POLG DNA testing as an emerging standard of care before instituting valproic acid therapy for pediatric seizure disorders.

PURPOSE: To review our clinical experience and determine if there are appropriate signs and symptoms to consider POLG sequencing prior to valproic acid (VPA) dosing in patients with seizures. METHODS: Four patients who developed VPA-induced hepatotoxicity were examined for POLG sequence variations. A subsequent chart review was used to describe clinical course prior to and after VPA dosing. RESULTS: Four patients of multiple different ethnicities, age 3-18 years, developed VPA-induced hepatotoxicity. All were given VPA due to intractable partial seizures. Three of the patients had developed epilepsia partialis continua. The time from VPA exposure to liver failure was between 2 and 3 months. Liver failure was reversible in one patient. Molecular studies revealed homozygous p.R597W or p.A467T mutations in two patients. The other two patients showed compound heterozygous mutations, p.A467T/p.Q68X and p.L83P/p.G888S. Clinical findings and POLG mutations were diagnostic of Alpers-Huttenlocher syndrome. CONCLUSION: Our cases underscore several important findings: POLG mutations have been observed in every ethnic group studied to date; early predominance of epileptiform discharges over the occipital region is common in POLG-induced epilepsy; the EEG and MRI findings varying between patients and stages of the disease; and VPA dosing at any stage of Alpers-Huttenlocher syndrome can precipitate liver failure. Our data support an emerging proposal that POLG gene testing should be considered in any child or adolescent who presents or develops intractable seizures with or without status epilepticus or epilepsia partialis continua, particularly when there is a history of psychomotor regression.

Significance of Increased Tissue Transglutaminase in Hormone Refractory Prostate Cancer

The progression of hormone responsive to hormone refractory prostate cancer poses a major clinical challenge in the successful treatment of prostate cancer. The hormone refractory prostate cancer cells exhibit resistance not only to castrate levels of testosterone, but also to other therapeutic modalities and hence become lethal. Currently, there is no effective treatment available for managing this cancer. These observations underscore the urgency to investigate mechanism(s) that contribute to the progression of hormone-responsive to hormone-refractory prostate cancer and to target them for improved clinical outcomes. Tissue transglutaminase (TG2) is a multifunctional pro-inflammatory protein involved in diverse physiological processes such as inflammation, tissue repair, and wound healing. Its expression is also implicated in pathological conditions such as cancer and fibrosis. Interestingly, we found that the androgen-independent prostate cancer cell lines, which lacked androgen receptor (AR) expression, contained high basal levels of tissue transglutaminase. Inversely, the cell lines that expressed androgen receptor lacked transglutaminase expression. This attracted our attention to investigate the possible role this protein may play in the progression of prostate cancer, especially in view of recent observations that its expression is linked with increased invasion, metastasis, and drug resistance in multiple cancer cell types. The results we obtained were rather surprising and revealed that stable expression of tissue transglutaminase in androgen-sensitive LNCaP prostate cancer cells rendered these cells independent of androgen for growth and survival by silencing the AR expression. The AR silencing in TG2 expressing cells (TG2-infected LNCaP and PC-3 cells) was due to TG2-induced activation of the inflammatory nuclear transcription factor-kB (NF-kB). Thus, TG2 induced NF-kB was found to directly bind to the AR promoter. Importantly, TG2 protein was specifically recruited to the AR promoter in complex with the p65 subunit of NF-kB. Moreover, TG2 expressing LNCaP and PC-3 cells exhibited epithelial-to-mesenchymal transition, as evidenced by gain of mesenchymal (such as fibronectin, vimentin, etc.) and loss of epithelial markers (such as E-cadherin, b-catenin). Taken together, these results suggested a new function for TG2 and revealed a novel mechanism that is responsible for the progression of prostate cancer to the aggressive hormone-refractory phenotype.

Professional musicians listen differently to music

INTRODUCTION: Experience-based adaptation of emotional responses is an important faculty for cognitive and emotional functioning. Professional musicians represent an ideal model in which to elicit experience-driven changes in the emotional processing domain. The changes of the central representation of emotional arousal due to musical expertise are still largely unknown. The aim of the present study was to investigate the electroencephalogram (EEG) correlates of experience-driven changes in the domain of emotional arousal. Therefore, the differences in perceived (subjective arousal via ratings) and physiologically measured (EEG) arousal between amateur and professional musicians were examined. PROCEDURE: A total of 15 professional and 19 amateur musicians listened to the first movement of Ludwig van Beethoven's 5th symphony (duration=∼7.4min), during which a continuous 76-channel EEG was recorded. In a second session, the participants evaluated their emotional arousal during listening. In a tonic analysis, we examined the average EEG data over the time course of the music piece. For a phasic analysis, a fast Fourier transform was performed and covariance maps of spectral power were computed in association with the subjective arousal ratings. RESULTS: The subjective arousal ratings of the professional musicians were more consistent than those of the amateur musicians. In the tonic EEG analysis, a mid-frontal theta activity was observed in the professionals. In the phasic EEG, the professionals exhibited an increase of posterior alpha, central delta, and beta rhythm during high arousal. DISCUSSION: Professionals exhibited different and/or more intense patterns of emotional activation when they listened to the music. The results of the present study underscore the impact of music experience on emotional reactions.

Impact of epinephrine and norepinephrine on two dynamic indices in a porcine hemorrhagic shock model

Abstract BACKGROUND: Pulse pressure variations (PPVs) and stroke volume variations (SVVs) are dynamic indices for predicting fluid responsiveness in intensive care unit patients. These hemodynamic markers underscore Frank-Starling law by which volume expansion increases cardiac output (CO). The aim of the present study was to evaluate the impact of the administration of catecholamines on PPV, SVV, and inferior vena cava flow (IVCF). METHODS: In this prospective, physiologic, animal study, hemodynamic parameters were measured in deeply sedated and mechanically ventilated pigs. Systemic hemodynamic and pressure-volume loops obtained by inferior vena cava occlusion were recorded. Measurements were collected during two conditions, that is, normovolemia and hypovolemia, generated by blood removal to obtain a mean arterial pressure value lower than 60 mm Hg. At each condition, CO, IVCF, SVV, and PPV were assessed by catheters and flow meters. Data were compared between the conditions normovolemia and hypovolemia before and after intravenous administrations of norepinephrine and epinephrine using a nonparametric Wilcoxon test. RESULTS: Eight pigs were anesthetized, mechanically ventilated, and equipped. Both norepinephrine and epinephrine significantly increased IVCF and decreased PPV and SVV, regardless of volemic conditions (p < 0.05). However, epinephrine was also able to significantly increase CO regardless of volemic conditions. CONCLUSION: The present study demonstrates that intravenous administrations of norepinephrine and epinephrine increase IVCF, whatever the volemic conditions are. The concomitant decreases in PPV and SVV corroborate the fact that catecholamine administration recruits unstressed blood volume. In this regard, understanding a decrease in PPV and SVV values, after catecholamine administration, as an obvious indication of a restored volemia could be an outright misinterpretation.

Predicting Psychotherapy Dropouts: A Multilevel Approach

The role of therapeutic processes in predicting premature termination of psychotherapy has been a particular focus of recent research. The purpose of this study was to contrast outpatients who completed therapy and those who dropped out with respect to their self-reported in-session experiences of self-esteem, mastery, clarification and the therapeutic alliance. The 296 patients with mixed disorders were treated with an integrative form of cognitive–behavioural therapy without pre-determined time limit (M = 20.2 sessions). Multilevel analyses indicated that patients who did not completetreatment reported, on average, lower levels of self-esteem, mastery and clarification and lower ratings of their therapeutic alliance in treatment in contrast to patients who completed therapy. Patient-reported change in self-esteem experiences over the course of treatment turned out to be the strongest predictor of dropout from psychotherapy or successful completion. When dropout occurred before the average treatment length was reached, patients reported fewer clarifying experiences as early as the first session and their ratings of the therapeutic alliance were characterized by an absence of positive development. Both of these aspects seem to be involved in patients' decisions to leave treatment early. The findings underscore the importance of the therapeutic process in understanding the mechanisms behind treatment dropout. Copyright © 2014 John Wiley & Sons, Ltd.

PreImplantation factor promotes neuroprotection by targeting microRNA let-7

Dysfunction and loss of neurons are the major characteristics of CNS disorders that include stroke, multiple sclerosis, and Alzheimer's disease. Activation of the Toll-like receptor 7 by extracellular microRNA let-7, a highly expressed microRNA in the CNS, induces neuronal cell death. Let-7 released from injured neurons and immune cells acts on neighboring cells, exacerbating CNS damage. Here we show that a synthetic peptide analogous to the mammalian PreImplantation factor (PIF) secreted by developing embryos and which is present in the maternal circulation during pregnancy inhibits the biogenesis of let-7 in both neuronal and immune cells of the mouse. The synthetic peptide, sPIF, destabilizes KH-type splicing regulatory protein (KSRP), a key microRNA-processing protein, in a Toll-like receptor 4 (TLR4)-dependent manner, leading to decreased production of let-7. Furthermore, s.c. administration of sPIF into neonatal rats following hypoxic-ischemic brain injury robustly rescued cortical volume and number of neurons and decreased the detrimental glial response, as is consistent with diminished levels of KSRP and let-7 in sPIF-treated brains. Our results reveal a previously unexpected mechanism of action of PIF and underscore the potential clinical utility of sPIF in treating hypoxic-ischemic brain damage. The newly identified PIF/TLR4/KSRP/let-7 regulatory axis also may operate during embryo implantation and development.

Mutations in SLC1A4, encoding the brain serine transporter, are associated with developmental delay, microcephaly and hypomyelination

BACKGROUND L-serine plays an essential role in neuronal development and function. Although a non-essential amino acid, L-serine must be synthesised within the brain because of its poor permeability by the blood-brain barrier. Within the brain, its synthesis is confined to astrocytes, and its shuttle to neuronal cells is performed by a dedicated neutral amino acid transporter, ASCT1. METHODS AND RESULTS Using exome analysis we identified the recessive mutations, p.E256K, p.L315fs, and p.R457W, in SLC1A4, the gene encoding ASCT1, in patients with developmental delay, microcephaly and hypomyelination; seizure disorder was variably present. When expressed in a heterologous system, the mutations did not affect the protein level at the plasma membrane but abolished or markedly reduced L-serine transport for p.R457W and p.E256K mutations, respectively. Interestingly, p.E256K mutation displayed a lower L-serine and alanine affinity but the same substrate selectivity as wild-type ASCT1. CONCLUSIONS The clinical phenotype of ASCT1 deficiency is reminiscent of defects in L-serine biosynthesis. The data underscore that ASCT1 is essential in brain serine transport. The SLC1A4 p.E256K mutation has a carrier frequency of 0.7% in the Ashkenazi-Jewish population and should be added to the carrier screening panel in this community.

Marital breakup in later adulthood and self-rated health: a cross-sectional survey in Switzerland

This research examines the impact of relationship status on self-rated health (SRH) by taking into account intrapersonal and social resources. Data stem from a Swiss-based survey of 1355 participants aged 40-65 years. Three groups are compared: continuously married (n = 399), single divorcees (n = 532) and repartnered divorcees (n = 424). Linear regression models are used to examine the predictive role of relationship status on SRH and to investigate the moderating role of intrapersonal and social resources on SRH. Single divorcees show the lowest SRH scores, whereas their repartnered counterparts reported scores comparable to the continuously married – even after controlling for socio-demographic and economic variables. Although single divorcees reported higher levels of loneliness and agreeableness in addition to lower levels of resilience when compared with the other groups, none of these variables had a significant modification effect on SRH. Our results underscore the positive effect of relationship status on SRH, and contribute new insights on the impact of later-life divorce. Given the growing number of divorcees, related public health challenges are likely to increase.

Simultaneous analysis of nuclear and mitochondrial DNA, mRNA and miRNA from backspatter from inside parts of firearms generated by shots at "triple contrast" doped ballistic models

When a firearm projectile hits a biological target a spray of biological material (e.g., blood and tissue fragments) can be propelled from the entrance wound back towards the firearm. This phenomenon has become known as "backspatter" and if caused by contact shots or shots from short distances traces of backspatter may reach, consolidate on, and be recovered from, the inside surfaces of the firearm. Thus, a comprehensive investigation of firearm-related crimes must not only comprise of wound ballistic assessment but also backspatter analysis, and may even take into account potential correlations between these emergences. The aim of the present study was to evaluate and expand the applicability of the "triple contrast" method by probing its compatibility with forensic analysis of nuclear and mitochondrial DNA and the simultaneous investigation of co-extracted mRNA and miRNA from backspatter collected from internal components of different types of firearms after experimental shootings. We demonstrate that "triple contrast" stained biological samples collected from the inside surfaces of firearms are amenable to forensic co-analysis of DNA and RNA and permit sequence analysis of the entire mtDNA displacement-loop, even for "low template" DNA amounts that preclude standard short tandem repeat DNA analysis. Our findings underscore the "triple contrast" method's usefulness as a research tool in experimental forensic ballistics.

Marital breakup in later adulthood and self-rated health: a cross-sectional survey in Switzerland

Objectives This research examines the impact of relationship status on self-rated health (SRH) by taking into account intrapersonal and social resources. Methods Data stem from a Swiss-based survey of 1355 participants aged 40–65 years. Three groups are compared: continuously married (n = 399), single divorcees (n = 532) and repartnered divorcees (n = 424). Linear regression models are used to examine the predictive role of relationship status on SRH and to investigate the moderating role of intrapersonal and social resources on SRH. Results Single divorcees show the lowest SRH scores, whereas their repartnered counterparts reported scores comparable to the continuously married—even after controlling for socio-demographic and economic variables. Although single divorcees reported higher levels of loneliness and agreeableness in addition to lower levels of resilience when compared with the other groups, none of these variables had a significant moderation effect on SRH. Conclusions Our results underscore the positive effect of relationship status on SRH, and contribute new insights on the impact of later-life divorce. Given the growing number of divorcees, related public health challenges are likely to increase.

Effect of endovascular reperfusion in relation to site of arterial occlusion

OBJECTIVE To assess whether the association between reperfusion and improved clinical outcomes after stroke differs depending on the site of the arterial occlusive lesion (AOL). METHODS We pooled data from Solitaire With the Intention for Thrombectomy (SWIFT), Solitaire FR Thrombectomy for Acute Revascularisation (STAR), Diffusion and Perfusion Imaging Evaluation for Understanding Stroke Evolution Study 2 (DEFUSE 2), and Interventional Management of Stroke Trial (IMS III) to compare the strength of the associations between reperfusion and clinical outcomes in patients with internal carotid artery (ICA), proximal middle cerebral artery (MCA) (M1), and distal MCA (M2/3/4) occlusions. RESULTS Among 710 included patients, the site of the AOL was the ICA in 161, the proximal MCA in 389, and the distal MCA in 160 patients (M2 = 131, M3 = 23, and M4 = 6). Reperfusion was associated with an increase in the rate of good functional outcome (modified Rankin Scale [mRS] score 0-2) in patients with ICA (odds ratio [OR] 3.5, 95% confidence interval [CI] 1.7-7.2) and proximal MCA occlusions (OR 6.2, 95% CI 3.8-10.2), but not in patients with distal MCA occlusions (OR 1.4, 95% CI 0.8-2.6). Among patients with M2 occlusions, a subset of the distal MCA cohort, reperfusion was associated with excellent functional outcome (mRS 0-1; OR 2.2, 95% CI 1.0-4.7). CONCLUSIONS The association between endovascular reperfusion and better clinical outcomes is more profound in patients with ICA and proximal MCA occlusions compared to patients with distal MCA occlusions. Because there are limited data from randomized controlled trials on the effect of endovascular therapy in patients with distal MCA occlusions, these results underscore the need for inclusion of this subgroup in future endovascular therapy trials.

FOXC2 and fluid shear stress stabilize postnatal lymphatic vasculature

Biomechanical forces, such as fluid shear stress, govern multiple aspects of endothelial cell biology. In blood vessels, disturbed flow is associated with vascular diseases, such as atherosclerosis, and promotes endothelial cell proliferation and apoptosis. Here, we identified an important role for disturbed flow in lymphatic vessels, in which it cooperates with the transcription factor FOXC2 to ensure lifelong stability of the lymphatic vasculature. In cultured lymphatic endothelial cells, FOXC2 inactivation conferred abnormal shear stress sensing, promoting junction disassembly and entry into the cell cycle. Loss of FOXC2-dependent quiescence was mediated by the Hippo pathway transcriptional coactivator TAZ and, ultimately, led to cell death. In murine models, inducible deletion of Foxc2 within the lymphatic vasculature led to cell-cell junction defects, regression of valves, and focal vascular lumen collapse, which triggered generalized lymphatic vascular dysfunction and lethality. Together, our work describes a fundamental mechanism by which FOXC2 and oscillatory shear stress maintain lymphatic endothelial cell quiescence through intercellular junction and cytoskeleton stabilization and provides an essential link between biomechanical forces and endothelial cell identity that is necessary for postnatal vessel homeostasis. As FOXC2 is mutated in lymphedema-distichiasis syndrome, our data also underscore the role of impaired mechanotransduction in the pathology of this hereditary human disease.

Predicting psychotherapy outcome based on therapist interpersonal skills: A five-year longitudinal study of a therapist assessment protocol

Objective: In the past decade, variation in outcomes between therapists (i.e., therapist effects) have become increasingly recognized as an important factor in psychotherapy. Less is known, however, about what accounts for differences between therapists. The present study investigates the possibility that therapists' basic therapy-related interpersonal skills may impact outcomes. Method: To examine this, psychotherapy postgraduate trainees completed both an observer- and an expert-rated behavioral assessment: the Therapy-Related Interpersonal Behaviors (TRIB). TRIB scores were used to predict trainees' outcomes over the course of the subsequent five years. Results: Results indicate that trainees' with more positively rated interpersonal behaviors assessed in the observer-rated group format but not in a single expert-rated format showed superior outcomes over the five-year period. This effect remained controlling for therapist characteristics (therapist gender, theoretical orientation [cognitive behavioral or psychodynamic], amount of supervision, patient's order within therapist's caseload), and patient characteristics (patient age, gender, number of comorbid diagnoses, global severity, and personality disorder diagnosis). Conclusions: These findings underscore the importance of therapists' interpersonal skills as a predictor of outcome and source of therapist effects. The potential utility of assessing therapists' and therapists-in-training interpersonal skills are discussed.

Chromosome fusions triggered by noncoding RNA

Chromosomal fusions are common in normal and cancer cells and can produce aberrant gene products that promote transformation. The mechanisms driving these fusions are poorly understood, but recurrent fusions are widespread. This suggests an underlying mechanism, and some authors have proposed a possible role for RNA in this process. The unicellular eukaryote Oxytricha trifallax displays an exorbitant capacity for natural genome editing, when it rewrites its germline genome to form a somatic epigenome. This developmental process provides a powerful model system to directly test the influence of small noncoding RNAs on chromosome fusion events during somatic differentiation. Here we show that small RNAs are capable of inducing chromosome fusions in four distinct cases (out of four tested), including one fusion of three chromosomes. We further show that these RNA-mediated chromosome fusions are heritable over multiple sexual generations and that transmission of the acquired fusion is associated with endogenous production of novel piRNA molecules that target the fused junction. We also demonstrate the capacity of a long noncoding RNA (lncRNA) to induce chromosome fusion of two distal germline loci. These results underscore the ability of short-lived, aberrant RNAs to act as drivers of chromosome fusion events that can be stably transmitted to future generations.

Economic Reforms and Pro-Poor Growth: Lessons for Africa and other Developing Regions and Economies in Transition

The paper discusses the meaning and measurement of pro-poor growth and also reviews evidence of pro-poor growth (or the lack of it) in a large cross-section of countries and time periods. The emerging story is that many episodes of growth are not pro-poor and also that although economic reforms have had positive effects in those countries that have been steadfast in implementing market reforms, the overall impact on growth has been small for many countries and in most cases not pro-poor. I present a general theory of pro-poor growth that includes ten principles that should be incorporated in all economic reforms that seek to generate pro-poor growth. These principles highlight the importance of understanding the poor, their economic activities, capabilities, constraints that impede their participation in markets and also an appreciation of linkages within sectors and regions. It is argued that pro-poor reforms cannot have the intended impact unless there are significant changes in the institutions of governance. Finally, the principles presented underscore the fact that pro-poor growth policies cannot be sustained without workable partnerships between markets and states in the ever changing and complex processes of social and economic development.