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The complex manifestations of chronic multiple sclerosis (MS)are due in part to widespread axonal abnormalities that affect lesional and nonlesional areas in the central nervous system. Wedescribe an association between microglial activation and axon/oligodendrocyte pathology at nodal and paranodal domains in normal-appearing white matter (NAWM) of MS cases and in experimental autoimmune encephalomyelitis (EAE). The extent ofparanodal axoglial (neurofascin-155/Caspr1) disruption correlated with local microglial inflammation and axonal injury (expression of nonphosphorylated neurofilaments) in MS NAWM. These changes were independent of demyelinating lesions and did not correlate with the density of infiltrating lymphocytes. Similar axoglial alterations were seen in the subcortical white matter of Parkinson disease cases and in preclinical EAE, at a time point when there is microglial activation before the infiltration of immune cells. Disruption of the axoglial unit in adjuvant-immunized animals was reversible and coincided with the resolution of microglial inflammation; paranodal damage and microglial inflammation persisted in chronic EAE. Axoglial integrity could be preserved by the administration of minocycline, which inhibited microglial activation, in actively immunized animals. These data indicate that, in MS NAWM, permanent disruption to axoglial domains in an environment of microglial inflammation is an early indicator of axonal injury that likely affects nerve conduction and may contribute to physiologic dysfunction.

Enhancing central nervous system (CNS) myelin regeneration is recognized as an important strategy to ameliorate the devastating consequences of demyelinating diseases such as multiple sclerosis. Previous findings have indicated that myelin proteins, which accumulate following demyelination, inhibit remyelination by blocking the differentiation of rat oligodendrocyte progenitor cells (OPCs) via modulation of PKCα. We therefore screened drugs for their potential to overcome this differentiation block. From our screening, tamoxifen emerges as a potent inducer of OPC differentiation in vitro . We show that the effects of tamoxifen rely on modulation of the estrogen receptors ERα, ERβ and GPR30. Furthermore, we demonstrate that administration of tamoxifen to demyelinated rats in vivo accelerates remyelination. Tamoxifen is a well-established drug and is thus a promising candidate for a drug to regenerate myelin, as it will not require extensive safety testing. In addition, Tamoxifen plays an important role in biomedical research as an activator of inducible genetic models. Our results highlight the importance of appropriate controls when using such models.

The increasing effectiveness of new disease‐modifying drugs that suppress disease activity in multiple sclerosis has opened up opportunities for regenerative medicines that enhance remyelination and potentially slow disease progression. Although several new targets for therapeutic enhancement of remyelination have emerged, few lend themselves readily to conventional drug development. Here, we used transcription profiling to identify mitogen‐activated protein kinase (Mapk) signalling as an important regulator involved in the differentiation of oligodendrocyte progenitor cells (OPCs) into oligodendrocytes. We show in tissue culture that activation of Mapk signalling by elevation of intracellular levels of cyclic adenosine monophosphate (cAMP) using administration of either dibutyryl‐cAMP or inhibitors of the cAMP‐hydrolysing enzyme phosphodiesterase‐4 (Pde4) enhances OPC differentiation. Finally, we demonstrate that systemic delivery of a Pde4 inhibitor leads to enhanced differentiation of OPCs within focal areas of toxin‐induced demyelination and a consequent acceleration of remyelination. These data reveal a novel approach to therapeutic enhancement of remyelination amenable to pharmacological intervention and hence with significant potential for translation. Graphical Abstract Mechanisms of re‐myelination failure in multiple sclerosis for example remain incompletely understood. Here, phosphodiesterase Pde4 inhibition is shown to increase OPC differentiation and remyelination via cAMP‐Erk1/2/p38Mapk‐Creb1 signaling axis.

Experimental autoimmune encephalomyelitis (EAE) is a spectrum of neurological disorders in laboratory animals that is used to model multiple sclerosis (MS). However, few agents have translated from efficacy in EAE to the treatment of human disease. Although this may reflect species differences in pathological disease mechanisms, importantly it may also relate to the practice of how drugs and models are currently used. This often bears very little resemblance to the clinical scenarios where treatments are investigated, such that lack of appreciation of the biology of disease may doom drugs to failure. The use of EAE is critically appraised with the aim of provoking thought, improving laboratory practise and aiding researchers and reviewers to address quality issues when undertaking, reporting and interpreting animal studies related to MS research. This is important as many researchers using EAE could and should do more to improve the quality of the studies.

The complex symptoms of chronic multiple sclerosis (MS) are due, in part, to widespread axonal pathology affecting lesioned and non-lesioned areas of the CNS. Here we describe an association between microglial activation and axon/ oligodendrocyte pathology at nodal and paranodal domains in normal appearing white matter (NAWM) of MS and experimental allergic encephalomyelitis (EAE). The extent of paranodal axo-glial (neurofascin-155+/Caspr1+) disruption correlated with the local degree of microglial inflammation and axonal injury (expression of nonphosphorylated neurofilaments) in MS NAWM. These changes were independent of demyelinating lesions and did not correlate with the density of infiltrating lymphocytes. Similar axo-glial alterations were seen in pre-symptomatic EAE, at a time-point characterised by microglia activation prior to the infiltration of immune cells. Disruption of the axo-glial unit in adjuvant immunised animals was reversible and coincided with the resolution of microglial inflammation, whereas paranodal damage and microglial inflammation persisted in chronic EAE. We were able to preserve axo-glial integrity by administering minocycline, which inhibited microglial activation, in actively immunised animals. Therefore, permanent disruption to axo-glial domains in an environment of microglial inflammation is an early indicator of axonal injury that would affect normal nerve conduction contributing to pathology outside of the demyelinated lesion.

This study sought to determine if direct application of the lentiviral (LV)-cyclooxygenase 2 (COX2) vector to the tendon-bone interface would promote osteointegration of the tendon graft in a rat model of biceps tenodesis. The LV-COX2 gene transfer strategy was chosen for investigation because a similar COX2 gene transfer strategy promoted bony bridging of the fracture gap during bone repair, which involves similar histologic transitions that occur in osteointegration. Briefly, a 1.14-mm diameter tunnel was drilled in the mid-groove of the humerus of adult Fischer 344 rats. The LV-COX2 or βgal control vector was applied directly into the bone tunnel and onto the end of the tendon graft, which was then pulled into the bone tunnel. A poly-L-lactide pin was press-fitted into the tunnel as interference fixation. Animals were sacrificed at 3, 5, or 8 weeks for histology analysis of osteointegration. The LV-COX2 gene transfer strategy enhanced neo-chondrogenesis at the tendon-bone interface but with only marginal effect on de novo bone formation. The tendon-bone interface of the LV-COX2-treated tenodesis showed the well-defined tendon-to-fibrocartilage-to-bone histologic transitions that are indicative of osteointegration of the tendon graft. The LV-COX2 in vivo gene transfer strategy also significantly enhanced angiogenesis at the tendon-bone interface. To determine if the increased osteointegration was translated into an improved pull-out mechanical strength property, the pull-out tensile strength of the LV-COX2-treated tendon grafts was determined with a pull-out mechanical testing assay. The LV-COX2 strategy yielded a significant improvement in the return of the pull-out strength of the tendon graft after 8 weeks. In conclusion, the COX2-based in vivo gene transfer strategy enhanced angiogenesis, osteointegration and improved return of the pull-out strength of the tendon graft. Thus, this strategy has great potential to be developed into an effective therapy to promote tendon-to-bone healing after tenodesis or related surgeries.

Traumatic brain injury (TBI) can affect bone by influencing the production/actions of pituitary hormones and neuropeptides that play significant regulatory roles in bone metabolism. Previously, we demonstrated that experimental TBI exerted a negative effect on the skeleton. Since mild TBI (mTBI) accounts for the majority of TBI cases, this study was undertaken to evaluate TBI effects using a milder impact model in female mice. Repetitive mTBI caused microhemorrhaging, astrocytosis, and increased anti-inflammatory protective actions in the brain of the impacted versus control mice 2 wk after the first impact. Serum levels of growth regulating insulin-like growth factor 1 (IGF-I) were reduced by 28.9%. Bone mass was reduced significantly in total body as well as individual skeletons. Tibial total cortical density was reduced by 7.0%, which led to weaker bones, as shown by a 31.3% decrease in femoral size adjusted peak torque. A 27.5% decrease in tibial trabecular bone volume per total volume was accompanied by a 34.3% (p = 0.07) decrease in bone formation rate (BFR) per total area. Based on our data, we conclude that repetitive mTBI exerted significant negative effects on accrual of both cortical and trabecular bone mass in mice caused by a reduced BFR.

Mr. [Helmut Ackermann] depends on natural gas to operate the massive boilers and heaters used to color and dry fabrics. He expects his December gas bill to have jumped to $600,000 from $132,000 last January. Hammered by the soaring costs, he has already closed one plant and dismissed 40 people. Now, he says the jobs of his remaining 660 workers are in jeopardy. \"If it stays the way it is, we won't be around very long,\" Mr. Ackermann says. Some Wall Street economists worry that California's problems could spill over and hurt the broader U.S. economy. In a report titled \"California Unplugged -- A Drag on Global Growth?\" Morgan Stanley Dean Witter warns that California's energy crisis threatens to push up production costs and make U.S. exports from the state, which totaled $102.9 billion in 1999, less competitive on world markets. Other states facing economic and financial trouble wouldn't warrant such attention. But California not only is the nation's largest state in terms of both population and economic heft, but the Golden State also seemed to epitomize the New Economy. Job growth in the state has been double that in the nation as a whole; of the 2.1 million jobs created in the U.S. during the first 11 months of last year, one of every five new hires was in California. The state produced more than $1.2 trillion in output in 1999, making it the sixth-largest economy in the world, slightly smaller than the economy of the United Kingdom and a little bigger than that of Italy. The state's economic output contributed about 12% of total U.S. gross domestic product. New York, in second place, had an 8.1% share of GDP.

Urokinase plasminogen activator (uPA) regulates a proteolytic cascade of extracellular matrix degradation that functions in tissue development and tissue repair. The development and remodeling of the skeletal extracellular matrix during wound healing suggests that uPA might regulate bone development and repair. To determine whether uPA functions regulate bone development and repair, we examined the basal skeletal phenotype and endochondral bone fracture repair in uPA-deficient mice. The skeletal phenotype of uPA knockout mice was compared with that of control mice under basal conditions by dual-energy X-ray absorptiometry and micro-CT analysis, and during femur fracture repair by micro-CT and histological examination of the fracture callus. No effects of uPA gene deficiency were observed in the basal skeletal phenotype of the whole body or the femur. However, uPA gene deficiency resulted in increased fracture callus cartilage abundance during femur fracture repair at 14 days healing. The increase in cartilage corresponded to reduced tartrate-resistant acid phosphatase (TRAP) staining for osteoclasts in the uPA knockout fracture callus at this time, consistent with impaired osteoclast-mediated remodeling of the fracture cartilage. CD31 staining was reduced in the knockout fracture tissues at this time, suggesting that angiogenesis was also reduced. Osteoclasts also colocalized with CD31 expression in the endothelial cells of the fracture tissues during callus remodeling. These results indicate that uPA promotes remodeling of the fracture cartilage by osteoclasts that are associated with angiogenesis and suggest that uPA promotes angiogenesis and remodeling of the fracture cartilage at this time of bone fracture repair.

It is 4 years since the subglacial lake community published its plans for accessing, sampling, measuring and studying the pristine, and hitherto enigmatic and very different, Antarctic subglacial lakes, Vostok, Whillans and Ellsworth. This paper summarizes the contrasting probe technologies designed for each of these subglacial environments and briefly updates how these designs changed or were used differently when compared to previously published plans. A detailed update on the final engineering design and technical aspects of the probe for Subglacial Lake Ellsworth is presented. This probe is designed for clean access, is negatively buoyant (350 kg), 5.2 m long, 200 mm in diameter, approximately cylindrical and consists of five major units: (i) an upper power and communications unit attached to an optical and electrical conducting tether, (ii)–(iv) three water and particle samplers, and (v) a sensors, imaging and instrumentation pack tipped with a miniature sediment corer. To date, only in Subglacial Lake Whillans have instruments been successfully deployed. Probe technologies for Subglacial Lake Vostok (2014/15) and Lake Ellsworth (2012/13) were not deployed for technical reasons, in the case of Lake Ellsworth because hot-water drilling was unable to access the lake during the field season window. Lessons learned and opportunities for probe technologies in future subglacial access missions are discussed.