Daratumumab for the treatment of multiple myeloma.

Since its initial approval in 2015, daratumumab has had a tremendous impact on the treatment of multiple myeloma. It is a monoclonal antibody that targets CD38, an antigen with high surface expression on multiple myeloma cells. While it initially received approval as a monotherapy for multiply relapsed multiple myeloma, its favorable toxicity profile allowed for combinations with other novel myeloma therapies leading to numerous indications as a component of triplet and quadruplet regimens. These indications now span relapsed/refractory populations and both transplant-eligible and transplant-ineligible patients with newly diagnosed myeloma. Further investigations are underway to continue to expand the reach of daratumumab, including large phase III collaborative trials to assess the efficacy of daratumumab as part of post-transplant maintenance and its impact on smoldering myeloma. The recent introduction of a subcutaneous formulation of daratumumab with proven noninferiority will improve the convenience and accessibility of the drug. In this review, we examine the preclinical development of daratumumab, its pharmacology and clinical investigations that demonstrated its safety and efficacy. Furthermore, we discuss the outstanding questions related to daratumumab and ongoing clinical trials seeking to answer them.

Canadian Stroke Best Practice Recommendations for Acute Stroke Management: Prehospital, Emergency Department, and Acute Inpatient Stroke Care, 6th Edition, Update 2018.

The 2018 update of the Canadian Stroke Best Practice Recommendations for Acute Stroke Management, 6th edition, is a comprehensive summary of current evidence-based recommendations, appropriate for use by healthcare providers and system planners caring for persons with very recent symptoms of acute stroke or transient ischemic attack. The recommendations are intended for use by a interdisciplinary team of clinicians across a wide range of settings and highlight key elements involved in prehospital and Emergency Department care, acute treatments for ischemic stroke, and acute inpatient care. The most notable changes included in this 6th edition are the renaming of the module and its integration of the formerly separate modules on prehospital and emergency care and acute inpatient stroke care. The new module, Acute Stroke Management: Prehospital, Emergency Department, and Acute Inpatient Stroke Care is now a single, comprehensive module addressing the most important aspects of acute stroke care delivery. Other notable changes include the removal of two sections related to the emergency management of intracerebral hemorrhage and subarachnoid hemorrhage. These topics are covered in a new, dedicated module, to be released later this year. The most significant recommendation updates are for neuroimaging; the extension of the time window for endovascular thrombectomy treatment out to 24 h; considerations for treating a highly selected group of people with stroke of unknown time of onset; and recommendations for dual antiplatelet therapy for a limited duration after acute minor ischemic stroke and transient ischemic attack. This module also emphasizes the need for increased public and healthcare provider's recognition of the signs of stroke and immediate actions to take; the important expanding role of paramedics and all emergency medical services personnel; arriving at a stroke-enabled Emergency Department without delay; and launching local healthcare institution code stroke protocols. Revisions have also been made to the recommendations for the triage and assessment of risk of recurrent stroke after transient ischemic attack/minor stroke and suggested urgency levels for investigations and initiation of management strategies. The goal of this updated guideline is to optimize stroke care across Canada, by reducing practice variations and reducing the gap between current knowledge and clinical practice.

The utility of the radionuclide probe in parathyroidectomy for primary hyperparathyroidism.

INTRODUCTION Parathyroidectomy is the definitive treatment for primary hyperparathyroidism but the intraoperative identification of adenomas is challenging. The aim of this study was to evaluate the utility of a radionuclide probe (RNP) in addition to intraoperative parathyroid hormone ( IOPTH) measurement as an intraoperative diagnostic adjunct in patients undergoing parathyroidectomy for primary hyperparathyroidism. METHODS This was a retrospective cohort study of patients treated between 2004 and 2015 in a university affiliated teaching hospital. Patients were grouped into those with RNP use (RNP+) and those without (RNP-). The primary outcome measure was rate of operative failure, which included false positives. The diagnostic sensitivity and positive predictive value of both RNP and IOPTH were also evaluated. RESULTS A total of 298 patients were included in the study, 127 (42.6%) being in the RNP+ group and 171 (57.4%) in the RNP- group. The false positive rate for the RNP+ patients was 1.6% compared with 9.4% for RNP- patients (p=0.006, hazard ratio [HR]: 6.45). The rates of operative failure were 6.3% and 11.7% respectively (p=0.159, HR: 1.97). RNP use had a sensitivity of 92.0% and a positive predictive value of 98.3% compared with 78.6% and 95.2% respectively for IOPTH monitoring. CONCLUSIONS RNP use is associated with fewer false positives and reduced operative failure than IOPTH measurement. It also has a higher sensitivity and positive predictive value. RNP use is recommended in centres that have the required facilities.

A Systematic Review Examining the Oral Health Status of Persons with Dementia.

While the oral health of persons with dementia has been shown to be poor, no systematic reviews have been published that examined the topic in depth, including participants with dementia representing the full spectrum of disease severity, and evaluating a broad scope of oral health assessments. The aim of this study was to conduct a current literature review to fill this gap in knowledge. A systematic search of 5 databases (CINAHL, PubMed, EMBASE, Scopus, and ISI Web of Science) was conducted to identify all relevant studies published up to May 2016. There were no exclusions related to study type, severity of dementia, dentate status, or living arrangements. Results were reported descriptively and summarized. Meta-analyses were performed where possible and reported as mean difference (MD) or standardized mean difference (SMD), with a 95% confidence interval (CI). Twenty-eight studies were identified. Assessments were conducted of tooth status, active dental caries, hygiene (plaque/calculus) of natural and artificial teeth, periodontal diseases, denture status (retention, stability, denture-related mucosal lesions), and oral health-related quality of life. Across all evaluations, persons with dementia generally had scores/results suggestive of poor oral health. In meta-analyses, compared with persons without dementia, those with dementia had a significantly fewer number of teeth (MD, -1.52; 95% CI, -0.2.52 to -0.52; P = 0.003; n = 13 studies), more carious teeth (SMD, 0.29; 95% CI, 0.03 to 0.48; P = 0.028; n = 9), significantly worse oral hygiene evaluated using a broad range of assessment tools (SMD, 0.88; 95% CI, 0.57 to 1.19, P < 0.0001; n = 7), and significantly poorer periodontal health (SMD, 0.38; 95% CI, 0.06 to 0.70; P = 0.02; n = 6 studies). The oral health status of persons with mild to severe forms of dementia, who were living in both the community and residential care facilities, was found to be poor across a broad range of dental assessments. Knowledge Transfer Statement: The results of this study define the scope of oral issues and quantify the degree of impairment in individuals with dementia, evaluated using a variety of oral health measures. The results revealed that poor oral health is associated with dementia.

BRAFV600E mutation as a predictor of thyroid malignancy in indeterminate nodules: A systematic review and meta-analysis.

BACKGROUND: Thyroid nodules are usually diagnosed using fine-needle aspiration (FNA). The sensitivity limitations of FNA result in 10-30% of nodules being classified as "indeterminate". The BRAFV600E mutation is associated with papillary thyroid carcinoma (PTC). We conducted a systemic review and meta-analysis to evaluate the diagnostic utility of the BRAFV600E mutation in indeterminate nodules. METHOD: PUBMED and EMBASE were searched for studies testing for the BRAFV600E involving indeterminate nodules (Thy3a, Thy3f, Thy4) and containing information on final surgical histopathology. Thirty two studies involving 3150 indeterminate nodules were included in the analysis. RESULTS: The overall sensitivity and specificity for BRAFV600E for the diagnosis of thyroid malignancy was 0.40 (95% CI: 0.32-0.48) and 1.00 (95% CI: 0.98-1.00) respectively. The diagnostic odds ratio (DOR) was 205.4 (95% CI: 40.1-1052). With a Fagan plot, the post-test probability of thyroid cancer, given a negative mutation was 6%, but this rose to 92% with a positive result. On subgroup analysis, for Thy3a nodules, the pooled sensitivity and specificity for thyroid malignancy was 0.21 (95% CI: 0.13-0.34) and 1.00 (95% CI: 0.98-1.00). For Thy3f nodules, the pooled sensitivity and specificity was 0.09 (95% CI: 0.03-0.20) and 1.00 (95% CI: 0.05-1.00) respectively. For Thy4 nodules, the corresponding sensitivity and specificity was 0.58 (95% CI: 0.5-0.64) and 0.99 (95% CI: 0.95-1.00) respectively. CONCLUSIONS: Despite a high specificity for thyroid cancer, BRAFV600E mutation has a low overall sensitivity and therefore has a limited diagnostic value as a single screening test.

PATI: Patient accessed tailored information: A pilot study to evaluate the effect on preoperative breast cancer patients of information delivered via a mobile application.

OBJECTIVES: The information needs of cancer patients are highly variable. Literature suggests an improved ability to modulate personalised stress, increased patient involvement with decision making, greater satisfaction with treatment choices and reduced anxiety levels in cancer patients who have access to information. The aim of this project was to evaluate the effects of a mobile information application on anxiety levels of patients undergoing surgery for breast cancer. MATERIALS AND METHODS: An application was developed for use with Apple iPad containing information on basic breast cancer biology, different treatments used and surgical techniques. Content and face validity studies were performed. A randomized control trial was designed, with a 1:2 allocation. Data collected include basic demographics and type of surgery. Questionnaires used included: the HADS, Mini-MAC, information technology familiarity and information satisfaction. RESULTS: A total of 39 women participated. 13 women had access to an iPad containing additional information and 26 women acted as controls. The mean age was 54 and technology familiarity was similar among both groups. Anxiety and depression scores at seven days were significantly lower in control patients without access to the additional information provided by the mobile application (p = 0.022 and 0.029 respectively). CONCLUSION: Anxiety and depression in breast cancer patients is both multifactorial and significant, with anxiety levels directly correlating with reduced quality of life. Intuitively, information should improve anxiety levels, however, we have demonstrated that surgical patients with less information reported significantly lower anxiety. We advise the thorough testing and auditing of information initiatives before deployment.

Effects of surgery on the cancer stem cell niche.

Recent identification of a cancer stem cell (CSC) phenotype in solid tumors has greatly enhanced the understanding of the mechanisms responsible for cancer cell metastasis. In keeping with Pagets 'seed and soil' theory, CSCs display dependence upon stromal derived factors found within the niche in which they reside. Inflammatory mediators act as a 'fertilizer' within this niche when interacting with CSCs at the tumor-stromal interface and can potentiate the metastatic ability of CSCs. Interestingly, the same components of the pro-inflammatory milieu experienced by cancer patients perioperatively are known to promote the metastagenic potential of CSCs. On the basis of this observation we discuss how surgery-induced inflammation potentiates colon CSC involvement in the metastatic process. We hypothesize that the high rates of recurrence and metastasis associated with tumor resection are potentiated by the effects of surgery-induced inflammation on CSCs. Finally we discuss potential therapeutic strategies for use in the perioperative window to protect cancer patients from the oncological effects of the pro-inflammatory milieu.

Examining the Association between Vitamin B12 Deficiency and Dementia in High-Risk Hospitalized Patients.

OBJECTIVES: To explore the association between vitamin B12 deficiency and dementia in patients at high risk for vitamin B12 deficiency. DESIGN: Chart review. SETTING: Emergency, critical care/ trauma, neurology, medicine, and rehabilitation units of two hospitals in Southwestern Ontario, Canada. PARTICIPANTS: Adult patients (n = 666) admitted from 2010 to 2012. Data collection included: reason for admission, gender, age, clinical signs and symptoms of B12 deficiency, serum B12 concentration, and B12 supplementation. Patients with dementia were identified based on their medication profile and medical history. Vitamin B12 deficiency (pmol/L) was defined as serum B12 concentration <148; marginal deficiency: ≥148-220 and adequate >220. Comparisons between B12-deficient patients with and without dementia were examined using parametric and non-parametric tests. RESULTS: Serum B12 values were available for 60% (399/666) of the patients, of whom 4% (16/399) were B12-deficient and 14% (57/399) were marginally deficient. Patients with dementia were not more likely to be B12-deficient or marginally deficient [21% (26/121)] compared to those with no dementia [17% (47/278), p=0.27)]. Based on documentation, 34% (25/73) of the B12-deficient and marginally-deficient patients did not receive B12 supplementation, of whom 40% (10/25) had dementia. CONCLUSION: In this sample of patients, there was no association between B12 deficiency and dementia. However, appropriate B12 screening protocols are necessary for high risk patient to identify deficiency and then receive B12 supplementation as needed.

An International Multicenter Review of the Malignancy Rate of Excised Papillomatous Breast Lesions.

BACKGROUND: Papillary lesions of the breast are a relatively rare, but heterogeneous group ranging from benign to atypical and malignant. Debate exists regarding the optimal management of these lesions. In the absence of more accurate risk-stratification models, traditional management guidelines recommend surgical excision, despite the majority of lesions proving benign. This study sought to determine the rate of malignancy in excised breast papillomas and to elucidate whether there exists a population in which surgical excision may be unnecessary. METHODS: A multicenter international retrospective review of core biopsy diagnosed breast papillomas and papillary lesions was performed between 2009 and 2013, following institutional ethical approval. Patient demographics, histopathological, and radiological findings were recorded. All data was tabulated, and statistical analysis performed using Stata. RESULTS: A total of 238 patients were included in the final analysis. The age profile of those with benign pathology was significantly younger than those with malignant pathology (p < 0.001). Atypia on core needle biopsy was significantly associated with a final pathological diagnosis of malignancy (OR = 2.73). The upgrade rate from benign core needle biopsy to malignancy on the final pathological sample was 14.4 %; however, only 3.7 % had invasive cancer. CONCLUSIONS: This international dataset is one of the largest in the published literature relating to breast papillomas. The overall risk of malignancy is significantly associated with older age and the presence of atypia on core needle biopsy. It may be possible to stratify higher-risk patients according to age and core needle biopsy findings, thereby avoiding surgery on low-risk patients.

Deep groundwater and potential subsurface habitats beneath an Antarctic dry valley.

The occurrence of groundwater in Antarctica, particularly in the ice-free regions and along the coastal margins is poorly understood. Here we use an airborne transient electromagnetic (AEM) sensor to produce extensive imagery of resistivity beneath Taylor Valley. Regional-scale zones of low subsurface resistivity were detected that are inconsistent with the high resistivity of glacier ice or dry permafrost in this region. We interpret these results as an indication that liquid, with sufficiently high solute content, exists at temperatures well below freezing and considered within the range suitable for microbial life. These inferred brines are widespread within permafrost and extend below glaciers and lakes. One system emanates from below Taylor Glacier into Lake Bonney and a second system connects the ocean with the eastern 18 km of the valley. A connection between these two basins was not detected to the depth limitation of the AEM survey (∼350 m).

Differential contributions of intra-cellular and inter-cellular mechanisms to the spatial and temporal architecture of the suprachiasmatic nucleus circadian circuitry in wild-type, cryptochrome-null and vasoactive intestinal peptide receptor 2-null mutant mice.

To serve as a robust internal circadian clock, the cell-autonomous molecular and electrophysiological activities of the individual neurons of the mammalian suprachiasmatic nucleus (SCN) are coordinated in time and neuroanatomical space. Although the contributions of the chemical and electrical interconnections between neurons are essential to this circuit-level orchestration, the features upon which they operate to confer robustness to the ensemble signal are not known. To address this, we applied several methods to deconstruct the interactions between the spatial and temporal organisation of circadian oscillations in organotypic slices from mice with circadian abnormalities. We studied the SCN of mice lacking Cryptochrome genes (Cry1 and Cry2), which are essential for cell-autonomous oscillation, and the SCN of mice lacking the vasoactive intestinal peptide receptor 2 (VPAC2-null), which is necessary for circuit-level integration, in order to map biological mechanisms to the revealed oscillatory features. The SCN of wild-type mice showed a strong link between the temporal rhythm of the bioluminescence profiles of PER2::LUC and regularly repeated spatially organised oscillation. The Cry-null SCN had stable spatial organisation but lacked temporal organisation, whereas in VPAC2-null SCN some specimens exhibited temporal organisation in the absence of spatial organisation. The results indicated that spatial and temporal organisation were separable, that they may have different mechanistic origins (cell-autonomous vs. interneuronal signaling) and that both were necessary to maintain robust and organised circadian rhythms throughout the SCN. This study therefore provided evidence that the coherent emergent properties of the neuronal circuitry, revealed in the spatially organised clusters, were essential to the pacemaking function of the SCN.

Unscheduled undergraduate teaching in surgery: a multi-institutional analysis.

A significant amount of valuable undergraduate medical teaching may be informal, unscheduled and delivered by non-consultant hospital doctors (NCHDs). 800 Questionnaires were distributed to consultants, NCHDs and medical students in Irish teaching hospitals. The aim was to quantify the level of unscheduled teaching carried out in these hospitals and the manner in which it was performed. The response rate was 46% (364/800). 71% of doctors who replied are independently teaching undergraduate medical students (77/109), including 71% of interns and senior house officers (48/68). Students tend to prefer small group teaching. Fifty-six percent of students suggest they would benefit from more surgical teaching time (144/255). No interns surveyed were scheduled to teach as part of a formal curriculum. A significant amount of unscheduled teaching by interns and senior house officers takes place in Irish hospitals. It may prove beneficial to incorporate interns into scheduled surgical teaching curricula.

Succinate is an inflammatory signal that induces IL-1ß through HIF-1α.

Macrophages activated by the Gram-negative bacterial product lipopolysaccharide switch their core metabolism from oxidative phosphorylation to glycolysis. Here we show that inhibition of glycolysis with 2-deoxyglucose suppresses lipopolysaccharide-induced interleukin-1ß but not tumour-necrosis factor-α in mouse macrophages. A comprehensive metabolic map of lipopolysaccharide-activated macrophages shows upregulation of glycolytic and downregulation of mitochondrial genes, which correlates directly with the expression profiles of altered metabolites. Lipopolysaccharide strongly increases the levels of the tricarboxylic-acid cycle intermediate succinate. Glutamine-dependent anerplerosis is the principal source of succinate, although the 'GABA (γ-aminobutyric acid) shunt' pathway also has a role. Lipopolysaccharide-induced succinate stabilizes hypoxia-inducible factor-1α, an effect that is inhibited by 2-deoxyglucose, with interleukin-1ß as an important target. Lipopolysaccharide also increases succinylation of several proteins. We therefore identify succinate as a metabolite in innate immune signalling, which enhances interleukin-1ß production during inflammation.

Modulation of neuroblastoma disease pathogenesis by an extensive network of epigenetically regulated microRNAs.

MicroRNAs (miRNAs) contribute to the pathogenesis of many forms of cancer, including the pediatric cancer neuroblastoma, but the underlying mechanisms leading to altered miRNA expression are often unknown. Here, a novel integrated approach for analyzing DNA methylation coupled with miRNA and mRNA expression data sets identified 67 epigenetically regulated miRNA in neuroblastoma. A large proportion (42%) of these miRNAs was associated with poor patient survival when underexpressed in tumors. Moreover, we demonstrate that this panel of epigenetically silenced miRNAs targets a large set of genes that are overexpressed in tumors from patients with poor survival in a highly redundant manner. The genes targeted by the epigenetically regulated miRNAs are enriched for a number of biological processes, including regulation of cell differentiation. Functional studies involving ectopic overexpression of several of the epigenetically silenced miRNAs had a negative impact on neuroblastoma cell viability, providing further support to the concept that inactivation of these miRNAs is important for neuroblastoma disease pathogenesis. One locus, miR-340, induced either differentiation or apoptosis in a cell context dependent manner, indicating a tumor suppressive function for this miRNA. Intriguingly, it was determined that miR-340 is upregulated by demethylation of an upstream genomic region that occurs during the process of neuroblastoma cell differentiation induced by all-trans retinoic acid (ATRA). Further biological studies of miR-340 revealed that it directly represses the SOX2 transcription factor by targeting of its 3'-untranslated region, explaining the mechanism by which SOX2 is downregulated by ATRA. Although SOX2 contributes to the maintenance of stem cells in an undifferentiated state, we demonstrate that miR-340-mediated downregulation of SOX2 is not required for ATRA induced differentiation to occur. In summary, our results exemplify the dynamic nature of the miRNA epigenome and identify a remarkable network of miRNA/mRNA interactions that significantly contribute to neuroblastoma disease pathogenesis.

Hombro doloroso hemipléjico en pacientes con ictus: causas y manejo / Painful hemiplegic shoulder in stroke patients: causes and management

Introducción: El hombro doloroso hemipléjico es frecuente después de un ictus. Su aparición conlleva además del dolor, una limitación para las actividades de la vida diaria, así como para la participación en programas específicos de neurorrehabilitación. Todo este conjunto determina un peor resultado funcional. El buen manejo de los pacientes puede reducir tanto la frecuencia de aparición de hombro doloroso, como la intensidad del mismo, mejorando así el pronóstico funcional.Desarrollo: Entre los años 1980 y 2008 se llevó a cabo una búsqueda de la literatura en diferentes bases de datos. La evaluación de los artículos se realizó con el sistema de puntuación PEDro. Se establecieron 5 niveles de evidencia para obtener las conclusiones.Conclusiones: La subluxación del hombro, ocurre de manera precoz tras el ictus y se asocia con subluxación de la articulación del hombro y con espasticidad (subescapular y pectoral mayor principalmente). Los cabestrillos previenen la subluxación del hombro. Es preferible realizar movimientos con un menor rango de movimiento y sin agresividad, para evitar la aparición del hombro doloroso. La inyección de corticoides no mejora el dolor ni el rango de movimiento de los pacientes hemipléjicos, mientras que la toxina botulínica combinada con fisioterapia parece reducir el dolor del hombro hemipléjico (AU)

Introduction: The hemiplegic shoulder pain is common after a stroke. Its appearance brings pain and limits daily living activities as well as participation in specific Neuro-rehabilitation programs. All this leads to a worse functional outcome. Good management of patients can reduce both the frequency and intensity of shoulder pain, improving functional outcome.Development: We conducted a literature search of various databases between 1980 and 2008. The articles were evaluated using the PEDro scoring system. Five evidence levels were established for the conclusions.Conclusions: Shoulder subluxation, occurs at an early stage after stroke and is associated with subluxation of the shoulder joint and spasticity (mainly subscapularis and pectoralis). Slings prevent subluxation of the shoulder. It is preferable to move within a lower range of motion and without aggression to prevent the occurrence of shoulder pain. The injection of corticosteroids does not improve pain and range of motion in hemiplegic patients, while botulinum toxin combined with physical therapy appears to reduce hemiplegic shoulder pain (AU)

Assessing the impact of thrombolysis on progress through inpatient rehabilitation after stroke: a multivariable approach.

BACKGROUND: Acute administration of tissue plasminogen activator has been shown to improve immediate and long-term patient recovery after ischaemic stroke. Yet, despite widespread clinical application, many patients who receive acute tissue plasminogen activator still require inpatient rehabilitation. AIMS AND HYPOTHESIS: This study aimed to examine the effect of tissue plasminogen activator administration on recovery among patients requiring inpatient rehabilitation after stroke in Ontario, Canada. It was hypothesized that after covariate adjustment, administration of tissue plasminogen activator would be associated with accelerated progress through inpatient rehabilitation. METHODS: Acute and rehabilitation data were retrieved from the Registry of the Canadian Stroke Network and the National Rehabilitation Reporting System for all ischaemic stroke patients admitted to an acute facility and a rehabilitation unit between July 1, 2003 and March 31, 2008. Patients were divided into two groups: those who received tissue plasminogen activator and those who were medically eligible but did not receive tissue plasminogen activator. Three rehabilitation progress indicators were compared between groups: Functional Independence Measure gain, active length of stay, and discharge destination. Indicators were modelled using multivariable generalized linear models or logistic regression as appropriate. RESULTS: Patients who received tissue plasminogen activator experienced shorter active lengths of stay (log estimate ± standard error: -0·04 ± 0·01 days), and were slightly more likely to be discharged home compared to controls (adjusted odds ratio 1·35, 95% confidence interval 1·004-1·82). No differences were noted on Functional Independence Measure gain during rehabilitation. CONCLUSION: Results suggest that tissue plasminogen activator may contribute to accelerated progress through inpatient rehabilitation; however, there is no evidence to suggest that it contributes to greater functional improvement as measured by the Functional Independence Measure.

[Painful hemiplegic shoulder in stroke patients: causes and management]. / Hombro doloroso hemipléjico en pacientes con ictus: causas y manejo.

INTRODUCTION: The hemiplegic shoulder pain is common after a stroke. Its appearance brings pain and limits daily living activities as well as participation in specific Neuro-rehabilitation programs. All this leads to a worse functional outcome. Good management of patients can reduce both the frequency and intensity of shoulder pain, improving functional outcome. DEVELOPMENT: We conducted a literature search of various databases between 1980 and 2008. The articles were evaluated using the PEDro scoring system. Five evidence levels were established for the conclusions. CONCLUSIONS: Shoulder subluxation, occurs at an early stage after stroke and is associated with subluxation of the shoulder joint and spasticity (mainly subscapularis and pectoralis). Slings prevent subluxation of the shoulder. It is preferable to move within a lower range of motion and without aggression to prevent the occurrence of shoulder pain. The injection of corticosteroids does not improve pain and range of motion in hemiplegic patients, while botulinum toxin combined with physical therapy appears to reduce hemiplegic shoulder pain.

MicroRNAs 10a and 10b are potent inducers of neuroblastoma cell differentiation through targeting of nuclear receptor corepressor 2.

MicroRNAs function as negative regulators of posttranscriptional gene expression, having major roles in cellular differentiation. Several neuroblastoma cell lines can be induced to undergo differentiation by all-trans-retinoic acid (ATRA) and are used for modeling signaling pathways involved in this process. To identify miRNAs contributing to differentiation, we profiled 364 loci following ATRA treatment of neuroblastoma cell lines and found miR-10a and miR-10b to be highly overexpressed in SK-N-BE, LAN5 and SHSY-5Y. Ectopic overexpression of these miRNAs led to a major reprogramming of the transcriptome and a differentiated phenotype that was similar to that induced by ATRA in each of these cell lines. One of the predicted downregulated miR-10a/b targets was nuclear receptor corepressor 2 (NCOR2), a corepressor of gene transcription, which is known to suppress neurite outgrowth. NCOR2 was experimentally validated as a direct target of miR-10a/b, and siRNA-mediated inhibition of this mRNA alone resulted in neural cell differentiation. Moreover, induction of differentiation could be blocked by ectopic upregulation of NCOR2 using an expression construct lacking the miR-10a/b 3' untranslated region target site. We conclude that miR-10a/b has major roles in the process of neural cell differentiation through direct targeting of NCOR2, which in turn induces a cascade of primary and secondary transcriptional alterations, including the downregulation of MYCN.

Does the treatment of spastic equinovarus deformity following stroke with botulinum toxin increase gait velocity? A systematic review and meta-analysis.

While botulinum toxin-A (BT-A) has been used to treat lower-limb focal spasticity successfully, its effect on characteristics of gait has not been well defined. The objective of this systematic review was to establish the treatment effect associated with the use of BT-A for equinovarus to improve gait velocity following stroke, using a meta-analytic technique. Relevant studies were identified through a literature search encompassing the years 1985 to November 2009. Studies were included if (i) the sample was composed of adult subjects recovering from either first or subsequent stroke, presenting with spastic equinovarus deformity of the ankle preventing full active dorsiflexion, and (ii) subjects who received BT-A were compared with subjects who had received a placebo, or (iii) in the absence of a placebo-controlled condition, subject had received BT-A and was assessed before and after treatment. A standardized mean difference (SMD) ± standard error and 95% confidence interval (CI) for gait velocity between the treatment and control group was calculated for each study, using Hedges's g, and the results pooled. Eight trials, five randomized controlled trials, and three single group intervention studies were included. Data representing 228 subjects were available for pooled analysis. Treatment with BT-A was associated with a small improvement in gait velocity (Hedge's g = 0.193 ± 0.081; 95% CI: 0.033 to 0.353, P < 0.018) representing an increase of 0.044 meters/s. The use of BT-A for lower-limb post-stroke equinovarus because of spasticity was associated with a small, but statistically significant increase in gait velocity.