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Background: There are no approved oral disease-modifying treatments for Alzheimer's disease (AD)., Objectives: The objective of this study was to assess efficacy and safety of blarcamesine (ANAVEX®2-73), an orally available small-molecule activator of the sigma-1 receptor (SIGMAR1) in early AD through restoration of cellular homeostasis including autophagy enhancement., Design: ANAVEX2-73-AD-004 was a randomized, double-blind, placebo-controlled, 48-week Phase IIb/III trial., Setting: Multicenter - 52 medical research centers/hospitals in 5 countries., Intervention: 508 participants with early AD (Stage 3) were randomized to receive either blarcamesine (n = 338) in medium dose group 30 mg or in high dose group 50 mg or placebo (n = 170) oral capsules once daily for 48 weeks. Participants in these groups were offered to enroll into the open-label-extension study ATTENTION-AD, which completed June 2024, ClinicalTrials.gov Identifier NCT04314934., Measurements: The co-primary cognitive and functional outcomes were assessed as change in ADAS-Cog13 and ADCS-ADL from baseline to 48 weeks. The outcomes include the secondary outcome CDR-SB and biomarkers from the A/T/N spectrum, plasma Aβ42/40-ratio and global brain volume changes measured by MRI. All clinical endpoints were analyzed using mixed model for repeated measures (MMRM), plasma biomarker measurements were analyzed by Welch's t-test, and volumetric MRI scans were analyzed by general linear model., Results: Among 462 randomized participants in the intent-to-treat population (mean age, 73.7 years; 225 [48.7%] women), 338 (73.2%) completed the trial. The co-primary outcome was met under the multiplicity control rule, since the differences in the least-squares mean (LSM) change from baseline to 48 weeks between the prespecified blarcamesine and placebo groups for ADAS-Cog13 was significant at a level of P < 0.025 and for CDR-SB was significant at a level of P < 0.025, while ADCS-ADL did not reach significance at Week 48 (ADAS-Cog13 difference of -2.027 [95% CI -3.522 to -0.533]; P = 0.008; CDR-SB difference of -0.483 [95% CI -0.853 to -0.114]; P = 0.010; ADCS-ADL difference of 0.775 [95%CI -0.874 to 2.423]; P = 0.357). Plasma Aβ42/40-ratio increased significantly with blarcamesine group vs. placebo, (P = 0.048) and whole brain volume loss was significantly decreased (P = 0.002). Participants in the full safety population with ≥1 serious treatment-emergent adverse events (TEAEs) occurred in 56 participants (16.7%) in the blarcamesine and 17 (10.1%) in the placebo group. Common TEAEs included dizziness, which was transient and mostly mild to moderate in severity. One death in the blarcamesine group and 1 in the placebo group were both not considered treatment related., Conclusions: Blarcamesine, demonstrating a safety profile with no associated neuroimaging adverse events, significantly slowed clinical progression by 36.3% at 48 weeks with blarcamesine group as well as the individual 30 mg (by 34.6%) and 50 mg (by 38.5%) blarcamesine groups vs. placebo on the prespecified primary cognitive endpoint ADAS-Cog13. The prespecified secondary endpoint CDR-SB, which is used as the sole primary endpoint in recent successful AD drug submissions, is significantly improved at Week 48 with blarcamesine relative to placebo. The findings are supported by biomarkers from the A/T/N spectrum, including plasma Aβ42/40-ratio and reduction of whole brain atrophy. Additionally, the prespecified SIGMAR1 gene variant subgroup analysis confirmed beneficial clinical effect of blarcamesine group through upstream SIGMAR1 activation - subjects with the common SIGMAR1 wild-type gene (excluding carriers of the mutated SIGMAR1 rs1800866 variant) experienced an even greater significant clinical benefit with slowed clinical progression by 49.8% at 48 weeks on the prespecified primary cognitive endpoint ADAS-Cog13. Oral once daily blarcamesine could represent a novel treatment in early AD and be complementary or alternative to anti-beta amyloid drugs., Competing Interests: Declaration of competing interest DISCLOSURES: Dr. Sabbagh discloses ownership interest (stock or stock options) in NeuroTau, Inc., uMETHOD, Athira Pharma, Inc., and CervoMed and Lighthouse Pharmaceuticals; consulting for Alzheon, Inc, Genentech (Roche Group), Prothena, Novo Nordisk, Anavex Life Sciences, T3D Therapeutics, Inc., Eisai Co., Ltd., Eli Lilly and Co., and KeifeRx. Dr. Macfarlane has received paid honoraria from the following pharmaceutical companies for various speaking engagements and advisory board services: Eisai, Eli Lilly, Janssen-Cilag, Lundbeck, Novo Nordisk. Dr. Macfarlane is contracted by Anavex Life Sciences to provide medical monitoring services for Anavex's Rett syndrome studies. Dr. Grimmer received consulting fees from AbbVie, Alector, Anavex Life Sciences, Biogen, Cogthera, Eli Lilly, Functional Neuromodulation, Grifols, Iqvia, Janssen, Noselab, Novo Nordisk, NuiCare, Orphanzyme, Roche Diagnostics, Roche Pharma, UCB, and Vivoryon; lecture fees from Biogen, Eisai, Grifols, Medical Tribune, Novo Nordisk, Roche Pharma, Schwabe, and Synlab; and has received grants to his institution from Biogen, Eisai, and Roche Diagnostics. Dr. O'Brien's institution has received consultancy and/research funding from Anavex Life Sciences, Eisai, UCB Pharma, ES Therapeutics, Kinoxis Pharmaceuticals, Supernus, Autobahn, Shanghai Zhimeng, Epidarex, and government grant funding from NHMRC (APP1176426), MRFF, DoD and NINDS. Dr. Woodward has received honoraria for speaking and expert advice from Actinogen, Biogen, Roche, MSD/Merck, Glaxo Smith Kline, Cognition Therapies, Eisai, Novo Nordisk and Pfizer. He was previously paid for his role as Chief National Investigator for Anavex Life Sciences. He owns no shares and has no direct employment with any pharmaceutical company or Biotech. Dr. Tartaglia is SAB member of Brain Injury Canada, PSP Awareness, and Women's Brain Project. Advisory to Eisai, Eli Lilly and QurAlis and received Grant funding from NIH, Weston Brain Institute, Tanenbaum Institute for Science in Sport and participated in clinical trials: Biogen, Novo Nordisk, Janssen, Roche, Anavex Life Sciences, Passage Bio, Green Valley. Dr. Frank received paid honoraria from the following pharmaceutical companies for advisory board services: Eisai, Eli Lilly, Roche Pharma, Novo Nordisk. Dr. Lai has received a paid honorarium for speaking engagements with INmune Bio. Dr. Lewis is supported by a National Health and Medical Research Council Leadership Fellowship (1195830) and has received research funding from The Michael J. Fox Foundation and the Australian Research Council, as well as consulting for Pharmaxis Ltd. Dr. Kurrle has received honoraria for educational activities from Roche Diagnostics and Novartis. Dr. Cohen discloses consulting work (no personal fees received) for: Alnylam, Biogen, Biohaven, Cassava, Cogstate, Cognivue, Eisai, Eli Lilly, INmune Bio, Novo Nordisk, ProMIS Neuroscience, Roche, RetiSpec, SciNeuro; and research grants (paid to institution only) from: AbbVie, AgeneBio, Alector, Alnylam, Alzheon, Anavex Life Sciences, Biogen, Cassava, Eisai, Eli Lilly, Janssen, Novo Nordisk, Roche, RetiSpec, UCB Biopharma. Dr. Grunfeld has received paid honoraria from the Janssen-Cilag for advisory board services. Dr. Morris has no financial conflicts of interest to declare. Dr. Connell does not have any professional conflicts of interest. Dr. Thompson does not have any conflicts of interests to declare. Dr. Tacik does not have any conflicts of interests to declare. Dr. Perry has received paid honoraria from the following pharmaceutical companies for various speaking engagements and advisory board services: Eisai, Eli Lilly, MSDF, Biogen, and Roche. Dr. Sharif does not have any conflicts of interest to disclose. Dr. Kalafatis does not have any conflicts of interests to declare. Dr. Munisamy does not have any conflicts of interests to declare. Dr. Pearson has received paid honoraria for speaking and advice from Biogen, Eli Lilly and Boehringer-Ingelheim. Dr. Sturm does not have any conflicts of interests to declare. Dr. Oschmann received research support as well as speaking fees and travel fees from Alexion, Bayer Health Care, Biogen, Janssen, Merck Serono, Novartis, Pfizer, Roche, Sanofi Genzyme, TEVA. Dr. Hsiung discloses that he has received grants or contracts from CIHR, NIA/NIH and has participated in expert advisory committee supported by Biogen, Roche, and NovoNordisk. Dr. Hsiung is the current president of C5R (Consortium of Canadian Centres for Clinical Cognitive Research). Dr. Lynch does not have any conflicts of interests to declare. Dr. Brew does not have any conflicts of interests to declare. Dr. Tucker is employed by Anavex Life Sciences as an independent consultant to provide medical monitoring services for the Alzheimer's disease program. Dr. Ingram discloses no financial ownership interest in any pharmaceutical company but has been paid honoraria by Eisai, Merck, Biogen, Roche, Janssen, Eli Lilly to participate in health care planning and messaging regarding their products’ impact on dementia. Anavex research responsibilities were contractually held by Kawartha Centre ∼ Redefining Healthy Aging, previously owned by Dr. Ingram. This company has changed ownership as of January 5, 2023. Dr. Pasternak has received grant support to his institution and hold shares in Zywie Bio LLC. He has received speakers fees from Eli Lilly. Dr. MacSweeney does not have any conflicts of interests to declare. Dr. Short has received paid honoraria from Roche and Eisai for Advisory Board services and speaking engagements. Dr. Bhatt does not have any conflicts of interests to declare. Dr. Drysdale discloses that he has been paid for conducted research by the following companies, Eli Lilly, Cassava Sciences, Roche, Anavex Life Sciences, Lundbeck and Biogen. Dr. Mannering does not have any conflicts of interests to declare. Dr. Henri-Bhargava has received paid honoraria for Advisory boards / speaking engagements for Roche, Lilly, Eisai, Boehringer Ingelheim; Clinical trial payments from: Lilly, Roche, Boheringer Ingelhiem, Anavex Life Sciences, Cerevel, Green Valley Shanghai, Intelgenx; Grants from Canadian Consortium on Neurodegeneration in Aging, Centre for Aging and Brain Health Innovation, Manning Cognitive Health Initiative. Dr. Froelich has received honoraria for consulting or presentations from Biogen, BioVie, Eisai, Grifols, Janssen Cilag, Neurimmune, Noselab, NovoNordisk, Roche, TauRX, Schwabe; Honoraria for Clinical study committees from Avanir/Otsuka, PharmatrophiX, Charité Berlin, Neuroscios, Vivoryon; Clinical trials (honoraria to his institution) from Axon Neuroscience, Anavex Life Sciences, Alector, Boehringer Ingelheim, Eisai, Hummingbird, NovoNordisk, Noselab. Dr. Chertkow has been supported by a Foundation Grant from the CIHR (Canadian Institutes for Health Research), along with funding from the National Institute of Health (US), the Weston Foundation and the Baycrest Health Sciences Foundation. He has participated as a site PI in pharmaceutical trial activities sponsored by Hoffmann-La Roche, TauRx, Lilly, Anavex Life Sciences, Alector, Biogen, Esai, and Immunocal (site investigator for trials). He has participated as an unpaid advisor in 2020 for establishment of an international database by Biogen. He has participated in advisory boards for Esai and Lilly Co., with honoraria going to the Rotman Research Institute. He is Scientific Director for the CCNA, which receives partner support from partners including Pfizer, Lilly, Sanofi. Dr. Mander does not have any conflicts of interests to declare. Dr. Wiltfang does not have any conflicts of interests to declare. Dr. Prins performed consultancy work for Aribio, Amylyx, Eli-Lilly and Janssen and received a speaker fee from Biogen. He is co‐PI of of a current trial with Fuji Film Toyama Chemical. He is CEO and co‐owner of Brain Research Center, the Netherlands. Dr. Peters received consulting or lecture fees from Biogen, Eisai, Eli Lilly, Grifols, Medical Tribune, Noselab, Novo Nordisk, Prinnovation, Priavoid, Roche Diagnostics and Roche Pharma; and has received grants to his institution from Biogen, Eisai, Eli Lilly, Noslab, Predemtec, Roche Pharma, Roche Diagnostics and Vivoryon. Dr. Smith has received personal consulting fees from Alnylam Pharmaceuticals and Eli Lilly. Dr. Dautzenberg has participated as PI in pharmaceutical trials activities sponsored by TauRx, Lilly, Anavex Life Sciences, Alector, Biogen Boehringer Ingelheim, Eisai, NovoNordisk, Green Valley Shanghai, Roche and received a speaker fee from NovoNordisk as National PI. Dr. Evans does not have any conflicts of interests to declare. Dr. Villa does not have any conflicts of interests to declare. Dr. Gordon does not have any conflicts of interests to declare. Dr. Jubault does not have any conflicts of interests to declare. Dr. Guizard does not have any conflicts of interests to declare. Dr. Kaufmann discloses being an employee of and ownership interest (stock or stock options) in Anavex Life Sciences. Dr. Kun Jin discloses being an employee of and ownership interest (stock or stock options) in Anavex Life Sciences. Dr. Chezem discloses being an employee of and ownership interest (stock or stock options) in Anavex Life Sciences. Dr. Missling discloses being an employee of and ownership interest (stock or stock options) in Anavex Life Sciences. Dr. Babajide does not have any conflicts of interest to declare. Dr. Brodtmann has received paid honoraria from the following pharmaceutical companies for advisory board services: Biogen, Roche and Eisai. Dr. Asher does not have any conflicts of interests to declare., (Copyright © 2024 Anavex Life Sciences Corp. Published by Elsevier Masson SAS.. All rights reserved.)

Previous studies have suggested that alterations in white matter (WM) microstructure are implicated in suicidal thoughts and behaviours (STBs). However, findings of diffusion tensor imaging (DTI) studies have been inconsistent. In this large-scale mega-analysis conducted by the ENIGMA Suicidal Thoughts and Behaviours (ENIGMA-STB) consortium, we examined WM alterations associated with STBs. Data processing was standardised across sites, and resulting WM microstructure measures (fractional anisotropy, axial diffusivity, mean diffusivity and radial diffusivity) for 25 WM tracts were pooled across 40 cohorts. We compared these measures among individuals with a psychiatric diagnosis and lifetime history of suicide attempt ( n =652; mean age=35.4±14.7; female=71.8%), individuals with a psychiatric diagnosis but no STB (i.e., clinical controls; n =1871; mean age=34±14.8; female=59.8%), and individuals with no mental disorder diagnosis and no STB (i.e., healthy controls; n =642; mean age=29.6±13.1; female=62.9%). We also compared these measures among individuals with recent suicidal ideation ( n =714; mean age=36.3±15.3; female=66.1%), clinical controls ( n =1184; mean age=36.8±15.6; female=63.1%), and healthy controls ( n =1240; mean age= 31.6±15.5; female=61.0%). We found subtle but statistically significant effects, such as lower fractional anisotropy associated with a history of suicide attempt, over and above the effect of psychiatric diagnoses. These effects were strongest in the corona radiata, thalamic radiation, fornix/stria terminalis, corpus callosum and superior longitudinal fasciculus. Effect sizes were small (Cohen's d < 0.25). Recent suicidal ideation was not associated with alterations in WM microstructure. This large-scale coordinated mega-analysis revealed subtle regional and global alterations in WM microstructure in individuals with a history of suicide attempt. Longitudinal studies are needed to confirm whether these alterations are a risk factor for suicidal behaviour., Competing Interests: Conflicts of interest ALvH receives consultancy fees from the Augeo foundation. CAZ is a full-time US government employee. He is listed as a co-inventor on a patent for the use of ketamine and its metabolites in major depression and suicidal ideation. Dr. Zarate has assigned his patent rights to the U.S. government but will share a percentage of any royalties that may be received by the government. HPB has consulted to the Milken Institute. MW is a member of the following advisory boards and gave presentations to the following companies: Bayer AG, Germany; Boehringer Ingelheim, Germany; and Biologische Heilmittel Heel GmbH, Germany. MW has further conducted studies with institutional research support from HEEL and Janssen Pharmaceutical Research for a clinical trial (IIT) on ketamine in patients with MDD, unrelated to this investigation. MW did not receive any financial compensation from the companies mentioned above. IA received speakers honorarium from Lundbeck. IBH is the Co-Director, Health and Policy at the Brain and Mind Centre (BMC) University of Sydney. The BMC operates an early-intervention youth services at Camperdown under contract to headspace. He is the Chief Scientific Advisor to, and a 3.2% equity shareholder in, InnoWell Pty Ltd which aims to transform mental health services through the use of innovative technologies. AC reports being currently an employee of the Regeneron Genetics Center, and may own Regeneron stock or stock options. JCS acknowledge to be related with the next companies ALKERMES (Advisory Board), BOEHRINGER Ingelheim (Consultant), COMPASS Pathways (Research Grant), JOHNSON & JOHNSON (Consultant), LIVANOVA (Consultant), RELMADA (Research Grant), SUNOVION (Research Grant),Mind Med (Research Grant). PMP received payment or honoraria for lectures and presentations in educational events for Sandoz, Daiichi Sankyo, Eurofarma, Abbot, Libbs, Instituto Israelita de Pesquisa e Ensino Albert Einstein, Instituto D’Or de Pesquisa e Ensino. All other authors report no biomedical financial interests, disclosures or potential conflicts of interest.

Lithium is an effective augmenting agent for depressed patients with inadequate response to standard antidepressant therapy, but numerous adverse effects limit its use. We previously reported that a lithium-mimetic agent, ebselen, promoted a positive emotional bias-an indicator of potential antidepressant activity in healthy participants. We therefore aimed to investigate the effects of short-term ebselen treatment on emotional processing and brain neurochemistry in depressed patients with inadequate response to standard antidepressants. We conducted a double-blind, placebo-controlled 7-day experimental medicine study in 51 patients with major depressive disorder who were currently taking antidepressants but had an inadequate response to treatment. Participants received either ebselen 600 mg twice daily for seven days or identical matching placebo. An emotional testing battery, magnetic resonance spectroscopy and depression and anxiety rating scales were conducted at baseline and after seven days of treatment. Ebselen did not increase the recognition of positive facial expressions in the depressed patient group. However, ebselen increased the response bias towards fear emotion in the signal detection measurement. In the anterior cingulate cortex, ebselen significantly reduced the concentrations of inositol and Glx (glutamate+glutamine). We found no significant differences in depression and anxiety rating scales between visits. Our study did not find any positive shift in emotional bias in depressed patients with an inadequate response to antidepressant medication. We confirmed the ability of ebselen to lower inositol and Glx in the anterior cingulate cortex. These latter effects are probably mediated through inhibition of inositol monophosphatase and glutaminase respectively., (© 2024. The Author(s).)

Background: By 2030, over 50% of individuals living with bipolar disorder (BD) are expected to be aged ≥50 years. However, older age bipolar disorder (OABD) remains understudied. There are limited large-scale prospectively collected data organized in key dimensions capable of addressing several fundamental questions about BD affecting this subgroup of patients., Methods: We developed initial recommendations for the essential dimensions for OABD data collection, based on (1) a systematic review of measures used in OABD studies, (2) a Delphi consensus of international OABD experts, (3) experience with harmonizing OABD data in the Global Aging & Geriatric Experiments in Bipolar Disorder Database (GAGE-BD, n ≥ 4500 participants), and (4) critical feedback from 34 global experts in geriatric mental health., Results: We identified 15 key dimensions and variables within each that are relevant for the investigation of OABD: (1) demographics, (2) core symptoms of depression and (3) mania, (4) cognition screening and subjective cognitive function, (5) elements for BD diagnosis, (6) descriptors of course of illness, (7) treatment, (8) suicidality, (9) current medication, (10) psychiatric comorbidity, (11) psychotic symptoms, (12) general medical comorbidities, (13) functioning, (14) family history, and (15) other. We also recommend particular instruments for capturing some of the dimensions and variables., Conclusion: The essential data dimensions we present should be of use to guide future international data collection in OABD and clinical practice. In the longer term, we aim to establish a prospective consortium using this core set of dimensions and associated variables to answer research questions relevant to OABD., (© 2023 John Wiley & Sons Ltd. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Background: The study is aimed to identify brain functional connectomes predictive of depressed and elevated mood symptomatology in individuals with bipolar disorder (BD) using the machine learning approach Connectome-based Predictive Modeling (CPM)., Methods: Functional magnetic resonance imaging data were obtained from 81 adults with BD while they performed an emotion processing task. CPM with 5000 permutations of leave-one-out cross-validation was applied to identify functional connectomes predictive of depressed and elevated mood symptom scores on the Hamilton Depression and Young Mania rating scales. The predictive ability of the identified connectomes was tested in an independent sample of 43 adults with BD., Results: CPM predicted the severity of depressed [concordance between actual and predicted values ( r = 0.23, p perm (permutation test) = 0.031) and elevated ( r = 0.27, p perm = 0.01) mood. Functional connectivity of left dorsolateral prefrontal cortex and supplementary motor area nodes, with inter- and intra-hemispheric connections to other anterior and posterior cortical, limbic, motor, and cerebellar regions, predicted depressed mood severity. Connectivity of left fusiform and right visual association area nodes with inter- and intra-hemispheric connections to the motor, insular, limbic, and posterior cortices predicted elevated mood severity. These networks were predictive of mood symptomatology in the independent sample ( r ⩾ 0.45, p = 0.002)., Conclusions: This study identified distributed functional connectomes predictive of depressed and elevated mood severity in BD. Connectomes subserving emotional, cognitive, and psychomotor control predicted depressed mood severity, while those subserving emotional and social perceptual functions predicted elevated mood severity. Identification of these connectome networks may help inform the development of targeted treatments for mood symptoms.

Background: Older adults with bipolar disorder (BD) have received little study, although they often have severe symptoms, treatment resistance and high suicide risk. Furthermore, a subset develops cognitive dysfunction for unknown reasons., Methods: Here, cortical thickness and subcortical gray matter volume were compared across individuals ages 40-79y: 103 with BD ("later-onset" at ages ≥25y, n = 21; "early-onset" < 25y, n = 82) and healthy controls (HCs, n = 98)., Results: Overall, those with BD showed lower prefrontal, cingulate, sensorimotor, parahippocampal, insula, temporal, parietal, and occipital cortical thickness (Cohen's d: 0.4 to 0.8) and hippocampal, amygdalar, thalamic, and striatal gray matter volume (d: 0.6 to 0.8). Later-onset BD showed negative relationships between age and parahippocampal, insular, temporal, parietal, and occipital cortical thickness, and hippocampal, thalamic and striatal volume (r: -0.7 to -0.4). Suicide attempt history was associated with lower dorsolateral prefrontal cortical thickness (d = 0.5)., Limitations: The study used a cross-sectional design and the sample of those with a later-onset of BD was relatively modest., Conclusions: Results support widespread gray matter decreases in older adults with BD, and also suggest a separable later-onset phenotype characterized by age-related gray matter reductions in regions subserving cognitive, emotional and perceptual processes. Moreover, the results are the first to demonstrate structural brain differences associated with a history of suicide attempts in older adults with BD., Competing Interests: Conflict of Interest GSA serves on the advisory board of Eisai, and of Janssen, and serves on the Speakers Bureaus of Otsuka, Allergan, and Lundbeck. HPB has consulted to the Milken Institute. All other authors have no competing interests to declare., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Objectives: The distinction between bipolar I disorder (BD-I) and bipolar II disorder (BD-II) has been a topic of long-lasting debate. This study examined differences between BD-I and BD-II in a large, global sample of OABD, focusing on general functioning, cognition and somatic burden as these domains are often affected in OABD., Methods: Cross-sectional analyses were conducted with data from the Global Aging and Geriatric Experiments in Bipolar Disorder (GAGE-BD) database. The sample included 963 participants aged ≥50 years (714 BD-I, 249 BD-II). Sociodemographic and clinical factors were compared between BD subtypes including adjustment for study cohort. Multivariable analyses were conducted with generalized linear mixed models (GLMMs) and estimated associations between BD subtype and (1) general functioning (GAF), (2) cognitive performance (g-score) and (3) somatic burden, with study cohort as random intercept., Results: After adjustment for study cohort, BD-II patients more often had a late onset ≥50 years (p = 0.008) and more current severe depression (p = 0.041). BD-I patients were more likely to have a history of psychiatric hospitalization (p < 0.001) and current use of anti-psychotics (p = 0.003). Multivariable analyses showed that BD subtype was not related to GAF, cognitive g-score or somatic burden., Conclusion: BD-I and BD-II patients did not differ in terms of general functioning, cognitive impairment or somatic burden. Some clinical differences were observed between the groups, which could be the consequence of diagnostic definitions. The distinction between BD-I and BD-II is not the best way to subtype OABD patients. Future research should investigate other disease specifiers in this population., (© 2022 The Authors. Bipolar Disorders published by John Wiley & Sons Ltd.)

Background: To reduce suicide in females with mood disorders, it is critical to understand brain substrates underlying their vulnerability to future suicidal ideation and behaviors (SIBs) in adolescence and young adulthood. In an international collaboration, grey and white matter structure was investigated in adolescent and young adult females with future suicidal behaviors ( f SB) and ideation ( f SI), and without SIBs ( f nonSIB)., Methods: Structural ( n = 91) and diffusion-weighted ( n = 88) magnetic resonance imaging scans at baseline and SIB measures at follow-up on average two years later (standard deviation, SD = 1 year) were assessed in 92 females [age(SD) = 16.1(2.6) years] with bipolar disorder (BD, 28.3%) or major depressive disorder (MDD, 71.7%). One-way analyses of covariance comparing baseline regional grey matter cortical surface area, thickness, subcortical grey volumes, or white matter tensor-based fractional anisotropy across f SB ( n = 40, 43.5%), f SI ( n = 33, 35.9%) and f nonSIB ( n = 19, 20.6%) groups were followed by pairwise comparisons in significant regions ( p < 0.05)., Results: Compared to f nonSIBs, f SIs and f SBs showed significant decreases in cortical thickness of right inferior frontal gyrus pars orbitalis and middle temporal gyrus, f SIs of left inferior frontal gyrus, pars orbitalis. F SIs and f SBs showed lower fractional anisotropy in left uncinate fasciculus and corona radiata, and f SBs in right uncinate and superior fronto-occipital fasciculi., Conclusions: The study provides preliminary evidence of grey and white matter alterations in brain regions subserving emotional and behavioral regulation and perceptual processing in adolescent and young adult females with mood disorders with, versus without, future SIBs. Findings suggest potential targets to prevent SIBs in female adolescents and young adults., Competing Interests: CONFLICTS OF INTEREST Hilary P. Blumberg received an honorarium for a talk at Aetna. The remaining authors have declared that they have no competing or potential conflicts of interest.

Identifying brain alterations associated with suicidal thoughts and behaviors (STBs) in young people is critical to understanding their development and improving early intervention and prevention. The ENIGMA Suicidal Thoughts and Behaviours (ENIGMA-STB) consortium analyzed neuroimaging data harmonized across sites to examine brain morphology associated with STBs in youth. We performed analyses in three separate stages, in samples ranging from most to least homogeneous in terms of suicide assessment instrument and mental disorder. First, in a sample of 577 young people with mood disorders, in which STBs were assessed with the Columbia Suicide Severity Rating Scale (C-SSRS). Second, in a sample of young people with mood disorders, in which STB were assessed using different instruments, MRI metrics were compared among healthy controls without STBs (HC; N = 519), clinical controls with a mood disorder but without STBs (CC; N = 246) and young people with current suicidal ideation (N = 223). In separate analyses, MRI metrics were compared among HCs (N = 253), CCs (N = 217), and suicide attempters (N = 64). Third, in a larger transdiagnostic sample with various assessment instruments (HC = 606; CC = 419; Ideation = 289; HC = 253; CC = 432; Attempt=91). In the homogeneous C-SSRS sample, surface area of the frontal pole was lower in young people with mood disorders and a history of actual suicide attempts (N = 163) than those without a lifetime suicide attempt (N = 323; FDR-p = 0.035, Cohen's d = 0.34). No associations with suicidal ideation were found. When examining more heterogeneous samples, we did not observe significant associations. Lower frontal pole surface area may represent a vulnerability for a (non-interrupted and non-aborted) suicide attempt; however, more research is needed to understand the nature of its relationship to suicide risk., (© 2022. Crown.)

Bipolar disorder (BD) and exposure to childhood maltreatment (CM), which is present at high rates in BD, are both associated with hippocampus and prefrontal cortex structural alterations thought to contribute to clinical features. Gender-related differences are implicated in BD for CM exposure, brain structure and clinical features. However, relationships among these factors in BD are understudied. This study aimed to investigate associations among gender, CM, hippocampus and prefrontal gray matter structure and clinical features in BD. Childhood trauma questionnaire, structured clinical assessments and 3 Tesla structural magnetic resonance imaging were obtained for 236 adults (18-63 years, 32.0 ± 12.6): 119 with BD (58.8% women) and 117 healthy controls (HCs, 50.4% women). Women with BD reported higher CM severity than men with BD and HCs (B=-14.34, 95% confidence intervals (CI)[-22.71,-5.97], p<.001). CM and gender showed a significant interaction for left hippocampus (B=-7.41, 95% CI[-14.10,-0.71], p<.05); CM severity was negatively associated with left hippocampus only in women with BD. In women with BD, CM was associated with post-traumatic stress disorder comorbidity (B = 25.68, 95% CI[15.11,36.25], p<.001). In men with BD, CM severity was associated with lower left frontal pole (B=-0.71, 95% CI[-1.14,-0.28], p<.05) and right superior frontal (B=-17.78, 95% CI[-30.66,-4.90], p<.05) surface area; the latter related to earlier age of first mood symptoms (B = 33.97, 95% CI[7.61, 60.33], p<.05). Findings support gender-related effects of CM on frontotemporal structure and clinical features of BD. The findings bring novel perspectives for gendered pathophysiological models of effects of CM in BD., Competing Interests: Declaration of Competing Interest Dr. Lippard receives funding for a Janssen-sponsored study through University of Texas-Austin. Dr. Blumberg received an honorarium for a talk at Aetna. All other authors declare that they have no conflicts of interest., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Objective: Harmonizing different depression severity scales often requires creation of categorical variables that may decrease the sensitivity of the measure. Our aim was to compare the associations between categorical and continuous and harmonized measures of depression and global functioning in a large dataset of older age patients with bipolar disorder (OABD)., Method: In the Global Aging & Geriatric Experiments in Bipolar Disorder Database (GAGE-BD) the 17-item Hamilton Depression scale (HAM-D), Montgomery Asberg Depression Rating Scale (MADRS) or the Center for Epidemiological Studies Depression scales (CES-D) was used to assess current depressive symptoms, while the Global Assessment of Functioning (GAF) assessed functional status. Data were harmonized from 8 OABD studies (n = 582). In each subsample, the relationship of depression severity as a continuous and categorical measure was compared to GAF. In the total sample, harmonized ordinal depression categories were compared to GAF., Results: Effect size and variance explained by the model for the categorical measure in the total sample was higher than both the categorical and continuous measure in the CES-D subsample, higher than the categorical but lower than the continuous measure in the HAM-D subsample, and lower than both the categorical and continuous measures in the MADRS subsample., Limitations: All included studies have different inclusion and exclusion criteria, study designs, and differ in aspects of sociodemographic variables., Conclusions: Associations were only slightly larger for the continuous vs categorical measures of depression scales. Harmonizing different depression scales into ordinal categories for analyses is feasible without losing statistical power., (Copyright © 2022. Published by Elsevier B.V.)

Objectives: Antipsychotic drugs (APS) are widely used to treat patients with bipolar disorder (BD), but there is limited information in older-age bipolar disorder (OABD). This analysis of the Global Aging & Geriatric Experiments in Bipolar Disorder Database (GAGE-BD) investigated characteristics of OABD patients prescribed APS vs. those not prescribed APS., Experimental Design: The observational analysis used baseline, cross-sectional data from 16 international studies for adults aged ≥ 50 years with BD comprising 1,007 individuals with mean age 63.2 years (SD = 9.0), 57.4% women, and mean age of onset 31.6 years (SD = 15.0). The dependent variable was current APS treatment status. The independent variables included demographic and clinical variables, and a random effect for study, that were included in generalized mixed models., Principal Observations: 46.6% of individuals (n = 469) were using APS. The multivariate model results suggest that those treated with APS were younger (p = 0.01), less likely to be employed (p < 0.001), had more psychiatric hospitalizations (p = 0.009) and were less likely to be on lithium (p < 0.001). Of individuals on APS, only 6.6% of those (n = 27) were on first-generation antipsychotics (FGAs) and experienced a greater burden of psychiatric hospitalizations (p = 0.012)., Conclusions: APS are widely prescribed in OABD, observed in nearly half of this sample with great variation across sites. Individuals with OABD on APS have more severe illness, more frequent hospitalizations and are more often unemployed vs. those not on APS. Future studies need to examine longitudinal outcomes in OABD prescribed APS to characterize underlying causal relationships., (Copyright © 1964–2022 by MedWorks Media Inc, Los Angeles, CA All rights reserved. Printed in the United States.)

Background: Elevated aggression and impulsivity are implicated in Bipolar Disorder (BD); however, relationships between these behavioral constructs have not been clarified, which can lead to misconceptions with negative consequences including stigma and adverse outcomes including suicide. The study aimed to clarify brain-based distinctions between the two constructs and their associations to risk factors, symptoms and suicide thoughts and behaviors., Methods: Self-rated Brown-Goodwin Aggression (BGA) and Barratt Impulsiveness Scale (BIS) scores were compared between adults with BD (n = 38, 74% female) and healthy controls (HC, n = 29, 64% female). Relationships were examined between BGA and BIS with childhood trauma questionnaire (CTQ), mood, comorbidities, and magnetic resonance imaging gray matter volume (GMV) assessments., Results: In BD, BGA and BIS total scores were both elevated and associated with childhood maltreatment (CM), particularly emotional CM, depression, substance use disorders (SUDs) and suicide attempts (SAs). BGA scores were increased by items corresponding to dysregulation of emotional and social behavior and associated with elevated mood states and suicide ideation and GMV decreases in bilateral orbitofrontal cortex and left posterior insula brain regions, previously associated with these behaviors and clinical features. BIS motor impulsiveness scores were associated with GMV decreases in anterior cingulate cortex implicated in mood and behavioral dyscontrol., Limitations: modest sample size, self-reports CONCLUSIONS: The findings suggest separable brain-based domains of dysfunction in BD of motor impulsiveness versus emotionally dysregulated feelings that are primarily self-directed. Both domains are associated with suicide behavior and modifiable risk factors of CM, depression and SUDs that could be targeted for prevention., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Spontaneous intramural small-bowel hematoma (SISBH) is an uncommon cause of acute abdominal pain in anticoagulated patients.

Brain targets to lower the high risk of suicide in Bipolar Disorder (BD) are needed. Neuroimaging studies employing analyses dependent on regional assumptions could miss hubs of dysfunction critical to the pathophysiology of suicide behaviors and their prevention. This study applied intrinsic connectivity distribution (ICD), a whole brain graph-theoretical approach, to identify hubs of functional connectivity (FC) disturbances associated with suicide attempts in BD. ICD, from functional magnetic resonance imaging data acquired while performing a task involving implicit emotion regulation processes important in BD and suicide behaviors, was compared across 40 adults with BD with prior suicide attempts (SAs), 49 with BD with no prior attempts (NSAs) and 51 healthy volunteers (HVs). Areas of significant group differences were used as seeds to identify regional FC differences and explore associations with suicide risk-related measures. ICD was significantly lower in SAs than in NSAs and HVs in bilateral ventromedial prefrontal cortex (vmPFC) and right anterior insula (RaIns). Seed connectivity revealed altered FC from vmPFC to bilateral anteromedial orbitofrontal cortex, left ventrolateral PFC (vlPFC) and cerebellum, and from RaIns to right vlPFC and temporopolar cortices. VmPFC and RaIns ICD were negatively associated with suicidal ideation severity, and vmPFC ICD with hopelessness and attempt lethality severity. The findings suggest that SAs with BD have vmPFC and RaIns hubs of dysfunction associated with altered FC to other ventral frontal, temporopolar and cerebellar cortices, and with suicidal ideation, hopelessness, and attempt lethality. These hubs may be targets for novel therapeutics to reduce suicide risk in BD., (© 2021. The Author(s).)

Bipolar disorder (BD) is a common mood disorder that can have severe consequences during later life, including suffering and impairment due to mood and cognitive symptoms, elevated risk for dementia and an especially high risk for suicide. Greater understanding of the brain circuitry differences involved in older adults with BD (OABD) in later life and their relationship to aging processes is required to improve outcomes of OABD. The current literature on gray and white matter findings, from high resolution structural and diffusion-weighted magnetic resonance imaging (MRI) studies, has shown that BD in younger age groups is associated with gray matter reductions within cortical and subcortical brain regions that subserve emotion processing and regulation, as well as reduced structural integrity of white matter tracts connecting these brain regions. While fewer neuroimaging studies have focused on OABD, it does appear that many of the structural brain differences found in younger samples are present in OABD. There is also initial suggestion that there are additional brain differences, for at least a subset of OABD, that may result from more pronounced gray and white matter declines with age that may contribute to adverse outcomes. Preclinical and clinical data supporting neuro-plastic and -protective effects of mood-stabilizing medications, suggest that treatments may reverse and/or prevent the progression of brain changes thereby reducing symptoms. Future neuroimaging research implementing longitudinal designs, and large-scale, multi-site initiatives with detailed clinical and treatment data, holds promise for reducing suffering, cognitive dysfunction and suicide in OABD., Competing Interests: CONFLICTS OF INTEREST HPB has consulted for the Milken Institute. All other authors have no conflicting interests to declare.

Background: Revisional bariatric surgery presents a challenge for bariatric surgeons. This procedure can be considered for patients with inadequate weight loss or weight regain after an initial satisfactory response following bariatric surgery. However, the surgical management of weight regain following RYGB remains controversial. We present a case of successful weight gain management after a single anastomosis duodenoileal bypass with sleeve gastrectomy (SADIS) as a revisional procedure for patients with weight regain after RYGB., Methods: A 23-year-old female with a body mass index (BMI) of 52 kg/m 2 and no comorbidities underwent RYGB. Postoperatively, she reached an excess weight loss of 75% of her initial body weight, with a BMI of 32 kg/m 2 . Eight years after her RYGB, she started regaining weight, reaching a BMI of 47 kg/m 2 . The surgical team decided to perform a revisional surgery, a conversion of RYGB to SADIS., Results: There were no intraoperative complications. An upper gastrointestinal series was obtained on the third postoperative day which resulted normal and oral feedings were resumed. The patient was then discharged on fifth postoperative day. There were no complications within the first 30 postoperative days., Conclusions: We attach a video that illustrates the management and technique used to deal with the weight regain after primary bariatric surgery RYGB. We consider that in patients with super morbid obesity refractory to RYGB, conversion to SADIS is an excellent alternative due to its safety and feasibility., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: Social rhythm irregularities are associated with increased bipolar disorder symptoms and suicide risk. This study was the first to examine the feasibility and acceptability of a 12-week social rhythm therapy (SRT) delivered predominantly via telehealth (three in-person sessions, nine via video teleconferencing) to adolescents and young adults with bipolar disorder. The primary aim was to determine the feasibility and acceptability of SRT delivered predominantly via telehealth. Secondary aims were to explore the intervention's impacts on social rhythm regularity, mood symptoms, and suicide propensity., Methods: Thirteen adolescents and young adults with bipolar disorder received a modified SRT called Brain Emotion circuitry-targeted Self-Monitoring And Regulation Therapy for Daily Rhythms (BE-SMART-DR) administered mostly remotely, adjunctive to treatment as usual. Retention rates, client satisfaction, therapeutic alliance, and pre- to postintervention changes in social rhythm regularity, mood symptoms, and suicide propensity were assessed., Results: BE-SMART-DR was associated with high retention rates (77%), high mean±SD scores on the Client Satisfaction Questionnaire (29.4±2.7), and high participant global scores on the Working Alliance Inventory (231.3±8.1), indicative of strong therapeutic alliance. Secondary outcome measures on social rhythm irregularities, mood symptoms, and suicide propensity decreased from pre- to posttherapy. Increased social rhythm regularity was associated with reduced suicide propensity after analyses were controlled for reductions in mood symptoms., Conclusions: These preliminary results indicate that SRT delivered largely by telemedicine is feasible and acceptable. The intervention appeared to reduce mood symptoms, and suicide propensity independent of mood symptoms, among adolescents and young adults with bipolar disorder.

Background: Whether the differences in brain structure and function, characteristic of adult major depressive disorder (MDD 1 ), are present in adolescent MDD is still unclear, but it has been shown that cognitive behavioral therapy (CBT 2 ) affects resting-state functional connectivity in both adult and adolescent MDD patients, with the claim that CBT has a normalizing effect on MDD-related functional disruption, but this has not been directly tested., Methods: 128 adolescent MDD patients and 40 adolescent controls were enrolled in the study. We investigated pre-treatment differences in cortical thickness, white matter volume, and resting-state functional connectivity. We also investigated the longitudinal effects of CBT on resting-state functional connectivity, and the relationship between pre-treatment functional disruption and CBT-related changes to resting-state functional connectivity was assessed by the correlation of pre-treatment cross-sectional effects and longitudinal CBT-related effects across multiple brain regions., Results: Patients had greater cortical thickness and white matter volume within fronto-limbic regions of the brain. Patients had greater pre-treatment resting-state functional connectivity within the default-mode, fronto-limbic, central-executive, and salience networks. CBT increased resting-state functional connectivity of the subgenual anterior cingulate and amygdala seeds with predominantly frontal regions. Regions showing the greatest pre-treatment functional disruption showed the weakest CBT-related changes., Limitations: For ethical reasons, there was no placebo group., Conclusions: Adolescent MDD is associated with structural and functional differences also seen in adult patients. CBT-related changes in resting-state functional connectivity do not appear to show a normalizing effect, but instead indicate rehabilitative effects on resting-state functional connectivity., Competing Interests: Declaration of Competing Interest Luca Villa, Professor Suckling, Dr. Wilkinson, Dr. Tait, and Professor Reynolds have no conflicts of interest to disclose. Professor Ian Goodyer has received consulting fees from Lundbeck Pharmaceuticals and is supported by a strategic award from the Wellcome Trust (095844/Z/11/Z). Dr. Raphael Kelvin has received consulting fees from Lundbeck Pharmaceuticals., (Copyright © 2020. Published by Elsevier B.V.)

The aim of this study was to evaluate stress distribution with different implant systems through photoelasticity. Five models were fabricated with photoelastic resin PL-2. Each model was composed of a block of photoelastic resin (10 × 40 × 45 mm) with an implant and a healing abutment: model 1, internal hexagon implant (4.0 × 10 mm; Conect AR, Conexão, São Paulo, Brazil); model 2, Morse taper/internal octagon implant (4.1 × 10 mm; Standard, Straumann ITI, Andover, Mass); model 3, Morse taper implant (4.0 × 10 mm; AR Morse, Conexão); model 4, locking taper implant (4.0 × 11 mm; Bicon, Boston, Mass); model 5, external hexagon implant (4.0 × 10 mm; Master Screw, Conexão). Axial and oblique load (45°) of 150 N were applied by a universal testing machine (EMIC-DL 3000), and a circular polariscope was used to visualize the stress. The results were photographed and analyzed qualitatively using Adobe Photoshop software. For the axial load, the greatest stress concentration was exhibited in the cervical and apical thirds. However, the highest number of isochromatic fringes was observed in the implant apex and in the cervical adjacent to the load direction in all models for the oblique load. Model 2 (Morse taper, internal octagon, Straumann ITI) presented the lowest stress concentration, while model 5 (external hexagon, Master Screw, Conexão) exhibited the greatest stress. It was concluded that Morse taper implants presented a more favorable stress distribution among the test groups. The external hexagon implant showed the highest stress concentration. Oblique load generated the highest stress in all models analyzed.

Pseudomonas aeruginosa infections cause high morbidity and mortality. We performed a descriptive analysis of the rates of antibiotic resistance in isolates of P. aeruginosa in 33 hospitals enrolled in a surveillance network in Colombia. The study was conducted between January 2005 and December 2009 .9905 isolates of P. aeruginosa were identified, (4.9% of all strains). In intensive care units (ICU) P. aeruginosa showed an overall resistance to aztreonam, cefepime , ceftazidime, imipenem, meropenem , and piperacillin / tazobactam of 31.8% , 23.9% , 24.8%, 22.5%, 20.3% and 22.3%, respectively. Resistance rates increased for piperacillin/tazobactam, cefepime, and imipenem; remained unchanged for meropenem; and decreased for aminoglycosides, quinolones and ceftazidime. Resistance to one, two and three or more families of antibiotics was found in 17%, 12.5%, and 32.1%, respectively. In samples collected from the wards, the resistance rate was lower but usually over 10%. Antibiotic resistance in P. aeruginosa isolates in hospitalized patients and particularly in those admitted to ICUs in Colombia is high.

A single polymerase chain reaction (PCR) reaction targeting the spliced-leader intergenic region of Trypanosoma cruzi I was standardised by amplifying a 231 bp fragment in domestic (TcIDOM) strains or clones and 450 and 550 bp fragments in sylvatic strains or clones. This reaction was validated using 44 blind coded samples and 184 non-coded T. cruzi I clones isolated from sylvatic triatomines and the correspondence between the amplified fragments and their domestic or sylvatic origin was determined. Six of the nine strains isolated from acute cases suspected of oral infection had the sylvatic T. cruzi I profile. These results confirmed that the sylvatic T. cruzi I genotype is linked to cases of oral Chagas disease in Colombia. We therefore propose the use of this novel PCR reaction in strains or clones previously characterised as T. cruzi I to distinguish TcIDOMfrom sylvatic genotypes in studies of transmission dynamics, including the verification of population selection within hosts or detection of the frequency of mixed infections by both T. cruzi I genotypes in Colombia.

Purpose: The aim of our study was to evaluate the impact of CYP3A4, CYP3A5, and ABCB1 polymorphisms on donepezil disposition and clinical outcome., Methods: Fifty-four Italian patients diagnosed with probable mild to moderate Alzheimer's disease, treated with donepezil (37 patients 5 mg/day, 17 patients 10 mg/day) were genotyped for CYP3A4 (*1B, *3, and *4), CYP3A5 (*2, *3, and *6) and ABCB1 (3435C>T, 2677G>T/A, and 1236C>T) polymorphisms. All patients were evaluated for the degree of cognitive impairment with Mini Mental State Examination (MMSE) screening test at baseline (before treatment) and after at least 3 months of donepezil treatment at stable dose, when the drug plasma levels were measured., Results: Three patients carried one detrimental CYP3A4 allelic variant, and 12 carried one functional CYP3A5*1 allele. No statistically significant association was found between CYP3A4 or CYP3A5 genotypes and plasma donepezil concentrations, or between genotypes and clinical response (as measured by change in MMSE score). Nine ABCB1 haplotypes were observed, the most common being 1236C/2677G/3435C (46%) and 1236T/2677T/3435T (41%). Patients homozygous for the T/T/T haplotype had slightly though not significantly lower plasma donepezil concentration-to-dose ratios than those carrying other genotypes [median (95% CI) 0.18 (0.13-0.45) vs. 0.31 (0.30-0.44) mg/l/mg/kg, respectively]. These patients also showed a slightly better clinical response (as measured by change in MMSE score) than the other genotype groups [median (95% CI) 0 (-1.3 to 3.3) vs. -1.0 (-2.1 to 0.0), respectively]., Conclusions: Our data suggest that the CYP3A4 and CYP3A5 polymorphisms are unlikely to influence donepezil metabolism and/or clinical outcome. On the other hand, the ABCB1 polymorphisms may play a role in donepezil disposition and clinical outcome.

The African clawed frog, Xenopus laevis, is used extensively as a model organism for studying both cell development and cell cycle regulation. For over 20 years now, this model organism has contributed to answering fundamental questions concerning the mechanisms that underlie cell cycle transitions--the cellular components that synthesize, modify, repair, and degrade nucleic acids and proteins, the signaling pathways that allow cells to communicate, and the regulatory pathways that lead to selective expression of subsets of genes. In addition, the remarkable simplicity of the Xenopus early cell cycle allows for tractable manipulation and dissection of the basic components driving each transition. In this organism, early cell divisions are characterized by rapid cycles alternating phases of DNA synthesis and division. The post-blastula stages incorporate gap phases, lengthening progression, and allowing more time for DNA repair. Various cyclin/Cdk complexes are differentially expressed during the early cycles with orderly progression being driven by both the combined action of cyclin synthesis and degradation and the appropriate selection of specific substrates by their Cdk components. Like other multicellular organisms, chief developmental events in early Xenopus embryogenesis coincide with profound remodeling of the cell cycle, suggesting that cell proliferation and differentiation events are linked and coordinated through crosstalk mechanisms acting on signaling pathways involving the expression of cell cycle control genes.

Objective: Surgical reconstruction and prosthetic obturation are alternatives for the treatment of cleft in the soft palate., Design: The present case reports the rehabilitation of a patient presenting cleft palate with obturator prosthesis associated with implant-supported retention system., Conclusions: The use of ball attachment system improved speech, masticatory efficiency, swallowing, and social behavior of the patient.

Introduction: Trypanosoma rangeli is a species of trypanosome second to T. cruzi, that is infective to humans in Latin America. Variability in the biological, biochemical and molecular characteristics between different isolates isolates of this parasite have been recorded., Objective: Morphological and molecular characteristics were recorded from strains of T. rangeli that were isolated from different species of Rhodnius and maintained in different vertebrate species., Materials and Methods: Nineteen strains of T. rangeli were isolated from R. prolixus, R. pallescens and R. colombiensis in Colombia, R. ecuadoriensis in Peru and R. pallescens in Panama. Polymorphism of blood trypomastigotes in ICR mice was evaluated and pleomorphism of P53 strain of T. rangeli KP1(-) inoculated in mouse, marsupial and canine was studied. RAPD analysis (randomly amplified polymorphic DNA analysis) of 12 strains isolated from four species of Rhodnius was performed., Result: Based on the total length of blood trypomastigotes, three discrete groups were observed. The P53 strain showed significant differences in the size of blood trypomastigotes in mouse, marsupial and canine. RAPD analysis showed that the strains segregated into two branches corresponding to strains of T. rangeli KP1(+) and T. rangeli KP1(-). All strains of T. rangeli KP1(-) clustered according to the species of Rhodnius from which they were isolated., Conclusion: These data reveal, for the first time, a close association amongst T. rangeli strains and Rhodnius species, confirming that each species of Rhodnius transmits to vertebrate hosts a parasite population with clear phenotypic and genotypic differences. This is further evidence that supports the concept of clonal evolution of these parasites.

Objective: The aims of this study were to evaluate the impact of the CYP2D6 polymorphism on both the steady-state plasma concentrations (Cp) and the clinical outcome of donepezil, a selective acetylcholinesterase inhibitor used in the treatment of Alzheimer's disease (AD)., Methods: Forty-two patients of Caucasian ethnicity affected by probable AD were included in the study. All had been receiving therapy with donepezil for at least 3 months: 31 patients with 5 mg/day and 11 patients with 10 mg/day. The CYP2D6 genotype was analysed, and donepezil Cp was measured by using high-performance liquid chromatography., Results: On the basis of their CYP2D6 genotype, 30 patients could be classified as homozygous extensive metabolizers (EM), 10 as heterozygous EM and 2 as ultrarapid metabolizers (UM). No poor metabolizer was found. The dose and body weight-corrected median donepezil Cp were slightly, though not significantly, lower in homozygous than in heterozygous EM (0.33 vs. 0.41 ng/ml/mg/kg, respectively). The latter group consistently showed a better clinical response to treatment, as measured by change in Mini-Mental State Examination score (median: 1.40 vs. -1.30, respectively). UM patients had lower Cp than EM patients and showed no clinical improvement., Conclusions: Our preliminary data suggest that the CYP2D6 polymorphism influences both donepezil metabolism and therapeutic outcome and that a knowledge of a patient's CYP2D6 genotype together with donepezil concentration measurements might be useful in the context of improving the clinical efficacy of donepezil therapy.

Aim: Charcot-Marie-Tooth disease (CMT) is a genetic neuropathy causing muscle weakening in the feet, legs and hands, with consequent impairment of ambulation and handgrip. For fast clinical evaluation and rehabilitation management of handgrip deficits, a functional classification in 4 stages or levels of clinical severity, based on the loss of handgrip types from the finest to the roughest, has been recently proposed. The aim of this study is to evaluate the prevalence of each level of handgrip impairment in a wide population of patients affected with demyelinating and axonal CMT., Methods: Two-hundred and forty-eight non-operated hands were examined to evaluate if and how the pinch between the pulp of the thumb and the pulp of the second or third finger was made, starting from the palm-up position with the fingers abducted or, in case of impossibility to do so, if a lateral pinch or only a grasp was possible. Following to this observation, each hand was fitted in 1 of the 4 stages described in the above-mentioned classification and then the frequency of each stage was determined., Results: As a whole, 75.4% hands were at stage 1; 9.7 were at stage 2; 10.9% at stage 3; 4% at stage 4., Conclusions: The results of this survey reveal that, in the majority of the CMT cases, handgrip is affected mildly so that only simple recommendations to prevent further muscle and joint damage are required; however, in more than 1 out 5 cases, the handrip impairment is quite severe and requires a detailed rehabilitative program with daily exercises, and, in a small number of cases, is so severe that independence in the daily living activities is lost or very reduced.

The effects of the oxidant species peroxynitrite (ONOO-) on coronary perfusion pressure and vasodilatation elicited by acetylcholine, isoproterenol, and S-nitroso-N-acetyl-DL-penicillamine were investigated in the isolated perfused rat heart. ONOO- (0.3-1000 microM) caused a concentration-dependent vasodilatation of the coronary vasculature. This dilator response was inhibited by oxyhemoglobin, indicating that it was due to the generation of nitric oxide. Tachyphylaxis to ONOO- developed rapidly, so that the response disappeared after three or four applications of this compound. ONOO- not only induced tachyphylaxis but also inhibited the vasodilatation induced by the three vasodilators studied. This latter effect of ONOO- was critically dependent on its concentration, since it occurred at 3 microM, which was subthreshold as a dilator, and at 1000 microM, which was supramaximal, but not at 30 and 100 microM. These latter concentrations inhibited the responses to vasodilators only in the presence of oxyhemoglobin. Thus, a wide range of concentrations of ONOO- induce a vascular dysfunction, as evidenced by the tachyphylaxis to its own vasodilator actions and the long-lasting impairment of the responses to other vasodilators. However, at the same time ONOO- generates nitric oxide, which at certain concentrations of ONOO- is sufficient to counteract its deleterious action. Coinfusion of S-nitroso-N-acetyl-DL-penicillamine or prostacyclin at low concentrations that did not produce vasodilatation also protected against ONOO(-)-induced vascular dysfunction: these compounds may be protective through a common mechanism, as yet undefined.

Segments of human saphenous vein, internal mammary artery, right gastroepiploic artery, and inferior epigastric artery were incubated in vitro in Krebs-Henseleit solution and compared in terms of their capacity to generate and release into the medium 6-keto-prostaglandin F1 alpha (PGF1 alpha), the stable metabolite of prostacyclin. The four vascular conduits were also challenged with endothelin-1 (40 ng/mL), and accumulation of the lipidic material in the bathing fluid was also studied. The results obtained show clearly that under both normal and endothelin-1-stimulated conditions, the four vascular segments generate a substantial amount of 6-keto-PGF1 alpha. Multiple-comparisons analysis of the results indicates that the rank order in producing 6-keto-PGF1 alpha is as follows: inferior epigastric artery > internal mammary artery > right gastroepiploic artery > saphenous vein (p < 0.01). A similar order of potency was obtained in vascular conduits stimulated with endothelin-1. The rate of formation of immunoreactive 6-keto-PGF1 alpha under both normal and stimulated conditions by the inferior epigastric artery (normal, 301 +/- 8 pg/mg of tissue; stimulated, 519 +/- 15 pg/mg of tissue) was at 10 minutes more than 2 times (p < 0.01) that of the saphenous vein and about 1.5 times (p < 0.01) that of the right gastroepiploic artery.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetaldehyde administered intravenously at various doses (20, 40 and 80 mg/kg) elicits a dose-dependent increase in intratracheal pressure (ITP) and a proportional rise in histamine blood concentration in anaesthetized guinea-pigs. Similar effects were observed in ovalbumin-sensitized guinea-pigs upon aerosol of acetaldehyde (20 mg/ml) which has been administered at the flow rate of 0.1 ml/min for 2 min. Theophylline (CAS 58-55-9) antagonized both the increase of ITP values and the rise of histamine in the blood caused by acetaldehyde given intravenously (ED50 = 5.8 mg/kg i.v.) or by aerosol (ED50 = 4.9 mg/kg i.v.). Furthermore, in animals where combined treatment with pyrilamine (2 mg/kg i.v.) and captopril (2 mg/kg i.v.) resulted in a remarkable potentiation of the bronchoconstrictor response to acetaldehyde (20 mg/kg i.v.), the administration of theophylline (5 mg/kg i.v.) or of the substance P (SP) receptor antagonist, [D-Pro4, D-Trp7.9] SP 4-11 (10 mg/kg i.v.) reduced the augmented action of acetaldehyde on respiratory airways induced by captopril by more than 50%. Moreover, the bronchoconstriction induced by acetaldehyde (40 mg/kg i.v.) was also associated with a significant increase of extravasation of Evans blue in tracheal tissue. Both these effects of acetaldehyde were inhibited by theophylline (10 mg/kg i.v.), whereas a NK1-TK (neurokinin 1-tachykinin) receptor antagonist (412 micrograms/kg i.v.) reduced (81%; p < 0.001) only the vascular permeability changes caused by acetaldehyde.(ABSTRACT TRUNCATED AT 250 WORDS)

Using isolated perfused rabbit heart electrically paced, we assessed the relevance of both nitric oxide (NO) and prostacyclin (PGI2) in regulation of resting coronary perfusion pressure (CPP). In preparations in which NO-synthase was inhibited by NG-monomethyl-L-arginine (L-NMMA, 10 microM), resting CPP increased significantly; this phenomenon was potentiated by indomethacin infusion (3 microM), prevented by L-arginine (100 microM) and significantly reduced by iloprost (55 nM) and defibrotide (200 micrograms/ml). Furthermore, the increase in resting CPP induced by graded doses of endothelin-1 (ET-1 0.6-160 pmol), was further augmented by blocking of prostaglandin biosynthesis with indomethacin (3 microM) and was substantially reduced when the rate of formation of PGI2 was enhanced by defibrotide (200 micrograms/ml). Moreover, the coronary vasoconstriction induced by ET-1 (2, 4, and 8 pmol) was increased in hearts in which NO-synthase was blocked by L-NMMA (10 microM) and this event was abolished in preparations in which PGI2 synthesis was stimulated by defibrotide (200 micrograms/ml). These results further emphasize that rabbit coronary vessels are continuously dilated by NO released from endothelial cells. They also indicate that PGI2 takes part in NO generation in the endothelial-derived relaxing mechanism. Inactivation of this mechanism, owing to decreased formation of NO and PGI2 in rabbit heart, induces hyperreactivity of coronary smooth muscles to ET-1. Finally, an increase in PGI2 production (such as that caused by defibrotide) may counterbalance impaired NO generation and attenuate hyperreactivity of the coronary vasculature.

The time to respiratory crisis in ovalbumin-sensitised guinea-pigs following exposure to aerosol administered antigen was dose dependently delayed by inhalation of nimesulide (0.1% to 1%), whereas indomethacin had no effect. At the same time, nimesulide significantly reduced blood histamine concentrations, in contrast to the slight increase observed with indomethacin. In human bronchial muscle preparations, nimesulide, but not indomethacin, antagonised H1-histamine-receptor activation by histamine and was without effect on acetylcholine-induced responses. Bronchoconstriction was also elicited in anaesthetised guinea-pigs by intravenous acetaldehyde (5% in saline, 1 ml/kg). This effect, which is paralleled by a rise in blood histamine concentrations, was significantly attenuated by inhaled nimesulide (0.1% to 1%), but not by indomethacin (1%). These data, which further support the antihistaminic and antiallergic activity of nimesulide, may have therapeutic relevance in patients who are affected by inflammation of the respiratory tract and who also have a history of allergic bronchoconstriction.

The antianaphylactic activity of inhaled frusemide was studied in ovalbumin-sensitized guinea-pigs. The exposure of the animals to frusemide aerosol (1% solution for 20 min) attenuated the respiratory response to ovalbumin challenge (aerosol 1% solution) and was associated with a significant reduction of blood histamine (70%; P less than 0.01) and thromboxane-B2 (35%; P less than 0.01) compared to control animals. Similar results were obtained in isolated lungs perfused via the trachea excised from ovalbumin-sensitized guinea-pigs exposed to frusemide aerosol (1% solution for 20 min). In this series of experiments frusemide significantly prevented the increase in tracheal perfusion pressure (45%; P less than 0.01) and the concomitant release into the pulmonary effluent of both histamine (75%; P less than 0.01) and thromboxane-B2 (39%; P less than 0.01). In another series of experiments, frusemide (1 x 10(-4) M) significantly reduced the immune release of histamine from mast cells of ovalbumin-sensitized rats. The inhibitory activity of frusemide was in the same range of potency (66%; P less than 0.01) as that of disodium cromoglycate (1 x 10(-4) M). These data taken together indicate that frusemide when given by inhalation prevents histamine release secondary to antigen-antibody reaction.

Nimesulide (4-nitro-2-phenoxymethane sulfonanilide, Aulin, Mesulid) is a non-steroidal anti-inflammatory compound which shows antihistaminic activity and inhibits the immune release of histamine. The antihistaminic activity of this compound is specific for H1-receptor and has been demonstrated on isolated strips of guinea-pig trachea and on histamine-induced multiphasic inotropic response in left atria of guinea pig electrically driven. The effect of nimesulide is of non competitive type and, at the concentration of 1 x 10(-5) mol/l, is nearly 2 time less potent than pyrilamine (mepyramine) at 1 x 10(-6) mol/l. Nimesulide (1.6 mumol/kg i.v.) inhibits both bronchoconstriction (69%) and TXB2 formation (93%) induced by histamine (0.05 mumol/kg i.v.) in anaesthetized guinea-pigs. In contrast indomethacin (1.6 mumol/kg i.v.) decreases the generation of TXB2 (89%) without affecting the enhancement in tracheal insufflation pressure induced by histamine. In actively sensitized guinea-pigs both nimesulide and indomethacin protect the animals from deadly anaphylactic crisis. The rise in tracheal pressure induced by the antigenic challenge is inhibited of 80% and 63% respectively by nimesulide and indomethacin (6.4 mumol/kg i.v.). At this dose the two compounds reduced of 90% approximately the immunological release of TXB2 in the circulation. The release of histamine, induced by the anaphylactic reaction caused in perfused lungs obtained from actively sensitized guinea-pigs, is lessened by nimesulide (EC50 = 3.06; fid. lim. 2.59-3.63 mumol/l) and potentiated by indomethacin (EC50 = 0.89; fid. lim. 0.67-1.17 mumol/l).(ABSTRACT TRUNCATED AT 250 WORDS)