Nodular lymphocyte predominant Hodgkin lymphoma behaves as a distinct clinical entity with good outcome: evidence from 14-year followup in the West of Scotland Cancer Network

Clinically and biologically, nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) has much more in common with germinal-center derived B-cell non-Hodgkin lymphoma (NHL) than with classical Hodgkin lymphoma (cHL). Management of NLPHL remains controversial. In a 14-year multicenter series, 69 cases were analyzed, and the median follow-up was 53 months (range 11–165.) B-symptoms were present in only 4.3% of patients, and 81.1% of patients had stage I/II disease. Treatment was with radiotherapy (53.6%), chemotherapy (21.7%), combined modality (17.4%), and observation (7.2%). In all, 10.1% of patients relapsed and 2.9% of patients developed high-grade transformation to DLBCL. All relapses and transformations were salvageable. No patient died of their disease. The 5-year relapse-free survival was 92%, transformation-free survival 98.4%, and overall survival 100%. We conclude that NLPHL behaves as a distinct clinical entity, often presenting at an early stage without risk factors. It has an excellent outcome. It may be possible, in early-stage disease, to reduce the intensity of therapy in NLPHL, to single-modality radiotherapy, without affecting OS

Trial protocol of an open label pilot study of lisdexamfetamine for the treatment of acute methamphetamine withdrawal

Introduction Methamphetamine (MA) use disorder is an important public health concern. MA withdrawal is often the first step in ceasing or reducing use. There are no evidence-based withdrawal treatments, and no medication is approved for the treatment of MA withdrawal. Lisdexamfetamine (LDX) dimesilate, used in the treatment of attention deficit hyperactivity disorder and binge eating disorder has the potential as an agonist therapy to ameliorate withdrawal symptoms, and improve outcomes for patients. Methods A single arm, open-label pilot study to test the safety and feasibility of LDX for the treatment of MA withdrawal. Participants will be inpatients in a drug and alcohol withdrawal unit, and will receive a tapering dose of LDX over five days: 250mg LDX on Day 1, reducing by 50mg per day to 50mg on Day 5. Optional inpatient Days 6 and 7 will allow for participants to transition to ongoing treatment. Participants will be followed-up on Days 14, 21 and 28. All participants will also receive standard inpatient withdrawal care. The primary outcomes are safety (measured by adverse events, changes in vital signs, changes in suicidality and psychosis) and feasibility (the time taken to enrol the sample, proportion of screen / pre-screen failures). Secondary outcomes are acceptability (treatment satisfaction questionnaire, medication adherence, concomitant medications, qualitative interviews), retention to protocol (proportion retained to primary and secondary endpoints), changes in withdrawal symptoms (Amphetamine Withdrawal Questionnaire) and craving for MA (visual analogue scale), and sleep outcomes (continuous actigraphy and daily sleep diary). Discussion This is the first study to assess lisdexamfetamine for the treatment of acute MA withdrawal. If safe and feasible results will go to informing the development of multi-centre randomised controlled trials to determine the efficacy of the intervention

Relative fat oxidation is higher in children than adults

Background: Prepubescent children may oxidize fatty acids more readily than adults. Therefore, dietary fat needs would be higher for children compared with adults. The dietary fat recommendations are higher for children 4 to 18 yrs (i.e., 25 to 35% of energy) compared with adults (i.e., 20 to 35% of energy). Despite this, many parents and children restrict dietary fat for health reasons. Methods: This study assessed whether rates of fat oxidation are similar between prepubescent children and adults. Ten children (8.7 ± 1.4 yr, 33 ± 13 kg mean ± SD) in Tanner stage 1 and 10 adults (41.6 ± 8 yr, 74 ± 13 kg) were fed a weight maintenance diet for three days to maintain body weight and to establish a consistent background for metabolic rate measurements (all foods provided). Metabolic rate was measured on three separate occasions before and immediately after breakfast and for 9 hrs using a hood system (twice) or a room calorimeter (once) where continuous metabolic measurements were taken. Results: During all three sessions whole body fat oxidation was higher in children (lower RQ) compared to adults (mean RQ= 0.84 ± .016 for children and 0.87 ± .02, for adults, p < 0.02). Although, total grams of fat oxidized was similar in children (62.7 ± 20 g/24 hrs) compared to adults (51.4 ± 19 g/24 hrs), the grams of fat oxidized relative to calorie expenditure was higher in children (0.047 ± .01 g/kcal, compared to adults (0.032 ± .01 p < 0.02). Females oxidized more fat relative to calorie expenditure than males of a similar age. A two way ANOVA showed no interaction between gender and age in terms of fax oxidation. Conclusion: These data suggest that fat oxidation relative to total calorie expenditure is higher in prepubescent children than in adults. Consistent with current dietary guidelines, a moderate fat diet is appropriate for children within the context of a diet that meets their energy and nutrient needs. Originally published Nutrition Journal, Vol. 6, No. 19, Aug 200

Clinically Translatable Cell Tracking and Quantification by MRI in Cartilage Repair Using Superparamagnetic Iron Oxides

Background: Articular cartilage has very limited intrinsic regenerative capacity, making cell-based therapy a tempting approach for cartilage repair. Cell tracking can be a major step towards unraveling and improving the repair process of these therapies. We studied superparamagnetic iron oxides (SPIO) for labeling human bone marrow-derived mesenchymal stem cells (hBMSCs) regarding effectivity, cell viability, long term metabolic cell activity, chondrogenic differentiation and hBMSC secretion profile. We additionally examined the capacity of synovial cells to endocytose SPIO from dead, labeled cells, together with the use of magnetic resonance imaging (MRI) for intra-articular visualization and quantification of SPIO labeled cells. Methodology/Prinicipal Findings: Efficacy and various safety aspects of SPIO cell labeling were determined using appropriate assays. Synovial SPIO re-uptake was investigated in vitro by co-labeling cells with SPIO and green fluorescent protein (GFP). MRI experiments were performed on a clinical 3.0T MRI scanner. Two cell-based cartilage repair techniques were mimicked for evaluating MRI traceability of labeled cells: intra-articular cell injection and cell implantation in cartilage defects. Cells were applied ex vivo or in vitro in an intra-articular environment and immediately scanned. SPIO labeling was effective and did not impair any of the studied safety aspects, including hBMSC secretion profile. SPIO from dead, labeled cells could be taken up by synovial cells. Both injected and implanted SPIO-labeled cells could accurately be visualized by MRI in a clinically relevant sized joint model using clinically applied cell doses. Finally, we quantified the amount of labeled cells seeded in cartilage defects using MR-based relaxometry. Conclusions: SPIO labeling appears to be safe without influencing cell behavior. SPIO labeled cells can be visualized in an intra-articular environment and quantified when seeded in cartilage defects.Biomechanical EngineeringMechanical, Maritime and Materials Engineerin

Supracervical hysterectomy versus total abdominal hysterectomy: perceived effects on sexual function

BACKGROUND: Our investigation sought to compare changes in sexual function following supracervical hysterectomy (SCH) and total abdominal hysterectomy (TAH). METHODS: A retrospective chart review was performed to identify all patients who underwent supracervical hysterectomy or total abdominal hysterectomy at a tertiary care center. Patients who met criteria for participation were sent a one page confidential, anonymous questionnaire to assess sexual function experienced both pre- and postoperatively. A total of 69 patients in each group were eligible for participation. A multiple logistic regression model was used to analyze measured variables. RESULTS: Forty-eight percent (n = 33) of women undergoing a SCH returned the questionnaire, while 39% (n = 27) of those undergoing a TAH chose to participate. There were no significant demographic differences between the two groups. Patients who underwent TAH reported worse postoperative sexual outcome than SCH patients with respect to intercourse frequency, orgasm frequency and overall sexual satisfaction (P = 0.01, 0.03, and 0.03, respectively). Irrespective of type of hysterectomy, 35% of patients who underwent bilateral salpingoophorectomy (BSO) with hysterectomy experienced worse overall sexual satisfaction compared to 3% of patients who underwent hysterectomy alone (P = 0.02). CONCLUSIONS: Our data suggest that TAH patients experienced worse postoperative sexual function than SCH patients with respect to intercourse frequency and overall sexual satisfaction. Irrespective of type of hysterectomy, patients who underwent bilateral salpingoophorectomy experienced worse overall sexual satisfaction

Methylation of HOXA9 and ISL1 predicts patient outcome in high-grade non-invasive bladder cancer

Introduction Inappropriate DNA methylation is frequently associated with human tumour development, and in specific cases, is associated with clinical outcomes. Previous reports of DNA methylation in low/intermediate grade non-muscle invasive bladder cancer (NMIBC) have suggested that specific patterns of DNA methylation may have a role as diagnostic or prognostic biomarkers. In view of the aggressive and clinically unpredictable nature of high-grade (HG) NMIBC, and the current shortage of the preferred treatment option (Bacillus:Calmette-Guerin), novel methylation analyses may similarly reveal biomarkers of disease outcome that could risk-stratify patients and guide clinical management at initial diagnosis. Methods Promoter-associated CpG island methylation was determined in primary tumour tissue of 36 initial presentation high-grade NMIBCs, 12 low/intermediate-grade NMIBCs and 3 normal bladder controls. The genes HOXA9, ISL1, NKX6-2, SPAG6, ZIC1 and ZNF154 were selected for investigation on the basis of previous reports and/or prognostic utility in low/intermediate-grade NMIBC. Methylation was determined by Pyrosequencing of sodium-bisulphite converted DNA, and then correlated with gene expression using RT-qPCR. Methylation was additionally correlated with tumour behaviour, including tumour recurrence and progression to muscle invasive bladder cancer or metastases. Results The ISL1 genes’ promoter-associated island was more frequently methylated in recurrent and progressive high-grade tumours than their non-recurrent counterparts (60.0% vs. 18.2%, p = 0.008). ISL1 and HOXA9 showed significantly higher mean methylation in recurrent and progressive tumours compared to non-recurrent tumours (43.3% vs. 20.9%, p = 0.016 and 34.5% vs 17.6%, p = 0.017, respectively). Concurrent ISL1/HOXA9 methylation in HG-NMIBC reliably predicted tumour recurrence and progression within one year (Positive Predictive Value 91.7%), and was associated with disease-specific mortality (DSM). Conclusions In this study we report methylation differences and similarities between clinical sub-types of high-grade NMIBC. We report the potential ability of methylation biomarkers, at initial diagnosis, to predict tumour recurrence and progression within one year of diagnosis. We found that specific biomarkers reliably predict disease outcome and therefore may help guide patient treatment despite the unpredictable clinical course and heterogeneity of high-grade NMIBC. Further investigation is required, including validation in a larger patient cohort, to confirm the clinical utility of methylation biomarkers in high-grade NMIBC

Continental mass change from GRACE over 2002-2011 and its impact on sea level

Present-day continental mass variation as observed by space gravimetry reveals secular mass decline and accumulation. Whereas the former contributes to sea-level rise, the latter results in sea-level fall. As such, consideration of mass accumulation (rather than focussing solely on mass loss) is important for reliable overall estimates of sea-level change. Using data from the Gravity Recovery And Climate Experiment satellite mission, we quantify mass-change trends in 19 continental areas that exhibit a dominant signal. The integrated mass change within these regions is representative of the variation over the whole land areas. During the integer 9-year period of May 2002 to April 2011, GIA-adjusted mass gain and mass loss in these areas contributed, on average, to −(0.7 ± 0.4) mm/year of sea-level fall and + (1.8 ± 0.2) mm/year of sea-level rise; the net effect was + (1.1 ± 0.6) mm/year. Ice melting over Greenland, Iceland, Svalbard, the Canadian Arctic archipelago, Antarctica, Alaska and Patagonia was responsible for + (1.4±0.2) mm/year of the total balance. Hence, land-water mass accumulation compensated about 20 % of the impact of ice-melt water influx to the oceans. In order to assess the impact of geocentre motion, we converted geocentre coordinates derived from satellite laser ranging (SLR) to degree-one geopotential coefficients. We found geocentre motion to introduce small biases to mass-change and sea-level change estimates; its overall effect is + (0.1 ± 0.1) mm/year. This value, however, should be taken with care owing to questionable reliability of secular trends in SLR-derived geocentre coordinates

Multi-objective optimization of genome-scale metabolic models: the case of ethanol production

Ethanol is among the largest fermentation product used worldwide, accounting for more than 90% of all biofuel produced in the last decade. However current production methods of ethanol are unable to meet the requirements of increasing global demand, because of low yields on glucose sources. In this work, we present an in silico multi-objective optimization and analyses of eight genome-scale metabolic networks for the overproduction of ethanol within the engineered cell. We introduce MOME (multi-objective metabolic engineering) algorithm, that models both gene knockouts and enzymes up and down regulation using the Redirector framework. In a multi-step approach, MOME tackles the multi-objective optimization of biomass and ethanol production in the engineered strain; and performs genetic design and clustering analyses on the optimization results. We find in silico E. coli Pareto optimal strains with a knockout cost of 14 characterized by an ethanol production up to 19.74mmolgDW−1h−1 (+832.88% with respect to wild-type) and biomass production of 0.02h−1 (−98.06% ). The analyses on E. coli highlighted a single knockout strategy producing 16.49mmolgDW−1h−1 (+679.29% ) ethanol, with biomass equals to 0.23h−1 (−77.45% ). We also discuss results obtained by applying MOME to metabolic models of: (i) S. aureus; (ii) S. enterica; (iii) Y. pestis; (iv) S. cerevisiae; (v) C. reinhardtii; (vi) Y. lipolytica. We finally present a set of simulations in which constrains over essential genes and minimum allowable biomass were included. A bound over the maximum allowable biomass was also added, along with other settings representing rich media compositions. In the same conditions the maximum improvement in ethanol production is +195.24%

Observation of associated near-side and away-side long-range correlations in √sNN=5.02 TeV proton-lead collisions with the ATLAS detector

Two-particle correlations in relative azimuthal angle (Δϕ) and pseudorapidity (Δη) are measured in √sNN=5.02  TeV p+Pb collisions using the ATLAS detector at the LHC. The measurements are performed using approximately 1  μb-1 of data as a function of transverse momentum (pT) and the transverse energy (ΣETPb) summed over 3.1<η<4.9 in the direction of the Pb beam. The correlation function, constructed from charged particles, exhibits a long-range (2<|Δη|<5) “near-side” (Δϕ∼0) correlation that grows rapidly with increasing ΣETPb. A long-range “away-side” (Δϕ∼π) correlation, obtained by subtracting the expected contributions from recoiling dijets and other sources estimated using events with small ΣETPb, is found to match the near-side correlation in magnitude, shape (in Δη and Δϕ) and ΣETPb dependence. The resultant Δϕ correlation is approximately symmetric about π/2, and is consistent with a dominant cos⁡2Δϕ modulation for all ΣETPb ranges and particle pT