Progesterone after previous preterm birth for prevention of neonatal respiratory distress syndrome (PROGRESS): a randomised controlled trial

Background: Neonatal respiratory distress syndrome, as a consequence of preterm birth, is a major cause of early mortality and morbidity during infancy and childhood. Survivors of preterm birth continue to remain at considerable risk of both chronic lung disease and long-term neurological handicap. Progesterone is involved in the maintenance of uterine quiescence through modulation of the calcium-calmodulin-myosin-light-chain-kinase system in smooth muscle cells. The withdrawal of progesterone, either actual or functional is thought to be an antecedent to the onset of labour. While there have been recent reports of progesterone supplementation for women at risk of preterm birth which show promise in this intervention, there is currently insufficient data on clinically important outcomes for both women and infants to enable informed clinical decision-making. The aims of this randomised, double blind, placebo controlled trial are to assess whether the use of vaginal progesterone pessaries in women with a history of previous spontaneous preterm birth will reduce the risk and severity of respiratory distress syndrome, so improving their infant's health, without increasing maternal risks. Methods Design: Multicentred randomised, double blind, placebo-controlled trial. Inclusion Criteria: pregnant women with a live fetus, and a history of prior preterm birth at less than 37 weeks gestation and greater than 20 weeks gestation in the immediately preceding pregnancy, where onset of labour occurred spontaneously, or in association with cervical incompetence, or following preterm prelabour ruptured membranes. Trial Entry & Randomisation: After obtaining written informed consent, eligible women will be randomised between 18 and 23+6 weeks gestation using a central telephone randomisation service. The randomisation schedule prepared by non clinical research staff will use balanced variable blocks, with stratification according to plurality of the pregnancy and centre where planned to give birth. Eligible women will be randomised to either vaginal progesterone or vaginal placebo. Study Medication & Treatment Schedules: Treatment packs will appear identical. Woman, caregivers and research staff will be blinded to treatment allocation. Primary Study Outcome: Neonatal Respiratory Distress Syndrome (defined by incidence and severity). Sample Size: of 984 women to show a 40% reduction in respiratory distress syndrome from 15% to 9% (p = 0.05, 80% power). Discussion: This is a protocol for a randomised trial.Jodie M. Dodd, Caroline A. Crowther, Andrew J. McPhee, Vicki Flenady, and Jeffrey S. Robinso

Light Converts Endosymbiotic Fungus to Pathogen, Influencing Seedling Survival and Niche-Space Filling of a Common Tropical Tree, Iriartea deltoidea

Pathogens are hypothesized to play an important role in the maintenance of tropical forest plant species richness. Notably, species richness may be promoted by incomplete filling of niche space due interactions of host populations with their pathogens. A potentially important group of pathogens are endophytic fungi, which asymptomatically colonize plants and are diverse and abundant in tropical ecosystems. Endophytes may alter competitive abilities of host individuals and improve host fitness under stress, but may also become pathogenic. Little is known of the impacts of endophytes on niche-space filling of their hosts

Influence of festival attribute qualities on Slow Food tourists’ experience, satisfaction level and revisit intention

The purpose of this study is to examine the impact of Slow Food festival attributes on visitors’ overall experience, their satisfaction level and revisit intention. A total of 209 useable questionnaires were collected from visitors at Mold Slow Food Festival and Exploratory Factor Analysis was conducted using AMOS 19.0. A theoretical model representing the relationships among festival attribute qualities, experience quality, satisfaction level and revisit intention is examined using path analysis. With the addition of new paths from programmes to satisfaction and food and other amenities to satisfaction, a revised theoretical model emerged. It indicated that all three festival attribute qualities (programmes, food and other amenities and entertainment) have direct impacts on the visitors’ overall experience and satisfaction; however only the quality of food and other amenities contributed directly to revisit intention of the Slow Food festival

Increased Fitness of Rice Plants to Abiotic Stress Via Habitat Adapted Symbiosis: A Strategy for Mitigating Impacts of Climate Change

Climate change and catastrophic events have contributed to rice shortages in several regions due to decreased water availability and soil salinization. Although not adapted to salt or drought stress, two commercial rice varieties achieved tolerance to these stresses by colonizing them with Class 2 fungal endophytes isolated from plants growing across moisture and salinity gradients

Clinical and Organizational Factors Related to the Reduction of Mechanical Restraint Application in an Acute Ward: An 8-Year Retrospective Analysis

Background: The purpose of this study was to describe the frequency of mechanical restraint use in an acute psychiatric ward and to analyze which variables may have significantly influenced the use of this procedure. Methods: This retrospective study was conducted in the Servizio Psichiatrico di Diagnosi e Cura (SPDC) of Modena Centro. The following variables of our sample, represented by all restrained patients admitted from 1-1-2005 to 31-12-2012, were analyzed: age, gender, nationality, psychiatric diagnoses, organic comorbidity, state and duration of admission, motivation and duration of restraints, nursing shift and hospitalization day of restraint, number of patients admitted at the time of restraint and institutional changes during the observation period. The above variables were statistically compared with those of all other non-restrained patients admitted to our ward in the same period. Results: Mechanical restraints were primarily used as a safety procedure to manage aggressive behavior of male patients, during the first days of hospitalization and night shifts. Neurocognitive disorders, organic comorbidity, compulsory state and long duration of admission were statistically significantly related to the increase of restraint use (p<.001, multivariate logistic regression). Institutional changes, especially more restricted guidelines concerning restraint application, were statistically significantly related to restraint use reduction (p<.001, chi2 test, multivariate logistic regression). Conclusion: The data obtained highlight that mechanical restraint use was influenced not only by clinical factors, but mainly by staff and policy factors, which have permitted a gradual but significant reduction in the use of this procedure through a multidimensional approach

Downregulation of Homologous Recombination DNA Repair Genes by HDAC Inhibition in Prostate Cancer Is Mediated through the E2F1 Transcription Factor

Histone deacetylase inhibitors (HDACis) re-express silenced tumor suppressor genes and are currently undergoing clinical trials. Although HDACis have been known to induce gene expression, an equal number of genes are downregulated upon HDAC inhibition. The mechanism behind this downregulation remains unclear. Here we provide evidence that several DNA repair genes are downregulated by HDAC inhibition and provide a mechanism involving the E2F1 transcription factor in the process.Applying Analysis of Functional Annotation (AFA) on microarray data of prostate cancer cells treated with HDACis, we found a number of genes of the DNA damage response and repair pathways are downregulated by HDACis. AFA revealed enrichment of homologous recombination (HR) DNA repair genes of the BRCA1 pathway, as well as genes regulated by the E2F1 transcription factor. Prostate cancer cells demonstrated a decreased DNA repair capacity and an increased sensitization to chemical- and radio-DNA damaging agents upon HDAC inhibition. Recruitment of key HR repair proteins to the site of DNA damage, as well as HR repair capacity was compromised upon HDACi treatment. Based on our AFA data, we hypothesized that the E2F transcription factors may play a role in the downregulation of key repair genes upon HDAC inhibition in prostate cancer cells. ChIP analysis and luciferase assays reveal that the downregulation of key repair genes is mediated through decreased recruitment of the E2F1 transcription factor and not through active repression by repressive E2Fs.Our study indicates that several genes in the DNA repair pathway are affected upon HDAC inhibition. Downregulation of the repair genes is on account of a decrease in amount and promoter recruitment of the E2F1 transcription factor. Since HDAC inhibition affects several pathways that could potentially have an impact on DNA repair, compromised DNA repair upon HDAC inhibition could also be attributed to several other pathways besides the ones investigated in this study. However, our study does provide insights into the mechanism that governs downregulation of HR DNA repair genes upon HDAC inhibition, which can lead to rationale usage of HDACis in the clinics

Spontaneous Abortion and Preterm Labor and Delivery in Nonhuman Primates: Evidence from a Captive Colony of Chimpanzees (Pan troglodytes)

Preterm birth is a leading cause of perinatal mortality, yet the evolutionary history of this obstetrical syndrome is largely unknown in nonhuman primate species.We examined the length of gestation during pregnancies that occurred in a captive chimpanzee colony by inspecting veterinary and behavioral records spanning a total of thirty years. Upon examination of these records we were able to confidently estimate gestation length for 93 of the 97 (96%) pregnancies recorded at the colony. In total, 78 singleton gestations resulted in live birth, and from these pregnancies we estimated the mean gestation length of normal chimpanzee pregnancies to be 228 days, a finding consistent with other published reports. We also calculated that the range of gestation in normal chimpanzee pregnancies is approximately forty days. Of the remaining fifteen pregnancies, only one of the offspring survived, suggesting viability for chimpanzees requires a gestation of approximately 200 days. These fifteen pregnancies constitute spontaneous abortions and preterm deliveries, for which the upper gestational age limit was defined as 2 SD from the mean length of gestation (208 days).The present study documents that preterm birth occurred within our study population of captive chimpanzees. As in humans, pregnancy loss is not uncommon in chimpanzees, In addition, our findings indicate that both humans and chimpanzees show a similar range of normal variation in gestation length, suggesting this was the case at the time of their last common ancestor (LCA). Nevertheless, our data suggest that whereas chimpanzees' normal gestation length is ∼20-30 days after reaching viability, humans' normal gestation length is approximately 50 days beyond the estimated date of viability without medical intervention. Future research using a comparative evolutionary framework should help to clarify the extent to which mechanisms at work in normal and preterm parturition are shared in these species

Differential Gene Repertoire in Mycobacterium ulcerans Identifies Candidate Genes for Patho-Adaptation

The emerging human disease Buruli ulcer, caused by Mycobacterium ulcerans, is of increasing challenge for public health systems in many countries, mainly in West and Central sub-Saharan Africa. Genetic differentiation of patient isolates, a prerequisite for scientific studies on and intervention of disease transmission and dispersal, is hampered by an exceptional lack of genetic diversity within this species. Comparative genomics on M. ulcerans of worldwide geographical origin has already allowed for distinguishing several haplotypes separated into two distinct lineages. Differences in prevalence and incidence of Buruli ulcer were already suspected, but biological relevance for this was unclear. Here, we show newly identified hot spot regions of genomic instability, a biased silencing of coding sequences belonging to distinct functional groups, and a differential gene repertoire across M. ulcerans strains. Gene inactivation mediated by different mechanisms in M. ulcerans adds to the concept of anti-virulence genes observed in an increasing number of bacterial species. According to this concept, loss of such genes—in addition to gain of function—may confer a selective advantage for a pathogen radiating into a new niche. In the case of M. ulcerans, a distinct set of disrupted genes may enhance virulence, particularly in the classical lineage

Somatostatin and dopamine receptors as targets for medical treatment of Cushing's Syndrome

Somatostatin (SS) and dopamine (DA) receptors are widely expressed in neuroendocrine tumours that cause Cushing's Syndrome (CS). Increasing knowledge of specific subtype expression within these tumours and the ability to target these receptor subtypes with high-affinity compounds, has driven the search for new SS- or DA-based medical therapies for the various forms of CS. In Cushing's disease, corticotroph adenomas mainly express dopamine receptor subtype 2 (D2) and somatostatin receptor subtype 5 (sst5), whereas sst2is expressed at lower levels. Activation of these receptors can inhibit ACTH-release in primary cultured corticotroph adenomas and compounds that target either sst5(pasireotide, or SOM230) or D2(cabergoline) have shown significant efficacy in subsets of patients in recent clinical studies. Combination therapy, either by administration of both types of compounds separately or by treatment with novel somatostatin-dopamine chimeric molecules (e.g. BIM-23A760), appears to be a promising approach in this respect. In selected cases of Ectopic ACTH-producing Syndrome (EAS), the sst2-preferring compound octreotide is able to reduce cortisol levels effectively. A recent study showed that D2receptors are also significantly expressed in the majority of EAS and that cabergoline may decrease cortisol levels in subsets of these patients. In both normal adrenal tissue as well as in adrenal adenomas and carcinomas that cause CS, sst and DA receptor expression has been demonstrated. Although selected cases of adrenal CS may benefit from sst or DA-targeted treatment, its total contribution to the treatment of these patients is likely to be low as surgery is effective in most cases

Dietary phytochemicals, HDAC inhibition, and DNA damage/repair defects in cancer cells

Genomic instability is a common feature of cancer etiology. This provides an avenue for therapeutic intervention, since cancer cells are more susceptible than normal cells to DNA damaging agents. However, there is growing evidence that the epigenetic mechanisms that impact DNA methylation and histone status also contribute to genomic instability. The DNA damage response, for example, is modulated by the acetylation status of histone and non-histone proteins, and by the opposing activities of histone acetyltransferase and histone deacetylase (HDAC) enzymes. Many HDACs overexpressed in cancer cells have been implicated in protecting such cells from genotoxic insults. Thus, HDAC inhibitors, in addition to unsilencing tumor suppressor genes, also can silence DNA repair pathways, inactivate non-histone proteins that are required for DNA stability, and induce reactive oxygen species and DNA double-strand breaks. This review summarizes how dietary phytochemicals that affect the epigenome also can trigger DNA damage and repair mechanisms. Where such data is available, examples are cited from studies in vitro and in vivo of polyphenols, organosulfur/organoselenium compounds, indoles, sesquiterpene lactones, and miscellaneous agents such as anacardic acid. Finally, by virtue of their genetic and epigenetic mechanisms, cancer chemopreventive agents are being redefined as chemo- or radio-sensitizers. A sustained DNA damage response coupled with insufficient repair may be a pivotal mechanism for apoptosis induction in cancer cells exposed to dietary phytochemicals. Future research, including appropriate clinical investigation, should clarify these emerging concepts in the context of both genetic and epigenetic mechanisms dysregulated in cancer, and the pros and cons of specific dietary intervention strategies