The stretching of single poly-ubiquitin molecules: Static versus dynamic disorder in the non-exponential kinetics of chain unfolding

Static disorder has recently been implicated in the non-exponential kinetics of the unfolding of single molecules of poly-ubiquitin under a constant force Kuo, Garcia-Manyes, Li, Barel, Lu, Berne, Urbakh, Klafter, and Fernandez, Proc. Natl. Acad. Sci. U. S. A. 107, 11336 (2010)]. In the present paper, it is suggested that dynamic disorder may provide a plausible, alternative description of the experimental observations. This suggestion is made on the basis of a model in which the barrier to chain unfolding is assumed to be modulated by a control parameter r that evolves in a parabolic potential under the action of fractional Gaussian noise according to a generalized Langevin equation. The treatment of dynamic disorder within this model is pursued using Zwanzig's indirect approach to noise averaging Acc. Chem. Res. 23, 148 (1990)]. In conjunction with a self-consistent closure scheme developed by Wilemski and Fixman J. Chem. Phys. 58, 4009 (1973); ibid. 60, 866 (1974)], this approach eventually leads to an expression for the chain unfolding probability that can be made to fit the corresponding experimental data very closely. (C) 2011 American Institute of Physics.

Temperature dependence of non-Debye disorder in doped manganites

Ca-doped manganite La1-xCaxMnO3 samples with x=0.2 and 0.4 were investigated by extended x-ray absorption fine structure (EXAFS) as a function of temperature and preparation method. The samples exhibit characteristic resistivity change across the metal-insulator (MI) transition temperature whose shape and position depend on Ca-doping concentration and sample thermal treatment. EXAFS results evidenced an increase of nonthermal disorder at the MI transition temperature which is significantly correlated with the resistivity behavior.

Vascular calcification and mineral bone disorder in chronic kidney disease

Chronic Kidney Disease (CKD), osteoporosis and mild hyponatremia are all prevalent chronic conditions that may coexist and are often under-recognized. Mineral-Bone Disorder begins early in the natural history of CKD and results in complex abnormalities of bone which ultimately confers a well-established increased risk of fragility fractures in End Stage Kidney Disease. Hyponatremia is a novel, usually renal mediated metabolic perturbation, that most commonly occurs independently of the stage of renal dysfunction but which may also predispose to increased fracture risk. The extent -if any- to which either early stages of renal dysfunction or the presence of hyponatremia contribute to fracture occurrence in the general population, independently of osteoporosis, is unclear. Renal transplantation is the treatment of choice for ESKD and although it restores endogenous renal function it typically fails to normalize either the long term cardiovascular or fracture risk. One potential mechanism contributing to these elevated long-term risks and to diminished Health Related Quality of Life is persistent, post-transplant hyperparathyroidism. In this study we retrospectively examine the association of renal function and serum sodium with Bone Mineral Density and fracture occurrence in a retrospective cohort of 1930 female members of the general population who underwent routine DXA scan. We then prospectively recruited a cohort of 90 renal transplant recipients in order to examine the association of post transplant parathyroid hormone (PTH) level with measures of CKD Mineral Bone Disorder, including, DXA Bone Mineral Density, Vascular Calcification (assessed using both abdominal radiography and CT techniques, as well as indirectly by carotid-femoral Pulse Wave Velocity) and Quality of Life (using the Short Form-12 and a PTH specific symptom score). In the retrospective DXA cohort, moderate CKD (eGFR 30-59ml/min/1.73m2) and hyponatremia (<135mmol/L) were associated with fracture occurrence, independently of BMD, with an adjusted Odds Ratio (95% Confidence Interval), of 1.37 (1.0, 1.89) and 2.25 (1.24, 4.09) respectively. In the renal transplant study, PTH was independently associated with the presence of osteoporosis, adjusted Odds Ratio (95% Confidence Interval), 1.15 (per 10ng/ml increment), (1.04, 1.26). The presence of osteoporosis but not PTH was independently associated with measures of vascular calcification, adjusted ß (95% Confidence Interval), 12.45, (1.16, 23.75). Of the eight quality-of-life domains examined, post-transplant PTH (per 10ng/ml increment), was only significantly and independently associated with reduced Physical Functioning, (95% Confidence Interval), 1.12 (1.01, 1.23). CKD and hyponatremia are both common health problems that may contribute to fracture occurrence in the general population, a major on-going public health concern. PTH and decreased Bone Mineral Density may signal sub-optimal long-term outcomes post renal transplantation, influencing bone and vascular health and to a limited extent long term Health Related Quality of Life

Serotonin synthesis, release and reuptake in terminals: a mathematical model.

BACKGROUND: Serotonin is a neurotransmitter that has been linked to a wide variety of behaviors including feeding and body-weight regulation, social hierarchies, aggression and suicidality, obsessive compulsive disorder, alcoholism, anxiety, and affective disorders. Full understanding of serotonergic systems in the central nervous system involves genomics, neurochemistry, electrophysiology, and behavior. Though associations have been found between functions at these different levels, in most cases the causal mechanisms are unknown. The scientific issues are daunting but important for human health because of the use of selective serotonin reuptake inhibitors and other pharmacological agents to treat disorders in the serotonergic signaling system. METHODS: We construct a mathematical model of serotonin synthesis, release, and reuptake in a single serotonergic neuron terminal. The model includes the effects of autoreceptors, the transport of tryptophan into the terminal, and the metabolism of serotonin, as well as the dependence of release on the firing rate. The model is based on real physiology determined experimentally and is compared to experimental data. RESULTS: We compare the variations in serotonin and dopamine synthesis due to meals and find that dopamine synthesis is insensitive to the availability of tyrosine but serotonin synthesis is sensitive to the availability of tryptophan. We conduct in silico experiments on the clearance of extracellular serotonin, normally and in the presence of fluoxetine, and compare to experimental data. We study the effects of various polymorphisms in the genes for the serotonin transporter and for tryptophan hydroxylase on synthesis, release, and reuptake. We find that, because of the homeostatic feedback mechanisms of the autoreceptors, the polymorphisms have smaller effects than one expects. We compute the expected steady concentrations of serotonin transporter knockout mice and compare to experimental data. Finally, we study how the properties of the the serotonin transporter and the autoreceptors give rise to the time courses of extracellular serotonin in various projection regions after a dose of fluoxetine. CONCLUSIONS: Serotonergic systems must respond robustly to important biological signals, while at the same time maintaining homeostasis in the face of normal biological fluctuations in inputs, expression levels, and firing rates. This is accomplished through the cooperative effect of many different homeostatic mechanisms including special properties of the serotonin transporters and the serotonin autoreceptors. Many difficult questions remain in order to fully understand how serotonin biochemistry affects serotonin electrophysiology and vice versa, and how both are changed in the presence of selective serotonin reuptake inhibitors. Mathematical models are useful tools for investigating some of these questions.

CARBON MONOXIDE AND PREGNANCY: A SEARCH FOR A POSSIBLE THERAPEUTIC IN THE TREATMENT OF PRE-ECLAMPSIA

Pre-eclampsia (PE) is a pregnancy disorder that affects roughly 5-7% of all pregnancies and is a leading cause of both maternal and fetal/neonatal morbidity and mortality. With no present cure for the disease, researchers are interested in the lower incidence of PE observed among the cigarette smoking pregnant population. However, women who use smokeless tobacco do not experience the same decreased incidence of PE, leading to hypothesis of protection against PE from the largest combustible product of cigarette smoke, carbon monoxide (CO). Studies evaluated levels of CO in PE women and found that they were statistically lower than those of healthy pregnancy. Researchers have found CO to possess many cytoprotective and regulatory properties and specifically within the placenta, it has been found to increase perfusion pressure, decrease oxidative stress, decreases ischemia/reperfusion induced apoptosis and maintain endothelial functioning. The idea for use of CO as a possible therapeutic for PE has thus become a real possibility. This study determined CO levels in pregnant women ± smoking as well as in PE women±smoking, as to discover a possible therapeutic range for future treatments. The best correlated automated CO measurement device with blood CO levels was determined, for use in future clinical studies. This thesis also sought a possible CO delivery concentration, in order to achieve the CO levels observed in the human correlation study. A threshold level of maternal CO exposure in a murine animal model was found, for which fetal and maternal negative toxicities were not observed. The results of this thesis lend a few more pieces to the complicated puzzle involving CO and PE and offer another step toward the possibility of a therapeutic treatment/prevention using this gaseous molecule.

The Emperor's new clothes: Eclecticism in autism treatment

Increasingly, Applied Behavior Analysis (ABA) is internationally recognised as the scientific basis for teaching and treatment in autism spectrum disorders. Yet, many governments and professionals across Europe promote an eclectic model as more child-centred and pragmatic. This paper addresses the issues of eclecticism and ABA by exploring how misinformation stands in the way of evidence-based procedures that are truly unified, practical, and child-centred.

Evaluation of quinazolin-4-piperidine sulfamides as inhibitors of human NPP1: relevance in the treatment of pathologic mineralization of valve interstitial cells

Le rétrécissement valvulaire aortique calcifié (RAC) est le trouble valvulaire le plus fréquent chez les personnes âgées des pays développés. La seule option de traitement possible le remplacement de la valve aortique. L’identification du rôle de l’enzyme ecto-nucleotidase NPP1 dans le processus de calcification suggère que cette enzyme pourrait être une cible potentielle pour le développement d’un inhibiteur pharmacologique contre la calcification de la valve aortique. Jusqu’à présent, les composés qui ont été développés en tant qu’inhibiteurs de NPP1 manquent de puissance et de spécificité. Dans la présente étude, nous avons démontré que les dérivés de sulfonamides quinazolin-4-pipéridine sont des inhibiteurs puissants, spécifiques, et non-compétitifs de NPP1. In vitro, dans des cellules isolées de valve aortique nous avons fourni des preuves que l’inhibition de NPP1 par ces dérivés bloque la minéralisation, l’apoptose et la transition ostéogénique des cellules interstitielles de valve aortique.

Psychiatric comorbidity and additional abuse of drugs in maintenance treatment with l- and d,l-methadone.

Sixty d,l- or l-methadone treated patients in maintenance therapy were interviewed for additional drug abuse and psychiatric comorbidity; 51.7% of the entire population had a comorbid Axis-I disorder, with a higher prevalence in females (P=0.05). Comorbid patients tended to have higher abuse of benzodiazepines, alcohol, cannabis, and cocaine, but not of heroin. They had received a significantly lower d,l- (P<0.05) and l-methadone dose than non-comorbid subjects. The duration of maintenance treatment showed an inverse relationship to frequency of additional heroin intake (P<0.01). Patients with additional heroin intake over the past 30 days had been treated with a significantly lower l-methadone dosage (P<0.05) than patients without. Axis-I comorbidity appears to be decreased when relatively higher dosages of d,l- (and l-methadone) are administered; comorbid individuals, however, were on significantly lower dosages. Finally, l-, but not d,l-methadone seems to be more effective in reducing additional heroin abuse.

Genetic and Electrophysiological Correlates of Self-Regulation in Adolescence

Self-regulation is considered a powerful predictor of behavioral and mental health outcomes during adolescence and emerging adulthood. In this dissertation I address some electrophysiological and genetic correlates of this important skill set in a series of four studies. Across all studies event-related potentials (ERPs) were recorded as participants responded to tones presented in attended and unattended channels in an auditory selective attention task. In Study 1, examining these ERPs in relation to parental reports on the Behavior Rating Inventory of Executive Function (BRIEF) revealed that an early frontal positivity (EFP) elicited by to-be-ignored/unattended tones was larger in those with poorer self-regulation. As is traditionally found, N1 amplitudes were more negative for the to-be-attended rather than unattended tones. Additionally, N1 latencies to unattended tones correlated with parent-ratings on the BRIEF, where shorter latencies predicted better self-regulation. In Study 2 I tested a model of the associations between selfregulation scores and allelic variations in monoamine neurotransmitter genes, and their concurrent links to ERP markers of attentional control. Allelic variations in dopaminerelated genes predicted both my ERP markers and self-regulatory variables, and played a moderating role in the association between the two. In Study 3 I examined whether training in Integra Mindfulness Martial Arts, an intervention program which trains elements of self-regulation, would lead to improvement in ERP markers of attentional control and parent-report BRIEF scores in a group of adolescents with self-regulatory difficulties. I found that those in the treatment group amplified their processing of attended relative to unattended stimuli over time, and reduced their levels of problematic behaviour whereas those in the waitlist control group showed little to no change on both of these metrics. In Study 4 I examined potential associations between self-regulation and attentional control in a group of emerging adults. Both event-related spectral perturbations (ERSPs) and intertrial coherence (ITC) in the alpha and theta range predicted individual differences in self-regulation. Across the four studies I was able to conclude that real-world self-regulation is indeed associated with the neural markers of attentional control. Targeted interventions focusing on attentional control may improve self-regulation in those experiencing difficulties in this regard.

Évaluation gastro-intestinale chez des chiens présentant un comportement de léchage excessif de surface

L’objectif de cette étude était de démontrer que le léchage excessif de surface (LES) chez le chien représente un signe clinique d’un trouble digestif sous-jacent plutôt qu’un trouble obsessionnel compulsif. Vingt chiens présentés pour LES (groupe L) ont été divisés en 2 sous-groupes de 10 chiens chacun : L0, sans, et LD, avec des signes cliniques digestifs concomitants. Dix chiens en santé ont été assignés à un groupe contrôle (groupe C). Une évaluation comportementale complète, un examen physique et neurologique ont été réalisés avant un bilan diagnostic gastro-intestinal (GI) complet (hématologie, biochimie, analyse urinaire, mesure des acides biliaires pré et post-prandiaux et de l’immunoréactivité spécifique de la lipase pancréatique canine, flottaison fécale au sulfate de zinc, culture de selles, échographie abdominale et endoscopie GI haute avec prise de biopsies). En fonction des résultats, un interniste recommandait un traitement approprié. Les chiens étaient suivis pendant 90 jours durant lesquels le comportement de léchage était enregistré. Des troubles GI ont été identifiés chez 14/20 chiens du groupe L. Ces troubles GI sous-jacents incluaient une infiltration éosinophilique du tractus GI, une infiltration lymphoplasmocytaire du tractus GI, un retard de vidange gastrique, un syndrome du côlon irritable, une pancréatite chronique, un corps étranger gastrique et une giardiose. Une amélioration >50% en fréquence ou en durée par rapport au comportement de léchage initial a été observée chez une majorité de chiens (56%). La moitié des chiens ont complètement cessé le LES. En dehors du LES, il n’y avait pas de différence significative de comportement (p.ex. anxiété), entre les chiens L et les chiens C. Les troubles GI doivent être considérés dans le diagnostic différentiel du LES chez le chien.

Évolution des émotions, des obsessions et des compulsions chez les personnes souffrant de Trouble obsessionnel-compulsif au cours d’une thérapie basée sur les inférences

L’approche cognitive du trouble obsessionnel-compulsif (TOC) propose un lien bidirectionnel entre les émotions et les cognitions. Cependant, même si des études montrent une association entre les émotions et le TOC, aucune étude ne s’est attardée à la relation entre les émotions, les cognitions et les comportements au cours d’une thérapie cognitive. La présente étude a pour but d’examiner la relation entre les processus cognitif, béhavioral et émotionnel au cours d’une thérapie basée sur les inférences (TBI) chez des personnes souffrant du TOC. Plus précisément, nous avons observé comment les émotions et les symptômes du TOC s’influencent et comment ils s’influencent à travers le temps. Les patients ont rempli un journal de bord tout au long du processus thérapeutique, notant (de 0 à 100) des émotions clés, ainsi que les croyances et les comportements ciblés durant la thérapie. Des analyses à mesures répétées ont été utilisées afin de maximiser le potentiel des données longitudinales. Les résultats montrent que l’anxiété, la tristesse et la joie ont des trajectoires similaires aux croyances et aux comportements au cours de la thérapie. Les forces et limites de l’étude sont discutées. Les implications des résultats pour le traitement des émotions et des pensées à différents moments de la thérapie sont aussi discutées.

Efectividad del tratamiento con neurofeedback en trastornos del estado del ánimo, ansiedad y fibromialgia: una revisión de literatura

El neurofeedback es una técnica no invasiva en la que se pretende corregir, mediante condicionamiento operante, ondas cerebrales que se encuentren alteradas en el electroencefalograma. Desde 1967, se han conducido numerosas investigaciones relacionadas con los efectos de la técnica en el tratamiento de alteraciones psicológicas. Sin embargo, a la fecha no existen revisiones sistemáticas que reúnan los temas que serán aquí tratados. El aporte de este trabajo es la revisión de 56 artículos, publicados entre los años 1995 y 2013 y la evaluación metodológica de 29 estudios incluidos en la revisión. La búsqueda fue acotada a la efectividad del neurofeedback en el tratamiento de depresión, ansiedad, trastorno obsesivo compulsivo (TOC), ira y fibromialgia. Los hallazgos demuestran que el neurofeedback ha tenido resultados positivos en el tratamiento de estos trastornos, sin embargo, es una técnica que aún está en desarrollo, con unas bases teóricas no muy bien establecidas y cuyos resultados necesitan de diseños metodológicamente más sólidos que ratifiquen su validez.

Cognitive-behavior therapy for compulsive checking in OCD

There is substantial evidence for the effectiveness of psychological treatments for OCD, and various approaches have been widely recommended. These approaches tend to be characterized by exposure and response prevention (ERP) and also tend to be applied equally to all forms of OCD. Patients/clients (and some therapists) often find ERP to be a difficult treatment, and both dropout and refusal rates are unacceptably high. Based on specific cognitive conceptualizations of different manifestations of OCD, new and refined cognitive treatment methods are now available. The present article describes a specific cognitively based approach to the treatment of compulsive checking.

A family study of co-morbidity between generalized social phobia and generalized anxiety disorder in a non-clinic sample

Background: High rates of co-morbidity between Generalized Social Phobia (GSP) and Generalized Anxiety Disorder (GAD) have been documented. The reason for this is unclear. Family studies are one means of clarifying the nature of co-morbidity between two disorders. Methods: Six models of co-morbidity between GSP and GAD were investigated in a family aggregation study of 403 first-degree relatives of non-clinical probands: 37 with GSP, 22 with GAD, 15 with co-morbid GSP/GAD, and 41 controls with no history of GSP or GAD. Psychiatric data were collected for probands and relatives. Mixed methods (direct and family history interviews) were utilised. Results: Primary contrasts (against controls) found an increased rate of pure GSP in the relatives of both GSP probands and co-morbid GSP/GAD probands, and found relatives of co-morbid GSP/GAD probands to have an increased rate of both pure GAD and comorbid GSP/GAD. Secondary contrasts found (i) increased GSP in the relatives of GSP only probands compared to the relatives of GAD only probands; and (ii) increased GAD in the relatives of co-morbid GSP/GAD probands compared to the relatives of GSP only probands. Limitations: The study did not directly interview all relatives, although the reliability of family history data was assessed. The study was based on an all-female proband sample. The implications of both these limitations are discussed. Conclusions: The results were most consistent with a co-morbidity model indicating independent familial transmission of GSP and GAD. This has clinical implications for the treatment of patients with both disorders. (C) 2006 Elsevier B.V. All fights reserved.

Towards the use of hydrogels in the treatment of limbal stem cell deficiency

Corneal blindness caused by limbal stem cell deficiency (LSCD) is a prevailing disorder worldwide. Clinical outcomes for LSCD therapy using amniotic membrane (AM) are unpredictable. Hydrogels can eliminate limitations of standard therapy for LSCD, because they present all the advantages of AM (i.e. biocompatibility, inertness and a biodegradable structure) but unlike AM, they are structurally uniform and can be easily manipulated to alter mechanical and physical properties. Hydrogels can be delivered with minimum trauma to the ocular surface and do not require extensive serological screening before clinical application. The hydrogel structure is also amenable to modifications which direct stem cell fate. In this focussed review we highlight hydrogels as biomaterial substrates which may replace and/or complement AM in the treatment of LSCD.