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Objective: The P3 is an event-related response observed in relation to task-relevant sensory events. Despite its ubiquitous presence, the neural generators of the P3 are controversial and not well identified., Methods: We compared source analysis of combined magneto- and electroencephalography (M/EEG) data with functional magnetic resonance imaging (fMRI) and simulation studies to better understand the sources of the P3 in an auditory oddball paradigm., Results: Our results suggest that the dominant source of the classical, postero-central P3 lies in the retro-splenial cortex of the ventral cingulate gyrus. A second P3 source in the anterior insular cortex contributes little to the postero-central maximum. Multiple other sources in the auditory, somatosensory, and anterior midcingulate cortex are active in an overlapping time window but can be functionally dissociated based on their activation time courses., Conclusion: The retro-splenial cortex is a dominant source of the parietal P3 maximum in EEG., Significance: These results provide a new perspective for the interpretation of the extensive research based on the P3 response., Competing Interests: Declaration of interest: None of the authors have potential conflicts of interest to be disclosed.

The objectives of this study were to investigate the long-term associations between changes in physical activity levels and hippocampal volumes over time, while considering the influence of age, sex, and APOE-ε4 genotype. We investigated the effects of change in physical activity on hippocampal volumes in 411 middle age (mean age = 47.2 years) and 375 older age (mean age = 63.1 years) adults followed up to 12 years. An annual volume decrease was observed in the left (middle age: 0.46%; older age: 0.51%) but not in the right hippocampus. Each additional 10 metabolic equivalents (METs, ~2 h of moderate exercise) increase in weekly physical activity was associated with 0.33% larger hippocampal volume in middle age (equivalent to ~1 year of typical aging). In older age, each additional MET was associated with 0.05% larger hippocampal volume; however, the effects declined with time by 0.005% per year. For older age APOE-ε4 carriers, each additional MET was associated with a 0.10% increase in hippocampal volume. No sex effects of physical activity change were found. Increasing physical activity has long-term positive effects on hippocampal volumes and appears especially beneficial for older APOE-ε4 carriers. To optimize healthy brain aging, physical activity programs should focus on creating long-term exercise habits., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Terbinafine is a commonly used antifungal medication. Its side effects, while widely known, are rarely described and can be missed by the medical community. We present a 55-year-old woman who visited her primary care physician with onychomycosis. She started treatment with terbinafine, and 1 week later developed a rash in the left flank that extended to the chest, back, and upper part of lower extremities. Laboratory results showed elevated liver enzymes. A treatment with steroids did not improve the rash and she was admitted to our institution. She was started with intravenous dexamethasone, topical hydrocortisone and triamcinolone. Seven days later the liver enzymes normalised, and the rash resolved on the chest and back. Our patient had concurrent acute generalised exanthematous pustulosis and hepatitis that together has been very rarely associated with terbinafine., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Squamous cell carcinoma (SCC) of the lip typically has a good prognosis when diagnosed at an early stage and treated properly. We present a 65-year-old man with a 3-month history of an ulcerative lesion of the lower lip. On physical examination, he had an ulceration of approximately 5×5 cm in the mucosa of the lower lip, extending through 50% of the lip, and multiple mandibular and neck lymph nodes. The biopsy confirmed SCC of the lip. Surgical treatment was recommended, but the patient was lost to follow-up. The patient eventually returned to the hospital for medical treatment. However, the physical examination, and the images obtained showed progression of the disease. Chemotherapy was started with improvement in the primary site, but he then developed a large submental mass compatible with SCC. The tumour was considered incurable at that time. Palliative radiation therapy was offered; however, he refused any further procedures or treatment., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Structural differences associated with depression have not been confirmed in brain regions apart from the hippocampus. Comorbid anxiety has been inconsistently assessed, and may explain discrepancies in previous findings. We investigated the link between depression, comorbid anxiety and brain structure., Methods: We followed Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) guidelines (PROSPERO CRD42018089286). We searched the Cochrane Library, MEDLINE, PsycInfo, PubMed and Scopus, from database inception to Sept. 13, 2018, for MRI case-control studies that reported brain volumes in healthy adults and adults with clinical depression. We summarized mean volumetric differences using meta-analyses, and we assessed demographics, depression factors and segmentation procedure as moderators using meta-regressions., Results: We included 112 studies in the meta-analyses, assessing 4911 healthy participants and 5934 participants with depression (mean age 49.8 yr, 68.2% female). Volume effects were greater in late-onset depression and in multiple episodes of depression. Adults with depression and no comorbidity showed significantly lower volumes in the putamen, pallidum and thalamus, as well as significantly lower grey matter volume and intracranial volume; the largest effects were in the hippocampus (6.8%, p < 0.001). Adults with depression and comorbid anxiety showed significantly higher volumes in the amygdala (3.6%, p < 0.001). Comorbid anxiety lowered depression effects by 3% on average. Sex moderated reductions in intracranial volume., Limitations: High heterogeneity in hippocampus effects could not be accounted for by any moderator. Data on symptom severity and medication were sparse, but other factors likely made significant contributions., Conclusion: Depression-related differences in brain structure were modulated by comorbid anxiety, chronicity of symptoms and onset of illness. Early diagnosis of anxiety symptomatology will prove crucial to ensuring effective, tailored treatments for improving long-term mental health and mitigating cognitive problems, given the effects in the hippocampus., Competing Interests: None declared., (© 2020 Joule Inc. or its licensors.)

Background: Epidemiological studies suggest physical activity (PA) can slow or prevent both cognitive decline and age-related atrophy in frontal and hippocampal gray matter volumes. However, much of this evidence is based on self-reported measures of PA., Methods: PA was measured objectively with a SenseWear™ Armband to examine the cross-sectional associations between the duration of light, moderate and vigorous intensity PA with gray matter volume in the dorsolateral prefrontal cortex (DLPFC) and hippocampus in 167 (female: 43%) cognitively healthy older adults aged 73 to 78., Results: The duration of objective moderate to vigorous intensity physical activity (MVPA) was associated with a greater volume of the right DLPFC (β ​= ​0.16; p ​= ​0.04). In addition, objective moderate-intensity PA alone was also associated with greater volume of the left (β ​= ​0.17; p ​= ​0.03) and right (β ​= ​0.19; p ​= ​0.01) DLPFC after controlling for covariates and adjustment for multiple comparisons. In contrast, there were no significant associations between light- or vigorous-intensity PA and gray matter volumes (all p ​> ​0.05). No associations between PA and cognitive performance were detected, and self-reported PA was not associated with any of the outcomes investigated., Conclusions: These findings suggest that an intensity-dependent relationship may exist, whereby a greater duration of MVPA, perhaps driven by moderate-intensity PA, is associated with preserved gray matter volume in frontal regions of the brain. Future research should investigate the mechanisms of this dose-effect and determine whether greater brain volumes associated with objective PA convey protective effects against cognitive decline., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: High BMI at midlife is associated with increased risk of dementia as well as faster decline in cognitive function. In late-life, however, high BMI has been found to be associated with both increased and decreased dementia risk. The objective of this study was to investigate the neural substrates of this age-related change in body mass index (BMI) risk., Methods: We measured longitudinal cortical thinning over the whole brain, based on magnetic resonance imaging scans for 910 individuals aged 44-66 years at baseline. Subjects were sampled from a large population study (PATH, Personality and Total Health through Life). After attrition and exclusions, the final analysis was based on 792 individuals, including 387 individuals aged 60-66 years and 405 individuals aged 44-49 years. A mixed-effects model was used to test the association between cortical thinning and baseline BMI, as well as percentage change in BMI., Results: Increasing BMI was associated with increased cortical thinning in posterior cingulate at midlife (0.014 mm kg -1  m -2 , confidence interval; CI=0.005, 0.023, P<0.05 false discovery rate (FDR) corrected). In late-life, increasing BMI was associated with reduced cortical thickness, most prominently in the right supramarginal cortex (0.010 mm kg -1  m -2 , CI=0.005-0.016, P<0.05 FDR corrected), as well as frontal regions. In late-life, decreasing BMI was also associated with increased cortical thinning, including right caudal middle frontal cortex (0.014 mm kg -1  m -2 (CI=0.006-0.023, P<0.05 FDR corrected)., Conclusions: The pattern of cortical thinning-in association with increasing BMI at both midlife and late-life-is consistent with known obesity-related dementia risk. Increased cortical thinning in association with decreasing BMI at late-life may help explain the 'obesity paradox', where high BMI in midlife appears to be a risk factor for dementia, but high BMI in late-life appears, at times, to be protective.

Background: While acceleration in age-related cerebral atrophy has been well documented in Alzheimer's disease, the cerebellar contributions to this effect have not been thoroughly investigated., Objective: This study investigated cerebellar volume and atrophy rate using magnetic resonance imaging in individuals with normal cognition (CN), mild cognitive impairment (MCI), and Alzheimer's disease (AD)., Methods: Two hundred twenty-nine CN, 398 MCI and 191 AD participants of stage I ADNI database with screening scans were evaluated for cerebellar volume. Of those, 758 individuals with two or more follow-up scans were categorized into stable, converted, and reverted CN, MCI and AD and evaluated for cerebellar atrophy rate., Results: Cerebellar volume was 2.5% larger in CN than in those with AD but there were no differences between CN and MCI and MCI and AD in cross-sectional analysis. Similarly, the atrophy rate was 49% larger in AD and 64% larger in MCI who converted to AD but no difference was detected between CN and MCI. There were no association between education and APOEe4 and cerebellar volume or cerebellar atrophy across the diagnostic groups., Conclusion: Cerebellar atrophy contributes to Alzheimer's clinical progression but mostly at the late stage of the disease. However, even in the late stage shrinkage rate is less than the average of the shrinkage in the cerebrum and is not associated with AD moderators. This suggests that cerebellar involvement is secondary to cerebral involvement and can be due to network connection spread regardless of the primary pathology. Hum Brain Mapp, 2017. © 2017 Wiley Periodicals, Inc. Hum Brain Mapp 38:3141-3150, 2017. © 2017 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc. Hum Brain Mapp 38:3141-3150, 2017. © 2017 Wiley Periodicals, Inc., (© 2017 Wiley Periodicals, Inc.)

Introduction: Although mild cognitive impairment (MCI) diagnosis is mainly based on cognitive assessment, reliable estimates of structural changes in specific brain regions, that could be contrasted against normal brain aging and inform diagnosis, are lacking. This study aimed to systematically review the literature reporting on MCI-related brain changes., Methods: The MEDLINE database was searched for studies investigating longitudinal structural changes in MCI. Studies with compatible data were included in the meta-analyses. A qualitative review was conducted for studies excluded from meta-analyses., Results: The analyses revealed a 2.2-fold higher volume loss in the hippocampus, 1.8-fold in the whole brain, and 1.5-fold in the entorhinal cortex in MCI participants., Discussion: Although the medial temporal lobe is likely to be more vulnerable to MCI pathology, atrophy in this brain area represents a relatively small proportion of whole brain loss, suggesting that future investigations are needed to identify the source of unaccounted volume loss in MCI.

The Muller F element (4.2 Mb, ~80 protein-coding genes) is an unusual autosome of Drosophila melanogaster; it is mostly heterochromatic with a low recombination rate. To investigate how these properties impact the evolution of repeats and genes, we manually improved the sequence and annotated the genes on the D. erecta, D. mojavensis, and D. grimshawi F elements and euchromatic domains from the Muller D element. We find that F elements have greater transposon density (25-50%) than euchromatic reference regions (3-11%). Among the F elements, D. grimshawi has the lowest transposon density (particularly DINE-1: 2% vs. 11-27%). F element genes have larger coding spans, more coding exons, larger introns, and lower codon bias. Comparison of the Effective Number of Codons with the Codon Adaptation Index shows that, in contrast to the other species, codon bias in D. grimshawi F element genes can be attributed primarily to selection instead of mutational biases, suggesting that density and types of transposons affect the degree of local heterochromatin formation. F element genes have lower estimated DNA melting temperatures than D element genes, potentially facilitating transcription through heterochromatin. Most F element genes (~90%) have remained on that element, but the F element has smaller syntenic blocks than genome averages (3.4-3.6 vs. 8.4-8.8 genes per block), indicating greater rates of inversion despite lower rates of recombination. Overall, the F element has maintained characteristics that are distinct from other autosomes in the Drosophila lineage, illuminating the constraints imposed by a heterochromatic milieu., (Copyright © 2015 Leung et al.)

The default network exhibits correlated activity at rest and has shown decreased activation during performance of cognitive tasks. There has been little investigation of changes in connectivity of this network during task performance. In this study, we examined task-related modulation of connectivity between two seed regions from the default network posterior cingulated cortex (PCC) and medial prefrontal cortex (mPFC) and the rest of the brain in 12 healthy adults. The purpose was to determine (1) whether connectivity within the default network differs between a resting state and performance of a cognitive (working memory) task and (2) whether connectivity differs between these nodes of the default network and other brain regions, particularly those implicated in cognitive tasks. There was little change in connectivity with the other main areas of the default network for either seed region, but moderate task-related changes in connectivity occurred between seed regions and regions outside the default network. For example, connectivity of the mPFC with the right insula and the right superior frontal gyrus decreased during task performance. Increased connectivity during the working memory task occurred between the PCC and bilateral inferior frontal gyri, and between the mPFC and the left inferior frontal gyrus, cuneus, superior parietal lobule, middle temporal gyrus and cerebellum. Overall, the areas showing greater correlation with the default network seed regions during task than at rest have been previously implicated in working memory tasks. These changes may reflect a decrease in the negative correlations occurring between the default and task-positive networks at rest., (Copyright © 2010 Wiley-Liss, Inc.)

Unlabelled: Working memory processing and resting-state connectivity in the default mode network are altered in patients with posttraumatic stress disorder (PTSD). Because the ability to effortlessly switch between concentration on a task and an idling state during rest is implicated in both these alterations, we undertook a functional magnetic resonance imaging study with a block design to analyze task-induced modulations in connectivity., Methods: We performed a working memory task and psychophysiologic interaction analyses with the posterior cingulate cortex and the medial prefrontal cortex as seed regions during fixation in 12 patients with severe, chronic PTSD and 12 healthy controls., Results: During the working memory task, the control group showed significantly stronger connectivity with areas implicated in the salience and executive networks, including the right inferior frontal gyrus and the right inferior parietal lobule. The PTSD group showed stronger connectivity with areas implicated in the default mode network, namely enhanced connectivity between the posterior cingulate cortex and the right superior frontal gyrus and between the medial prefrontal cortex and the left parahippocampal gyrus., Limitations: Because we were studying alterations in patients with severe, chronic PTSD, we could not exclude patients taking medication. The small sample size may have limited the power of our analyses. To avoid multiple testing in a small sample, we only used 2 seed regions for our analyses., Conclusion: The different patterns of connectivity imply significant group differences with task-induced switches (i.e., engaging and disengaging the default mode network and the central-executive network).

The complete nucleotide sequences of the two plasmids from the phytoplasma beet leafhopper-transmitted virescence agent (BLTVA) have been determined. The larger plasmid, pBLTVA-1, was 10 785 nt in length and contained 11 putative ORFs, almost all of which were duplicated or triplicated on the plasmid due to the presence of large repeated regions. The sequence contained a series of tandem repeats, the largest of which was 338 nt long. The sequences of ORFs 4 and 11 showed homology with the replication genes of plasmids from other phytoplasmas and from geminiviruses. ORF9, the only ORF present as a single copy, showed homology with DNA primase genes from bacterial chromosomes and contained the conserved zinc finger and topoisomerase/primase domains. None of the other eight ORFs showed homology with known sequences in the GenBank database. pBLTVA-2 was 2587 nt in length, and all of its sequence was nearly identical to sequences from pBLTVA-1, most of which spanned ORFs 10 and 11, including the 338 nt tandem repeat. Analysis of 30 strains of BLTVA showed that most of the 11 putative ORFs were present, but the size of the plasmids varied in these strains.

To identify common regions of deletion in human bladder tumors, we have screened 83 cases of transitional cell carcinoma for loss of heterozygosity (LOH) on all autosomal chromosome arms. Seventy-two restriction fragment length polymorphism, variable number of tandem repeats, and minisatellite markers and 18 microsatellite markers were used to obtain a minimum of 50% informative results for each chromosome arm. A mean of 29.6 informative results per patient was obtained from 39 chromosome arms studied, representing information for 76% of chromosome arms. The most frequent losses were apparent monosomies of chromosome 9 (9p, 51%; 9q, 57%). Other frequent losses were on chromosomes 11p (32%), 17p (32%), 8p (23%), 4p (22%), and 13q (15%). LOH of 4p has not been reported previously in bladder carcinoma. The frequency of LOH on all other chromosome arms was < 12%. LOH on chromosome 8p showed a significant association with both high tumor grade and stage, and LOH on 13q showed a significant association with high tumor grade. Fractional allelic loss was calculated for all tumors and had a mean of 0.125 and a median of 0.110. A significant association was found between increased fractional allelic loss and higher tumor grade. An association was also found between LOH of chromosomes 8p and 9q and values for fractional allelic loss > or = the median value. No associations were found between LOH on different pairs of chromosome arms.

Inactivation of a suppressor gene by deletion of chromosome 9 is a candidate initiating event in bladder carcinogenesis. We have used 13 polymorphic markers spanning the length of chromosome 9 in order to map the region of deletion in human bladder carcinomas. In the majority of tumors loss of heterozygosity was found at all informative sites along the chromosome, indicating deletion of the entire chromosome. Nine tumors had selective deletions of chromosome 9. Mapping of the deleted region in these tumors suggests that the target gene is located between D9S22 at 9q22 and D9S18 at 9p12-13.

The oxytocin-sensitive myoepithelial cells of the mammary gland form a system with characteristics of a potentially useful model for studying the mechanism of action of oxytocin and coupling phenomena of excitation-contraction. Our objectives were to develop a method for isolating mammary actomyosin, to determine the amount of actomyosin in the glands of lactating and nonlactating animals, and to investigate control of contractile protein interaction. Actomyosin in mammary glands represented a substantial portion of the soluble protein in the gland ranging from 9% of the total in lactating to 17% in weaned rats. The isolated actomyosin had a molecular composition like that of actomyosin of smooth muscle and the isolated actomyosin contained a light chain kinase that phosphorylated the 20,000 dalton light chain of myosin (L20). The kinase isolated as a component of actomyosin preparations did not show calcium control, but it did when isolated from mammary cytosol. Strips of involuted mammary tissue from rats developed tension when oxytocin was added to the bathing medium; thus, the myoepithelial cells appeared to retain their sensitivity to oxytocin even in nonlactating animals and may be a useful model for studying the action of oxytocin. We suggest that one of the final steps in the milk-ejection reflex is phosphorylation of myosin causing a contraction of the myoepithelial cells of the mammary gland.

This study analyzed the effects of nitrogen dioxide (NO2) on alveolar epithelial permeability and transport properties. Primary cultured monolayers of rat Type II pneumocytes, cultured on both nonporous and porous surfaces, were used as models of isolated alveolar epithelium for in vitro exposure to nitrogen dioxide. The effects of nitrogen dioxide exposure for monolayers cultured on nonporous substrata were monitored by observing the changes in the net volume of fluid under the monolayer; for cells cultured on porous substrata, alterations in tissue bioelectric properties were noted. As a first step, primary cultured monolayers of rat Type II pneumocytes plated on nonporous plastic Petri dishes were used to investigate the effects of nitrogen dioxide on alveolar epithelial barrier properties. Such monolayers form fluid filled domes that are thought to result from active solute transport from medium to substratum, with water following passively. We used dome formation as a transport marker. Five-day-old cultures were directly exposed to 30 ppm NO2 in 5 percent CO2 in air at 25 degrees C, by cyclically tilting culture plates from side to side, so that both halves of the monolayer were exposed during each cycle. Exposures consisted of 10 cycles of four minutes each (two minutes per side), for a cell exposure time of 20 minutes. Control plates were simultaneously exposed to 5 percent CO2 in air under identical conditions. One day after the exposure, nitrogen dioxide-exposed monolayers exhibited significant decreases in dome density and individual dome volume, compared to the controls. By 48 hours post-exposure, differences between nitrogen dioxide-exposed and control monolayers were less, but remained significant. These results showed that short-term sublethal exposures to nitrogen dioxide produce a decrease in dome formation in Type II alveolar epithelial cell monolayers. This finding is most likely due to a decrease in the active transepithelial sodium transport rate, or an increase in the permeability of cell membranes or tight junctions, or both. Addition of vitamin E-containing liposomes to the culture media 24 hours pre-exposure did not affect the nitrogen dioxide-induced decrease in dome formation, indicating that under these circumstances no protective effect was provided by the antioxidant.(ABSTRACT TRUNCATED AT 400 WORDS)

Primary cultured monolayers of rat Type II pneumocytes were used to investigate the effects of NO2 on alveolar epithelial barrier properties. Such monlayers form fluid-filled domes which are thought to result from active solute transport from medium to substratum, with water following passively. Using dome formation as a transport marker, 5-day-old cultures were directly exposed to 30 ppm NO2 in 5% CO2/air at 25 degrees C by cyclically tilting culture plates from side to side such that both halves of the monolayer were exposed during each cycle. Exposures consisted of 10 cycles of 4 min each (2 min per side), for a cell exposure time of 20 min. Control plates were simultaneously exposed to 5% CO2/air under identical conditions. Twenty-four hours after exposure, NO2-exposed monolayers exhibited significant decreases in dome density and individual dome volume as compared to controls. By 48 hr postexposure, differences between NO2-exposed and control values were less but remained significant. Control monolayers were essentially unaffected by exposure to 5% CO2/air. These results show that short-term sublethal exposures to NO2 produce a decrease in dome formation in Type II alveolar epithelial cell monolayers. This finding is most likely due to a decrease in the active transepithelial sodium transport rate and/or an increase in the permeability of cell membranes or tight junctions.