Primary prevention of gestational diabetes mellitus and large-for-gestational-age newborns by lifestyle counseling: a cluster-randomized controlled trial

Background

Our objective was to examine whether gestational diabetes mellitus (GDM) or newborns'' high birthweight can be prevented by lifestyle counseling in pregnant women at high risk of GDM.

Method and Findings

We conducted a cluster-randomized trial, the NELLI study, in 14 municipalities in Finland, where 2,271 women were screened by oral glucose tolerance test (OGTT) at 8–12 wk gestation. Euglycemic (n = 399) women with at least one GDM risk factor (body mass index [BMI] ≥25 kg/m², glucose intolerance or newborn''s macrosomia (≥4,500 g) in any earlier pregnancy, family history of diabetes, age ≥40 y) were included. The intervention included individual intensified counseling on physical activity and diet and weight gain at five antenatal visits. Primary outcomes were incidence of GDM as assessed by OGTT (maternal outcome) and newborns'' birthweight adjusted for gestational age (neonatal outcome). Secondary outcomes were maternal weight gain and the need for insulin treatment during pregnancy. Adherence to the intervention was evaluated on the basis of changes in physical activity (weekly metabolic equivalent task (MET) minutes) and diet (intake of total fat, saturated and polyunsaturated fatty acids, saccharose, and fiber). Multilevel analyses took into account cluster, maternity clinic, and nurse level influences in addition to age, education, parity, and prepregnancy BMI. 15.8% (34/216) of women in the intervention group and 12.4% (22/179) in the usual care group developed GDM (absolute effect size 1.36, 95% confidence interval [CI] 0.71–2.62, p = 0.36). Neonatal birthweight was lower in the intervention than in the usual care group (absolute effect size −133 g, 95% CI −231 to −35, p = 0.008) as was proportion of large-for-gestational-age (LGA) newborns (26/216, 12.1% versus 34/179, 19.7%, p = 0.042). Women in the intervention group increased their intake of dietary fiber (adjusted coefficient 1.83, 95% CI 0.30–3.25, p = 0.023) and polyunsaturated fatty acids (adjusted coefficient 0.37, 95% CI 0.16–0.57, p<0.001), decreased their intake of saturated fatty acids (adjusted coefficient −0.63, 95% CI −1.12 to −0.15, p = 0.01) and intake of saccharose (adjusted coefficient −0.83, 95% CI −1.55 to −0.11, p  =  0.023), and had a tendency to a smaller decrease in MET minutes/week for at least moderate intensity activity (adjusted coefficient 91, 95% CI −37 to 219, p = 0.17) than women in the usual care group. In subgroup analysis, adherent women in the intervention group (n = 55/229) had decreased risk of GDM (27.3% versus 33.0%, p = 0.43) and LGA newborns (7.3% versus 19.5%, p = 0.03) compared to women in the usual care group.

Conclusions

The intervention was effective in controlling birthweight of the newborns, but failed to have an effect on maternal GDM.

Trial registration

Current Controlled Trials ISRCTN33885819 Please see later in the article for the Editors'' Summary     

Phylogeography of the ant Myrmica rubra and its inquiline social parasite

Widely distributed Palearctic insects are ideal to study phylogeographic patterns owing to their high potential to survive in many Pleistocene refugia and-after the glaciation-to recolonize vast, continuous areas. Nevertheless, such species have received little phylogeographic attention. Here, we investigated the Pleistocene refugia and subsequent postglacial colonization of the common, abundant, and widely distributed ant Myrmica rubra over most of its Palearctic area, using mitochondrial DNA (mtDNA). The western and eastern populations of M. rubra belonged predominantly to separate haplogroups, which formed a broad secondary contact zone in Central Europe. The distribution of genetic diversity and haplogroups implied that M. rubra survived the last glaciation in multiple refugia located over an extensive area from Iberia in the west to Siberia in the east, and colonized its present areas of distribution along several routes. The matrilineal genetic structure of M. rubra was probably formed during the last glaciation and subsequent postglacial expansion. Additionally, because M. rubra has two queen morphs, the obligately socially parasitic microgyne and its macrogyne host, we tested the suggested speciation of the parasite. Locally, the parasite and host usually belonged to the same haplogroup but differed in haplotype frequencies. This indicates that genetic differentiation between the morphs is a universal pattern and thus incipient, sympatric speciation of the parasite from its host is possible. If speciation is taking place, however, it is not yet visible as lineage sorting of the mtDNA between the morphs.     

Tet1 and Tet2 regulate 5-hydroxymethylcytosine production and cell lineage specification in mouse embryonic stem cells

TET family enzymes convert 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) in DNA. Here, we show that Tet1 and Tet2 are Oct4-regulated enzymes that together sustain 5hmC in mouse embryonic stem cells (ESCs) and are induced concomitantly with 5hmC during reprogramming of fibroblasts to induced pluripotent stem cells. ESCs depleted of Tet1 by RNAi show diminished expression of the Nodal antagonist Lefty1 and display hyperactive Nodal signaling and skewed differentiation into the endoderm-mesoderm lineage in embryoid bodies in?vitro. In Fgf4- and heparin-supplemented culture conditions, Tet1-depleted ESCs activate the trophoblast stem cell lineage determinant Elf5 and can colonize the placenta in midgestation embryo chimeras. Consistent with these findings, Tet1-depleted ESCs?form aggressive hemorrhagic teratomas with increased endoderm, reduced neuroectoderm, and ectopic appearance of trophoblastic giant cells. Thus, 5hmC is an epigenetic modification associated with the pluripotent state, and Tet1 functions to regulate the lineage differentiation potential of ESCs.     

Spatial frequency-based analysis of mean red blood cell speed in single microvessels: investigation of microvascular perfusion in rat cerebral cortex

Background

Our previous study has shown that prenatal exposure to X-ray irradiation causes cerebral hypo-perfusion during the postnatal development of central nervous system (CNS). However, the source of the hypo-perfusion and its impact on the CNS development remains unclear. The present study developed an automatic analysis method to determine the mean red blood cell (RBC) speed through single microvessels imaged with two-photon microscopy in the cerebral cortex of rats prenatally exposed to X-ray irradiation (1.5 Gy).

Methodology/Principal Findings

We obtained a mean RBC speed (0.9±0.6 mm/sec) that ranged from 0.2 to 4.4 mm/sec from 121 vessels in the radiation-exposed rats, which was about 40% lower than that of normal rats that were not exposed. These results were then compared with the conventional method for monitoring microvascular perfusion using the arteriovenous transit time (AVTT) determined by tracking fluorescent markers. A significant increase in the AVTT was observed in the exposed rats (1.9±0.6 sec) as compared to the age-matched non-exposed rats (1.2±0.3 sec). The results indicate that parenchyma capillary blood velocity in the exposed rats was approximately 37% lower than in non-exposed rats.

Conclusions/Significance

The algorithm presented is simple and robust relative to monitoring individual RBC speeds, which is superior in terms of noise tolerance and computation time. The demonstrative results show that the method developed in this study for determining the mean RBC speed in the spatial frequency domain was consistent with the conventional transit time method.     

Effects of Lactobacillus helveticus fermented milk on bone cells in vitro

Milk fermented with Lactobacillus helveticus (L. helveticus) contains small peptides such as isoleucyl-prolyl-proline (IPP) and valyl-prolyl-proline (VPP), which inhibit the angiotensin converting enzyme (ACE). We investigated the effects of L. helveticus fermented milk whey (Lh-whey) and its components, sour milk whey, calcium and IPP and VPP peptides, on bone cells in vitro. An osteoblast assay was performed by determining the amount of deposited calcium as an index of bone formation in cultures of mouse osteoblasts formed from bone marrow-derived osteoblast precursor cells. An osteoclast assay was performed by determining the activity of tartrate-resistant acid phosphatase released into the culture medium in cultures of mouse osteoclasts formed from bone marrow-derived osteoclast precursor cells. The Lh-whey increased bone formation 1.3-1.4 times with the 1 × 10⁻⁵, 1 × 10⁻⁴ and 1 × 10⁻³ solutions. The IPP and VPP peptides also demonstrated a significant 5-fold activation of bone formation in in vitro osteoblast cultures, whereas the sour milk whey and calcium had no effect. No significant effects were observed on osteoclasts in vitro with any of the study products. L. helveticus fermented milk whey contains bioactive components that increase osteoblastic bone formation in vitro. The effect may be due to the ACE-inhibitory IPP and VPP peptides, which showed a similar effect to that of the L. helveticus fermented milk whey.     

Solar UV-B radiation affects leaf quality and insect herbivory in the southern beech tree<Emphasis Type="Italic"> Nothofagus antarctica</Emphasis>

We examined the effects of solar ultraviolet-B (UV-B) radiation on plant-insect interactions in Tierra del Fuego (55°S), Argentina, an area strongly affected by ozone depletion because of its proximity to Antarctica. Solar UV-B under Nothofagus antarctica branches was manipulated using a polyester plastic film to attenuate UV-B (uvb–) and an Aclar film to provide near-ambient UV-B (uvb+). The plastic films were placed on both north-facing (i.e., high solar radiation in the Southern Hemisphere) and south-facing branches. Insects consumed 40% less leaf area from north- than from south-facing branches, and at least 30% less area from uvb+ branches than from uvb– branches. The reduced herbivory on leaves from uvb+ branches occurred for both branch orientations. Leaf mass per area increased and relative water content decreased on north- versus south-facing branches, while no differences were apparent between the UV-B treatments. Solar UV-B did lead to lower gallic acid concentration and higher flavonoid aglycone concentration in uvb+ leaves relative to uvb– leaves. Both the flavonoid aglycone and quercetin-3-arabinopyranoside were higher on north-facing branches. In laboratory preference experiments, larvae of the dominant insect in the natural community, Geometridae Brown (Lepidoptera), consumed less area from field-grown uvb+ leaves than from uvb– leaves in 1996–97, but not in 1997–98. Correlation analyses suggested that the reduction in insect herbivory in the field under solar UV-B may be mediated in part by the UV-B effects on gallic acid and flavonoid aglycone.     

Responses of Strawberry (Fragaria × ananassa) to Supplemental UV-B Radiation and Selenium Under Field Conditions

In greenhouse experiments, selenium (Se) has been shown to defend plants against detrimental effects of heavy UV-B radiation stress. The aim of this study was to investigate whether this positive effect can be found in open-field conditions with enhancement of UV-B radiation. In the experiment, conducted with strawberry (Fragaria×ananassa, cultivars “Jonsok” and “Polka”) over two growing seasons, plants were exposed to UV-B radiation (including UV-A) and cultivated without Se or supplied with Se added at two levels (0.1 and 1.0 mg kg⁻¹). The plants were monitored for growth, flavonoids, chlorophyll fluorescence, net photosynthesis as well as tissue and cell structure. Photosystem II was observed to be sensitive to UV-B stress under field conditions. In the leaves, a decrease in F_v/F_m was seen at the end of the growing season, implying a cumulative effect of UV-B stress. Several parameters, especially cell and tissue structures, were affected by UV-B and UV-A treatments, which proves the need for UV-A control in outdoor UV-B supplementation studies. Addition of Se did not ameliorate the harmful effects of UV-B but the lower Se-increment level increased leaf growth. The effects of UV-B and Se differed during the two experimental years, indicating the need to repeat experiments during several growing seasons.     

The tumour-suppressor genes NF2/Merlin and Expanded act through Hippo signalling to regulate cell proliferation and apoptosis

Merlin, the protein product of the Neurofibromatosis type-2 gene, acts as a tumour suppressor in mice and humans. Merlin is an adaptor protein with a FERM domain and it is thought to transduce a growth-regulatory signal. However, the pathway through which Merlin acts as a tumour suppressor is poorly understood. Merlin, and its function as a negative regulator of growth, is conserved in Drosophila, where it functions with Expanded, a related FERM domain protein. Here, we show that Drosophila Merlin and Expanded are components of the Hippo signalling pathway, an emerging tumour-suppressor pathway. We find that Merlin and Expanded, similar to other components of the Hippo pathway, are required for proliferation arrest and apoptosis in developing imaginal discs. Our genetic and biochemical data place Merlin and Expanded upstream of Hippo and identify a pathway through which they act as tumour-suppressor genes.     

Mapping of the Interaction Site between Sortilin and the p75 Neurotrophin Receptor Reveals a Regulatory Role for the Sortilin Intracellular Domain in p75 Neurotrophin Receptor Shedding and Apoptosis

Neurotrophins comprise a group of neuronal growth factors that are essential for the development and maintenance of the nervous system. However, the immature pro-neurotrophins promote apoptosis by engaging in a complex with sortilin and the p75 neurotrophin receptor (p75^NTR). To identify the interaction site between sortilin and p75^NTR, we analyzed binding between chimeric receptor constructs and truncated p75^NTR variants by co-immunoprecipitation experiments, surface plasmon resonance analysis, and FRET. We found that complex formation between sortilin and p75^NTR relies on contact points in the extracellular domains of the receptors. We also determined that the interaction critically depends on an extracellular juxtamembrane 23-amino acid sequence of p75^NTR. Functional studies further revealed an important regulatory function of the sortilin intracellular domain in p75^NTR-regulated intramembrane proteolysis and apoptosis. Thus, although the intracellular domain of sortilin does not contribute to p75^NTR binding, it does regulate the rates of p75^NTR cleavage, which is required to mediate pro-neurotrophin-stimulated cell death.     

Increased resistance of Bt aspens to Phratora vitellinae (Coleoptera) leads to increased plant growth under experimental conditions

One main aim with genetic modification (GM) of trees is to produce plants that are resistant to various types of pests. The effectiveness of GM-introduced toxins against specific pest species on trees has been shown in the laboratory. However, few attempts have been made to determine if the production of these toxins and reduced herbivory will translate into increased tree productivity. We established an experiment with two lines of potted aspens (Populus tremula×Populus tremuloides) which express Bt (Bacillus thuringiensis) toxins and the isogenic wildtype (Wt) in the lab. The goal was to explore how experimentally controlled levels of a targeted leaf beetle Phratora vitellinae (Coleoptera; Chrysomelidae) influenced leaf damage severity, leaf beetle performance and the growth of aspen. Four patterns emerged. Firstly, we found clear evidence that Bt toxins reduce leaf damage. The damage on the Bt lines was significantly lower than for the Wt line in high and low herbivory treatment, respectively. Secondly, Bt toxins had a significant negative effect on leaf beetle survival. Thirdly, the significant decrease in height of the Wt line with increasing herbivory and the relative increase in height of one of the Bt lines compared with the Wt line in the presence of herbivores suggest that this also might translate into increased biomass production of Bt trees. This realized benefit was context-dependent and is likely to be manifested only if herbivore pressure is sufficiently high. However, these herbivore induced patterns did not translate into significant affect on biomass, instead one Bt line overall produced less biomass than the Wt. Fourthly, compiled results suggest that the growth reduction in one Bt line as indicated here is likely due to events in the transformation process and that a hypothesized cost of producing Bt toxins is of subordinate significance.