immunosuppression, which trigger viral dissemination in the CNS. However, childhood encephalopathy is not always associated with HIV replication in the CNS at the time of death, and mild dementia in HIV-infected adults were described without signs of HIV replication in autopsy CNS samples. Those findings suggest that persistent, productive viral infection is not required for the development of HIV encephalopathy. Therefore, if the relationship between HIV CNS infection and AIDS encephalopathy in adults and children is clearly demonstrated, the pathogenesis of the neurological disease and the kinetics of HIV replication in the CNS are unclear. In addition, the very high incidence of AIDS encephalopathy in children could be related to HIV infection of microglia which is differentiating in fetal or newborn brain.     

脑源性神经营养因子研究现状

近年来神经科学的研究表明,神经营养因子是选择性调节周围神经和中枢神经系统神经生长和存活的一类蛋白质。脑源性神经营养因子（brain derived neurotrophic factor,BDNF）是神经生长因子（nerve growth fac-tor,NGF)发现后约30年由德国神经生物学家Barde^[1]报告的另一神经营养因子,它对CNS多种类型神经元的生长、发育、分化、维持和损伤修复都具有重要作用,对神经系统疾病诸如早老性痴呆、帕金森氏病和肌萎缩侧索硬化等退变性疾病的治疗具有潜在应用前景。本文就脑源性神经营养因子的结构、功能及应用前景作一综述。     

Susac syndrome: retinocochleocerebral vasculopathy

Susac syndrome is a rare microangiopathy of cochlea, retina, and brain. We report a case of a 30-year-old man with Susac syndrome. The patient initially suffered from unilateral hearing loss associated with peripheral vestibular syndrome, and followed with recurrent arterial retinal occlusions and encephalopathy. The patient underwent clinical, laboratory, and neuroradiological examination. Laboratory tests were negative for systemic inflammatory or infectious disease. Signs of encephalopathy and vestibular syndrome regressed after 6 weeks, retinal obstructions were partially improved, and deafness remained unchanged. Two unexplained epileptic seizures had been documented 7 years before the development of typical clinical course. The etiology is still unknown and diagnosis was suggested by the clinical triad of bilateral sensorineural hearing loss on low frequency on audiology, recurrent bilateral retinal branch artery occlusions, and small multiple areas of signal hyperintensity in the white and gray matter on brain magnetic resonance T2-weighted images. The clinical course is self-limited and treatment options are not codified. Epileptic seizures, as those in our patient, may extend the clinical spectrum of Susac syndrome. This case also documents the possibility of multiphasic disease course.     

Breast cancer metastasis to the central nervous system

Clinically symptomatic metastases to the central nervous system (CNS) occur in approximately 10 to 15% of patients with metastatic beast cancer. CNS metastases are traditionally viewed as a late complication of systemic disease, for which few effective treatment options exist. Recently, patients with Her-2-positive breast tumors who were treated with trastuzumab have been reported to develop CNS metastases at higher rates, often while responding favorably to treatment. The blood:brain barrier and the unique brain microenvironment are hypothesized to promote distinct molecular features in CNS metastases that may require tailored therapeutic approaches. New research approaches using cell lines that reliably and preferentially metastasize in vivo to the brain have been reported. Using such model systems, as well as in vitro analogs of blood-brain barrier penetration and tissue-based studies, new molecular leads into this disease are unfolding.     

Monitoring the safety of annual and pandemic influenza vaccines: lessons from the US experience

Annual use of influenza vaccines represents the largest vaccine campaign conducted in the USA. Recent expansions in influenza vaccine recommendations suggest a move toward 'universal' vaccination strategies. Although a great deal of safety data has been accumulated, concerns remain regarding rare, serious adverse events following immunization. A proven association between the 1976-1977 swine influenza vaccine and Guillain-Barré syndrome halted that particular national vaccination campaign. Recently, annual influenza vaccines have been associated with novel adverse events, for example, oculorespiratory syndrome in Canada. Any vaccine used against an influenza strain of pandemic potential will have an incompletely described safety profile. Thus, the challenge of influenza vaccine safety is to detect new safety concerns that may arise during seasonal campaigns, while preparing vaccine safety systems for the timely detection of adverse events in the setting of a pandemic.     

Expression of CTLA-4 (CD152) in peripheral blood T cells of children with influenza virus infection including encephalopathy in comparison with respiratory syncytial virus infection

Influenza virus and respiratory syncytial virus (RSV) are the most common causes of acute severe respiratory infection in children during the winter. There have been few reports about peripheral blood T cell activation in vivo in influenza virus infection and conflicting results concerning peripheral blood T cells activation in RSV infection. Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4, CD152) is a receptor present on T cells that plays a critical role in the down-regulation of antigen-activated immune responses. To clarify the status of peripheral blood T cells, we investigated intracellular CTLA-4 expression in T cells in patients with influenza virus and RSV infection. We collected blood samples from 15 patients with influenza virus infection, including three with complications of influenza virus-associated encephalopathy and 18 patients with RSV infection, as well as 44 healthy children. We determined the intracellular expression of CTLA-4 in CD4+ and CD8+ T cells by flow cytometry. There were no significant differences in the percentages of intracellular CTLA-4-positive CD4+ T cells and CD8+ T cells by age. The percentages of intracellular CTLA-4-positive CD4+ T cells in the patients with influenza virus infection were significantly higher than those in healthy children (P < 0.01). In particular, the patients with influenza virus-associated encephalopathy had sevenfold higher percentages of CTLA-4-positive CD4+ T cells than influenza patients without encephalopathy (P < 0.05). The patients with influenza virus-associated encephalopathy had increased percentages of CTLA-4-positive CD8+ cells at the acute stage in comparison with the convalescent stage and in control subjects (P < 0.01, respectively). RSV patients showed no increase in CTLA-4-positive CD4+ T cells or CD8+ T cells. The immunological status of peripheral T cell activation is substantially different in influenza virus infection and RSV infection. The patients with RSV infection did not show any increase in CTLA-4-positive peripheral blood T cells. There was a remarkable increase in intracellular CTLA-4 in CD4+ and CD8+ T cells in influenza virus-associated encephalopathy. Down-regulation of antigen-activated peripheral blood T cell activation might play an important role in the pathogenesis of influenza virus-associated encephalopathy and host defence against influenza virus infection.     

Neuronal apoptosis and inflammatory responses in the central nervous system of a rabbit treated with Shiga toxin-2

Background  

Shiga toxins (Stxs) are the major agents responsible for hemorrhagic colitis and hemolytic-uremic syndrome (HUS) during infections caused by Stx-producing Escherichia coli (STEC) such as serotype O157:H7. Central nervous system (CNS) involvement is an important determinant of mortality in diarrhea associated-HUS. It has been suggested that vascular endothelial injuries caused by Stxs play a crucial role in the development of the disease. The current study investigates the relationship between the cytotoxic effects of Stxs and inflammatory responses in a rabbit brain treated with Stx2.     

CD4 and chemokine receptors on human brain microvascular endothelial cells, implications for human immunodeficiency virus type 1 pathogenesis.

Central nervous system (CNS) dysfunction is commonly observed in children with human immunodeficiency virus type 1 (HIV-1) infection, but the mechanism(s) whereby HIV-1 causes encephalopathy remains incompletely understood. Human brain microvascular endothelial cells (HBMECs), which constitute the blood-brain barrier, are likely to contribute to HIV-1 encephalopathy, but it is unclear whether HIV-1 receptors (CD4, chemokine receptors) are present on HBMECs. In the present study, the presence of CD4 in six different children was demonstrated. Moreover, the presence of CD4 in situ on brain sections was shown. Distribution of CD4 expression was heterogeneous among microvessels; staining for CD4 was strong in some vessels and absent in other adjacent vessels. CD4 and chemokine coreceptors were found to be functional as intercellular adhesion molecule (ICAM)-1 expression increased upon incubation of HBMECs with activating anti-CD4 and anti-chemokine receptor antibodies. The presence of CD4 and chemokine receptors in human brain endothelium of children may have implications for the pathogenesis of HIV-1 encephalopathy and explain the higher incidence of CNS involvement in HIV-1-infected children as compared to adults.     

The role of intrauterine infection of the central nervous system with herpes simplex viruses in development of encephalopathies in infants

Intrauterine infections often affect the infant brain and cause meningoencephalitis and long-term encephalopathy. In this study we have analysed morphological changes in different parts of CNS of 22 deceased infants who had suffered from encephalopathy of different degree due to persistence of herpes simplex viruses. Morphological, immunofluorescent, serological methods were used. Antigens of herpes simplex viruses I and/or II were detected in the CNS of most examinees. Relevant antibodies were detected in the serum and cerebrospinal fluid. Intrauterine infection was confirmed by the presence of specific for herpes simplex viruses morphological changes in the placentas. Hydrocephaly, secondary microencephaly, false cysts, microgyria were found macroscopically. There were herpes simplex viruses specific histological changes such as nuclear hyperchromatosis, intranuclear basophilic and acidophilic inclusions and nonspecific changes (gliosis, productive vasculitis). The data demonstrate that intrauterine herpes simplex viruses persistence in the CNS is an important cause of infantile encephalopathy, specific and nonspecific changes indicate a chronic course of the infection and depend on the degree of clinical symptoms.     

凝血酶在HIV-1感染小胶质细胞中作用的研究进展

凝血酶是凝血连锁反应的主要效应蛋白酶.除了能够切割纤维蛋白原外,还发现凝血酶能够特异性切割HIV-1 V3环保守的冠部并促进HIV-1介导的细胞融合;此外,凝血酶及细胞表面凝血酶受体表达的上调可能与HIV-1相关脑病的发生相关.小胶质细胞是中枢神经系统固有的免疫细胞,在脑损害时,这些细胞迅速被激活并发挥巨噬细胞一样的功...