Treatments for spasticity and pain in multiple sclerosis: a systematic review

Objectives: To identify the drug treatments currently available for the management of spasticity and pain in multiple sclerosis (MS), and to evaluate their clinical and cost-effectiveness. Data sources: Electronic bibliographic databases, National Research Register, MRC Clinical Trials Register and the US National Institutes of Health Clinical Trials Register. Review methods: Systematic searches identified 15 interventions for the treatment of spasticity and 15 interventions for treatment of pain. The quality and outcomes of the studies were evaluated. Reviews of the treatment of spasticity and pain when due to other aetiologies were also sought. Results: There is limited evidence of the effectiveness of four oral drugs for spasticity: baclofen, dantrolene, diazepam and tizanidine. Tizanidine appears to be no more effective than comparator drugs such as baclofen and has a slightly different side-effects profile. Despite claims that it causes less muscle weakness, there was very little evidence that tizanidine performed any better in this respect than other drugs, although it is more expensive. The findings of this review are consistent with reviews of the same treatments for spasticity derived from other aetiologies. There is good evidence that both botulinum toxin (BT) and intrathecal baclofen are effective in reducing spasticity, and both are associated with functional benefit. However, they are invasive, and substantially more expensive. None of the studies included in the review of pain were designed specifically to evaluate the alleviation of pain in patients with MS and there was no consistency regarding the use of validated outcome measures. It was suggested that, although expensive, the use of intrathecal baclofen may be associated with significant savings in hospitalisation costs in relation to bed-bound patients who are at risk of developing pressure sores, thus enhancing its cost-effectiveness. No studies of cost-effectiveness were identified in the review of pain. There is evidence, albeit limited, of the clinical effectiveness of baclofen, dantrolene, diazepam, tizanidine, intrathecal baclofen and BT and of the potential cost-effectiveness of intrathecal baclofen in the treatment of spasticity in MS. Conclusions: Many of the interventions identified are not licensed for the alleviation of pain or spasticity in MS and the lack of evidence relating to their effectiveness may also limit their widespread use. Indeed, forthcoming information relating to the use of cannabinoids in MS may result in there being better evidence of the effectiveness of new treatments than of any of the currently used drugs. It may therefore be of value to carry out double-blind randomised controlled trials of interventions used in current practice, where outcomes could include functional benefit and impact on quality of life. Further research into the development and validation of outcomes measures for pain and spasticity may also be useful, as perhaps would cost–utility studies

Towards a More Equal City: Framing the Challenges and Opportunities

Cities are growing differently today than before. As much as 70 percent of people in emerging cities in Asia, Africa and Latin America is under-served. Furthermore, cities face challenges in four areas:Highest rates of urbanization are in sub-Saharan Africa, South and Southeast AsiaUrbanization is now happening in more low-income countries than in the pastThe share of poor people living in urban areas is on the rise worldwideCities in the Global South have the fewest public resources per capitaWe need a new approach that will benefit all urban residents and create sustainable, productive cities for the 21st century. The World Resources Report (WRR) examines if prioritizing access to core urban services, we can create cities that are prosperous and sustainable for all people.This first installment of the WRR developed a new categorization of cities into emerging, struggling, thriving, and stabilizing cities. It focuses on solutions for struggling and emerging cities—over half the cities included in the analysis—because they have the greatest opportunity to alter their development trajectory

Engineering study of the rotary-vee engine concept

The applicable thermodynamic cycle and performance considerations when the rotary-vee mechanism is used as an internal combustion (I.C.) heat engine are reviewed. Included is a simplified kinematic analysis and studies of the effects of design parameters on the critical pressures, torques and parasitic losses. A discussion of the principal findings is presented

Putting Soybeans into Permanent Farming

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Electromagnetic properties of ice coated surfaces

The electromagnetic scattering from ice coated structures is examined. The influence of ice is shown from a measurement standpoint and related to a simple analytical model. A hardware system for the realistic measurement of ice coated structures is also being developed to use in an existing NASA Lewis icing tunnel. Presently, initial measurements have been performed with a simulated tunnel to aid in the development

Large collection of astrophysical S-factors and its compact representation

Numerous nuclear reactions in the crust of accreting neutron stars are strongly affected by dense plasma environment. Simulations of superbursts, deep crustal heating and other nuclear burning phenomena in neutron stars require astrophysical S-factors for these reactions (as a function of center-of-mass energy E of colliding nuclei). A large database of S-factors is created for about 5000 non-resonant fusion reactions involving stable and unstable isotopes of Be, B, C, N, O, F, Ne, Na, Mg, and Si. It extends the previous database of about 1000 reactions involving isotopes of C, O, Ne, and Mg. The calculations are performed using the Sao Paulo potential and the barrier penetration formalism. All calculated S-data are parameterized by an analytic model for S(E) proposed before [Phys. Rev. C 82, 044609 (2010)] and further elaborated here. For a given reaction, the present S(E)-model contains three parameters. These parameters are easily interpolated along reactions involving isotopes of the same elements with only seven input parameters, giving an ultracompact, accurate, simple, and uniform database. The S(E) approximation can also be used to estimate theoretical uncertainties of S(E) and nuclear reaction rates in dense matter, as illustrated for the case of the 34Ne+34Ne reaction in the inner crust of an accreting neutron star.Comment: 13 pages, 2 figures, Phys. Rev. C, accepte

Investigating the Regulation and Function of the NR4A Nuclear Receptors in Cancer

The nuclear receptor (NR) superfamily represents a structurally-conserved group of ligand-regulated transcription factors. These proteins have critical roles in various physiological and pathological processes, including cancer, and have been targets of drug therapy. The orphan NR subfamily 4A (NR4A), which includes the NR4A1 (Nur77), NR4A2 (Nurr1), and NR4A3 (Nor-1) genes, has been implicated in adult solid tumors and has been characterized as pro-tumorigenic mediator of cell proliferation, transformation, migration, and drug resistance. Alternatively, in leukemia, NR4A1 and NR4A3 have been described as tumor suppressors in hematologic malignancies. Members of the NR4A family are commonly overexpressed in cancer and this has been attributed to their regulation by other oncogenic signaling pathways. Despite the understanding of signaling cascades that lead to overexpression of the NR4A members, little is known about their regulation by microRNAs (miRNAs). miRNAs are small, non-coding, endogenous RNAs that are transcribed, processed, and used to direct cellular proteins that destabilize or block translation of target mRNA. In this study, we first sought to determine the miRNAs that are responsible for regulating NR4A2. Using a 3ʹ UTR reporter assay, we identified miR-34 as a regulator of the NR4A2 through its 3ʹ UTR, which was confirmed using mutagenesis of the predicted binding region of the miR-34 seed region to its target site. We demonstrated that overexpression of exogenous or induction of endogenous miR-34 expression downstream of p53 activation by Nutlin-3a was associated with decreased endogenous NR4A2. Additionally, overexpression of NR4A2 was capable of suppressing the activation of p53 target genes, and was also able to attenuate the sensitivity of cells to the anti-proliferative effect of Nutlin-3a. We further explored the roles of the NR4A family in pediatric cancer, an area that has not been fully investigated. We first determined that the members of the NR4A family are overexpressed in rhabdomyosarcoma (RMS) cell lines compared to normal muscle cells. Knockdown of NR4A1 or NR4A2 led to a reduction in cell proliferation and transformation, while knockdown of NR4A2 could also affect cell migration. Using a microarray approach, we sought to investigate the transcriptome-level changes in response to NR4A knockdown, and determined that knockdown of NR4A2 led to a unique gene signature, while NR4A1 and NR4A3 knockdown had large overlaps in expression changes. These unique gene expression changes in response to NR4A2 knockdown could explain the unique effects that NR4A2 has on migration. Overall, this study has discovered miR-34 as a novel regulator of NR4A2, and places NR4A2 in a potential feedback mechanism involving p53, miR-34, and NR4A2. This could indicate that NR4A2 mediates at least some of its pro-oncogenic effects through the inhibition of p53, which is relieved by p53 itself upon activation. Alternatively, NR4A2, is shown to have other roles in cancer progression, potentially through novel downstream target genes. These data may be used in understanding the effects of miR-34 replacement therapy, as this method of treatment is progressing through clinical trials, allowing us to understand the diverse regulator cascades being modulated