Refined diagnostic criteria for the bipolar disorders: phase two of the AREDOC project.

OBJECTIVE: As limitations exist across DSM criteria sets for defining and differentiating the bipolar disorders generally and their component bipolar I (BP-1) and bipolar II (BP-II) sub-types, we sought to generate empirically based criteria. METHOD: We formed an international Task Force (TF) comprising members with bipolar disorder expertise, and who recruited 74 patients with a TF-diagnosed bipolar I and 104 with a bipolar II condition (with patients responding to definitional queries and symptom questionnaires), while 33 unipolar depressed patients recruited by the first author also completed the symptom questionnaire. A factor analysis sought to determine granular hypo/manic constructs. RESULTS: The bipolar disorder subjects strongly affirmed a new general definition of a bipolar disorder (capturing both manic and hypomanic episodes). While DSM-5 requires impaired functioning, we established that a high percentage of individuals with a BP-I or a BP-II disorder reported improved functioning and therefore modified this criterion. Analyses identified syptoms with differential high rates in individuals with bipolar disorder and its sub-types (and thus not simply capturing happiness), while a factor analysis generated seven symptom constructs both linked with and differing from DSM-5 bipolar symptom criteria. CONCLUSION: This second-stage report details a new set of criteria for differentiating the bipolar disorders from unipolar depressive conditions, while arguing for BP-I and BP-II disorders being differentiated principally by the respective presence or absence of psychotic features. Future studies will evaluate whether further modifications are required and examine for differential treatment benefits for those with a BP-I versus a BP-II condition.

Prediction of lithium response using clinical data.

OBJECTIVE: Promptly establishing maintenance therapy could reduce morbidity and mortality in patients with bipolar disorder. Using a machine learning approach, we sought to evaluate whether lithium responsiveness (LR) is predictable using clinical markers. METHOD: Our data are the largest existing sample of direct interview-based clinical data from lithium-treated patients (n = 1266, 34.7% responders), collected across seven sites, internationally. We trained a random forest model to classify LR-as defined by the previously validated Alda scale-against 180 clinical predictors. RESULTS: Under appropriate cross-validation procedures, LR was predictable in the pooled sample with an area under the receiver operating characteristic curve of 0.80 (95% CI 0.78-0.82) and a Cohen kappa of 0.46 (0.4-0.51). The model demonstrated a particularly low false-positive rate (specificity 0.91 [0.88-0.92]). Features related to clinical course and the absence of rapid cycling appeared consistently informative. CONCLUSION: Clinical data can inform out-of-sample LR prediction to a potentially clinically relevant degree. Despite the relevance of clinical course and the absence of rapid cycling, there was substantial between-site heterogeneity with respect to feature importance. Future work must focus on improving classification of true positives, better characterizing between- and within-site heterogeneity, and further testing such models on new external datasets.

An update on the Enzyme Portal: an integrative approach for exploring enzyme knowledge.

14: Enzymes are a key part of life processes and are increasingly important for various areas of research such as medicine, biotechnology, bioprocessing and drug research. The goal of the Enzyme Portal is to provide an interface to all European Bioinformatics Institute (EMBL-EBI) data about enzymes (de Matos, P., et al. , (2013), BMC Bioinformatics , (1), 103). These data include enzyme function, sequence features and family classification, protein structure, reactions, pathways, small molecules, diseases and the associated literature. The sources of enzyme data are: the UniProt Knowledgebase (UniProtKB) (UniProt Consortium, 2015), the Protein Data Bank in Europe (PDBe), (Valenkar, S., et al ., Nucleic Acids Res. 2016; , D385-D395) Rhea-a database of enzyme-catalysed reactions (Morgat, A., et al .,  Nucleic Acids Res.  2015; , D459-D464), Reactome-a database of biochemical pathways (Fabregat, A., et al ., Nucleic Acids Res. 2016;  , D481-D487), IntEnz-a resource with enzyme nomenclature information (Fleischmann, A., et al ., Nucleic Acids Res.  2004 , D434-D437) and ChEBI (Hastings, J., et al .,  Nucleic Acids Res. 2013) and ChEMBL (Bento, A. P., et al ., Nucleic Acids Res.  2014 , 1083-1090)-resources which contain information about small-molecule chemistry and bioactivity. This article describes the redesign of Enzyme Portal and the increased functionality added to maximise integration and interpretation of these data. Use case examples of the Enzyme Portal and the versatile workflows its supports are illustrated. We welcome the suggestion of new resources for integration.

Influence of birth cohort on age of onset cluster analysis in bipolar I disorder.

PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Neuroprotective effect of lithium on hippocampal volumes in bipolar disorder independent of long-term treatment response.

BACKGROUND: Neuroimaging studies have demonstrated an association between lithium (Li) treatment and brain structure in human subjects. A crucial unresolved question is whether this association reflects direct neurochemical effects of Li or indirect effects secondary to treatment or prevention of episodes of bipolar disorder (BD). METHOD: To address this knowledge gap, we compared manually traced hippocampal volumes in 37 BD patients with at least 2 years of Li treatment (Li group), 19 BD patients with <3 months of lifetime Li exposure over 2 years ago (non-Li group) and 50 healthy controls. All BD participants were followed prospectively and had at least 10 years of illness and a minimum of five episodes. We established illness course and long-term treatment response to Li using National Institute of Mental Health (NIMH) life charts. RESULTS: The non-Li group had smaller hippocampal volumes than the controls or the Li group (F 2,102 = 4.97, p = 0.009). However, the time spent in a mood episode on the current mood stabilizer was more than three times longer in the Li than in the non-Li group (t(51) = 2.00, p = 0.05). Even Li-treated patients with BD episodes while on Li had hippocampal volumes comparable to healthy controls and significantly larger than non-Li patients (t(43) = 2.62, corrected p = 0.02). CONCLUSIONS: Our findings support the neuroprotective effects of Li. The association between Li treatment and hippocampal volume seems to be independent of long-term treatment response and occurred even in subjects with episodes of BD while on Li. Consequently, these effects of Li on brain structure may generalize to patients with neuropsychiatric illnesses other than BD.

The energy cost of playing active video games in children with obesity and children of a healthy weight.

BACKGROUND: Increasing physical activity and reducing sedentary behaviour form a large part of the treatment of paediatric obesity. However, many children today spend prolonged periods of time playing sedentary video games. Active video games (AVGs) represent a novel and child friendly form of physical activity. OBJECTIVES: To measure the energy cost of playing two AVGs in children with obesity and healthy age- and gender-matched children. METHODS: The energy cost of gaming and heart rates achieved during gaming conditions were compared between groups. RESULTS: AVG play can result in light-to-moderate intensity physical activity (2.7-5.4 metabolic equivalents). When corrected for fat-free mass those with obesity expended significantly less energy than healthy weight peers playing Nintendo Wii Fit Free Jogging (P = 0.017). No significant difference was seen between groups in the energy cost of playing Boxing. CONCLUSION: Certain AVGs, particularly those that require lower limb movement, could be used to increase total energy expenditure, replace more sedentary activities, or achieve moderate intensity physical activity among children with obesity. There seems to be some differences in how children with obesity and children of a healthy weight play AVGs. This could result in those with obesity expending less energy than their lean peers during AVG play.

Active video games as a form of exercise and the effect of gaming experience: a preliminary study in healthy young adults.

OBJECTIVES: To examine the energy expenditure and heart rate response while playing active video games, and the effect of gaming experience on energy expenditure. DESIGN: Cross-sectional study. PARTICIPANTS AND INTERVENTIONS: Twenty-eight healthy participants (18 male, age 19 to 27 years) played either Wii Sports Boxing, Tennis and Baseball, or Wii Sports Boxing and Wii Fit Free Jogging. MAIN OUTCOME MEASURES: Percentage maximal heart rate (%HRmax) and metabolic equivalents (METs) were measured during 15 minutes of rest and during each game. RESULTS: Mean %HRmax and METs while playing each of the four games were as follows: Wii Fit Free Jogging 71% [standard deviation (SD) 13%], 5.9 (SD 1.8); Wii Sports Boxing 58% (SD 13%), 3.2 (SD 1.1); Wii Sports Baseball 42% (SD 6%), 2.0 (SD 0.5); and Wii Sports Tennis 42% (SD 7%), 2.0 (SD 0.4). Subjects with gaming experience achieved a lower heart rate playing Wii Sports Tennis compared with subjects without gaming experience. CONCLUSIONS: Wii Sports Boxing, Tennis and Baseball are light-intensity activities, and Wii Fit Free Jogging is a moderate-intensity activity. Experience of gaming may affect the exercise intensity of games requiring controller skill.

Energy expended playing Xbox Kinect™ and Wii™ games: a preliminary study comparing single and multiplayer modes.

OBJECTIVES: It has been reported that a higher galvanic skin response is seen when playing video games against another human player than when playing alone, which suggests increased effort. The objectives of this study were to compare energy expenditure when playing two popular active video game consoles, and to compare energy expenditure when playing in single and multiplayer modes. DESIGN: Crossover trial with randomised playing order. PARTICIPANTS: Fourteen healthy adults with a mean age of 21 [standard deviation (SD) 3] years. METHODS AND INTERVENTIONS: Energy expenditure was measured using an indirect calorimeter at rest, during 10 minutes of play on Xbox Kinect™ Reflex Ridge in both single and multiplayer modes, and during 10 minutes of play on Wii™ Sports Boxing in both single and multiplayer modes. MAIN OUTCOME MEASURES: Metabolic equivalents (METs), heart rate, oxygen consumption and kilocalories expended. RESULTS: The energy expenditure during all gaming conditions was of a light intensity. Playing on the Xbox Kinect elicited greater energy expenditure than playing on the Wii [mean difference=0.9 METs, 95% confidence interval (CI) 0.2 to 1.5]. Playing games in multiplayer mode led to greater energy expenditure (mean difference=0.5 METs, 95% CI 0.1 to 0.9) and heart rate (mean difference=7.9 beats/minute, 95% CI 2.0 to 13.8) than playing in single player mode. CONCLUSIONS: No gaming condition required moderate-intensity activity in this group of young healthy adults. Potential explanations for the difference in energy expenditure seen between consoles and modes are discussed.

Spatial correlations in polydisperse, frictionless, two-dimensional packings.

We investigate next-nearest-neighbor correlations of the contact number in simulations of polydisperse, frictionless packings in two dimensions. We find that disks with few contacting neighbors are predominantly in contact with disks that have many neighbors and vice versa at all packing fractions. This counterintuitive result can be explained by drawing a direct analogy to the Aboav-Weaire law in cellular structures. We find an empirical one parameter relation similar to the Aboav-Weaire law that satisfies an exact sum rule constraint. Surprisingly, there are no correlations in the radii between neighboring particles, despite correlations between contact number and radius.

Sudden death in epileptic rats exposed to nocturnal magnetic fields that simulate the shape and the intensity of sudden changes in geomagnetic activity: an experiment in response to Schnabel, Beblo and May.

To test the hypothesis that sudden unexplained death (SUD) in some epileptic patients is related to geomagnetic activity we exposed rats in which limbic epilepsy had been induced to experimentally produced magnetic fields designed to simulate sudden storm commencements (SSCs). Prior studies with rats had shown that sudden death in groups of rats in which epilepsy had been induced months earlier was associated with the occurrence of SSCs and increased geomagnetic activity during the previous night. Schnabel et al. [(2000) Neurology 54:903-908] found no relationship between SUD in human patients and geomagnetic activity. A total of 96 rats were exposed to either 500, 50, 10-40 nT or sham (less than 10 nT) magnetic fields for 6 min every hour between midnight and 0800 hours (local time) for three successive nights. The shape of the complex, amplitude-modulated magnetic fields simulated the shape and structure of an average SSC. The rats were then seized with lithium and pilocarpine and the mortality was monitored. Whereas 10% of the rats that had been exposed to the sham field died within 24 h, 60% of the rats that had been exposed to the experimental magnetic fields simulating natural geomagnetic activity died (P<.001) during this period. These results suggest that correlational analyses between SUD in epileptic patients and increased geomagnetic activity can be simulated experimentally in epileptic rats and that potential mechanisms might be testable directly.

New-onset mesial temporal lobe epilepsy in a 90-year-old: clinical and EEG features.

Although there is a peak in the incidence of epilepsy in the elderly compared with the general population, complex partial seizures represent less than 15% of the seizure types reported. We report on a 92-year-old woman with a 2-year history of daily complex partial seizures. Prolonged video/EEG recording showed bilateral anterior mesial temporal interictal spikes, which predominated on the left, and two typical seizures arising from the left temporal area. Cranial MRI scanning showed multiple lacunar infarcts without temporal lobe involvement or mesial temporal atrophy. Our case appears to be oldest patient in the literature with newly diagnosed mesial temporal lobe epilepsy confirmed by video/EEG recording.

Bone anchored hearing aids: reality, failure and current status.

Bone Anchored Hearing Aids have both cosmetic and acoustic advantages over most conventional hearing aids and hence is a popular choice today. We report the first Irish group of patients who received a BAHA over a six year period of time and evaluated outcomes of these subjects using subjective assessment. The medical records of all patients who received a BAHA at the Mater and Children's University Hospital, Dublin, were reviewed. A questionnaire had been sent to the patients to obtain long-term subjective information. Twenty three patients were identified. The commonest indication for surgery was found to be the presence of a discharging mastoid cavity, followed by congenital ear malformations. Surgical procedures were carried out as a single stage in 16 patients. Questionnaires were sent to 19 patients; sixteen patients responded in total. BAHA has a beneficial outcome to the quality of life and has significantly reduced ear discharge. The one stage technique was found to have a lower complication rate.

Prion protein fragment PrP-(106-126) induces apoptosis via mitochondrial disruption in human neuronal SH-SY5Y cells.

The synthetic peptide PrP-(106-126) has previously been shown to be neurotoxic. Here, for the first time, we report that it induces apoptosis in the human neuroblastoma cell line SH-SY5Y. The earliest detectable apoptotic event in this system is the rapid depolarization of mitochondrial membranes, occurring immediately upon treatment of cells with PrP-(106-126). Subsequent to this, cytochrome c release and caspase activation were observed. Caspase inhibitors demonstrated that while the peptide activates caspases they are not an absolute requirement for apoptosis. Parallel to caspase activation, PrP-(106-126) was also observed to trigger a rise in intracellular calcium through release of mitochondrial calcium stores. This leads to the activation of calpains, another family of proteases. A calpain inhibitor demonstrated that while calpains are activated by the peptide they also are not an absolute requirement for apoptosis. Interestingly a combination of caspase and calpain inhibitors significantly inhibited apoptosis. This illustrates alternative pathways leading to apoptosis via caspases and calpains and that blocking both pathways is required to inhibit apoptosis. These results implicate the mitochondrion as a primary site of action of PrP-(106-126).

Neuronal hypertrophy in the neocortex of patients with temporal lobe epilepsy.

The underlying cause of neocortical involvement in temporal lobe epilepsy (TLE) remains a fundamental and unanswered question. Magnetic resonance imaging has shown a significant loss in temporal lobe volume, and it has been proposed that neocortical circuits are disturbed functionally because neurons are lost. The present study used design-based stereology to estimate the volume and cell number of Brodmann's area 38, a region commonly resected in anterior temporal lobectomy. Studies were conducted on the neocortex of patients with or without hippocampal sclerosis (HS). Results provide the surprising finding that TLE patients have significant atrophy of neocortical gray matter but no loss of neurons. Neurons are also significantly larger, dendritic trees appear sparser, and spine density is noticeably reduced in TLE specimens compared with controls. The increase in neuronal density we found in TLE patients is therefore attributable to large neurons occupying a much smaller volume than in normal brain. Neurons in the underlying white matter are also increased in size but, in contrast to other reports, are not significantly elevated in number or density. Neuronal hypertrophy affects HS and non-HS brains similarly. The reduction in neuropil and its associated elements therefore appears to be a primary feature of TLE, which is not secondary to cell loss. In both gray and white matter, neuronal hypertrophy means more perikaryal surface area is exposed for synaptic contacts and emerges as a hallmark of this disease.

The human proteomics initiative (HPI).

The availability of the human genome sequence has enabled the exploration and exploitation of the human genome and proteome to begin. Research has now focussed on the annotation of the genome and in particular of the proteome. With expert annotation extracted from the literature by biologists as the foundation, it has been possible to expand into the areas of data mining and automatic annotation. With further development and integration of pattern recognition methods and the application of alignments clustering, proteome analysis can now be provided in a meaningful way. These various approaches have been integrated to attach, extract and combine as much relevant information as possible to the proteome. This resource should be valuable to users from both research and industry.

Hyperglycemia associated with protease inhibitors in an urban HIV-infected minority patient population.

BACKGROUND: Hyperglycemia and new-onset diabetes mellitus have been reported to occur in HIV-infected patients treated with protease inhibitors. OBJECTIVE: To determine the effect of protease inhibitor therapy on serum glucose in a predominantly minority patient population. DESIGN: Retrospective record review. SETTING: Clinical HIV program of an urban Veterans Affairs medical center. PATIENTS: All HIV-infected patients receiving a protease inhibitor over a one-year period from September 1996 through August 1997. RESULTS: One hundred seventeen patients not previously known to be diabetic received protease inhibitors; seven (6%) developed symptomatic diabetes mellitus. Eight other patients had one or more serum glucose values >150 mg/dL. Mean random glucose values for patients who did not develop diabetes were higher during therapy than prior to initiation of protease inhibitors. CONCLUSIONS: Urban minority HIV-infected patients receiving combination antiretroviral therapy including a protease inhibitor may be at increased risk for the development of hyperglycemia and diabetes mellitus. Risk factors for diabetes mellitus should be identified and blood glucose monitored in all patients receiving protease inhibitors.

The role SWISS-PROT and TrEMBL play in the genome research environment.

SWISS-PROT, a curated protein sequence data bank, contains not only sequence data but also annotation relevant to a particular sequence. The annotation added to each entry is done by a team of biologists and comes, primarily, from articles in journals reporting the actual sequencing and sometimes characterisation. Review articles and collaboration with external experts also play a role along with the use of secondary databases like PROSITE and Pfam in addition to a variety of feature prediction methods. Annotation added by these methods is checked for relevance and likelihood to a particular sequence. The onset of genome sequencing has led to a dramatic increase in sequence data to be included in SWISS-PROT. This has led to the production of TrEMBL (Translation of the EMBL database). TrEMBL consists of entries in a SWISS-PROT format that are derived from the translation of all coding sequences in the EMBL nucleotide sequence database, that are not in SWISS-PROT. Unlike SWISS-PROT entries those in TrEMBL are awaiting manual annotation. However, rather than just representing basic sequence and source information, steps have been taken to add features and annotation automatically. In taking these steps it is hoped that TrEMBL entries are enhanced with some indication as to what a protein is, could or may be.

Vagus nerve stimulation therapy for epilepsy in older adults.

The authors assessed the efficacy, safety, and tolerability of vagus nerve stimulation (VNS) for refractory epilepsy in 45 adults 50 years of age and older. They determined seizure frequency, adverse effects, and quality of life. At 3 months, 12 patients had a >50% decrease in seizure frequency; at 1 year, 21 of 31 studied individuals had a >50% seizure decrease. Side effects were mild and transient. Quality of life scores improved significantly with time.