DCLK1 variants are associated across schizophrenia and attention deficit/hyperactivity disorder

Doublecortin and calmodulin like kinase 1 (DCLK1) is implicated in synaptic plasticity and neurodevelopment. Genetic variants in DCLK1 are associated with cognitive traits, specifically verbal memory and general cognition. We investigated the role of DCLK1 variants in three psychiatric disorders that have neuro-cognitive dysfunctions: schizophrenia (SCZ), bipolar affective disorder (BP) and attention deficit/hyperactivity disorder (ADHD). We mined six genome wide association studies (GWASs) that were available publically or through collaboration; three for BP, two for SCZ and one for ADHD. We also genotyped the DCLK1 region in additional samples of cases with SCZ, BP or ADHD and controls that had not been whole-genome typed. In total, 9895 subjects were analysed, including 5308 normal controls and 4,587 patients (1,125 with SCZ, 2,496 with BP and 966 with ADHD). Several DCLK1 variants were associated with disease phenotypes in the different samples. The main effect was observed for rs7989807 in intron 3, which was strongly associated with SCZ alone and even more so when cases with SCZ and ADHD were combined (P-value = 4 × 10(-5) and 4 × 10(-6), respectively). Associations were also observed with additional markers in intron 3 (combination of SCZ, ADHD and BP), intron 19 (SCZ+BP) and the 3'UTR (SCZ+BP). Our results suggest that genetic variants in DCLK1 are associated with SCZ and, to a lesser extent, with ADHD and BP. Interestingly the association is strongest when SCZ and ADHD are considered together, suggesting common genetic susceptibility. Given that DCLK1 variants were previously found to be associated with cognitive traits, these results are consistent with the role of DCLK1 in neurodevelopment and synaptic plasticity.

Effectiveness of integrated care including therapeutic assertive community treatment in severe schizophrenia spectrum and bipolar I disorders: the 24-month follow-up ACCESS II study

OBJECTIVE The ACCESS treatment model offers assertive community treatment embedded in an integrated care program to patients with psychoses. Compared to standard care and within a controlled study, it proved to be more effective in terms of service disengagement and illness outcomes in patients with schizophrenia spectrum disorders over 12 months. ACCESS was implemented into clinical routine and its effectiveness assessed over 24 months in severe schizophrenia spectrum disorders and bipolar I disorder with psychotic features (DSM-IV) in a cohort study. METHOD All 115 patients treated in ACCESS (from May 2007 to October 2009) were included in the ACCESS II study. The primary outcome was rate of service disengagement. Secondary outcomes were change of psychopathology, severity of illness, psychosocial functioning, quality of life, satisfaction with care, medication nonadherence, length of hospital stay, and rates of involuntary hospitalization. RESULTS Only 4 patients (3.4%) disengaged with the service. Another 11 (9.6%) left because they moved outside the catchment area. Patients received a mean of 1.6 outpatient contacts per week. Involuntary admissions decreased from 34.8% in the 2 previous years to 7.8% during ACCESS (P < .001). Mixed models repeated-measures analyses revealed significant improvements among all patients in psychopathology (effect size d = 0.64, P < .001), illness severity (d = 0.84, P = .03), functioning level (d = 0.65, P < .001), quality of life (d = 0.50, P < .001), and client satisfaction (d = 0.11, P < .001). At 24 months, 78.3% were fully adherent to medication, compared to 25.2% at baseline (P = .002). CONCLUSIONS ACCESS was successfully implemented in clinical routine and maintained excellent rates of service engagement and other outcomes in patients with schizophrenia spectrum disorders or bipolar I disorder with psychotic features over 24 months. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT01888627.

Pattern recognition analyses of brain activation elicited by happy and neutral faces in unipolar and bipolar depression

Objectives: Recently, pattern recognition approaches have been used to classify patterns of brain activity elicited by sensory or cognitive processes. In the clinical context, these approaches have been mainly applied to classify groups of individuals based on structural magnetic resonance imaging (MRI) data. Only a few studies have applied similar methods to functional MRI (fMRI) data. Methods: We used a novel analytic framework to examine the extent to which unipolar and bipolar depressed individuals differed on discrimination between patterns of neural activity for happy and neutral faces. We used data from 18 currently depressed individuals with bipolar I disorder (BD) and 18 currently depressed individuals with recurrent unipolar depression (UD), matched on depression severity, age, and illness duration, and 18 age- and gender ratio-matched healthy comparison subjects (HC). fMRI data were analyzed using a general linear model and Gaussian process classifiers. Results: The accuracy for discriminating between patterns of neural activity for happy versus neutral faces overall was lower in both patient groups relative to HC. The predictive probabilities for intense and mild happy faces were higher in HC than in BD, and for mild happy faces were higher in HC than UD (all p < 0.001). Interestingly, the predictive probability for intense happy faces was significantly higher in UD than BD (p = 0.03). Conclusions: These results indicate that patterns of whole-brain neural activity to intense happy faces were significantly less distinct from those for neutral faces in BD than in either HC or UD. These findings indicate that pattern recognition approaches can be used to identify abnormal brain activity patterns in patient populations and have promising clinical utility as techniques that can help to discriminate between patients with different psychiatric illnesses.

Hyperprolinemia as a clue in the diagnosis of a patient with a psychiatric disorder

Background: Over the last few years, microdeletions of the 22q11.2 region responsible for DiGeorge syndrome, or velocardiofacial syndrome, have been increasingly related to neuropsychiatric disorders including schizophrenia and bipolar disorders. These signs seem to be related to certain genes located in the hemideleted region as the proline dehydrogenase (PRODH) and the catecholo-methyltransferase (COMT) genes. The PRODH or proline oxidase deficiency is responsible for hyperprolinemia type 1 (HPI) also causing psychiatric manifestations. Case Report: We describe a 17 year old boy with previous mild psychomotor and speech delay, mild cognitive impairment, and obsessive behaviours who started his adolescent psychiatric care presenting irritablemood and aggressive behaviour with schizophrenia symptoms that scored a “severely ill” level PANSS assessment. Symptoms got worse when he was treated with valproic acid and plasma aminoacids showing increase in alanine and proline, suggested a mitochondrial involvement of the proline metabolic pathway. Results: Mild dysmorphia suggested a possible 22q11.2 deletion genetically confirmed involving both the PRODH and COMT regions. HPI that can present with psychiatric features is however a recessive disorder and therefore the symptoms could not be solely explained by this genetic deletion. Additional investigations also showed disclosed a p.L289m (c.1865 T > A) mutation in the PRODH gene. Discussion: We believe that the association of this mutation together with the 22q11.2 deletion would lead to a decrease of functional protein. Although it may be difficult to diagnosis chromosomal abnormalities in patients with no clear malformations and mild dysmorphic features as in this patient we emphasize need to investigate the aetiology in patients with psychiatric symptoms, especially if they have other systemic manifestations such as developmental delay or psychotic symptoms, as it may be important in the management of the patients.

Bipolar Tribocharging Signal During Friction Force Fluctuations At Metal-insulator Interfaces.

Friction and triboelectrification of materials show a strong correlation during sliding contacts. Friction force fluctuations are always accompanied by two tribocharging events at metal-insulator [e.g., polytetrafluoroethylene (PTFE)] interfaces: injection of charged species from the metal into PTFE followed by the flow of charges from PTFE to the metal surface. Adhesion maps that were obtained by atomic force microscopy (AFM) show that the region of contact increases the pull-off force from 10 to 150 nN, reflecting on a resilient electrostatic adhesion between PTFE and the metallic surface. The reported results suggest that friction and triboelectrification have a common origin that must be associated with the occurrence of strong electrostatic interactions at the interface.

46,XX Male - Testicular Disorder of Sexual Differentiation (DSD): hormonal, molecular and cytogenetic studies

The XX male syndrome - Testicular Disorder of Sexual Differentiation (DSD) is a rare condition characterized by a spectrum of clinical presentations, ranging from ambiguous to normal male genitalia. We report hormonal, molecular and cytogenetic evaluations of a boy presenting with this syndrome. Examination of the genitalia at age of 16 months, showed: penis of 3.5 cm, proximal hypospadia and scrotal testes. Pelvic ultrasound did not demonstrate Mullerian duct structures. Karyotype was 46,XX. Gonadotrophin stimulation test yielded insufficient testosterone production. Gonadal biopsy showed seminiferous tubules without evidence of Leydig cells. Molecular studies revealed that SRY and TSPY genes and also DYZ3 sequences were absent. In addition, the lack of deletions or duplications of SOX9, NR5A1, WNT4 and NROB1 regions was verified. The infant was heterozygous for all microsatellites at the 9p region, including DMRT1 gene, investigated. Only 10% of the patients are SRY-negative and usually they have ambiguous genitalia, as the aforementioned patient. The incomplete masculinization suggests gain of function mutation in one or more genes downstream to SRY gene.

Segmental LeFort I osteotomy for treatment of a class III malocclusion with temporomandibular disorder

This article reports the case of a 19-year-old young man with Class III malocclusion and posterior crossbite with concerns about temporomandibular disorder (TMD), esthetics and functional problems. Surgical-orthodontic treatment was carried out by decompensation of the mandibular incisors and segmentation of the maxilla in 4 pieces, which allowed expansion and advancement. Remission of the signs and symptoms occurred after surgical-orthodontic intervention. The maxillary dental arch presented normal transverse dimension. Satisfactory static and functional occlusion and esthetic results were achieved and remained stable. Three years after the surgical-orthodontic treatment, no TMD sign or symptom was observed and the occlusal results had not changed. When vertical or horizontal movements of the maxilla in the presence of moderate maxillary constriction are necessary, segmental LeFort I osteotomy can be an important part of treatment planning.

Orbitofrontal Cortex Volumes in Medication Naive Children with Major Depressive Disorder: A Magnetic Resonance Imaging Study

Objectives: Adults with major depressive disorder (MDD) are reported to have reduced orbitofrontal cortex (OFC) volumes, which could be related to decreased neuronal density. We conducted a study on medication naive children with MDD to determine whether abnormalities of OFC are present early in the illness course. Methods: Twenty seven medication naive pediatric Diagnostic and Statistical Manual of Mental Disorders, 4(th) edition (DSM-IV) MDD patients (mean age +/- SD = 14.4 +/- 2.2 years; 10 males) and 26 healthy controls (mean age +/- SD = 14.4 +/- 2.4 years; 12 males) underwent a 1.5T magnetic resonance imaging (MRI) with 3D spoiled gradient recalled acquisition. The OFC volumes were compared using analysis of covariance with age, gender, and total brain volume as covariates. Results: There was no significant difference in either total OFC volume or total gray matter OFC volume between MDD patients and healthy controls. Exploratory analysis revealed that patients had unexpectedly larger total right lateral (F = 4.2, df = 1, 48, p = 0.05) and right lateral gray matter (F = 4.6, df = 1, 48, p = 0.04) OFC volumes compared to healthy controls, but this finding was not significant following statistical correction for multiple comparisons. No other OFC subregions showed a significant difference. Conclusions: The lack of OFC volume abnormalities in pediatric MDD patients suggests the abnormalities previously reported for adults may develop later in life as a result of neural cell loss.

Phase-disorder-induced double resonance of neuronal activity

It is well known that resonance can be induced by external noise or diversity. Here we show that resonance can be induced even by a phase disorder in coupled excitable neurons with subthreshold activity. In contrast to the case of identical phase, we find that phase disorder plays an active role in enhancing neuronal activity. We also uncover that the presence of phase disorder can induce a double resonance phenomenon: phase disorder and coupling strength both can enhance neuronal firing activity. A physical theory is formulated to help understand the mechanism behind this double resonance phenomenon.

Liquid polymorphism, order-disorder transitions and anomalous behavior: A Monte Carlo study of the Bell-Lavis model for water

The Bell-Lavis model for liquid water is investigated through numerical simulations. The lattice-gas model on a triangular lattice presents orientational states and is known to present a highly bonded low density phase and a loosely bonded high density phase. We show that the model liquid-liquid transition is continuous, in contradiction with mean-field results on the Husimi cactus and from the cluster variational method. We define an order parameter which allows interpretation of the transition as an order-disorder transition of the bond network. Our results indicate that the order-disorder transition is in the Ising universality class. Previous proposal of an Ehrenfest second order transition is discarded. A detailed investigation of anomalous properties has also been undertaken. The line of density maxima in the HDL phase is stabilized by fluctuations, absent in the mean-field solution. (C) 2009 American Institute of Physics. [doi:10.1063/1.3253297]

Unraveling effects of disorder on the electronic structure of SiO(2) from first principles

We present a first-principles systematic study of the electronic structure of SiO(2) including the crystalline polymorphs alpha quartz and beta cristobalite, and different types of disorder leading to the amorphous phase. We start from calculations within density functional theory and proceed to more sophisticated quasiparticle calculations according to the GW scheme. Our results show that different origins of disorder have also different impact on atomic and electronic-density fluctuations, which affect the electronic structure and, in particular, the size of the mobility gap in each case.

Spin filtering and disorder-induced magnetoresistance in carbon nanotubes: Ab initio calculations

Nitrogen-doped carbon nanotubes can provide reactive sites on the porphyrin-like defects. It is well known that many porphyrins have transition-metal atoms, and we have explored transition-metal atoms bonded to those porphyrin-like defects inN-doped carbon nanotubes. The electronic structure and transport are analyzed by means of a combination of density functional theory and recursive Green's function methods. The results determined the heme B-like defect (an iron atom bonded to four nitrogens) is the most stable and has a higher polarization current for a single defect. With randomly positioned heme B defects in nanotubes a few hundred nanometers long, the polarization reaches near 100%, meaning they are effective spin filters. A disorder-induced magnetoresistance effect is also observed in those long nanotubes, and values as high as 20 000% are calculated with nonmagnectic eletrodes.

Observation of a Cooperative Radiation Force in the Presence of Disorder

Cooperative scattering of light by an extended object such as an atomic ensemble or a dielectric sphere is fundamentally different from scattering from many pointlike scatterers such as single atoms. Homogeneous distributions tend to scatter cooperatively, whereas fluctuations of the density distribution increase the disorder and suppress cooperativity. In an atomic cloud, the amount of disorder can be tuned via the optical thickness, and its role can be studied via the radiation force exerted by the light on the atomic cloud. Monitoring cold (87)Rb atoms released from a magneto-optical trap, we present the first experimental signatures of radiation force reduction due to cooperative scattering. The results are in agreement with an analytical expression interpolating between the disorder and the cooperativity-dominated regimes.

A study of disorder effects in random (Al(x)Ga(1-x)As)(n)(Al(y)Ga(1-y)As)(m) superlattices embedded in a wide parabolic potential

A photoluminescence (PL) study of the individual electron states localized in a random potential is performed in artificially disordered superlattices embedded in a wide parabolic well. The valence band bowing of the parabolic potential provides a variation of the emission energies which splits the optical transitions corresponding to different wells within the random potential. The blueshift of the PL lines emitted by individual random wells, observed with increasing disorder strength, is demonstrated. The variation of temperature and magnetic field allowed for the behavior of the electrons localized in individual wells of the random potential to be distinguished.