The Roles of PPARs in the Fetal Origins of Metabolic Health and Disease

Beyond the short-term effects on fertility, there is increasing evidence that obesity or the consumption of an inappropriate diet by the mother during pregnancy adversely affects the long-term health of her offspring. PPAR and RXR isotypes are widely expressed in reproductive tissues and in the developing fetus. Through their interactions with fatty acids, they may mediate adaptive responses to the changes in the maternal diet. In the maturing follicle, PPAR-γ has an important role in the granulosa cells that surround the maturing oocyte. After fertilisation, PPAR-γ and PPAR-β/δ are essential regulators of placentation and the subsequent development of key metabolic tissues such as skeletal muscle and adipose cells. Activation of PPAR-γ and PPAR-β/δ during fetal development has the potential to modify the growth and development of these tissues. PPAR-α is expressed at low levels in the fetal liver, however, this expression may be important, as changes in the methylation of DNA in its promoter region are reported to take place during this period of development. This epigenetic modification then programmes subsequent expression. These findings suggest that two separate PPAR-dependent mechanisms may be involved in the fetal adaptations to the maternal diet, one, mediated by PPAR-γ and PPAR-β/δ, regulating cell growth and differentiation; and another adapting long-term lipid metabolism via epigenetic changes in PPAR-α to optimise postnatal survival

ASCA Observation of an X-Ray-Luminous Active Nucleus in Markarian 231

We have obtained a moderately long (100 kilosecond) ASCA observation of the Seyfert 1 galaxy Markarian 231, the most luminous of the local ultraluminous infrared galaxy (ULIRG) population. In the best-fitting model we do not see the X-ray source directly; the spectrum consists of a scattered power-law component and a reflection component, both of which have been absorbed by a column N_H \approx 3 X 10^(22)/cm^2. About 3/4 of the observed hard X-rays arise from the scattered component, reducing the equivalent width of the iron K alpha line. The implied ratio of 1-10 keV X-ray luminosity to bolometric luminosity, L_x/L_bol \sim 2%, is typical of Sy 1 galaxies and radio-quiet QSOs of comparable bolometric luminosities, and indicates that the bolometric luminosity is dominated by the AGN. Our estimate of the X-ray luminosity also moves Mrk 231 in line with the correlations found for AGN with extremely strong Fe II emission. A second source separated by about 2 arcminutes is also clearly detected, and contributes about 25% of the total flux.Comment: 11 pages, 3 figures; to appear in ApJ Letter

Safety of overlapping inpatient orthopaedic surgery: A multicenter study

BackgroundAlthough overlapping surgery is used to maximize efficiency, more empirical data are needed to guide patient safety. We conducted a retrospective cohort study to evaluate the safety of overlapping inpatient orthopaedic surgery, as judged by the occurrence of perioperative complications.MethodsAll inpatient orthopaedic surgical procedures performed at 5 academic institutions from January 1, 2015, to December 31, 2015, were included. Overlapping surgery was defined as 2 skin incisions open simultaneously for 1 surgeon. In comparing patients who underwent overlapping surgery with those who underwent non-overlapping surgery, the primary outcome was the occurrence of a perioperative complication within 30 days of the surgical procedure, and secondary outcomes included all-cause 30-day readmission, length of stay, and mortality. To determine if there was an association between overlapping surgery and a perioperative complication, we tested for non-inferiority of overlapping surgery, assuming a null hypothesis of an increased risk of 50%. We used an inverse probability of treatment weighted regression model adjusted for institution, procedure type, demographic characteristics (age, sex, race, comorbidities), admission type, admission severity of illness, and clustering by surgeon.ResultsAmong 14,135 cases, the frequency of overlapping surgery was 40%. The frequencies of perioperative complications were 1% in the overlapping surgery group and 2% in the non-overlapping surgery group. The overlapping surgery group was non-inferior to the non-overlapping surgery group (odds ratio [OR], 0.61 [90% confidence interval (CI), 0.45 to 0.83]; p < 0.001), with reduced odds of perioperative complications (OR, 0.61 [95% CI, 0.43 to 0.88]; p = 0.009). For secondary outcomes, there was a significantly lower chance of all-cause 30-day readmission in the overlapping surgery group (OR, 0.67 [95% CI, 0.52 to 0.87]; p = 0.003) and shorter length of stay (e, 0.94 [95% CI, 0.89 to 0.99]; p = 0.012). There was no difference in mortality.ConclusionsOur results suggest that overlapping inpatient orthopaedic surgery does not introduce additional perioperative risk for the complications that we evaluated. The suitability of this practice should be determined by individual surgeons on a case-by-case basis with appropriate informed consent.Level of evidenceTherapeutic Level III. See Instructions for Authors for a complete description of levels of evidence

Erythroid Kruppel-like factor directly activates the basic Kruppel-like factor gene in erythroid cells

The Sp/Kriippel-like factor (Sp/KIf) family is comprised of around 25 zinc finger transcription factors that recognize CACCC boxes and GC-rich elements. We have investigated basic Kruppel-like factor (Bklf/Klf3) and show that in erythroid tissues its expression is highly dependent on another family member, erythroid Kruppel-like factor (Eklf/Kif1). We observe that Bklf mRNA is significantly reduced in erythroid tissues from Eklf-null murine embryos. We find that Bklf is driven primarily by two promoters, a ubiquitously active GC-rich upstream promoter, la, and an erythroid downstream promoter, 1b. Transcripts from the two promoters encode identical proteins. Interestingly, both the ubiquitous and the erythroid promoter are dependent on Eklf in erythroid cells. Eklf also activates both promoters in transient assays. Experiments utilizing an inducible form of Eklf demonstrate activation of the endogenous Bklf gene in the presence of an inhibitor of protein synthesis. The kinetics of activation are also consistent with Bklf being a direct Eklf target. Chromatin immunoprecipitation assays confirm that Eklf associates with both Bklf promoters. Eklf is typically an activator of transcription, whereas Bklf is noted as a repressor. Our results support the hypothesis that feedback cross-regulation occurs within the Sp/Klf family in vivo

How High? Trends in Cannabis Use Prior to First Admission to Inpatient Psychiatry in Ontario, Canada, between 2007 and 2017

Objectives: To examine the trends in cannabis use within 30 days of first admission to inpatient psychiatry in Ontario, Canada, between 2007 and 2017, and the characteristics of persons reporting cannabis use. Methods: A retrospective cross-sectional analysis was conducted for first-time admissions to nonforensic inpatient psychiatric beds in Ontario, Canada, between January 1, 2007, and December 31, 2017, using data from the Ontario Mental Health Reporting System (N = 81,809). Results: Across all years, 20.1% of patients reported cannabis use within 30 days of first admission. Use increased from 16.7% in 2007 to 25.9% in 2017, and the proportion with cannabis use disorders increased from 3.8% to 6.0%. In 2017, 47.9% of patients aged 18 to 24 and 39.2% aged 25 to 34 used cannabis, representing absolute increases of 8.3% and 10.7%, respectively. Increases in cannabis use were found across almost all diagnostic groups, with the largest increases among patients with personality disorders (15% increase), schizophrenia or other psychotic disorders (14% increase), and substance use disorders (14% increase). A number of demographic and clinical factors were significantly associated with cannabis use, including interactions between schizophrenia and gender (area under the curve = 0.88). Conclusions: As medical cannabis policies in Canada have evolved, cannabis use reported prior to first admission to inpatient psychiatry has increased. The findings of this study establish a baseline for evaluating the impact of changes in cannabis-related policies in Ontario on cannabis use prior to admission to inpatient psychiatry

A deep X-ray observation of NGC 4258 and its surrounding field

We present a deep X-ray observation of the low-luminosity active galactic nucleus in NGC4258 (M106) using ASCA. The soft X-ray spectrum <2keV is dominated by thermal emission from optically-thin plasma with kT~0.5keV. The hard X-ray emission is clearly due to a power-law component with photon index Gamma=1.8 absorbed by a column density of N_H=8x10^22/cm^2. The power-law is readily identified with primary X-ray emission from the AGN central engine. We also clearly detect a narrow iron K-alpha emission line at 6.4keV. No broad component is detected. We suggest that the bulk of this narrow line comes from the accretion disk and, furthermore, that the power-law X-ray source which excites this line emission (which is typically identified with a disk corona) must be at least 100GM/c^2 in extent. This is in stark contrast to many higher-luminosity Seyfert galaxies which display a broad iron line indicating a small 10 GM/c^2 X-ray emitting region. It must be stressed that this study constrains the size of the X-ray emitting corona rather than the presence/absence of a radiatively efficient accretion disk in the innermost regions. If, instead, a substantial fraction of the observed narrow line originates from material not associated with the accretion disk, limits can be placed on the parameter space of possible allowed relativistically broad iron lines. By comparing our data with previous ASCA observations, we find marginal evidence for a change in absorbing column density through to the central engine, and good evidence for a change in the AGN flux.Comment: 11 pages, 9 postscript figures. Accepted for publication in Ap

Impact of acamprosate on plasma amyloid-β precursor protein in youth: a pilot analysis in fragile X syndrome-associated and idiopathic autism spectrum disorder suggests a pharmacodynamic protein marker

BACKGROUND: Understanding of the pathophysiology of autism spectrum disorder (ASD) remains limited. Brain overgrowth has been hypothesized to be associated with the development of ASD. A derivative of amyloid-β precursor protein (APP), secreted APPα (sAPPα), has neuroproliferative effects and has been shown to be elevated in the plasma of persons with ASD compared to control subjects. Reduction in sAPPα holds promise as a novel molecular target of treatment in ASD. Research into the neurochemistry of ASD has repeatedly implicated excessive glutamatergic and deficient GABAergic neurotransmission in the disorder. With this in mind, acamprosate, a novel modulator of glutamate and GABA function, has been studied in ASD. No data is available on the impact of glutamate or GABA modulation on sAPPα function. METHODS: Plasma APP derivative levels pre- and post-treatment with acamprosate were determined in two pilot studies involving youth with idiopathic and fragile X syndrome (FXS)-associated ASD. We additionally compared baseline APP derivative levels between youth with FXS-associated or idiopathic ASD. RESULTS: Acamprosate use was associated with a significant reduction in plasma sAPP(total) and sAPPα levels but no change occurred in Aβ40 or Aβ42 levels in 15 youth with ASD (mean age: 11.1 years). Youth with FXS-associated ASD (n = 12) showed increased sAPPα processing compared to age-, gender- and IQ-match youth with idiopathic ASD (n = 11). CONCLUSIONS: Plasma APP derivative analysis holds promise as a potential biomarker for use in ASD targeted treatment. Reduction in sAPP (total) and sAPPα may be a novel pharmacodynamic property of acamprosate. Future study is required to address limitations of the current study to determine if baseline APP derivative analysis may predict subgroups of persons with idiopathic or FXS-associated ASD who may respond best to acamprosate or to potentially other modulators of glutamate and/or GABA neurotransmission

Can voluntary exercise improve renal changes in offspring induced by maternal obesity

Obesity in the mother is known to affect offspring, making them more prone to obesity, diabetes, and kidney disease. A recent study reported that children of obese mothers have a 22% increased risk of developing kidney disease suggesting that its development may be programmed in utero. However, the link between maternal obesity and offspring kidney disease remains unclear. Exercise is known to be beneficial in kidney disease, but whether it impacts renal effects of maternal obesity is not known. Thus we studied the impact of maternal obesity on siblings that were either sedentary or given access to a running wheel. Female Sprague-Dawley rats were fed either chow diet or high-fat diet (HFD) for 6 weeks before mating. Female offspring were weaned onto either chow diet or HFD and after 7 weeks, half of offspring were exercised for 5 weeks. Offspring were killed at 15 weeks; kidneys were collected for gene expression. The body weight, kidney mass, and kidney triglyceride levels were measured. Offspring of obese mothers had significantly increased body weight which was reduced by exercise in offspring consuming HFD. Kidney weight was significantly increased by maternal diet and post-weaning HFD. Maternal diet was associated with a significant increase in kidney triglyceride accumulation; chow fed offspring of obese mother showed a 91% increase in renal triglyceride content (P<0.001). Post-weaning HFD consumption also increased kidney triglyceride content by 37% and 20% in offspring of lean and obese mothers, respectively (P<0.01). However, exercise also increases renal triglyceride accumulation in offspring of both obese and lean mother consuming HFD. Lipid accumulation was associated with dysregulation of lipid metabolism genes. Maternal diet was associated with an upregulation of fatty acid transporter Cd36. Ldl receptor (Ldlr), involved in uptake of fat, was significantly upregulated by both post-weaning HFD and exercise. Downregulation of renal lipoprotein lipase (Lpl) which is involved in hydrolyzing circulating triglyceride was observed by current HFD and upregulated by exercise. Sterol regulatory element binding protein 1 (Srebp 1) and acetyl-CoA carboxylase alpha (Acaca), involve in lipogenesis, were upregulated by exercise. Significant upregulation of kidney injury molecule 1 (Kim 1) and neutrophil gelatinase-associated lipocalin (Ngal) was also induced by post-weaning HFD. Our data suggest that maternal diet has a greater effect than current HFD consumption on triglyceride accumulation in offspring kidney. Voluntary exercise in offspring did not reduce this triglyceride content in the kidney. Dysregulation of lipid metabolism genes may explain renal lipid accumulation which may further result in renal injury

Lifespan profiles of Alzheimer's disease–associated genes and their products in monkeys and mice.

Alzheimer's disease (AD) is characterized by plaques of amyloid–beta (Aβ) peptide, cleaved from amyloid–β precursor protein (AβPP). Our hypothesis is that lifespan profiles of AD-associated mRNA and protein levels in monkeys would differ from mice, and that differential lifespan expression profiles would be useful to understand human AD pathogenesis. We compared profiles of AβPP mRNA, AβPP protein, and Aβ levels in rodents and primates. We also tracked a transcriptional regulator of the AβPP gene, specificity protein 1 (SP1), and the β amyloid precursor cleaving enzyme (BACE1). In mice, AβPP and Sp1 mRNA and their protein products were elevated late in life; Aβ levels declined in old age. In monkeys, Sp1, AβPP, and BACE1 mRNA declined in old age, while protein products and Aβ levels rose. Proteolytic processing in both species did not match production of Aβ. In primates, AβPP and Sp1 mRNA levels coordinate, but an inverse relationship exists with corresponding protein products, as well as Aβ levels. Comparison of human DNA and mRNA sequences to monkey and mouse counterparts revealed structural features that may explain differences in transcriptional and translational processing. These findings are important for selecting appropriate models for AD and other age–related diseases

Alzheimer\u27s Disease (AD)-Like Pathology in Aged Monkeys after Infantile Exposure to Environmental Metal Lead (Pb): Evidence for a Developmental Origin and Environmental Link for AD

The sporadic nature of Alzheimer\u27s disease (AD) argues for an environmental link that may drive AD pathogenesis; however, the triggering factors and the period of their action are unknown. Recent studies in rodents have shown that exposure to lead (Pb) during brain development predetermined the expression and regulation of the amyloid precursor protein (APP) and its amyloidogenic β-amyloid (Aβ) product in old age. Here, we report that the expression of AD-related genes [APP, BACE1 (β-site APP cleaving enzyme 1)] as well as their transcriptional regulator (Sp1) were elevated in aged (23-year-old) monkeys exposed to Pb as infants. Furthermore, developmental exposure to Pb altered the levels, characteristics, and intracellular distribution of Aβ staining and amyloid plaques in the frontal association cortex. These latent effects were accompanied by a decrease in DNA methyltransferase activity and higher levels of oxidative damage to DNA, indicating that epigenetic imprinting in early life influenced the expression of AD-related genes and promoted DNA damage and pathogenesis. These data suggest that AD pathogenesis is influenced by early life exposures and argue for both an environmental trigger and a developmental origin of AD