Narrative discourse in young children with histories of early corrective heart surgery.

Narrative attainment was assessed in a group of 76 four-year-old children at risk for brain injury because of histories of early corrective heart surgery. Elicited personal experience narratives were coded for narrative components, evaluative devices, and information adequacy and were contrasted with narratives produced by a comparison group of typically developing 4-year-olds. The production of autonomous narrative discourse was identified as an area of special vulnerability for children with this medical history. Despite considerable heterogeneity in narrative performance, children with early corrective heart surgery produced fewer narrative components than typically developing children. Results suggest that the elaboration of events and contextual information, the expression of subjective evaluation and causality, and clarity and explicitness of information reporting may constitute special challenges for this population of children. Implications of these findings for clinical assessment and possible risks for socioemotional relationships and academic achievement are discussed.     

Fluorescence in Situ Hybridization (FISH) Utility for Risk Score Assessment in Patients With MDS With Normal Metaphase Karyotype

BackgroundCytogenetic profile is an essential parameter in myelodysplastic syndromes (MDS) risk stratification by both International Prognostic Symptom Score (IPSS) and Revised (R)-IPSS. Almost one-half of patients with MDS have normal cytogenetics by metaphase karyotype. Here we report the yield of MDS fluorescence in situ hybridization (FISH) panel detecting cytogenetic abnormalities in these patients and its impact on risk stratification.Patients and MethodsAmong patients with normal metaphase karyotype, we assessed those patients who had cytogenetic abnormalities detected by an MDS FISH panel, which included probes for del (5), del (7), del (20), trisomy 8, and del (17p). Risk stratification was calculated by both IPSS and R-IPSS.ResultsOf 1600 patients with MDS with normal metaphase karyotype, 53 (3%) patients had cytogenetic abnormality detected by MDS FISH panel. Integrating the MDS FISH panel cytogenetics (IPSS + FISH restaging) resulted in upstaging the score, where 53% of low-risk IPSS were upstaged to intermediate (int)-1, 56% of int-1 were upstaged to int-2, and 78% of int-2 were upstaged to high risk. Based on the R-IPSS, 61% of very low-risk patients, all low-risk patients, 92% of intermediate-risk patients, and 50% of high-risk patients with FISH abnormalities were upstaged, respectively.ConclusionThe yield of MDS FISH panel detecting cytogenetic abnormalities in patients with normal karyotype by G-banding is low and may not warrant ordering the panel in all patients. Among the 3% of patients with normal karyotype who had cytogenetic abnormality detected by FISH, the risk score assignment by IPSS and R-IPSS was upstaged.     

U-RT1 – A new model for Richter transformation

The advent of highly effective treatments targeting the disease biology of chronic lymphocytic leukemia (CLL) has transformed the therapeutic field tremendously. However, transformation into an aggressive B-cell lymphoma, called Richter syndrome (RS), remains highly challenging since the treatment options for this condition are still insufficient. Exploratory drug testing and experimental studies are restricted by the lack of satisfactory models. We have established U-RT1, a cell line derived from a highly proliferating RS clonally related to the patient''s underlying CLL. The cell line shows morphological features and an immunophenotype of RS-DLBCL (non-GCB). Molecular analysis revealed a complex karyotype with driver aberrations characteristic for RS such as loss of TP53 and CDKN2A. Furthermore, U-RT1 displays a chromosomal gain of the NOTCH1 gene locus and strong immunoreactivity for BCL-2. These features suggest that U-RT1 is the first eligible model system for investigations on the pathogenesis of RS and novel treatment options.     

Brain changes associated with thromboxane receptor antagonist SQ 29,548 treatment in a mouse model

The purpose of this study was to characterize behavioral and physiological effects of a selective thromboxane (TP) receptor antagonist, SQ 29,548, in the C57Bl/6 mouse model. At 6 months of age, male mice were given either sham or drug i.p. injections for 3 days at a dose of 2 mg/kg each day. On the day after the final injection, mice were subjected to behavioral testing before brain collection. Left hemisphere hippocampi were collected from all mice for protein analysis via Western blot. Right brain hemispheres were fixed and embedded in gelatin and then serially sectioned. The sections were immunostained with anti‐c‐Fos antibodies. Prostaglandin analysis was performed from remaining homogenized brain samples, minus the hippocampi. Injection of SQ 29,548 decreased selective brain prostaglandin levels compared with sham controls. This correlated with robust increases in limbic‐region c‐Fos immunoreactivity in the SQ 29,548‐injected mice. However, drug‐treated mice demonstrated no significant changes in relevant hippocampal protein levels compared with sham treatments, as determined from Western blots. Surprisingly, injection of SQ 29,548 caused mixed changes in parameters of depression and anxiety‐like behavior in the mice. In conclusion, the results indicate that administration of peripheral TP receptor antagonists alters brain levels of prostanoids and influences neuronal activity, with only minimal alterations of behavior. Whether the drug affects neurons directly or through a secondary pathway involving endothelium or other tissues remains unclear. © 2015 Wiley Periodicals, Inc.     

Negative regulators of the RIG‐I‐like receptor signaling pathway

Upon recognition of specific molecular patterns on microbes, host cells trigger an innate immune response, which culminates in the production of type I interferons, proinflammatory cytokines and chemokines, and restricts pathogen replication and spread within the host. At each stage of this response, there are stimulatory and inhibitory signals that regulate the magnitude, quality, and character of the response. Positive regulation promotes an antiviral state to control and eventually clear infection, whereas negative regulation dampens inflammation and prevents immune‐mediated tissue damage. An overexuberant innate response can lead to cell and tissue destruction, and the development of spontaneous autoimmunity. The retinoic acid‐inducible gene I (RIG‐I)‐like receptors (RLRs), RIG‐I and melanoma differentiation‐associated gene 5 (MDA5), belong to a family of cytosolic host RNA helicases that recognize distinct nonself RNA signatures and trigger innate immune responses against several RNA viruses by signaling through the essential adaptor protein mitochondrial antiviral signaling (MAVS). The RLR signaling pathway is tightly regulated to maximize antiviral immunity and minimize immune‐mediated pathology. This review highlights contemporary findings on negative regulators of the RLR signaling pathway, with specific focus on the proteins and biological processes that directly regulate RIG‐I, MDA5 and MAVS signaling function.     

From the Cover: Dietary changes of large herbivores in the Turkana Basin,Kenya from 4 to 1 Ma

A large stable isotope dataset from East and Central Africa from ca. 30 regional collection sites that range from forest to grassland shows that most extant East and Central African large herbivore taxa have diets dominated by C₄ grazing or C₃ browsing. Comparison with the fossil record shows that faunal assemblages from ca. 4.1–2.35 Ma in the Turkana Basin had a greater diversity of C₃–C₄ mixed feeding taxa than is presently found in modern East and Central African environments. In contrast, the period from 2.35 to 1.0 Ma had more C₄-grazing taxa, especially nonruminant C₄-grazing taxa, than are found in modern environments in East and Central Africa. Many nonbovid C₄ grazers became extinct in Africa, notably the suid Notochoerus, the hipparion equid Eurygnathohippus, the giraffid Sivatherium, and the elephantid Elephas. Other important nonruminant C₄-grazing taxa switched to browsing, including suids in the lineage Kolpochoerus-Hylochoerus and the elephant Loxodonta. Many modern herbivore taxa in Africa have diets that differ significantly from their fossil relatives. Elephants and tragelaphin bovids are two groups often used for paleoecological insight, yet their fossil diets were very different from their modern closest relatives; therefore, their taxonomic presence in a fossil assemblage does not indicate they had a similar ecological function in the past as they do at present. Overall, we find ecological assemblages of C₃-browsing, C₃–C₄-mixed feeding, and C₄-grazing taxa in the Turkana Basin fossil record that are different from any modern ecosystem in East or Central Africa.The expansion of C₄ biomass beginning in the late Miocene marks a major vegetation change in the history of Earth. Today C₄ plants comprise ca. 50% of net primary productivity (NPP) in the tropics (1) yet contributed less than 1% of NPP only 10 million years ago. C₄ plants are primarily grasses and sedges, although C₄ photosynthesis is known to be used in ∼20 plant families (2, 3). C₄ photosynthesis is an adaptation to low (ca. <500 ppm by volume) concentrations of CO₂ in Earth’s atmosphere along with high growing-season temperatures (4). Although genetic evidence indicates an Oligocene origin of C₄ photosynthesis in the grasses (5, 6), macrofossil evidence for C₄ photosynthesis in grasses is extremely sparse (7, 8).The expansion of C₄ biomass has been documented through stable isotopes in paleosols (9–12), grass phytoliths (13), herbivore tooth enamel (14–16), and biomarkers in deep-sea sediments (17, 18). At 10 Ma in Africa, Asia, and North America, the δ¹³C values for equid tooth enamel indicate a diet dominated by C₃ vegetation; by ca. 7 Ma, equids in Africa have a diet dominated (>75%) by C₄ vegetation (14, 15). In East Africa today there is a distinct difference in diets of major herbivores, with most mammals either being predominantly browsing (>ca. 75% C₃) or grazing (>ca. 75% C₄), and there are relatively few mixed feeders (Fig. 1).Open in a separate windowFig. 1.δ¹³C₁₇₅₀ values for tooth enamel (or equivalent) for >1,900 mammals from East and Central Africa (principal localities in SI Appendix, Table S1; data from Dataset S1).A recent study of the early transition of C₃ to C₄ dietary change in the Turkana Basin from 10 Ma to ca. 4 Ma (15) showed that equids were the earliest mammals to fully exploit the C₄ dietary resource, attaining a predominantly C₄-grazing diet by 7 Ma. Other mammal groups (hippopotamids, elephantids, and bovids) changed to a C₄ diet later than did the equids. In this paper we document dietary changes in the major Artiodactyla-Perissodactyla-Proboscidea (APP) taxa in the Turkana Basin between ca. 4 Ma and 1 Ma and compare those to dietary preferences of extant APP taxa in East and Central Africa. The Turkana Basin has an excellent stratigraphy (19–22) with excellent preservation of fossils from 4 to 1 Ma; this study focuses on fossils recovered from the Koobi Fora, Kanapoi, and Nachukui Formations of northern Kenya.We compare dietary changes within the major APP taxa through the past 4 Ma in the formations listed above using >900 individual fossils that represent the major taxa collected within the principal stratigraphic intervals of these formations. Fossil mammalian diets are compared with those of >1,900 extant mammal individuals sampled from >30 different regions and habitats in eastern and central Africa. We compare the ecosystem structure (C₃ browsers, C₃/C₄ mixed diets, and C₄ grazers) through the Pliocene and Pleistocene and document changes in ungulate diets over time.     

Prediction and prevention of relapse of acute lymphoblastic leukaemia after bone marrow transplantation

Results of bone marrow transplantation (BMT) in 63 adults and children with ALL transplanted in the 5-year period 1979-83 were analysed. Twenty-one patients (33%) relapsed, 25% of the group died in relapse and 19% died from complications of BMT. The actuarial disease-free survival at 6 years was 38%. Relapse after BMT could be predicted by standard prognostic diagnostic features such as age, sex, cell type and presenting blast cell count. Patients transplanted in first remission selected for their poor prognosis had a lower relapse risk than a similar group of poor prognosis patients transplanted in second or subsequent remission (P less than 0.05). Relapse following second and subsequent remission BMT was predicted by a score based on standard prognostic features or by the pace of the disease: patients with an interval of less than 2 years between diagnosis and first relapse having a 15% actuarial disease-free survival, compared with 81% for patients with an interval greater than 2 years (P less than 0.001). These results emphasize that ALL is a heterogeneous disease and establishes the importance of determining relapse risk when selecting BMT and other treatment schedules for ALL patients.