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The purpose of the present study was to evaluate the efficacy and safety of (−)-OSU6162 in doses up to 30 mg b.i.d. in patients suffering from mental fatigue following stroke or traumatic brain injury (TBI).
This 4 + 4 weeks double-blind randomised cross-over study included 30 patients afflicted with mental fatigue following a stroke or head trauma occurring at least 12 months earlier. Efficacy was assessed using the Mental Fatigue Scale (MFS), the Self-rating Scale for Affective Syndromes [Comprehensive Psychopathological Rating Scale (CPRS)], the Frenchay Activity Index (FAI), and a battery of neuropsychological tests. Safety was evaluated by recording spontaneously reported adverse events (AEs).
There were significant differences on the patients’ total FAI scores (p = 0.0097), the subscale FAI outdoor scores (p = 0.0243), and on the trail making test (TMT-B) (p = 0.0325) in favour of (−)-OSU6162 treatment. Principal component analysis showed a clear overall positive treatment effect in 10 of 28 patients; those who responded best to treatment had their greatest improvements on the MFS. Reported AEs were mild or moderate in severity and did not differ between the (−)-OSU6162 and the placebo period.
The most obvious beneficial effects of (−)-OSU6162 were on the patients’ activity level, illustrated by the improvement on the FAI scale. Moreover, a subgroup of patients showed substantial improvements on the MFS. Based on these observed therapeutic effects, in conjunction with the good tolerability of (−)-OSU6162, this compound may offer promise for treating at least part of the symptomatology in patients suffering from stroke- or TBI-induced mental fatigue.
In summary, genetics, as well as foetal and early life environmental factors shape the size or capacity of our monoamine systems, of which the serotonergic one might play a leading role. Those constitutional properties then form the biological basis for personality traits, such as impulsiveness and “sensation seeking”, which interact with psychosocial settings and life events to form a pattern of reactivity to a current life event or psychosocial situation, shown as a high or low order of magnitude of gene-environment interaction. In the present paper emphasis is put on the role of genotypes of the serotonin transporter, of monoamine oxidases A and B, and of platelet monoamine oxidase B activity, which all have been shown to be of importance for behaviour and with obvious effects of interactions with environment. Under unfortunate circumstances constitutional properties might be strong enough to result in vulnerability for suicide, even with a modest influence of environment.
In a community sample of 418 persons diagnosed with schizophrenia, subjective needs and perceived help was measured by the Camberwell Assessment of Need (CAN). The mean number of reported needs was 6.2 and the mean number of unmet needs 2.6. The prevalence of needs varied substantially between the need areas from 3.6% (‘telephone’) to 84.0% (‘psychotic symptoms’). The rate of satisfaction estimated as the percentage of persons satisfied with the help provided within an area varied between 20.0% (‘telephone’) and 80.6% (‘food’).
The need areas concerning social and interpersonal functioning demonstrated the highest proportion of unmet to total needs.
In a majority of need areas the patients received more help from services than from relatives, but in the areas of social relations the informal network provided substantial help. In general the patients reported a need for help from services clearly exceeding the actual amount of help received.
In a linear regression model symptom load (BPRS) and impaired functioning (GAF) were significant predictors of the need status, explaining 30% of the variance in total needs and 20% of the variance in unmet needs.
It is concluded that the mental health system fails to detect and alleviate needs in several areas of major importance to schizophrenic patients. Enhanced collaboration between the care system and the informal network to systematically map the need profile of the patients seems necessary to minimise the gap between perceived needs and received help.
Patients with schizophrenia suffer from a broad range of cognitive disturbances. The impact in terms of functional outcome is significant. There are also several reports of disturbed autonomic regulation in the disease. The present study examined cognitive function as well as psychophysiological parameters in patients with schizophrenia and healthy controls.
Twenty-five patients and 14 controls were investigated with electrodermal activity (EDA), an oral niacin skin flush test and a comprehensive neurocognitive test program including the Wechsler battery (WAIS-R), Fingertapping Test, Trail Making Test, Verbal Fluency, Benton Visual Retention Test, Wisconsin Card Sorting Test and Rey Auditory Verbal Learning Test.
The patients generally had inferior test results compared to controls. Further analysis revealed that the EDA non-responding patient group explained this variation with significant lower test results than controls. On executive tests, EDA non-responders also performed significantly worse than EDA responding patients. The small group of niacin non-responding patients exhibited an even lower overall test performance. Delayed niacin flush also correlated inversely with psychomotor function and IQ in the patients.
The findings support the hypothesis of a neurodevelopment disturbance affecting both autonomic function and higher cortical function in schizophrenia.
Despite massive research on weight gain and metabolic complications in schizophrenia there are few studies on energy expenditure and no current data on physical capacity.
To determine oxygen uptake capacity, respiratory quotient (RQ) and energy expenditure during a submaximal exercise test in patients with schizophrenia and healthy controls.
Ten male patients and 10 controls were included. RQ and energy expenditure were investigated with indirect calorimetry during a cycle ergometer test. The submaximal work level was defined by heart rate and perceived exhaustion. Physical capacity was determined from predicted maximal oxygen uptake capacity (VO2-max).
The patients exhibited significantly higher RQ on submaximal workloads and lower physical capacity. A significant lower calculated VO2-max remained after correction for body weight and fat free mass (FFM). Energy expenditure did not differ on fixed workloads.
RQ was rapidly increasing in the patients during exercise indicating a faster transition to carbohydrate oxidation and anaerobic metabolism that also implies a performance closer to maximal oxygen uptake even at submaximal loads. This may restrict the capacity for everyday activity and exercise and thus contribute to the risk for weight gain. Physical capacity was consequently significantly lower in the patients.
To investigate the effects of atomoxetine on emotional control in adults with ADHD.
We performed an integrated analysis using individual patient data pooled from three Eli Lilly-sponsored studies. An integrated analysis can be viewed as a meta-analysis of individual patient-level data, rather than study-level summary data.
Two populations were identified: a large sample of patients with pre-treatment baseline data (the “overall population”; n = 2846); and a subset of these patients with placebo-controlled efficacy data from baseline to 10 or 12 weeks after initiating treatment (the “placebo-controlled population”; n = 829). At baseline, in the overall population, ∼50% of ADHD patients had BRIEF-AS (Behavior Rating Inventory of Executive Function-Adult Version Self-Report) Emotional control subscores between 21 and 30, compared with ∼10% of normative subjects in the BRIEF-A manual. At endpoint, in the placebo-controlled population, atomoxetine led to a small (effect size 0.19) but significant (P = 0.013) treatment effect for emotional control. The effect size was 0.32 in patients with BRIEF-AS Emotional control scores > 20 at baseline. Improvements in emotional control correlated with improvements in the core ADHD symptoms and quality-of-life.
As deficient emotional control is associated with impaired social, educational and occupational functioning over and above that explained by core ADHD symptoms alone, improvements in emotional control may be clinically relevant.
At baseline, adults with ADHD were more likely to have impaired emotional control than normative subjects. In the adult ADHD patients, atomoxetine treatment was associated with improvements in emotional control, as well as in core ADHD symptoms and quality-of-life.
Epistatic effects between gene variants of 5-HTTLPR (L=long, S=short), MAOA-VNTR (L=long, S=short), and BDNF Val/Met have been found with regard to behaviour in experimental animals as well as indicated in human samples in relation to neuroticism and depression. In the present study we studied epistatic effects of the above gene variations in an interaction with environmental adversity on adolescent criminality.
Family maltreatment, sexual abuse and criminality were measured by self-reports in a Swedish adolescent population-based sample (n=1819). Genomic DNA was isolated from saliva and used for genotyping of the BDNF, the 5-HTT and MAOA genes.
BDNF genotype showed a main effect on adolescent criminality. BDNF also showed a two-way interaction with 5- HTT and Family maltreatment. 5HTT showed two-way interactions with MAOA and Family maltreatment. MAOA also showed a two-way interaction with Family maltreatment. Significant three-way interactions were found for; BDNF-5-HTT-Family maltreatment; BDNF-MAOA-Family maltreatment; BDNF-MAOA-Sexual abuse; and 5HTT-MAOA-Family maltreatment. Significant four-way (G*G*G*E) interactions were found for BDNF-5-HTT-MAOA-Family maltreatment and BDNF-5-HTTMAOA- Sexual abuse, respectively.
Boys showed a stronger effect of environmental adversity compared to girls. However, there were no significant sex-gene interactions. Furthermore, the two most genotypically divergent groups, according to expression levels, showed the highest criminality scores (MAOA-LL + 5-HTT-LL + BDNF Val-Val vs. MAOA S/LS + 5-HTT-S/LS + BDNF Val-Met/Met-Met), when exposed to environmental adversity.
There are significant epistatic effects between 5-HTT, MAOA and BDNF genotypes and environmental adversity for criminal behavior. Two distinct “types” can be recognized with regard to genotype.
Blazar OJ287 exhibits large thermal flares at least twice every 12 years. The times of these flares have been predicted successfully using the model of a quasi-Keplerian eccentric black hole binary where the secondary impacts the accretion disk of the primary, creating the thermal flares. New measurements of the historical light curve have been combined with the observations of the 2015 November/December flare to identify the impact record since year 1886, and to constrain the orbit of the binary. The orbital solution shows that the binary period, now 12.062 years, is decreasing at the rate of 36 days per century. This corresponds to an energy loss to gravitational waves that is 6.5 ± 4 % less than the rate predicted by the standard quadrupolar gravitational wave (GW) emission. We show that the difference is due to higher order gravitational radiation reaction terms that include the dominant order tail contributions.
Obsessive–compulsive disorder (OCD) is a chronic psychiatric disorder leading to considerable distress and disability. Therapies are effective in a majority of paediatric patients, however, many only get partial response. It is therefore important to study the underlying pathophysiology of the disorder.
1H magnetic resonance spectroscopy (MRS) was used to study the concentration of brain metabolites in four different locations (cingulate gyrus and sulcus, occipital cortex, thalamus and right caudate nucleus). Treatment-naive children and adolescents with OCD (13 subjects) were compared with a group of healthy age- and gender-matched subjects (11 subjects). Multivariate analyses were performed on the concentration values.
No separation between controls and patients was found. However, a correlation between metabolite concentrations and symptom severity as measured with the Children’s Yale-Brown Obsessive–Compulsive Scale (CY-BOCS) was found. Strongest was the correlation with the CY-BOCS obsession subscore and aspartate and choline in the caudate nucleus (positively correlated with obsessions), lipids at 2 and 0.9 ppm in thalamus, and occipital glutamate+glutamine, N-acetylaspartate and myo-inosytol (negatively correlated with obsessions).
The observed correlations between 1H MRS and CY-BOCS in treatment-naive patients further supports an occipital involvement in OCD. The results are consistent with our previous study on adult OCD patients. The 1H MRS data were not supportive of a separation between the patient and control groups.
Hippocampal volume reductions in major depression have been frequently reported. However, evidence for functional abnormalities in the same region in depression has been less clear. We investigated hippocampal function in depression using functional magnetic resonance imaging (fMRI) and neuropsychological tasks tapping spatial memory function, with complementing measures of hippocampal volume and resting blood flow to aid interpretation.
A total of 20 patients with major depressive disorder (MDD) and a matched group of 20 healthy individuals participated. Participants underwent multimodal magnetic resonance imaging (MRI): fMRI during a spatial memory task, and structural MRI and resting blood flow measurements of the hippocampal region using arterial spin labelling. An offline battery of neuropsychological tests, including several measures of spatial memory, was also completed.
The fMRI analysis showed significant group differences in bilateral anterior regions of the hippocampus. While control participants showed task-dependent differences in blood oxygen level-dependent (BOLD) signal, depressed patients did not. No group differences were detected with regard to hippocampal volume or resting blood flow. Patients showed reduced performance in several offline neuropsychological measures. All group differences were independent of differences in hippocampal volume and hippocampal blood flow.
Functional abnormalities of the hippocampus can be observed in patients with MDD even when the volume and resting perfusion in the same region appear normal. This suggests that changes in hippocampal function can be observed independently of structural abnormalities of the hippocampus in depression.
To examine the use of vitamin D supplements during infancy among the participants in an international infant feeding trial.
Information about vitamin D supplementation was collected through a validated FFQ at the age of 2 weeks and monthly between the ages of 1 month and 6 months.
Infants (n 2159) with a biological family member affected by type 1 diabetes and with increased human leucocyte antigen-conferred susceptibility to type 1 diabetes from twelve European countries, the USA, Canada and Australia.
Daily use of vitamin D supplements was common during the first 6 months of life in Northern and Central Europe (>80 % of the infants), with somewhat lower rates observed in Southern Europe (>60 %). In Canada, vitamin D supplementation was more common among exclusively breast-fed than other infants (e.g. 71 % v. 44 % at 6 months of age). Less than 2 % of infants in the USA and Australia received any vitamin D supplementation. Higher gestational age, older maternal age and longer maternal education were study-wide associated with greater use of vitamin D supplements.
Most of the infants received vitamin D supplements during the first 6 months of life in the European countries, whereas in Canada only half and in the USA and Australia very few were given supplementation.
Studies suggest a role for cardiovascular fitness in the prevention of
To determine whether cardiovascular fitness at age 18 is associated with
future risk of serious affective illness.
Population-based Swedish cohort study of male conscripts
(n = 1 117 292) born in 1950–1987 with no history of
mental illness who were followed for 3–40 years. Data on cardiovascular
fitness at conscription were linked with national hospital registers to
calculate future risk of depression (requiring in-patient care) and
In fully adjusted models low cardiovascular fitness was associated with
increased risk for serious depression (hazard ratios (HR)=1.96, 95%, CI
1.71–2.23). No such association could be shown for bipolar disorder
(HR=1.11, 95% CI 0.84–1.47).
Lower cardiovascular fitness at age 18 was associated with increased risk
of serious depression in adulthood. These results strengthen the theory
of a cardiovascular contribution to the aetiology of depression.
Objective: Mental fatigue occurring after a stroke or traumatic brain injury (TBI) often results in difficulties returning to work and pursuing social activities. No effective treatment of this condition is available today. In this study, we have tested a novel pharmacological strategy using the monoaminergic stabiliser (−)-OSU6162.
Methods: (−)-OSU6162 was given orally for 4 weeks in doses increasing from 15 to 45 mg b.i.d. to 12 patients suffering from mental fatigue, following upon stroke (n=6) or TBI (n=6). (−)-OSU6162 was compared with placebo using a double-blind, randomised cross-over design. Patients included were well rehabilitated physically with no gross impairment in cognitive functions other than those related to the mental fatigue.
Results: (−)-OSU6162 caused a remarkable improvement in mental stamina, as evaluated by a self-assessment scale on mental fatigue. Statistical significance was reached on the primary endpoint (Mental Fatigue Scale). There was a trend towards improvement in the secondary endpoints processing speed and attention. Principal component analysis showed an overall positive treatment effect in 7 of 12 patients. Beneficial responses were seen already during the first few days of active drug treatment. Increasing dosage caused no further improvement. Adverse reactions consisted of short-lasting mild nausea and attenuated appetite. These side effects disappeared upon dose reduction.
Conclusion: The monoaminergic stabiliser (−)-OSU6162 offers promise as a candidate for treatment of mental fatigue after a stroke or TBI.
Renewable energy can provide a host of benefits to society. In addition to the reduction of carbon dioxide (CO2) emissions, governments have enacted renewable energy (RE) policies to meet a number of objectives including the creation of local environmental and health benefits; facilitation of energy access, particularly for rural areas; advancement of energy security goals by diversifying the portfolio of energy technologies and resources; and improving social and economic development through potential employment opportunities. Energy access and social and economic development have been the primary drivers in developing countries whereas ensuring a secure energy supply and environmental concerns have been most important in developed countries.
An increasing number and variety of RE policies–motivated by a variety of factors–have driven substantial growth of RE technologies in recent years. Government policies have played a crucial role in accelerating the deployment of RE technologies. At the same time, not all RE policies have proven effective and efficient in rapidly or substantially increasing RE deployment. The focus of policies is broadening from a concentration almost entirely on RE electricity to include RE heating and cooling and transportation.
RE policies have promoted an increase in RE capacity installations by helping to overcome various barriers. Barriers specific to RE policymaking (e.g., a lack of information and awareness), to implementation (e.g., a lack of an educated and trained workforce to match developing RE technologies) and to financing (e.g., market failures) may further impede deployment of RE.
Disaster medicine is a young discipline and there is a need for the development of methods for evaluation and research. This includes full-scale disaster exercises that are quite costly. Within each organization these exercises are seldom conducted. If there was a standardized concept on how to conduct as well as evaluate these exercises, this could lead to better knowledge and cost effectiveness. The aim of this study was to increase awareness of the possibility to develop and conduct full-scale exercises in different settings using performance indicators combined with indicators related to patient outcome serving as a basis for comparison and evaluation process.
Two full-scale exercises in different organizations were studied. Identical panorama with the same number and type of casualties was used. Sets of performance indicators combined with indicators for unfavorable patient outcome, according to the Emergo Train System®, were recorded as well as all transportation times and the patient distribution to selected hospitals. Qualified observers scored the results on predetermined locations; on the scene, hospital and strategic command and control.
The lowest scored performance indicators were “first report to dispatch”, “second report from scene” and “first patient evacuated”. Due to insufficient response and evacuation times of victims to the receiving hospitals the unfavourable patient outcome, regarding preventable deaths and preventable complications were 28% (n = 18) and 41% (n = 17), respectively.
Standardized full-scale exercises where the same type of results is recorded can be conducted. This combination of performance indicators and Emergo Train System® leads to probabilities of development and better command and control response. Future use of the same concept may demonstrate important results that will lead to new and better knowledge that can be applied during real incidents.