Modeling hormonal and inflammatory contributions to preterm and term labor using uterine temporal transcriptomics

BACKGROUND: Preterm birth is now recognized as the primary cause of infant mortality worldwide. Interplay between hormonal and inflammatory signaling in the uterus modulates the onset of contractions; however, the relative contribution of each remains unclear. In this study we aimed to characterize temporal transcriptome changes in the uterus preceding term labor and preterm labor (PTL) induced by progesterone withdrawal or inflammation in the mouse and compare these findings with human data. METHODS: Myometrium was collected at multiple time points during gestation and labor from three murine models of parturition: (1) term gestation; (2) PTL induced by RU486; and (3) PTL induced by lipopolysaccharide (LPS). RNA was extracted and cDNA libraries were prepared and sequenced using the Illumina HiSeq 2000 system. Resulting RNA-Seq data were analyzed using multivariate modeling approaches as well as pathway and causal network analyses and compared against human myometrial transcriptome data. RESULTS: We identified a core set of temporal myometrial gene changes associated with term labor and PTL in the mouse induced by either inflammation or progesterone withdrawal. Progesterone withdrawal initiated labor without inflammatory gene activation, yet LPS activation of uterine inflammation was sufficient to override the repressive effects of progesterone and induce a laboring phenotype. Comparison of human and mouse uterine transcriptomic datasets revealed that human labor more closely resembles inflammation-induced PTL in the mouse. CONCLUSIONS: Labor in the mouse can be achieved through inflammatory gene activation yet these changes are not a requisite for labor itself. Human labor more closely resembles LPS-induced PTL in the mouse, supporting an essential role for inflammatory mediators in human "functional progesterone withdrawal." This improved understanding of inflammatory and progesterone influence on the uterine transcriptome has important implications for the development of PTL prevention strategies

Specific Lipopolysaccharide Serotypes Induce Differential Maternal and Neonatal Inflammatory Responses in a Murine Model of Preterm Labor.

Intrauterine inflammation is recognized as a key mediator of both normal and preterm birth but is also associated with neonatal neurological injury. Lipopolysaccharide (LPS) is often used to stimulate inflammatory pathways in animal models of infection/inflammation-induced preterm labor; however, inconsistencies in maternal and neonatal responses to LPS are frequently reported. We hypothesized that LPS serotype-specific responses may account for a portion of these inconsistencies. Four different Escherichia coli LPS serotypes (O111:B4, O55:B5, O127:B8, and O128:B12) were administered to CD1 mice via intrauterine injection at gestational day 16. Although control animals delivered at term 60 ± 15 hours postinjection (p.i.), those administered with O111:B4 delivered 7 ± 2 hours p.i., O55:B5 delivered 10 ± 3 hours p.i., O127:B8 delivered 16 ± 10 hours p.i., and O128:B12 delivered 17 ± 2 hours p.i. (means ± SD). A correlation between the onset of preterm labor and myometrial activation of the inflammatory transcription factor, activator protein 1, but not NF-κB was observed. Specific LPS serotypes induced differential activation of downstream contractile and inflammatory pathways in myometrium and neonatal pup brain. Our findings demonstrate functional disparity in inflammatory pathway activation in response to differing LPS serotypes. Selective use of LPS serotypes may represent a useful tool for targeting specific inflammatory response mechanisms in these models

Functional rewiring of G protein-coupled receptor signaling in human labo

Current strategies to manage preterm labor center around inhibition of uterine myometrial contractions, yet do not improve neonatal outcomes as they do not address activation of inflammation. Here, we identify that during human labor, activated oxytocin receptor (OTR) reprograms the prostaglandin E2 receptor, EP2, in the pregnant myometrium to suppress relaxatory/Gαs-cAMP signaling and promote pro-labor/inflammatory responses via altered coupling of EP2 from Gαq/11 to Gαi/o. The ability of EP2 to signal via Gαi/o is recapitulated with in vitro OT and only following OTR activation, suggesting direct EP2-OTR crosstalk. Super-resolution imaging with computational modeling reveals OT-dependent reorganization of EP2-OTR complexes to favor conformations for Gαi over Gαs activation. A selective EP2 ligand, PGN9856i, activates the relaxatory/Gαs-cAMP pathway but not the pro-labor/inflammatory responses in term-pregnant myometrium, even following OT. Our study reveals a mechanism, and provides a potential therapeutic solution, whereby EP2-OTR functional associations could be exploited to delay preterm labor

"Delirium Day": A nationwide point prevalence study of delirium in older hospitalized patients using an easy standardized diagnostic tool

Background: To date, delirium prevalence in adult acute hospital populations has been estimated generally from pooled findings of single-center studies and/or among specific patient populations. Furthermore, the number of participants in these studies has not exceeded a few hundred. To overcome these limitations, we have determined, in a multicenter study, the prevalence of delirium over a single day among a large population of patients admitted to acute and rehabilitation hospital wards in Italy. Methods: This is a point prevalence study (called "Delirium Day") including 1867 older patients (aged 65 years or more) across 108 acute and 12 rehabilitation wards in Italian hospitals. Delirium was assessed on the same day in all patients using the 4AT, a validated and briefly administered tool which does not require training. We also collected data regarding motoric subtypes of delirium, functional and nutritional status, dementia, comorbidity, medications, feeding tubes, peripheral venous and urinary catheters, and physical restraints. Results: The mean sample age was 82.0 \ub1 7.5 years (58 % female). Overall, 429 patients (22.9 %) had delirium. Hypoactive was the commonest subtype (132/344 patients, 38.5 %), followed by mixed, hyperactive, and nonmotoric delirium. The prevalence was highest in Neurology (28.5 %) and Geriatrics (24.7 %), lowest in Rehabilitation (14.0 %), and intermediate in Orthopedic (20.6 %) and Internal Medicine wards (21.4 %). In a multivariable logistic regression, age (odds ratio [OR] 1.03, 95 % confidence interval [CI] 1.01-1.05), Activities of Daily Living dependence (OR 1.19, 95 % CI 1.12-1.27), dementia (OR 3.25, 95 % CI 2.41-4.38), malnutrition (OR 2.01, 95 % CI 1.29-3.14), and use of antipsychotics (OR 2.03, 95 % CI 1.45-2.82), feeding tubes (OR 2.51, 95 % CI 1.11-5.66), peripheral venous catheters (OR 1.41, 95 % CI 1.06-1.87), urinary catheters (OR 1.73, 95 % CI 1.30-2.29), and physical restraints (OR 1.84, 95 % CI 1.40-2.40) were associated with delirium. Admission to Neurology wards was also associated with delirium (OR 2.00, 95 % CI 1.29-3.14), while admission to other settings was not. Conclusions: Delirium occurred in more than one out of five patients in acute and rehabilitation hospital wards. Prevalence was highest in Neurology and lowest in Rehabilitation divisions. The "Delirium Day" project might become a useful method to assess delirium across hospital settings and a benchmarking platform for future surveys

Oral health and malocclusion in 10-to-11 years-old children in southern Italy

AIM: This study had two main goals: the evaluation of caries experience in permanent teeth and the analysis of malocclusion prevalence. Study design: Observational cross-sectional survey. METHODS: The sample consisted of all the 5th graders of 'Gio Leonardo di Bona', the only Public School in Cutro, a small urban area in Southern Italy (10,000 inhabitants). The clinical examination was performed by a trained dentist at the school infirmary, and no radiographs, study casts, or previous written records of the children were available. DMFS-DMFT and Index of Orthodontic Treatment Need (IOTN) were used to fulfil the study objectives. After the examination, parents received a report on presence/absence of dental caries and possible orthodontic treatment need. Statistics All data were analysed with StatView and Stata 8.0 software. The Chi-square test was applied to compare prevalence rates. The Chi-square linearity was used to evaluate whether caries and malocclusion prevalence changed with a steady trend with reference to sex. RESULTS: The 94% (n. 97) of the whole sample gave a positive consent to the screening. The overall mean of DFS was 4.30 (4.74 SD) while the mean of DFT was 2.60 (2.03 SD). The 22.7% of the sample had DFS/T = 0. Statistically significant difference between genders according to DFS (p = 0.017) and DFT (p = 0.002) distribution was found, being females' significantly lower than males'. Using the DHC-IOTN, 51.6% of the children were assigned to the no/little need, 26.8% to borderline need and 21.6% to a great need for orthodontic treatment. There was no statistically significant difference by gender according to distribution of occlusal traits (p> 0.05), except in the anterior cross bite, being males significantly more affected (p = 0.030). CONCLUSIONS: We believe that oral health and orthodontic surveys performed on a higher number of patients at an early age are critical in order to enhance early treatment, thus avoiding severe malocclusions and progression of dental caries. The results of our study indicate that 21.6% of the sample had an objective orthodontic treatment need (grades 4-5 DHC-IOTN). The single Aesthetic Component (AC) score of the IOTN failed to identify orthodontic treatment needs in our sample: only 13% rated themselves as being in categories 5-10 (great aesthetic need for treatment). With reference to dental caries, males had a mean DFT (3.20) higher than the WHO's 2000 Oral Health Goal for 12-years-olds (DFT = 3) while females (DFT = 1.96) were significantly under this target. The children were advised to undergo regular examinations and to change their lifestyle habits

Improving geographic distribution data for a putatively extinct species, a test case with a disappeared fly

Abstract Global biodiversity loss by anthropogenic impacts is an under-recognized form of global environmental change. Global defaunation is still poorly documented in the case of insects, showing a significant decrease in populations and diversity. The blowfly Neta chilensis (Walker 1837) is poorly known and presumed to be confined to southern-South America, with an unclear distributional pattern. It was last collected in 1984. We aimed, through Ecological Niche Models, to identify regions highly suitable for N. chilensis; to test the suitability of regions with doubtful records; to understand the impact that climatic change and human activities have had; and to identify regions with high chances to find it. We compiled 130 presence records from Argentina and Chile and 117 localities where it was sought but not found between 1987 and 2018. Results indicate that suitable conditions are restricted to southern and central Chile and to southwestern Argentina, that doubtful records are predicted in unsuitable areas, that N. chilensis occupies a narrow niche and that its decline is not mainly caused by climate changes but more probably to habitat loss and to the biological invasion. We identified two regions where the chances of finding the species are higher in the case that it is not extinct already

Modeling hormonal and inflammatory contributions to preterm and term labor using uterine temporal transcriptomics

BACKGROUND: Preterm birth is now recognized as the primary cause of infant mortality worldwide. Interplay between hormonal and inflammatory signaling in the uterus modulates the onset of contractions; however, the relative contribution of each remains unclear. In this study we aimed to characterize temporal transcriptome changes in the uterus preceding term labor and preterm labor (PTL) induced by progesterone withdrawal or inflammation in the mouse and compare these findings with human data. METHODS: Myometrium was collected at multiple time points during gestation and labor from three murine models of parturition: (1) term gestation; (2) PTL induced by RU486; and (3) PTL induced by lipopolysaccharide (LPS). RNA was extracted and cDNA libraries were prepared and sequenced using the Illumina HiSeq 2000 system. Resulting RNA-Seq data were analyzed using multivariate modeling approaches as well as pathway and causal network analyses and compared against human myometrial transcriptome data. RESULTS: We identified a core set of temporal myometrial gene changes associated with term labor and PTL in the mouse induced by either inflammation or progesterone withdrawal. Progesterone withdrawal initiated labor without inflammatory gene activation, yet LPS activation of uterine inflammation was sufficient to override the repressive effects of progesterone and induce a laboring phenotype. Comparison of human and mouse uterine transcriptomic datasets revealed that human labor more closely resembles inflammation-induced PTL in the mouse. CONCLUSIONS: Labor in the mouse can be achieved through inflammatory gene activation yet these changes are not a requisite for labor itself. Human labor more closely resembles LPS-induced PTL in the mouse, supporting an essential role for inflammatory mediators in human “functional progesterone withdrawal.” This improved understanding of inflammatory and progesterone influence on the uterine transcriptome has important implications for the development of PTL prevention strategies. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12916-016-0632-4) contains supplementary material, which is available to authorized users