Flow cytometric characterization and clinical outcome of CD4+ T-cell lymphoma in dogs: 67 cases.

BackgroundCanine T-cell lymphoma (TCL) is conventionally considered an aggressive disease, but some forms are histologically and clinically indolent. CD4 TCL is reported to be the most common subtype of TCL. We assessed flow cytometric characteristics, histologic features when available, and clinical outcomes of CD4+ TCL to determine if flow cytometry can be used to subclassify this group of lymphomas.ObjectiveTo test the hypothesis that canine CD4+ T-cell lymphoma (TCL) is a homogeneous group of lymphomas with an aggressive clinical course.AnimalsSixty-seven dogs diagnosed with CD4+ TCL by flow cytometry and treated at 1 of 3 oncology referral clinics.MethodsRetrospective multivariable analysis of outcome in canine CD4+ TCL including patient characteristics, treatment, and flow cytometric features.ResultsThe majority of CD4+ TCL were CD45+, expressed low class II MHC, and exhibited an aggressive clinical course independent of treatment regimen (median survival, 159 days). Histologically, CD4+ TCL were classified as lymphoblastic or peripheral T cell. Size of the neoplastic lymphocytes had a modest effect on both PFI and survival in this group. A small number of CD4+ TCL were CD45- and class II MHC high, and exhibited an apparently more indolent clinical course (median survival not yet reached).Conclusions and clinical importanceAlthough the majority of CD4+ TCL in dogs had uniform clinical and flow cytometric features and an aggressive clinical course, a subset had a unique immunophenotype that predicts significantly longer survival. This finding strengthens the utility of flow cytometry to aid in the stratification of canine lymphoma

Pulse-Administered Toceranib Phosphate Plus Lomustine for Treatment of Unresectable Mast Cell Tumors in Dogs.

BackgroundNonresectable mast cell tumors (MCT) in dogs remain a therapeutic challenge, and investigation of novel combination therapies is warranted. Intermittent administration of tyrosine kinase inhibitors (TKI) combined with cytotoxic chemotherapy may effectively chemosensitize canine MCT while decreasing cost and adverse effects associated with either agent administered as monotherapy.Hypothesis/objectivesThe primary study objectives were to (1) identify the maximally tolerated dose (MTD), (2) determine the objective response rate (ORR) and (3) describe the adverse event profile of pulse-administered toceranib phosphate (TOC) combined with lomustine.AnimalsForty-seven client-owned dogs with measurable MCT.MethodsToceranib phosphate was given PO on days 1, 3 and 5 of a 21-day cycle at a target dosage of 2.75 mg/kg. Lomustine was given PO on day 3 of each cycle at a starting dosage of 50 mg/m(2) . All dogs were concurrently treated with diphenhydramine, omeprazole, and prednisone.ResultsThe MTD of lomustine was established at 50 mg/m(2) when combined with pulse-administered TOC; the dose-limiting toxicity was neutropenia. Forty-one dogs treated at the MTD were evaluable for outcome assessment. The ORR was 46% (4 complete response, 15 partial response) and the overall median progression-free survival (PFS) was 53 days (1 to >752 days). On multivariate analysis, variables significantly associated with improved PFS included response to treatment, absence of metastasis, and no previous chemotherapy.Conclusions and clinical importanceCombined treatment with pulse-administered TOC and lomustine generally is well tolerated and may be a reasonable treatment option for dogs with unresectable or metastatic MCT

Effective Feedback to Improve Primary Care Prescribing Safety (EFIPPS) a pragmatic three-arm cluster randomised trial:designing the intervention (ClinicalTrials.gov registration NCT01602705)

Peer reviewedPublisher PD

An assessment of western North Pacific ozone photochemistry based on springtime observations from NASA's PEM-West B (1994) and TRACE-P (2001) field studies

The current study provides a comparison of the photochemical environments for two NASA field studies focused on the western North Pacific (PEM-West-B (PWB) and TRACE-P (TP)). These two studies were separated in calendar time by approximately 7 years. Both studies were carried out under springtime conditions, with PWB being launched in 1994 and TP being deployed in 2001 (i.e., 23 February - 15 March 1994 and 10 March-15 April 2001, respectively). Because of the 7-year time separation, these two studies presented a unique scientific opportunity to assess whether evidence could be found to support the Department of Energy\u27s projections in 1997 that increases in anthropogenic emissions from East Asia could reach 5%/yr. Such projections would lead one to the conclusion that a significant shift in the atmospheric photochemical properties of the western North Pacific would occur. To the contrary, the findings from this study support the most recent emission inventory data [Streets et al., 2003] in that they show no significant systematic trend involving increases in any O3 precursor species and no evidence for a significant shift in the level of photochemical activity over the western North Pacific. This conclusion was reached in spite of there being real differences in the concentration levels of some species as well as differences in photochemical activity between PWB and TP. However, nearly all of these differences were shown to be a result of a near 3-week shift in TP\u27s sampling window relative to PWB, thus placing it later in the spring season. The photochemical enhancements seen during TP were most noticeable for latitudes in the range of 25-45°N. Most important among these were increases in J(O1D), OH, and HO2 and values for photochemical ozone formation and destruction, all of which were typically two times larger than those calculated for PWB. A comparison of these airborne results with ozonesonde data from four Japanese stations provided further evidence showing that the 3-week shift in the respective sampling windows of PWB and TP was a likely cause for the differences seen in O3 levels and in photochemical activity between the two airborne studies. Copyright 2003 by the American Geophysical Union

Sample size calculations for cluster randomised controlled trials with a fixed number of clusters

Background\ud Cluster randomised controlled trials (CRCTs) are frequently used in health service evaluation. Assuming an average cluster size, required sample sizes are readily computed for both binary and continuous outcomes, by estimating a design effect or inflation factor. However, where the number of clusters are fixed in advance, but where it is possible to increase the number of individuals within each cluster, as is frequently the case in health service evaluation, sample size formulae have been less well studied. \ud \ud Methods\ud We systematically outline sample size formulae (including required number of randomisation units, detectable difference and power) for CRCTs with a fixed number of clusters, to provide a concise summary for both binary and continuous outcomes. Extensions to the case of unequal cluster sizes are provided. \ud \ud Results\ud For trials with a fixed number of equal sized clusters (k), the trial will be feasible provided the number of clusters is greater than the product of the number of individuals required under individual randomisation ($n_i$) and the estimated intra-cluster correlation ($\rho$). So, a simple rule is that the number of clusters ($\kappa$) will be sufficient provided: \ud \ud $\kappa$ > $n_i$ x $\rho$\ud \ud Where this is not the case, investigators can determine the maximum available power to detect the pre-specified difference, or the minimum detectable difference under the pre-specified value for power. \ud \ud Conclusions\ud Designing a CRCT with a fixed number of clusters might mean that the study will not be feasible, leading to the notion of a minimum detectable difference (or a maximum achievable power), irrespective of how many individuals are included within each cluster. \ud \u

Caenorhabditis elegans behavioral genetics: where are the knobs?

Thousands of behavioral mutants of Caenorhabditis elegans have been studied. I suggest a set of criteria by which some genes important in the evolution of behavior might be recognized, and identify neuropeptide signaling pathways as candidates

Acceptability, Feasibility and Preliminary Evaluation of a Novel, Personalised, Home based Physical Activity Intervention for Chronic Heart Failure (Active-at-Home-HF)::A Pilot Study

Purpose: Less than 10% of heart failure patients in the UK participate in cardiac rehabilitation programmes. The present pilot study evaluated feasibility, acceptability and physiological effects of a novel, personalised, home-based physical activity intervention in chronic heart failure. Methods: Twenty patients (68±7 years old, 20% females) with stable chronic heart failure due to reduced left ventricular ejection fraction (31±8 %) participated in a single group, pilot study assessing the feasibility and acceptability of a 12-week personalised home-based physical activity intervention aiming to increase daily number of steps by 2000 from baseline (Active-at-Home-HF). Patients completed cardiopulmonary exercise testing with non-invasive gas exchange and haemodynamic measurements and quality of life questionnaire pre- and post-intervention. Patients were supported weekly via telephone and average weekly step count data collected using pedometers. Results: 43 patients were screened and 20 recruited into the study. Seventeen patients (85%) completed the intervention, and 15 (75%) achieved the target step count. Average step count per day increased significantly from baseline to 3 weeks by 2546 (5108±3064 to 7654±3849 P=0.03, n=17), and was maintained until week 12 (9022±3942). Following completion of the intervention, no adverse events were recorded, quality of life improved by 4 points (26±18 vs. 22±19). Peak exercise stroke volume increased by 19% (127±34 vs 151±34 m/beat, P=0.05), while cardiac index increased by 12% (6.8±1.5 vs. 7.6±2.0 L/min/m2, P=0.19). Workload and oxygen consumption at anaerobic threshold also increased by 16% (49±16 vs. 59±14 watts, P=0.01) and 10% (11.5±2.9 vs. 12.8±2.2 ml/kg/min, P=0.39). Conclusion: The Active-at-Home-HF intervention is feasible, acceptable and effective for increasing physical activity in CHF. It may lead to improvements in quality of life, exercise tolerance and haemodynamic function

Perspective from a Younger Generation -- The Astro-Spectroscopy of Gisbert Winnewisser

Gisbert Winnewisser's astronomical career was practically coextensive with the whole development of molecular radio astronomy. Here I would like to pick out a few of his many contributions, which I, personally, find particularly interesting and put them in the context of newer results.Comment: 14 pages. (Co)authored by members of the MPIfR (Sub)millimeter Astronomy Group. To appear in the Proceedings of the 4th Cologne-Bonn-Zermatt-Symposium "The Dense Interstellar Medium in Galaxies" eds. S. Pfalzner, C. Kramer, C. Straubmeier, & A. Heithausen (Springer: Berlin

Mitochondria are the main source and one of the targets of Pb (lead)-induced oxidative stress in the yeast Saccharomyces cerevisiae

The yeast Saccharomyces cerevisiae is a useful model organism for studying lead (Pb) toxicity. Yeast cells of a laboratory S. cerevisiae strain (WT strain) were incubated with Pb concentrations up to 1,000 μmol/l for 3 h. Cells exposed to Pb lost proliferation capacity without damage to the cell membrane, and they accumulated intracellular superoxide anion (O2 .−) and hydrogen peroxide (H2O2). The involvement of the mitochondrial electron transport chain (ETC) in the generation of reactive oxygen species (ROS) induced by Pb was evaluated. For this purpose, an isogenic derivative ρ0 strain, lacking mitochondrial DNA, was used. The ρ0 strain, without respiratory competence, displayed a lower intracellular ROS accumulation and a higher resistance to Pb compared to the WT strain. The kinetic study of ROS generation in yeast cells exposed to Pb showed that the production of O2 .− precedes the accumulation of H2O2, which is compatible with the leakage of electrons from the mitochondrial ETC. Yeast cells exposed to Pb displayed mutations at the mitochondrial DNA level. This is most likely a consequence of oxidative stress. In conclusion, mitochondria are an important source of Pb-induced ROS and, simultaneously, one of the targets of its toxicity.The authors thank the FCT Strategic Project PEst-OE/EQB/LA0023/2013

Uniform electron gases

We show that the traditional concept of the uniform electron gas (UEG) --- a homogeneous system of finite density, consisting of an infinite number of electrons in an infinite volume --- is inadequate to model the UEGs that arise in finite systems. We argue that, in general, a UEG is characterized by at least two parameters, \textit{viz.} the usual one-electron density parameter $\rho$ and a new two-electron parameter $\eta$. We outline a systematic strategy to determine a new density functional $E(\rho,\eta)$ across the spectrum of possible $\rho$ and $\eta$ values.Comment: 8 pages, 2 figures, 5 table