How I treat newly diagnosed T-cell acute lymphoblastic leukemia and T-cell lymphoblastic lymphoma in children

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy that has historically been associated with a very poor prognosis. Nevertheless, despite a lack of incorporation of novel agents, the development of intensified T-ALL–focused protocols has resulted in significant improvements in outcome in children. Through the use of several representative cases, we highlight the key changes that have driven these advances including asparaginase intensification, the use of induction dexamethasone, and the safe omission of cranial radiotherapy. We discuss the results of recent trials to explore key topics including the implementation of risk stratification with minimal residual disease measurement and how to treat high-risk subtypes such as early T-cell precursor ALL. In particular, we address current discrepancies in treatment between different cooperative groups, including the use of nelarabine, and provide rationales for current treatment protocols for both T-ALL and T-lymphoblastic lymphoma

Warm temperature acclimation impacts metabolism of paralytic shellfish toxins from Alexandrium minutum in commercial oysters

© 2015 John Wiley & Sons Ltd. Species of Alexandrium produce potent neurotoxins termed paralytic shellfish toxins and are expanding their ranges worldwide, concurrent with increases in sea surface temperature. The metabolism of molluscs is temperature dependent, and increases in ocean temperature may influence both the abundance and distribution of Alexandrium and the dynamics of toxin uptake and depuration in shellfish. Here, we conducted a large-scale study of the effect of temperature on the uptake and depuration of paralytic shellfish toxins in three commercial oysters (Saccostrea glomerata and diploid and triploid Crassostrea gigas, n = 252 per species/ploidy level). Oysters were acclimated to two constant temperatures, reflecting current and predicted climate scenarios (22 and 27 °C), and fed a diet including the paralytic shellfish toxin-producing species Alexandrium minutum. While the oysters fed on A. minutum in similar quantities, concentrations of the toxin analogue GTX1,4 were significantly lower in warm-acclimated S. glomerata and diploid C. gigas after 12 days. Following exposure to A. minutum, toxicity of triploid C. gigas was not affected by temperature. Generally, detoxification rates were reduced in warm-acclimated oysters. The routine metabolism of the oysters was not affected by the toxins, but a significant effect was found at a cellular level in diploid C. gigas. The increasing incidences of Alexandrium blooms worldwide are a challenge for shellfish food safety regulation. Our findings indicate that rising ocean temperatures may reduce paralytic shellfish toxin accumulation in two of the three oyster types; however, they may persist for longer periods in oyster tissue

Immunological characterization of chromogranins A and B and secretogranin II in the bovine pancreatic islet

Antisera against chromogranin A and B and secretogranin II were used for analysing the bovine pancreas by immunoblotting and immunohistochemistry. All three antigens were found in extracts of fetal pancreas by one dimensional immunoblotting. A comparison with the soluble proteins of chromaffin granules revealed that in adrenal medulla and in pancreas antigens which migrated identically in electrophoresis were present. In immunohistochemistry, chromogranin A was found in all pancreatic endocrine cell types with the exception of most pancreatic polypeptide-(PP-) producing cells. For chromogranin B, only a faint immunostaining was obtained. For secretorgranin II, A-and B-cells were faintly positive, whereas the majority of PP-cells exhibited a strong immunostaining for this antigen. These results establish that chromogranins A and B and secretogranin II are present in the endocrine pancreas, but that they exhibit a distinct cellular localization

Dopamine Beta Hydroxylase Genotype Identifies Individuals Less Susceptible to Bias in Computer-Assisted Decision Making

Computerized aiding systems can assist human decision makers in complex tasks but can impair performance when they provide incorrect advice that humans erroneously follow, a phenomenon known as “automation bias.” The extent to which people exhibit automation bias varies significantly and may reflect inter-individual variation in the capacity of working memory and the efficiency of executive function, both of which are highly heritable and under dopaminergic and noradrenergic control in prefrontal cortex. The dopamine beta hydroxylase (DBH) gene is thought to regulate the differential availability of dopamine and norepinephrine in prefrontal cortex. We therefore examined decision-making performance under imperfect computer aiding in 100 participants performing a simulated command and control task. Based on two single nucleotide polymorphism (SNPs) of the DBH gene, −1041 C/T (rs1611115) and 444 G/A (rs1108580), participants were divided into groups of low and high DBH enzyme activity, where low enzyme activity is associated with greater dopamine relative to norepinephrine levels in cortex. Compared to those in the high DBH enzyme activity group, individuals in the low DBH enzyme activity group were more accurate and speedier in their decisions when incorrect advice was given and verified automation recommendations more frequently. These results indicate that a gene that regulates relative prefrontal cortex dopamine availability, DBH, can identify those individuals who are less susceptible to bias in using computerized decision-aiding systems

A theory of organizational readiness for change

<p>Abstract</p> <p>Background</p> <p>Change management experts have emphasized the importance of establishing organizational readiness for change and recommended various strategies for creating it. Although the advice seems reasonable, the scientific basis for it is limited. Unlike individual readiness for change, organizational readiness for change has not been subject to extensive theoretical development or empirical study. In this article, I conceptually define organizational readiness for change and develop a theory of its determinants and outcomes. I focus on the organizational level of analysis because many promising approaches to improving healthcare delivery entail collective behavior change in the form of systems redesign--that is, multiple, simultaneous changes in staffing, work flow, decision making, communication, and reward systems.</p> <p>Discussion</p> <p>Organizational readiness for change is a multi-level, multi-faceted construct. As an organization-level construct, readiness for change refers to organizational members' shared resolve to implement a change (change commitment) and shared belief in their collective capability to do so (change efficacy). Organizational readiness for change varies as a function of how much organizational members value the change and how favorably they appraise three key determinants of implementation capability: task demands, resource availability, and situational factors. When organizational readiness for change is high, organizational members are more likely to initiate change, exert greater effort, exhibit greater persistence, and display more cooperative behavior. The result is more effective implementation.</p> <p>Summary</p> <p>The theory described in this article treats organizational readiness as a shared psychological state in which organizational members feel committed to implementing an organizational change and confident in their collective abilities to do so. This way of thinking about organizational readiness is best suited for examining organizational changes where collective behavior change is necessary in order to effectively implement the change and, in some instances, for the change to produce anticipated benefits. Testing the theory would require further measurement development and careful sampling decisions. The theory offers a means of reconciling the structural and psychological views of organizational readiness found in the literature. Further, the theory suggests the possibility that the strategies that change management experts recommend are equifinal. That is, there is no 'one best way' to increase organizational readiness for change.</p

Simulating Food Web Dynamics along a Gradient: Quantifying Human Influence

Realistically parameterized and dynamically simulated food-webs are useful tool to explore the importance of the functional diversity of ecosystems, and in particular relations between the dynamics of species and the whole community. We present a stochastic dynamical food web simulation for the Kelian River (Borneo). The food web was constructed for six different locations, arrayed along a gradient of increasing human perturbation (mostly resulting from gold mining activities) along the river. Along the river, the relative importance of grazers, filterers and shredders decreases with increasing disturbance downstream, while predators become more dominant in governing eco-dynamics. Human activity led to increased turbidity and sedimentation which adversely impacts primary productivity. Since the main difference between the study sites was not the composition of the food webs (structure is quite similar) but the strengths of interactions and the abundance of the trophic groups, a dynamical simulation approach seemed to be useful to better explain human influence. In the pristine river (study site 1), when comparing a structural version of our model with the dynamical model we found that structurally central groups such as omnivores and carnivores were not the most important ones dynamically. Instead, primary consumers such as invertebrate grazers and shredders generated a greater dynamical response. Based on the dynamically most important groups, bottom-up control is replaced by the predominant top-down control regime as distance downstream and human disturbance increased. An important finding, potentially explaining the poor structure to dynamics relationship, is that indirect effects are at least as important as direct ones during the simulations. We suggest that our approach and this simulation framework could serve systems-based conservation efforts. Quantitative indicators on the relative importance of trophic groups and the mechanistic modeling of eco-dynamics could greatly contribute to understanding various aspects of functional diversity

Embryonic Lethality in Mice Lacking the Nuclear Factor of Activated T Cells 5 Protein Due to Impaired Cardiac Development and Function

Nuclear factor of activated T cells 5 protein (NFAT5) is thought to be important for cellular adaptation to osmotic stress by regulating the transcription of genes responsible for the synthesis or transport of organic osmolytes. It is also thought to play a role in immune function, myogenesis and cancer invasion. To better understand the function of NFAT5, we developed NFAT5 gene knockout mice. Homozygous NFAT5 null (NFAT5−/−) mouse embryos failed to develop normally and died after 14.5 days of embryonic development (E14.5). The embryos showed peripheral edema, and abnormal heart development as indicated by thinner ventricular wall and reduced cell density at the compact and trabecular areas of myocardium. This is associated with reduced level of proliferating cell nuclear antigen and increased caspase-3 in these tissues. Cardiomyocytes from E14.5 NFAT5−/− embryos showed a significant reduction of beating rate and abnormal Ca2+ signaling profile as a consequence of reduced sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA) and ryanodine receptor (RyR) expressions. Expression of NFAT5 target genes, such as HSP 70 and SMIT were reduced in NFAT5−/− cardiomyocytes. Our findings demonstrated an essential role of NFAT5 in cardiac development and Ca2+ signaling. Cardiac failure is most likely responsible for the peripheral edema and death of NFAT5−/− embryos at E14.5 days

Relationships between anopheline mosquitoes and topography in West Timor and Java, Indonesia

<p>Abstract</p> <p>Background</p> <p>Malaria is a serious health issue in Indonesia. Mosquito control is one aspect of an integrated malaria management programme. To focus resources on priority areas, information is needed about the vectors and their habitats. This research aimed to identify the relationship between anopheline mosquitoes and topography in West Timor and Java.</p> <p>Methods</p> <p>Study areas were selected in three topographic types in West Timor and Java. These were: coastal plain, hilly (rice field) and highland. Adult mosquitoes were captured landing on humans identified to species level and counted.</p> <p>Results</p> <p>Eleven species were recorded, four of which were significant for malaria transmission: <it>Anopheles aconitus, Anopheles barbirostris, Anopheles subpictus </it>and <it>Anopheles sundaicus</it>. Each species occupied different topographies, but only five were significantly associated: <it>Anopheles annularis, Anopheles vagus </it>and <it>Anopheles subpictus </it>(Java only) with hilly rice fields; <it>Anopheles barbirostris, Anopheles maculatus </it>and <it>Anopheles subpictus </it>(West Timor only) with coastal areas.</p> <p>Conclusion</p> <p>Information on significant malaria vectors associated with specific topography is useful for planning the mosquito control aspect of malaria management.</p

Psychometric Curve and Behavioral Strategies for Whisker-Based Texture Discrimination in Rats

The rodent whisker system is a major model for understanding neural mechanisms for tactile sensation of surface texture (roughness). Rats discriminate surface texture using the whiskers, and several theories exist for how texture information is physically sensed by the long, moveable macrovibrissae and encoded in spiking of neurons in somatosensory cortex. However, evaluating these theories requires a psychometric curve for texture discrimination, which is lacking. Here we trained rats to discriminate rough vs. fine sandpapers and grooved vs. smooth surfaces. Rats intermixed trials at macrovibrissa contact distance (nose >2 mm from surface) with trials at shorter distance (nose <2 mm from surface). Macrovibrissae were required for distant contact trials, while microvibrissae and non-whisker tactile cues were used for short distance trials. A psychometric curve was measured for macrovibrissa-based sandpaper texture discrimination. Rats discriminated rough P150 from smoother P180, P280, and P400 sandpaper (100, 82, 52, and 35 µm mean grit size, respectively). Use of olfactory, visual, and auditory cues was ruled out. This is the highest reported resolution for rodent texture discrimination, and constrains models of neural coding of texture information