Splanchnic vein thromboses associated with myeloproliferative neoplasms: An international,retrospective study on 518 cases

Myeloproliferative Neoplasms (MPN) course can be complicated by thrombosis involving unusual sites as the splanchnic veins (SVT). Their management is challenging, given their composite vascular risk. We performed a retrospective, cohort study in the framework of the International Working Group for MPN Research and Treatment (IWG-MRT), and AIRC-Gruppo Italiano Malattie Mieloproliferative (AGIMM). A total of 518 MPN-SVT cases were collected and compared with 1628 unselected, control MPN population, matched for disease subtype. Those with MPN-SVT were younger (median 44 years) and enriched in females compared to controls; PV (37.1%) and ET (34.4%) were the most frequent diagnoses. JAK2V617F mutation was highly prevalent (90.2%), and 38.6% of cases had an additional hypercoagulable disorder. SVT recurrence rate was 1.6 per 100 patient-years. Vitamin K-antagonists (VKA) halved the incidence of recurrence (OR 0.48), unlike cytoreduction (OR 0.96), and were not associated with overall or gastrointestinal bleeding in multivariable analysis. Esophageal varices were the only independent predictor for major bleeding (OR 17.4). Among MPN-SVT, risk of subsequent vascular events was skewed towards venous thromboses compared to controls. However, MPN-SVT clinical course was overall benign: SVT were enriched in PMF with lower IPSS, resulting in significantly longer survival than controls; survival was not affected in PV and slightly reduced in ET. MPN-U with SVT (n = 55) showed a particularly indolent phenotype, with no signs of disease evolution. In the to-date largest, contemporary cohort of MPN-SVT, VKA were confirmed effective in preventing recurrence, unlike cytoreduction, and safe; the major risk factor for bleeding was esophageal varices that therefore represent a major therapeutic target.     

Estimating steatosis and fibrosis: Comparison of acoustic structure quantification with established techniques

AIM:To compare ultrasound-based acoustic structure quantification(ASQ) with established non-invasive techniques for grading and staging fatty liver disease.METHODS:Type 2 diabetic patients at risk of nonalcoholic fatty liver disease(n = 50) and healthy volunteers(n = 20) were evaluated using laboratory analysis and anthropometric measurements, transient elastography(TE), controlled attenuation parameter(CAP), proton magnetic resonance spectroscopy(1H-MRS; only available for the diabetic cohort), and ASQ.ASQ parameters mode, average and focal disturbance(FD) ratio were compared with:(1) the extent of liver fibrosis estimated from TE and nonalcoholic fatty liver disease(NAFLD) fibrosis scores; and(2) the amount of steatosis, which was classified according to CAP values.RESULTS:Forty-seven diabetic patients(age 67.0±8.6 years;body mass index 29.4±4.5 kg/m2)with reliable CAP measurements and all controls(age 26.5±3.2 years;body mass index 22.0±2.7 kg/m2)were included in the analysis.All ASQ parameters showed differences between healthy controls and diabetic patients(P0.001,respectively).The ASQ FD ratio(logarithmic)correlated with the CAP(r=-0.81,P0.001)and 1H-MRS(r=-0.43,P=0.004)results.The FD ratio[CAP250 d B/m:107(102-109),CAP between 250 and 300 d B/m:106(102-114);CAP between 300 and 350 d B/m:105(100-112),CAP≥350 d B/m:102(99-108)]as well as mode and average parameters,were reduced in cases with advanced steatosis(ANOVA P0.05).However,none of the ASQ parameters showed a significant difference in patients with advanced fibrosis,as determined by TE and the NAFLD fibrosis score(P0.08,respectively).CONCLUSION:ASQ parameters correlate with steatosis,but not with fibrosis in fatty liver disease.Steatosis estimation with ASQ should be further evaluated in biopsy-controlled studies.     

Complex health problems among the oldest old in Sweden: increased prevalence rates between 1992 and 2002 and stable rates thereafter

Studies of health trends in older populations usually focus on single health indicators. We include multiple medical and functional indicators, which together indicate the broader impact of health problems experienced by individuals and the need for integrated care from several providers of medical and long-term care. The study identified severe problems in three health domains (diseases/symptoms, mobility, and cognition/communication) in three nationally representative samples of the Swedish population aged 77+ in 1992, 2002, and 2011 (n ≈ 1900; response rate >85 %). Institutionalized people and proxy interviews were included. People with severe problems in two or three domains were considered to have complex health problems. Results showed a significant increase of older adults with complex health problems from 19 % in 1992 to 26 % in 2002 and no change thereafter. Changes over time remained when controlling for age and sex. When stratified by education, complex health problems increased significantly for people with lower education between 1992 and 2002 and did not change significantly between 2002 and 2011. For higher-educated people, there was no significant change over time. Among the people with severe problems in the symptoms/disease domain, about half had no severe problems in the other domains. People with severe mobility problems, on the other hand, were more likely to also have severe problems in other domains. Even stable rates may imply an increasing number of very old people with complex health problems, resulting in a need for improved coordination between providers of medical care and social services.     

Right parietal cortex mediates recognition memory for melodies

Functional brain imaging studies have highlighted the significance of right‐lateralized temporal, frontal and parietal brain areas for memory for melodies. The present study investigated the involvement of bilateral posterior parietal cortices (PPCs) for the recognition memory of melodies using transcranial direct current stimulation (tDCS). Participants performed a recognition task before and after tDCS. The task included an encoding phase (12 melodies), a retention period, as well as a recognition phase (24 melodies). Experiment 1 revealed that anodal tDCS over the right PPC led to a deterioration of overall memory performance compared with sham. Experiment 2 confirmed the results of Experiment 1 and further showed that anodal tDCS over the left PPC did not show a modulatory effect on memory task performance, indicating a right lateralization for musical memory. Furthermore, both experiments revealed that the decline in memory for melodies can be traced back to an interference of anodal stimulation on the recollection process (remember judgements) rather than to familiarity judgements. Taken together, this study revealed a causal involvement of the right PPC for memory for melodies and demonstrated a key role for this brain region in the recollection process of the memory task.     

The maize disease resistance gene Htn1 against northern corn leaf blight encodes a wall-associated receptor-like kinase

Northern corn leaf blight (NCLB) caused by the hemibiotrophic fungus Exserohilum turcicum is an important foliar disease of maize that is mainly controlled by growing resistant maize cultivars. The Htn1 locus confers quantitative and partial NCLB resistance by delaying the onset of lesion formation. Htn1 represents an important source of genetic resistance that was originally introduced from a Mexican landrace into modern maize breeding lines in the 1970s. Using a high-resolution map-based cloning approach, we delimited Htn1 to a 131.7-kb physical interval on chromosome 8 that contained three candidate genes encoding two wall-associated receptor-like kinases (ZmWAK-RLK1 and ZmWAK-RLK2) and one wall-associated receptor-like protein (ZmWAK-RLP1). TILLING (targeting induced local lesions in genomes) mutants in ZmWAK-RLK1 were more susceptible to NCLB than wild-type plants, both in greenhouse experiments and in the field. ZmWAK-RLK1 contains a nonarginine-aspartate (non-RD) kinase domain, typically found in plant innate immune receptors. Sequence comparison showed that the extracellular domain of ZmWAK-RLK1 is highly diverse between different maize genotypes. Furthermore, an alternative splice variant resulting in a truncated protein was present at higher frequency in the susceptible parents of the mapping populations compared with in the resistant parents. Hence, the quantitative Htn1 disease resistance in maize is encoded by an unusual innate immune receptor with an extracellular wall-associated kinase domain. These results further highlight the importance of this protein family in resistance to adapted pathogens.Plants are constantly attacked by potential pathogenic microbes, specifically, viruses, bacteria, and fungi. Although lacking an adaptive immune system comparable to the one found in vertebrates, plants have evolved a plethora of strategies to fend off microbial pathogens. The first tier of defense is formed by plasma membrane-anchored pattern recognition receptors (PRRs). These receptor proteins monitor the extracellular space for the presence of microbial- or host-derived elicitors, also called pathogen-associated molecular patterns (PAMP) or danger-associated molecular patterns (DAMP), respectively. Perception of PAMPs and DAMPs triggers a signaling cascade that activates numerous defense responses, called PAMP-triggered immunity and DAMP-triggered immunity, respectively. PAMPs are often highly conserved microbial structures that are characteristic for entire pathogen classes (1, 2). Examples are the fungal cell wall component chitin or bacterial flagellin. Perception of highly conserved PAMPs therefore results in broad-spectrum resistance against whole groups of nonadapted microbes, also referred to as nonhost resistance. To avoid PAMP-triggered immunity and DAMP-triggered immunity, pathogens are equipped with specific effectors that are tailored to suppress the plant’s immune response. These virulence effectors are injected into the host cytoplasm, where they can then, in turn, be recognized by cytoplasmic receptor proteins, which results in effector-triggered immunity (ETI) (3). The intracellular recognition of effector molecules is mediated by structurally related proteins belonging to the nucleotide-binding site-leucine-rich repeat (NBS-LRR) family (4). ETI forms the second tier of the plant immune response. In contrast to nonhost resistance, the ETI response against adapted pathogens is much stronger and often results in the death of the infected cell through hypersensitive reaction. Hence, there is a strong selective pressure on the pathogen to avoid ETI by evolving new virulence effectors that escape recognition by NBS-LRR immune receptors. This coevolutionary arms race is the major reason for rapid breakdown of NBS-LRR-based disease resistance in crop plants, which often occurs within only a few years (5, 6).Cell surface PRRs are encoded by receptor-like kinase (RLK) and receptor-like protein (RLP) genes. Both RLKs and RLPs contain an extracellular elicitor-binding domain and a transmembrane domain. In contrast to RLKs, RLPs lack a cytoplasmic serine/threonine kinase domain (7). The best-studied PRR is the leucine-rich repeat (LRR) receptor-like kinase flagellin-sensitive-2 (FLS2) of Arabidopsis, which binds an epitope of bacterial flagellin. On flagellin perception, this kinase initiates a signaling cascade that results in nonhost resistance (8). Most PRRs described until today contain such an extracellular LRR domain. Not all PRRs, however, are involved in nonhost resistance. The rice LRR-RLK Xa21, for example, confers race-specific resistance against the bacterial rice blast pathogen Xanthomonas oryzae pv. oryzae (9). The effector recognized by Xa21 is still unknown. In addition, plants have evolved the ability to perceive endogenous molecules through PRRs that are produced during pathogen infection. For example, the Arabidopsis wall-associated kinase 1 (WAK1) binds cell wall-derived oligogalacturonides that are released during pathogen infection and serve as DAMPs (10). AtDORN1, an Arabidopsis lectin-RLK, binds plant-derived extracellular ATP likely produced during pathogen infection or wounding (11).Maize (Zea mays L.) is the most widely grown crop in the world and represents an important source of food, feed, biofuel, and industrial products. Fungal diseases are a major threat to maize production and can result in severe crop losses. Northern corn leaf blight (NCLB) is the most devastating foliar disease of maize. It is caused by the hemibiotrophic ascomycete fungus Exserohilum turcicum (teleomorph Setosphaeria turcica) (12). The fungus spreads biotrophically during the initial infection process before switching to a necrotrophic lifestyle. Infections manifest as local lesions and necrosis, which lead to reduced photosynthetically active leaf area and yield losses. The disease occurs prevalently under conditions of high humidity and moderate temperatures and can be found in most regions where maize is grown (13–15). The Htn1 locus confers quantitative and partial resistance against NCLB by delaying lesion formation. Htn1 was originally introgressed into modern maize cultivars from the Mexican landrace Pepitilla in the 1970s (16). The Htn1 resistance reaction is different from the other known major NCLB resistance genes Ht1, Ht2, and Ht3, which confer qualitative resistance, resulting in chlorotic-necrotic lesions. In contrast, Htn1 leads to a delay of sporulation without chlorotic lesions (17, 18). The dominant and race-specific Htn1 gene is effective against the most prevalent NCLB races, but virulent isolates have been found (18). The strength of the Htn1 resistance depends on environmental conditions and maize genotype (19). Htn1 has been mapped to maize chromosome 8 ∼10 cM distal to the NCLB resistance gene Ht2 (20–23).Here, we describe the map-based isolation of the Htn1 gene, which encodes for a pattern recognition receptor with a putative extracellular, wall-associated domain.