Rhythm in the speech of a person with right hemisphere damage: Applying the pairwise variability index

Although several aspects of prosody have been studied in speakers with right hemisphere damage (RHD), rhythm remains largely uninvestigated. This study compares the rhythm of an Australian English speaker with right hemisphere damage (due to a stroke, but with no concomitant dysarthria) to that of a neurologically unimpaired individual. The speakers' rhythm is compared using the pairwise variability index (PVI) which allows for an acoustic characterization of rhythm by comparing the duration of successive vocalic and intervocalic intervals. A sample of speech from a structured interview between a speech and language therapist and each participant was analysed. Previous research has shown that speakers with RHD may have difficulties with intonation production, and therefore it was hypothesized that there may also be rhythmic disturbance. Results show that the neurologically normal control uses a similar rhythm to that reported for British English (there are no previous studies available for Australian English), whilst the speaker with RHD produces speech with a less strongly stress-timed rhythm. This finding was statistically significant for the intervocalic intervals measured (t(8) = 4.7, p < .01), and suggests that some aspects of prosody may be right lateralized for this speaker. The findings are discussed in relation to previous findings of dysprosody in RHD populations, and in relation to syllable-timed speech of people with other neurological conditions.     

Manipulation of liver regeneration with macrophages to influence the hepatic progenitor cell niche

Insufficient regeneration of the adult liver is believed to cause failure to recover from severe liver disease. An undifferentiated cell population with stem-cell-like qualities known as hepatic progenitor cells (HPCs) is hypothesised to have a central role in regeneration of the adult liver during massive or chronic liver disease. Stem cells in other organ systems are believed to reside in a specialised microenvironment or niche that supports their maintenance and function. The existence of a hepatic stem cell niche might provide a means of therapeutically manipulating endogenous HPCs in vivo as a regenerative therapy.To investigate the physiological potential of HPCs to regenerate the mammalian liver, we have established a novel model of hepatocellular injury and HPC activation using genetic manipulation of hepatocytes. After hepatocyte senescence and death in this model (AhCre Mdm2^flox), HPCs expand and bring about the complete regeneration of the liver parenchyma.We demonstrate that a stereotypical niche, consisting partly of macrophages, exists in both animal models and correlating human disease. Using cell tracking, we show active recruitment of extrahepatic macrophages into this niche during injury. In health, intravenous injection of macrophages results in macrophage engraftment to the liver niche, with subsequent HPC activation and changes to liver structure and function.Within the niche, macrophages use paracrine signalling to control both HPC proliferation and cell fate via TWEAK (tumour-necrosis-factor-like weak inducer of apoptosis) and the Wnt signalling pathway, respectively. After hepatocellular injury, macrophages ingest hepatocyte debris, and release Wnt which promotes HPC differentiation into hepatocytes. TWEAK is vital for HPC proliferation in the AhCre Mdm2^flox model of regeneration. Here, the absence of TWEAK signalling results in liver failure and mortality.This work has demonstrated for the first time the ability of a solid organ to fully regenerate in the adult mammal from progenitor cells, and additionally highlights mechanisms by which this process can be modulated by either small molecule or cell therapy.FundingUniversity of Edinburgh.     

Integration host factor interactions with Neisseria gene sequences: correlation between predicted binding sites and in vitro binding of Neisseria -derived IHF protein

Putative integration host factor (IHF) binding sites are frequently being identified in Neisseria gene sequences on the basis of similarity to a degenerate Escherichia coli -derived consensus binding sequence. In this report, three different Neisseria genetic systems that contain predicted IHF binding sites were assessed for IHF binding through gel retardation analysis. The results show a positive correlation between the identification of a predicted Neisseria IHF binding site and in vitro binding of Neisseria -derived IHF protein.     

Large scale integration of drug-target information reveals poly-pharmacological drug action mechanisms in tumor cell line growth inhibition assays

Understanding therapeutic mechanisms of drug anticancer cytotoxicity represents a key challenge in preclinical testing. Here we have performed a meta-analysis of publicly available tumor cell line growth inhibition assays (~ 70 assays from 6 independent experimental groups covering ~ 500 000 molecules) with the primary goal of understanding molecular therapeutic mechanisms of cancer cytotoxicity. To implement this we have collected currently available information on protein targets for molecules that were tested in the assays. We used a statistical methodology to identify protein targets overrepresented among molecules exhibiting cancer cytotoxicity with the particular focus of identifying overrepresented patterns consisting of several proteins (i.e. proteins “A” and “B” and “C”). Our analysis demonstrates that targeting individual proteins can result in a significant increase (up to 50-fold) of the observed odds for a molecule to be an efficient inhibitor of tumour cell line growth. However, further insight into potential molecular mechanisms reveals a multi-target mode of action: targeting a pattern of several proteins drastically increases the observed odds (up to 500-fold) for a molecule to be tumour cytotoxic. In contrast, molecules targeting only one protein but not targeting an additional set of proteins tend to be nontoxic. Our findings support a poly-pharmacology drug discovery paradigm, demonstrating that anticancer cytotoxicity is a product, in most cases, of multi-target mode of drug action     

Host immunity contributes to the anti-melanoma activity of BRAF inhibitors

The BRAF mutant, BRAF^V600E, is expressed in nearly half of melanomas, and oral BRAF inhibitors induce substantial tumor regression in patients with BRAF^V600E metastatic melanoma. The inhibitors are believed to work primarily by inhibiting BRAF^V600E-induced oncogenic MAPK signaling; however, some patients treated with BRAF inhibitors exhibit increased tumor immune infiltration, suggesting that a combination of BRAF inhibitors and immunotherapy may be beneficial. We used two relatively resistant variants of Braf^V600E-driven mouse melanoma (SM1 and SM1WT1) and melanoma-prone mice to determine the role of host immunity in type I BRAF inhibitor PLX4720 antitumor activity. We found that PLX4720 treatment downregulated tumor Ccl2 gene expression and decreased tumor CCL2 expression in both Braf^V600E mouse melanoma transplants and in de novo melanomas in a manner that was coincident with reduced tumor growth. While PLX4720 did not directly increase tumor immunogenicity, analysis of SM1 tumor-infiltrating leukocytes in PLX4720-treated mice demonstrated a robust increase in CD8⁺ T/FoxP3⁺CD4⁺ T cell ratio and NK cells. Combination therapy with PLX4720 and anti-CCL2 or agonistic anti-CD137 antibodies demonstrated significant antitumor activity in mouse transplant and de novo tumorigenesis models. These data elucidate a role for host CCR2 in the mechanism of action of type I BRAF inhibitors and support the therapeutic potential of combining BRAF inhibitors with immunotherapy.     

A technique for the rapid diagnosis of atrial tachycardia in the electrophysiology laboratory

OBJECTIVE: The purpose of this study was to determine if the atrial response upon cessation of ventricular pacing associated with 1:1 ventriculoatrial conduction during paroxysmal supraventricular tachycardia is a useful diagnostic maneuver in the electrophysiology laboratory. BACKGROUND: Despite various maneuvers, it can be difficult to differentiate atrial tachycardia from other forms of paroxysmal supraventricular tachycardia. METHODS: The response upon cessation of ventricular pacing associated with 1:1 ventriculoatrial conduction was studied during four types of tachycardia: 1) atrioventricular nodal reentry (n = 102), 2) orthodromic reciprocating tachycardia (n = 43), 3) atrial tachycardia (n = 19) and 4) atrial tachycardia simulated by demand atrial pacing in patients with inducible atrioventricular nodal reentry or orthodromic reciprocating tachycardia (n = 32). The electrogram sequence upon cessation of ventricular pacing was, categorized as "atrial-ventricular" (A-V) or "atrial-atrial-ventricular" (A-A-V). RESULTS: The A-V response was observed in all cases of atrioventricular nodal reentrant and orthodromic reciprocating tachycardia. In contrast, the A-A-V response was observed in all cases of atrial tachycardia and simulated atrial tachycardia, even in the presence of dual atrioventricular nodal pathways or a concealed accessory atrioventricular pathway. CONCLUSIONS: In conclusion, an A-A-V response upon cessation of ventricular pacing associated with 1:1 ventriculoatrial conduction is highly sensitive and specific for the identification of atrial tachycardia in the electrophysiology laboratory.     

A comparison of U.S. and Canadian cardiac catheterization practices in detecting severe coronary artery disease after myocardial infarction: efficiency, yield and long-term implications.

OBJECTIVES: We sought to compare U.S. and Canada's post-myocardial infarction (MI) cardiac catheterization practices in the detection of severe coronary artery disease (CAD). BACKGROUND: Little is known about the efficiency with which the aggressive post-MI catheterization strategy observed in the U.S. detects severe CAD compared with the more conservative strategy observed in Canada. METHODS: From the U.S. and Canadian patients who had participated in the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Arteries trial (n = 22,280, 11.5% Canadian), we examined the frequency of in-hospital cardiac catheterization, the prevalence of severe CAD observed at catheterization (diagnostic efficiency) and the total number of MI patients with severe CAD identified (diagnostic yield). RESULTS: The rate of catheterization in the U.S. was more than 2.5 times that in Canada (71% vs. 27%, respectively, p < 0.001). With identical prevalences of severe CAD at catheterization (17%) in the two countries, the higher frequency of catheterization in the U.S. resulted in the identification of more than two and a half times as many cases of severe CAD compared with Canada (12 severe CAD cases identified per 100 post-MI patients in the U.S., vs. 4.6 per 100 in Canada). If considered in isolation, we estimated that these differences in severe disease detection might effect a small long-term survival advantage in favor of the U.S. strategy (estimated 5.0 lives saved per 1,000 MI patients). CONCLUSIONS: Canada's more restrictive post-MI cardiac catheterization strategy is no more efficient in identifying severe CAD than the aggressive U.S. strategy, and may fail to identify a substantial number of post-MI patients with high risk coronary anatomy. The long-term impact of these differences in practice patterns requires further evaluation.     

Methods for in vitro characterization of multichannel nerve tubes

Multichannel conduits have been developed for experimental peripheral nerve and spinal cord repair. We present a series of methods to characterize multichannel nerve tubes for properties of bending, deformation, swelling, and degradation and introduce a new method to test the permeability of multichannel nerve tubes from the rate of diffusion of different-sized fluorescent dextran molecules (10, 40, and 70 kDa). First, single-lumen nerve tubes made with different poly(lactic-co-glycolic acid) (PLGA) ratios (50:50, 75:25, and 85:15) were compared. One ratio (75:25 PLGA) was subsequently used to compare single-lumen and multichannel nerve tubes. Nerve tubes made with lower PLGA ratios were found to be more flexible than nerve tubes made with a higher PLGA ratio. For low ratios, however, swelling was also greater as a result of a faster rate of degradation. Multichannel structure did not interfere with the permeability of the tube; the rate of diffusion into multichannel 75:25 PLGA nerve tubes appeared to be even higher than that into single-lumen ones, but this was only significant for 70-kDa molecules. Also, multichannel 75:25 PLGA nerve tubes were more flexible and, at the same time, more resistant to deformation. However, swelling significantly decreased the total cross-sectional lumen area, especially in multichannel 75:25 PLGA nerve tubes. Permeability, bending, deformation, swelling, and degradation are important properties to characterize in the development of multichannel nerve tubes. The methods presented in this study can be used as a basis for optimizing these properties for future, possibly clinical, application.