Destruction Of Brain Tissue Research Articles

Longitudinal diffusion tensor and manganese-enhanced MRI detect delayed cerebral gray and white matter injury after hypoxia–ischemia and hyperoxia

Hypoxia-ischemia (HI) induces delayed inflammation and long-term gray and white matter brain injury that may be altered by hyperoxia. HI and 2 h of hyperoxia (100% O2) or room air (21% O2) in 7-d-old (P7) rats were studied by magnetic resonance imaging at 7 Tesla during 42 d: apparent diffusion coefficient (ADC) maps on day 1; T(1)-weighted manganese-enhanced images on day 7; diffusion tensor images on days 21 and 42; and T2 maps at all time points. The long-term brain tissue destruction on T2 maps was more severe in HI+hyperoxia than HI+room air. ADC was lower in HI+hyperoxia vs. HI+room air and sham and was correlated with long-term outcome. Manganese enhancement indicating inflammation was seen in both the groups along with more microglial activation in HI+hyperoxia on day 7. Fractional anisotropy (FA) in corpus callosum was lower and radial diffusivity was higher in HI+hyperoxia than that in HI+room air and sham on day 21. From day 21 to day 42, FA and radial diffusivity in HI+hyperoxia were unchanged, whereas in HI+room air, FA increased and radial diffusivity decreased to values similar to sham. Hyperoxia caused a more severe tissue destruction, delayed irreversible white matter injury, and increased inflammatory response resulting in a worsening in the trajectory of injury after HI in developing gray and white matter.

Cerebrovascular disease and mechanisms of cognitive impairment: evidence from clinicopathological studies in humans.

Cerebrovascular disease (CVD) is an important cause of disability and dementia. Accumulating evidence from clinical, neuroimaging, and pathological studies indicates a durable link between CVD and cognitive impairment. To distinguish this relationship, over the years various disorders have been progressively refined to include arteriosclerotic dementia, multi-infarct dementia, vascular dementia (VaD), subcortical ischemic vascular dementia, and vascular cognitive impairment (VCI).1–4 VCI is attributed to conditions resulting from a variety of cerebrovascular lesions or impaired brain perfusion,5 but the pathological diagnosis of VCI, however, requires systematic evaluation of potentially relevant clinical and other phenotypic features. Although vascular pathology substrates that explain cognitive dysfunction have been narrowed down, debate still abounds as to what is the gold standard for confirming the clinical diagnosis of these conditions. In the late 1960s, the seminal clinicopathological studies in Newcastle provided evidence that destruction of brain tissue by ischemic injury is associated arteriosclerotic dementia.6 Cognitive impairment was attributed to cerebral softening with loss of a relatively large volume (∼100 mL) of tissue that was reported to be overdiagnosed clinically in comparison to Alzheimer disease (AD).7,8 These views are now disputed. Nonetheless, identifying the pathological substrates of CVD causing cognitive and behavior dysfunction has been a lasting challenge. In this review, I discuss available clinicopathological evidence to link cerebrovascular changes to cognitive impairment and highlight key substrates as well as consider relevant mechanisms. The contribution of Alzheimer type of pathology to CVD-related impairment9 is not discussed in detail although this remains an intriguing area of overlap with the selected topic. Previously published articles in English until December 2011 derived from various popular databases including PubMed of specific interest were searched online. Several search terms were used initially to obtain wider coverage of articles from studies in which cognitive function …

Prenatal diagnosis of intracranial immature teratoma in the third trimester using 2D and 3D sonography.

Intracranial tumors are uncommon and represent 0.5-1.5% of all pediatric tumors. Teratoma is the most frequent intracranial tumor found at birth.Large teratomas are extremely rare and have a guarded prognosis since they grow fast and cause brain tissue destruction. A 31-week primigravida was referred to our hospital for investigation of an intracranial mass seen in the fetus. Two-dimensional ultrasound showed a large heterogeneous solid mass with calcifications inside, measuring 5.3×4.8cm. It was in the right cerebral hemisphere at the level of the middle and posterior fossa, thereby shifting the midline and causing severe ventriculomegaly that measured 3.5cm at the level of the lateral ventricle. Three-dimensional ultrasound (3DUS) in multiplanar mode allowed us to assess the anatomical relationships between the mass and the midline structures. The neurosurgical team, who had suspected that the case was inoperable, was thus able to gain a better understanding of the case. Transfontanellar ultrasound was performed on the day after the birth and confirmed the previous findings. Moreover, a biopsy confirmed the histology of the mass: it was an immature teratoma. The infant died on the 24th day of life after a large expansion of head circumference. Intracranial teratomas are extremely severe because of their quick growth and mass effect, often leading to neonatal death within days. 3DUS is a new prenatal diagnostic method that makes it possible to assess the anatomical relationships between the mass and the intracranial structures, thus enabling better preoperative planning.

Dissection of mitogenic and neurodegenerative actions of cystine and glutamate in malignant gliomas.

Malignant glioma represents one of the most aggressive and lethal human neoplasias. A hallmark of gliomas is their rapid proliferation and destruction of vital brain tissue, a process in which excessive glutamate release by glioma cells takes center stage. Pharmacologic antagonism with glutamate signaling through ionotropic glutamate receptors attenuates glioma progression in vivo, indicating that glutamate release by glioma cells is a prerequisite for rapid glioma growth. Glutamate has been suggested to promote glioma cell proliferation in an autocrine or paracrine manner, in particular by activation of the (RS)-α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid hydrate (AMPA) subtype of glutamate receptors. Here, we dissect the effects of glutamate secretion on glioma progression. Glioma cells release glutamate through the amino-acid antiporter system X(c)(-), a process that is mechanistically linked with cystine incorporation. We show that disrupting glutamate secretion by interfering with the system X(c)(-) activity attenuates glioma cell proliferation solely cystine dependently, whereas glutamate itself does not augment glioma cell growth in vitro. Neither AMPA receptor agonism nor antagonism affects glioma growth in vitro. On a molecular level, AMPA insensitivity is concordant with a pronounced transcriptional downregulation of AMPA receptor subunits or overexpression of the fully edited GluR2 subunit, both of which block receptor activity. Strikingly, AMPA receptor inhibition in tumor-implanted brain slices resulted in markedly reduced tumor progression associated with alleviated neuronal cell death, suggesting that the ability of glutamate to promote glioma progression strictly requires the tumor microenvironment. Concerning a potential pharmacotherapy, targeting system X(c)(-) activity disrupts two major pathophysiological properties of glioma cells, that is, the induction of excitotoxic neuronal cell death and incorporation of cystine required for rapid proliferation.

S100B in the cerebrospinal fluid—A marker for glial damage in the rabbit model of pneumococcal meningitis

The rabbit model provides an important experimental setting for the evaluation of antibiotic agents against pneumococcal meningitis. One of the primary targets of this model is the study of neuronal and glial cell damage in bacterial meningitis. The aim of this investigation was to evaluate whether a significant increase of S100B in the cerebrospinal fluid (CSF) as an indicator of white matter damage could be observed in this meningitis model. Seven rabbits were infected intracisternally with S. pneumoniae, and CSF S100B concentrations were examined serially before infection, at 12 h, 14 h, 17 h, 20 h, and at 24 h after infection. The course of CSF S100B increase and its relation to other parameters of brain tissue destruction and CSF inflammation were measured. Axonal damage was visualized by amyloid precursor protein (APP) immunostaining and demyelination by Luxol Fast Blue/Periodic Acid Schiff (LFB-PAS) stain. In each animal, we observed a distinct rise in S100B concentration in the CSF due to pneumococcal meningitis. We conclude that the CSF concentration of the glial S100B protein can be used as an additional parameter for future interventional studies focusing on glial cell damage in the rabbit model of bacterial meningitis.

Role of stereotactic radiosurgery and fractionated stereotactic radiotherapy for the treatment of recurrent glioblastoma multiforme

Glioblastoma multiforme (GBM) is a devastating malignant brain tumor characterized by resistance to available therapeutic approaches and relentless malignant progression that includes widespread intracranial invasion, destruction of normal brain tissue, progressive disability, and death. Stereotactic radiosurgery (SRS) and fractionated stereotactic radiotherapy (fSRT) are increasingly used in patients with recurrent GBM to complement traditional treatments such as resection, conventional external beam radiotherapy, and chemotherapy. Both SRS and fSRT are powerful noninvasive therapeutic modalities well suited to treat focal neoplastic lesions through the delivery of precise, highdose radiation. Although no randomized clinical trials have been performed, a variety of retrospective studies have been focused on the use of SRS and fSRT for recurrent GBMs. In addition, state-of-the-art neuroimaging techniques, such as MR spectroscopic imaging, diffusion tensor tractography, and nuclear medicine imaging, have enhanced treatment planning methods leading to potentially improved clinical outcomes. In this paper the authors reviewed the current applications and efficacy of SRS and fSRT in the treatment of GBM, highlighting the value of these therapies for recurrent focal disease.

RNAi-mediated downregulation of MMP-2 activates the extrinsic apoptotic pathway in human glioma xenograft cells

Malignant gliomas are characterized by invasive and infiltrative behavior that generally involves the destruction of normal brain tissue. Strategies to treat infiltrating gliomas, such as chemotherapy and gene therapy, have remained largely unsuccessful. The infiltrative nature of gliomas can be attributed largely to proteases, which include serine, metallo- and cysteine- proteases. Our previous work and that of others strongly suggest a relationship between the expression of uPAR, MMP-9, and MMP-2; this relationship is generally indicative of the infiltrative phenotype of gliomas. In the present study, we have demonstrated that the RNAi-mediated downregulation of MMP-2 induces apoptosis in the 4910 human glioma xenograft cell line. Using Western blot analysis, we observed that caspase-8 levels increased in MMP-2-downregulated cells whereas TRADD and TRAF-2 levels decreased. Further, NIK levels increased in MMP-2-downregulated cells. To determine the nuclear localization of AIF and IkappaBalpha, we analyzed the levels of AIF, IkappaBalpha and pIkappaBalpha in the cytosolic and nuclear fractions of MMP-2-downregulated cells. Western blot analysis revealed that MMP-2 downregulation resulted in the translocation of AIF to the nucleus and also inhibited the nuclear localization of pIkappaBalpha. To confirm the involvement of AIF, we performed FACS analysis to determine the integrity of the mitochondrial membrane using the MitoPT method. FACS analysis showed that the downregulation of MMP-2 caused a collapse in the mitochondrial cell membrane. Immunolocalization of AIF revealed that in MMP-2-downregulated cells, AIF translocates to the nucleus, thereby enabling the induction of apoptosis. RT-PCR analysis revealed that caspase-8 was overexpressed 57-fold, whereas p73 was downregulated 28-fold. Evidence of apoptosis was determined by TUNEL assay and visualization of nuclear fragmentation by DAPI staining. In summary, it is evident from our results that MMP-2 downregulation induces caspase-8 and AIF-mediated apoptosis and, as such, shows potential for glioma therapy.

Absence of the complement regulatory molecule CD59a leads to exacerbated neuropathology after traumatic brain injury in mice

BackgroundComplement represents a crucial mediator of neuroinflammation and neurodegeneration after traumatic brain injury. The role of the terminal complement activation pathway, leading to generation of the membrane attack complex (MAC), has not been thoroughly investigated. CD59 is the major regulator of MAC formation and represents an essential protector from homologous cell injury after complement activation in the injured brain.MethodsMice deleted in the Cd59a gene (CD59a-/-) and wild-type littermates (n = 60) were subjected to focal closed head injury. Sham-operated (n = 60) and normal untreated mice (n = 14) served as negative controls. The posttraumatic neurological impairment was assessed for up to one week after trauma, using a standardized Neurological Severity Score (NSS). The extent of neuronal cell death was determined by serum levels of neuron-specific enolase (NSE) and by staining of brain tissue sections in TUNEL technique. The expression profiles of pro-apoptotic (Fas, FasL, Bax) and anti-apoptotic (Bcl-2) mediators were determined at the gene and protein level by real-time RT-PCR and Western blot, respectively.ResultsClinically, the brain-injured CD59a-/- mice showed a significantly impaired neurological outcome within 7 days, as determined by a higher NSS, compared to wild-type controls. The NSE serum levels, an indirect marker of neuronal cell death, were significantly elevated in CD59a-/- mice at 4 h and 24 h after trauma, compared to wild-type littermates. At the tissue level, increased neuronal cell death and brain tissue destruction was detected by TUNEL histochemistry in CD59a-/- mice within 24 hours to 7 days after head trauma. The analysis of brain homogenates for potential mediators and regulators of cell death other than the complement MAC (Fas, FasL, Bax, Bcl-2) revealed no difference in gene expression and protein levels between CD59a-/- and wild-type mice.ConclusionThese data emphasize an important role of CD59 in mediating protection from secondary neuronal cell death and further underscore the key role of the terminal complement pathway in the pathophysiology of traumatic brain injury. The exact mechanisms of complement MAC-induced secondary neuronal cell death after head injury require further investigation.

Endogenous Intoxication in Pulmonary Complications in Patients with Severe Brain Injury

Objective: to evaluate changes in the laboratory markers of endogenous intoxication in acute severe brain injury (SBI) and to define their prognostic significance in the development of pneumonias. Subjects and methods. Sixty-six patients with isolated severe brain injury in the acute phase of the disease were examined and divided into two groups: 1) 35 (53%) patients who were not observed to have pneumonias in the acute period; 2) 31 (47%) who had developed pneumonia on an average of 7.7±2.8 days after injury. Endogenous intoxication was evaluated from the erythrocytic sedimentation rate (ESR), leukocytic indoxication index (LII), the spectrum of serum medium molecular-weight peptides and red blood cells, complements C3, C4, C-reactive protein, soluble fibrin monomer complexes, dienic conjugates, lactic acid, urea, and creatinine. Immunological parameters, such as the total count of lymphocytes and the level of CD3+ lymphocytes (a marker of mature lymphocytes), were studied by indirect monoclonal antibody immunofluorescence. A control group comprised 24 healthy individuals. The data were statistically processed by the Statistica-6 program, by applying Student’s test, and Pearson’s correlation coefficient. Results. Endogenous intoxication was found to be attended by immunodeficiency and to show two waves; just after injury it was caused by diseased and ischemic brain tissue destruction products and its second wave was associated with the development of pneumonias by the end of the first week after injury when an increase in proteolysis products along bacterial toxemia proved to be of significance. The markers, the predictors of pneumonia development in SBI, are increases in ESR up to more than 40 mm/hour on day 3, ESR up to more than 50 mm/hour, and in complement C3 levels up to more than 1.5 g/l on day 5. The early markers of pulmonary complications are increases in serum medium molecular-weight peptide levels up to over 0.3 optical density units at 262 nm, in C-reactive protein up to more than 100 mg/l, and in dienic conjugates up to above 1.2 mmol/l on day 7. The good predictor of the course of pneumonia is an increase in complement C4 levels up to over 0.4 g/l after day 7 and a reduction in LII to less than 3 relative units. Conclusion. The findings show it necessary to include the diagnostic markers: medium molecular-weight peptides, C-reactive protein, and dienic conjugates into the comprehensive examination of patients with severe brain injury. Key words: severe brain injury, endogenous intoxication, C-reactive protein, dienic conjugates, medium molecular-weight peptides, pneumonias.

Peripheral tolerance limits CNS accumulation of CD8 T cells specific for an antigen shared by tumor cells and normal astrocytes

T cell mediated immunotherapies are proposed for many cancers including malignant astrocytoma. As such therapies become more potent, but not necessarily more tumor-specific, the risk of collateral autoimmune damage to normal tissue increases. Tumors of the brain present significant challenges in this respect, as autoimmune destruction of brain tissue could have severe consequences. To investigate local immune reactivity toward a tumor-associated antigen in the brain, transgenic mice were generated that express a defined antigen (CW3 170-179) in astroglial cells. The resulting six transgenic mouse lines expressed the transgenic self-antigen in cells of the gastrointestinal tract and CNS compartments, or in the CNS alone. By challenging transgenic mice with tumor cells that express CW3, self/tumor-specific immune responses were visualized within a normal polyclonal T cell repertoire. A large expansion of the endogenous CW3 170-179-specific CD8 T cell population was observed in nontransgenic mice after both subcutaneous and intracerebral implantation of tumor cells. In contrast, CW3 170-179-specific immune responses were not observed in transgenic mice that exhibited extracerebral transgene expression. Importantly, in certain groups of mice in which transgene expression was restricted to the CNS, antigen-specific immune responses occurred when tumor was implanted subcutaneously, but not intracerebrally. This local immune tolerance in the brain was induced via peripheral (extrathymic) rather than central (thymic) tolerance mechanisms. Thus, this study highlights the role of regional immune regulation in the prevention of autoimmunity in the brain, and the potential impact of these mechanisms for brain tumor immunotherapy.

Neural Stimulation Successfully Treats Depression in Patients With Prior Ablative Cingulotomy

In this article, we describe the case of a patient who, under the direction of a multidisciplinary case committee, underwent both an ablative cingulotomy and subsequent bilateral deep brain stimulation placement in the Cg25 area. Review of this case provides a means of comparing the two techniques and of illustrating what we feel are some important advantages to using stimulation in the treatment of major depression. This report also provides potential insight into common and unique mechanisms mediating the two procedures.

The Assessment of Structural Changes in MS Plaques and Normal Appearing White Matter Using Quantitative Magnetization Transfer Imaging (MTI)

Introduction: Multiple sclerosis (MS) is a demyelinating disease of the central nervous system (CNS), affecting mostly young people at a mean age of 30 years. Magnetic resonance imaging (MRI) is one of the most specific and sensitive methods in diagnosing and detecting the evolution of multiple sclerosis disease. But it does not have the ability to differentiate between distinct histopathological heterogeneities that occur in MS lesions and brain tissue.Quantitative magnetization transfer imaging (qMTI) is a relatively new MRI technique which can be used to examine the pathological processes of the brain parenchyma which occur in MS patients.This quantitative MRI technique can provide more complete information about the extent and nature of the brain tissue destruction in multiple sclerosis, which cannot be detected by conventional MRI. Material and Methods: In this study, twelve patients with relapsing-remitting MS and twelve healthy control subjects underwent conventional MR imaging including: T2-FSE, T1-SE and FLAIR sequences as well as quantitative magnetization transfer imaging. All the focal lesions were identified on T2-weighted images and were classified according to their signal hypointensity on T1-weighted scans. The white matter and MS lesions were segmented using a semi-automated system. MT ratio (MTR) histogram analysis was performed for the brain white matter and the average MTR value was calculated for the classified MS lesions. Results: A significant reduction was found in MTR value of the normal appearing white matter (NAWM) in patients with relapsing-remitting MS, suggesting that MS is a more diffuse disease, affecting the whole brain tissue. A wide range changes in MTR values can be observed in MS lesions. MTR reduction is correlated with the degree of lesion hypointensity on T1-weighted scans. The lower MTR values of lesions that appear progressively more hypointense on T1-weigted images reflect varying degrees of demyelination and breakdown in the macromolecular structure of MS lesions. There was also a significant difference in MTR histogram parameters between the patients and control groups, accompanied by a total shift of NAWM-MTR histogram to the left. Discussion and Conclusion: Based on theobtained result itcan be stated that MS has a diffused nature and the white matter abnormalities occurring outside T2-visible lesions affect the whole brain tissue. Quantitative magnetization transfer imaging can be used as a reliable method to assess both the overall disease burden and the intrinsic nature of the individual lesions in MS patients

Malignant astrocytic glioma: genetics, biology, and paths to treatment

Malignant astrocytic gliomas such as glioblastoma are the most common and lethal intracranial tumors. These cancers exhibit a relentless malignant progression characterized by widespread invasion throughout the brain, resistance to traditional and newer targeted therapeutic approaches, destruction of normal brain tissue, and certain death. The recent confluence of advances in stem cell biology, cell signaling, genome and computational science and genetic model systems have revolutionized our understanding of the mechanisms underlying the genetics, biology and clinical behavior of glioblastoma. This progress is fueling new opportunities for understanding the fundamental basis for development of this devastating disease and also novel therapies that, for the first time, portend meaningful clinical responses.

New Neuroprotective Approaches for Stroke: Use of Decoy Peptides Targeting Specific Molecular Events

Stroke is characterized by the relatively rapid onset of neurological impairment, most often caused by the reduction or abrupt cessation of blood flow to the brain (cerebral ischemia). The interruption of cerebral blood flow is generally caused by a thrombus formed in an artery or the lodging of an embolus from a distant site. Behind heart disease and cancer, stroke is the third leading cause of death in the USA and is considered to be the most common cause of disability in adults [1–3]. Despite years of research and millions of dollars invested in finding an appropriate therapy, pharmacological intervention has made little, if any, impact in preventing neurological damage in patients suffering an acute stroke [4]. Thus, stroke clearly qualifies as a severe and prevalent national health problem with inadequate existing therapies. It is now generally believed that irreversible neurological damage occurs over a period of hours following stroke [1]. During this time, a cascade of cellular and biochemical events, triggered by the initial vascular insult, leads to the production of neurotoxic mediators and, ultimately, a continuing wave of destruction of neural tissue. This cascade is believed to cause neurological damage that spreads beyond the initial necrotic core (i.e., the tissue directly supplied by the occluded vasculature) into the surrounding penumbral tissue [1]. Some therapeutic strategies for stroke, such as the use of the thrombolytic enzyme tissue plasminogen activator, have focused on removing the initial vascular obstruction. Another class of strategies has been directed at more ‘downstream’ events, and aimed at blocking or reversing steps hypothesized to be crucial in the cascade of tissue destruction that occurs in the hours following the occlusion. The hope is that the latter type of intervention will halt or reduce neurological damage, even if administration is delayed until hours after stroke has occurred. This is important because clinical studies have shown that, most often, hours have elapsed by the time a stroke is diagnosed [2]. This implies that, in many clinical circumstances, removal of the vascular obstruction might not be accomplished early enough to prevent significant neurological impairment. Thus, pharmacological strategies for blocking later neurotoxic events might serve to increase the crucial ‘window of opportunity’ for the treatment of stroke. To facilitate design of such downstream therapeutic strategies, much research has been devoted to understanding the cascade of events that are responsible for brain-tissue destruction following the initial stroke, and on identifying key steps for potential intervention. Not surprisingly, this research has shown that the cascade is extremely complicated [5]. Nonetheless, several potential targets of intervention have been identified.

Loss of Cell Adhesion Causes Hydrocephalus in Nonmuscle Myosin II-B–ablated and Mutated Mice

Ablation of nonmuscle myosin (NM) II-B in mice during embryonic development leads to marked enlargement of the cerebral ventricles and destruction of brain tissue, due to hydrocephalus. We have identified a transient mesh-like structure present at the apical border of cells lining the spinal canal of mice during development. This structure, which only contains the II-B isoform of NM, also contains beta-catenin and N-cadherin, consistent with a role in cell adhesion. Ablation of NM II-B or replacement of NM II-B with decreased amounts of a mutant (R709C), motor-impaired NM II-B in mice results in collapse of the mesh-like structure and loss of cell adhesion. This permits the underlying neuroepithelial cells to invade the spinal canal and obstruct cerebral spinal fluid flow. These defects in the CNS of NM II-B-ablated mice seem to be the cause of hydrocephalus. Interestingly, the mesh-like structure and patency of the spinal canal can be restored by increasing expression of the motor-impaired NM II-B, which also rescues hydrocephalus. However, the mutant isoform cannot completely rescue neuronal cell migration. These studies show that the scaffolding properties of NM II-B play an important role in cell adhesion, thereby preventing hydrocephalus during mouse brain development.

IFN' synergizes with IL‐1α to up‐regulate MMP‐9 secretion in a cellular model of central nervous system tuberculosis

Matrix metalloproteinase-9 (MMP-9) activity is implicated in pathogenesis of central nervous system tuberculosis (CNS-TB). IFNgamma, a key cytokine in TB, usually inhibits MMP-9 secretion. Addition of IFNgamma to conditioned media from M. tb-infected monocytes (CoMTB) resulted in a 7-fold increase in MMP-9 activity detected by gelatin zymography (P<0.01). In contrast, tissue inhibitor of metalloproteinase (TIMP)-1 and -2 secretion, measured by ELISA, was suppressed. Dexamethasone abolished the synergistic increase in MMP-9 activity. Interleukin (IL)-1beta in CoMTB is a critical mediator of synergy with IFNgamma, and IL-1beta alone synergizes with IFNgamma to increase MMP-9 secretion from 51 +/- 31 to 762 +/- 136 U. IL-1beta activity is dependent on p38 mitogen-activated protein (MAPK) kinase, which was found to be phosphorylated in tissue specimens from patients with CNS-TB. Extracellular signal regulated kinase (Erk) and p38 MAPK activation did not affect IFNgamma signaling pathways. Inhibition of janus-activated kinase (JAK)-2 by 50 microM AG540 decreased MMP-9 secretion to 124 +/- 11.1 from 651 +/- 229 U of activity (P<0.01). However, signal transducer and activator of transcription (STAT)-3 but not STAT-1 phosphorylation was synergistically up-regulated by IFNgamma and CoMTB. In summary, synergy between IL-1beta and STAT-3 dependent IFNgamma signaling is key in control of up-regulation of MMP-9 activity in CNS-TB and may be a significant mechanism of brain tissue destruction.

Alzheimer’s disease Braak Stage progressions: Reexamined and redefined as Borrelia infection transmission through neural circuits

Brain structure in health is a dynamic energized equation incorporating chemistry, neuronal structure, and circuitry components. The chemistry "piece" is represented by multiple neurotransmitters such as Acetylcholine, Serotonin, and Dopamine. The neuronal structure "piece" incorporates synapses and their connections. And finally circuits of neurons establish "architectural blueprints" of anatomic wiring diagrams of the higher order of brain neuron organizations. In Alzheimer's disease, there are progressive losses in all of these components. Brain structure crumbles. The deterioration in Alzheimer's is ordered, reproducible, and stepwise. Drs. Braak and Braak have described stages in the Alzheimer disease continuum. "Progressions" through Braak Stages benchmark "Regressions" in Cognitive function. Under the microscope, the Stages of Braak commence in brain regions near to the hippocampus, and over time, like a tsunami wave of destruction, overturn healthy brain regions, with neurofibrillary tangle damaged neurons "marching" through the temporal lobe, neocortex and occipital cortex. In effect the destruction ascends from the limbic regions to progressively destroy the higher brain centers. Rabies infection also "begins low and finishes high" in its wave of destruction of brain tissue. Herpes Zoster infections offer the paradigm of clinical latency of infection inside of nerves before the "marching commences". Varicella Zoster virus enters neurons in the pediatric years. Dormant virus remains inside the neurons for 50-80 years, tissue damage late in life (shingles) demonstrates the "march of the infection" down neural pathways (dermatomes) as linear areas of painful blisters loaded with virus from a childhood infection. Amalgamation of Zoster with Rabies models produces a hybrid model to explain all of the Braak Stages of Alzheimer's disease under a new paradigm, namely "Alzheimer's neuroborreliosis" in which latent Borrelia infections ascend neural circuits through the hippocampus to the higher brain centers, creating a trail of neurofibrillary tangle injured neurons in neural circuits of cholinergic neurons by transsynaptic transmission of infection from nerve to nerve.

TNF Is Important for Pathogen Control and Limits Brain Damage in Murine Cerebral Listeriosis

Cerebral listeriosis is a life-threatening disease. However, little is known about the bacterial virulence factors responsible for the severe course of disease and the factors of the immune system contributing to the control of Listeria monocytogenes (LM) or even to the damage of the brain. To analyze the importance of the actA gene of LM, which mediates cell-to-cell spread of intracellular LM, the function of TNF in murine cerebral listeriosis was studied. C57BL/6 mice survived an intracerebral (i.c.) infection with actA-deficient LM, but succumbed to infection with wild-type (WT) LM. Upon infection with actA-deficient LM, macrophages and microglial cells rapidly, and later LM-specific CD4 and CD8 T cells, produced TNF. In contrast to WT mice, TNF-deficient animals succumbed to the infection within 4 days due to failure of control of LM. Histology identified a more severe meningoencephalitis, brain edema, and neuronal damage, but a reduced inducible NO synthase expression in TNF-deficient mice. Reciprocal bone marrow chimeras between WT and TNF-deficient mice revealed that hematogenously derived TNF was essential for survival, whereas TNF produced by brain-resident cells was less important. Death of TNF-deficient mice could be prevented by LM-specific T cells induced by an active immunization before i.c. infection. However, brain pathology and inflammation of immunized TNF-deficient mice were still more severe. In conclusion, these findings identify a crucial role of TNF for the i.c. control of LM and survival of cerebral listeriosis, whereas TNF was not responsible for the destruction of brain tissue.

Brain Temperature During 340-kHz Pulsed Ultrasound Insonation

Because ultrasound is used for improving thrombolysis of cerebral infarction but continuous ultrasound insonation also has significant thermal effects, we evaluated brain temperature increase and tissue destruction during pulsed ultrasound emission. We examined 340-kHz pulsed ultrasound effects in male Wistar rats. Ultrasound was applied transcranially for 30 minutes on different power levels (1 to 7 W/cm2). Temperature was measured at different locations (brain, in the focus of ultrasound beam, inner ear, temporalis muscle, and rectum). The cooling time after 30-minute insonation for every power level was recorded, and animals were examined by postmortem brain histology (TUNEL and hematoxylin/eosin). Brain temperature increased within 2 to 5 minutes of insonation. Brain temperature increase and cooling time were in proportion to power level, and even with the highest intensity of 7 W/cm2 for 30 minutes, the maximum elevation of mean brain temperature was 0.9 degrees C, with the highest cooling time of 40 minutes. No deleterious side effects of this treatment could be found in histological examination. Using a pulsed ultrasound design, only a moderate temperature increase could be observed with no histopathological abnormalities. Deleterious side effects of mid-kilohertz ultrasound (eg, intracerebral hemorrhage) are therefore not a consequence of local brain temperature increase.

Inflammation in stroke: the good, the bad, and the unknown.

It has been known for a very long time (Spielmeyer 1922) that in ‘apoplectic’ brains the hallmarks of inflammation may be found, including pus-filled cavities. Until very recently it was generally believed that brain inflammation following stroke is a secondary reaction to the destruction of brain tissue, which is cleared by invading leukocytes, in particular macrophages (Manoonkitiwongsa et al. 2001). Accordingly, inflammation is supposed to free the brain from the debris of dead cells, but in itself does not participate in ischemic cell damage. Quite clearly, this concept must be modified in view of recent research. Numerous experimental as well as clinical studies have linked stroke-induced brain inflammation to the acute and delayed evolution of brain infarction, as well as to scattered selective neuronal injury in the infarct perimeter. These studies have been reviewed (e.g., Barone and Feuerstein 1999; del Zoppo et al. 2000, 2001; Kumar 2001; Iadecola and Alexander 2001; Emsley and Tyrrell 2002; Frijns and Kappelle 2002; Danton and Dietrich 2003) and we wrote an overview entitled ‘Inflammation in Stroke — A Potential Target for Neuroprotection’ (Priller and Dirnagl 2002) for the 2001 Ernst Schering Foundation Workshop ‘Neuroinflammation — From Bench to Bedside.’