A vision of the future for BMC Medicine: serving science, medicine and authors

In June 2009, BMC Medicine received its first official impact factor of 3.28 from Thomson Reuters. In recognition of this landmark event, the BMC Medicine editorial team present and discuss the vision and aims of the journal

Targeting CXCR7/ACKR3 as a therapeutic strategy to promote remyelination in the adult central nervous system

Current treatment modalities for the neurodegenerative disease multiple sclerosis (MS) use disease-modifying immunosuppressive compounds but do not promote repair. Although several potential targets that may induce myelin production have been identified, there has yet to be an approved therapy that promotes remyelination in the damaged central nervous system (CNS). Remyelination of damaged axons requires the generation of new oligodendrocytes from oligodendrocyte progenitor cells (OPCs). Although OPCs are detected in MS lesions, repair of myelin is limited, contributing to progressive clinical deterioration. In the CNS, the chemokine CXCL12 promotes remyelination via CXCR4 activation on OPCs, resulting in their differentiation into myelinating oligodendrocytes. Although the CXCL12 scavenging receptor CXCR7/ACKR3 (CXCR7) is also expressed by OPCs, its role in myelin repair in the adult CNS is unknown. We show that during cuprizone-induced demyelination, in vivo CXCR7 antagonism augmented OPC proliferation, leading to increased numbers of mature oligodendrocytes within demyelinated lesions. CXCR7-mediated effects on remyelination required CXCR4 activation, as assessed via both phospho-S339-CXCR4–specific antibodies and administration of CXCR4 antagonists. These findings identify a role for CXCR7 in OPC maturation during remyelination and are the first to use a small molecule to therapeutically enhance myelin repair in the demyelinated adult CNS

CXCR7 influences leukocyte entry into the CNS parenchyma by controlling abluminal CXCL12 abundance during autoimmunity

During CNS autoimmunity, brain endothelial cell CXCR7 internalizes CXCL12 from the perivascular space, thereby permitting leukocyte migration into the CNS parenchyma

Conventional and microwave induced synthesis of various azetidinone and thiazolidinone derivatives from 3-[(1E)-1-aza-2-(2-chloro-7-methoxy-3-quinolyl)-vinyl]-4-(aryldiazenyl) phenol and their antimicrobial screening

1695-17003-Chloro-4-(2-chloro-7-methoxy-3-quinolyl)-1-[3-hydroxy-6-(aryldiazenyl) phenyl] azetidin-2-one 2 and 2-(2-chloro-7-methoxy-3-quinolyl)-3-[3-hydroxy-6-(aryldiazenyl) phenyl]-1, 3-thiazolidin-4-one 3 have been synthesized by the reaction of 3-[(1E)-1-aza-2-(2-chloro-7-methoxy-3-quinolyl)-vinyl]-4-(aryldiazenyl) phenol 1 with chloroacetylchloride and mercapto acetic acid, respectively. Both the reactions have been carried out by conventional and microwave methods. These compounds have been screened for their antibacterial, antifungal and antitubercular activity against different microorganisms

Central nervous system pathology progresses independently of KC and CXCR2 in globoid-cell leukodystrophy.

Globoid-cell Leukodystrophy (GLD; Krabbe's disease) is a rapidly progressing inherited demyelinating disease caused by a deficiency of the lysosomal enzyme Galactosylceramidase (GALC). Deficiency of GALC leads to altered catabolism of galactosylceramide and the cytotoxic lipid, galactosylsphingosine (psychosine). This leads to a rapidly progressive fatal disease with spasticity, cognitive disability and seizures. The murine model of GLD (Twitcher; GALC-/-) lacks the same enzyme and has similar clinical features. The deficiency of GALC leads to oligodendrocyte death, profound neuroinflammation, and the influx of activated macrophages into the CNS. We showed previously that keratinocyte chemoattractant factor (KC) is highly elevated in the CNS of untreated Twitcher mice and significantly decreases after receiving a relatively effective therapy (bone marrow transplantation combined with gene therapy). The action of KC is mediated through the CXCR2 receptor and is a potent chemoattractant for macrophages and microglia. KC is also involved in oligodendrocyte migration and proliferation. Based on the commonalities between the disease presentation and the functions of KC, we hypothesized that KC and/or CXCR2 contribute to the pathogenesis of GLD. Interestingly, the course of the disease is not significantly altered in KC- or CXCR2-deficient Twitcher mice. There is also no alteration in inflammation or demyelination patterns in these mice. Furthermore, transplantation of CXCR2-deficient bone marrow does not alter the progression of the disease as it does in other models of demyelination. This study highlights the role of multiple redundant cytokines and growth factors in the pathogenesis of GLD

Cytokine and chemokine levels in the CNS of Twitcher mice.

<p>The fold-elevation of various cytokines/chemokines in the brain is shown. Among all the assayed molecules, the chemokine KC showed the greatest fold change in the brains (>15-fold increase) of the Twitcher mice (A). The levels of KC in the brains (B) and the spinal cords (C) of the Twitcher mice showed a progressive increase with time. The vertical bars represent the means and the error bars represent one SEM; **p<0.01, ***p<0.001.</p

Altered cytokine and growth factor levels in the spinal cord of Twitcher mice that could possibly compensate for the lack of KC or CXCR2.

<p>MIP-2 (CXCL2) (A), PDGF-BB (B), and FGF-2 (C) levels are significantly and progressively elevated in the spinal cords of the Twitcher mice. Vertical bars represent the mean and the error bars represent one SEM (**p<0.01, ***p<0.001).</p

Flow cytometric characterization of inflammatory cells in the KC−/−GALC−/− brains.

<p>The upper row of Panel A contains representative bivariate contour plots showing CD8 and CD4 T-cells at day 36 in various groups of mice. The lower row in panel A contain representative bivariate contour plots showing activated microglia (CD45^hi CD11b+, upper right quadrant) isolated from the brain at 36 days of age. There is no significant increase in CD8+ T-cells in KC−/−GALC+/+, KC+/+GALC−/− or KC−/−GALC−/− mice compared to the KC+/+GALC+/+ mice (B). There is no significant difference in the CD4+ T-cells in the brains of the KC−/−GALC−/− and KC+/+GALC−/− mice compared to the KC+/+GALC+/+ mice (C). There is no significant difference between the KC+/+GALC−/− mice and KC−/−GALC−/− mice in the number of activated microglia (D).</p