Publications by authors named "Michael Gregory"

103 Publications

Genetic mechanisms and correlated risk factors of antimicrobial-resistant ESKAPEE pathogens isolated in a tertiary hospital in Malaysia.

Antimicrob Resist Infect Control 2021 Apr 23;10(1):70. Epub 2021 Apr 23.

Department of Medical Microbiology, Faculty of Medicine, Universiti Malaya, 50603, Kuala Lumpur, Malaysia.

Background: Knowledge on the epidemiology, genotypic and phenotypic features of antimicrobial-resistant (AMR) ESKAPEE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter spp., and Escherichia coli) and their association with hospital-acquired infections (HAIs) are limited in Malaysia. Therefore, we evaluated the AMR features and resistance mechanisms of the ESKAPEE pathogens collected in a tertiary hospital located in the capital of Malaysia.

Methods: A total of 378 AMR-ESKAPEE strains were obtained based on convenience sampling over a nine-month study period (2019-2020). All strains were subjected to disk diffusion and broth microdilution assays to determine the antimicrobial susceptibility profiles. Polymerase chain reaction (PCR) and DNA sequence analyses were performed to determine the AMR genes profiles of the non-susceptible strains. Chi-square test and logistic regression analyses were used to correlate the AMR profiles and clinical data to determine the risk factors associated with HAIs.

Results: High rates of multidrug resistance (MDR) were observed in A. baumannii, K. pneumoniae, E. coli, and S. aureus (69-89%). All organisms except E. coli were frequently associated with HAIs (61-94%). Non-susceptibility to the last-resort drugs vancomycin (in Enterococcus spp. and S. aureus), carbapenems (in A. baumannii, P. aeruginosa, and Enterobacteriaceae), and colistin (in Enterobacteriaceae) were observed. Both A. baumannii and K. pneumoniae harbored a wide array of extended-spectrum β-lactamase genes (bla, bla, bla, bla). Metallo-β-lactamase genes (bla, bla, bla) were detected in carbapenem-resistant strains, at a higher frequency compared to other local reports. We detected two novel mutations in the quinolone-resistant determining region of the gyrA in fluoroquinolone-resistant E. coli (Leu-102-Ala; Gly-105-Val). Microbial resistance to ampicillin, methicillin, and cephalosporins was identified as important risk factors associated with HAIs in the hospital.

Conclusion: Overall, our findings may provide valuable insight into the microbial resistance pattern and the risk factors of ESKAPEE-associated HAIs in a tertiary hospital located in central Peninsular Malaysia. The data obtained in this study may contribute to informing better hospital infection control in this region.
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http://dx.doi.org/10.1186/s13756-021-00936-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8062948PMC
April 2021

The NIMH Intramural Longitudinal Study of the Endocrine and Neurobiological Events Accompanying Puberty: Protocol and rationale for methods and measures.

Neuroimage 2021 Mar 24;234:117970. Epub 2021 Mar 24.

Section on Integrative Neuroimaging, Clinical & Translational Neuroscience Branch, National Institute of Mental Health, Bethesda, MD USA.

Delineating the relationship between human neurodevelopment and the maturation of the hypothalamic-pituitary-gonadal (HPG) axis during puberty is critical for investigating the increase in vulnerability to neuropsychiatric disorders that is well documented during this period. Preclinical research demonstrates a clear association between gonadal production of sex steroids and neurodevelopment; however, identifying similar associations in humans has been complicated by confounding variables (such as age) and the coactivation of two additional endocrine systems (the adrenal androgenic system and the somatotropic growth axis) and requires further elucidation. In this paper, we present the design of, and preliminary observations from, the ongoing NIMH Intramural Longitudinal Study of the Endocrine and Neurobiological Events Accompanying Puberty. The aim of this study is to directly examine how the increase in sex steroid hormone production following activation of the HPG-axis (i.e., gonadarche) impacts neurodevelopment, and, additionally, to determine how gonadal development and maturation is associated with longitudinal changes in brain structure and function in boys and girls. To disentangle the effects of sex steroids from those of age and other endocrine events on brain development, our study design includes 1) selection criteria that establish a well-characterized baseline cohort of healthy 8-year-old children prior to the onset of puberty (e.g., prior to puberty-related sex steroid hormone production); 2) temporally dense longitudinal, repeated-measures sampling of typically developing children at 8-10 month intervals over a 10-year period between the ages of eight and 18; 3) contemporaneous collection of endocrine and other measures of gonadal, adrenal, and growth axis function at each timepoint; and 4) collection of multimodal neuroimaging measures at these same timepoints, including brain structure (gray and white matter volume, cortical thickness and area, white matter integrity, myelination) and function (reward processing, emotional processing, inhibition/impulsivity, working memory, resting-state network connectivity, regional cerebral blood flow). This report of our ongoing longitudinal study 1) provides a comprehensive review of the endocrine events of puberty; 2) details our overall study design; 3) presents our selection criteria for study entry (e.g., well-characterized prepubertal baseline) along with the endocrinological considerations and guiding principles that underlie these criteria; 4) describes our longitudinal outcome measures and how they specifically relate to investigating the effects of gonadal development on brain development; and 5) documents patterns of fMRI activation and resting-state networks from an early, representative subsample of our cohort of prepubertal 8-year-old children.
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http://dx.doi.org/10.1016/j.neuroimage.2021.117970DOI Listing
March 2021

Polymorphism in the ZNF804A Gene and Variation in D and D/D Dopamine Receptor Availability in the Healthy Human Brain: A Dual Positron Emission Tomography Study.

Biol Psychiatry Cogn Neurosci Neuroimaging 2021 Mar 9. Epub 2021 Mar 9.

Clinical and Translational Neuroscience Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland. Electronic address:

Background: The rs1344706 single nucleotide polymorphism in the ZNF804A gene has been associated with risk for psychosis in multiple genome-wide association studies, yet mechanisms underlying this association are not known. Given preclinical work suggesting an impact of ZNF804A on dopamine receptor gene transcription and clinical studies establishing dopaminergic dysfunction in patients with schizophrenia, we hypothesized that the ZNF804A risk single nucleotide polymorphism would be associated with variation in dopamine receptor availability in the human brain.

Methods: In this study, 72 healthy individuals genotyped for rs1344706 completed both [F]fallypride and [C]NNC-112 positron emission tomography scans to measure D/D and D receptor availability, respectively. Genetic effects on estimates of binding potential for each ligand were tested first with canonical subject-specific striatal regions of interest analyses, followed by exploratory whole-brain voxelwise analyses to test for more localized striatal signals and for extrastriatal effects.

Results: Region of interest analyses revealed significantly less D/D receptor availability in risk-allele homozygotes (TT) compared with non-risk allele carriers (G-allele carrier group: TG and GG) in the associative striatum and sensorimotor striatum, but no significant differences in striatal D receptor availability.

Conclusions: These data suggest that ZNF804A genotype may be meaningfully linked to dopaminergic function in the human brain. The results also may provide information to guide future studies of ZNF804A-related mechanisms of schizophrenia risk.
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http://dx.doi.org/10.1016/j.bpsc.2020.12.006DOI Listing
March 2021

Beyond linearity in neuroimaging: Capturing nonlinear relationships with application to longitudinal studies.

Neuroimage 2021 06 3;233:117891. Epub 2021 Mar 3.

Section on Integrative Neuroimaging, Clinical and Translational Neuroscience Branch, National Institute of Mental Health, USA.

The ubiquitous adoption of linearity for quantitative predictors in statistical modeling is likely attributable to its advantages of straightforward interpretation and computational feasibility. The linearity assumption may be a reasonable approximation especially when the variable is confined within a narrow range, but it can be problematic when the variable's effect is non-monotonic or complex. Furthermore, visualization and model assessment of a linear fit are usually omitted because of challenges at the whole brain level in neuroimaging. By adopting a principle of learning from the data in the presence of uncertainty to resolve the problematic aspects of conventional polynomial fitting, we introduce a flexible and adaptive approach of multilevel smoothing splines (MSS) to capture any nonlinearity of a quantitative predictor for population-level neuroimaging data analysis. With no prior knowledge regarding the underlying relationship other than a parsimonious assumption about the extent of smoothness (e.g., no sharp corners), we express the unknown relationship with a sufficient number of smoothing splines and use the data to adaptively determine the specifics of the nonlinearity. In addition to introducing the theoretical framework of MSS as an efficient approach with a counterbalance between flexibility and stability, we strive to (a) lay out the specific schemes for population-level nonlinear analyses that may involve task (e.g., contrasting conditions) and subject-grouping (e.g., patients vs controls) factors; (b) provide modeling accommodations to adaptively reveal, estimate and compare any nonlinear effects of a predictor across the brain, or to more accurately account for the effects (including nonlinear effects) of a quantitative confound; (c) offer the associated program 3dMSS to the neuroimaging community for whole-brain voxel-wise analysis as part of the AFNI suite; and (d) demonstrate the modeling approach and visualization processes with a longitudinal dataset of structural MRI scans.
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http://dx.doi.org/10.1016/j.neuroimage.2021.117891DOI Listing
June 2021

How Shared Resource Laboratories have risen and adapted to the challenges of a global pandemic.

Cytometry A 2021 Jan 23;99(1):8-10. Epub 2020 Dec 23.

Flow Cytometry Support Services, LLC, Alexandria, Virginia, USA.

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http://dx.doi.org/10.1002/cyto.a.24283DOI Listing
January 2021

Neanderthal-Derived Genetic Variation is Associated with Functional Connectivity in the Brains of Living Humans.

Brain Connect 2021 Feb 29;11(1):38-44. Epub 2020 Dec 29.

Section on Integrative Neuroimaging and Clinical and Translational Neurosciences Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland, USA.

To determine whether Neanderthal-derived genetic variation relates to functional connectivity patterns in the brains of living modern humans. Nearly 50,000 years ago, Neanderthals interbred with ancestors of modern humans, imparting a genetic legacy that lives on today. The vestiges of this Neanderthal-derived genetic variation have been previously shown to be enriched in genes coding for neurogenesis and myelination and to alter skull shape and brain structure in living people. Using two independent cohorts totaling 553 healthy individuals, we employed multivariate distance matrix regression (MDMR) to determine whether any brain areas exhibited whole-brain functional connectivity patterns that significantly related to the degree of Neanderthal introgression. Identified clusters were then used as regions of interest in follow-up seed-based functional connectivity analyses to determine the connectivity patterns driving the relationships. The MDMR analysis revealed that the percentage of Neanderthal-originating polymorphisms was significantly associated with the functional connectivity patterns of an area of the intraparietal sulcus (IPS) that was nearly identical in both cohorts. Using these IPS clusters as regions of interest in seed-based connectivity analyses, we found, again in both cohorts, that individuals with a higher proportion of Neanderthal-derived genetic variation showed increased IPS functional connectivity with visual processing regions, but decreased IPS connectivity with regions underlying social cognition. These findings demonstrate that the remnants of Neanderthal admixture continue to influence human brain function today, in ways that are consistent with anthropological conceptualizations of Neanderthal phenotypes, including the possibility that Neanderthals may have depended upon visual processing capabilities at the expense of social cognition, and this may have contributed to the extinction of this species through reduced cultural maintenance and inability to cope with fluctuating resources. This and other studies capitalizing on the emerging science surrounding ancient DNA provide a window through which to view an ancient lineage long past.
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http://dx.doi.org/10.1089/brain.2020.0809DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7891204PMC
February 2021

Evaluation of the Immunogenicity and Protective Efficacy of an Enterotoxigenic Escherichia coli CFA/I Adhesin-Heat-Labile Toxin Chimera.

Infect Immun 2020 10 19;88(11). Epub 2020 Oct 19.

Enteric Diseases Department, Naval Medical Research Center, Silver Spring, Maryland, USA.

Recent efforts to develop an enterotoxigenic (ETEC) vaccine have focused on the antigenically conserved tip adhesins of colonization factors. We showed previously that intranasal immunization with dscCfaE, a soluble variant of the in donor strand-complemented tip adhesin of a colonization factor of the class 5 family (CFA/I) fimbria, is highly immunogenic and protects against oral challenge with CFA/I-positive (CFA/I) ETEC strain H10407 in the nonhuman primate. We also reported a cholera toxin (CT)-like chimera (called dscCfaE-CTA2/CTB) in which the CTA1 domain of CT was replaced by dscCfaE that was strongly immunogenic when administered intranasally or orogastrically in mice. Here, we evaluate the immunogenicity and protective efficacy (PE) of a refined and more stable chimera comprised of a pentameric B subunit of ETEC heat-labile toxin (LTB) in lieu of the CTB pentamer and a donor strand truncation (dsc) of CfaE. The refined chimera, dscCfaE-sCTA2/LTB, was highly immunogenic in mice when administered intranasally or intradermally, eliciting serum and fecal antibody responses against CfaE and LTB, as well as strong hemagglutination inhibition titers, a surrogate for neutralization of intestinal adhesion mediated by CfaE. Moreover, the chimera was safe and highly immunogenic when administered intradermally to guinea pigs. In , intradermal (i.d.) immunization with chimera plus single-mutant heat-labile toxin [LT(R192G)] elicited strong serum anti-CfaE and anti-LTB antibody responses and conferred significant reduction of diarrhea compared to phosphate-buffered saline (PBS) controls (PE = 84.1%; 0.02). These data support the further evaluation of dscCfaE-sCTA2/LTB as an ETEC vaccine in humans.
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http://dx.doi.org/10.1128/IAI.00252-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7573451PMC
October 2020

Tracking Antimicrobial Resistance Determinants in Diarrheal Pathogens: A Cross-Institutional Pilot Study.

Int J Mol Sci 2020 Aug 18;21(16). Epub 2020 Aug 18.

US Naval Research Laboratory, Center for Biomolecular Science & Engineering, Washington, DC 20375, USA.

Infectious diarrhea affects over four billion individuals annually and causes over a million deaths each year. Though not typically prescribed for treatment of uncomplicated diarrheal disease, antimicrobials serve as a critical part of the armamentarium used to treat severe or persistent cases. Due to widespread over- and misuse of antimicrobials, there has been an alarming increase in global resistance, for which a standardized methodology for geographic surveillance would be highly beneficial. To demonstrate that a standardized methodology could be used to provide molecular surveillance of antimicrobial resistance (AMR) genes, we initiated a pilot study to test 130 diarrheal pathogens ( spp., , , and spp.) from the USA, Peru, Egypt, Cambodia, and Kenya for the presence/absence of over 200 AMR determinants. We detected a total of 55 different determinants conferring resistance to ten different categories of antimicrobials: genes detected in ≥ 25 samples included , (A), (B), (A), (B), , , , , , Δ1, , and . The number of determinants per strain ranged from none (several spp. strains) to sixteen, with isolates from Egypt harboring a wider variety and greater number of genes per isolate than other sites. Two samples harbored carbapenemase genes, or . Genes conferring resistance to azithromycin ((A), (A)/(K), (B)), a first-line therapeutic for severe diarrhea, were detected in over 10% of all Enterobacteriaceae tested: these included >25% of the Enterobacteriaceae from Egypt and Kenya. Forty-six percent of the Egyptian Enterobacteriaceae harbored genes encoding CTX-M-1 or CTX-M-9 families of extended-spectrum β-lactamases. Overall, the data provide cross-comparable resistome information to establish regional trends in support of international surveillance activities and potentially guide geospatially informed medical care.
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http://dx.doi.org/10.3390/ijms21165928DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7460656PMC
August 2020

An Observational Study of Sepsis in Takeo Province Cambodia: An in-depth examination of pathogens causing severe infections.

PLoS Negl Trop Dis 2020 08 17;14(8):e0008381. Epub 2020 Aug 17.

Austere environments Consortium for Enhanced Sepsis Outcomes (ACESO), Biological Defense Research Directorate, Naval Medical Research Center-Frederick, Ft. Detrick, Maryland, United States of America.

The world's most consequential pathogens occur in regions with the fewest diagnostic resources, leaving the true burden of these diseases largely under-represented. During a prospective observational study of sepsis in Takeo Province Cambodia, we enrolled 200 patients over an 18-month period. By coupling traditional diagnostic methods such as culture, serology, and PCR to Next Generation Sequencing (NGS) and advanced statistical analyses, we successfully identified a pathogenic cause in 46.5% of our cohort. In all, we detected 25 infectious agents in 93 patients, including severe threat pathogens such as Burkholderia pseudomallei and viral pathogens such as Dengue virus. Approximately half of our cohort remained undiagnosed; however, an independent panel of clinical adjudicators determined that 81% of those patients had infectious causes of their hospitalization, further underscoring the difficulty of diagnosing severe infections in resource-limited settings. We garnered greater insight as to the clinical features of severe infection in Cambodia through analysis of a robust set of clinical data.
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http://dx.doi.org/10.1371/journal.pntd.0008381DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7430706PMC
August 2020

Subcortical Signatures of Hemizygosity and Psychosis in 22q11.2 Deletion Syndrome: Finding Common Ground in Rare Genetic Variation.

Am J Psychiatry 2020 07;177(7):564-566

Clinical and Translational Neuroscience Branch, NIMH, Intramural Research Program, Bethesda, Md.

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http://dx.doi.org/10.1176/appi.ajp.2020.20050598DOI Listing
July 2020

A Survey of Antimicrobial Resistance Determinants in Category A Select Agents, Exempt Strains, and Near-Neighbor Species.

Int J Mol Sci 2020 Feb 29;21(5). Epub 2020 Feb 29.

US Naval Research Laboratory, Center for Biomolecular Science & Engineering, Washington, DC 20375, USA.

A dramatic increase in global antimicrobial resistance (AMR) has been well documented. Of particular concern is the dearth of information regarding the spectrum and prevalence of AMR within Category A Select Agents. Here, we performed a survey of horizontally and vertically transferred AMR determinants among Category A agents and their near neighbors. Microarrays provided broad spectrum screening of 127 spp., spp., and spp. strains for the presence/absence of 500+ AMR genes (or families of genes). Detecting a broad variety of AMR genes in each genus, microarray analysis also picked up the presence of an engineered plasmid in a strain. High resolution melt analysis (HRMA) was also used to assess the presence of quinolone resistance-associated mutations in 100 of these strains. Though HRMA was able to detect resistance-causing point mutations in strains, it was not capable of discriminating these point mutations from other nucleotide substitutions (e.g., arising from sequence differences in near neighbors). Though these technologies are well-established, to our knowledge, this is the largest survey of Category A agents and their near-neighbor species for genes covering multiple mechanisms of AMR.
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http://dx.doi.org/10.3390/ijms21051669DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7084191PMC
February 2020

Longitudinal Positron Emission Tomography of Dopamine Synthesis in Subjects with GBA1 Mutations.

Ann Neurol 2020 04 22;87(4):652-657. Epub 2020 Feb 22.

Section on Integrative Neuroimaging, Clinical and Translational Neuroscience Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD.

Mutations in GBA1, the gene mutated in Gaucher disease, are a common genetic risk factor for Parkinson disease, although the penetrance is low. We performed [ F]-fluorodopa positron emission tomography studies of 57 homozygous and heterozygous GBA1 mutation carriers (15 with parkinsonism) and 98 controls looking for early indications of dopamine loss using voxelwise analyses to identify group differences in striatal [ F]-fluorodopa uptake (K ). Forty-eight subjects were followed longitudinally. Cross-sectional and longitudinal comparisons of K and K change found significant effects of Parkinson disease. However, at baseline and over time, striatal [ F]-fluorodopa uptake in mutation carriers without parkinsonism did not significantly differ from controls. ANN NEUROL 2020;87:652-657.
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http://dx.doi.org/10.1002/ana.25692DOI Listing
April 2020

Distinct Polygenic Score Profiles in Schizophrenia Subgroups With Different Trajectories of Cognitive Development.

Am J Psychiatry 2020 04 16;177(4):298-307. Epub 2019 Dec 16.

Clinical and Translational Neuroscience Branch, NIMH, Bethesda, Md.

Objective: Different cognitive development histories in schizophrenia may reflect variation across dimensions of genetic influence. The authors derived and characterized cognitive development trajectory subgroups within a schizophrenia sample and profiled the subgroups across polygenic scores (PGSs) for schizophrenia, cognition, educational attainment, and attention deficit hyperactivity disorder (ADHD).

Methods: Demographic, clinical, and genetic data were collected at the National Institute of Mental Health from 540 schizophrenia patients, 247 unaffected siblings, and 844 control subjects. Cognitive trajectory subgroups were derived through cluster analysis using estimates of premorbid and current IQ. PGSs were generated using standard methods. Associations were tested using general linear models and logistic regression.

Results: Cluster analyses identified three cognitive trajectory subgroups in the schizophrenia group: preadolescent cognitive impairment (19%), adolescent disruption of cognitive development (44%), and cognitively stable adolescent development (37%). Together, the four PGSs significantly predicted 7.9% of the variance in subgroup membership. Subgroup characteristics converged with genetic patterns. Cognitively stable individuals had the best adult clinical outcomes and differed from control subjects only in schizophrenia PGSs. Those with adolescent disruption of cognitive development showed the most severe symptoms after diagnosis and were cognitively impaired. This subgroup had the highest schizophrenia PGSs and had disadvantageous cognitive PGSs relative to control subjects and cognitively stable individuals. Individuals showing preadolescent impairment in cognitive and academic performance and poor adult outcome exhibited a generalized PGS disadvantage relative to control subjects and were the only subgroup to differ significantly in education and ADHD PGSs.

Conclusions: Subgroups derived from patterns of premorbid and current IQ showed different premorbid and clinical characteristics, which converged with broad genetic profiles. Simultaneous analysis of multiple PGSs may contribute to useful clinical stratification in schizophrenia.
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http://dx.doi.org/10.1176/appi.ajp.2019.19050527DOI Listing
April 2020

Williams syndrome hemideletion and LIMK1 variation both affect dorsal stream functional connectivity.

Brain 2019 12;142(12):3963-3974

Section on Integrative Neuroimaging, Clinical and Translational Neuroscience Branch, National Institute of Mental Health, Intramural Research Program, National Institutes of Health, Bethesda, MD, USA.

Williams syndrome is a rare genetic disorder caused by hemizygous deletion of ∼1.6 Mb affecting 26 genes on chromosome 7 (7q11.23) and is clinically typified by two cognitive/behavioural hallmarks: marked visuospatial deficits relative to verbal and non-verbal reasoning abilities and hypersocial personality. Clear knowledge of the circumscribed set of genes that are affected in Williams syndrome, along with the well-characterized neurobehavioural phenotype, offers the potential to elucidate neurogenetic principles that may apply in genetically and clinically more complex settings. The intraparietal sulcus, in the dorsal visual processing stream, has been shown to be structurally and functionally altered in Williams syndrome, providing a target for investigating resting-state functional connectivity and effects of specific genes hemideleted in Williams syndrome. Here, we tested for effects of the LIMK1 gene, deleted in Williams syndrome and important for neuronal maturation and migration, on intraparietal sulcus functional connectivity. We first defined a target brain phenotype by comparing intraparietal sulcus resting functional connectivity in individuals with Williams syndrome, in whom LIMK1 is hemideleted, with typically developing children. Then in two separate cohorts from the general population, we asked whether intraparietal sulcus functional connectivity patterns similar to those found in Williams syndrome were associated with sequence variation of the LIMK1 gene. Four independent between-group comparisons of resting-state functional MRI data (total n = 510) were performed: (i) 20 children with Williams syndrome compared to 20 age- and sex-matched typically developing children; (ii) a discovery cohort of 99 healthy adults stratified by LIMK1 haplotype; (iii) a replication cohort of 32 healthy adults also stratified by LIMK1 haplotype; and (iv) 339 healthy adolescent children stratified by LIMK1 haplotype. For between-group analyses, differences in intraparietal sulcus resting-state functional connectivity were calculated comparing children with Williams syndrome to matched typically developing children and comparing LIMK1 haplotype groups in each of the three general population cohorts separately. Consistent with the visuospatial construction impairment and hypersocial personality that typify Williams syndrome, the Williams syndrome cohort exhibited opposite patterns of intraparietal sulcus functional connectivity with visual processing regions and social processing regions: decreased circuit function in the former and increased circuit function in the latter. All three general population groups also showed LIMK1 haplotype-related differences in intraparietal sulcus functional connectivity localized to the fusiform gyrus, a visual processing region also identified in the Williams syndrome-typically developing comparison. These results suggest a neurogenetic mechanism, in part involving LIMK1, that may bias neural circuit function in both the general population and individuals with Williams syndrome.
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http://dx.doi.org/10.1093/brain/awz323DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6906590PMC
December 2019

Soluble Intercellular Adhesion Molecule-1 (sICAM-1) as a Biomarker of Vascular Cognitive Impairment in Older Adults.

Dement Geriatr Cogn Disord 2019 13;47(4-6):243-253. Epub 2019 Aug 13.

Research Division, Universidad Nacional Autónoma de México (UNAM), Mexico City, Mexico,

Background: Endothelial dysfunction and subsequent inflammation contribute to the development of vascular cognitive impairment (VCI). Soluble intercellular adhesion molecule-1 (sICAM-1) is upregulated in endothelial dysfunction and promotes an inflammatory response; however, the relationship between sICAM-1 and VCI remains equivocal.

Objective: To determine whether sICAM-1 contributes to the prediction of VCI.

Methods: Community-dwelling older adults (n = 172) from the "Cohort of Obesity, Sarcopenia and Frailty of Older Mexican Adults" (COSFOMA) study were identified as VCI or controls using standard neuropsychological evaluations and neuroimaging. sICAM-1 was quantified using ELISA, and multivariate logistic regression determined the association between sICAM-1 and VCI.

Results: A total of 31 VCI cases were identified. sICAM-1 was higher in VCI (VCI: 450.7 [241.6] ng/mL vs. controls: 296.9 [140.9] ng/mL). sICAM-1 concentrations above the 90th percentile (464.1 ng/mL) were associated with VCI group membership in all models (OR: 6.9, 95% CI: 1.1-42.2). The final saturated model explained 64% of the variance in VCI group membership.

Conclusion: High concentrations of sICAM-1 are independently associated with VCI group membership. Efforts to further characterize the relationship between indices of endothelial dysfunction and pathological changes to the aging brain should be further pursued.
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http://dx.doi.org/10.1159/000500068DOI Listing
January 2020

Distribution of Capsular Types of Isolates from Symptomatic and Asymptomatic Children in Peru.

Am J Trop Med Hyg 2019 09;101(3):541-548

Enteric Diseases Department, Infectious Diseases Directorate, Naval Medical Research Center, Silver Spring, Maryland.

is the leading bacterial cause of diarrhea worldwide. A capsular polysaccharide (CPS) conjugate vaccine is under development and requires determination of the valency. However, distribution of CPS types circulating globally is presently poorly described. We aimed to determine whether CPS type distribution in Peru differs from that in other endemic regions. We used a multiplex polymerase chain reaction (PCR) assay for the detection of CPS encoding genes capable of distinguishing all 35 CPS types on isolates in two prospective communities based studies conducted in cohorts of children less than 59 months of age in Peru. Results showed that CPS type HS4 complex was the most prevalent, followed by HS3 complex and HS15. Differences in CPS type for symptomatology were not statistically significant. Most subjects demonstrated repeated infections over time with different CPS types, suggesting that CPS types may confer of a level of homologous protective immunity. In this dataset, some differences in CPS type distribution were observed in comparison to other low-middle income countries. Further studies need to be conducted in endemic areas to increase our knowledge of CPS type distribution and guide vaccine development.
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http://dx.doi.org/10.4269/ajtmh.18-0994DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6726929PMC
September 2019

Examining the Association between Life-Space Mobility and Cognitive Function in Older Adults: A Systematic Review.

J Aging Res 2019 2;2019:3923574. Epub 2019 Jun 2.

School of Rehabilitation Science, McMaster University, Hamilton, ON, Canada L8S 1C7.

Purpose: The purpose of this review is to investigate the relationship between life-space mobility and cognition in older adults.

Methods: MEDLINE, Embase, CINAHL, and PsycINFO were searched through December 2018 for studies containing measures of life-space mobility and cognitive function. Two independent reviewers screened studies. Eligible studies were combined using a random-effects model, and heterogeneity was assessed using the .

Results: Thirty-five articles were identified for review. A moderate and statistically significant association (pooled  = 0.30, 95% confidence interval 0.19 to 0.40.) was observed between life-space mobility and cognition among nine studies. Life-space mobility demonstrated small-to-moderate associations with domain-specific cognitive functioning, particularly executive function, learning, memory, and processing speed. Furthermore, individuals who had restricted life-space mobility (Life-Space Assessment ≤ 40) experienced a steeper decline in cognition ( = 0.56 and  = 0.0471) compared to those who did not (Life-Space Assessment ≥ 41).

Conclusion: This review examined the association between life-space mobility and cognitive function in older adults. The results suggest that a moderate relationship between life-space mobility and cognition exists, whether adjusted or unadjusted for covariates such as sociodemographics, mental health, functional capacity, and comorbidities.
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http://dx.doi.org/10.1155/2019/3923574DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6589294PMC
June 2019

Monocyte chemoattractant protein-1 (MCP-1) and fibroblast growth factor-21 (FGF-21) as biomarkers of subclinical atherosclerosis in women.

Exp Gerontol 2019 09 29;124:110624. Epub 2019 May 29.

Research Unit in Epidemiology and Health Services, Centro Medico Nacional, Instituto Mexicano del Seguro Social (IMSS), Mexico. Electronic address:

Background: Atherosclerosis is a primary risk factor for cardiovascular disease (CVD). Proinflammatory biochemical factors can influence vascular health; monocyte chemoattractant protein-1 (MCP-1) is elevated in patients with CVD while fibroblast growth factor-21 (FGF-21) acts directly on cardiac tissue to reduce infarction damage. However, the relationship between plasma concentrations of MCP-1, FGF-21 and subclinical CVD indices remains equivocal.

Aim: To determine the association between MCP-1, FGF-21 and subclinical atherosclerosis [i.e., carotid intima-media thickness (cIMT)] in women without clinical evidence of CVD.

Methods: A cross-sectional analysis of 140 women without history of CVD was performed. Anthropometrics were collected, serum concentrations of MCP-1 and FGF-21 were determined by enzyme-linked immunosorbent assay, and cIMT was quantified (B-mode ultrasonography). The correlations between MCP-1, FGF-21 and the presence of clinical and laboratory of subclinical atherosclerosis (i.e., cIMT ≥0.70 mm), comparison intergroup and odd ratio with multiple logistic regression were analyzed.

Results: MCP-1, but not FGF-21 correlated with some obesity indicators. In median comparison among groups, subclinical atherosclerosis showed higher serum concentrations of MCP-1and lower serum concentrations of FGF-21. In postmenopausal women, there were significant differences MCP-1 (p = 0.001), and FGF-21 (p = 0.010). Multiple logistic regression analysis in postmenopausal women with subclinical atherosclerosis, between MCP-1 (p = 0.001) and FGF-21 (p = 0.037) showed association with cIMT, along with age.

Conclusions: MCP-1 and FGF-21 levels are associated with subclinical atherosclerosis disease severity (i.e., cIMT) in postmenopausal women without CVD. Further efforts focused on characterizing the relationship between novel blood-borne markers of early CVD pathology are warranted and should be pursued.
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http://dx.doi.org/10.1016/j.exger.2019.05.013DOI Listing
September 2019

Sequence Variation Associated with SLC12A5 Gene Expression Is Linked to Brain Structure and Function in Healthy Adults.

Cereb Cortex 2019 12;29(11):4654-4661

Section on Integrative Neuroimaging, Clinical and Translational Neuroscience Branch, National Institute of Mental Health Intramural Research Program, National Institutes of Health, Bethesda, MD, USA.

A single-nucleotide polymorphism in the promoter region of the Matrix Metalloproteinase-9 (MMP9) gene, rs3918242, has been shown to affect MMP9 expression in macrophages and was associated with schizophrenia by two independent groups. However, rs3918242's effects on MMP9 expression were not replicable in cell lines or brain tissue. Additionally, publically available data indicate that rs3918242 genotype is related not to MMP9 expression, but rather to expression of SLC12A5, a nearby gene coding for a K+/Cl- cotransporter, whose expression has also been related to schizophrenia. Here, we studied brain structure and function in healthy participants stratified by rs3918242 genotype using structural MRI (N = 298), functional MRI during an N-back working memory task (N = 554), and magnetoencephalography (MEG) during the same task (N = 190). We found rs3918242 was associated with gray matter volume (GMV) in the insula and dorsolateral prefrontal cortex bilaterally, closely replicated in discovery and replication samples; and with inferior parietal lobule (IPL) GMV when the samples were meta-analytically combined. Additionally, using both fMRI and MEG, rs3918242 was associated with right IPL working memory-related activation, replicated in two cohorts and across imaging modalities. These convergent results provide further impetus for examinations of the relationship of SLC12A5 with brain structure and function in neuropsychiatric disease.
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http://dx.doi.org/10.1093/cercor/bhy344DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6917513PMC
December 2019

Influence of Transmembrane Helix Mutations on Cytochrome P450-Membrane Interactions and Function.

Biophys J 2019 02 3;116(3):419-432. Epub 2019 Jan 3.

Molecular and Cellular Modeling Group, Heidelberg Institute for Theoretical Studies, Heidelberg, Germany; Zentrum für Molekulare Biologie der Universität Heidelberg, DKFZ-ZMBH Alliance, Heidelberg, Germany; Interdisciplinary Center for Scientific Computing, Heidelberg University, Heidelberg, Germany. Electronic address:

Human cytochrome P450 (CYP) enzymes play an important role in the metabolism of drugs, steroids, fatty acids, and xenobiotics. Microsomal CYPs are anchored in the endoplasmic reticulum membrane by an N-terminal transmembrane (TM) helix that is connected to the globular catalytic domain by a flexible linker sequence. However, the structural and functional importance of the TM-helix is unclear because it has been shown that CYPs can still associate with the membrane and have enzymatic activity in reconstituted systems after truncation or modification of the N-terminal sequence. Here, we investigated the effect of mutations in the N-terminal TM-helix residues of two human steroidogenic enzymes, CYP 17A1 and CYP 19A1, that are major drug targets for cancer therapy. These mutations were originally introduced to increase the expression of the proteins in Escherichia coli. To investigate the effect of the mutations on protein-membrane interactions and function, we carried out coarse-grained and all-atom molecular dynamics simulations of the CYPs in a phospholipid bilayer. We confirmed the orientations of the globular domain in the membrane observed in the simulations by linear dichroism measurements in a Nanodisc. Whereas the behavior of CYP 19A1 was rather insensitive to truncation of the TM-helix, mutations in the TM-helix of CYP 17A1, especially W2A and E3L, led to a gradual drifting of the TM-helix out of the hydrophobic core of the membrane. This instability of the TM-helix could affect interactions with the allosteric redox partner, cytochrome b5, required for CYP 17A1's lyase activity. Furthermore, the simulations showed that the mutant TM-helix influenced the membrane interactions of the CYP 17A1 globular domain. In some simulations, the mutated TM-helix obstructed the substrate access tunnel from the membrane to the CYP active site, indicating a possible effect on enzyme function.
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http://dx.doi.org/10.1016/j.bpj.2018.12.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6369400PMC
February 2019

Evaluating the discriminating capacity of cell death (apoptotic) biomarkers in sepsis.

J Intensive Care 2018 13;6:72. Epub 2018 Nov 13.

1Biological Defense Research Directorate, Naval Medical Research Center, 503 Robert Grant Avenue, Silver Spring, MD 20910 USA.

Background: Sepsis biomarker panels that provide diagnostic and prognostic discrimination in sepsis patients would be transformative to patient care. We assessed the mortality prediction and diagnostic discriminatory accuracy of two biomarkers reflective of cell death (apoptosis), circulating cell-free DNA (cfDNA), and nucleosomes.

Methods: The cfDNA and nucleosome levels were assayed in plasma samples acquired in patients admitted from four emergency departments with suspected sepsis. Subjects with non-infectious systemic inflammatory response syndrome (SIRS) served as controls. Samples were acquired at enrollment (T0) and 24 h later (T24). We assessed diagnostic (differentiating SIRS from sepsis) and prognostic (28-day mortality) predictive power. Models incorporating procalcitonin (diagnostic prediction) and APACHE II scores (mortality prediction) were generated.

Results: Two hundred three subjects were included (107 provided procalcitonin measurements). Four subjects exhibited uncomplicated sepsis, 127 severe sepsis, 35 septic shock, and 24 had non-infectious SIRS. There were 190-survivors and 13 non-survivors. Mortality prediction models using cfDNA, nucleosomes, or APACHEII yielded AUC values of 0.61, 0.75, and 0.81, respectively. A model combining nucleosomes with the APACHE II score improved the AUC to 0.84. Diagnostic models distinguishing sepsis from SIRS using procalcitonin, cfDNA(T0), or nucleosomes(T0) yielded AUC values of 0.64, 0.65, and 0.63, respectively. The three parameter model yielded an AUC of 0.74.

Conclusions: To our knowledge, this is the first head-to-head comparison of cfDNA and nucleosomes in diagnosing sepsis and predicting sepsis-related mortality. Both cfDNA and nucleosome concentrations demonstrated a modest ability to distinguish sepsis survivors and non-survivors and provided additive diagnostic predictive accuracy in differentiating sepsis from non-infectious SIRS when integrated into a diagnostic prediction model including PCT and APACHE II. A sepsis biomarker strategy incorporating measures of the apoptotic pathway may serve as an important component of a sepsis diagnostic and mortality prediction tool.
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http://dx.doi.org/10.1186/s40560-018-0341-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6234551PMC
November 2018

The Impact of Blood Pressure Dipping Status on Cognition, Mobility, and Cardiovascular Health in Older Adults Following an Exercise Program.

Gerontol Geriatr Med 2018 Jan-Dec;4:2333721418770333. Epub 2018 Apr 23.

Western University, London, Ontario, Canada.

To determine whether a dual-task gait and aerobic exercise intervention differentially impacted older adults with normal blood pressure (BP) dipping status (dippers) compared to those with nondipping status (nondippers). This study was a secondary analysis involving participants (mean age = 70.3 years, 61% women) who attended a laboratory-based exercise intervention over a 6-month period (40 min/day and 3 days/week). Participants were assessed in measures of cognition, mobility, and cardiovascular health at baseline, 3, 6, and 12 months (after a 6-month no-contact follow-up). We observed improvements in cognition in both groups at 6 and 12 months, although no between-group differences were seen. Nondippers demonstrated superior improvements in usual gait velocity and step length after the exercise intervention compared to dippers. Dippers reduced daytime systolic BP at 6 and 12 months to a greater extent than nondippers. BP dipping status at baseline did not influence exercise benefits to cognition but did mediate changes in mobility and cardiovascular health.
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http://dx.doi.org/10.1177/2333721418770333DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5946337PMC
April 2018

Human Cytochrome CYP17A1: The Structural Basis for Compromised Lyase Activity with 17-Hydroxyprogesterone.

J Am Chem Soc 2018 06 5;140(23):7324-7331. Epub 2018 Jun 5.

Department of Chemistry , Marquette University , Milwaukee , Wisconsin 53233 , United States.

The multifunctional enzyme, cytochrome P450 (CYP17A1), plays a crucial role in the production of androgens, catalyzing two key reactions on pregnenolone (PREG) and progesterone (PROG), the first being a 17-hydroxylation to generate 17-OH PREG and 17-OH PROG, with roughly equal efficiencies. The second is a C-C bond scission or "lyase" reaction in which the C17-C20 bond is cleaved, leading to the eventual production of powerful androgens, whose involvement in the proliferation of prostate cancer has generated intense interest in developing inhibitors of CYP17A1. For humans, the significance of the C-C bond cleavage of 17-OH PROG is lessened, because it is about 50 times less efficient than for 17-OH PREG in terms of k/K. Recognizing the need to clarify relevant reaction mechanisms involved with such transformations, we first report studies of solvent isotope effects, results of which are consistent with a Compound I mediated PROG hydroxylase activity, yet exclude this intermediate as a participant in the formation of androstenedione (AD) via the lyase reaction. This finding is also supported by a combination of cryoreduction and resonance Raman spectroscopy that traps and structurally characterizes the key hemiketal reaction intermediates. Adding to a previous study of PREG and 17-OH PREG metabolism, the current work provides definitive evidence for a more facile protonation of the initially formed ferric peroxo-intermediate for 17-OH PROG-bound CYP17A1, compared to the complex with 17-OH PREG. Importantly, Raman characterization also reveals an H-bonding interaction with the terminal oxygen of the peroxo fragment, rather than with the proximal oxygen, as is present for 17-OH PREG. These factors would favor a diminished lyase activity of the sample with 17-OH PROG relative to the complex with 17-OH PREG, thereby providing a convincing structural explanation for the dramatic differences in activity for these lyase substrates in humans.
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http://dx.doi.org/10.1021/jacs.8b03901DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5999583PMC
June 2018

A method for determining haploid and triploid genotypes and their association with vascular phenotypes in Williams syndrome and 7q11.23 duplication syndrome.

BMC Med Genet 2018 04 4;19(1):53. Epub 2018 Apr 4.

Section on Integrative Neuroimaging, Clinical and Translational Neuroscience Branch, National Institute of Mental Health, National Institutes of Health, 10 Center Drive 3C-216, Bethesda, MD, 20892, USA.

Background: Williams syndrome ([WS], 7q11.23 hemideletion) and 7q11.23 duplication syndrome (Dup7) show contrasting syndromic symptoms. However, within each group there is considerable interindividual variability in the degree to which these phenotypes are expressed. Though software exists to identify areas of copy number variation (CNV) from commonly-available SNP-chip data, this software does not provide non-diploid genotypes in CNV regions. Here, we describe a method for identifying haploid and triploid genotypes in CNV regions, and then, as a proof-of-concept for applying this information to explain clinical variability, we test for genotype-phenotype associations.

Methods: Blood samples for 25 individuals with WS and 13 individuals with Dup7 were genotyped with Illumina-HumanOmni5M SNP-chips. PennCNV and in-house code were used to make genotype calls for each SNP in the 7q11.23 locus. We tested for association between the presence of aortic arteriopathy and genotypes of the remaining (haploid in WS) or duplicated (triploid in Dup7) alleles.

Results: Haploid calls in the 7q11.23 region were made for 99.0% of SNPs in the WS group, and triploid calls for 98.8% of SNPs in those with Dup7. The G allele of SNP rs2528795 in the ELN gene was associated with aortic stenosis in WS participants (p < 0.0049) while the A allele of the same SNP was associated with aortic dilation in Dup7.

Conclusions: Commonly available SNP-chip information can be used to make haploid and triploid calls in individuals with CNVs and then to relate variability in specific genes to variability in syndromic phenotypes, as demonstrated here using aortic arteriopathy. This work sets the stage for similar genotype-phenotype analyses in CNVs where phenotypes may be more complex and/or where there is less information about genetic mechanisms.
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http://dx.doi.org/10.1186/s12881-018-0563-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5883342PMC
April 2018

Nanodiscs: A Controlled Bilayer Surface for the Study of Membrane Proteins.

Annu Rev Biophys 2018 May 1;47:107-124. Epub 2018 Mar 1.

Department of Biochemistry, University of Illinois, Urbana, Illinois 61801, USA; email:

The study of membrane proteins and receptors presents many challenges to researchers wishing to perform biophysical measurements to determine the structure, function, and mechanism of action of such components. In most cases, to be fully functional, proteins and receptors require the presence of a native phospholipid bilayer. In addition, many complex multiprotein assemblies involved in cellular communication require an integral membrane protein as well as a membrane surface for assembly and information transfer to soluble partners in a signaling cascade. Incorporation of membrane proteins into Nanodiscs renders the target soluble and provides a native bilayer environment with precisely controlled composition of lipids, cholesterol, and other components. Likewise, Nanodiscs provide a surface of defined area useful in revealing lipid specificity and affinities for the assembly of signaling complexes. In this review, we highlight several biophysical techniques made possible through the use of Nanodiscs.
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http://dx.doi.org/10.1146/annurev-biophys-070816-033620DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6370528PMC
May 2018

The other Campylobacters: Not innocent bystanders in endemic diarrhea and dysentery in children in low-income settings.

PLoS Negl Trop Dis 2018 02 7;12(2):e0006200. Epub 2018 Feb 7.

Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, United States of America.

Background: Campylobacter is one of the main causes of gastroenteritis worldwide. Most of the current knowledge about the epidemiology of this food-borne infection concerns two species, C. coli and C. jejuni. Recent studies conducted in developing countries and using novel diagnostic techniques have generated evidence of the increasing burden and importance of other Campylobacter species, i.e. non-C. coli/jejuni. We performed a nested case-control study to compare the prevalence of C. coli/jejuni and other Campylobacter in children with clinical dysentery and severe diarrhea as well as without diarrhea to better understand the clinical importance of infections with Campylobacter species other than C. coli/jejuni.

Methodology/principal Findings: Our nested case-control study of 439 stool samples included dysenteric stools, stools collected during severe diarrhea episodes, and asymptomatic stools which were systematically selected to be representative of clinical phenotypes from 9,160 stools collected during a birth cohort study of 201 children followed until two years of age. Other Campylobacter accounted for 76.4% of the 216 Campylobacter detections by qPCR and were more prevalent than C. coli/jejuni across all clinical groups. Other Campylobacter were also more prevalent than C. coli/jejuni across all age groups, with older children bearing a higher burden of other Campylobacter. Biomarkers of intestinal inflammation and injury (methylene blue, fecal occult test, myeloperoxidase or MPO) showed a strong association with dysentery, but mixed results with infection. MPO levels were generally higher among children infected with C. coli/jejuni, but Shigella-infected children suffering from dysentery recorded the highest levels (26,224 ng/mL); the lowest levels (10,625 ng/mL) were among asymptomatic children infected with other Campylobacter. Adjusting for age, sex, and Shigella infection, dysentery was significantly associated with C. coli/jejuni but not with other Campylobacter, whereas severe diarrhea was significantly associated with both C. coli/jejuni and other Campylobacter. Compared to asymptomatic children, children suffering from dysentery had a 14.6 odds of C. coli/jejuni infection (p-value < 0.001, 95% CI 5.5-38.7) but were equally likely to have other Campylobacter infections-odds ratio of 1.3 (0.434, 0.7-2.4). Children suffering from severe diarrhea were more likely than asymptomatic children to test positive for both C. coli/jejuni and other Campylobacter-OR of 2.8 (0.034, 1.1-7.1) and 1.9 (0.018, 1.1-3.1), respectively. Compared to the Campylobacter-free group, the odds of all diarrhea given C. coli/jejuni infection and other Campylobacter infection were 8.8 (<0.001, 3.0-25.7) and 2.4 (0.002, 1.4-4.2), respectively. Eliminating other Campylobacter in this population would eliminate 24.9% of the diarrhea cases, which is almost twice the population attributable fraction of 15.1% due to C. coli/jejuni.

Conclusions/significance: Eighty-seven percent of the dysentery and 59.5% of the severe diarrhea samples were positive for Campylobacter, Shigella, or both, emphasizing the importance of targeting these pathogens to limit the impact of dysentery and severe diarrhea in children. Notably, the higher prevalence of other Campylobacter compared to C. coli/jejuni, their increasing burden during early childhood, and their association with severe diarrhea highlight the importance of these non-C. coli/jejuni Campylobacter species and suggest a need to clarify their importance in the etiology of clinical disease across different epidemiological contexts.
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http://dx.doi.org/10.1371/journal.pntd.0006200DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5819825PMC
February 2018

Human P450 CYP17A1: Control of Substrate Preference by Asparagine 202.

Biochemistry 2018 02 24;57(5):764-771. Epub 2018 Jan 24.

Department of Biochemistry, University of Illinois at Urbana-Champaign , 505 South Goodwin Avenue, Urbana, Illinois 61801, United States.

CYP17A1 is a key steroidogenic enzyme known to conduct several distinct chemical transformations on multiple substrates. In its hydroxylase activity, this enzyme adds a hydroxyl group at the 17α position of both pregnenolone and progesterone at approximately equal rates. However, the subsequent 17,20 carbon-carbon scission reaction displays variable substrate specificity in the numerous CYP17A1 isozymes operating in vertebrates, manifesting as different K and k values when presented with 17α-hydroxypregnenlone (OHPREG) versus 17α-hydroxyprogesterone (OHPROG). Here we show that the identity of the residue at position 202 in human CYP17A1, thought to form a hydrogen bond with the A-ring alcohol substituent on the pregnene- nucleus, is a key driver of this enzyme's native preference for OHPREG. Replacement of asparagine 202 with serine completely reverses the preference of CYP17A1, more than doubling the rate of turnover of the OHPROG to androstenedione reaction and substantially decreasing the rate of formation of dehydroepiandrosterone from OHPREG. In a series of resonance Raman experiments, it was observed that, in contrast with the case for the wild-type protein, in the mutant the 17α alcohol of OHPROG tends to form a H-bond with the proximal rather than terminal oxygen of the oxy-ferrous complex. When OHPREG was a substrate, the mutant enzyme was found to have a H-bonding interaction with the proximal oxygen that is substantially weaker than that of the wild type. These results demonstrate that a single-point mutation in the active site pocket of CYP17A1, even when far from the heme, has profound effects on steroidogenic selectivity in androgen biosynthesis.
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http://dx.doi.org/10.1021/acs.biochem.7b01067DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5801141PMC
February 2018

Multiple-modality exercise and mind-motor training to improve mobility in older adults: A randomized controlled trial.

Exp Gerontol 2018 03 17;103:17-26. Epub 2017 Dec 17.

School of Kinesiology, Faculty of Health Sciences, Western University, London, ON, Canada; Lawson Health Research Institute, London, ON, Canada; Health & Rehabilitation Sciences, Faculty of Health Sciences, Western University, London, ON, Canada; Centre for Studies in Family Medicine, Department of Family Medicine, Western University, London, ON, Canada; Canadian Centre for Activity and Aging, Western University, London, ON, Canada. Electronic address:

Objective: To investigate the effects of multiple-modality exercise with or without additional mind-motor training on mobility outcomes in older adults with subjective cognitive complaints.

Methods: This was a 24-week randomized controlled trial with a 28-week no-contact follow-up. Community-dwelling older adults underwent a thrice -weekly, Multiple-Modality exercise and Mind-Motor (M4) training or Multiple-Modality (M2) exercise with an active control intervention (balance, range of motion and breathing exercises). Study outcomes included differences between groups at 24weeks and after the no-contact follow-up (i.e., 52weeks) in usual and dual-task (DT, i.e., serial sevens [S7] and phonemic verbal fluency [VF] tasks) gait velocity, step length and cycle time variability, as well as DT cognitive accuracy.

Results: 127 participants (mean age 67.5 [7.3] years, 71% women) were randomized to either M2 (n=64) or M4 (n=63) groups. Participants were assessed at baseline, intervention endpoint (24weeks), and study endpoint (52weeks). At 24weeks, the M2 group demonstrated greater improvements in usual gait velocity, usual step length, and DT gait velocity (VF) compared to the M4 group, and no between- or within-group changes in DT accuracy were observed. At 52weeks, the M2 group retained the gains in gait velocity and step length, whereas the M4 group demonstrated trends for improvement (p=0.052) in DT cognitive accuracy (VF).

Conclusions: Our results suggest that additional mind-motor training was not effective to improve mobility outcomes. In fact, participants in the active control group experienced greater benefits as a result of the intervention.
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http://dx.doi.org/10.1016/j.exger.2017.12.011DOI Listing
March 2018

Melioidosis in lower provincial Cambodia: A case series from a prospective study of sepsis in Takeo Province.

PLoS Negl Trop Dis 2017 Sep 13;11(9):e0005923. Epub 2017 Sep 13.

Naval Medical Research Center, Biological Defense Research Directorate, Ft. Detrick, Maryland, United States of America.

Melioidosis is a severe infectious disease caused by the gram-negative soil bacterium Burkholderia pseudomallei. Melioidosis is well known to be a major cause of morbidity and mortality in Southeast Asia, particularly in Thailand. However, melioidosis remains underreported in surrounding areas such as Cambodia. We report a case series of melioidosis in seven patients from Takeo Province, Cambodia. The patients, aged 24-65 years, were enrolled from May 2014 to May 2015 during a one year prospective study of sepsis at Takeo Provincial Hospital. They presented with fever, rigors, dyspnea, fatigue, diaphoresis, productive cough, and skin abscesses. Six of the seven patients were also hyponatremic. B. pseudomallei was cultured from the blood of six patients and the sputum of one patient. In this manuscript, we provide a detailed description of the clinical presentation, case management and laboratory confirmation of B. pseudomallei, as well as discuss the difficulties of identifying and treating melioidosis in low resource settings.
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http://dx.doi.org/10.1371/journal.pntd.0005923DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5612750PMC
September 2017