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J Neurovirol. 2003;9 Suppl 1:25-31.
Inflammatory reaction in progressive multifocal leukoencephalopathy: harmful or beneficial?

Du Pasquier RA, Koralnik IJ.

Department of Neurology and Division of Viral Pathogenesis, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA.

Progressive multifocal leukoencephalopathy (PML) occurs in patients with profound immunosuppression. Although lesions are usually devoid of lymphoplasmocytic infiltrates, inflammatory forms of PML have been described, in both human immunodeficiency virus (HIV)-seropositive (HIV+) and -seronegative (HIV-) patients. In addition, PML has been shown to develop in HIV+ patients shortly after introduction of highly active antiretroviral therapy (HAART), despite a recovery of the immune system. Therefore, one could postulate that PML might arise in the context of an immune reconstitution syndrome. To examine the clinical and neuroradiological characteristics of inflammatory forms of PML, the authors performed a retrospective analysis of the patients seen at their institution since 1996 as well as a review of the literature. Of 39 HIV+ and HIV- PML patients, 5 (13%) presented with an inflammatory form of this disease. Two HIV+ patients developed PML soon after the onset of HAART, concomitant to immune recovery, as demonstrated by a decrease of HIV viral load (VL) and an increase of CD4+ T-cell count. Three patients (2 HIV+ and 1 HIV-) had signs of inflammation in the central nervous system (CNS) characterized by contrast-enhancing lesions on neuroimaging studies, and/or inflammatory infiltrates on brain biopsy. The presence of JC virus-specific cytotoxic T lymphocytes was demonstrated in 4/4 patients tested and the outcome was favorable in 3 of them. In agreement with previously published case reports, the data indicate that inflammatory reactions in PML are not infrequent, and that they are generally associated with a favorable prognosis. Therefore clinicians should not disregard the diagnosis of PML in presence of contrast-enhancing brain lesions, and should use caution before treating these immunosuppressed individuals with steroids.

online pharmacy ref. source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12709868&dopt=Abstract

Med Res Rev. 2003 Jul;23(4):488-518.
Genetic variability: The key problem in the prevention and therapy of RNA-based virus infections.

Figlerowicz M, Alejska M, Kurzynska-Kokorniak A, Figlerowicz M.

Department of Infectious Diseases, University of Medical Sciences, Poznan, Poland.

Despite extraordinary progress that has recently been made in biomedical sciences, viral infectious diseases still remain one of the most serious world health problems. Among the different types of viruses, those using RNA as their genetic material (RNA viruses and retroviruses) are especially dangerous. At present there is no medicine allowing an effective treatment of RNA-based virus infections. Many RNA viruses and retroviruses need only a few weeks to escape immune response or to produce drug-resistant mutants. This seems to be the obvious consequence of the unusual genetic variability of RNA-based viruses. An individual virus does not form a homogenous population but rather a set of similar but not identical variants. In consequence, RNA-based viruses can easily adapt to environmental changes, also those resulting from immune system response or therapy. The modifications identified within viral genes can be divided into two groups: point mutations and complex genome rearrangements. The former arises mainly during error-prone replication, whereas RNA recombination and generic reassortment are responsible for the latter. This article shortly describes major strategies used to control virus infections. Then, it presents the various mechanisms generating the genetic diversity of RNA-based viruses, which are most probably the main cause of clinical problems. 2003 Wiley Periodicals, Inc. Med Res Rev, 23, No. 4, 488-518, 2003

online pharmacy ref. source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12710021&dopt=Abstract [PubMed - in process]

georgetown.edu

Neuropeptide Y (NPY(1-36)), a sympathetic cotransmitter and neurohormone, has pleiotropic activities ranging from the control of obesity to anxiolysis and cardiovascular function. Its actions are mediated by multiple Gi/o-coupled receptors (Y1-Y5) and modulated by dipeptidyl peptidase IV (DPPIV/cd26), which inactivates NPY's Y1-agonistic activity but generates the Y2 and Y5-agonist, NPY(3-36). Released by sympathetic activity, NPY is a major mediator of stress, responsible for prolonged vasoconstriction via Y1 receptors. Y1 receptors also mediate NPY's potent vascular growth-promoting activity leading in vivo in rodents to neointima formation. This and the association of a polymorphism of the NPY signal peptide with increased lipidemia and carotid artery thickening in humans strongly suggest NPY's role in atherosclerosis. NPY and DPPIV/cd26 are also coexpressed in the endothelium, where the peptide activates angiogenesis. A similar system exists in immune cells, where NPY and DPPIV/cd26 are coactivated and involved in the modulation of cytokine release and immune cell functions. Thus, NPY, both a messenger and a modulator for all three systems, is poised to play an important regulatory role facilitating interactions among sympathetic, vascular and immune systems in diverse pathophysiological conditions such as hypertension, atherosclerosis and stress-related alterations of immunity.

online pharmacy ref. source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12710520&dopt=Abstract [PubMed - in process]

Med Hypotheses. 2003 May;60(5):702-6.
Effects of heavy alcohol consumption on the cardiovascular system may be mediated in part by the influence of alcohol-induced depression on the immune system.

Sher L.

Fort Lee, New Jersey, USA

The harmful effects of heavy alcohol use are well-documented and wide-ranging. Heavy drinking may cause or exacerbate cardiovascular disorders. The author suggests that effects of heavy alcohol consumption on the cardiovascular system may be mediated in part by the influence of alcohol-induced depression on the immune system. This hypothesis is based on the following data: (1) alcohol misuse may cause or exacerbate depression; (2) depressive disorders are associated with increased incidence, morbidity, and mortality of cardiovascular disorders; (3) the immune system may mediate effects of depressive disorders on the cardiovascular system. Further studies are needed to clarify the etiopathogenesis of alcohol-related disorders and develop new treatment modalities.

online pharmacy ref. source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12710906&dopt=Abstract [PubMed - in process]

Aquat Toxicol. 2003 May 8;63(3):293-306.
Effects of PCB congeners on the immune function of Mytilus hemocytes: alterations of tyrosine kinase-mediated cell signaling.

Canesi L, Ciacci C, Betti M, Scarpato A, Citterio B, Pruzzo C, Gallo G.

Facolta di Scienze Ambientali, Istituto di Scienze Fisiologiche, Universita di Urbino, Loc Crocicchia, 61029 (PU), Urbino, Italy. canesniurb.it

Polychlorinated biphenyls (PCBs) are industrial chemicals which have been released into the environment resulting in widespread and persistent contamination. PCBs exist as 209 different congeners depending on the chlorine substitution on the biphenyl rings; the physical properties and the toxic effects of a PCB congener are structure-dependent. In this work, individual ortho-substituted non coplanar PCB congeners were tested for their effects on the function of mussel (Mytilus galloprovincialis Lam.) hemocytes. Moreover, the possibility that in mussel hemocytes different PCBs may affect the signal transduction pathways involved in the immune response was investigated, with particular regards to relevant components of tyrosine-kinase mediated cell signaling. The results were compared with those obtained with a model of non-ortho-substituted coplanar congener. The results demonstrate that the di-ortho-substituted, non coplanar PCB congeners P47 (2,2',4,4'-tetrachlorobiphenyl) and P153 (2,2',4,4',5,5'-hexachlorobiphenyl) can alter immune parameters of mussel hemocytes, such as microbicidal activity and lysosomal enzyme release, respectively. Both congeners, as well as the non-ortho, coplanar congener P77 (3,3',4,4'-tetrachlorobiphenyl) significantly reduced hemocyte lysosomal membrane stability; however, P77 had no effect on either bacterial killing or lysozyme release. P47, P153 and P77 affected different components of tyrosine kinase-mediated cell signalling; in particular, they lead to a time-dependent increase in the phosphorylation level of the stress activated p38 and JNK Mitogen Activated Protein Kinases (MAPKs), as evaluated by Western blotting of hemocyte protein extracts with specific anti-phospho-MAPK antibodies. P153 also increased the level of phosphorylated ERK (extracellularly regulated) MAPKs. Moreover, non coplanar P47 and P153 caused increased tyrosine phosphorylation of the transcription factor STAT5, thus possibly affecting gene expression, whereas coplanar P77 was ineffective. The results demonstrate that MAPKs, and in particular the stress-activated p38 and JNK MAPKs, that represents a key step in the response of mussel hemocytes to bacterial infection, are a target for different non coplanar and coplanar PCB congeners. The results also show functional differences between different PCB congeners with respect to the hemocyte functions. However, chlorine substitution at the ortho positions is not necessarily related to immunotoxicity: the hexachlorinated P128 (2,2',3,3',4,4'-hexachlorobiphenyl) had no significant effect on mussel hemocytes, whereas its isomer P153, that represents a major component of environmental PCBs, and that is accumulated in mussel tissues, significantly affected both aspects of the immune response and relevant signal transduction pathways. These are the first data on the effects and possible mechanisms of immunotoxicity of non coplanar PCBs in mussel hemocytes. The results support the hypothesis that the innate immune system is a sensitive target for these contaminants in both vertebrates and invertebrates. Moreover, when considering that non coplanar congeners are present both in commercial mixtures and, in higher proportions, in environmental samples, the results suggest that bivalve hemocytes represent a useful model for evaluating the potential immunotoxicity of PCB contamination.

online pharmacy ref. source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12711418&dopt=Abstract

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