Matrigel modulates a stem cell phenotype and promotes tumor cell formation in a mantle cell lymphoma cell line

Tumors may be maintained by subpopulations of cells possessing stem cell-like properties. We evaluated the stem cell-like and tumor-forming properties of side population (SP) and CD133+/ CD44+ cells in Granta 519, a human mantle cell lymphoma cell line. The in-vitro Cobblestone Area Forming Cell (CAFC) assay, designed to detect stem and progenitor cells, revealed that SP cells contained the greatest proportion of stem cell-like cells. The addition of Matrigel to CAFC assays of SP and non-SP cells both increased their respective stem cell frequencies in comparison to those cultures without Matrigel, and additionally resulted in observed stem cell frequencies which were the same between SP and non-SP cells. Contrary, Matrigel decreased the stem cell frequencies of CD133+/CD44+ or CD133-/CD44- cells. In-vivo assays revealed tumor formation from Matrigel-mixed SP and non-SP cells, and in one instance, occurred with as few as one Matrigel-mixed SP cell. Vehicle-mixed injections of SP and non-SP tumor cells resulted in tumor formation from SP cells only. Tumor formation did not occur from Matrigel nor hyaluronan (cellular substrate for CD44-expressing cells)-mixed populations of CD133+/CD44+ or CD133-/CD44- cells. These data demonstrate that Matrigel modulates a stem cell phenotype and promotes tumor formation from SP and non-SP cells. The tumor micro-environmental niche and tumor cell to micro-environmental interactions may be important future targets for novel chemotherapeutic agent

Surgical therapy for atrial tachycardia in adults

AbstractEighteen adult patients with atrial tachycardia refractory to treatment with a mean of four drugs underwent attempted surgical cure. Atrial tachycardia originated in the right atrium in 17 patients and the left atrium in 1 patient. Tachycardia could be reproducibly induced and terminated by atrial extrastimuli or atrial pacing in 8 patients (44%). Resection of the arrhythmogenic area was performed in 16 patients (89%), and an isolation procedure was performed in 1 patient. In seven cases (39%), the area of isolation or excision included the sinoatrial node. One patient underwent His bundle section because the arrhythmogenic region was too close to the atrioventricular (AV) conduction system to enable resection.The mean duration of clinical follow-up was 56 ± 34 months. Clinical tachycardia recurred in five patients (28%), but in two patients it did not recur until >1 year after surgery. A permanent pacemaker was implanted in 3 (18%) of the 17 patients whose His-Purkinje system was left intact. One other patient had required permanent pacing before surgery. Only one of the seven patients undergoing sinoatrial node resection or isolation required permanent pacing for symptomatic bradycardia. Apart from the requirement for permanent pacing, no significant complications occurred.Surgical therapy for atrialtachycardia is a safe procedure, but the rate of cure appears to be less than that of supraventricular tachycardias associated with accessory AV connections. Excision or isolation of the sinoatrial node does not necessitate permanent pacing in most patients

Narrowing the "digital divide" - facilitating access to computer technology to enhance the lives of those with aphasia: a feasibility study

Background: Despite advances in technology and the universal accessibility of the Internet, the aptly named “digital divide” still prevents equal access to, and use of, computer technology by people with aphasia. The use of technology has clear potential for improved quality of life in terms of increased methods for communicating as well as the facilitation of self-management; however, substantial barriers still pervade. Aims: The aims of this study were to evaluate a bespoke computer training course appropriate for people with aphasia and examine the personal experiences of a small sample of individuals with aphasia following their participation on the course. Methods & Procedures: This feasibility study with mixed-methods evaluation recruited participants with a range of aphasia severity and different experiences in using computers. Participants (n = 17) discussed their personal experiences of attending the computer course, gathered through topic-guided small focus groups, immediately postcourse and follow-up Refresher class. A Framework Method approach was considered an appropriate methodological design and data were analysed using thematic analysis. Participants also self-rated their skills in using computers before and following this bespoke computer course (n = 16) and at follow-up (n = 10), which was statistically analysed. Outcomes & Results: Statistically significant differences were found in the improved self-rated ability of a range of computer skills following course attendance. However, participants who attended a Refresher class (5, 9, or 12 months following course completion) reported that without support a number of these skills had notably declined. Three main themes emerged from the focus group data: (i) Facilitation of Social Engagement—technology offered new opportunities to communicate and more independently self-manage day-to-day tasks; (ii) Course Framework—participants reflected on their preferred model of delivery of the course; and finally (iii) Overcoming Barriers to Technology—the advantages of bespoke computer training, and requirements for ongoing support were highlighted as essential components of a training course appropriate for people with aphasia. Conclusions: The personal experiences of this group of people with aphasia highlight the advantages of accessing technology as a way of facilitating increased communication and an enhanced ability to manage their day-to-day lives. Yet, despite these benefits and the necessity for many people with aphasia to learn or relearn computer skills, finding courses that can accommodate individual needs is problematic. This research highlights the need for bespoke computer training and follow-on support, and highlights the necessary components of such training as identified by this group of people with aphasia

Improved Therapy for Medulloblastoma: Targeting Hedgehog and PI3K-mTOR Signaling Pathways in Combination with Chemotherapy

Aberrant activation and interactions of hedgehog (HH) and PI3K/AKT/mTOR signaling pathways are frequently associated with high-risk medulloblastoma (MB). Thus, combined targeting of the HH and PI3K/AKT/mTOR pathways could be a viable therapeutic strategy to treat high-risk patients. Therefore, we investigated the anti-MB efficacies of combined HH inhibitor Vismodegib and PI3K-mTOR dual-inhibitor BEZ235 together or combined individually with cisplatin against high-risk MB. Using non-MYC- and MYC-amplified cell lines, and a xenograft mouse model, the in vitro and in vivo efficacies of these therapies on cell growth/survival and associated molecular mechanism(s) were investigated. Results showed that combined treatment of Vismodegib and BEZ235 together, or with cisplatin, significantly decreased MB cell growth/survival in a dose-dependent-fashion. Corresponding changes in the expression of targeted molecules following therapy were observed. Results demonstrated that inhibitors not only suppressed MB cell growth/survival when combined, but also significantly enhanced cisplatin-mediated cytotoxicity. Of these combinations, BEZ235 exhibited a significantly greater efficacy in enhancing cisplatin-mediated MB cytotoxicity. Results also demonstrated that the MYC-amplified MB lines showed a higher sensitivity to combined therapies compared to non-MYC-amplified cell lines. Therefore, we tested the efficacy of combined approaches against MYC-amplified MB growing in NSG mice. In vivo results showed that combination of Vismodegib and BEZ235 or their combination with cisplatin, significantly delayed MB tumor growth and increased survival of xenografted mice by targeting HH and mTOR pathways. Thus, our studies lay a foundation for translating these combined therapeutic strategies to the clinical setting to determine their efficacies in high-risk MB patients

RApid Primary care Initiation of Drug treatment for Transient Ischaemic Attack (RAPID-TIA): study protocol for a pilot randomised controlled trial.

BACKGROUND: People who have a transient ischaemic attack (TIA) or minor stroke are at high risk of a recurrent stroke, particularly in the first week after the event. Early initiation of secondary prevention drugs is associated with an 80% reduction in risk of stroke recurrence. This raises the question as to whether these drugs should be given before being seen by a specialist--that is, in primary care or in the emergency department. The aims of the RAPID-TIA pilot trial are to determine the feasibility of a randomised controlled trial, to analyse cost effectiveness and to ask: Should general practitioners and emergency doctors (primary care physicians) initiate secondary preventative measures in addition to aspirin in people they see with suspected TIA or minor stroke at the time of referral to a specialist? METHODS/DESIGN: This is a pilot randomised controlled trial with a sub-study of accuracy of primary care physician diagnosis of TIA. In the pilot trial, we aim to recruit 100 patients from 30 general practices (including out-of-hours general practice centres) and 1 emergency department whom the primary care physician diagnoses with TIA or minor stroke and randomly assign them to usual care (that is, initiation of aspirin and referral to a TIA clinic) or usual care plus additional early initiation of secondary prevention drugs (a blood-pressure lowering protocol, simvastatin 40 mg and dipyridamole 200 mg m/r bd). The primary outcome of the main study will be the number of strokes at 90 days. The diagnostic accuracy sub-study will include these 100 patients and an additional 70 patients in whom the primary care physician thinks the diagnosis of TIA is possible, rather than probable. For the pilot trial, we will report recruitment rate, follow-up rate, a preliminary estimate of the primary event rate and occurrence of any adverse events. For the diagnostic study, we will calculate sensitivity and specificity of primary care physician diagnosis using the final TIA clinic diagnosis as the reference standard. DISCUSSION: This pilot study will be used to estimate key parameters that are needed to design the main study and to estimate the accuracy of primary care diagnosis of TIA. The planned follow-on trial will have important implications for the initial management of people with suspected TIA. TRIAL REGISTRATION: ISRCTN62019087.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

Prevalence of Neuroradiological Abnormalities in First-Episode Psychosis: A Systematic Review and Meta-analysis

IMPORTANCE: Individuals presenting with first-episode psychosis (FEP) may have a secondary ("organic") etiology to their symptoms that can be identified using neuroimaging. Because failure to detect such cases at an early stage can have serious clinical consequences, it has been suggested that brain magnetic resonance imaging (MRI) should be mandatory for all patients presenting with FEP. However, this remains a controversial issue, partly because the prevalence of clinically relevant MRI abnormalities in this group is unclear. OBJECTIVE: To derive a meta-analytic estimate of the prevalence of clinically relevant neuroradiological abnormalities in FEP. DATA SOURCES: Electronic databases Ovid, MEDLINE, PubMed, Embase, PsychINFO, and Global Health were searched up to July 2021. References and citations of included articles and review articles were also searched. STUDY SELECTION: Magnetic resonance imaging studies of patients with FEP were included if they reported the frequency of intracranial radiological abnormalities. DATA EXTRACTION AND SYNTHESIS: Independent extraction was undertaken by 3 researchers and a random-effects meta-analysis of pooled proportions was calculated. Moderators were tested using subgroup and meta-regression analyses. Heterogeneity was evaluated using the I2 index. The robustness of results was evaluated using sensitivity analyses. Publication bias was assessed using funnel plots and Egger tests. MAIN OUTCOMES AND MEASURES: Proportion of patients with a clinically relevant radiological abnormality (defined as a change in clinical management or diagnosis); number of patients needed to scan to detect 1 such abnormality (number needed to assess [NNA]). RESULTS: Twelve independent studies (13 samples) comprising 1613 patients with FEP were included. Of these patients, 26.4% (95% CI, 16.3%-37.9%; NNA of 4) had an intracranial radiological abnormality, and 5.9% (95% CI, 3.2%-9.0%) had a clinically relevant abnormality, yielding an NNA of 18. There were high degrees of heterogeneity among the studies for these outcomes, 95% to 73%, respectively. The most common type of clinically relevant finding was white matter abnormalities, with a prevalence of 0.9% (95% CI, 0%-2.8%), followed by cysts, with a prevalence of 0.5% (95% CI, 0%-1.4%). CONCLUSIONS AND RELEVANCE: This systematic review and meta-analysis found that 5.9% of patients presenting with a first episode of psychosis had a clinically relevant finding on MRI. Because the consequences of not detecting these abnormalities can be serious, these findings support the use of MRI as part of the initial clinical assessment of all patients with FEP

Inter-rater reliability of the Dysexecutive Questionnaire (DEX): comparative data from non-clinician respondents – all raters are not equal

Primary objective: The Dysexecutive Questionnaire (DEX) is used to obtain information about executive and emotional problems after neuropathology. The DEX is self-completed by the patient (DEX-S) and an independent rater such as a family member (DEX-I). This study examined the level of inter-rater agreement between either two or three non-clinician raters on the DEX-I in order to establish the reliability of DEX-I ratings. Methods and procedures: Family members and/or carers of 60 people with mixed neuropathology completed the DEX-I. For each patient, DEX-I ratings were obtained from either two or three raters who knew the person well prior to brain injury. Main outcomes and results: We obtained two independent-ratings for 60 patients and three independent-ratings for 36 patients. Intra-class correlations revealed that there was only a modest level of agreement for items, subscale and total DEX scores between raters for their particular family member. Several individual DEX items had low reliability and ratings for the emotion sub-scale had the lowest level of agreement. Conclusions: Independent DEX ratings completed by two or more non-clinician raters show only moderate correlation. Suggestions are made for improving the reliability of DEX-I ratings.</p

Assembling places and persons: a tenth-century Viking boat burial from Swordle Bay on the Ardnamurchan peninsula, western Scotland

A rare, intact Viking boat burial in western Scotland contained a rich assemblage of grave goods, providing clues to the identity and origins of both the interred individual and the people who gathered to create the site. The burial evokes the mundane and the exotic, past and present, as well as local, national and international identities. Isotopic analysis of the teeth hints at a possible Scandinavian origin for the deceased, while Scottish, Irish and Scandinavian connections are attested by the grave goods. Weapons indicate a warrior of high status; other objects imply connections to daily life, cooking and work, farming and food production. The burial site is itself rich in symbolic associations, being close to a Neolithic burial cairn, the stones of which may have been incorporated into the grave

Spatial organisation of groundwater dynamics and streamflow response from different hydropedological units in a montane catchment

Funding was provided by the Leibniz Association (SAW-2012-IGB 4167) within the International Leibniz Graduate School: Aquatic boundaries and linkages- Aqualink. We would like to thank the NRI staff for their help during field work.Peer reviewedPostprin