Variance parameter estimation for age at puberty phenotypes under 2 levels of phenotype censorship.

Age at puberty (AGEP) is a moderately heritable trait in cattle that may be predictive of an animal's genetic merit for reproductive success later in life. In addition, under some mating strategies (for example, where mating begins before all animals have attained puberty) animals that attain puberty at a relatively young age will also likely conceive earlier than their herd mates, and thus begin their productive life earlier. Unfortunately, AGEP is challenging to measure because animals must be observed over a period of several months. Our objectives for this study were twofold. The first objective was to produce variance components for AGEP. The second objective was to investigate the implications of a simplified phenotyping strategy for AGEP, when the interval between repeated blood plasma progesterone measures was extended from weekly to monthly, increasing the extent of left, interval, and right censoring. We measured AGEP in a closely monitored population of around 500 Holstein-Friesian heifers, born in 2015 and managed under a seasonal, pasture-based dairy system. Animals were blood tested weekly from approximately 240 to 440 d of age and were deemed to have reached puberty when blood plasma progesterone elevation (>1 ng/mL) was detected in 2 of 3 consecutive blood tests (AGEP_Weekly). To simulate a simplified phenotyping strategy based on monthly herd visits (AGEP_Monthly), we selectively disregarded data from all but 3 blood test events, when animals were around 300, 330, and 360 d of age (standard deviation = 14.5 d). The posterior mean of estimated heritabilities for AGEP_Weekly was 0.54, with a 90% credibility interval (90% CRI) of 0.41 to 0.66, whereas it was 0.44 (90% CRI 0.32 to 0.57) for AGEP_Monthly. The correlation between EBVs for AGEP_Weekly and AGEP_Monthly was 0.87 (90% CRI, 0.84 to 0.89). We conclude that in this population, AGEP is a moderately heritable trait. Further, increasing phenotype censorship from weekly to monthly observations would not have altered the main conclusions of this analysis. Our results support the strategic use of censoring to reduce costs and animal ethics considerations associated with collection of puberty phenotypes.

Adaptive immune response ranking is associated with reproductive phenotypes in grazing dairy cows divergent in genetic merit for fertility traits.

A strong adaptive immune response has been reported to have positive effects on fertility; therefore, we investigated antibody- and cell-mediated adaptive immune responses (AMIR and CMIR, respectively) and their associations with reproductive phenotypes using a population of animals that differed in their estimated genetic merit for fertility traits (fertility breeding value; FertBV). Holstein-Friesian heifers (n = 528) grazed on pasture in 4 herds based on age. These herds included 277 heifers of positive (POS) FertBV and 251 of negative (NEG) FertBV. The adaptive immune response (IR) was evaluated before puberty at 7.5 mo of age and used to rank animals as high, average, or low for AMIR, CMIR, and overall IR (combined CMIR and AMIR). The animals were studied from 12 wk of age through to the end of their second lactation to measure growth, puberty, and timing and success of fertility phenotypes, including those related to ovulation and pregnancy. Initial analysis indicated no difference in fertility outcomes between cows ranked as high or average for AMIR (n = 55, n = 407, respectively), CMIR (n = 87, n = 354, respectively), and IR (n = 29, n = 470, respectively), so these groups were pooled as HiAv-IR. Proportions of heifers of POS FertBV were similar within HiAv and low categories across AMIR (0.52 and 0.58, respectively), CMIR (0.51 and 0.59, respectively), and IR (0.53 and 0.48, respectively). Heifers with HiAv-IR had a greater average daily weight gain from 13 to 52 wk of age (661 g, 95% confidence interval 652, 669 vs. 619 g, 95% confidence interval 591, 647) and tended to be younger at puberty (371 d, 95% confidence interval 366, 377 vs. 385 d, 95% confidence interval 369, 401) than low-IR heifers. Low-CMIR cows of a NEG FertBV had a >40 d longer calving to first ovulation interval during their first lactation compared with HiAv-CMIR NEG FertBV cows. Low-CMIR cows also had decreased pregnancy rates at both 3 wk (25% ± 7% vs. 42% ± 3%; least squares means ± standard error) and 6 wk (33% ± 7% vs. 54% ± 3%; least squares means ± standard error) into the seasonal breeding period during their first lactation, compared with HiAv-CMIR cows. In summary, although the number of POS and NEG FertBV cows was similar in each immune group; interaction effects between FertBV and immune ranking on reproductive phenotypes are evident when cows were ranked by the overall IR. There were also associations between dairy cows' CMIR ranking and ability to return to estrus and become pregnant early in the breeding period, which will have benefits in seasonal breeding systems.

Investigating anogenital distance and antral follicle count as novel markers of fertility within a herd of cows with positive or negative genetic merit for fertility traits.

Using early-in-life markers of reproductive characteristics may enhance the speed and success of genetic improvement in fertility. We investigated 2 phenotypes that can be measured early in life and are moderately heritable to determine their association with traditional measures of reproductive success and genetic variation under a seasonal-calving, pasture-based system. Cows were bred to be divergent in the New Zealand Fertility Breeding Value, which estimates genetic merit for fertility. Cows consisted of 2 groups with an average positive (+5%) or negative (-5%) genetic merit for fertility traits and were expected to have large diversity in reproductive outcomes. Calves were genotyped at 41 ± 3.1 d of age (mean ± SD; n = 538), and antral follicle counts (AFC) were measured when they were postpubertal heifers before their first breeding (416 ± 15 d old; 92-d range; n = 520). The anogenital distance (AGD) was measured in 478 primiparous cows of this same population 50 to 60 d after the breeding start date when they were 881 ± 25 d old (145-d range). The AGD was shorter in animals with a positive genetic merit for fertility traits (based on parent averages). An indicator of herd reproductive success in a seasonal-calving system (recalving by 6 wk in lactation 2) was chosen for logistic regression with cross-validation, and if significant, a cut-off was calculated that categorized animals into groups. Both linear and quadratic regression was undertaken, and the model with the greatest sensitivity for detection of nonpregnant cows used. The AGD linear model was significant with a sensitivity of 64% and a specificity of 48%. This model resulted in a cut-off of 102 mm, which we used to classify cows as short (≤102 mm) or long (>102 mm) AGD animals. Primiparous cows with a short AGD were more likely to be pregnant within the first 3 and 6 wk of mating, and become pregnant as a primiparous cow, than those with a long AGD. The time from calving to conception was 20 d earlier in short AGD compared with long-AGD cows. None of the models tested for AFC were significant; therefore cows were categorized into 3 groups based on previous work in seasonal systems. However, associations between fertility phenotypes and AFC group were limited. Genomic regions of interest for AGD and AFC did not overlap, indicating phenotypes were genetically independent. Overall, AGD appears as a promising early marker of fertility in seasonal grazing systems.

Mobile gastrointestinal and endoscopic surgery in rural Ecuador: 20 years' experience of Cinterandes.

INTRODUCTION: Five billion people worldwide do not have timely access to surgical care. Cinterandes is one of the only mobile surgical units in low- and middle-income countries. This paper examines the methodology that Cinterandes uses to deliver mobile surgery. METHODS: Founding and core staff were interviewed, four missions were participated in, and internal documents and records were analysed between 1 May and 1 July 2014. RESULTS: Cinterandes performed 7641 operations over the last 20 years (60% gastrointestinal/laparoscopic), travelling 300,000 km to remote areas of Ecuador. The mobile surgery programme was initiated by a local Ecuadorian surgeon in 1980. Funding was acquired from businesses, private hospitals, and individuals, to fund a low-cost surgical truck, simple equipment, and running costs. The mobile surgical unit is a 24-foot modified Isuzu truck containing a preparation room with general equipment storage and running water, together with an operating room including the operating table, anaesthetic and surgical equipment. Mission structure includes: patient identification by a network of local medical personnel in remote regions; pre-operative assessment at 1 week by core team via teleconsultations; four-day surgical missions; post-operative recovery in tents or a local clinic; post-operative follow-up care by local personnel and remote teleconsultations. The permanent core team includes seven members; lead surgeon, lead anaesthetist, operating-room technician, medical coordinator, driver, general coordinator, and receptionist. Additional support members include seven regular surgeons, residents, medical students, and volunteers. CONCLUSION: Surgery is a very effective way to gain the trust of the community, due to immediate results. Trust opens doors to other programmes (e.g. family medicine). Surgery can be incorporated with all other aspects of health care, which can in turn be incorporated with all other aspects of human development, education, food production and nutrition, housing, work and productivity, communication, and recreation.

Increased trophoblast expression of NFAT5/TonEBP in pre-eclamptic placentas and hyperosmolar-treated BeWo cells.

OBJECTIVES: To assess the concentrations of inositol and sorbitol, and determine the expression of related osmolyte factors [nuclear factor of activated T cells 5, also known as tonicity responsive binding protein (NFAT5/TonEBP); sodium myo-inositol transporter (SLC5A3); and aldose reductase] in placentas of pre-eclamptic (PE) patients and trophoblast BeWo cells subjected to hypertonic stress in vitro. STUDY DESIGN: Control and PE placentas were collected. BeWo cells were cultured and subjected to a hyperosmolar solution for 4h. Western blot analysis was performed on NFAT5, SLC5A3, aldose reductase and ERK proteins. High-performance liquid chromatography was used to determine the levels of inositol and sorbitol in cell lysates. RESULTS: Compared with control placentas, PE placentas showed higher levels of inositol and NFAT5, and lower levels of SLC5A3. Treated BeWo cells showed higher levels of inositol, sorbitol, NFAT5 total protein, SLC5A3 and aldose reductase, and increased ERK activation compared with control BeWo cells. CONCLUSIONS: Hyperosmolar conditions increase the expression of NFAT5 in PE placentas and BeWo cells, and may account for the increased osmolyte levels. NFAT5 may accomplish this through aldose reductase and SLC5A3 in trophoblast cells.

Different expression of placental pyruvate kinase in normal, preeclamptic and intrauterine growth restriction pregnancies.

INTRODUCTION: Preeclampsia (PE) and intrauterine growth restriction (IUGR) are two diseases that affect pregnant women and their unborn children. These diseases cause low birth weight, pre-term delivery, and neurological and cardiovascular disorders in babies. Combined they account for 20% of preterm deliveries. Pyruvate kinase M2 (PKM2) is a metabolism enzyme found in developing embryonic and cancer tissues. Our objective is to determine the expression of PKM2 in human PE and IUGR compared to normal pregnancies. Understanding expression of PKM2 in PE and IUGR could help us to better understand the mechanisms and find treatments for PE and IUGR. METHODS: Human placental tissues were obtained for PKM2 determination and analyzed by immunohistochemistry, Western blot, and a pyruvate assay. Placental samples were homogenized and cytoplasmic and nuclear proteins were extracted for Western blot analysis. RESULTS: Preeclampsia samples had elevated levels of p-PKM2, p-ERK, and ERK in the cytoplasm. Beta-catenin and lactose dehydrogenase (LDH) were also elevated in preeclampsia placenta samples. DISCUSSION AND CONCLUSION: We conclude that PKM2 is expressed in normal, PE and IUGR pregnancies. Also, that this expression is increased in the PE placenta at delivery. These results suggest placental metabolism through PKM2 could play a role in human preeclampsia.

Coil-by-coil image reconstruction with SMASH.

The SiMultaneous Acquisition of Spatial Harmonics (SMASH) technique uses linear combinations of undersampled datasets from the component coils of an RF coil array to reconstruct fully sampled composite datasets in reduced imaging times. In previously reported implementations, SMASH reconstructions were designed to reproduce the images that would otherwise be obtained by simple sums of fully gradient encoded component coil images. This strategy has left SMASH images vulnerable to phase cancellation artifacts when the sensitivities of RF coil array elements are not suitably phase-aligned. In fully gradient encoded imaging schemes these artifacts can be eliminated using a variety of methods for combining the individual coil images, including matched filter combinations as well as sum of squares combinations. Until now, these reconstruction schemes have been unavailable to SMASH reconstructions as SMASH produced a final composite image directly from the raw component coil k-space datasets. This article demonstrates a modification to SMASH that allows reconstruction of a full set of accelerated individual component coil images by fitting component coil sensitivity functions to a complete set of spatial harmonics tailored for each coil in the array. Standard component coil combinations applied to the individual reconstructed images produce final composite images free of phase cancellation artifacts.

Construction and implementation of NMR quantum logic gates for two spin systems.

The implementation of small prototype quantum computers has been studied through ensemble quantum computing via NMR measurements. In such laboratory studies it is convenient to have access to a wide array of logic gates. Here a systematic approach to reduce the logic gate to an NMR pulse sequence is introduced. This approach views the truth table for a quantum logic operation as a permutation matrix that corresponds to a propagator for an NMR transition. This propagator is then used as the starting point for the derivation of a pulse sequence. Pulse sequences for all the permutations of a four level system are reported along with implementations of representative examples on a two spin-1/2 system, 13C-labeled chloroform.

The yan gene is highly conserved in Drosophila and its expression suggests a complex role throughout development.

Competence for cell fate determination and cellular differentiation is under tight control of regulatory genes. Yan, a nuclear target of receptor tyrosine kinase (RTK) signaling, is an E twenty six (ETS) DNA-binding protein that functions as a negative regulator of cell differentiation and proliferation in Drosophila. Most members of RTK signaling pathways are highly conserved through evolution, yet no yan orthologues have been identified to date in vertebrates. To investigate the degree of yan conservation during evolution, we have characterized a yan homologue from a sibling species of D. melanogaster, D. virilis. Our results show that the organization, primary structure and expression pattern of yan are highly conserved. Both genes span over 20 kb and contain four exons with introns at identical positions. The areas with highest amino acid similarity include the Pointed and ETS domain but there are other discrete regions with a high degree of similarity. Phylogenetic analysis reveals that yan's closest relative is the human tel gene, a negative regulator of differentiation in hematopoetic precursors. In both species, Yan is dynamically expressed beginning as early as stage 4/5 and persisting throughout embryogenesis. In third instar larvae, Yan is expressed in and behind the morphogenetic furrow of the eye imaginal disc as well as in the laminar precursor cells of the brain. Ovarian follicle cells also contain Yan protein. Conservation of the structure and expression patterns of yan genes strongly suggests that regulatory mechanisms for their expression are also conserved in these two species.

Lipid and apolipoprotein levels during therapy with pinacidil combined with hydrochlorothiazide.

This study determined the effect of pinacidil on the concentration of plasma lipids and apolipoproteins in male patients previously equilibrated with 25 mg hydrochlorothiazide twice daily. Pinacidil therapy given to 52 hypertensives at 25 to 100 mg daily for 8 weeks resulted in a reduction of systolic and diastolic blood pressure concurrently to reductions in plasma cholesterol and triglycerides with no change in low density lipoprotein-cholesterol (LDL-C) and high density lipoprotein-cholesterol (HDL-C). There was an associated decrease in apolipoproteins (Apo)B, C-III and E and elevation in ApoA-I. A parallel placebo group of 44 patients experienced reduction in diastolic blood pressure and an elevation in ApoA-I. These changes indicate that pinacidil will be a useful antihypertensive agent having properties on lipoprotein metabolism which would favor decreased risks of atherosclerosis.

CI-924 effects on plasma lipids in patients with type II and type IV hyperlipoproteinaemia.

CI-924 (CI), 5,5'-[[1,1'-biphenyl]-2,5-diylbis(oxy)]bis[2,2- dimethylpentanoic acid] is chemically similar to gemfibrozil. Patients with Type II (n = 13) and Type IV (n = 22) hyperlipoproteinaemia (HLP) were maintained 12 weeks on a baseline diet containing 55% sugar, 15% protein 30% fat and less than 300 mg cholesterol daily to stabilize weight and lipids. They were then entered in a parallel group double-blinded protocol and received 0, 300, 600, or 1200 mg CI p.o. daily for 12 weeks. CI consistently elevated anti-atherogenic HDL and lowered VLDL at 600 mg/day in both Type II and Type IV HPL at 8 weeks. In Type II patients, CI lowered cholesterol, decreased LDL/HDL and increased ApoA-I. In Type IV patients, CI also lowered TC while elevating LDL and ApoA-II. CI had no effect on Apo-B, LDL-ApoB, or Apo-E.