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

Diversity of Bacteria Associated with Bursaphelenchus xylophilus and Other Nematodes Isolated from Pinus pinaster Trees with Pine Wilt Disease

The pinewood nematode (PWN), Bursaphelenchus xylophilus, has been thought to be the only causal agent of pine wilt disease (PWD), however, since bacteria have been suggested to play a role in PWD, it is important to know the diversity of the microbial community associated to it. This study aimed to assess the microbial community associated with B. xylophilus and with other nematodes isolated from pine trees, Pinus pinaster, with PWD from three different affected forest areas in Portugal. One hundred and twenty three bacteria strains were isolated from PWN and other nematodes collected from 14 P. pinaster. The bacteria strains were identified by comparative analysis of the 16S rRNA gene partial sequence. All except one Gram-positive strain (Actinobacteria) belonged to the Gram-negative Beta and Gammaproteobacteria. Most isolates belonged to the genus Pseudomonas, Burkholderia and to the family Enterobacteriaceae. Species isolated in higher percentage were Pseudomonas lutea, Yersinia intermedia and Burkholderia tuberum. The major bacterial population associated to the nematodes differed according to the forest area and none of the isolated bacterial species was found in all different forest areas. For each of the sampled areas, 60 to 100% of the isolates produced siderophores and at least 40% produced lipases. The ability to produce siderophores and lipases by most isolates enables these bacteria to have a role in plant physiological response. This research showed a high diversity of the microbial community associated with B. xylophilus and other nematodes isolated from P. pinaster with PWD

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

Increased Virulence of an Epidemic Strain of Mycobacterium massiliense in Mice

Chronic pulmonary disease and skin/soft tissue infections due to non-tuberculous mycobacteria (NTM) of the Mycobacterium chelonae-abscessus-massiliense group is an emerging health problem worldwide. Moreover, the cure rate for the infections this group causes is low despite aggressive treatment. Post-surgical outbreaks that reached epidemic proportions in Brazil recently were caused by M. massiliense isolates resistant to high-level disinfection with glutaraldehyde (GTA). Understanding the differences in the virulence and host immune responses induced by NTM differing in their sensitivity to disinfectants, and therefore their relative threat of causing outbreaks in hospitals, is an important issue.We compared the replication and survival inside macrophages of a GTA-susceptible reference Mycobacterium massiliense clinical isolate CIP 108297 and an epidemic strain from Brazil, CRM-0019, and characterized the immune responses of IFNγ knockout mice exposed to a high dose aerosol with these two isolates. CRM-0019 replicated more efficiently than CIP 108297 inside mouse bone marrow macrophages. Moreover, the animals infected with CRM-0019 showed a progressive lung infection characterized by a delayed influx of CD4+ and CD8+ T cells, culminating in extensive lung consolidation and demonstrated increased numbers of pulmonary CD4+ Foxp3+ regulatory T cells compared to those infected with the reference strain. Immunosuppressive activity of regulatory T cells may contribute to the progression and worsening of NTM disease by preventing the induction of specific protective immune responses.These results provide the first direct evidence of the increased virulence in macrophages and mice and pathogenicity in vivo of the Brazilian epidemic isolate and the first observation that NTM infections can be associated with variable levels of regulatory T cells which may impact on their virulence and ability to persist in the host

Preconceptional Folate Supplementation and the Risk of Spontaneous Preterm Birth: A Cohort Study

In an analysis of a cohort of pregnant women, Radek Bukowski and colleagues describe an association between taking folic acid supplements and a reduction in the risk of preterm birth

Patterns of Reproductive Isolation in Toads

Understanding the general features of speciation is an important goal in evolutionary biology, and despite significant progress, several unresolved questions remain. We analyzed an extensive comparative dataset consisting of more than 1900 crosses between 92 species of toads to infer patterns of reproductive isolation. This unique dataset provides an opportunity to examine the strength of reproductive isolation, the development and sex ratios of hybrid offspring, patterns of fertility and infertility, and polyploidization in hybrids all in the context of genetic divergence between parental species. We found that the strength of intrinsic postzygotic isolation increases with genetic divergence, but relatively high levels of divergence are necessary before reproductive isolation is complete in toads. Fertilization rates were not correlated to genetic divergence, but hatching success, the number of larvae produced, and the percentage of tadpoles reaching metamorphosis were all inversely related with genetic divergence. Hybrids between species with lower levels of divergence developed to metamorphosis, while hybrids with higher levels of divergence stopped developing in gastrula and larval stages. Sex ratios of hybrid offspring were biased towards males in 70% of crosses and biased towards females in 30% of crosses. Hybrid females from crosses between closely related species were completely fertile, while approximately half (53%) of hybrid males were sterile, with sterility predicted by genetic divergence. The degree of abnormal ploidy in hybrids was positively related to genetic divergence between parental species, but surprisingly, polyploidization had no effect on patterns of asymmetrical inviability. We discuss explanations for these patterns, including the role of Haldane's rule in toads and anurans in general, and suggest mechanisms generating patterns of reproductive isolation in anurans

Altered Trabecular Bone Structure and Delayed Cartilage Degeneration in the Knees of Collagen VI Null Mice

Mutation or loss of collagen VI has been linked to a variety of musculoskeletal abnormalities, particularly muscular dystrophies, tissue ossification and/or fibrosis, and hip osteoarthritis. However, the role of collagen VI in bone and cartilage structure and function in the knee is unknown. In this study, we examined the role of collagen VI in the morphology and physical properties of bone and cartilage in the knee joint of Col6a1−/− mice by micro-computed tomography (microCT), histology, atomic force microscopy (AFM), and scanning microphotolysis (SCAMP). Col6a1−/− mice showed significant differences in trabecular bone structure, with lower bone volume, connectivity density, trabecular number, and trabecular thickness but higher structure model index and trabecular separation compared to Col6a1+/+ mice. Subchondral bone thickness and mineral content increased significantly with age in Col6a1+/+ mice, but not in Col6a1−/− mice. Col6a1−/− mice had lower cartilage degradation scores, but developed early, severe osteophytes compared to Col6a1+/+mice. In both groups, cartilage roughness increased with age, but neither the frictional coefficient nor compressive modulus of the cartilage changed with age or genotype, as measured by AFM. Cartilage diffusivity, measured via SCAMP, varied minimally with age or genotype. The absence of type VI collagen has profound effects on knee joint structure and morphometry, yet minimal influences on the physical properties of the cartilage. Together with previous studies showing accelerated hip osteoarthritis in Col6a1−/− mice, these findings suggest different roles for collagen VI at different sites in the body, consistent with clinical data

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