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

Pectic substances from white mustard

In both plant, animal and bacterial cells the active protoplasm is bounded by a lipid membrane known as the plasmalemma. This performs a large variety of functions but is basically concerned with transport of materials in and out of the protoplast. In plants and bacteria however the membrane is itself surrounded by another structure known as the cell wall which imparts protection and firmness to the cell.The osmotic pressure exerted by the protoplast, by uptake of water from a hypotonic environment, on the cell wall can be considerable and thus a fundamental property of the wall must be a high tensile strength to withstand this pressure from within. Polysaccharides account for by far the majority of wall material in young plant tissue and these polymers must be arranged so as to surround the protoplast with a mesh of the necessary properties.In the polarising light microscope the cell wall shows birefringence whereas the layer between adjacent cells (the middle lamella) appears to be amorphous. In the electron microscope the cell wall has been shown to be composed of microfibrils of indefinite length embedded in an apparently structureless matrix (17). In higher plants the microfibrils are made up of bundles of highly orientated cellulose molecules. The staining properties of the wall and middle lamella with the basic dyes methylene blue and ruthenium red (18) indicate that the matrix is composed, in part, of the acidic pectic substances, although hemicellulosic polysaccharides and in older cells the non -carbohydrate polymer, lignin, are also present

Poly-substance use and sexual risk behaviours: a cross-sectional comparison of adolescents in mainstream and alternative education settings

Background: Surveys of young people under-represent those in alternative education settings (AES), potentially disguising health inequalities. We present the first quantitative UK evidence of health inequalities between AES and mainstream education school (MES) pupils, assessing whether observed inequalities are attributable to socioeconomic, familial, educational and peer factors. Methods: Cross-sectional, self-reported data on individual- and poly-substance use (PSU: combined tobacco, alcohol and cannabis use) and sexual risk-taking from 219 pupils in AES (mean age 15.9 years) were compared with data from 4024 pupils in MES (mean age 15.5 years). Data were collected from 2008 to 2009 as part of the quasi-experimental evaluation of Healthy Respect 2 (HR2). Results: AES pupils reported higher levels of substance use, including tobacco use, weekly drunkenness, using cannabis at least once a week and engaging in PSU at least once a week. AES pupils also reported higher levels of sexual health risk behaviours than their MES counterparts, including: earlier sexual activity; less protection against sexually transmitted infections (STIs); and having 3+ lifetime sexual partners. In multivariate analyses, inequalities in sexual risk-taking were fully explained after adjusting for higher deprivation, lower parental monitoring, lower parent-child connectedness, school disengagement and heightened intentions towards early parenthood among AES vs MES pupils. However, an increased risk (OR = 1.73, 95% CI 1.15, 2.60) of weekly PSU was found for AES vs MES pupils after adjusting for these factors and the influence of peer behaviours. Conclusion: AES pupils are more likely to engage in health risk behaviours, including PSU and sexual risk-taking, compared with MES pupils. AES pupils are a vulnerable group who may not be easily targeted by conventional population-level public health programmes. Health promotion interventions need to be tailored and contextualised for AES pupils, in particular for sexual health and PSU. These could be included within interventions designed to promote broader outcomes such as mental wellbeing, educational engagement, raise future aspirations and promote resilience

Transforming the NHS through transforming ourselves

Abstract Background: Leadership development impacts on quality of care and workplace cultures for staff. Clinical Leadership embracing transformational and other collective leadership approaches are key enablers to developing effective workplace cultures at the micro-systems level. Following the development of a shared purpose and values framework, an internal, inter-professional clinical leadership programme was set up to grow a critical community of transformational leaders across one NHS organisation in England. This programme had previously been unsuccessful in engaging medical doctors. Aims and Objectives: This paper shares how a dedicated practice development based clinical leadership programme set out to support medical doctors across one organisation with their leadership journey, equipping them to become both transformational and collective leaders and facilitators with the skills to begin to develop and sustain effective workplace cultures, that are person centred, safe and effective. Methods: Practice development methodology with its collaborative, inclusive and participative approach for developing person centred cultures combined with clinical leadership strategies, formed the basis of the programme which emphasised the use of active and action learning drawing on the workplace as the main resource for learning, development and improvement. Self-assessment and co-creation of insights about clinical leadership together with collaborative analysis of evaluation data led to the syntheses of insights through the use of reflection and action planning. Findings/Results: Findings are presented at two levels: 1) Five individual authentic reflections by authors to illustrate their leadership journeys which also demonstrate how a range of tools were used and their impact from reflections. Insights and learning include recognition of the benefits of peer support and networking; development of a disciplined approach to learning and self-management; 2) A collaborative reflection and critique that embraced the feeling of a sense of team ethos and community cohesion, for the first time in a safe environment; as well as, a sense of collective shared purpose and values. Conclusions: We conclude that the programme helped to identify the impact of leadership on workplace cultures and to begin to embed ways of working that are collaborative, inclusive, participative and celebratory. This unique approach by one organisation to leadership development has enabled a journey of self-transformation for medical clinical leaders to commence. Practical implications arising from our learning: • An internal model grows clinical leadership capacity across the organisation through peer support and networking and collective leadership. • Investing in a safe confidential space for clinical leads and other staff groups is a strategy for leadership development practice. • There is need to develop more skilled critical companions to support leadership, improvement and development activities • Clinical leadership development, informed by practice development methodology, demonstrates potential for enabling transformative and collective leadership for achieving person-centred cultures in the workplace. Keywords: Clinical leadership, collective leadership, critical companionship, micro-systems, transformational leadership, workplace cultur

Calcutta Botanic Garden and the colonial re-ordering of the Indian environment

This article examines three hand-painted colour maps that accompanied the annual report of the Calcutta Botanic Garden for 1846 to illustrate how the Garden’s layout, uses and functions had changed over the previous 30 years. The evolution of the Calcutta Botanic Garden in the first half of the nineteenth-century reflects a wider shift in attitudes regarding the relationship between science, empire and the natural world. On a more human level the maps result from, and illustrate, the development of a vicious personal feud between the two eminent colonial botanists charged with superintending the garden in the 1840s

Excision of Integrated Human Herpesvirus 6A Genomes Using CRISPR/Cas9 Technology

Human herpesviruses 6A and 6B are betaherpesviruses that can integrate their genomes into the telomeres of latently infected cells. Integration can also occur in germ cells, resulting in individuals who harbor the integrated virus in every cell of their body and can pass it on to their offspring. This condition is termed inherited chromosomally integrated HHV-6 (iciHHV-6) and affects about 1% of the human population. The integrated HHV-6A/B genome can reactivate in iciHHV-6 patients and in rare cases can also cause severe diseases including encephalitis and graft-versus-host disease. Until now, it has remained impossible to prevent virus reactivation or remove the integrated virus genome. Therefore, we developed a system that allows the removal of HHV-6A from the host telomeres using the CRISPR/Cas9 system. We used specific guide RNAs (gRNAs) targeting the direct repeat region at the ends of the viral genome to remove the virus from latently infected cells generated in vitro and iciHHV-6A patient cells. Fluorescence-activated cell sorting (FACS), quantitative PCR (qPCR), and fluorescence in situ hybridization (FISH) analyses revealed that the virus genome was efficiently excised and lost in most cells. Efficient excision was achieved with both constitutive and transient expression of Cas9. In addition, reverse transcription-qPCR (RT-qPCR) revealed that the virus genome did not reactivate upon excision. Taken together, our data show that our CRISPR/Cas9 approach allows efficient removal of the integrated virus genome from host telomeres

Chromatin Profiles of Chromosomally Integrated Human Herpesvirus-6A

Human herpesvirus-6A (HHV-6A) and 6B (HHV-6B) are two closely related betaherpesviruses that are associated with various diseases including seizures and encephalitis. The HHV-6A/B genomes have been shown to be present in an integrated state in the telomeres of latently infected cells. In addition, integration of HHV-6A/B in germ cells has resulted in individuals harboring this inherited chromosomally integrated HHV-6A/B (iciHHV-6) in every cell of their body. Until now, the viral transcriptome and the epigenetic modifications that contribute to the silencing of the integrated virus genome remain elusive. In the current study, we used a patient-derived iciHHV-6A cell line to assess the global viral gene expression profile by RNA-seq, and the chromatin profiles by MNase-seq and ChIP-seq analyses. In addition, we investigated an in vitro generated cell line (293-HHV-6A) that expresses GFP upon the addition of agents commonly used to induce herpesvirus reactivation such as TPA. No viral gene expression including miRNAs was detected from the HHV-6A genomes, indicating that the integrated virus is transcriptionally silent. Intriguingly, upon stimulation of the 293-HHV-6A cell line with TPA, only foreign promoters in the virus genome were activated, while all HHV-6A promoters remained completely silenced. The transcriptional silencing of latent HHV-6A was further supported by MNase-seq results, which demonstrate that the latent viral genome resides in a highly condensed nucleosome-associated state. We further explored the enrichment profiles of histone modifications via ChIP-seq analysis. Our results indicated that the HHV-6 genome is modestly enriched with the repressive histone marks H3K9me3/H3K27me3 and does not possess the active histone modifications H3K27ac/H3K4me3. Overall, these results indicate that HHV-6 genomes reside in a condensed chromatin state, providing insight into the epigenetic mechanisms associated with the silencing of the integrated HHV-6A genome

Impact of Host Telomere Length on HHV-6 Integration

Human herpesvirus 6A and 6B are two closely related viruses that infect almost all humans. In contrast to most herpesviruses, HHV-6A/B can integrate their genomes into the telomeres during the infection process. Both viruses can also integrate in germ cells and subsequently be inherited in children. How HHV-6A/B integrate into host telomeres and the consequences of this remain a subject of active research. Here, we developed a method to measure telomere length by quantitative fluorescence in situ hybridization, confocal microscopy, and computational processing. This method was validated using a panel of HeLa cells having short or long telomeres. These cell lines were infected with HHV-6A, revealing that the virus could efficiently integrate into telomeres independent of their length. Furthermore, we assessed the telomere lengths after HHV-6A integration and found that the virus-containing telomeres display a variety of lengths, suggesting that either telomere length is restored after integration or telomeres are not shortened by integration. Our results highlight new aspects of HHV-6A/B biology and the role of telomere length on virus integration