Network analysis of impulse dyscontrol in mild cognitive impairment and subjective cognitive decline.

OBJECTIVES: To investigate conditional dependence relationships of impulse dyscontrol symptoms in mild cognitive impairment (MCI) and subjective cognitive decline (SCD). DESIGN: A prospective, observational study. PARTICIPANTS: Two hundred and thirty-five patients with MCI (n = 159) or SCD (n = 76) from the Prospective Study for Persons with Memory Symptoms dataset. MEASUREMENTS: Items of the Mild Behavioral Impairment Checklist impulse dyscontrol subscale. RESULTS: Stubbornness/rigidity, agitation/aggressiveness, and argumentativeness were frequent and the most central symptoms in the network. Impulsivity, the fourth most central symptom in the network, served as the bridge between these common symptoms and less central and rare symptoms. CONCLUSIONS: Impulse dyscontrol in at-risk states for dementia is characterized by closely connected symptoms of irritability, agitation, and rigidity. Compulsions and difficulties in regulating rewarding behaviors are relatively isolated symptoms.

Network Meta-Analysis Techniques for Synthesizing Prevention Science Evidence.

Network meta-analysis is a popular statistical technique for synthesizing evidence from studies comparing multiple interventions. Benefits of network meta-analysis, over more traditional pairwise meta-analysis approaches, include evaluating efficacy/safety of interventions within a single framework, increased precision, comparing pairs of interventions that have never been directly compared in a trial, and providing a hierarchy of interventions in terms of their effectiveness. Network meta-analysis is relatively underutilized in prevention science. This paper therefore presents a primer of network meta-analysis for prevention scientists who wish to apply this method or to critically appraise evidence from publications using the method. We introduce the key concepts and assumptions of network meta-analysis, namely, transitivity and consistency, and demonstrate their applicability to the field of prevention science. We then illustrate the method using a network meta-analysis examining the comparative effectiveness of brief alcohol interventions for preventing hazardous drinking among college students. We provide data and code for all examples. Finally, we discuss considerations that are particularly relevant in network meta-analyses in the field of prevention, such as including non-randomized evidence.

Statin treatment and accrual of covert cerebral ischaemia on neuroimaging: a systematic review and meta-analysis of randomized trials.

BACKGROUND AND PURPOSE: Prevention of ischaemic stroke and cardiovascular events is an established benefit of statin therapy, but the effects of statin treatment on the accrual of magnetic resonance imaging (MRI) markers of ischaemic cerebral injury remain unknown. A systematic review was performed to identify all studies that randomized patients with cardiovascular risk factors to statin treatment and assessed the effect of statin treatment on covert infarcts (asymptomatic, evident only on neuroimaging) and white matter hyperintensity (WMH) accrual on MRI. METHODS: A systematic review in MEDLINE and Scopus from inception to 23 October 2019 was performed. A random-effects model was used to calculate the pooled estimates of the crude risk ratios and standardized mean differences. RESULTS: Data from three randomized controlled trials (1430 participants) were included evaluating the effect of rosuvastatin (10 mg/day) in 668 hypertensive patients older than 60 years of age over 5 years, pravastatin (40 mg/day) in 554 elderly people more than 70 years of age over 3 years and simvastatin (20 mg/day) in 208 patients with asymptomatic middle cerebral artery stenosis over 2 years. Patients randomized to statin treatment had decreased accrual of new covert infarcts (risk ratio 0.63, 95% confidence interval 0.46-0.88) during a mean follow-up of 2-6 years. Only one study reported WMH decreased volume change in patients randomized to statin treatment compared to patients randomized to non-statin treatment (standardized mean difference -1.17; 95% confidence interval -1.33, -1.00). CONCLUSION: Our findings suggest that, in addition to stroke prevention, statin treatment can reduce the accrual of covert MRI markers of ischaemic cerebral injury.

Brain Mechanisms of Social Threat Effects on Working Memory.

Social threat can have adverse effects on cognitive performance, but the brain mechanisms underlying its effects are poorly understood. We investigated the effects of social evaluative threat on working memory (WM), a core component of many important cognitive capabilities. Social threat impaired WM performance during an N-back task and produced widespread reductions in activation in lateral prefrontal cortex and intraparietal sulcus (IPS), among other regions. In addition, activity in frontal and parietal regions predicted WM performance, and mediation analyses identified regions in the bilateral IPS that mediated the performance-impairing effects of social threat. Social threat also decreased connectivity between the IPS and dorsolateral prefrontal cortex, while increasing connectivity between the IPS and the ventromedial prefrontal cortex, a region strongly implicated in the generation of autonomic and emotional responses. Finally, cortisol response to the stressor did not mediate WM impairment but was rather associated with protective effects. These results provide a basis for understanding interactions between social and cognitive processes at a neural systems level.

Sex Moderates the Association between Frailty and Mild Behavioral Impairment.

BACKGROUND: Frailty has been associated with cognitive markers of dementia but its relationship with behavioral markers of dementia are poorly understood. OBJECTIVES: To investigate the association between frailty and mild behavioral impairment (MBI), and whether this association is moderated by sex. DESIGN: Cross-sectional observational study. PARTICIPANTS/SETTING: 219 non-dementia participants (cognitively normal and mild cognitive impairment) from the Comprehensive Assessment of Neurodegeneration and Dementia (COMPASS-ND) study. MEASUREMENTS: Frailty was measured using the frailty index (FI) with higher scores indicating more health deficits/greater frailty. MBI symptoms were derived from Neuropsychiatric Inventory Questionnaire scores using a published algorithm with a cut-off of >0 indicating MBI symptom presence and higher scores indicating greater severity. Multivariable logistic and linear regressions adjusted for age, sex, education, and cognitive diagnosis were used to test the association between FI and MBI symptom presence and severity, respectively, with MBI as the outcome variable. An FI-by-sex interaction term was included to test for sex-dependent effects. RESULTS: The FI mean and SD across the entire cohort was 0.14 ± 0.06 (median = 0.14, IQR = 0.09-0.17, range = 0.02-0.38). Higher FI scores were associated with the presence of MBI symptoms both globally and in the domains of decreased motivation, affective dysregulation, and psychosis. Higher FI scores were also associated with more severe MBI symptoms in a sex-dependent manner: both sexes reported similarly low MBI symptom severity at low (-1 SD) levels of FI but males reported 1.9x higher MBI symptom severity relative to females at high (+1 SD) levels of FI. CONCLUSIONS: The FI is associated with both the presence and severity of MBI, especially for males. This suggests that screening for early dementia risk should incorporate assessments of MBI for patients with frailty, and assessments of frailty for patients with MBI.

"If it helps someone, then I want to do it": Perspectives of persons living with dementia on research registry participation.

Registries are an important platform to which persons with dementia and other cognitive impairments can contribute to research studies. Registries also provide an opportunity for patients to stay informed about current studies. Engaging patients in registry development can increase sustainability of a registry and patient retention in clinical registries. We sought the perspective of persons with dementia and their accompanying family members about their registry participation experiences, barriers and facilitators to participation, and potential avenues for improvement of registry processes such as recruitment, data collection, and knowledge translation. Two semi-structured focus groups with persons with dementia and their family members (n = 18) were conducted and analyzed using thematic content analysis. Participants were recruited from an existing patient registry made up of patients currently being seen in a dementia assessment clinic. The main themes identified included altruistic motives with regards to registry participation; and access to and privacy of personal health information. As electronic health records are becoming more common, understanding barriers and facilitators from the perspectives of people with dementia is essential to inform the future development of cognitive condition-related registries. The results from our focus groups identified engagement strategies and solutions to overcome perceived barriers for individuals experiencing progressive cognitive decline to participate in longitudinal registry projects.

Storage and executive processes in the frontal lobes.

The human frontal cortex helps mediate working memory, a system that is used for temporary storage and manipulation of information and that is involved in many higher cognitive functions. Working memory includes two components: short-term storage (on the order of seconds) and executive processes that operate on the contents of storage. Recently, these two components have been investigated in functional neuroimaging studies. Studies of storage indicate that different frontal regions are activated for different kinds of information: storage for verbal materials activates Broca's area and left-hemisphere supplementary and premotor areas; storage of spatial information activates the right-hemisphere premotor cortex; and storage of object information activates other areas of the prefrontal cortex. Two of the fundamental executive processes are selective attention and task management. Both processes activate the anterior cingulate and dorsolateral prefrontal cortex.

Starch-gel electrophoresis of human tissue enzymes which hydrolyze L-leucyl-beta-naphthylamide.

Electrophoretically distinct formls of the enzyme or enzymes which catalyze the hydrolysis of L-leucyl-beta-naphthylamide were demonstrated in various human tissues. There were characteristic patterns for different tissues. Unlike the enzymes found in normnal serum, some tissue-specific enzymes were unaffected or activated L-methionine.

Genetic adaptation of Pseudomonas aeruginosa to the airways of cystic fibrosis patients is catalyzed by hypermutation.

In previous work (E. E. Smith, D. G. Buckley, Z. Wu, C. Saenphimmachack, L. R. Hoffman, D. A. D'Argenio, S. I. Miller, B. W. Ramsey, D. P. Speert, S. M. Moskowitz, J. L. Burns, R. Kaul, and M. V. Olson, Proc. Natl. Acad. Sci. USA 103:8487-8492, 2006) it was shown that Pseudomonas aeruginosa undergoes intense genetic adaptation during chronic respiratory infection (CRI) in cystic fibrosis (CF) patients. We used the same collection of isolates to explore the role of hypermutation in this process, since one of the hallmarks of CRI is the high prevalence of DNA mismatch repair (MMR) system-deficient mutator strains. The presence of mutations in 34 genes (many of them positively linked to adaptation in CF patients) in the study collection of 90 P. aeruginosa isolates obtained longitudinally from 29 CF patients was not homogeneous; on the contrary, mutations were significantly concentrated in the mutator lineages, which represented 17% of the isolates (87% MMR deficient). While sequential nonmutator lineages acquired a median of only 0.25 mutation per year of infection, mutator lineages accumulated more than 3 mutations per year. On the whole-genome scale, data for the first fully sequenced late CF isolate, which was also shown to be an MMR-deficient mutator, also support these findings. Moreover, for the first time the predicted amplification of mutator populations due to hitchhiking with adaptive mutations in the course of natural human infections is clearly documented. Interestingly, increased accumulation of mutations in mutator lineages was not a consequence of overrepresentation of mutations in genes involved in antimicrobial resistance, the only adaptive trait linked so far to hypermutation in CF patients, demonstrating that hypermutation also plays a major role in P. aeruginosa genome evolution and adaptation during CRI.

Bioengineered Tooth Buds Exhibit Features of Natural Tooth Buds.

Tooth loss is a significant health issue currently affecting millions of people worldwide. Artificial dental implants, the current gold standard tooth replacement therapy, do not exhibit many properties of natural teeth and can be associated with complications leading to implant failure. Here we propose bioengineered tooth buds as a superior alternative tooth replacement therapy. We describe improved methods to create highly cellularized bioengineered tooth bud constructs that formed hallmark features that resemble natural tooth buds such as the dental epithelial stem cell niche, enamel knot signaling centers, transient amplifying cells, and mineralized dental tissue formation. These constructs were composed of postnatal dental cells encapsulated within a hydrogel material that were implanted subcutaneously into immunocompromised rats. To our knowledge, this is the first report describing the use of postnatal dental cells to create bioengineered tooth buds that exhibit evidence of these features of natural tooth development. We propose future bioengineered tooth buds as a promising, clinically relevant tooth replacement therapy.

Canadian Stroke Best Practice Recommendations for Acute Stroke Management: Prehospital, Emergency Department, and Acute Inpatient Stroke Care, 6th Edition, Update 2018.

The 2018 update of the Canadian Stroke Best Practice Recommendations for Acute Stroke Management, 6th edition, is a comprehensive summary of current evidence-based recommendations, appropriate for use by healthcare providers and system planners caring for persons with very recent symptoms of acute stroke or transient ischemic attack. The recommendations are intended for use by a interdisciplinary team of clinicians across a wide range of settings and highlight key elements involved in prehospital and Emergency Department care, acute treatments for ischemic stroke, and acute inpatient care. The most notable changes included in this 6th edition are the renaming of the module and its integration of the formerly separate modules on prehospital and emergency care and acute inpatient stroke care. The new module, Acute Stroke Management: Prehospital, Emergency Department, and Acute Inpatient Stroke Care is now a single, comprehensive module addressing the most important aspects of acute stroke care delivery. Other notable changes include the removal of two sections related to the emergency management of intracerebral hemorrhage and subarachnoid hemorrhage. These topics are covered in a new, dedicated module, to be released later this year. The most significant recommendation updates are for neuroimaging; the extension of the time window for endovascular thrombectomy treatment out to 24 h; considerations for treating a highly selected group of people with stroke of unknown time of onset; and recommendations for dual antiplatelet therapy for a limited duration after acute minor ischemic stroke and transient ischemic attack. This module also emphasizes the need for increased public and healthcare provider's recognition of the signs of stroke and immediate actions to take; the important expanding role of paramedics and all emergency medical services personnel; arriving at a stroke-enabled Emergency Department without delay; and launching local healthcare institution code stroke protocols. Revisions have also been made to the recommendations for the triage and assessment of risk of recurrent stroke after transient ischemic attack/minor stroke and suggested urgency levels for investigations and initiation of management strategies. The goal of this updated guideline is to optimize stroke care across Canada, by reducing practice variations and reducing the gap between current knowledge and clinical practice.

GelMA-Encapsulated hDPSCs and HUVECs for Dental Pulp Regeneration.

Pulpal revascularization is commonly used in the dental clinic to obtain apical closure of immature permanent teeth with thin dentinal walls. Although sometimes successful, stimulating bleeding from the periapical area of the tooth can be challenging and in turn may deleteriously affect tooth root maturation. Our objective here was to define reliable methods to regenerate pulp-like tissues in tooth root segments (RSs). G1 RSs were injected with human dental pulp stem cells (hDPSCs) and human umbilical vein endothelial cells (HUVECs) encapsulated in 5% gelatin methacrylate (GelMA) hydrogel. G2 RSs injected with acellular GelMA alone, and G3 empty RSs were used as controls. White mineral trioxide aggregate was used to seal one end of the tooth root segment, while the other was left open. Samples were cultured in vitro in osteogenic media (OM) for 13 d and then implanted subcutaneously in nude rats for 4 and 8 wk. At least 5 sample replicates were used for each experimental group. Analyses of harvested samples found that robust pulp-like tissues formed in G1, GelMA encapsulated hDPSC/HUVEC-filled RSs, and less cellularized host cell-derived pulp-like tissue was observed in the G2 acellular GelMA and G3 empty RS groups. Of importance, only the G1, hDPSC/HUVEC-encapsulated GelMA constructs formed pulp cells that attached to the inner dentin surface of the RS and infiltrated into the dentin tubules. Immunofluorescent (IF) histochemical analysis showed that GelMA supported hDPSC/HUVEC cell attachment and proliferation and also provided attachment for infiltrating host cells. Human cell-seeded GelMA hydrogels promoted the establishment of well-organized neovasculature formation. In contrast, acellular GelMA and empty RS constructs supported the formation of less organized host-derived vasculature formation. Together, these results identify GelMA hydrogel combined with hDPSC/HUVECs as a promising new clinically relevant pulpal revascularization treatment to regenerate human dental pulp tissues.

Working memory for order information: multiple cognitive and neural mechanisms.

Working memory for order information is mediated by different cognitive mechanisms that rely on different neural circuits. Here we discuss evidence that order memory involves mechanisms that range from general supervisory processes to process that maintenance fine-grained temporal position information. We suggest that neural regions-including the prefrontal cortex, motor cortex, parietal cortex and medial temporal structures-operate at different levels and processing stages to give rise to working memory for order information.

Working memory for order and the parietal cortex: an event-related functional magnetic resonance imaging study.

Memory for order information has been tied to the frontal lobes, however, parietal activation is observed in many functional neuroimaging studies. Here we report functional magnetic resonance findings from an event-related experiment involving working memory for order. Five letters were presented for storage, followed after a delay by two probe items. Probe items could be separated by zero to three positions in the memory set and subjects had to indicate whether the items were in the correct order. Analyses indicate that activation in left parietal cortex shows a systematic decrease in activation with increasing probe distance. This finding is consistent with an earlier study in which we suggested that parietal cortical regions mediate the representation of order information via magnitude codes.

Atrazine concentrations, gonadal gross morphology and histology in ranid frogs collected in Michigan agricultural areas.

The triazine herbicide atrazine has been suggested to be a potential disruptor of normal sexual development in male frogs. The goals of this study were to collect native ranid frogs from sites in agricultural and non-agricultural areas and determine whether hypothesised atrazine effects on the gonads could be observed at the gross morphological and histological levels. Juvenile and adult green frogs (Rana clamitans), bullfrogs (R. catesbeiana) and leopard frogs (R. pipiens) were collected in the summers of 2002 and 2003. Atrazine concentrations were below the limit of quantification at non-agricultural sites, and concentrations did not exceed 2 microg/L at most agricultural sites. One concentration greater than 200 microg atrazine/L was measured once at one site in 2002. Hermaphroditic individuals with both male and female gonad tissue in either one or both gonads, were found at a low incidence at both non-agricultural and agricultural sites, and in both adults and juveniles. Testicular oocytes (TO) were found in male frogs at most of the sites, with the greatest incidence occurring in juvenile leopard frogs. TO incidence was not significantly different between agricultural and non-agricultural sites with the exception of juveniles collected in 2003. Atrazine concentrations were not significantly correlated with the incidence of hermaphroditism, but maximum atrazine concentrations were correlated with TO incidence in juvenile frogs in 2003. However, given the lack of a consistent relationship between atrazine concentrations and TO incidence, it is more likely the TOs observed in this study result from natural processes in development rather than atrazine exposure.

Plasma steroid hormone concentrations, aromatase activities and GSI in ranid frogs collected from agricultural and non-agricultural sites in Michigan (USA).

The triazine herbicide atrazine has been hypothesized to disrupt sexual development in frogs by up-regulating aromatase activity, resulting in greater estradiol (E2) concentrations and causing feminization in males. The goal of this study was to collect native ranid frogs from atrazine-exposed ponds and determine whether relationships exist between measured atrazine concentrations and the gonadosomatic index (GSI), plasma concentrations of testosterone (T), E2 or 11-ketotestosterone (KT), or with aromatase activity. In the summer of 2002 and 2003, adult and juvenile green frogs (Rana clamitans), bullfrogs (R. catesbeiana) and Northern leopard frogs (R. pipiens) were collected from areas with extensive corn cultivation and areas where there was little agricultural activity in south-central Michigan. Atrazine concentrations were below the limit of quantification at non-agricultural sites. Atrazine concentrations did not exceed 2 microg/L at most agricultural sites, but a concentration of 250 microg atrazine/L was measured in one sample from one site in 2002. Plasma steroid concentrations varied among locations. Aromatase activity was measurable in less than 11% of testes in adult males, and in less than 4% of testes in juvenile males. Median aromatase activities in ovaries of adult females ranged from 3 to 245 pmol/h/mg protein, and maximum activities were 2.5-fold greater in juveniles than in adults. Atrazine concentrations were not significantly correlated with any of the parameters measured in this study. These results indicate that atrazine does not up-regulate aromatase in green frogs in the wild, and does not appear to affect plasma steroid hormone concentrations.

Differential effects of long-chain (sphingoid) bases on the monocytic differentiation of human leukemia (HL-60) cells induced by phorbol esters, 1 alpha, 25-dihydroxyvitamin D3, or ganglioside GM3.

Conditions were developed to prolong the ability of sphinganine, a potent inhibitor of protein kinase C, to block the phorbol ester-induced adherence of HL-60 cells beyond 24 h. The loss of inhibition after this time seen previously (A.H. Merrill, Jr., A.M. Sereni, V.L. Stevens, Y.A. Hannun, R.M. Bell, and J.M. Kinkade, Jr., J. Biol. Chem., 261: 12610-12615, 1986), which appeared to be due to metabolism of this long-chain base, was overcome by supplying sphinganine daily. After 4 days, phorbol myristate acetate-induced adherence was inhibited approximately 50% by sphinganine. Sphinganine significantly decreased the expression of nonspecific esterase induced by phorbol myristate acetate in the nonadherent cells, indicating that other aspects of maturation besides adherence were blocked. The effects of daily sphinganine treatments on the monocytic differentiation induced by 1 alpha-25-dihydroxyvitamin D3 or ganglioside GM3 were also investigated. The increases in nonspecific esterase expression, nitroblue tetrazolium reduction, and morphological maturation caused by either agent were unaffected by the long-chain base. In addition, the changes in several cell surface antigens caused by 1 alpha,25-dihydroxyvitamin D3 were unaltered by sphinganine. Although phorbol esters, 1 alpha,25-dihydroxyvitamin D3, and ganglioside GM3 all induce the maturation of HL-60 cells along the monocytic lineage, the finding that sphinganine only affected the differentiation initiated by phorbol esters, in which protein kinase C clearly is a major regulator, suggests that this enzyme does not play a major role in these other pathways of differentiation.

Seasonal exposures to triazine and other pesticides in surface waters in the western Highveld corn-production region in South Africa.

The objective of this study was to characterize concentrations of atrazine, terbuthylazine, and other pesticides in amphibian habitats in surface waters of a corn-production area of the western Highveld region (North-West Province) of South Africa. The study was conducted from November 2001 to June 2002, coinciding with the corn-production season. Pesticide residues were measured at regular intervals in surface water from eight ponds, three in a non-corn-growing area (NCGA) and five within the corn-growing area (CGA). Measured atrazine concentrations differed significantly among sites and between samples. In the five CGA sites, the maximum atrazine concentrations measured during the study ranged from 1.2 to 9.3 microg/L. Although no atrazine was recorded as being applied in the catchment of the three NCGA sites, maximum concentrations from 0.39 to 0.84 microg/L were measured during the study, possibly as a result of atmospheric transport. Maximum measured concentrations of terbuthylazine ranged from 1.22 to 2.1 microg/L in the NCGA sites and from 1.04 to 4.1 microg/L in the CGA sites. The source of terbuthylazine in the NCGA sites may have been in use other than in corn. The triazine degradation products, deisopropylatrazine (DIA) and deethylatrazine (DEA) and diaminochlorotriazine (DACT) were also found in water from both the CGA and NCGA sites. Concentrations of DIA were > or = 1 microg/L throughout the season, while DEA concentrations were mostly <0.5 microg/L before planting but increased after planting and application of herbicides to concentrations >2 microg/L in some locations. Concentrations of DACT were highly variable (LOD to 8 microg/L) both before and after planting and application, suggesting that they resulted from historical use of triazines in the area. Other herbicides such as simazine and acetochlor were only detected infrequently and pesticides such as S-metolachlor, cypermethrin, monocrotophos, and terbuphos, known to be used in the CGA, were not detected in any of the samples. Because of dilution by higher than normal rainfall in the study period, these concentrations may not be predictive of those in years of normal rainfall.

Morphometric studies in dominant olivopontocerebellar atrophy. Comparison of cell losses with amino acid decreases.

We present a correlation of the morphometric cell density analysis with previous biochemical findings for the inferior olivary nucleus and Purkinje cell layer of the cerebellum from 10 patients (three kindreds) with dominant olivopontocerebellar atrophy. We have analyzed brain amino compounds of these patients and found a decrease of aspartic acid and glutamic acid in the cerebellar cortex and of aspartic acid in the inferior olives. The cell density analysis revealed decreased cell counts, with a mean of 34% of olivary cells and 42% of Purkinje cells surviving when compared with 10 control brains. The cell counts were then correlated with the amino acid analyses. The correlation coefficient for aspartic acid content and surviving neurons in the inferior olive was .87 and that for aspartic acid content and Purkinje cell density was .86. Comparison of glutamic acid content and Purkinje cell density yielded a correlation coefficient of .75. The correlations appear to indicate a relationship between these particular cells or the area they occupy and the decreased content of the two amino acids.