Early Prevention of Severe Neurodevelopmental Behavior Disorders: An Integration

This is an Accepted Manuscript of an article published by Taylor & Francis in Journal of Mental Health Research in Intellectual Disabilities on 1/1/2012, available online: http://www.tandfonline.com/10.1080/19315864.2011.593697.There is a very substantial literature over the past 50 years on the advantages of early detection and intervention on the cognitive, communicative, and social-emotional development of infants and toddlers at risk for developmental delay due to premature birth or social disadvantage. Most of these studies excluded children with severe delays or other predisposing conditions, such as genetic or brain disorders. Many studies of children with biological or socio-developmental risk suggest that behavior disorders appear as early as three years and persist into adulthood if not effectively treated. By contrast, little is known about the infants and toddlers with established risk for severe delays, who make up a significant proportion of the population with dual diagnoses later in life. In the past decade, there has been a growing interest in early detection and intervention with children aged birth to three years, e.g. the P.L.99-457, Part C Birth-Three population, who may have disabilities and severe behavior problems, e.g. aggression, self-injury, and repetitive stereotyped behaviors. The available research is scattered in the behavior analytic literature, in the child development literature, as well as in the child mental health and psychiatry literature, the developmental disability literature, the animal modeling literature, and the genetics literature. The goal of this introductory overview is to integrate these literatures, by cross-referencing members of these various groups who have worked in this field, in order to provide the reader with an integrated picture of what is known and of future directions that need more research

The Role of Gut Health in Parkinson’s disease: The Impact on Motor Symptoms and Fitness Levels

While Parkinson’s disease (PD) has traditionally been considered a central nervous system disease, recent groundbreaking research argues that PD symptomology is influenced by gut microbiota alterations (dysbiosis).1 People with PD suffer from dysbiosis,2-6 and gut symptoms characteristic of dysbiosis, like constipation.7,8 Given this evidence, strategies that improve gut health in PD are warranted. One possible strategy is exercise. In non-PD populations, fitness status is linked to gut health,9-13 and exercise which increases fitness status improves the gut.14-19 It is now known that exercise improves motor symptoms in PD,20-23 but the gut may be a moderator of these improvements. However, no study has taken the crucial first step to link fitness with motor and gut symptoms in PD. In addition, there is a need to determine whether norms for fitness status 24 indicate PD symptom severity to provide clinicians with a benchmark by which they can improve the fitness of people with PD. PURPOSE: We aimed to 1) associate fitness, motor symptoms, and constipation and 2) determine the influence of aerobic fitness norms on motor symptoms and constipation in 19 people with PD. METHODS: Constipation was measured via the ROME-IV survey (summing nine symptom questions). Fitness was defined as estimated oxygen consumption (VO2) via a 6-minute walk test (6MW). Normative classifications were used to determine whether participants met (HI) or did not meet aerobic fitness status (LO).25 Motor symptoms were assessed via the Unified Parkinson’s Disease Rating Scale III (UPDRS-III). A linear regression was used to associate VO2 peak, UPDRS-III, and constipation. A MANOVA was used to compare symptoms between HI and LO groups. RESULTS: VO2 peak was inversely associated with constipation (t= 2.67, p=.018, effect size = -.48, 95% CI= -.86 to -.10) and UPDRS-III scores (t= -2.35, p= .033, effect size= -.48, 95% CI= -.92 to -.04). The HI group had lower constipation (p=.018) and UPDRS-III scores (p=.03) than the LO group. DISCUSSION: Not only is there a link between aerobic fitness, motor function, and constipation in people with PD, but there seems to be aerobic fitness benchmarks (i.e., HI vs. LO) that clinicians can use to improve the fitness status of their patients. In doing so, this can not only lead to improvements in motor function, but also improved gut health in people with PD. REFERENCES 1. McCann H, Cartwright H, Halliday GM. Neuropathology of alpha-synuclein propagation and braak hypothesis. Mov Disord. 2016;31(2):152-160. 2. Aho VTE, Pereira PAB, Voutilainen S, et al. Gut microbiota in Parkinson\u27s disease: Temporal stability and relations to disease progression. EBioMedicine. 2019;44:691-707. 3. Scheperjans F, Aho V, Pereira PA, et al. Gut microbiota are related to Parkinson\u27s disease and clinical phenotype. Mov Disord. 2015;30(3):350-358. 4. Heintz-Buschart A, Pandey U, Wicke T, et al. The nasal and gut microbiome in Parkinson\u27s disease and idiopathic rapid eye movement sleep behavior disorder. Mov Disord. 2018;33(1):88-98. 5. Cilia R, Piatti M, Cereda E, et al. Does Gut Microbiota Influence the Course of Parkinson\u27s Disease? A 3-Year Prospective Exploratory Study in de novo Patients. J Parkinsons Dis. 2021;11(1):159-170. 6. Ren T, Gao Y, Qiu Y, et al. Gut Microbiota Altered in Mild Cognitive Impairment Compared With Normal Cognition in Sporadic Parkinson\u27s Disease. Front Neurol. 2020;11:137. 7. Fasano A, Visanji NP, Liu LW, Lang AE, Pfeiffer RF. Gastrointestinal dysfunction in Parkinson\u27s disease. Lancet Neurol. 2015;14(6):625-639. 8. Adams-Carr KL, Bestwick JP, Shribman S, Lees A, Schrag A, Noyce AJ. Constipation preceding Parkinson\u27s disease: a systematic review and meta-analysis. J Neurol Neurosurg Psychiatry. 2016;87(7):710-716. 9. Clarke SF, Murphy EF, O\u27Sullivan O, et al. Exercise and associated dietary extremes impact on gut microbial diversity. Gut. 2014;63(12):1913-1920. 10. Durk RP, Castillo E, Marquez-Magana L, et al. Gut Microbiota Composition Is Related to Cardiorespiratory Fitness in Healthy Young Adults. Int J Sport Nutr Exerc Metab. 2019;29(3):249-253. 11. Yang Y, Shi Y, Wiklund P, et al. The Association between Cardiorespiratory Fitness and Gut Microbiota Composition in Premenopausal Women. Nutrients. 2017;9(8). 12. Estaki M, Pither J, Baumeister P, et al. Cardiorespiratory fitness as a predictor of intestinal microbial diversity and distinct metagenomic functions. Microbiome. 2016;4(1):42. 13. Barton W, Penney NC, Cronin O, et al. The microbiome of professional athletes differs from that of more sedentary subjects in composition and particularly at the functional metabolic level. Gut. 2018;67(4):625-633. 14. Cronin O, Barton W, Skuse P, et al. A Prospective Metagenomic and Metabolomic Analysis of the Impact of Exercise and/or Whey Protein Supplementation on the Gut Microbiome of Sedentary Adults. mSystems. 2018;3(3). 15. Resende AS, Leite GSF, Lancha Junior AH. Changes in the Gut Bacteria Composition of Healthy Men with the Same Nutritional Profile Undergoing 10-Week Aerobic Exercise Training: A Randomized Controlled Trial. Nutrients. 2021;13(8). 16. Louis S, Tappu RM, Damms-Machado A, Huson DH, Bischoff SC. Characterization of the Gut Microbial Community of Obese Patients Following a Weight-Loss Intervention Using Whole Metagenome Shotgun Sequencing. PLoS One. 2016;11(2):e0149564. 17. Kang SS, Jeraldo PR, Kurti A, et al. Diet and exercise orthogonally alter the gut microbiome and reveal independent associations with anxiety and cognition. Mol Neurodegener. 2014;9:36. 18. Campbell SC, Wisniewski PJ, Noji M, et al. The Effect of Diet and Exercise on Intestinal Integrity and Microbial Diversity in Mice. PLoS One. 2016;11(3):e0150502. 19. Allen JM, Mailing LJ, Cohrs J, et al. Exercise training-induced modification of the gut microbiota persists after microbiota colonization and attenuates the response to chemically-induced colitis in gnotobiotic mice. Gut Microbes. 2018;9(2):115-130. 20. Uhrbrand A, Stenager E, Pedersen MS, Dalgas U. Parkinson\u27s disease and intensive exercise therapy--a systematic review and meta-analysis of randomized controlled trials. J Neurol Sci. 2015;353(1-2):9-19. 21. Li Y, Song H, Shen L, Wang Y. The efficacy and safety of moderate aerobic exercise for patients with Parkinson\u27s disease: a systematic review and meta-analysis of randomized controlled trials. Ann Palliat Med. 2021;10(3):2638-2649. 22. Fisher BE, Wu AD, Salem GJ, et al. The effect of exercise training in improving motor performance and corticomotor excitability in people with early Parkinson\u27s disease. Arch Phys Med Rehabil. 2008;89(7):1221-1229. 23. Tabak R, Aquije G, Fisher BE. Aerobic exercise to improve executive function in Parkinson disease: a case series. J Neurol Phys Ther. 2013;37(2):58-64. 24. Rikli RE, Jones CJ. Senior fitness test manual. Champaign, IL: Human Kinetics; 2001. 25. Enright PL, Sherrill DL. Reference equations for the six-minute walk in healthy adults. Am J Respir Crit Care Med. 1998;158(5 Pt 1):1384-1387

Aerobic Fitness Levels Relate to Cognitive Function in People with Parkinson’s Disease as Assessed by the 6 Minute Walk Test

While individuals with Parkinson’s disease (PD) present with impaired motor control, 26% demonstrate cognitive impairment independent of dementia1. In fact, cognitive dysfunction often predates motor impairments and can diminish quality of life2 as well as life expectancy3. Fortunately, aerobic exercise has been shown to improve cognition in older adults4 as well as PD patients5-7. However, only a limited number of studies have determined a clear relationship between aerobic fitness levels and cognition in people with PD. Determining whether cognitive status and aerobic fitness levels are associated in people with PD would provide greater evidence for intervention focused on aerobic fitness that has a goal of improving cognition. Using the 6-minute walk test (6MWT), we were able to categorize participants based on their aerobic fitness levels9. This categorization allowed us to test the relationship between cognitive status and aerobic fitness. PURPOSE:The purpose of this study is to identify differences in cognition in people with PD who meet aerobic fitness norms compared to those who do not meet aerobic fitness norms. METHODS:19 people with PD (Hoehn & Yahr stages I-III) were recruited. Aerobic fitness was assessed via estimated oxygen consumption using the 6MWT (VO2 peak) This test has shown test-retest reliability in people with PD8. 6MWT classifications were used to determine if participants met (PD-HI) or did not meet fitness norms (PD-LO). Cognitive function was assessed via the Montreal Cognitive Assessment (MoCA) and scored out of 30 points. To compare the two groups, a Welch’s Two Sample T-Test was performed using the R Statistical Program, and p-values were set to \u3c0.05. RESULTS: The PD-HI group (n=9) had a mean MoCA score of 26.0(+/-1.5). The PD-LO group (n=10) had a mean MoCA score of 22.4(+/-3.2). The PD-HI group had significantly higher MoCA scores compared with the PD-LO group (p=0.004). CONCLUSION: This study is one of the first to observe a relationship between increased MoCA scores and high aerobic fitness status in populations with PD

Principles to Guide the Office of Legal Counsel

Former members of Office of Legal Counsel ( OLC ) in the Department of Justice offer guidance for their successors. Among the document\u27s recommendations are suggestions that the OLC provide an accurate and honest appraisal of applicable law, even if that advice will constrain the administration’s pursuit of desired policies; and publicly disclose its written legal opinions in a timely manner, absent strong reasons for delay or nondisclosure

On the ground states of the Bernasconi model

The ground states of the Bernasconi model are binary +1/-1 sequences of length N with low autocorrelations. We introduce the notion of perfect sequences, binary sequences with one-valued off-peak correlations of minimum amount. If they exist, they are ground states. Using results from the mathematical theory of cyclic difference sets, we specify all values of N for which perfect sequences do exist and how to construct them. For other values of N, we investigate almost perfect sequences, i.e. sequences with two-valued off-peak correlations of minimum amount. Numerical and analytical results support the conjecture that almost perfect sequences do exist for all values of N, but that they are not always ground states. We present a construction for low-energy configurations that works if N is the product of two odd primes.Comment: 12 pages, LaTeX2e; extended content, added references; submitted to J.Phys.

Stretching the Rules: Monocentric Chromosomes with Multiple Centromere Domains

The centromere is a functional chromosome domain that is essential for faithful chromosome segregation during cell division and that can be reliably identified by the presence of the centromere-specific histone H3 variant CenH3. In monocentric chromosomes, the centromere is characterized by a single CenH3-containing region within a morphologically distinct primary constriction. This region usually spans up to a few Mbp composed mainly of centromere-specific satellite DNA common to all chromosomes of a given species. In holocentric chromosomes, there is no primary constriction; the centromere is composed of many CenH3 loci distributed along the entire length of a chromosome. Using correlative fluorescence light microscopy and high-resolution electron microscopy, we show that pea (Pisum sativum) chromosomes exhibit remarkably long primary constrictions that contain 3-5 explicit CenH3-containing regions, a novelty in centromere organization. In addition, we estimate that the size of the chromosome segment delimited by two outermost domains varies between 69 Mbp and 107 Mbp, several factors larger than any known centromere length. These domains are almost entirely composed of repetitive DNA sequences belonging to 13 distinct families of satellite DNA and one family of centromeric retrotransposons, all of which are unevenly distributed among pea chromosomes. We present the centromeres of Pisum as novel ``meta-polycentric'' functional domains. Our results demonstrate that the organization and DNA composition of functional centromere domains can be far more complex than previously thought, do not require single repetitive elements, and do not require single centromere domains in order to segregate properly. Based on these findings, we propose Pisum as a useful model for investigation of centromere architecture and the still poorly understood role of repetitive DNA in centromere evolution, determination, and function

Parallelization and Visual Analysis of Multidimensional Fields: Application to Ozone Production, Destruction, and Transport in Three Dimensions

The three-dimensional, spectral transport model used in the current project was first successfully integrated over climatological time scales by Dr. Guang Ping Lou for the simulation of atmospheric N2O using the United Kingdom Meteorological Office (UKMO) 4-dimensional, assimilated wind and temperature data set. A non-parallel, FORTRAN version of this integration using a fairly simple N2O chemistry package containing only photo-chemical reactions was used to verify our initial parallel model results. The integrations reproduced the gross features of the observed stratospheric climatological N2O distributions but also simulated the structure of the stratospheric Antarctic vortex and its evolution. Subsequently, Dr. Thomas Kindler, who produced much of the parallel version of our model, enlarged the N2O model chemistry package to include N2O reactions involving O(D-1) and also introduced assimilated wind data from NASA as well as UKMO. Initially, transport calculations without chemistry were run using Carbon-14 as a non-reactive tracer gas with the result that large differences in the transport properties of the two assimilated wind data sets were apparent from the resultant Carbon-14 distributions. Subsequent calculations for N2O, including its chemistry, with the two input winds data sets with verification from UARS satellite observations have refined the transport differences between the two such that the model's steering capabilities could be used to infer the correct climatological vertical velocity fields required to support the N2O observations. During this process, it was also discovered that both the NASA and the UKMO data contained spurious values in some of the higher frequency wave components, leading to incorrect local transport calculations and ultimately affecting the large scale properties of the model's N2O distributions, particularly at tropical latitudes. Subsequent model runs with wind data that had been filtered to remove some of the high frequency components produced much more realistic N2O distributions. During the past few months, the UKMO wind data base for a complete two-year period was processed into spectral form for model use. This new version of the input transport data base now includes complete temperature fields as well as the necessary wind data. This was done to facilitate advanced chemical calculations in the parallel model which often depend upon temperature. Additional UKMO data is being added as it becomes available

Associations between Polycyclic Aromatic Hydrocarbon–Related Exposures and p53 Mutations in Breast Tumors

Background: Previous studies have suggested that polycyclic aromatic hydrocarbons (PAHs) may be associated with breast cancer. However, the carcinogenicity of PAHs on the human breast remains unclear. Certain carcinogens may be associated with specific mutation patterns in the p53 tumor suppressor gene, thereby contributing information about disease etiology. Objectives: We hypothesized that associations of PAH-related exposures with breast cancer would differ according to tumor p53 mutation status, effect, type, and number. Methods: We examined this possibility in a population-based case–control study using polytomous logistic regression. As previously reported, 151 p53 mutations among 859 tumors were identified using Surveyor nuclease and confirmed by sequencing. Results: We found that participants with p53 mutations were less likely to be exposed to PAHs (assessed by smoking status in 859 cases and 1,556 controls, grilled/smoked meat intake in 822 cases and 1,475 controls, and PAH–DNA adducts in peripheral mononuclear cells in 487 cases and 941 controls) than participants without p53 mutations. For example, active and passive smoking was associated with p53 mutation–negative [odds ratio (OR) = 1.55; 95% confidence interval (CI), 1.11–2.15] but not p53 mutation–positive (OR = 0.77; 95% CI, 0.43–1.38) cancer (ratio of the ORs = 0.50, p < 0.05). However, frameshift mutations, mutation number, G:C→A:T transitions at CpG sites, and insertions/deletions were consistently elevated among exposed subjects. Conclusions: These findings suggest that PAHs may be associated with specific breast tumor p53 mutation subgroups rather than with overall p53 mutations and may also be related to breast cancer through mechanisms other than p53 mutation