Canine models of Charcot-Marie-Tooth: MTMR2, MPZ, and SH3TC2 variants in golden retrievers with congenital hypomyelinating polyneuropathy.

Congenital hypomyelinating polyneuropathy (HPN) restricted to the peripheral nervous system was reported in 1989 in two Golden Retriever (GR) littermates. Recently, four additional cases of congenital HPN in young, unrelated GRs were diagnosed via neurological examination, electrodiagnostic evaluation, and peripheral nerve pathology. Whole-genome sequencing was performed on all four GRs, and variants from each dog were compared to variants found across >1,000 other dogs, all presumably unaffected with HPN. Likely causative variants were identified for each HPN-affected GR. Two cases shared a homozygous splice donor site variant in MTMR2, with a stop codon introduced within six codons following the inclusion of the intron. One case had a heterozygous MPZ isoleucine to threonine substitution. The last case had a homozygous SH3TC2 nonsense variant predicted to truncate approximately one-half of the protein. Haplotype analysis using 524 GR established the novelty of the identified variants. Each variant occurs within genes that are associated with the human Charcot-Marie-Tooth (CMT) group of heterogeneous diseases, affecting the peripheral nervous system. Testing a large GR population (n = >200) did not identify any dogs with these variants. Although these variants are rare within the general GR population, breeders should be cautious to avoid propagating these alleles

Androgen Receptor Inhibition Suppresses Anti-Tumor Neutrophil Response Against Bone Metastatic Prostate Cancer via Regulation of TβRI Expression

Bone metastatic disease of prostate cancer (PCa) is incurable and progression in bone is largely dictated by tumor-stromal interactions in the bone microenvironment. We showed previously that bone neutrophils initially inhibit bone metastatic PCa growth yet metastatic PCa becomes resistant to neutrophil response. Further, neutrophils isolated from tumor-bone lost their ability to suppress tumor growth through unknown mechanisms. With this study, our goal was to define the impact of metastatic PCa on neutrophil function throughout tumor progression and to determine the potential of neutrophils as predictive biomarkers of metastatic disease. Using patient peripheral blood polymorphonuclear neutrophils (PMNs), we identified that PCa progression dictates PMN cell surface markers and gene expression, but not cytotoxicity against PCa. Importantly, we also identified a novel phenomenon in which second generation androgen deprivation therapy (ADT) suppresses PMN cytotoxicity via increased transforming growth factor beta receptor I (TβRI). High dose testosterone and genetic or pharmacologic TβRI inhibition rescued androgen receptor-mediated neutrophil suppression and restored neutrophil anti-tumor immune response. These studies highlight the ability to leverage standard-care ADT to generate neutrophil anti-tumor responses against bone metastatic PCa

Parental agreement of reporting parent to child aggression using the Conflict Tactics Scales

Objectives: This study examined mothers’ and fathers’ reporting congruency using the Parent–Child Conflict Tactics Scales. We asked if the mother’s report of the father’s parenting aggression was consistent with the father’s self-report of parenting aggression and if the father’s report of the mother’s parenting aggression was consistent with the mother’s selfreport of those same behaviors. We assessed moderators of parental reporting congruency: severity of the aggression, interparental conflict, child temperament, and child gender. Methods: Participants were from the Child Development Project, a longitudinal study beginning when children were in kindergarten. The analyses herein included 163 children for whom 2 parents provided data about their own and their spouse or partner’s behavior toward the child. Most parents (87%) were married. Mothers and fathers independently completed the Parent–Child Conflict Tactics Scale, both with respect to their own behavior toward the child and with respect to their partner’s behavior toward the child. Mothers completed the retrospective Infant Characteristics Questionnaire to assess child temperament. Mothers and fathers completed measures of interparental conflict. Results: Both fathers and mothers self-reported more frequently engaging in each behavior than the other parent reported they did. Parents were more congruent on items assessing harsher parenting behavior. Furthermore, there was more agreement between parents regarding fathers’ behavior than mothers’ behavior. Analyses of interparental conflict, child difficult temperament, and child gender as moderators yielded findings suggesting that mothers’ and fathers’ reports of their own and their spouses’ harsh parenting behaviors were more concordant in couples with low levels of conflict, for children with easy temperaments, and for boys versus girls. Conclusions: Prior studies indicate only a moderate level of agreement in couples’ reports of violence between intimate partners and suggest that perpetrators tend to underreport their use of aggression. The results of this study suggest that parents may be more consistent in their reports of parent to child violence using the Parent–Child Conflict Tactics Scales than they are when reporting intimate partner violence. The results suggest that parental reports of their spouse’s parent to child aggression are reliable.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/106161/1/2012-Lee Lansford et al CTSPC.pd

The motivations for the adoption of management innovation by local governments and its performance effects

This article analyses the economic, political and institutional antecedents and performance effects of the adoption of shared Senior Management Teams (SMTs) – a management innovation (MI) that occurs when a team of senior managers oversees two or more public organizations. Findings from statistical analysis of 201 English local governments and interviews with organizational leaders reveal that shared SMTs are adopted to develop organisational capacity in resource‐challenged, politically risk‐averse governments, and in response to coercive and mimetic institutional pressures. Importantly, sharing SMTs may reduce rather than enhance efficiency and effectiveness due to redundancy costs and the political transaction costs associated with diverting resources away from a high‐performing partner to support their lower‐performing counterpart

ABCG2 Polymorphisms and Predictive Fluoroquinolone Phototoxicity in Nondomestic Felids

Fluoroquinolones are a widely used class of chemotherapeutics within veterinary medicine, prized for their broad-spectrum bactericidal activity. These drugs present a known risk of retinal phototoxicity in domestic cats (Felis catus); therefore, using lower doses and alternative antibiotic classes is encouraged in this species. This adverse drug effect of fluoroquinolones, and enrofloxacin specifically, has been determined to be species-specific in domestic felids. Four feline-specific missense variants in ABCG2 result in four amino acid changes (E159M, S279L, H283Q, and T644I) that are unique to the domestic cat compared with multiple other nonfeline mammalian species. These changes alter the ABCG2 protein involved with the cellular transmembrane transport of drugs, including fluoroquinolones, making the protein functionally defective in domestic cats. The predisposition to fluoroquinolone-mediated phototoxicity in nondomestic felids was explored in this study. At least eight nondomestic felids share the four ABCG2 missense variants with domestic cats, and eleven other felids shared at least three of the four domestic cat variants. Taken together, these results suggest the genetic potential for nondomestic felids to also experience fluoroquinolone-induced retinal phototoxicity; therefore, cautions similar to those for domestic cats should be followed for these drugs in the entire feline taxon

Association Between Sarcopenic Obesity and Falls in a Multiethnic Cohort of Postmenopausal Women

ObjectivesTo investigate associations between sarcopenia, obesity, and sarcopenic obesity and incidence of falls in a racially and ethnically diverse cohort of healthy postmenopausal women.DesignProspective cohort study.SettingThree Women's Health Initiative (WHI) clinical centers (Tucson-Phoenix, AZ; Pittsburgh, PA; Birmingham, AL).ParticipantsPostmenopausal women aged 50 to 79 enrolled in the WHI who underwent bone and body composition scans using dual-energy x-ray absorptiometry at baseline (N = 11,020).MeasurementsSarcopenia was defined as the lowest 20th percentile of appendicular lean mass, correcting for height and body fat. Obesity was defined as a body fat percentage greater than 42%. Sarcopenic obesity was defined as co-occurrence of sarcopenia and obesity. The fall outcome was defined as falling 2 or more times in any year during 7 years of follow-up. The risk of falls associated with sarcopenic obesity were analyzed using log binomial regression models stratified according to age and race/ethnicity.ResultsSarcopenic obesity was associated with greater risk of falls in women aged 50 to 64 (relative risk (RR) = 1.35, 95% confidence interval (CI)=1.17-1.56) and 65 to 79 (RR = 1.21, 95% CI=1.05-1.39). Sarcopenic obesity related fall risk was higher in Hispanic women (RR = 2.40, 95% CI=1.56-3.67) than non-Hispanic white women (RR = 1.24, 95% CI=1.11-1.39).ConclusionIn a multiethnic cohort of postmenopausal women, sarcopenic obesity-related fall risk was high in women younger than 65 and those age 65 and older. Sarcopenic obesity posed the highest risk for falls in Hispanic women. The findings support identification of causal factors and health disparities in sarcopenic obesity to customize fall prevention strategies and ameliorate this significant public health burden. J Am Geriatr Soc 66:2314-2320, 2018