Pamidronate Administration During Pregnancy and Lactation Induces Temporal Preservation of Maternal Bone Mass in a Mouse Model of Osteogenesis Imperfecta

During pregnancy and lactation, the maternal skeleton undergoes significant bone loss through increased resorption to provide the necessary calcium supply to the developing fetus and suckling neonate. This period of skeletal vulnerability has not been clearly associated with increased maternal fracture risk, but these physiological conditions can exacerbate an underlying metabolic bone condition like osteogenesis imperfecta. Although bisphosphonates (BPs) are commonly used in postmenopausal women, there are cases where premenopausal women taking BPs become pregnant. Given BPs’ long half‐life, there is a need to establish how BPs affect the maternal skeleton during periods of demanding metabolic bone changes that are critical for the skeletal development of their offspring. In the present study, pamidronate‐ (PAM‐) amplified pregnancy‐induced bone mass gains and lactation‐induced bone loss were prevented. This preservation of bone mass was less robust when PAM was administered at late stages of lactation compared with early pregnancy and first day of lactation. Pregnancy‐induced osteocyte osteolysis was also observed and was unaffected with PAM treatment. No negative skeletal effects were observed in offspring from PAM‐treated dams despite lactation‐induced bone loss prevention. These findings provide important insight into (1) a treatment window for when PAM is most effective in preserving maternal bone mass, and (2) the maternal changes in bone metabolism that maintain calcium homeostasis crucial for fetal and neonatal bone development. © 2019 American Society for Bone and Mineral ResearchPeer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/153136/1/jbmr3831.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/153136/2/jbmr3831_am.pd

Landscape of coordinated immune responses to H1N1 challenge in humans

Influenza is a significant cause of morbidity and mortality worldwide. Here we show changes in the abundance and activation states of more than 50 immune cell subsets in 35 individuals over 11 time points during human A/California/2009 (H1N1) virus challenge monitored using mass cytometry along with other clinical assessments. Peak change in monocyte, B cell, and T cell subset frequencies coincided with peak virus shedding, followed by marked activation of T and NI< cells. Results led to the identification of C038 as a critical regulator of plasmacytoid dendritic cell function in response to influenza virus. Machine learning using study-derived clinical parameters and single-cell data effectively classified and predicted susceptibility to infection. The coordinated immune cell dynamics defined in this study provide a framework for identifying novel correlates of protection in the evaluation of future influenza therapeutics

Voluntary exercise inhibits intestinal tumorigenesis in ApcMin/+ mice and azoxymethane/dextran sulfate sodium-treated mice

<p>Abstract</p> <p>Background</p> <p>Epidemiological studies suggest that physical activity reduces the risk of colon cancer in humans. Results from animal studies, however, are inconclusive. The present study investigated the effects of voluntary exercise on intestinal tumor formation in two different animal models, <it>Apc</it>^Min/+mice and azoxymethane (AOM)/dextran sulfate sodium (DSS)-treated mice.</p> <p>Methods</p> <p>In Experiments 1 and 2, five-week old female <it>Apc</it>^Min/+mice were either housed in regular cages or cages equipped with a running wheel for 6 weeks (for mice maintained on the AIN93G diet; Experiment 1) or 9 weeks (for mice on a high-fat diet; Experiment 2). In Experiment 3, male CF-1 mice at 6 weeks of age were given a dose of AOM (10 mg/kg body weight, i.p.) and, 12 days later, 1.5% DSS in drinking fluid for 1 week. The mice were then maintained on a high-fat diet and housed in regular cages or cages equipped with a running wheel for 16 weeks.</p> <p>Results</p> <p>In the <it>Apc</it>^Min/+mice maintained on either the AIN93G or the high-fat diet, voluntary exercise decreased the number of small intestinal tumors. In the AOM/DSS-treated mice maintained on a high-fat diet, voluntary exercise also decreased the number of colon tumors. In <it>Apc</it>^Min/+mice, voluntary exercise decreased the ratio of serum insulin like growth factor (IGF)-1 to IGF binding protein (BP)-3 levels. It also decreased prostaglandin E₂and nuclear ��-catenin levels, but increased E-cadherin levels in the tumors.</p> <p>Conclusion</p> <p>These results indicate hat voluntary exercise inhibited intestinal tumorigenesis in <it>Apc</it>^Min/+mice and AOM/DSS-treated mice, and the inhibitory effect is associated with decreased IGF-1/IGFBP-3 ratio, aberrant β-catenin signaling, and arachidonic acid metabolism.</p

A communal catalogue reveals Earth's multiscale microbial diversity

Our growing awareness of the microbial world's importance and diversity contrasts starkly with our limited understanding of its fundamental structure. Despite recent advances in DNA sequencing, a lack of standardized protocols and common analytical frameworks impedes comparisons among studies, hindering the development of global inferences about microbial life on Earth. Here we present a meta-analysis of microbial community samples collected by hundreds of researchers for the Earth Microbiome Project. Coordinated protocols and new analytical methods, particularly the use of exact sequences instead of clustered operational taxonomic units, enable bacterial and archaeal ribosomal RNA gene sequences to be followed across multiple studies and allow us to explore patterns of diversity at an unprecedented scale. The result is both a reference database giving global context to DNA sequence data and a framework for incorporating data from future studies, fostering increasingly complete characterization of Earth's microbial diversity.Peer reviewe

A communal catalogue reveals Earth’s multiscale microbial diversity

Our growing awareness of the microbial world’s importance and diversity contrasts starkly with our limited understanding of its fundamental structure. Despite recent advances in DNA sequencing, a lack of standardized protocols and common analytical frameworks impedes comparisons among studies, hindering the development of global inferences about microbial life on Earth. Here we present a meta-analysis of microbial community samples collected by hundreds of researchers for the Earth Microbiome Project. Coordinated protocols and new analytical methods, particularly the use of exact sequences instead of clustered operational taxonomic units, enable bacterial and archaeal ribosomal RNA gene sequences to be followed across multiple studies and allow us to explore patterns of diversity at an unprecedented scale. The result is both a reference database giving global context to DNA sequence data and a framework for incorporating data from future studies, fostering increasingly complete characterization of Earth’s microbial diversity

Harmonizing DTI measurements across scanners to examine the development of white matter microstructure in 803 adolescents of the NCANDA study

Neurodevelopment continues through adolescence, with notable maturation of white matter tracts comprising regional fiber systems progressing at different rates. To identify factors that could contribute to regional differences in white matter microstructure development, large samples of youth spanning adolescence to young adulthood are essential to parse these factors. Recruitment of adequate samples generally relies on multi-site consortia but comes with the challenge of merging data acquired on different platforms. In the current study, diffusion tensor imaging (DTI) data were acquired on GE and Siemens systems through the National Consortium on Alcohol and NeuroDevelopment in Adolescence (NCANDA), a multi-site study designed to track the trajectories of regional brain development during a time of high risk for initiating alcohol consumption. This cross-sectional analysis reports baseline Tract-Based Spatial Statistic (TBSS) of regional fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (L1), and radial diffusivity (LT) from the five consortium sites on 671 adolescents who met no/low alcohol or drug consumption criteria and 132 adolescents with a history of exceeding consumption criteria. Harmonization of DTI metrics across manufacturers entailed the use of human-phantom data, acquired multiple times on each of three non-NCANDA participants at each site’s MR system, to determine a manufacturer-specific correction factor. Application of the correction factor derived from human phantom data measured on MR systems from different manufacturers reduced the standard deviation of the DTI metrics for FA by almost a half, enabling harmonization of data that would have otherwise carried systematic error. Permutation testing supported the hypothesis of higher FA and lower diffusivity measures in older adolescents and indicated that, overall, the FA, MD, and L1 of the boys was higher than that of the girls, suggesting continued microstructural development notable in the boys. The contribution of demographic and clinical differences to DTI metrics was assessed with General Additive Models (GAM) testing for age, sex, and ethnicity differences in regional skeleton mean values. The results supported the primary study hypothesis that FA skeleton mean values in the no/low-drinking group were highest at different ages. When differences in intracranial volume were covaried, FA skeleton mean reached a maximum at younger ages in girls than boys and varied in magnitude with ethnicity. Our results, however, did not support the hypothesis that youth who exceeded exposure criteria would have lower FA or higher diffusivity measures than the no/low-drinking group; detecting the effects of excessive alcohol consumption during adolescence on DTI metrics may require longitudinal study

An analysis of the effects of various compounds on alcohol and high-fat-diet-induced steatosis in rats and mice:

Excessive alcohol consumption is known to result in fatty liver, or steatosis. A high-fat, low-carbohydrate diet also results in fatty liver. Furthermore, fatty liver is known to precede cirrhosis in both animals and humans, and cirrhosis precedes primary hepatocellular carcinoma in humans. A series of studies was first undertaken to determine whether exercise and/or certain dietary manipulations could affect fatty liver. Long-Evans rats were given either a high-fat, low-carbohydrate or a high-carbohydrate, low-fat version of liquid diet with or without alcohol. Livers were analyzed for fat and measures of carbohydrate metabolism in liver and plasma were taken, as well as blood glucose alcohol concentrations. Next, added exercise (run wheel), caffeine, antioxidants such as Vitamin E, diphenyl-para-phenylene diamine (DPPD), and selenium were examined as were the dietary additives cranberry powder and soy protein. Finally, based on ambiguous results involving each agent separately, caffeine and DPPD were combined. Following the conclusion of rat studies, C57BL6 mice were given a modified version of the Leiber-deCarli liquid diet with alcohol. The calorie manipulation described above was repeated in mice to determine whether alcohol-induced fatty liver would be exacerbated in the presence of a high-fat diet. Subsequently, the dietary additives Vitamin E, DPPD and Trolox were added. Striatum was taken for HPLC, and livers were taken for liver fat analysis and malondialdehyde (MDA) assay (as a measure of oxidative stress) respectively. Finally, an experiment was undertaken to determine a time course for withdrawal seizures in mice. In rats, differences in liver glycogen did not account for differences in liver fat. Exercise and caffeine both resulted in significant changes in weight gain, and while combined they appeared to reduce alcohol-induced fatty liver, the effect was not significant. Separately, no protective properties of either exercise or caffeine were observed. Vitamin E and selenium were found to exacerbate alcohol-induced fatty liver, while DPPD did not. Neither cranberry powder nor soy protein affected alcohol-induced fatty liver. DPPD combined with caffeine reduced alcohol-induced fatty liver significantly (p<0.05). Adult mice were able to tolerate 4.5% ethanol in a high-fat liquid diet. The high-fat diet resulted in liver fat values significantly higher than high-carbohydrate when combined with alcohol. Vitamin E appeared to exacerbate fatty liver in mice, but differences were not significant. There were significant differences in oxidative stress; Vitamin E and Trolox reduced MDA significantly over diet plus alcohol alone. All animals experienced withdrawal seizures between 3 and 5 hours after removal of alcohol. There were significant differences in serotonin turnover (5HIAA/5HT) in animals fed a high-fat diet without alcohol vs. chow controls.Ph.D.Includes bibliographical references (p. 52-60)by Bonnie Nola

Preoperative Clinical, EEG, and Imaging Findings Do Not Predict Seizure Outcome Following Temporal Lobectomy in Childhood

Although certain clinical, electroencephalographic (EEG), magnetic resonance imaging (MRI), and pathologic findings in adults with intractable temporal lobe epilepsy predict seizure outcome following temporal lobectomy, predictors of seizure outcome have not been studied systematically in pediatric temporal lobectomy series. We retrospectively analyzed preoperative clinical, EEG, and neuroimaging findings with reference to seizure outcome (seizure free or non-seizure free) in 33 children (mean age, 9.3 years) who underwent tailored temporal lobe resections for intractable temporal lobe epilepsy. Trends were apparent with (1) younger age at seizure onset, younger age at surgery, shorter duration of epilepsy, localized unilateral temporal lesions on MRI, and right-sided surgery more frequently associated with a seizure-free outcome, and (2) significant prior history, daily preoperative seizures, generalized motor seizures, mental retardation, and localized unilateral temporal epileptiform EEG activity more frequently associated with a non-seizure-free outcome. However, none of these findings, alone or in combination, correlated with postoperative seizure status at a statistically significant level. Submitting the four variables generally considered to be most predictive of favorable outcome (ie, normal intelligence, unilateral ictal and interictal EEG discharges, and focal temporal MRI lesion) to a multiple-cutoff procedure did not predict seizure freedom. Our data indicate that predictors of outcome of temporal lobectomy in adults may not apply in children, perhaps due to inherent neurobiologic differences in the etiology and expression of temporal lobe epilepsy, and should therefore not be used as sole determinants of surgical candidacy in children. (J Child Neurol 1996;11:445-450)

The effects of bone marrow stem and progenitor cell seeding on urinary bladder tissue regeneration.

Complications associated with urinary bladder augmentation provide the motivation to delineate alternative bladder tissue regenerative engineering strategies. We describe the results of varying the proportion of bone marrow (BM) mesenchymal stem cells (MSCs) to CD34 + hematopoietic stem/progenitor cells (HSPCs) co-seeded onto synthetic POC [poly(1,8 octamethylene citrate)] or small intestinal submucosa (SIS) scaffolds and their contribution to bladder tissue regeneration. Human BM MSCs and CD34 + HSPCs were co-seeded onto POC or SIS scaffolds at cell ratios of 50&nbsp;K CD34 + HSPCs/15&nbsp;K MSCs (CD34-50/MSC15); 50&nbsp;K CD34 + HSPCs/30&nbsp;K MSCs (CD34-50/MSC30); 100&nbsp;K CD34 + HSPCs/15&nbsp;K MSCs (CD34-100/MSC15); and 100&nbsp;K CD34 + HSPCs/30&nbsp;K MSCs (CD34-100/MSC30), in male (M/POC; M/SIS; n = 6/cell seeded scaffold) and female (F/POC; F/SIS; n = 6/cell seeded scaffold) nude rats (n = 96 total animals). Explanted scaffold/composite augmented bladder tissue underwent quantitative morphometrics following histological staining taking into account the presence (S+) or absence (S-) of bladder stones. Urodynamic studies were also performed. Regarding regenerated tissue vascularization, an upward shift was detected for some higher seeded density groups including the CD34-100/MSC30 groups [F/POC S- CD34-100/MSC30 230.5 ± 12.4; F/POC S+ CD34-100/MSC30 245.6 ± 23.4; F/SIS S+ CD34-100/MSC30 278.1; F/SIS S- CD34-100/MSC30 187.4 ± 8.1; (vessels/mm2)]. Similarly, a potential trend toward increased levels of percent muscle (≥ 45% muscle) with higher seeding densities was observed for F/POC S- [CD34-50/MSC30 48.8 ± 2.2; CD34-100/MSC15 53.9 ± 2.8; CD34-100/MSC30 50.7 ± 1.7] and for F/SIS S- [CD34-100/MSC15 47.1 ± 1.6; CD34-100/MSC30 51.2 ± 2.3]. As a potential trend, higher MSC/CD34 + HSPCs cell seeding densities generally tended to increase levels of tissue vascularization and aided with bladder muscle growth. Data suggest that increasing cell seeding density has the potential to enhance bladder tissue regeneration in our model