Incidence of myeloproliferative neoplasms - trends by subgroup and age in a population-based study in Sweden.

BACKGROUND: The reported incidence of Philadelphia-negative myeloproliferative neoplasms (MPNs) differs substantially between previous reports, likely due to true regional differences in incidence and/or variations in the quality and coverage of the cancer registers. OBJECTIVE: We therefore assessed MPN incidence in Sweden during recent years using prospectively collected information captured in Swedish health registers. METHODS: Patients with MPNs were identified through the Swedish Cancer Register and Swedish Blood Cancer Register between 2000 and 2014. Information on the Swedish population was obtained from the Human Mortality Database. Crude and age-standardized incidence rates of MPNs with 95% confidence intervals (CIs) were calculated. RESULTS: A total of 6281 MPN cases were reported to the Swedish Cancer Register and Swedish Blood Cancer Register during 2000-2014. The age-standardized, to the Swedish population in 2000, incidence for all MPNs was 4.45 (95% confidence interval [CI] 4.34-4.56)/100 000 person-years. The age-standardized incidence for polycythemia vera was 1.48 (1.42-1.54), for essential thrombocythemia 1.60 (1.53-1.66) and for primary myelofibrosis 0.52 (0.48-0.56)/100 000 person-years, respectively. The incidence rate of MPNs was substantially higher in the older compared to the younger age groups. The incidence increased during the study period, likely to do better reporting and increasing age of the general population. CONCLUSION: The reported MPN incidences in our study, which were in the higher interval of previously published studies, are likely more accurate compared to previous reports due to the population-based setting and high level of coverage in the Swedish Cancer and Blood Cancer Registers.

Drones may be used to save lives in out of hospital cardiac arrest due to drowning.

BACKGROUND: Drowning leading to out-of-hospital cardiac arrest (OHCA) and death is a major public health concern. Submersion with duration of less than 10min is associated with favorable neurological outcome and nearby bystanders play a considerable role in rescue and resuscitation. Drones can provide a visual overview of an accident scene, their potential as lifesaving tools in drowning has not been evaluated. AIM: The aim of this simulation study was to evaluate the efficiency of a drone for providing earlier location of a submerged possible drowning victim in comparison with standard procedure. METHOD: This randomized simulation study used a submerged manikin placed in a shallow (<2m) 100×100-m area at Tylösand beach, Sweden. A search party of 14 surf-lifeguards (control) was compared to a drone transmitting video to a tablet (intervention). Time from start to contact with the manikin was the primary endpoint. RESULTS: Twenty searches were performed in total, 10 for each group. The median time from start to contact with the manikin was 4:34min (IQR 2:56-7:48) for the search party (control) and 0:47min (IQR 0:38-0:58) for the drone-system (intervention) respectively (p<0.001). The median time saved by using the drone was 3:38min (IQR 2:02-6:38). CONCLUSION: A drone transmitting live video to a tablet is feasible, time saving in comparison to traditional search parties and may be used for providing earlier location of submerged victims at a beach. Drone search can possibly contribute to earlier onset of CPR in drowning victims.

No benefit from adding GM-CSF to induction chemotherapy in transforming myelodysplastic syndromes: better outcome in patients with less proliferative disease.

In this prospective randomized multicenter trial 93 patients, median age 72 years, with RAEB-t (n=25) and myelodysplastic syndrome (MDS)-AML (n=68) were allocated to a standard induction chemotherapy regimen (TAD 2+7) with or without addition of granulocyte-macrophage-CSF (GM-CSF). The overall complete remission (CR) rate was 43% with no difference between the arms. Median survival times for all patients, CR patients, and non-CR patients were 280, 550, and 100 days, respectively, with no difference between the arms. Response rates were significantly better in patients with serum lactate dehydrogenase (S-LDH) levels

Diagnostic double-guarded low-volume uterine lavage in mares.

Endometritis constitutes a major problem in the management of broodmares; hence, diagnostic tests with a high sensitivity and specificity are highly appreciated. The aim of this study was to compare the results from endometrial, cytologic, and bacteriologic examinations obtained by a newly developed, double-guarded, flushing technique versus standard diagnostic tests, the double-guarded swab and biopsy. The described double-guarded flush technique requires the use of a disposable uterine flushing tube, a sanitary sleeve, a sterile steel speculum, and a 250 mL fluid bag. Endometrial biopsies, swabs, and low-volume lavage samples were obtained from 34 research mares at six different time points in four estrous cycles and were evaluated cytologically and bacteriologically. Endometrial biopsies from the first cycle (n = 34) were examined for the presence of polymorphonuclear neutrophils (PMNs) in the stratum compactum and stratum spongiosum and used as a gold standard for calculation of diagnostic sensitivity and specificity. In all samples, Escherichia coli was most frequently isolated (lavage, 30%; swab, 21%; and biopsy, 12%) followed by ß-hemolytic streptococci (lavage, 11%; swab, 8%; and biopsy, 7%). Positive cytology was less likely to occur when E coli was isolated from the diagnostic tests compared with the growth of ß-hemolytic streptococci. Isolation of pathogens from uterine samples was highly associated with the presence of PMNs in the stratum compactum and straum spongiosum on histology. Using the presence of PMNs in the tissue specimens as the gold standard for diagnosing endometritis, the sensitivity of low-volume lavage culture was 0.75 and the specificity was 0.72. In conclusion, the double-guarded, low-volume, lavage technique was a rapid and accurate method for diagnosing mares with endometritis, and the risk of false-positive samples is considered to be minimal compared with other flushing techniques described.

Clinical end points for drug treatment trials in BCR-ABL1-negative classic myeloproliferative neoplasms: consensus statements from European LeukemiaNET (ELN) and Internation Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT).

The discovery of somatic mutations, primarily JAK2V617F and CALR, in classic BCR-ABL1-negative myeloproliferative neoplasms (MPNs) has generated interest in the development of molecularly targeted therapies, whose accurate assessment requires a standardized framework. A working group, comprised of members from European LeukemiaNet (ELN) and International Working Group for MPN Research and Treatment (IWG-MRT), prepared consensus-based recommendations regarding trial design, patient selection and definition of relevant end points. Accordingly, a response able to capture the long-term effect of the drug should be selected as the end point of phase II trials aimed at developing new drugs for MPNs. A time-to-event, such as overall survival, or progression-free survival or both, as co-primary end points, should measure efficacy in phase III studies. New drugs should be tested for preventing disease progression in myelofibrosis patients with early disease in randomized studies, and a time to event, such as progression-free or event-free survival should be the primary end point. Phase III trials aimed at preventing vascular events in polycythemia vera and essential thrombocythemia should be based on a selection of the target population based on new prognostic factors, including JAK2 mutation. In conclusion, we recommended a format for clinical trials in MPNs that facilitates communication between academic investigators, regulatory agencies and drug companies.

1-O-hexadecyl-2-metoxy-glycero-3-phosphatidylcholine--a methoxy ether lipid inhibiting platelet activating factor-induced platelet aggregation and neutrophil oxidative metabolism.

Whether or not two alkylglycerols could initiate a functional response in human platelets or modify responses induced by platelet activating factor (PAF) was evaluated. It was found that 1-100 microM 1-O-hexadecyl-2-metoxy-glycero-3-phosphatidylcholine (Et-16-OCH3) induced platelet aggregation but 1-O-hexadecyl-sn-glycerol (chimyl alcohol; CA) did not. Et-16-OCH3-induced platelet aggregation was abolished by pretreatment with the PAF receptor antagonist WEB 2086. While CA had no effect on platelet aggregation induced by PAF, pretreatment with Et-16-OCH3 (0.1 microM or higher) significantly inhibited platelet aggregation induced by PAF, but had no effect on aggregation caused by ADP, thrombin or phorbol myristate acetate (PMA). A receptor binding study using radiolabelled [3H]WEB 2086 showed that Et-16-OCH3 exerts its actions through interaction with the PAF receptor. Moreover, Et-16-OCH3 inhibited neutrophil chemiluminescence responses induced by PAF, but not reactions to PMA or a formyl peptide. Finally, 1 microM Et-16-OCH3 induced a rise in the intracellular calcium concentration in platelets equal to that induced by PAF and also had an calcium ionophore-like effect at 100 microM. Thus, this study shows that Et-16-OCH3 is both a potent inducer of platelet aggregation and an inhibitor of PAF-induced platelet aggregation and neutrophil chemiluminescence, through interaction with the PAF receptor.

Unusual clinical presentation in a patient with myelodysplastic syndrome, with subsequent hematological remission and suppression of the malignant clone following treatment with cyclosporine A, erythropoietin and granulocyte colony-stimulating factor.

A 35-year-old female presented with isolated thrombocytopenia of autoimmune origin. One and a half years later, hypoplastic myelodysplastic (MDS) was diagnosed. Following treatment with cyclosporin A, erythropoietin and granulocyte colony-stimulating factor, the patient has achieved a sustained hematological remission which is still ongoing after 3 years. Furthermore, to the best of our knowledge, this is the third case described in the literature where treatment with cytokines alone or in combination with immunosuppressive agents has resulted in a long standing cytogenetic response in MDS.

Acute quadriplegic myopathy following autologous peripheral blood stem cell transplantation for breast cancer.

Autologous peripheral blood stem cell transplantation (APSCT) is increasingly used in the treatment of breast cancer. We report a patient who experienced septic shock, and after treatment with antibiotics, high-dose corticosteroids and mechanical ventilation due to respiratory insufficiency, developed quadriplegia. Electroneurophysiological examination, as well as a muscle biopsy, showed a typical picture of acute quadriplegic myopathy with loss of thick filament proteins. This is, to the best of our knowledge, the first reported case of this complication following APSCT.

Survival in a patient with polycythaemia vera for over thirty years: implications for treatment decisions in younger patients.

Modern treatment has dramatically improved the prognosis for patients with polycythaemia vera (PV). Here a patient is described who has been followed and treated for PV for over 30 years, demonstrating that very long term survival can be achieved in PV. However, effective treatment modalities such as radioactive phosphorus, alkylating agents and, most recently, hydroxyurea, have all been shown to increase the risk to develop acute leukaemia when used in the treatment of myeloproliferative disorders. Hopefully, the prolonged survival of this patient may help to emphasize the need to use non-leukaemogenic agents when treating younger PV patients.

Impaired activation of phospholipase D in polycythaemia vera-implications for the pathogenesis of the disease?

A series of studies have demonstrated a stimulus-specific defect in PMN oxidative metabolism after stimulation with surface receptor dependent stimuli such as fMLP, leukotriene B4 and platelet activating factor (PAF), whereas the response to phorbol myristate acetate was normal. Having discovered this defect, studies of the stimulus response coupling for oxidative responses were performed showing a normal interaction of fMLP with it's receptor, as well as an intact activation of phospholipase C, as measured by the generation of 1,4,5-inositoltrisphosphate, and the subsequent rise of intracellular calcium. In contrast, the formation of diacylglycerol and phosphatidylethanol was decreased in PV PMN, denoting an impaired activation of phospholipase D (PLD). It was shown by flow cytometry analyses that the hampered oxidative response was present both in single PMN and monocytes. Moreover, platelets from PV patients, whose PMN exhibit a lower oxidative response to PAF, also have a diminished aggregatory response to PAF. Thus three different cell lineages in PV have been revealed to respond abnormally to surface receptor dependent stimuli, indicating that the proposed impairment of PLD might be relevant for changes in the malignant stem cell clone. Since phosphatidic acid, produced as a result of PLD activation, may be implicated in the regulation of several oncogenes, perturbations of the PLD system could theoretically be important for the development of PV.

Spontaneous remission during two pregnancies in a patient with essential thrombocythaemia.

A woman with untreated essential thrombocythaemia (ET) exhibited spontaneous normalization of her elevated platelet count during two pregnancies. After delivery the platelet count increased rapidly to the same high level as before. Low platelet adhesion as well as adrenalin- and collagen-induced platelet aggregation, present before pregnancy, increased to normal values during pregnancy. Furthermore, no erythropoietin-independent colony growth was observed during pregnancy, while such colonies were clearly demonstrated when the patient was assayed after pregnancy. This is the second case in the literature demonstrating that remission of ET can occur without treatment during pregnancy.

Impaired platelet binding of fibrinogen due to a lower number of GPIIB/IIIA receptors in polycythemia vera.

We have previously described a stimulus-specific defect in platelet aggregation in polycythaemia vera (PV) after stimulation with surface receptor dependent agonists such as platelet activating factor (PAF). In contrast, responses to phorbol myristate acetate (PMA) were normal. We now report that after PAF stimulation, using flow cytometry, the amount of fibrinogen bound to its receptor was significantly lower in PV platelets with a median MFI of 6.0 (range 4.1-17.3) compared to controls, 12.8 (range 8-21.3; n=11; p<0.01). We found no evidence of preactivation of PV platelets. Quantitative analysis of GPIIIa gave a significantly lower number of GPIIIa on resting PV platelets, 14300 subunits of GPIIIa (range 8500-15500) vs. 19800 for controls (range 13400-26800; n=12; p<0.01). Both patients and controls increased their number of receptors on the cell surface after stimulation with PAF and PMA, but the significant difference in the number of receptors per cell remained. Indirect evaluation of PAF receptor function showed that activation of CD 62 did not differ in PV and controls after PAF stimulation. Additionally, although the basal level of serotonin in platelet-rich plasma was significantly lower in PV, there was a threefold increase of the basal level after stimulation with PAF for both PV and control platelets, also indicating a normal interaction of PAF with its receptor. Although our results indicate both an impaired PAF induced aggregation in PV and a lower number of GPIIb/IIIa complexes on single platelets, whether these phenomena are related remains uncertain.

A new computer-assisted two-way avoidance conditioning equipment for rats: behavioral and pharmacological validation.

A new PC-controlled two-way avoidance conditioning equipment for rats is described. The position of the rat within the two-compartment shuttle-box is monitored by means of 4 + 4 horizontal photocell beams. Experimental conditions and procedures, such as CS-UCS interval, photocell operations, shock strength, and so on, can conveniently be preset by the experimenter. The successful operation of the shuttle-box is evidenced by rapid and efficient acquisition of the avoidance behavior, and approximately 100% median avoidance performance was obtained within 5 successive days of training (20-25 trials per day). In a separate experiment, different groups of rats received avoidance training (0-5 sessions) at 8 weeks of age, and a retention test was performed at 14 weeks of age. The correlation between acquisition and retention avoidance performance was weak (r = 0.33, NS), and performance during the acquisition process appears to be a poor predictor of final performance. As expected, a number of dopamine (DA) receptor blocking agents (DA D1 and/or D2 selective) produced a selective suppression of the avoidance behavior, that is, the suppression of avoidance responding was matched by a corresponding increase in escape responding (with no escape failures).

Ordovician chitinozoan biozonation of the Brabant Massif, Belgium.

Chitinozoans from seven Ordovician units (Abbaye de Villers, Tribotte, Rigenée, Ittre, Bornival, and Brutia formations and a new unnamed unit, here provisionally called the Asquempont unit) belonging to the mainly concealed Brabant Massif, Belgium are described herein. Fifty-six samples were taken from rocks cropping out at the south-eastern rim of the massif in the Orneau, Dyle-Thyle and Senne-Sennette valleys. Microfossil preservation is moderate to poor, and the chitinozoans occur in low numbers. Taxonomically, the recovered chitinozoans are distributed into 29 taxa, some placed under open nomenclature. Together with earlier published graptolite and acritarch data, the analysis of the chitinozoan assemblages resulted in an improved chronostratigraphy of the investigated formations. We propose a local chitinozoan biozonation with 11 zones for the Brabant Massif. The oldest investigated units yielded chitinozoans typical for North Gondwana, and younger units (starting in the middle Caradoc), yielded some taxa also common in Baltica. As the Brabant Massif formed part of the microcontinent Avalonia, the chitinozoan assemblages recovered from the massif support the inferred drifting of Avalonia from high latitudes towards middle latitudes in the Ordovician as was suggested earlier.

Quantitative evaluation of microplankton palaeobiogeography in the Ordovician-Early Silurian of the northern Trans European Suture Zone: implications for the timing of the Avalonia-Baltica collision.

Quantitative analysis of assemblage similarity among chitinozoan and acritarch associations recovered from various sedimentary sequences across the Trans European Suture Zone (TESZ; southern Baltic Sea and northern Germany region), permits evaluation of changes in microplankton palaeobiogeography during the Ordovician in the study area. The present data confirm strong palaeobiogeographic differences between the lower Ordovician of the Rügen area, and the coeval domains of the East European Platform (EEP), corroborating the idea that the subsurface of Rügen should be considered palaeogeographically as the eastern extension of Avalonia.Cluster analysis of chitinozoan assemblages from numerous wells in the Rügen area, and one well from the southern margin of the EEP indicates that chitinozoan bioprovincialism reached its maximum during the Llanvirn; during this period, the Rügen microplankton communities were clearly Gondwanan in character. Calculations using the coefficient of similarity support the conclusion of a high similarity between Llanvirn acritarch assemblages from the Rügen subsurface and from coeval Perigondwana localities (e.g. Tunisia). Since the early Caradoc, this Gondwanan affinity of the Rügen microfossils starts to lessen, and becomes negligible during the late Caradoc. During latest Caradoc-early Ashgill through Llandovery times the chitinozoan assemblages from either side of the TESZ are undistinguishable. If palaeobiogeographical differentiation is primarily related to palaeolatitudinal distance, then the present data support closure of the Tornquist Ocean during late Caradoc-Ashgill times. The presence of reworked Llanvirn acritarchs of Perigondwanan affinity in middle Ashgill sedimentary sequences at the southern margin of the EEP, clearly shows that by this time erosion of an uplifted area was taking place. Accordingly, the closure of the Tornquist Ocean, and consequent Avalonia-Baltica collision must have taken place during the time interval between the middle Caradoc and the early middle Ashgill (Rawtheyan).New chitinozoan data from boreholes H 2 and K 5, offshore of Rügen Island, northern Germany, allow for precise biostratigraphic dating. In the pre-Devonian part of H 2, Siphonochitina formosa indicates an Abereiddian (Early Llanvirn) age, facilitating correlation with boreholes Binz 1/73 and Lohme 2/70 of Rügen. In borehole K 5, the occurrence of Belonechitina robusta and Tanuchitina bergstroemi permits attribution of the investigated pre-Carboniferous sequence to the middle-late Caradoc, and, possibly, early Ashgill.

Chitinozoan faunas from the Rügen Ordovician (Rügen 5/66 and Binz 1/73 wells), NE Germany.

The island of Rügen (NE Germany), situated close to the Trans-European Suture Zone (TESZ), in the southern Baltic Sea is underlain by sedimentary rocks of an Early Palaeozoic age, known only from boreholes. The wells, Rügen 5/66 and Binz 1/73, were investigated for their chitinozoan assemblages to improve the earlier biostratigraphic dating (graptolites and acritarchs) and to facilitate comparisons with other chitinozoan assemblages on both sides of the TESZ. In the lower part of the Rügen 5/66 core (3794.7-3615.8m), Lagenochitina destombesi Elaouad-Debbaj is indicative of an early late Tremadoc age. In the upper part of the same well (3287.3-1709.7m), the observed chitinozoan taxa suggest an age spanning the early Llanvirn to the Caradoc. The entire sampled interval of the Binz 1/73 core (5217.6-5041.8m) is interpreted as belonging to the Siphonochitina formosa Biozone (early-early late Abereiddian, corresponding to the early Llanvirn). The chitinozoan data corroborate the earlier suggested biostratigraphic ages, based on acritarchs and graptolites. The chitinozoans from the Binz 1/73 well point to a high latitude provenance of the investigated host sediments at time of deposition.

DNA demethylation in normal colon tissue predicts predisposition to multiple cancers.

Some colon cancer (CC) patients present synchronous cancers at diagnosis and others develop metachronous neoplasms, but the risk factors are unclear for non-hereditary CC. We showed previously that global DNA demethylation increased with aging and correlated with genomic damage in CC, and we show now that preferentially associates to CCs with wild-type p53. This study aimed to elucidate the extent of DNA hypomethylation in patients with single and multiple CC, its relationship with aging, and its potential as predictive tool. We compared by real-time methylation-specific PCR the relative demethylation level (RDL) of long interspersed nucleotide element-1 (LINE-1) sequences in matched cancer tissues and non-cancerous colonic mucosa (NCM) from patients with single and multiple right-sided CCs. Although no RDL difference was found in NCM from single CC patients and healthy volunteers (P=0.5), there was more demethylation (higher RDL) in NCM from synchronous cancer patients (P=1.1 × 10(-5)) multiple CCs also were more demethylated than single CCs (P=0.0014). High NCM demethylation was predictive for metachronous neoplasms (P=0.003). In multivariate logistic regression analyses RDL was the only independent predictor for metachronous (P=0.02) and multiple (P=4.9 × 10(-5)) tumors. The higher LINE-1 demethylation in NCM from patients with multiple (synchronous and metachronous) tumors (P=9.6 × 10(-7)) was also very significant in patients with tumors without (P=3.8 × 10(-6)), but not with (P=0.16) microsatellite instability. NCM demethylation increased with aging in patients with single tumors, but decreased in those with multiple tumors. Moreover, the demethylation difference between patients with single vs multiple tumors appeared higher in younger (P=3.6 × 10(-4)) than in older (P=0.0016) patients. These results predict that LINE-1 hypomethylation in NCM can be used as an epigenetic predictive biomarker for multiple CC risk. The stronger association of demethylation in NCM with multiple CC risk from younger patients also suggests an inherited predisposition for the apparent field cancerization effect of somatic demethylation.

Quantification of multiple methane emission sources at landfills using a double tracer technique.

A double tracer technique was used successfully to quantify whole-site methane (CH(4)) emissions from Fakse Landfill. Emissions from different sections of the landfill were quantified by using two different tracers. A scaled-down version of the tracer technique measuring close-by to localized sources having limited areal extent was also used to quantify emissions from on-site sources at the landfill facility, including a composting area and a sewage sludge storage pit. Three field campaigns were performed. At all three field campaigns an overall leak search showed that the CH(4) emissions from the old landfill section were localized to the leachate collection wells and slope areas. The average CH(4) emissions from the old landfill section were quantified to be 32.6 ± 7.4 kg CH(4)h(-1), whereas the source at the new section was quantified to be 10.3 ± 5.3 kg CH(4)h(-1). The CH(4) emission from the compost area was 0.5 ± 0.25 kg CH(4)h(-1), whereas the carbon dioxide (CO(2)) and nitrous oxide (N(2)O) flux was quantified to be in the order of 332 ± 166 kg CO(2)h(-1) and 0.06 ± 0.03 kg N(2)Oh(-1), respectively. The sludge pit located west of the compost material was quantified to have an emission of 2.4 ± 0.63 kg h(-1) CH(4), and 0.03 ± 0.01 kg h(-1) N(2)O.