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Porous metals represent a class of materials where the interplay of ligament length, width, node structure, and local geometry/curvature offers a rich parameter space for the study of critical length scales on mechanical behavior. Colloidal crystal templating of three-dimensionally ordered macroporous (3DOM, i.e., inverse opal) tungsten provides a unique structure to investigate the mechanical behavior at small length scales across the brittle–ductile transition. Micropillar compression tests show failure at 50 MPa contact pressure at 30 °C, implying a ligament yield strength of approximately 6.1 GPa for a structure with 5% relative density. In situ SEM frustum indentation tests with in-plane strain maps perpendicular to loading indicate local compressive strains of approximately 2% at failure at 30 °C. Increased sustained contact pressure is observed at 225 °C, although large (20%) nonlocal strains appear at 125 °C. The elevated-temperature mechanical performance is limited by cracks that initiate on planes of greatest shear under the indenter.
Serotonergic neurotransmission plays a key role in seasonal changes of mood and behaviour. Higher serotonin transporter availability in healthy human subjects in times of lesser light has been reported in recent studies. Furthermore, seasonal alterations of postsynaptic serotonin-1A receptors have been suggested by a recent animal study. Following that, this study aimed at identifying seasonal alterations of serotonin-1A receptor binding in the living human brain.
Thirty-six healthy, drug-naïve subjects were investigated using PET and the specific tracer [carbonyl-11C]WAY-100635. Regional serotonin-1A receptor binding (5-HT1A BPND) was related to the individual exposure to global radiation. Furthermore, the subjects were divided into two groups depending on individual exposure to global radiation, and the group differences in regional 5-HT1A BPND were determined.
Correlation analysis controlled for age and gender revealed highly significant positive correlations between regional postsynaptic 5-HT1A BPND and global radiation accumulated for 5 days (r=.32 to .48, p=.030 to .002). Highly significant differences in 5-HT1A BPND binding between subjects with low compared to high exposure to global radiation were revealed (T=-2.63 to -3.77, p .013 to .001). 20% to 30% lower 5-HT1A BPND was found in the subject group exposed to lower amount of global radiation.
Seasonal factors such as exposure to global radiation influence postsynaptic serotonin-1A receptor binding in various brain regions in healthy human subjects. In combination with seasonal alterations in serotonin turnover and 5-HTT availability revealed in recent studies, our results provide an essential contribution of molecular mechanisms in seasonal changes of human serotonergic neurotransmission.
Regional alterations of serotonergic neurotransmission and functional activation in the amygdalar region of patients with major depression are underpinning its important role in affective disorders. In this study we used fMRI and PET to describe functional and molecular alterations associtated with an astrocytoma in the left amygdalar region in a patient with organic depressive disorder compared to control subjects.
The serotonin-1A (5-HT1A) receptor binding (BPND) was quantified with PET (30 frames, 90 min, 4.4 mm FWHM) in 36 subjects using the radioligand [carbonyl-11C]WAY-100635, and a reference tissue model (MRTM2). In fMRI (3T, EPI inplane resolution 1.6*2.7 mm, 10 AC-PC orientated slices, ST = 3 mm, TE/TR = 31/1000 ms), 32 participants performed emotion discrimination and sensorimotor control tasks. Statistical analysis with SPM5 and unpaired t-tests were performed on molecular and functional data separately.
The astrocytoma was delineated in the serotonin-1A receptor distribution showing (p < 0.01, uncorrected) regional BPND decrease. The ipsilateral thalamus and bilateral habenula regions displayed (p < 0.001; uncorrected) BPND increase. The fMRI data showed significantly (p < 0.05; uncorrected) reduced activation in the affected amygdalar region, ipsilateral fusiform gyrus, bilateral orbitofrontal cortex and temporal regions and increased activation in the contralateral temporal pole.
Lower serotonin-1A receptor binding in the left amydala region reflects the glial provenance of the tumor. The increased receptor binding in the habenulae might be associated with altered monoaminergic neurotransmission and depressive symptoms according to the influence of the habenulae on monoaminergic nuclei. The functional data demonstrate neuroplastic changes beyond affected areas and might indicate compensatory mechanisms.
Recent data support the view that the neurodegeneration underlying sporadic Alzheimer's Disease (AD) is in part related to brain insulin deficiency and brain insulin resistance. There is a higher incidence of AD in patients with diabetes mellitus type II (T2D) and both diseases show a decline in memory function. In a preceding trial intranasal insulin improved memory function in healthy volunteers so that an increase of central-nervous insulin concentration may improve cognitive function in both amnestic patient groups.
We want to analyse the effects of intranasal insulin on patients with early Alzheimers's disease (eAD) and patients with T2D in the state of amnestic mild cognitive impairment (aMCI).
Recruitment of 30 patients with eAD, 30 patients with T2D in aMCI state and 30 age-matched healthy controls. All patients undergo a run-in period of 2 weeks with 4 × daily administration of placebo. It follows a double blinded trial with daily intranasal administration of 4 × 40 I.U. insulin vs. placebo for 8 weeks and another 8 weeks of follow-up. At 4 defined time points memory function is assessed by word lists comprising 30 items of emotional, nutritional and neutral content which have to be memorized and are recalled after one week. To assess structural changes of the brain, a quantitative analysis for hippocampal N-acetyl-aspartate, choline and creatine is performed by 3 Tesla magnetic resonance spectroscopy.
Results: Since the study has not finished yet, we present experiences from the initiation and the beginning phase.
This study assessed the efficacy of agomelatine (1,2,3), in the prevention of relapse in non-depressed out-patients with DSM-IV-TR defined Generalized Anxiety Disorder (GAD) and the tolerability.
GAD patients received open label agomelatine (25–50 mg/day). At week 4 the dose was increased for patients with insufficient improvement (blinded criteria). At week 16, responders were randomised to maintenance treatment with either agomelatine, or placebo for a 26 week period. Then, agomelatine treated-patients were re-randomised to an agomelatine arm or to a placebo arm, to confirm the lack of discontinuation symptoms (on the DESS check-list).
The primary outcome was the time to relapse (days) during the 26 week double-blind treatment period, as estimated using the Kaplan-Meier method. Relapse was defined as HAMA total score > = 15 or withdrawal for lack of efficacy (in the investigator's opinion, based on both HAM-A and CGI scores).
477 patients entered the open-label phase and 329 completed this period. 228 patients were randomly assigned to receive agomelatine (114 patients) or placebo (114 patients).
The incidence over time of relapse was significantly lower with agomelatine compared to placebo (19.7% versus 31.7% log rank test p = 0.046) during the double-blind treatment period.
During the double-blind treatment period 12.4% patients with agomelatine and 9.6% with placebo reported at least one emergent adverse event related to the study treatment. There was no discontinuation syndrome in agomelatine treated patients.
Agomelatine was efficacious in preventing relapse in GAD, with maintenance of efficacy over 6 months, and good tolerability.
This pooled analysis evaluated the predictors of clinical outcome in the short-term treatment of panic disorder.
Data were pooled from 4 randomized, placebo-controlled studies of venlafaxine XR in adult outpatients with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) panic disorder with or without agoraphobia (n=1595). Patients were randomly assigned to 10 to 12 weeks' treatment with either placebo or venlafaxine (fixed or flexible dosing, range from 75 mg/d to 225 mg/d). The primary efficacy measure was the proportion of patients free of full-symptom panic attacks at end point. Predictors included panic severity (<8 or ≥8 full-symptom panic attacks during each 2 week period in the 4 weeks prior to baseline) and gender. Other predictors included panic disorder, clinical global impressions, anxiety, somatic and psychic anxiety, depression, mood, phobias, fear, and avoidance.
In both the active treatment and placebo groups, males (65% and 50%, respectively) and those with low symptom severity (69% and 53%, respectively) were significantly (P<0.05) more likely to be panic-free at end point. For nearly all baseline ratings on clinical measures, greater symptom severity was associated with lower proportions of patients who were free from full-symptom panic attacks at end point. Change scores showing improvement in symptom severity following treatment were associated with higher proportions of patients who were free from full-symptom panic attacks at end point.
Panic-free status at end point was predicted by gender, panic disorder severity, and most baseline and change scores of clinical ratings scales.
To investigate associations between social anxiety and smoking behaviour in order to explore whether social anxiety predicts the first onset of cigarette smoking, regular smoking and the development of nicotine dependence.
Baseline and four-year follow-up data from the Early Developmental Stages of Psychopathology Study (EDSP), a prospective-longitudinal community study of 3,021 adolescents and young adults, are used. Smoking behaviour and psychopathology were assessed with the M-CIDI and its DSM-IV algorithms. At baseline, 35.7% of the sample were regular smokers, and 18.7% fulfilled criteria for DSM-IV nicotine dependence. Twenty-seven point two percent reported at least one social fear, and 7.2% met criteria for DSM-IV social phobia, most of whom reported first onset of social fear problems clearly prior to smoking initiation. Cross-sectional retrospective baseline analyses based on retrospective reports revealed that social fears and DSM-IV social phobia were both significantly associated with higher rates of nicotine dependence. Prospective-longitudinal analyses that were conducted in an attempt to confirm cross-sectional retrospective results showed that baseline non-users with social fears (OR = 3.85) and baseline non-dependent users with social fears (OR = 1.5) had an increased risk of onset of nicotine dependence during the follow-up period of four years. These findings remained significant even when controlling for co-morbid depressive disorders. Social anxiety was found to be significantly associated with nicotine dependence in both cross-sectional retrospective and prospective-longitudinal analyses. It is suggested that social fears could lead to heavy tobacco use as smoking is a socially acceptable behaviour that relieves anxiety in social situations. Possible differential effects of social anxiety on the early stages of smoking behaviour compared to effects on nicotine dependence are discussed. These findings should stimulate a continued search into potentially causal links between social fear symptoms and the development of tobacco consumption and nicotine dependence in adolescence.
Alterations of the serotonin-1A receptor (5-HT1A) and the hypothalamic-pituitary-adrenal (HPA) axis have been reported in depression and anxiety disorders. We previously showed a strong negative correlation between cortisol plasma levels and 5-HT1A receptor binding potential (BP) in patients with social anxiety disorder but not in healthy controls using PET .
To investigate the relationship of cortisol and the 5-HT1A BP in postmenopausal women, a population that is at increased risk of suffering from depressive symptoms.
Subjects: 19 postmenopausal women, aged 55.26 ± 4.98, medication free, no current substance abuse or hormone replacement therapy.
Dynamic measurements (50 frames, 90 min) were performed using the radioligand [carbonyl-11C]WAY100635 and a GE-Advance scanner. PET data were normalized to a ligand-specific template . Regions-of-interest (ROI) were defined as given in . TACs within ROIs were averaged and the 5-HT1A receptor BP was quantified using Logan-plot and PMOD 3.1. Measurement of total cortisol plasma levels was done using electrochemoluminescence.
We found negative correlations between cortisol and 5-HT1A BP in the midbrain (Spearman's rs = −0.54, p = 0.02), the median raphe nucleus (rs = −0.47, p = 0.04) and the nucleus accumbens (rs = −0.505, p = 0.03).
In line with our previous findings , the observed negative association between cortisol plasma levels and 5-HT1A BP might reflect an increased vulnerability for mood disorders in postmenopausal women.
Three adolescent and two adult patients suffering from chronic excited psychoses (either schizophrenia or schizoaffective disorder) resistant to traditional neuroleptics and clozapine were treated with combined clozapine-lithium. Improvement was assessed with the Positive and Negative Symptoms Scale, the Brief Psychiatric Rating Scale and the Clinical Global Impressions, administered before and during combined clozapine-lithium treatment. All patients demonstrated a significant improvement with this combination. There was no occurrence of agranulocytosis, neuroleptic malignant syndrome or other clinically significant adverse effects.
Two common approaches to identify subgroups of patients with bipolar disorder are clustering methodology (mixture analysis) based on the age of onset, and a birth cohort analysis. This study investigates if a birth cohort effect will influence the results of clustering on the age of onset, using a large, international database.
The database includes 4037 patients with a diagnosis of bipolar I disorder, previously collected at 36 collection sites in 23 countries. Generalized estimating equations (GEE) were used to adjust the data for country median age, and in some models, birth cohort. Model-based clustering (mixture analysis) was then performed on the age of onset data using the residuals. Clinical variables in subgroups were compared.
There was a strong birth cohort effect. Without adjusting for the birth cohort, three subgroups were found by clustering. After adjusting for the birth cohort or when considering only those born after 1959, two subgroups were found. With results of either two or three subgroups, the youngest subgroup was more likely to have a family history of mood disorders and a first episode with depressed polarity. However, without adjusting for birth cohort (three subgroups), family history and polarity of the first episode could not be distinguished between the middle and oldest subgroups.
These results using international data confirm prior findings using single country data, that there are subgroups of bipolar I disorder based on the age of onset, and that there is a birth cohort effect. Including the birth cohort adjustment altered the number and characteristics of subgroups detected when clustering by age of onset. Further investigation is needed to determine if combining both approaches will identify subgroups that are more useful for research.
Obsessive-compulsive disorder (OCD) is a highly disabling condition, with frequent early onset. Adult/adolescent OCD has been extensively investigated, but little is known about prevalence and clinical characterization of geriatric patients with OCD (G-OCD = 65 years). The present study aimed to assess prevalence of G-OCD and associated socio-demographic and clinical correlates in a large international sample.
Data from 416 outpatients, participating in the ICOCS network, were assessed and categorized into 2 groups, age < vs = 65 years, and then divided on the basis of the median age of the sample (age < vs = 42 years). Socio-demographic and clinical variables were compared between groups (Pearson Chi-squared and t tests).
G-OCD compared with younger patients represented a significant minority of the sample (6% vs 94%, P < .001), showing a significantly later age at onset (29.4 ± 15.1 vs 18.7 ± 9.2 years, P < .001), a more frequent adult onset (75% vs 41.1%, P < .001) and a less frequent use of cognitive-behavioural therapy (CBT) (20.8% vs 41.8%, P < .05). Female gender was more represented in G-OCD patients, though not at a statistically significant level (75% vs 56.4%, P = .07). When the whole sample was divided on the basis of the median age, previous results were confirmed for older patients, including a significantly higher presence of women (52.1% vs 63.1%, P < .05).
G-OCD compared with younger patients represented a small minority of the sample and showed later age at onset, more frequent adult onset and lower CBT use. Age at onset may influence course and overall management of OCD, with additional investigation needed.
An experiment was conducted to test the hypothesis that meat products have digestible indispensable amino acid scores (DIAAS) >100 and that various processing methods will increase standardised ileal digestibility (SID) of amino acids (AA) and DIAAS. Nine ileal-cannulated gilts were randomly allotted to a 9 × 8 Youden square design with nine diets and eight 7-d periods. Values for SID of AA and DIAAS for two reference patterns were calculated for salami, bologna, beef jerky, raw ground beef, cooked ground beef and ribeye roast heated to 56, 64 or 72°C. The SID of most AA was not different among salami, bologna, beef jerky and cooked ground beef, but was less (P < 0·05) than the values for raw ground beef. The SID of AA for 56°C ribeye roast was not different from the values for raw ground beef and 72°C ribeye roast, but greater (P < 0·05) than those for 64°C ribeye roast. For older children, adolescents and adults, the DIAAS for all proteins, except cooked ground beef, were >100 and bologna and 64°C ribeye roast had the greatest (P < 0·05) DIAAS. The limiting AA for this age group were sulphur AA (beef jerky), leucine (bologna, raw ground beef and cooked ground beef) and valine (salami and the three ribeye roasts). In conclusion, meat products generally provide high-quality protein with DIAAS >100 regardless of processing. However, overcooking meat may reduce AA digestibility and DIAAS.
Tuberous sclerosis complex is a rare genetic disorder leading to the growth of hamartomas in multiple organs, including cardiac rhabdomyomas. Children with symptomatic cardiac rhabdomyoma require frequent admissions to intensive care units, have major complications, namely, arrhythmias, cardiac outflow tract obstruction and heart failure, affecting the quality of life and taking on high healthcare cost. Currently, there is no standard pharmacological treatment for this condition, and the management includes a conservative approach and supportive care. Everolimus has shown positive effects on subependymal giant cell astrocytomas, renal angiomyolipoma and refractory seizures associated with tuberous sclerosis complex. However, evidence supporting efficacy in symptomatic cardiac rhabdomyoma is limited to case reports. The ORACLE trial is the first randomised clinical trial assessing the efficacy of everolimus as a specific therapy for symptomatic cardiac rhabdomyoma.
ORACLE is a phase II, prospective, randomised, placebo-controlled, double-blind, multicentre protocol trial. A total of 40 children with symptomatic cardiac rhabdomyoma secondary to tuberous sclerosis complex will be randomised to receive oral everolimus or placebo for 3 months. The primary outcome is 50% or more reduction in the tumour size related to baseline. As secondary outcomes we include the presence of arrhythmias, pericardial effusion, intracardiac obstruction, adverse events, progression of tumour reduction and effect on heart failure.
ORACLE protocol addresses a relevant unmet need in children with tuberous sclerosis complex and cardiac rhabdomyoma. The results of the trial will potentially support the first evidence-based therapy for this condition.
To investigate the association of prenatal alcohol exposure (PAE) and early neurodevelopment in the first 2 years of life, adjusting for maternal socio-demographic and psychosocial factors, in the Drakenstein Child Health Study (DCHS), a South African birth cohort study.
The DCHS comprises a population-based birth cohort of 1143 children, of which a subsample completed the Bayley Scales of Infant Development-III (BSID-III) at 6 (n = 260) and 24 months of age (n = 734). A subset of alcohol-exposed and -unexposed children was included in this analysis at age 6 (n = 52 exposed; n = 104 unexposed) and 24 months (n = 92 exposed; n = 184 unexposed). Multiple hierarchical regression was used to explore the associations of PAE with motor and language development.
PAE was significantly associated with decreased gross motor [odds ratio (OR) = 0.16, 95% confidence interval (CI) = 0.06–0.44, p = 0.001] or fine motor (OR = 0.16, 95% CI = 0.06–0.46, p = 0.001) functioning after adjusting for maternal socio-demographic and psychosocial factors at 6 months of age only. No significant effects were found in either receptive or expressive communication and cognitive outcomes at either time points.
PAE has potentially important consequences for motor development in the first 2 years of life, a period during which the most rapid growth and maturation occur. These findings highlight the importance of identifying high-risk families in order to provide preventive interventions, particularly in antenatal clinics and early intervention services.
Intermittent explosive disorder (IED) is characterised by impulsive anger attacks that vary greatly across individuals in severity and consequence. Understanding IED subtypes has been limited by lack of large, general population datasets including assessment of IED. Using the 17-country World Mental Health surveys dataset, this study examined whether behavioural subtypes of IED are associated with differing patterns of comorbidity, suicidality and functional impairment.
IED was assessed using the Composite International Diagnostic Interview in the World Mental Health surveys (n = 45 266). Five behavioural subtypes were created based on type of anger attack. Logistic regression assessed association of these subtypes with lifetime comorbidity, lifetime suicidality and 12-month functional impairment.
The lifetime prevalence of IED in all countries was 0.8% (s.e.: 0.0). The two subtypes involving anger attacks that harmed people (‘hurt people only’ and ‘destroy property and hurt people’), collectively comprising 73% of those with IED, were characterised by high rates of externalising comorbid disorders. The remaining three subtypes involving anger attacks that destroyed property only, destroyed property and threatened people, and threatened people only, were characterised by higher rates of internalising than externalising comorbid disorders. Suicidal behaviour did not vary across the five behavioural subtypes but was higher among those with (v. those without) comorbid disorders, and among those who perpetrated more violent assaults.
The most common IED behavioural subtypes in these general population samples are associated with high rates of externalising disorders. This contrasts with the findings from clinical studies of IED, which observe a preponderance of internalising disorder comorbidity. This disparity in findings across population and clinical studies, together with the marked heterogeneity that characterises the diagnostic entity of IED, suggests that it is a disorder that requires much greater research.
Evidence from high-income countries suggests that childhood trauma is associated with schizophrenia. Studies of childhood trauma and schizophrenia in low and middle income (LMIC) countries are limited. This study examined the prevalence of childhood traumatic experiences among cases and controls and the relationship between specific and cumulative childhood traumatic experiences and schizophrenia in a sample in South Africa.
Data were from the Genomics of Schizophrenia in the South African Xhosa people study. Cases with schizophrenia and matched controls were recruited from provincial hospitals and clinics in the Western and Eastern Cape regions in South Africa. Childhood traumatic experiences were measured using the Childhood Trauma Questionnaire (CTQ). Adjusted logistic regression models estimated associations between individual and cumulative childhood traumatic experiences and schizophrenia.
Traumatic experiences were more prevalent among cases than controls. The odds of schizophrenia were 2.44 times higher among those who experienced any trauma than those who reported no traumatic experiences (95% CI 1.77–3.37). The odds of schizophrenia were elevated among those who experienced physical/emotional abuse (OR 1.59, CI 1.28–1.97), neglect (OR 1.39, CI 1.16–1.68), and sexual abuse (OR 1.22, CI 1.03–1.45) compared to those who did not. Cumulative physical/emotional abuse and neglect experiences increased the odds of schizophrenia as a dose–response relationship.
Childhood trauma is common in this population. Among many other benefits, interventions to prevent childhood trauma may contribute to a decreasing occurrence of schizophrenia.
Bipolar disorder (BD) and obsessive compulsive disorder (OCD) are prevalent, comorbid, and disabling conditions, often characterized by early onset and chronic course. When comorbid, OCD and BD can determine a more pernicious course of illness, posing therapeutic challenges for clinicians. Available reports on prevalence and clinical characteristics of comorbidity between BD and OCD showed mixed results, likely depending on the primary diagnosis of analyzed samples.
We assessed prevalence and clinical characteristics of BD comorbidity in a large international sample of patients with primary OCD (n = 401), through the International College of Obsessive–Compulsive Spectrum Disorders (ICOCS) snapshot database, by comparing OCD subjects with vs without BD comorbidity.
Among primary OCD patients, 6.2% showed comorbidity with BD. OCD patients with vs without BD comorbidity more frequently had a previous hospitalization (p < 0.001) and current augmentation therapies (p < 0.001). They also showed greater severity of OCD (p < 0.001), as measured by the Yale–Brown Obsessive Compulsive Scale (Y-BOCS).
These findings from a large international sample indicate that approximately 1 out of 16 patients with primary OCD may additionally have BD comorbidity along with other specific clinical characteristics, including more frequent previous hospitalizations, more complex therapeutic regimens, and a greater severity of OCD. Prospective international studies are needed to confirm our findings.
Childhood maltreatment (CM) plays an important role in the development of major depressive disorder (MDD). The aim of this study was to examine whether CM severity and type are associated with MDD-related brain alterations, and how they interact with sex and age.
Within the ENIGMA-MDD network, severity and subtypes of CM using the Childhood Trauma Questionnaire were assessed and structural magnetic resonance imaging data from patients with MDD and healthy controls were analyzed in a mega-analysis comprising a total of 3872 participants aged between 13 and 89 years. Cortical thickness and surface area were extracted at each site using FreeSurfer.
CM severity was associated with reduced cortical thickness in the banks of the superior temporal sulcus and supramarginal gyrus as well as with reduced surface area of the middle temporal lobe. Participants reporting both childhood neglect and abuse had a lower cortical thickness in the inferior parietal lobe, middle temporal lobe, and precuneus compared to participants not exposed to CM. In males only, regardless of diagnosis, CM severity was associated with higher cortical thickness of the rostral anterior cingulate cortex. Finally, a significant interaction between CM and age in predicting thickness was seen across several prefrontal, temporal, and temporo-parietal regions.
Severity and type of CM may impact cortical thickness and surface area. Importantly, CM may influence age-dependent brain maturation, particularly in regions related to the default mode network, perception, and theory of mind.