A latent class analysis of parental bipolar disorder: examining associations with offspring psychopathology

Bipolar disorder (BD) is highly heterogeneous, and course variations are associated with patient outcomes. This diagnostic complexity challenges identification of patients in greatest need of intervention. Additionally, course variations have implications for offspring risk. First, latent class analysis (LCA) categorized parents with BD based on salient illness characteristics: BD type, onset age, polarity of index episode, pole of majority of episodes, rapid cycling, psychosis, anxiety comorbidity, and substance dependence. Fit indices favored three parental classes with some substantively meaningful patterns. Two classes, labeled “Earlier-Onset Bipolar-I” (EO-I) and “Earlier-Onset Bipolar-II” (EO-II), comprised parents who had a mean onset age in mid-adolescence, with EO-I primarily BD-I parents and EO-II entirely BD-II parents. The third class, labeled “Later-Onset BD” (LO) had an average onset age in adulthood. Classes also varied on probability of anxiety comorbidity, substance dependence, psychosis, rapid cycling, and pole of majority of episodes. Second, we examined rates of disorders in offspring (ages 4–33, Mage=13.46) based on parental latent class membership. Differences emerged for offspring anxiety disorders only such that offspring of EO-I and EO-II parents had higher rates, compared to offspring of LO parents, particularly for daughters. Findings may enhance understanding of BD and its nosologyThis study was funded by two Brain & Behavior Research Foundation (formerly NARSAD) Independent Investigator Awards (PI: Nierenberg), a Brain & Behavior Research Foundation Young Investigator Award (PI: Henin) generously supported in part by the SHINE Initiative, and an MGH Claflin Award (PI: Henin). We thank David A. Langer, Ph.D., Thomas M. Olino, Ph.D., and Meredith Lotz Wallace, Ph.D. for their consultation. (Brain & Behavior Research Foundation; Brain & Behavior Research Foundation Young Investigator Award; SHINE Initiative; MGH Claflin Award)Accepted manuscrip

Implant surfaces exposed to the oral cavity and treated with toothpaste containing oxygen releasing compound : a morphological controlled clinical trial

Aim of the present in vivo study is to assess if a toothpaste containing an oxygen releasing compound (AX) is able to reduce the biofilm formation on implants with rough surface compared to a control toothpaste, without affecting the microstructure of the tested surface. Methods: In this double blind, cross-over, controlled clinical trial, a total of fourteen healthy volunteers were recruited. For each subject, two mandibular splints (test and control) were created with one implant fixed on the right lingual side of the mandibular arch. The splint was continuously worn for 5 days and the daily hygiene was performed wearing the splint and using the test (AX) or control toothpaste. Implants were analyzed at scanning-electron-microscopy and at laser profilometer for the assessment of biofilm adhesion (% of areas free from biofilm-FA) and surface changes (morphology and roughness). Results: FA resulted significantly higher in test than in control implants. No differences were found between groups in term of biofilm organization, surface microstructure and roughness. Discussion: Daily use of toothpaste containing AX seems to reduce the amount of biofilm adherent to the rough implant surface without corrosion or degradation of the titanium surface

Learning hierarchical sequence representations across human cortex and hippocampus

Sensory input arrives in continuous sequences that humans experience as segmented units, e.g., words and events. The brain’s ability to discover regularities is called statistical learning. Structure can be represented at multiple levels, including transitional probabilities, ordinal position, and identity of units. To investigate sequence encoding in cortex and hippocampus, we recorded from intracranial electrodes in human subjects as they were exposed to auditory and visual sequences containing temporal regularities. We find neural tracking of regularities within minutes, with characteristic profiles across brain areas. Early processing tracked lower-level features (e.g., syllables) and learned units (e.g., words), while later processing tracked only learned units. Learning rapidly shaped neural representations, with a gradient of complexity from early brain areas encoding transitional probability, to associative regions and hippocampus encoding ordinal position and identity of units. These findings indicate the existence of multiple, parallel computational systems for sequence learning across hierarchically organized cortico-hippocampal circuits

Histomorphometrical evaluation of the effects of Aminogam® gel in oral healing process of post-surgical soft tissue

Wound healing is a dynamic process that involves a complex interaction of inflammatory cells, cytokines and mediators of extracellular matrix [1]. One of the processes that occur during tissue regeneration is angiogenesis and it is considered to have a pivotal role in wound repair. Previous studies have shown that a topical application of proteins and sodium hyaluronate to wounds can expedite the repair of damaged tissue [2]. The aim of this preliminary study is to evaluate the efficacy of Aminogam\uae gel (A\uae) (ErreKappa Euroterapici SpA, Milano), a topical medication which contains 4 amino acids (glycine, leucine, proline, lysine) and sodium hyaluronate, used to improve and accelerate gingival flap healing following molar extraction by analyzing collagen fibers amount, orientation and microvascular distribution (MVD). Ten patients (mean age 49ys) were included in the study. Two teeth (38 and 48) were extracted at an interval of 30 days. The \u201ctest\u201d site (AM) was treated with A\uae while the \u201ccontrol\u201d site (no AM) was not. Dental extraction was performed and the flaps were sutured with a consequent excess of tissue for histological processing (T0). A\uae had been applied only at the AM site for 10 days post-extraction. At suture removal, a gingivoplasty was performed and the exceeding tissue was histologically analysed (T1). Paraffin blocks were cut and slides were stained with haematoxylin-eosin and Sirius Red. No signs of inflammatory infiltrate or necrosis were observed. Sirius Red staining highlighted a lower degree of organized collagen fibers at T1 vs T0. At T0 the fibers were organized in closely packed and well-oriented bundles. At T1-no AM fibers were thin and formed a disorganized grid. At T1-AM fibers appeared thicker and the tissue appeared more mature compared to T1-no AM. Immunohistochemistry against CD31 was performed to mark endothelial cells and to calculate MVD by stereological method [3]. MVD resulted highest at T1-AM. The T1 data normalized on T0 presented a statistically significant difference (p=0.012) between AM and no AM group. In conclusion, A\uae gel seems to increase new blood vessels formation and to promote collagen deposition and organization. References [1] Gurtner et al. Nature. 2008;453(7193):314-21. [2] Zhu et al. BMC Oral Health. 2015;15:60. [3] Canullo et al. J Clin Periodontol. 2016;38:86-94

Hydrophobic and ionic-interactions in bulk and confined water with implications for collapse and folding of proteins

Water and water-mediated interactions determine thermodynamic and kinetics of protein folding, protein aggregation and self-assembly in confined spaces. To obtain insights into the role of water in the context of folding problems, we describe computer simulations of a few related model systems. The dynamics of collapse of eicosane shows that upon expulsion of water the linear hydrocarbon chain adopts an ordered helical hairpin structure with 1.5 turns. The structure of dimer of eicosane molecules has two well ordered helical hairpins that are stacked perpendicular to each other. As a prelude to studying folding in confined spaces we used simulations to understand changes in hydrophobic and ionic interactions in nano droplets. Solvation of hydrophobic and charged species change drastically in nano water droplets. Hydrophobic species are localized at the boundary. The tendency of ions to be at the boundary where water density is low increases as the charge density decreases. Interaction between hydrophobic, polar, and charged residue are also profoundly altered in confined spaces. Using the results of computer simulations and accounting for loss of chain entropy upon confinement we argue and then demonstrate, using simulations in explicit water, that ordered states of generic amphiphilic peptide sequences should be stabilized in cylindrical nanopores

Brain function and clinical characterization in the Boston adolescent neuroimaging of depression and anxiety study

We present a Human Connectome Project study tailored toward adolescent anxiety and depression. This study is one of the first studies of the Connectomes Related to Human Diseases initiative and is collecting structural, functional, and diffusion-weighted brain imaging data from up to 225 adolescents (ages 14–17 years), 150 of whom are expected to have a current diagnosis of an anxiety and/or depressive disorder. Comprehensive clinical and neuropsychological evaluations and long-itudinal clinical data are also being collected. This article provides an overview of task functional magnetic resonance imaging (fMRI) protocols and preliminary findings (N = 140), as well as clinical and neuropsychological characterization of adolescents. Data collection is ongoing for an additional 85 adolescents, most of whom are expected to have a diagnosis of an anxiety and/or depressive disorder. Data from the first 140 adolescents are projected for public release through the National Institutes of Health Data Archive (NDA) with the timing of this manuscript. All other data will be made publicly-available through the NDA at regularly scheduled intervals. This article is intended to serve as an introduction to this project as well as a reference for those seeking to clinical, neurocognitive, and task fMRI data from this public resource

Circulating adrenomedullin estimates survival and reversibility of organ failure in sepsis: the prospective observational multinational Adrenomedullin and Outcome in Sepsis and Septic Shock-1 (AdrenOSS-1) study

Background: Adrenomedullin (ADM) regulates vascular tone and endothelial permeability during sepsis. Levels of circulating biologically active ADM (bio-ADM) show an inverse relationship with blood pressure and a direct relationship with vasopressor requirement. In the present prospective observational multinational Adrenomedullin and Outcome in Sepsis and Septic Shock 1 (, AdrenOSS-1) study, we assessed relationships between circulating bio-ADM during the initial intensive care unit (ICU) stay and short-term outcome in order to eventually design a biomarker-guided randomized controlled trial. Methods: AdrenOSS-1 was a prospective observational multinational study. The primary outcome was 28-day mortality. Secondary outcomes included organ failure as defined by Sequential Organ Failure Assessment (SOFA) score, organ support with focus on vasopressor/inotropic use, and need for renal replacement therapy. AdrenOSS-1 included 583 patients admitted to the ICU with sepsis or septic shock. Results: Circulating bio-ADM levels were measured upon admission and at day 2. Median bio-ADM concentration upon admission was 80.5 pg/ml [IQR 41.5-148.1 pg/ml]. Initial SOFA score was 7 [IQR 5-10], and 28-day mortality was 22%. We found marked associations between bio-ADM upon admission and 28-day mortality (unadjusted standardized HR 2.3 [CI 1.9-2.9]; adjusted HR 1.6 [CI 1.1-2.5]) and between bio-ADM levels and SOFA score (p < 0.0001). Need of vasopressor/inotrope, renal replacement therapy, and positive fluid balance were more prevalent in patients with a bio-ADM > 70 pg/ml upon admission than in those with bio-ADM ≤ 70 pg/ml. In patients with bio-ADM > 70 pg/ml upon admission, decrease in bio-ADM below 70 pg/ml at day 2 was associated with recovery of organ function at day 7 and better 28-day outcome (9.5% mortality). By contrast, persistently elevated bio-ADM at day 2 was associated with prolonged organ dysfunction and high 28-day mortality (38.1% mortality, HR 4.9, 95% CI 2.5-9.8). Conclusions: AdrenOSS-1 shows that early levels and rapid changes in bio-ADM estimate short-term outcome in sepsis and septic shock. These data are the backbone of the design of the biomarker-guided AdrenOSS-2 trial. Trial registration: ClinicalTrials.gov, NCT02393781. Registered on March 19, 2015

Behavioral inhibition in childhood predicts smaller hippocampal volume in adolescent offspring of parents with panic disorder

Behavioral inhibition (BI) is a genetically influenced behavioral profile seen in 15–20% of 2-year-old children. Children with BI are timid with people, objects and situations that are novel or unfamiliar, and are more reactive physiologically to these challenges as evidenced by higher heart rate, pupillary dilation, vocal cord tension and higher levels of cortisol. BI predisposes to the later development of anxiety, depression and substance abuse. Reduced hippocampal volumes have been observed in anxiety disorders, depression and posttraumatic stress disorder. Animal models have demonstrated that chronic stress can damage the hippocampal formation and implicated cortisol in these effects. We, therefore, hypothesized that the hippocampi of late adolescents who had been behaviorally inhibited as children would be smaller compared with those who had not been inhibited. Hippocampal volume was measured with high-resolution structural magnetic resonance imaging in 43 females and 40 males at 17 years of age who were determined to be BI+ or BI− based on behaviors observed in the laboratory as young children. BI in childhood predicted reduced hippocampal volumes in the adolescents who were offspring of parents with panic disorder, or panic disorder with comorbid major depression. We discuss genetic and environmental factors emanating from both child and parent that may explain these findings. To the best of our knowledge, this is the first study to demonstrate a relationship between the most extensively studied form of temperamentally based human trait anxiety, BI, and hippocampal structure. The reduction in hippocampal volume, as reported by us, suggests a role for the hippocampus in human trait anxiety and anxiety disorder that warrants further investigation

Two Dimensional Window Exchange Umbrella Sampling for Transmembrane Helix Assembly

The method of window exchange umbrella sampling molecular dynamics (WEUSMD) with a pre-optimized parameter set was recently used to obtain the most probable conformations and the energetics of transmembrane (TM) helix assembly of a generic TM sequence. When applied to glycophorin A TM domain (GpA-TM) using the restraint potentials along the helix-helix distance, however, tight interfacial packing of GpA-TM resulted in insufficient conformational sampling at short helix-helix separation. This sampling issue is addressed by extending the WEUSMD into two dimensions with the restraint potentials along the helix-helix distance and crossing angle. The two-dimensional WEUSMD results demonstrate that the incomplete sampling in the one-dimensional WEUSMD arises from high barriers along the crossing angle between the GpA-TM helices. Together with the faster convergence in both the assembled conformations and the potential of mean force, the 2D-WEUSMD can be a general and efficient approach in computational studies of TM helix assembly