Cortical effects of shifting letter position in letter strings of varying length

Neuroimaging and lesion studies suggest that occipito-temporal brain areas play a necessary role in recognizing a wide variety of objects, be they faces, letters, numbers, or household items. However, many questions remain regarding the details of exactly what kinds of information are processed by the occipito-temporal cortex. Here, we address this question with respect to reading. Ten healthy adult subjects performed a single word reading task. We used whole-head magnetoencephalography to measure the spatio-temporal dynamics of brain responses, and investigated their sensitivity to: (1) lexicality (defined here as the difference between words and consonant strings), (2) word length, and (3) variation in letter position. Analysis revealed that midline occipital activity around 100 msec, consistent with low-level visual feature analysis, was insensitive to lexicality and variation in letter position, but was slightly affected by string length. Bilateral occipito-temporal activations around 150 msec were insensitive to lexicality and reacted to word length only in the timing (and not strength) of activation. However, vertical shifts in letter position revealed a hemispheric imbalance: The right hemisphere activation increased with the shifts, whereas the opposite pattern was evident in the left hemisphere. The results are discussed in the light of Caramazza and Hillis's (1990) model of early reading.     

Somatostatin receptor 2 knockout/lacZ knockin mice show impaired motor coordination and reveal sites of somatostatin action within the striatum

The peptide somatostatin can modulate the functional output of the basal ganglia. The exact sites and mechanisms of this action, however, are poorly understood, and the physiological context in which somatostatin acts is unknown. Somatostatin acts as a neuromodulator via a family of five 7-transmembrane G protein-coupled receptors, SSTR1-5, one of which, SSTR2, is known to be functional in the striatum. We have investigated the role of SSTR2 in basal ganglia function using mice in which Sstr2 has been inactivated and replaced by the lacZ reporter gene. Analysis of Sstr2lacZ expression in the brain by beta-galactosidase histochemistry demonstrated a widespread pattern of expression. By comparison to previously published in situ hybridization and immunohistochemical data, Sstr2lacZ expression was shown to accurately recapitulate that of Sstr2 and thus provided a highly sensitive model to investigate cell-type-specific expression of Sstr2. In the striatum, Sstr2 expression was identified in medium spiny projection neurons restricted to the matrix compartment and in cholinergic interneurons. Sstr2 expression was not detected in any other nuclei of the basal ganglia except for a sparse number of nondopaminergic neurons in the substantia nigra. Microdialysis in the striatum showed Sstr2-null mice were selectively refractory to somatostatin-induced dopamine and glutamate release. In behavioural tests, Sstr2-null mice showed normal levels of locomotor activity and normal coordination in undemanding tasks. However, in beam-walking, a test of fine motor control, Sstr2-null mice were severely impaired. Together these data implicate an important neuromodulatory role for SSTR2 in the striatum.     

Effect of positive expiratory pressure breathing in patients with cystic fibrosis.

The effect of positive expiratory pressure breathing, alone and in combination with coughing, was investigated in eight patients with cystic fibrosis. Functional residual capacity and total lung capacity was measured with a body plethysmograph before, during, and immediately after breathing with expiratory pressure of 5 and 15 cm H2O, and after a coughing period. The positive expiratory pressure breathing was carried out five times for two minutes with a two minute interval between each period. Mucus transport was measured in a peripheral lung region and over the whole lung by a radioactive aerosol tracer technique. Clearance measurements were carried out continuously during positive expiratory pressure breathing and during a control period. Two minutes' breathing with an expiratory pressure of 5 and 15 cm H2O caused an increase in mean (SEM) functional residual capacity from 2.6 (0.1) to 3.6 (0.3) and 4.4 (0.5) 1 and an increase in total lung capacity from 5.1 (0.2) to 5.9 (0.3) and 6.9 (0.4) 1. Lung volumes were higher during breathing with an expiratory pressure of 15 cm H2O than with 5 cm H2O; both returned to baseline values immediately after positive expiratory pressure breathing. Spontaneous mucus clearance and mucus clearance by coughing were not influenced by positive expiratory pressure breathing at either expiratory pressure. Thus in patients with cystic fibrosis positive expiratory pressure breathing increases lung volumes in relation to the expiratory pressure imposed; these changes in lung volume did not, however, lead to an improvement of mucus transport.     

Tumor oxygenation using direct injection of oxygenated saline

Direct injection of oxygen into an in-vivo tumor system was performed using saline lavage through a double-lumen catheter inserted into a Walker 256 carcinoma implanted in the flank of a rat. Ten extremely hypoxic tumors (core pO2 0 to 1 mm Hg) were examined. The mean pO2 in these tumors increased from 66 to 112 mm Hg after 5 minutes of lavage with oxygenated saline. These results indicate a substantial increase in tumor pO2 can be obtained with this system, possibly resulting in improved radioresponsiveness. More general applications of this system may also be feasible.     

Additive manufactured push‐fit implant fixation with screw‐strength pull out

Additive manufacturing offers exciting new possibilities for improving long‐term metallic implant fixation in bone through enabling open porous structures for bony ingrowth. The aim of this research was to investigate how the technology could also improve initial fixation, a precursor to successful long‐term fixation. A new barbed fixation mechanism, relying on flexible struts was proposed and manufactured as a push‐fit peg. The technology was optimized using a synthetic bone model and compared with conventional press‐fit peg controls tested over a range of interference fits. Optimum designs, achieving maximum pull‐out force, were subsequently tested in a cadaveric femoral condyle model. The barbed fixation surface provided more than double the pull‐out force for less than a third of the insertion force compared to the best performing conventional press‐fit peg (p < 0.001). Indeed, it provided screw‐strength pull out from a push‐fit device (1,124 ± 146 N). This step change in implant fixation potential offers new capabilities for low profile, minimally invasive implant design, while providing new options to simplify surgery, allowing for one‐piece push‐fit components with high levels of initial stability. © 2017 The Authors. Journal of Orthopaedic Research® Published by Wiley Periodicals, Inc. on behalf of the Orthopaedic Research Society. J Orthop Res 36:1508–1518, 2018.     

Integrating lipid screening with ideal cardiovascular health assessment in pediatric settings

Pediatric lipid screening and management with the aim of reducing and preventing adult disease is an internationally accepted concept, and guidelines have been published in several countries. However, implementation by the practicing pediatric community in the United States has been less than expected and delays have been attributed to uncertainty among providers. Reduced screening rates have also been reported for conditions contributing to arterial wall pathology such as obesity, hypertension, and prediabetes despite accumulating evidence that detection and intervention can lead to risk reversal. Consistent with graded and evidence-based national guidelines for comprehensive cardiovascular risk assessment and management, we present how the American Heart Association ideal cardiovascular health (ICVH) model can be integrated with lipid screening, and how it can be compatible with comprehensive pediatric lipidology practice and enhanced familial hypercholesterolemia detection. Since being introduced and retrospectively validated in adults and children in cross-sectional studies, ICVH evaluates thresholds for seven ideal health metrics representing measurements of obesity, dyslipidemia, diabetes risk, and blood pressure, and includes exercise, diet, and smoking behaviors. When each metric is valued as a point, the maximum health score is 7, but national surveys have shown unacceptable low scores in adolescence. Inverse correlation of scores with arterial structural change supports use of ICVH as a collection of treatable targets forming a cardiovascular prevention construct including and supporting lipid screening in pediatric settings, but implementation in clinical practice requires more expertise and administrative support than lipid screening alone.     

Inhibition of Chk1 by the G2 DNA damage checkpoint inhibitor isogranulatimide

Inhibitors of the G(2) DNA damage checkpoint can selectively sensitize cancer cells with mutated p53 to killing by DNA-damaging agents. Isogranulatimide is a G(2) checkpoint inhibitor containing a unique indole/maleimide/imidazole skeleton identified in a phenotypic cell-based screen; however, the mechanism of action of isogranulatimide is unknown. Using natural and synthetic isogranulatimide analogues, we show that the imide nitrogen and a basic nitrogen at position 14 or 15 in the imidazole ring are important for checkpoint inhibition. Isogranulatimide shows structural resemblance to the aglycon of UCN-01, a potent bisindolemaleimide inhibitor of protein kinase C beta (IC(50), 0.001 micromol/L) and of the checkpoint kinase Chk1 (IC(50), 0.007 micromol/L). In vitro kinase assays show that isogranulatimide inhibits Chk1 (IC(50), 0.1 micromol/L) but not protein kinase C beta. Of 13 additional protein kinases tested, isogranulatimide significantly inhibits only glycogen synthase kinase-3beta (IC(50), 0.5 micromol/L). We determined the crystal structure of the Chk1 catalytic domain complexed with isogranulatimide. Like UCN-01, isogranulatimide binds in the ATP-binding pocket of Chk1 and hydrogen bonds with the backbone carbonyl oxygen of Glu(85) and the amide nitrogen of Cys(87). Unlike UCN-01, the basic N15 of isogranulatimide interacts with Glu(17), causing a conformation change in the kinase glycine-rich loop that may contribute importantly to inhibition. The mechanism by which isogranulatimide inhibits Chk1 and its favorable kinase selectivity profile make it a promising candidate for modulating checkpoint responses in tumors for therapeutic benefit.