Putative protective neural mechanisms in prereaders with a family history of dyslexia who subsequently develop typical reading skills

Developmental dyslexia affects 40–60% of children with a familial risk (FHD+) compared to a general prevalence of 5–10%. Despite the increased risk, about half of FHD+ children develop typical reading abilities (FHD+Typical). Yet the underlying neural characteristics of favorable reading outcomes in at‐risk children remain unknown. Utilizing a retrospective, longitudinal approach, this study examined whether putative protective neural mechanisms can be observed in FHD+Typical at the prereading stage. Functional and structural brain characteristics were examined in 47 FHD+ prereaders who subsequently developed typical (n = 35) or impaired (n = 12) reading abilities and 34 controls (FHD?Typical). Searchlight‐based multivariate pattern analyses identified distinct activation patterns during phonological processing between FHD+Typical and FHD?Typical in right inferior frontal gyrus (RIFG) and left temporo‐parietal cortex (LTPC) regions. Follow‐up analyses on group‐specific classification patterns demonstrated LTPC hypoactivation in FHD+Typical compared to FHD?Typical, suggesting this neural characteristic as an FHD+ phenotype. In contrast, RIFG showed hyperactivation in FHD+Typical than FHD?Typical, and its activation pattern was positively correlated with subsequent reading abilities in FHD+ but not controls (FHD?Typical). RIFG hyperactivation in FHD+Typical was further associated with increased interhemispheric functional and structural connectivity. These results suggest that some protective neural mechanisms are already established in FHD+Typical prereaders supporting their typical reading development.     

Validation of a small molecule inhibitor of PDE6D-RAS interaction with favorable anti-leukemic effects

RAS mutations prevalent in high-risk leukemia have been linked to relapse and chemotherapy resistance. Efforts to directly target RAS proteins have been largely unsuccessful. However, since RAS-mediated transformation is dependent on signaling through the RAS-related C3 botulinum toxin substrate (RAC) small GTPase, we hypothesized that targeting RAC may be an effective therapeutic approach in RAS mutated tumors. Here we describe multiple small molecules capable of inhibiting RAC activation in acute lymphoblastic leukemia cell lines. One of these, DW0254, also demonstrates promising anti-leukemic activity in RAS-mutated cells. Using chemical proteomics and biophysical methods, we identified the hydrophobic pocket of phosphodiester 6 subunit delta (PDE6D), a known RAS chaperone, as a target for this compound. Inhibition of RAS localization to the plasma membrane upon DW0254 treatment is associated with RAC inhibition through a phosphatidylinositol-3-kinase/AKT-dependent mechanism. Our findings provide new insights into the importance of PDE6D-mediated transport for RAS-dependent RAC activation and leukemic cell survival.Subject terms: Acute lymphocytic leukaemia, Acute myeloid leukaemia, Drug development, Targeted therapies     

Retrospective study investigating the prevalence and clinical significance of hepatitis B virus precore and basal core promoter variants

BACKGROUND:

Hepatitis B virus (HBV) precore (PC) and basal core promoter (BCP) variants are well known; however, their prevalence in North America is unclear, especially among hepatitis B e antigen-negative patients.

OBJECTIVE:

To investigate the prevalence of PC/BCP mutations and their clinical significance.

METHODS:

One hundred twenty-eight patients positive for both hepatitis B surface antigen and hepatitis B e antibody were selected, and PC/BCP mutations were identified using a line probe assay. The subjects’ charts were reviewed for race/ethnicity, HBV genotype, HBV viral load, sex, liver enzyme levels, imaging and biopsy results up to 10 years before the study.

RESULTS:

The prevalence of PC and BCP variants were 47.6% and 62.5%, respectively. Older age was associated with aspartate aminotransferase-to-platelet index ratio (APRI) ≥0.7 (P=0.011) and abnormal imaging/biopsy results (P=0.0008). Although the presence of BCP variant(s) was associated with APRI ≥0.7 (P=0.029), it was not associated with abnormal imaging/biopsy results. The combination of age ≥50 years and the presence of BCP variant(s) was associated with abnormal imaging/biopsy results, suggestive of either cirrhosis or hepatocellular carcinoma (not observed with PC mutation). Neither sex or genotype, or median HBV viral load showed significant influence on any of these outcomes.

CONCLUSIONS:

The present study suggests that the prevalence of PC and BCP mutations are higher than what has been previously reported. One potential explanation would be increased immigration in the past decade. Considering the potential public health and clinical implications of these variants, long-term multicentre and prospective studies could further unravel the uncertainty around these variants.     

Prescribing Patterns and Awareness of Adverse Effects of Infliximab: A Health Survey of Gastroenterologists

We sought to determine prescribing patterns and awareness of adverse drug reactions to infliximab among gastroenterologists. A questionnaire was developed and mailed to all gastroenterologists in Maryland and Washington, D.C. Ninety-six of 336 (28.6%) gastroenterologists responded; 86% of respondents use infliximab often or sometimes and 48% infuse infliximab on-site. Only 48% of respondents use immunomodulators prior to infusing infliximab. Thirty-three percent of respondents do not prescribe maintenance infliximab. Respondents reported that infusion reactions occur in 12.9% of infliximab infusions. Most respondents order a purified protein derivative prior to starting infliximab. Respondents underestimated the risk of serious infection, death, demyelinating diseases, and malignancy and overestimated the risk of congestive heart failure. We conclude that a substantial number of gastroenterologists underutilize immunomodulators and fail to prescribe maintenance infliximab. Further, respondents were unaware of the frequency of major adverse events associated with infliximab. Education regarding treatment algorithms in CD and infliximab-related side effects is needed.     

Entecavir exhibits inhibitory activity against human immunodeficiency virus under conditions of reduced viral challenge

Entecavir (ETV) was developed for the treatment of chronic hepatitis B virus (HBV) infection and is globally approved for that indication. Initial preclinical studies indicated that ETV had no significant activity against human immunodeficiency virus type 1 (HIV-1) in cultured cell lines at physiologically relevant ETV concentrations, using traditional anti-HIV assays. In response to recent clinical observations of anti-HIV activity of ETV in HIV/HBV-coinfected patients not receiving highly active antiretroviral therapy (HAART), additional investigative studies were conducted to expand upon earlier results. An extended panel of HIV-1 laboratory and clinical strains and cell types was tested against ETV, along with a comparison of assay methodologies and resistance profiling. These latest studies confirmed that ETV has only weak activity against HIV, using established assay systems. However, a >100-fold enhancement of antiviral activity (equivalent to the antiviral activity of lamivudine) could be obtained when assay conditions were modified to reduce the initial viral challenge. Also, the selection of a M184I virus variant during the passage of HIV-1 at high concentrations of ETV confirmed that ETV can exert inhibitory pressure on the virus. These findings may have a significant impact on how future assays are performed with compounds to be used in patients infected with HIV. These results support the recommendation that ETV therapy should be administered in concert with HAART for HIV/HBV-coinfected patients.     

Eye, head, and body coordination during large gaze shifts in rhesus monkeys: movement kinematics and the influence of posture

Coordinated movements of the eye, head, and body are used to redirect the axis of gaze between objects of interest. However, previous studies of eye-head gaze shifts in head-unrestrained primates generally assumed the contribution of body movement to be negligible. Here we characterized eye-head-body coordination during horizontal gaze shifts made by trained rhesus monkeys to visual targets while they sat upright in a standard primate chair and assumed a more natural sitting posture in a custom-designed chair. In both postures, gaze shifts were characterized by the sequential onset of eye, head, and body movements, which could be described by predictable relationships. Body motion made a small but significant contribution to gaze shifts that were > or =40 degrees in amplitude. Furthermore, as gaze shift amplitude increased (40-120 degrees ), body contribution and velocity increased systematically. In contrast, peak eye and head velocities plateaued at velocities of approximately 250-300 degrees /s, and the rotation of the eye-in-orbit and head-on-body remained well within the physical limits of ocular and neck motility during large gaze shifts, saturating at approximately 35 and 60 degrees , respectively. Gaze shifts initiated with the eye more contralateral in the orbit were accompanied by smaller body as well as head movement amplitudes and velocities were greater when monkeys were seated in the more natural body posture. Taken together, our findings show that body movement makes a predictable contribution to gaze shifts that is systematically influenced by factors such as orbital position and posture. We conclude that body movements are part of a coordinated series of motor events that are used to voluntarily reorient gaze and that these movements can be significant even in a typical laboratory setting. Our results emphasize the need for caution in the interpretation of data from neurophysiological studies of the control of saccadic eye movements and/or eye-head gaze shifts because single neurons can code motor commands to move the body as well as the head and eyes.