Markov state modelling reveals heterogeneous drug-inhibition mechanism of Calmodulin.

Calmodulin (CaM) is a calcium sensor which binds and regulates a wide range of target-proteins. This implicitly enables the concentration of calcium to influence many downstream physiological responses, including muscle contraction, learning and depression. The antipsychotic drug trifluoperazine (TFP) is a known CaM inhibitor. By binding to various sites, TFP prevents CaM from associating to target-proteins. However, the molecular and state-dependent mechanisms behind CaM inhibition by drugs such as TFP are largely unknown. Here, we build a Markov state model (MSM) from adaptively sampled molecular dynamics simulations and reveal the structural and dynamical features behind the inhibitory mechanism of TFP-binding to the C-terminal domain of CaM. We specifically identify three major TFP binding-modes from the MSM macrostates, and distinguish their effect on CaM conformation by using a systematic analysis protocol based on biophysical descriptors and tools from machine learning. The results show that depending on the binding orientation, TFP effectively stabilizes features of the calcium-unbound CaM, either affecting the CaM hydrophobic binding pocket, the calcium binding sites or the secondary structure content in the bound domain. The conclusions drawn from this work may in the future serve to formulate a complete model of pharmacological modulation of CaM, which furthers our understanding of how these drugs affect signaling pathways as well as associated diseases.

Electroconvulsive therapy and autobiographical memory in patients with treatment-resistant depression. / Terapia elektrowstrzasowa i pamiec autobiograficzna u pacjentów z depresja lekooporna.

OBJECTIVES: Electroconvulsive therapy (ECT) is the most effective treatment for drugresistant depression. In most studies, cognitive functions including working and semantic memory showed only transient impairment after ECT. However, the deficits of episodic (autobiographical) memory were demonstrated to be long-lasting. METHODS: We investigated autobiographical memory in 20 patients (8 male, 12 female), aged 21-64 years, with drug-resistant depression, treated with ECT, using the Polish adaptation of the Autobiographical Memory Interview-Short Form (AMI-SF). The assessments were performed before, immediately after 10-12 ECT sessions, and 3 months thereafter. RESULTS: Before the ECT, the mean severity of depression was 30 ± 6 points on the 17-item Hamilton Depression Rating Scale and the treatment produced a significant clinical improvement in all patients. The indices of autobiographical memory, as assessed by the AMI-SF, were significantly lower immediately after ECT and 3 months thereafter. The impairment in autobiographical memory did not show correlation with clinical improvement and with any other clinical factors. CONCLUSIONS: The results obtained in patients with drug-resistant depression confirm that ECT treatment produces a significant impairment of autobiographical memory persisting also three months after the procedure, suggesting that it may be the most important adverse cognitive effect of the ECT.

Mentalization deficit in bipolar patients during an acute depressive and manic episode: association with cognitive functions.

BACKGROUND: A number of studies in bipolar patients have shown a deficit in mentalization (theory of mind), one of the main aspects of social cognition. The aim of current study was to assess both cognitive and affective mentalization in well-defined groups of depressed and manic bipolar patients, compared to healthy control subjects, using a battery of tests measuring mentalization processes. The second aim was to investigate a possible relationship between cognitive and affective mentalization and cognitive functions in bipolar patients during a depressive and manic episode. METHODS: The study involved 25 bipolar disorder type I patients (10 male, 15 female) during a depressive episode (mean 24 ± 2 points in the 17-item Hamilton Depression Rating Scale) and 25 patients (10 male, 15 female) during a manic episode (mean 27 ± 4 points in the Young Mania Rating Scale). The control group consisted of 25 healthy subjects (10 male, 15 female) without psychiatric disorders. To measure mentalization, a revised version of the Reading the Mind in the Eyes (R-MET), the Strange Stories (SS), the Faux Pas Recognition (FPR), and the Moving Shapes Paradigm (MSP) tests were used. Assessment of cognitive functioning was made using the Digit Span, Trail Making, and Wisconsin Card Sorting Tests. RESULTS: In bipolar patients significant deficits in both cognitive and affective mentalization were demonstrated during both acute depressive and manic episodes. The impairment in FPR in manic patients was more severe than that in the depressive ones. On the other hand, in MSP, manic patients showed significantly increased intentionality for non-mentalization animations, compared with depressive patients and for "cause and effect" animations compared with control subjects. A significant relationship was found between the decrease in cognitive and affective mentalization and deficits of cognitive functions during both the depressive and manic episodes. CONCLUSIONS: The results obtained confirm the deficits of mentalization in bipolar I patients, during both acute depressive and manic episodes. We found that in such patients mentalization deficits significantly correlated with cognitive dysfunctions more so during depressive episodes.

Increased affective empathy in bipolar patients during a manic episode

Objective: To assess both cognitive and affective empathy in patients with bipolar disorder (BD) during an acute manic or depressive episode. Methods: The study included 25 patients with BD (aged 35±14 years) during an acute manic episode, 25 bipolar patients (aged 41±14 years) during a depressive episode, and 25 healthy control subjects (aged 36±11 years). Cognitive and affective empathy were assessed using the Multifaceted Empathy Test. Results: In both manic and depressive patients, a significant deficit in cognitive empathy was demonstrated. However, indices of affective empathy were significantly higher in the manic group than in depressed and control subjects. In the depressed patients, indices did not differ from those of healthy controls. For affective empathy, a significant positive correlation was found with intensity of manic symptoms and a negative correlation was found with intensity of depressive symptoms. No such correlations were observed with cognitive empathy. Conclusion: We found evidence of increased affective empathy (overempathizing) during a manic episode in bipolar patients. This phenomenon may be connected with disturbances in emotion inhibition related to anastrophic thinking and associated with increased activity of mirror neurons, all of which occur during a manic episode.

Increased affective empathy in bipolar patients during a manic episode.

OBJECTIVE: To assess both cognitive and affective empathy in patients with bipolar disorder (BD) during an acute manic or depressive episode. METHODS: The study included 25 patients with BD (aged 35±14 years) during an acute manic episode, 25 bipolar patients (aged 41±14 years) during a depressive episode, and 25 healthy control subjects (aged 36±11 years). Cognitive and affective empathy were assessed using the Multifaceted Empathy Test. RESULTS: In both manic and depressive patients, a significant deficit in cognitive empathy was demonstrated. However, indices of affective empathy were significantly higher in the manic group than in depressed and control subjects. In the depressed patients, indices did not differ from those of healthy controls. For affective empathy, a significant positive correlation was found with intensity of manic symptoms and a negative correlation was found with intensity of depressive symptoms. No such correlations were observed with cognitive empathy. CONCLUSION: We found evidence of increased affective empathy (overempathizing) during a manic episode in bipolar patients. This phenomenon may be connected with disturbances in emotion inhibition related to anastrophic thinking and associated with increased activity of mirror neurons, all of which occur during a manic episode.

A comparison of two methods to evaluate a narrow spinal canal: routine magnetic resonance imaging versus three-dimensional reconstruction.

BACKGROUND CONTEXT: In routine clinical practice, the presence of lumbar spinal stenosis (LSS) is assessed on axial magnetic resonance images (MRI) typically acquired using a preselected spine sagittal angle. Given the natural lordosis of the lumbar spine, not all axial slices will be parallel to the disc and perpendicular to the spinal canal and, thus, are not optimal for the assessment of dural sac cross-sectional area (DCSA). PURPOSE: The objective of this study was to compare DCSA measurements from routinely acquired clinical images with three-dimensional (3D)-reconstructed images. STUDY DESIGN: This is a cross-sectional study. PATIENT SAMPLE: The sample consists of 390 patients referred for lumbar imaging with some aspect of anatomical LSS found, with no prior back surgery, 40 years of age or older, and with available volumetric MR images to allow 3D reconstruction of the spine. OUTCOME MEASURES: The outcome of interest in this study was dural sac cross sectional area. METHODS: Spine images were 3D reconstructed at the level of the disc, perpendicular to the spinal canal. Dural sac cross-sectional area was measured for both 3D-reconstructed and routinely acquired clinical images using the slice orientation captured. RESULTS: Dural sac cross-sectional area for the lower lumbar levels (L4-L5 and L5-S1) was significantly different between routinely acquired clinical images and 3D-reconstructed images, with a standard error of measurement of 12.98 and 19.73 mm(2), respectively. CONCLUSIONS: When canal size is of interest, particularly when LSS affecting the lower lumbar levels is of concern, 3D reconstruction of clinical images should be considered.

Ketamine Anesthesia, Efficacy of Electroconvulsive Therapy, and Cognitive Functions in Treatment-Resistant Depression.

OBJECTIVES: Electroconvulsive therapy (ECT) is the most effective treatment for drug-resistant depression (DRD). Because a single infusion of ketamine may exert both a rapid antidepressant effect and a quick improvement of cognition, the aim of the present study was to assess whether ketamine, as an anesthetic drug for ECT, can augment the antidepressant activity of the procedure and/or exert a beneficial effect on cognition. METHODS: A total of 11 male and 34 female patients with DRD, aged 21 to 75 years, were included in the study. Fifteen patients (group 1) received only thiopental anesthesia, 15 patients (group 2) had their second and third ECT sessions with ketamine, and 15 patients (group 3) had ketamine for the second, fourth, sixth, eighth, and tenth sessions. Depression intensity was measured by the 17-item Hamilton Depression Rating Scale. Cognitive functions were measured before and after ECT, assessing visual-spatial abilities, verbal auditory memory, working memory, and executive functions. RESULTS: Before the ECT, the mean (SD) intensity of depression was 32 (6) points on the Hamilton Depression Rating Scale and the mean number of ECT sessions was 10.8 (1.5), with no difference between groups. After the last ECT session, the intensity of depression was significantly lower in group 3, compared with group 1. Cognitive assessments after ECT showed a more marked worsening in verbal memory in patients with added ketamine anesthesia. CONCLUSIONS: The addition of ketamine may be connected with better antidepressant efficacy of ECT, compared with only thiopental anesthesia. However, patients with added ketamine had worse results on some of the indices measuring verbal memory.

Electroconvulsive therapy and cognitive functions in treatment-resistant depression.

OBJECTIVES: Electroconvulsive therapy (ECT) is the most effective treatment for drug-resistant depression (DRD). We estimated the short- and long-term effects of ECT on cognitive functions in patients with unipolar and bipolar DRD. METHODS: We investigated 63 patients (18 male, 45 female), aged 34-75 years. Cognitive assessments were performed before, immediately after 6-12 ECT sessions, and 3 months thereafter, using the Benton Visual Retention, Trail Making (TMT), Rey-Osterrieth Complex Figure (ROCF) tests, the Digit Span of the Wechsler Adult Intelligence Scale, and the Rey Auditory Verbal Learning (RAVLT), verbal fluency and Stroop tests. RESULTS: Immediately after ECT, a significant worsening was noted in some indices of memory and verbal fluency. However, 3 months after ECT, the indices of both RAVLT and verbal fluency significantly improved compared to baseline, and those of the Benton and ROCF were significantly better than before ECT. The Digit Span, Stroop and TMT were not affected by the treatment. CONCLUSIONS: The negative effects of ECT on the reported measures of cognition are transient. After 3 months, the indices of memory were significantly better than before the treatment. In addition to its antidepressant effect in DRD, ECT may also exert a long-term favourable influence on some cognitive functions.

[Disturbances of social cognition in schizophrenia and bipolar disorder--similarities and differences]. / Zaburzenia poznania spolecznego w schizofrenii i chorobie afektywnej dwubiegunowej--podobienstwa i róznice.

In the first part of the article, two aspects of social cognition, such as the Theory of Mind (ToM), i.e. the ability to infer about mental and affective states of other people, having both cognitive and perceptive aspects as well as empathy, i.e. the ability to understand other person's perspective and take an emotional response of the observer to the affective state of the other person, were presented. Next, research on social cognition in schizophrenia and bipolar disorder (BD) has been reviewed, and the disturbances, observed in these two illnesses were compared, with particular emphasis on studies investigating social cognition in both schizophrenia and BD. The results of studies show that ToM disturbances occur both in schizophrenia and BD patients, however, in schizophrenia they are of greater severity. As for empathy, patients with schizophrenia have significant disturbances of recognizing emotions, as well as of cognitive and affective empathy. Patients with BD do not have abnormalities in cognitive empathy, have lesser disturbances of emotion recognition disorder compared with schizophrenia and show a connection between disturbances of affective empathy and the course of the disease (time period after manic or depressive episode). Further exploration of these issues seems important in order to determine to what extent the disturbances of social cognition can influence social and professional life of patients. It is also a potential area for therapeutic interventions supportive to pharmacotherapy.

Respiratory outcomes of the surfactant positive pressure and oximetry randomized trial (SUPPORT).

OBJECTIVE: To explore the early childhood pulmonary outcomes of infants who participated in the National Institute of Child Health and Human Development's Surfactant Positive Airway Pressure and Pulse Oximetry Randomized Trial (SUPPORT), using a factorial design that randomized extremely preterm infants to lower vs higher oxygen saturation targets and delivery room continuous positive airway pressure (CPAP) vs intubation/surfactant. STUDY DESIGN: The Breathing Outcomes Study, a prospective secondary study to the Surfactant Positive Airway Pressure and Pulse Oximetry Randomized Trial, assessed respiratory morbidity at 6-month intervals from hospital discharge to 18-22 months corrected age (CA). Two prespecified primary outcomes-wheezing more than twice per week during the worst 2-week period and cough longer than 3 days without a cold-were compared for each randomized intervention. RESULTS: One or more interviews were completed for 918 of the 922 eligible infants. The incidences of wheezing and cough were 47.9% and 31.0%, respectively, and did not differ between the study arms of either randomized intervention. Infants randomized to lower vs higher oxygen saturation targets had a similar risk of death or respiratory morbidity (except for croup and treatment with oxygen or diuretics at home). Infants randomized to CPAP vs intubation/surfactant had fewer episodes of wheezing without a cold (28.9% vs 36.5%; P<.05), respiratory illnesses diagnosed by a doctor (47.7% vs 55.2%; P<.05), and physician or emergency room visits for breathing problems (68.0% vs 72.9%; P<.05) by 18-22 months CA. CONCLUSION: Treatment with early CPAP rather than intubation/surfactant is associated with less respiratory morbidity by 18-22 months CA. Longitudinal assessment of pulmonary morbidity is necessary to fully evaluate the potential benefits of respiratory interventions for neonates.

Neurodevelopmental outcomes in the early CPAP and pulse oximetry trial.

BACKGROUND: Previous results from our trial of early treatment with continuous positive airway pressure (CPAP) versus early surfactant treatment in infants showed no significant difference in the outcome of death or bronchopulmonary dysplasia. A lower (vs. higher) target range of oxygen saturation was associated with a lower rate of severe retinopathy but higher mortality. We now report longer-term results from our prespecified hypotheses. METHODS: Using a 2-by-2 factorial design, we randomly assigned infants born between 24 weeks 0 days and 27 weeks 6 days of gestation to early CPAP with a limited ventilation strategy or early surfactant administration and to lower or higher target ranges of oxygen saturation (85 to 89% or 91 to 95%). The primary composite outcome for the longer-term analysis was death before assessment at 18 to 22 months or neurodevelopmental impairment at 18 to 22 months of corrected age. RESULTS: The primary outcome was determined for 1234 of 1316 enrolled infants (93.8%); 990 of the 1058 surviving infants (93.6%) were evaluated at 18 to 22 months of corrected age. Death or neurodevelopmental impairment occurred in 27.9% of the infants in the CPAP group (173 of 621 infants), versus 29.9% of those in the surfactant group (183 of 613) (relative risk, 0.93; 95% confidence interval [CI], 0.78 to 1.10; P=0.38), and in 30.2% of the infants in the lower-oxygen-saturation group (185 of 612), versus 27.5% of those in the higher-oxygen-saturation group (171 of 622) (relative risk, 1.12; 95% CI, 0.94 to 1.32; P=0.21). Mortality was increased with the lower-oxygen-saturation target (22.1%, vs. 18.2% with the higher-oxygen-saturation target; relative risk, 1.25; 95% CI, 1.00 to 1.55; P=0.046). CONCLUSIONS: We found no significant differences in the composite outcome of death or neurodevelopmental impairment among extremely premature infants randomly assigned to early CPAP or early surfactant administration and to a lower or higher target range of oxygen saturation. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Heart, Lung, and Blood Institute; SUPPORT ClinicalTrials.gov number, NCT00233324.).

Screening for autism spectrum disorders in extremely preterm infants.

BACKGROUND: Extremely preterm (EP) infants screen positive for autism spectrum disorders (ASD) at high rates. However, it is not clear whether this is because of high rates of ASD in EPs or to high rates of false-positive screens for ASD in children with a high rate of underlying neurodevelopmental impairments. Combining a parent questionnaire designed to distinguish developmental delay from ASD with direct observation of infant behavior may more accurately screen for ASD in EPs. OBJECTIVES: To determine rates of positive screen for ASD at 18 to 22 months(m) in EPs using 3 screens; to determine factors associated with a positive screen. METHODS: Five hundred fifty-four infants born <27 weeks were screened at 18 to 22 m using the Pervasive Developmental Disorders Screening test, second edition Stage 2, and the response to name and response to joint attention items from the Autism Diagnostic Observation Schedule. Infants with severe cerebral palsy, deafness, and blindness were excluded. Associations between positive screen and neonatal/ infant characteristics were determined. RESULTS: Of 554 infants, 113 (20%) had ≥ 1 positive screen. 10% had a positive Pervasive Developmental Disorders Screening test, second edition, 6% response to name, 9% response to joint attention; in only 1 % all 3 screens were positive. Positive screen was associated with male gender, more hospital days, white race, lower maternal education, abnormal behavioral scores, and cognitive/ language delay. CONCLUSIONS: The use of 3 screens for ASD in EPs results in higher screen positive rates than use of 1 screen alone. Diagnostic confirmation is needed before true rates of ASD in EPs are known.

Are outcomes of extremely preterm infants improving? Impact of Bayley assessment on outcomes.

OBJECTIVES: To compare 18- to 22-month cognitive scores and neurodevelopmental impairment (NDI) in 2 time periods using the National Institute of Child Health and Human Development's Neonatal Research Network assessment of extremely low birth weight infants with the Bayley Scales of Infant Development, Second Edition (Bayley II) in 2006-2007 (period 1) and using the Bayley Scales of Infant and Toddler Development, Third Edition (Bayley III), with separate cognitive and language scores, in 2008-2011 (period 2). STUDY DESIGN: Scores were compared with bivariate analysis, and regression analyses were run to identify differences in NDI rates. RESULTS: Mean Bayley III cognitive scores were 11 points higher than mean Bayley II cognitive scores. The NDI rate was reduced by 70% (from 43% in period 1 to 13% in period 2; P < .0001). Multivariate analyses revealed that Bayley III contributed to a decreased risk of NDI by 5 definitions: cognitive score <70 and <85, cognitive or language score <70; cognitive or motor score <70, and cognitive, language, or motor score <70 (P < .001). CONCLUSION: Whether the Bayley III is overestimating cognitive performance or whether it is a more valid assessment of emerging cognitive skills than the Bayley II is uncertain. Because the Bayley III identifies significantly fewer children with disability, it is recommended that all extremely low birth weight infants be offered early intervention services at the time of discharge from the neonatal intensive care unit, and that Bayley scores be interpreted with caution.