Relevance of JAK2V617F positivity to hematological diseases - survey of samples from a clinical genetics laboratory

<p>Abstract</p> <p>Background</p> <p>JAK2V617F is found in the majority of patients with Ph- myeloproliferative neoplasms (MPNs) and has become a valuable marker for diagnosis of MPNs. However, it has also been found in many other hematological diseases, and some studies even detected the presence of JAK2V617F in normal blood samples. This casts doubt on the primary role of JAK2V617F in the pathogenesis of MPNs and its diagnostic value.</p> <p>Methods</p> <p>In the present study, we analyzed JAK2V617F positivity with 232 normal blood samples and 2663 patient blood, bone marrow, and amniotic fluid specimens obtained from a clinical genetics laboratory by using a simple DNA extraction method and a sensitive nested allele-specific PCR strategy.</p> <p>Results</p> <p>We found JAK2V617F present in the majority (78%) of MPN patients and in a small fraction (1.8-8.7%) of patients with other specific hematological diseases but not at all in normal healthy donors or patients with non-hematological diseases. We also revealed associations of JAK2V617F with novel as well as known chromosomal abnormalities.</p> <p>Conclusions</p> <p>Our study suggests that JAK2V617F positivity is associated with specific hematological malignancies and is an excellent diagnostic marker for MPNs. The data also indicate that the nested allele-specific PCR method provides clinically relevant information and should be conducted for all cases suspected of having MPNs as well as for other related diseases.</p

The Temporal Singularity: time-accelerated simulated civilizations and their implications

Provided significant future progress in artificial intelligence and computing, it may ultimately be possible to create multiple Artificial General Intelligences (AGIs), and possibly entire societies living within simulated environments. In that case, it should be possible to improve the problem solving capabilities of the system by increasing the speed of the simulation. If a minimal simulation with sufficient capabilities is created, it might manage to increase its own speed by accelerating progress in science and technology, in a way similar to the Technological Singularity. This may ultimately lead to large simulated civilizations unfolding at extreme temporal speedups, achieving what from the outside would look like a Temporal Singularity. Here we discuss the feasibility of the minimal simulation and the potential advantages, dangers, and connection to the Fermi paradox of the Temporal Singularity. The medium-term importance of the topic derives from the amount of computational power required to start the process, which could be available within the next decades, making the Temporal Singularity theoretically possible before the end of the century.Comment: To appear in the conference proceedings of the AGI-18 conference (published in the Springer's Lecture Notes in AI series

Topology by Design in Magnetic nano-Materials: Artificial Spin Ice

Artificial Spin Ices are two dimensional arrays of magnetic, interacting nano-structures whose geometry can be chosen at will, and whose elementary degrees of freedom can be characterized directly. They were introduced at first to study frustration in a controllable setting, to mimic the behavior of spin ice rare earth pyrochlores, but at more useful temperature and field ranges and with direct characterization, and to provide practical implementation to celebrated, exactly solvable models of statistical mechanics previously devised to gain an understanding of degenerate ensembles with residual entropy. With the evolution of nano--fabrication and of experimental protocols it is now possible to characterize the material in real-time, real-space, and to realize virtually any geometry, for direct control over the collective dynamics. This has recently opened a path toward the deliberate design of novel, exotic states, not found in natural materials, and often characterized by topological properties. Without any pretense of exhaustiveness, we will provide an introduction to the material, the early works, and then, by reporting on more recent results, we will proceed to describe the new direction, which includes the design of desired topological states and their implications to kinetics.Comment: 29 pages, 13 figures, 116 references, Book Chapte

Quantitative analysis of residual protein contamination of podiatry instruments reprocessed through local and central decontamination units

&lt;p&gt;Background: The cleaning stage of the instrument decontamination process has come under increased scrutiny due to the increasing complexity of surgical instruments and the adverse affects of residual protein contamination on surgical instruments. Instruments used in the podiatry field have a complex surface topography and are exposed to a wide range of biological contamination. Currently, podiatry instruments are reprocessed locally within surgeries while national strategies are favouring a move toward reprocessing in central facilities. The aim of this study was to determine the efficacy of local and central reprocessing on podiatry instruments by measuring residual protein contamination of instruments reprocessed by both methods. Methods&lt;/p&gt; &lt;p&gt;The residual protein of 189 instruments reprocessed centrally and 189 instruments reprocessed locally was determined using a fluorescent assay based on the reaction of proteins with o-phthaldialdehyde/sodium 2-mercaptoethanesulfonate.&lt;/p&gt; &lt;p&gt;Results: Residual protein was detected on 72% (n = 136) of instruments reprocessed centrally and 90% (n = 170) of instruments reprocessed locally. Significantly less protein (p &#60; 0.001) was recovered from instruments reprocessed centrally (median 20.62 μg, range 0 - 5705 μg) than local reprocessing (median 111.9 μg, range 0 - 6344 μg).&lt;/p&gt; &lt;p&gt;Conclusions: Overall, the results show the superiority of central reprocessing for complex podiatry instruments when protein contamination is considered, though no significant difference was found in residual protein between local decontamination unit and central decontamination unit processes for Blacks files. Further research is needed to undertake qualitative identification of protein contamination to identify any cross contamination risks and a standard for acceptable residual protein contamination applicable to different instruments and specialities should be considered as a matter of urgency.&lt;/p&gt

Tenofovir gel for the prevention of herpes simplex virus type 2 infection.

CAPRISA, 2015.Abstract available in pdf

Longitudinal investigation of training status and cardiopulmonary responses in pre- and early-pubertal children

PurposeThe presence of a maturational threshold that modulates children’s physiological responses to exercise training continues to be debated, not least due to a lack of longitudinal evidence to address this question. The purpose of this study was to investigate the interaction between swim-training status and maturity in nineteen trained (T, 10 ± 1 years, −2.4 ± 1.9 years pre-peak height velocity, 8 boys) and fifteen untrained (UT, 10 ± 1 years, −2.3 ± 0.9 years pre-peak height velocity, 5 boys) children, at three annual measurements.MethodsIn addition to pulmonary gas exchange measurements, stroke volume (SV) and cardiac output ( Q˙) were estimated by thoracic bioelectrical impedance during incremental ramp exercise.ResultsAt baseline and both subsequent measurement points, trained children had significantly (P &#60; 0.05) higher peak oxygen uptake (year 1 T 1.75 ± 0.34 vs. UT 1.49 ± 0.22; year 2 T 2.01 ± 0.31 vs. UT 1.65 ± 0.08; year 3 T 2.07 ± 0.30 vs. UT 1.77 ± 0.16 l min−1) and Q˙ (year 1 T 15.0 ± 2.9 vs. UT 13.2 ± 2.2; year 2 T 16.1 ± 2.8 vs. UT 13.8 ± 2.9; year 3 T 19.3 ± 4.4 vs. UT 16.0 ± 2.7 l min−1). Furthermore, the SV response pattern differed significantly with training status, demonstrating the conventional plateau in UT but a progressive increase in T. Multilevel modelling revealed that none of the measured pulmonary or cardiovascular parameters interacted with maturational status, and the magnitude of the difference between T and UT was similar, irrespective of maturational status.ConclusionThe results of this novel longitudinal study challenge the notion that differences in training status in young people are only evident once a maturational threshold has been exceeded

The implication of identifying JAK2V617F in myeloproliferative neoplasms and myelodysplastic syndromes with bone marrow fibrosis

The myeloproliferative neoplasms (MPN) and myelodysplastic syndromes (MDS) occasionally demonstrate overlapping morphological features including hypercellularity, mild/nonspecific dysplastic changes and variable bone marrow fibrosis. Thus, when the associated bone marrow fibrosis results in a suboptimal specimen for morphological evaluation, the descriptive diagnosis “fibrotic marrow with features indeterminate for MDS versus MPN” is often applied. The JAK2V617F mutation was recently shown to be frequently identified in MPN, but it is rarely present in other myeloid disorders. However, the diagnostic utility of JAK2V617F screening in hypercellular bone marrow specimens with fibrosis has not been previously investigated. Using a real-time polymerase chain reaction melting-curve assay capable of detecting JAK2V617F in archived fixed materials, we retrospectively studied JAK2V617F in 45 cases with fibrotic hypercellular bone marrow at initial presentation, including 19 cases initially described as “with features indeterminate for MDS versus MPN”. These 19 cases were reclassified into more specific categories of MDS (n = 14) or MPN (n = 5) based on the availability of subsequent clinical data and/or bone marrow examinations. The JAK2V617F allele was identified in 17 out of 18 BCR/ABL gene-negative MPN cases with marrow fibrosis, whereas only wild-type alleles were identified in the remaining non-MPN cases. Importantly, JAK2V617F alleles were seen in all five cases of “with features indeterminate for MDS versus MPN” at initial presentation that were later determined to be MPN, but they were absent in the 14 cases later determined to be MDS. Our results suggest that JAK2V617F allele evaluation can be a useful ancillary test for discriminating MDS from MPN in specimens with bone marrow fibrosis

Global Analysis of Arabidopsis/Downy Mildew Interactions Reveals Prevalence of Incomplete Resistance and Rapid Evolution of Pathogen Recognition

Interactions between Arabidopsis thaliana and its native obligate oomycete pathogen Hyaloperonospora arabidopsidis (Hpa) represent a model system to study evolution of natural variation in a host/pathogen interaction. Both Arabidopsis and Hpa genomes are sequenced and collections of different sub-species are available. We analyzed ∼400 interactions between different Arabidopsis accessions and five strains of Hpa. We examined the pathogen's overall ability to reproduce on a given host, and performed detailed cytological staining to assay for pathogen growth and hypersensitive cell death response in the host. We demonstrate that intermediate levels of resistance are prevalent among Arabidopsis populations and correlate strongly with host developmental stage. In addition to looking at plant responses to challenge by whole pathogen inoculations, we investigated the Arabidopsis resistance attributed to recognition of the individual Hpa effectors, ATR1 and ATR13. Our results suggest that recognition of these effectors is evolutionarily dynamic and does not form a single clade in overall Arabidopsis phylogeny for either effector. Furthermore, we show that the ultimate outcome of the interactions can be modified by the pathogen, despite a defined gene-for-gene resistance in the host. These data indicate that the outcome of disease and disease resistance depends on genome-for-genome interactions between the host and its pathogen, rather than single gene pairs as thought previously

Quantitative assay for the detection of the V617F variant in the Janus kinase 2 (JAK2) gene using the Luminex xMAP technology

<p>Abstract</p> <p>Background</p> <p>The availability of clinically valid biomarkers contribute to improve the diagnosis and clinical management of diseases. A valine-to-phenylalanine substitution at position 617 (V617F) in the Janus kinase 2 (JAK2) gene has been recently associated with key signaling abnormalities in the transduction of haemopoietic growth-factor receptors and is now considered as a useful clinical marker of myeloproliferative neoplasms. Several methods have recently been reported to detect the JAK2 V617F point mutation and show variable sensitivity.</p> <p>Methods</p> <p>Using the Luminex xMAP technology, we developed a quantitative assay to detect the JAK2V617F variant. The method was based on polymerase chain reaction (PCR) followed by hybridization to specific probes coupled with internally dyed microspheres. The assay comprises 3 steps: genomic DNA extraction, end point PCR reaction, direct hybridization of PCR fragments and quantification. It has been tested with different sources of nucleic acid.</p> <p>Results</p> <p>Applied to whole blood samples, this quantitative assay showed a limit of detection of 2%. A highly sensitive allele-specific primer extension reaction performed in parallel allowed to validate the results and to identify the specimens with values below 2%.</p> <p>Conclusion</p> <p>Direct hybridization assay using the Luminex xMAP technology allows sensitive quantification of JAK2V617F from blood spots. It is simple and can be easily performed in a clinical setting.</p