An investigation of minimisation criteria

Minimisation can be used within treatment trials to ensure that prognostic factors are evenly distributed between treatment groups. The technique is relatively straightforward to apply but does require running tallies of patient recruitments to be made and some simple calculations to be performed prior to each allocation. As computing facilities have become more widely available, minimisation has become a more feasible option for many. Although the technique has increased in popularity, the mode of application is often poorly reported and the choice of input parameters not justified in any logical way

Decreased functional connectivity within a language subnetwork in benign epilepsy with centrotemporal spikes.

OBJECTIVE: Benign epilepsy with centrotemporal spikes (BECTS, also known as Rolandic epilepsy) is a common epilepsy syndrome that is associated with literacy and language impairments. The neural mechanisms of the syndrome are not known. The primary objective of this study was to test the hypothesis that functional connectivity within the language network is decreased in children with BECTS. We also tested the hypothesis that siblings of children with BECTS have similar abnormalities. METHODS: Echo planar magnetic resonance (MR) imaging data were acquired from 25 children with BECTS, 12 siblings, and 20 healthy controls, at rest. After preprocessing with particular attention to intrascan motion, the mean signal was extracted from each of 90 regions of interest. Sparse, undirected graphs were constructed from adjacency matrices consisting of Spearman's rank correlation coefficients. Global and nodal graph metrics and subnetwork and pairwise connectivity were compared between groups. RESULTS: There were no significant differences in graph metrics between groups. Children with BECTS had decreased functional connectivity relative to controls within a four-node subnetwork, which consisted of the left inferior frontal gyrus, the left superior frontal gyrus, the left supramarginal gyrus, and the right inferior parietal lobe (p = 0.04). A similar but nonsignificant decrease was also observed for the siblings. The BECTS groups had significant increases in connectivity within a five-node, five-edge frontal subnetwork. SIGNIFICANCE: The results provide further evidence of decreased functional connectivity between key mediators of speech processing, language, and reading in children with BECTS. We hypothesize that these decreases reflect delayed lateralization of the language network and contribute to specific cognitive impairments

Human α2β1HI CD133+VE epithelial prostate stem cells express low levels of active androgen receptor

Stem cells are thought to be the cell of origin in malignant transformation in many tissues, but their role in human prostate carcinogenesis continues to be debated. One of the conflicts with this model is that cancer stem cells have been described to lack androgen receptor (AR) expression, which is of established importance in prostate cancer initiation and progression. We re-examined the expression patterns of AR within adult prostate epithelial differentiation using an optimised sensitive and specific approach examining transcript, protein and AR regulated gene expression. Highly enriched populations were isolated consisting of stem (α(2)β(1)(HI) CD133(+VE)), transiently amplifying (α(2)β(1)(HI) CD133(-VE)) and terminally differentiated (α(2)β(1)(LOW) CD133(-VE)) cells. AR transcript and protein expression was confirmed in α(2)β(1)(HI) CD133(+VE) and CD133(-VE) progenitor cells. Flow cytometry confirmed that median (±SD) fraction of cells expressing AR were 77% (±6%) in α(2)β(1)(HI) CD133(+VE) stem cells and 68% (±12%) in α(2)β(1)(HI) CD133(-VE) transiently amplifying cells. However, 3-fold lower levels of total AR protein expression (peak and median immunofluorescence) were present in α(2)β(1)(HI) CD133(+VE) stem cells compared with differentiated cells. This finding was confirmed with dual immunostaining of prostate sections for AR and CD133, which again demonstrated low levels of AR within basal CD133(+VE) cells. Activity of the AR was confirmed in prostate progenitor cells by the expression of low levels of the AR regulated genes PSA, KLK2 and TMPRSS2. The confirmation of AR expression in prostate progenitor cells allows integration of the cancer stem cell theory with the established models of prostate cancer initiation based on a functional AR. Further study of specific AR functions in prostate stem and differentiated cells may highlight novel mechanisms of prostate homeostasis and insights into tumourigenesis

Eosinophilic and neutrophilic leukemoid reaction in a woman with spindle cell sarcoma: a case report

<p>Abstract</p> <p>Introduction</p> <p>We report a case of a patient with marked eosinophilia and neutrophilia as a manifestation of a spindle cell sarcoma.</p> <p>Case presentation</p> <p>A 41-year-old African American woman presented with an enlarging, painful mass in her right knee area. Four years previously, she had had a mass similar to this diagnosed as an osteosarcoma, and had undergone a radical resection and hinge-knee replacement. Before the surgery, she was treated with neoadjuvant docetaxel and gemcitabine. A biopsy was taken from the recurrent mass, and histological examination revealed high-grade soft-tissue sarcoma. The patient received no further treatment. Complete blood counts revealed a white blood cell (WBC) count of 13.6 to 17.9 × 10⁹/L, with neutrophils being 8.2 to 10.9 × 10⁹/L and eosinophils 1.8 to 1.9 × 10⁹/L. At readmission six months later, WBC was 126.7 × 10⁹/L, with neutrophils being 57.02 × 10⁹/L and eosinophils 60.82 × 10⁹/L. The eosinophils peaked at 77.79 × 10⁹/L two days later. Evaluations for allergies, infection, and autoimmune mechanisms were negative. Bone marrow revealed increased eosinophils without blasts. After resection, blood counts abruptly decreased to the normal range. Pathology confirmed high-grade spindle cell sarcoma. Approximately one year after resection, the patient was readmitted with metastatic disease to her lungs. During this presentation, her eosinophil and neutrophil count was again increased. WBC was 107.8 × 10⁹/L, with eosinophil count of 47.43 × 10⁹/L and neutrophil count of 44.10 × 10⁹/L. Interleukin-5 was normal, and granulocyte–macrophage colony-stimulating factor (GM-CSF) was elevated at 208.8 (normal < 4.8).</p> <p>Conclusion</p> <p>In our case, the patient had eosinophilia and neutrophilia associated with a spindle cell sarcoma, possibly representing a paraneoplastic syndrome secondary to GM-CSF. There were no signs of infectious, allergic, or autoimmune causes for the eosinophilia or neutrophilia. Even though the occurrence of eosinophilia and neutrophilia with malignancy is rare, patients who have either condition without an apparent cause should be checked for malignancy.</p

Weight-loss intervention using implementation intentions and mental imagery: A randomised control trial study protocol

Background: Overweight and obesity are major health problems worldwide. This protocol describes the HEALTHI (Healthy Eating and Active LifesTyle Health Intervention) Program, a 12-week randomised-controlled weight-loss intervention that adopts two theory-based intervention techniques, mental imagery and implementation intentions, a behaviour-change technique based on planning that have been shown to be effective in promoting health-behaviour change in previous research. The effectiveness of goal-reminder text messages to augment intervention effects will also be tested. The trial will determine the effects of a brief, low cost, theory-based weight-loss intervention to improve dietary intake and physical activity behaviour and facilitate weight-loss in overweight and obese individuals. Methods/Design: Overweight or obese participants will be randomly allocated to one of three conditions: (1) a psycho-education plus an implementation intentions and mental imagery condition; (2) a psycho-education plus an implementation intentions and mental imagery condition with text messages; or (3) a psycho-education control condition. The intervention will be delivered via video presentation to increase the intervention's applicability in multiple contexts and keep costs low. We hypothesise that the intervention conditions will lead to statistically-significant changes in the primary and secondary outcome variables measured at 6 and 12 weeks post-intervention relative to the psycho-education control condition after controlling for baseline values. The primary outcome variable will be body weight and secondary outcome variables will be biomedical (body mass, body fat percentage, muscle mass, waist-hip circumference ratio, systolic and diastolic blood pressure, low-density lipoprotein, high-density lipoprotein, total cholesterol, triglycerides, blood glucose and insulin levels), psychological (quality of life, motivation, risk perception, outcome expectancy, intention, action self-efficacy, maintenance self-efficacy, goal setting and planning), and behavioural (self-reported diet intake, and physical activity involvement) measures. We also expect the intervention condition augmented with text messages to lead to statistically significant differences in the primary and secondary outcome variables at the follow up periods after controlling for baseline values. Discussion: The planned trial will test the effectiveness of the theory-based HEALTHI program intervention to reduce weight and salient psychological, biomedical, and behavioural outcomes in overweight and obese adults. The study has been designed to maximise applicability to real world settings and could be integrated into existing weight management practices

Deriving a mutation index of carcinogenicity using protein structure and protein interfaces

With the advent of Next Generation Sequencing the identification of mutations in the genomes of healthy and diseased tissues has become commonplace. While much progress has been made to elucidate the aetiology of disease processes in cancer, the contributions to disease that many individual mutations make remain to be characterised and their downstream consequences on cancer phenotypes remain to be understood. Missense mutations commonly occur in cancers and their consequences remain challenging to predict. However, this knowledge is becoming more vital, for both assessing disease progression and for stratifying drug treatment regimes. Coupled with structural data, comprehensive genomic databases of mutations such as the 1000 Genomes project and COSMIC give an opportunity to investigate general principles of how cancer mutations disrupt proteins and their interactions at the molecular and network level. We describe a comprehensive comparison of cancer and neutral missense mutations; by combining features derived from structural and interface properties we have developed a carcinogenicity predictor, InCa (Index of Carcinogenicity). Upon comparison with other methods, we observe that InCa can predict mutations that might not be detected by other methods. We also discuss general limitations shared by all predictors that attempt to predict driver mutations and discuss how this could impact high-throughput predictions. A web interface to a server implementation is publicly available at http://inca.icr.ac.uk/

Decreased functional connectivity within a language subnetwork in benign epilepsy with centrotemporal spikes

Objective: Benign epilepsy with centrotemporal spikes (BECTS, also known as Rolandic epilepsy) is a common epilepsy syndrome that is associated with literacy and language impairments. The neural mechanisms of the syndrome are not known. The primary objective of this study was to test the hypothesis that functional connectivity within the language network is decreased in children with BECTS. We also tested the hypothesis that siblings of children with BECTS have similar abnormalities. Methods: Echo planar magnetic resonance (MR) imaging data were acquired from 25 children with BECTS, 12 siblings, and 20 healthy controls, at rest. After preprocessing with particular attention to intrascan motion, the mean signal was extracted from each of 90 regions of interest. Sparse, undirected graphs were constructed from adjacency matrices consisting of Spearman's rank correlation coefficients. Global and nodal graph metrics and subnetwork and pairwise connectivity were compared between groups. Results: There were no significant differences in graph metrics between groups. Children with BECTS had decreased functional connectivity relative to controls within a four‐node subnetwork, which consisted of the left inferior frontal gyrus, the left superior frontal gyrus, the left supramarginal gyrus, and the right inferior parietal lobe (p = 0.04). A similar but nonsignificant decrease was also observed for the siblings. The BECTS groups had significant increases in connectivity within a five‐node, five‐edge frontal subnetwork. Significance: The results provide further evidence of decreased functional connectivity between key mediators of speech processing, language, and reading in children with BECTS. We hypothesize that these decreases reflect delayed lateralization of the language network and contribute to specific cognitive impairments

Changes in the flexion-relaxation response induced by hip extensor and erector spinae muscle fatigue

<p>Abstract</p> <p>Background</p> <p>The flexion-relaxation phenomenon (FRP) is defined by reduced lumbar erector spinae (ES) muscle myoelectric activity during full trunk flexion. The objectives of this study were to quantify the effect of hip and back extensor muscle fatigue on FRP parameters and lumbopelvic kinematics.</p> <p>Methods</p> <p>Twenty-seven healthy adults performed flexion-extension tasks under 4 different experimental conditions: no fatigue/no load, no fatigue/load, fatigue/no load, and fatigue/load. Total flexion angle corresponding to the onset and cessation of myoelectric silence, hip flexion angle, lumbar flexion angle and maximal trunk flexion angle were compared across different experimental conditions by 2 × 2 (Load × Fatigue) repeated-measures ANOVA.</p> <p>Results</p> <p>The angle corresponding to the ES onset of myoelectric silence was reduced after the fatigue task, and loading the spine decreased the lumbar contribution to motion compared to the hip during both flexion and extension. A relative increment of lumbar spine motion compared to pelvic motion was also observed in fatigue conditions.</p> <p>Conclusions</p> <p>Previous results suggested that ES muscles, in a state of fatigue, are unable to provide sufficient segmental stabilization. The present findings indicate that, changes in lumbar-stabilizing mechanisms in the presence of muscle fatigue seem to be caused by modulation of lumbopelvic kinematics.</p

Anticancer Gene Transfer for Cancer Gene Therapy

Gene therapy vectors are among the treatments currently used to treat malignant tumors. Gene therapy vectors use a specific therapeutic transgene that causes death in cancer cells. In early attempts at gene therapy, therapeutic transgenes were driven by non-specific vectors which induced toxicity to normal cells in addition to the cancer cells. Recently, novel cancer specific viral vectors have been developed that target cancer cells leaving normal cells unharmed. Here we review such cancer specific gene therapy systems currently used in the treatment of cancer and discuss the major challenges and future directions in this field