Maternally Derived Egg Hormones,Antibodies and Antimicrobial Proteins: Common and Different Pathways of Maternal Effects in Japanese Quail

Avian eggs contain a variety of maternally-derived substances that can influence the development and performance of offspring. The levels of these egg compounds vary in relation to environmental and genetic factors, but little is known about whether there are correlative links between maternal substances in the egg underlying common and different pathways of maternal effects. In the present study, we investigated genetically determined variability and mutually adjusted deposition of sex hormones (testosterone-T, androstenedione-A₄ and progesterone-P₄), antibodies (IgY) and antimicrobial proteins (lysozyme) in eggs of Japanese quail (Coturnix japonica). We used different genetic lines that were independently selected for yolk T concentrations, duration of tonic immobility and social reinstatement behaviour, since both selections for behavioural traits (fearfulness and social motivation, respectively) produced considerable correlative responses in yolk androgen levels. A higher selection potential was found for increased rather than decreased yolk T concentrations, suggesting that there is a physiological minimum in egg T levels. Line differences in yolk IgY concentrations were manifested within each selection experiment, but no consistent inter-line pattern between yolk IgY and T was revealed. On the other hand, a consistent inverse inter-line pattern was recorded between yolk IgY and P₄ in both selections for behavioural traits. In addition, selections for contrasting fearfulness and social motivation were associated with changes in albumen lysozyme concentrations and an inverse inter-line pattern between the deposition of yolk IgY and albumen lysozyme was found in lines selected for the level of social motivation. Thus, our results demonstrate genetically-driven changes in deposition of yolk T, P₄, antibodies and albumen lysozyme in the egg. This genetic variability can partially explain mutually adjusted maternal deposition of sex hormones and immune-competent molecules but the inconsistent pattern of inter-line differences across all selections indicates that there are other underlying mechanisms, which require further studies.     

Supplementing Exposure to Hypoxia with a Copper Depleted Diet Does Not Exacerbate Right Ventricular Remodeling in Mice

Background

Pulmonary hypertension and subsequent right ventricular (RV) failure are associated with high morbidity and mortality. Prognosis is determined by occurrence of RV failure. Currently, adequate treatment for RV failure is lacking. Further research into the molecular basis for the development of RV failure as well as the development of better murine models of RV failure are therefore imperative. We hypothesize that adding a low-copper diet to chronic hypoxia in mice reinforces their individual effect and that the combination of mild pulmonary vascular remodeling and capillary rarefaction, induces RV failure.

Methods

Six week old mice were subjected to normoxia (N; 21% O₂) or hypoxia (H; 10% O₂) during a period of 8 weeks and received either a normal diet (Cu+) or a copper depleted diet (Cu-). Cardiac function was assessed by echocardiography and MRI analysis.

Results and Conclusion

Here, we characterized a mouse model of chronic hypoxia combined with a copper depleted diet and demonstrate that eight weeks of chronic hypoxia (10%) is sufficient to induce RV hypertrophy and subsequent RV failure. Addition of a low copper diet to hypoxia did not have any further deleterious effects on right ventricular remodeling.     

Cardiac Repolarization and Autonomic Regulation during Short-Term Cold Exposure in Hypertensive Men: An Experimental Study

Objectives

The aim of our study was to assess the effect of short-term cold exposure, typical in subarctic climate, on cardiac electrical function among untreated middle-aged hypertensive men.

Methods

We conducted a population-based recruitment of 51 hypertensive men and a control group of 32 men without hypertension (age 55–65 years) who underwent whole-body cold exposure (15 min exposure to temperature −10°C, wind 3 m/s, winter clothes). Conduction times and amplitudes, vectorcardiography, arrhythmias, and heart rate variability (autonomic nervous function) were assessed.

Results

Short-term cold exposure increased T-peak to T-end interval from 67 to 72 ms (p<0.001) and 71 to 75 ms (p<0.001) and T-wave amplitude from 0.12 to 0.14 mV (p<0.001) and from 0.17 to 0.21 mV (p<0.001), while QTc interval was shortened from 408 to 398 ms (p<0.001) and from 410 to 401 ms (p<0.001) among hypertensive men and controls, respectively. Cold exposure increased both low (from 390 to 630 ms² (p<0.001) and 380 to 700 ms² (p<0.001), respectively) and high frequency heart rate variability (from 90 to 190 ms² (p<0.001) and 150 to 300 ms² (p<0.001), respectively), while low-to-high frequency-ratio was reduced. In addition, the frequency of ventricular ectopic beats increased slightly during cold exposure. The cold induced changes were similar between untreated hypertensive men and controls.

Conclusions

Short-term cold exposure with moderate facial and mild whole body cooling resulted in prolongation of T-peak to T-end interval and higher T-wave amplitude while QTc interval was shortened. These changes of ventricular repolarization may have resulted from altered cardiac autonomic regulation and were unaffected by untreated hypertension.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT02007031","term_id":"NCT02007031"}}NCT02007031     

A Seminomadic Population in Bangladesh with Extensive Exposure to Macaques Does Not Exhibit High Levels of Zoonotic Simian Foamy Virus Infection

Simian foamy viruses (SVF) are ubiquitous in nonhuman primates (NHP). SFV can be zoonotically transmitted to humans who either work with or live commensally with NHP. We analyzed the blood of 45 Bangladeshi performing monkey owners (an ethnic group called the Bedey) for SFV infection. Surprisingly, a PCR assay failed to detect SFV infection in any of these participants. This is in contrast to our previously reported infection rate of about 5% among Bangladeshi villagers.     

Prenatal Exposure to Maternal Bereavement and Childbirths in the Offspring: A Population-Based Cohort Study

IntroductionThe decline in birth rates is a concern in public health. Fertility is partly determined before birth by the intrauterine environment and prenatal exposure to maternal stress could, through hormonal disturbance, play a role. There has been such evidence from animal studies but not from humans. We aimed to examine the association between prenatal stress due to maternal bereavement following the death of a relative and childbirths in the offspring.ResultsA total of 4,121,596 subjects were followed-up until up to 41 years of age. Of these subjects, 93,635 (2.3%) were exposed and 981,989 (23.8%) had at least one child during follow-up time. Compared to unexposed, the hazard ratio (HR) [95% confidence interval] of having at least one child for exposed males and females were 0.98 [0.96–1.01] and 1.01 [0.98–1.03], respectively. We found a slightly reduced probability of having children in females born to mothers who lost a parent with HR = 0.97 [0.94–0.99] and increased probability in females born to mothers who lost another child (HR = 1.09 [1.04–1.14]), the spouse (HR = 1.29 [1.12–1.48]) or a sibling (HR = 1.13 [1.01–1.27]).ConclusionsOur results suggested no overall association between prenatal exposure to maternal stress and having a child in early adulthood but a longer time of follow-up is necessary in order to reach a firmer conclusion.     

Modulation of Protein Fermentation Does Not Affect Fecal Water Toxicity: A Randomized Cross-Over Study in Healthy Subjects

Objective

Protein fermentation results in production of metabolites such as ammonia, amines and indolic, phenolic and sulfur-containing compounds. In vitro studies suggest that these metabolites might be toxic. However, human and animal studies do not consistently support these findings. We modified protein fermentation in healthy subjects to assess the effects on colonic metabolism and parameters of gut health, and to identify metabolites associated with toxicity.

Design

After a 2-week run-in period with normal protein intake (NP), 20 healthy subjects followed an isocaloric high protein (HP) and low protein (LP) diet for 2 weeks in a cross-over design. Protein fermentation was estimated from urinary p-cresol excretion. Fecal metabolite profiles were analyzed using GC-MS and compared using cluster analysis. DGGE was used to analyze microbiota composition. Fecal water genotoxicity and cytotoxicity were determined using the Comet assay and the WST-1-assay, respectively, and were related to the metabolite profiles.

Results

Dietary protein intake was significantly higher during the HP diet compared to the NP and LP diet. Urinary p-cresol excretion correlated positively with protein intake. Fecal water cytotoxicity correlated negatively with protein fermentation, while fecal water genotoxicity was not correlated with protein fermentation. Heptanal, 3-methyl-2-butanone, dimethyl disulfide and 2-propenyl ester of acetic acid are associated with genotoxicity and indole, 1-octanol, heptanal, 2,4-dithiapentane, allyl-isothiocyanate, 1-methyl-4-(1-methylethenyl)-benzene, propionic acid, octanoic acid, nonanoic acid and decanoic acid with cytotoxicity.

Conclusion

This study does not support a role of protein fermentation in gut toxicity. The identified metabolites can provide new insight into colonic health.

Trial Registration

ClinicalTrial.gov {"type":"clinical-trial","attrs":{"text":"NCT01280513","term_id":"NCT01280513"}}NCT01280513     

Epidural Analgesia during Open Radical Prostatectomy Does Not Improve Long-Term Cancer-Related Outcome: A Retrospective Study in Patients with Advanced Prostate Cancer

Background

A beneficial effect of regional anesthesia on cancer related outcome in various solid tumors has been proposed. The data on prostate cancer is conflicting and reports on long-term cancer specific survival are lacking.

Methods

In a retrospective, single-center study, outcomes of 148 consecutive patients with locally advanced prostate cancer pT3/4 who underwent retropubic radical prostatectomy (RRP) with general anesthesia combined with intra- and postoperative epidural analgesia (n=67) or with postoperative ketorolac-morphine analgesia (n=81) were reviewed. The median observation time was 14.00 years (range 10.87-17.75 yrs). Biochemical recurrence (BCR)-free, local and distant recurrence-free, cancer-specific, and overall survival were estimated using the Kaplan-Meier technique. Multivariate Cox proportional-hazards regression models were used to analyze clinicopathologic variables associated with disease progression and death.

Results

The survival estimates for BCR-free, local and distant recurrence-free, cancer-specific survival and overall survival did not differ between the two groups (P=0.64, P=0.75, P=0.18, P=0.32 and P=0.07). For both groups, higher preoperative PSA (hazard ratio (HR) 1.02, 95% confidence interval (CI) 1.01-1.02, P<0.0001), increased specimen Gleason score (HR 1.24, 95% CI 1.06-1.46, P=0.007) and positive nodal status (HR 1.66, 95% CI 1.03-2.67, P=0.04) were associated with higher risk of BCR. Increased specimen Gleason score predicted death from prostate cancer (HR 2.46, 95% CI 1.65-3.68, P<0.0001).

Conclusions

General anaesthesia combined with epidural analgesia did not reduce the risk of cancer progression or improve survival after RRP for prostate cancer in this group of patients at high risk for disease progression with a median observation time of 14.00 yrs.     

Attentional Bias in Snus Users: An Experimental Study

The use of nicotine in the form of “snus” is substantial and increasing in some geographic areas, in particular among young people. It has previously been suggested that addictions may operate through a mechanism of attentional bias, in which stimuli representative of the dependent substance increase in salience, thus increasing the addictive behavior. However, this hypothesis has not been tested for the case of snus. The current experiment used a modified Stroop task and a dot-probe task to investigate whether 40 snus users show an attentional bias towards snus-relevant stimuli, compared to 40 non-snus users. There were no significant differences between the two groups on reaction times or accuracy on either Stroop or dot-probe task, thus failing to show an attentional bias towards snus-relevant stimuli for snus users. This could imply that other mechanisms may contribute to maintenance of snus use than for other addictions. However, this is the first experimental study investigating attentional bias in snus users, and more research is warranted.     

Effect of Prenatal Alcohol Exposure on Childhood Academic Outcomes: Contrasting Maternal and Paternal Associations in the ALSPAC Study

Background

The impact of low-to-moderate levels of alcohol consumption during pregnancy on child cognitive outcomes has been of recent concern. This study has tested the hypothesis that low-to-moderate maternal alcohol use in pregnancy is associated with lower school test scores at age 11 in the offspring via intrauterine mechanisms.

Methods

We used data from the Avon Longitudinal Study of Parents and Children (ALSPAC), a birth cohort study based in the South West of England. Analyses were conducted on 7062 participants who had complete data on: maternal and paternal patterns of alcohol use in the first trimester and at 18 weeks'' gestation, child''s academic outcomes measured at age 11, gender, maternal age, parity, marital status, ethnicity, household crowding, home ownership status and parental education. We contrasted the association of mother''s alcohol consumption during pregnancy with child''s National Curriculum Key Stage 2 (KS2) test scores with the association for father''s alcohol consumption (during the time the mother was pregnant) with child''s National Curriculum Key Stage 2 (KS2) test scores. We used multivariate linear regression to estimate mean differences and 95% confidence intervals [CI] in KS2 scores across the exposure categories and computed f statistics to compare maternal and paternal associations.

Findings and conclusions

Drinking up to 1 unit of alcohol a day during pregnancy was not associated with lower test scores. However, frequent prenatal consumption of 4 units (equivalent to 32 grams of alcohol) on each single drinking occasion was associated with reduced educational attainment [Mean change in offspring KS2 score was −0.68 (−1.03, −0.33) for maternal alcohol categories compared to 0.27 (0.07, 0.46) for paternal alcohol categories]. Frequent consumption of 4 units of alcohol during pregnancy may adversely affect childhood academic outcomes via intrauterine mechanisms.     

Free-Riding Behavior in Vaccination Decisions: An Experimental Study

Individual decision-making regarding vaccination may be affected by the vaccination choices of others. As vaccination produces externalities reducing transmission of a disease, it can provide an incentive for individuals to be free-riders who benefit from the vaccination of others while avoiding the cost of vaccination. This study examined an individual''s decision about vaccination in a group setting for a hypothetical disease that is called “influenza” using a computerized experimental game. In the game, interactions with others are allowed. We found that higher observed vaccination rate within the group during the previous round of the game decreased the likelihood of an individual''s vaccination acceptance, indicating the existence of free-riding behavior. The free-riding behavior was observed regardless of parameter conditions on the characteristics of the influenza and vaccine. We also found that other predictors of vaccination uptake included an individual''s own influenza exposure in previous rounds increasing the likelihood of vaccination acceptance, consistent with existing empirical studies. Influenza prevalence among other group members during the previous round did not have a statistically significant effect on vaccination acceptance in the current round once vaccination rate in the previous round was controlled for.     

Case-control study of rhinoconjunctivitis associated with IL5RA polymorphisms in Japanese women: The Kyushu Okinawa Maternal and Child Health Study

BackgroundEpidemiological research on the relationship between single nucleotide polymorphisms (SNPs) in the IL5RA gene and allergic disorders is limited. We examined the relationship between IL5RA SNPs and risk of rhinoconjunctivitis in young adult Japanese women.MethodsIncluded were 393 women who met the criteria of the International Study of Asthma and Allergies in Childhood (ISAAC) for rhinoconjunctivitis. Controls were 767 women without rhinoconjunctivitis according to the ISAAC criteria who had not been diagnosed with allergic rhinitis by a doctor. Adjustment was made for age, region of residence, presence of older siblings, smoking, and education.ResultsCompared with the CC genotype of SNP rs6771148, the CG genotype, but not the GG genotype, was significantly associated with a reduced risk of rhinoconjunctivitis: the adjusted OR for the CG genotype was 0.76 (95% CI: 0.58–0.99). No evident associations were found between SNPs rs17882210, rs3804797, rs334809, rs9831572, or rs17881144 and rhinoconjunctivitis. The ACTAGA haplotype of rs17882210, rs3804797, rs334809, rs9831572, rs6771148, and rs17881144 was significantly inversely associated with rhinoconjunctivitis (crude OR = 0.58, 95% CI: 0.37–0.88) while the GTAGCA haplotype was significantly positively related to rhinoconjunctivitis (crude OR = 1.74, 95% CI: 1.14–2.65). No significant interactions affecting rhinoconjunctivitis were observed between any of the six SNPs and smoking.ConclusionThis is the first study to show significant associations between IL5RA SNP rs6771148, the ACTAGA haplotype, and the GTAGCA haplotype and the risk of rhinoconjunctivitis. We did not find evidence for interactions affecting rhinoconjunctivitis between any of the IL5RA SNPs and smoking.     

Blue–Green Eggs in Pied Flycatchers: An Experimental Demonstration that a Supernormal Stimulus Elicits Improved Nestling Condition

It has been proposed that blue–green egg colouration in certain avian species has evolved as a signal of female and egg quality to males, affecting their investment in the brood according to the differential allocation scenario. A recent experiment has successfully manipulated male investment by placing dummy eggs simulating the extremes in the blue–green natural reflectance. Here we have substituted one egg in certain pied flycatcher clutches with a single deep‐blue (blue) or light‐blue (pale) dummy egg and used other clutches as controls. Blue dummy eggs reflected more in the blue–green part of the spectrum than natural and pale dummy eggs, which were similar in reflectance. Nestlings in nests with one blue dummy egg during laying and incubation attained a significantly higher mass and condition than those in nests with one pale dummy egg or in control broods, when controlling for phenology, brood size and blue–green chroma of the clutch. Only a shift in parental investment can have induced this highly significant effect. Preference for deeply coloured clutches associated with high‐quality females and their maternal effects may explain stimulation by a single supernormal stimulus emanating from multiple objects like clutches.     

Maternal Condition Affects the Offspring Testosterone Concentration in Early Nestling Period: An Experimental Test on Tawny Owls

This study addressed the question of whether maternal condition during egg laying or the rearing environment has a greater effect on offspring testosterone levels. We tested this in field experiments on a population of tawny owls Strix aluco in Duna‐Ipoly National Park, Hungary. In the experiments with females of poor condition, when broods were supplied with extra food none of the nestlings died, whereas in control broods, which were not supplied with extra food, some nestlings did die. Large differences in testosterone levels were correlated positively with hatching order both in experimental and control broods. However, it was only in control broods that the later‐hatched nestlings with low testosterone concentrations, died. In the experiments with females of good condition, the males were removed and females and their broods were supplied with restricted amounts of food. In these broods starving nestlings, whose growth had stopped, were considered as having died and were removed from the nest and hand‐reared. In control broods all nestlings fledged, and both in experimental and control broods testosterone concentrations were more even between siblings. Both types of trials confirmed a maternal influence on offspring testosterone concentration: large between‐sibling differences in concentrations in the broods of females of poor condition, where some nestlings died, could not be reduced with increased food supply, and the more even concentrations in the broods of females in good condition, where all nestlings survived, could also not be increased by restricting the food supply.     

Ticagrelor Does Not Inhibit Adenosine Transport at Relevant Concentrations: A Randomized Cross-Over Study in Healthy Subjects In Vivo

Background and Purpose

In patients with myocardial infarction, ticagrelor reduces cardiovascular and sepsis-related mortality, and can cause dyspnea. It is suggested that this is caused by adenosine receptor stimulation, because in preclinical studies, ticagrelor blocks the nucleoside transporter and increases cellular ATP release. We now investigated the effects of ticagrelor on the adenosine system in humans in vivo.

Experimental Approach

In a double-blinded, placebo-controlled cross-over trial in 14 healthy subjects, we have tested whether ticagrelor (180 mg) affects adenosine- and dipyridamole-induced forearm vasodilation, as surrogates of nucleoside uptake inhibition and adenosine formation, respectively. Also, ex vivo uptake of adenosine and uridine in isolated red blood cells was measured. Primary endpoint was adenosine-induced vasodilation.

Key Results

Ticagrelor did not affect adenosine- or dipyridamole-induced forearm vasodilation. Also, ex vivo uptake of adenosine and uridine in isolated red blood cells was not affected by ticagrelor. In vitro, ticagrelor dose-dependently inhibited nucleoside uptake, but only at supra-physiological concentrations.

Conclusion and Implications

In conclusion, at relevant plasma concentration, ticagrelor does not affect adenosine transport, nor adenosine formation in healthy subjects. Therefore, it is unlikely that this mechanism is a relevant pleiotropic effect of ticagrelor.

Trial Registration

ClinicalTrials.gov NCT01996735     

Neurotoxic Sequelae of Mercury Exposure: An Intervention and Follow-up Study in the Brazilian Amazon

Since 1995, the Caruso Project used an Ecosystem Approach to Human Health to examine mercury (Hg) exposure in fish-eating communities in the Brazilian Amazon and develop interventions to maximise nutrition from traditional diet and minimise toxic risk. In 1995, 2000 and 2006, this study followed fish consumption, Hg levels, and visual and motor functions in 31 villagers. Questionnaires gathered information on socio-demographics and diet. Hair Hg (H-Hg) levels were measured. Visual acuity, colour vision, manual dexterity and grip strength were assessed. Data was analysed using general linear models of repeated measures. Total fish consumption, similar in 1995 and 2000, decreased in 2006. Carnivorous fish consumption initially decreased and then remained stable, whereas non-carnivorous fish consumption first increased and then decreased. H-Hg declined from 17.6 to 7.8 μg/g. Visual functions showed a significant decrease over time, with those with H-Hg ≥ 20 μg/g in 1995 showing greater loss. Motor functions showed initial improvement and then returned to the 1995 performance level. Decrease in Hg exposure is attributed to the intervention and socio-economic changes in the village. While there may be a certain reversibility of motor deficits, visual capacities may decrease progressively with respect to exposure prior to the intervention.     

An Evaluation of the Implementation of Maternal Obesity Pathways of Care: A Mixed Methods Study with Data Integration

ObjectivesMaternal obesity has multiple associated risks and requires substantial intervention. This research evaluated the implementation of maternal obesity care pathways from multiple stakeholder perspectives.ResultsStudy 1: Four themes were identified: women’s overall (positive and negative) views of the pathways; knowledge and understanding of the pathways; views on clinical and weight management advice and support; and views on the information leaflet. Key results included positive views of receiving additional clinical care, negative experiences of risk communication, and weight management support was considered a priority. Study 2: Healthcare professionals felt the pathways were worthwhile, facilitated good practice, and increased confidence. Training was consistently identified as being required. Healthcare professionals predominantly focussed on women’s response to sensitive obesity communication. Study 3: There was good compliance with antenatal clinical interventions. However, there was poor compliance with public health and postnatal interventions. There were some strong areas of agreement between component studies which can inform future development of the pathways. However, disagreement between studies included a lack of shared priorities between healthcare professionals and women, different perspectives on communication issues, and different perspectives on women’s prioritisation of weight management.ConclusionThe differences between healthcare professionals’ and women’s priorities and perspectives are important factors to consider when developing care pathways. Shared perspectives could help facilitate more effective implementation of the pathway interventions that have poor compliance.