Docosahexaenoic Acid Status in Pregnancy Determines the Maternal Docosahexaenoic Acid Status 3-, 6- and 12 Months Postpartum. Results from a Longitudinal Observational Study

Background

Essential fatty acid status as well as docosahexaenoic acid (DHA, 22:6n-3) declines during pregnancy and lactation. As a result, the DHA status may not be optimal for child development and may increase the risk for maternal postpartum depression. The objective of this study was to assess changes in the maternal fatty acid status from pregnancy to 12 months postpartum, and to study the impact of seafood consumption on the individual fatty acid status.

Methods

Blood samples and seafood consumption habits (gestation week 28, and three-, six- and 12 months postpartum) were collected in a longitudinal observational study of pregnant and postpartum women (n = 118). Multilevel linear modeling was used to assess both changes over time in the fatty acid status of red blood cells (RBC), and in the seafood consumption.

Results

Six fatty acids varied the most (>80%) across the four time points analyzed, including the derivative of the essential α-linoleic acid (ALA, 18:3n-3), DHA; the essential linoleic acid (LA, 18:2 n-6); and the LA derivative, arachidonic acid (AA, 20:4n-6). Over all, a large variation in individuals’ DHA- and AA status was observed; however, over the 15-month study period only small inter-individual differences in the longitudinal trajectory of DHA- and AA abundance in the RBC were detected. The median intake of seafood was lower than recommended. Regardless, the total weekly frequency of seafood and eicosapentaenoic acid (EPA, 20:5n-3)/DHA-supplement intake predicted the maternal level of DHA (μg/g RBC).

Conclusion

The period of depletion of the maternal DHA status during pregnancy and lactation, seem to turn to repletion from about six months postpartum towards one year after childbirth, irrespective of RBC concentration of DHA during pregnancy. Seafood and EPA/DHA-supplement intake predicted the DHA levels over time.

Trial Registration

www.helseforskning.etikkom.no 2009/570/REC, project number: 083.09     

Sexual Risk Behaviours and Willingness to Be Circumcised among Uncircumcised Adult Men in Uganda

Background

There has been substantial demand for safe male circumcision (SMC) in Uganda in the early programme scale-up phase. Research indicates that early adopters of new interventions often differ from later adopters in relation to a range of behaviours. However, there is limited knowledge about the risk profile of men who were willing to be circumcised at the time of launching the SMC programme, i.e., potential early adopters, compared to those who were reluctant. The aim of this study was to address this gap to provide indications on whether it is likely that potential early adopters of male circumcision were more in need of this new prevention measure than others.

Methods

Data were from the 2011 Uganda AIDS Indictor Survey (UAIS), with a nationally representative sample of men 15 to 59 years. The analysis was based on generalized linear models, obtaining prevalence risk ratios (PRR) with 95% confidence intervals (CI) as measures of association between willingness to be circumcised and multiple sexual partners, transactional sex, non-marital sex and non-use of condoms at last non-marital sex.

Results

Of the 5,776 men in the survey, 44% expressed willingness to be circumcised. Willingness to be circumcised was higher among the younger, urban and educated men. In the unadjusted analyses, all the sexual risk behaviours were associated with willingness to be circumcised, while in the adjusted analysis, non-marital sex (Adj PRR 1.27; CI: 1.16–1.40) and non-use of condoms at last such sex (Adj PRR 1.18; CI: 1.07–1.29) were associated with higher willingness to be circumcised.

Conclusion

Willingness to be circumcised was relatively high at the launch of the SMC programme and was more common among uncircumcised men reporting sexual risk behaviours. This indicates that the early adopters of SMC were likely to be in particular need of such additional HIV protective measures.     

Physiology and pathophysiology of vascular signaling controlled by guanosine 3',5'-cyclic monophosphate-dependent protein kinase

Recent medical advances suggest that the cellular natriuretic peptide/cGMP and NO/cGMP effector systems represent important signal transduction pathways especially in the cardiovascular system. These pathways also appear to be very interesting targets for the possible prevention of cardiovascular diseases. Exciting candidates for prevention include cGMP-dependent signaling networks initiated by natriuretic peptides (NP) and nitric oxide (NO) which are currently explored for their diagnostic and therapeutic potential. cGMP signaling contributes to the function and interaction of several vascular cell types, and its dysfunction is involved in the progression of major cardiovascular diseases such as atherosclerosis, hypertension and diabetic complications. This review will take a focussed look at key elements of the cGMP signaling cascade in vascular tissue. Recent advances in our knowledge of cGMP-dependent protein kinases (cGK, also known as PKG), the potential for assessing the functional status of cGMP signaling and the possible cross talk with insulin signaling will be reviewed.     

cAMP-dependent protein kinase regulates ubiquitin-proteasome-mediated degradation and subcellular localization of the nuclear receptor coactivator GRIP1

Nuclear receptors and their coactivators are key regulators of numerous physiological functions. GRIP1 (glucocorticoid receptor-interacting protein) is a member of the steroid receptor coactivator family. Here, we show that GRIP1 is regulated by cAMP-dependent protein kinase (PKA) that induces its degradation through the ubiquitin-proteasome pathway. GRIP1 was down-regulated in transiently transfected COS-1 cells after treatment with 8-para-chlorophenylthio-cAMP or forskolin and 3-isobutyl-1-methylxanthine and in adrenocortical Y1 cells after incubation with adrenocorticotropic hormone. Pulse-chase experiments with transiently transfected COS-1 cells demonstrated that the half-life of GRIP1 was markedly reduced in cells overexpressing the PKA catalytic subunit, suggesting that activation of PKA increases the turnover of GRIP1 protein. The proteasome inhibitors MG132 and lactacystin abolished the PKA-mediated degradation of GRIP1. Using ts20 cells, a temperature-sensitive cell line that contains a thermolabile ubiquitin-activating E1 enzyme, it was confirmed that PKA-mediated degradation of GRIP1 is dependent upon the ubiquitin-proteasome pathway. Coimmunoprecipitation studies of COS-1 cells transfected with expression vectors encoding GRIP1 and ubiquitin using anti-GRIP1 and anti-ubiquitin antibodies showed that the ubiquitination of GRIP1 was increased by overexpression of PKA. Finally, we show that PKA regulates the intracellular distribution pattern of green fluorescent protein-GRIP1 and stimulates recruitment of GRIP1 to subnuclear foci that are colocalized with the proteasome. Taken together, these data demonstrate that GRIP1 is ubiquitinated and degraded through activation of the PKA pathway. This may represent a novel regulatory mechanism whereby hormones down-regulate a nuclear receptor coactivator.     

Engineering, biophysical characterisation and binding properties of a soluble mutant form of annexin A2 domain IV that adopts a partially folded conformation

The four approximately 75-residue domains (repeats) that constitute the annexin core structure all possess an identical five-alpha-helix bundle topology, but the physico-chemical properties of the isolated domains are different. Domain IV of the annexins has previously been expressed only as inclusion bodies, resistant to solubilisation. Analysis of the conserved, exposed hydrophobic residues of the four annexin domains reveals that domain IV contains the largest number of hydrophobic residues involved in interfacial contacts with the other domains. We designed five constructs of domain IV of annexin A2 in which several interfacial hydrophobic residues were substituted by hydrophilic residues. The mutant domain, in which all fully exposed hydrophobic interfacial residues were substituted, was isolated as a soluble protein. Circular dichroism measurements indicate that it harbours a high content of alpha-helical secondary structure and some tertiary structure. The CD-monitored (lambda=222 nm) thermal melting profile suggests a weak cooperative transition. Nuclear magnetic resonance (1H-15N) correlation spectroscopy reveals heterogeneous line broadening and an intermediate spectral dispersion. These properties are indicative of a partially folded protein in which some residues are in a fairly structured conformation, whereas others are in an unfolded state. This conclusion is corroborated by 1-anilinonaphthalene-8-sulfonate fluorescence (ANS) analyses. Surface plasmon resonance measurements also indicate that this domain binds heparin, a known ligand of domain IV in the full-length annexin A2, although with lower affinity.     

Secular decline in mortality from coronary heart disease in adults with diabetes mellitus: cohort study

Objective To examine trends in fatal coronary heart disease in adults with and without diabetes.Design Cohort study.Setting Two surveys of the Nord-Trøndelag health study (HUNT), a population based study in Norway.Participants 74 914 men and women from the first survey (1984-6) and 64 829 from the second survey (1995-7).Main outcome measure Age specific mortality from coronary heart disease among adults with and without diabetes during two consecutive nine year follow-up periods.Results A total of 2623 men and 1583 women died from coronary heart disease. Mortality rates were substantially lower during the most recent follow-up period: among men aged 70-79 without diabetes, deaths per 1000 person years declined from 16.38 to 8.79 (reduction 48%, 95% confidence interval 39% to 55%) and among women aged 70-79 from 6.84 to 2.68 (62%, 52% to 70%). Among the same age group with diabetes, deaths per 1000 person years in men declined from 38.97 to 17.89 (54%, 32% to 69%) and in women from 28.15 to 11.83 (59%, 37% to 73%). The reduction was more noticeable in age groups younger than 70 at baseline, and less pronounced among people aged 80 or more. Mortality from coronary heart disease was more than twofold higher in people with than without diabetes, with a slightly stronger association in women. The difference in mortality by diabetes status remained almost unchanged from the first to the second survey.Conclusion The strong general reduction in mortality rates from coronary heart disease from the first to the second follow-up period also benefited people with diabetes, but the more than twofold higher mortality from coronary heart disease associated with diabetes persisted over time.     

Genome sequence of the Arctic methanotroph Methylobacter tundripaludum SV96

Methylobacter tundripaludum SV96^T (ATCC BAA-1195) is a psychrotolerant aerobic methane-oxidizing gammaproteobacterium (Methylococcales, Methylococcaceae) living in High Arctic wetland soil. The strain was isolated from soil harvested in July 1996 close to the settlement Ny-Ålesund, Svalbard, Norway (78°56′N, 11°53′E), and described as a novel species in 2006. The genome includes pmo and pxm operons encoding copper membrane monooxygenases (Cu-MMOs), genes required for nitrogen fixation, and the nirS gene implicated in dissimilatory nitrite reduction to NO but no identifiable inventory for further processing of nitrogen oxides. These genome data provide the basis to investigate M. tundripaludum SV96, identified as a major player in the biogeochemistry of Arctic environments.     

Monocarboxylate Transporters 1–4 in NSCLC: MCT1 Is an Independent Prognostic Marker for Survival

Introduction

Monocarboxylate transporters (MCTs) 1–4 are lactate transporters crucial for cancers cells adaption to upregulated glycolysis. Herein, we aimed to explore their prognostic impact on disease-specific survival (DSS) in both cancer and tumor stromal cells in NSCLC.

Methods

Tissue micro arrays (TMAs) were constructed, representing both cancer and stromal tumor tissue from 335 unselected patients diagnosed with stage I–IIIA NSCLC. Immunohistochemistry was used to evaluate the expression of MCT1-4.

Results

In univariate analyses; ↓MCT1 (P = 0.021) and ↑MCT4 (P = 0.027) expression in cancer cells, and ↑MCT1 (P = 0.003), ↓MCT2 (P = 0.006), ↓MCT3 (P = 0.020) expression in stromal cells correlated significantly with a poor DSS. In multivariate analyses; ↓MCT1 expression in cancer cells (HR: 1.9, CI 95%: 1.3–2.8, P = 0.001), ↓MCT2 (HR: 2.4, CI 95%: 1.5–3.9, P<0.001), ↓MCT3 (HR: 1.9, CI 95%: 1.1–3.5, P = 0.031) and ↑MCT1 expression in stromal cells (HR: 1.7, CI 95%: 1.1–2.7, P = 0.016) were significant independent poor prognostic markers for DSS.

Conclusions

We provide novel information of MCT1 as a candidate marker for prognostic stratification in NSCLC. Interestingly, MCT1 shows diverging, independent prognostic impact in the cancer cell and stromal cell compartments.