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Background: Risk assessment in pulmonary arterial hypertension (PAH) is fundamental to guiding treatment and improved outcomes. Clinical models are excellent at identifying high-risk patients, but leave uncertainty amongst moderate-risk patients., Research Question: Can a multiple blood biomarker model of PAH, using previously described biomarkers, improve risk discrimination over current models?, Study Design and Methods: Using a multiplex enzyme-linked immunosorbent assay, we measured N-terminal pro-B-type natriuretic peptide (NT-proBNP), soluble suppressor of tumorigenicity, IL-6, endostatin, galectin 3, hepatoma derived growth factor, and insulin-like growth factor binding proteins (IGFBP1-7) in training (n = 1,623), test (n = 696), and validation (n = 237) cohorts. Clinical variables and biomarkers were evaluated by principal component analysis. NT-proBNP was not included to develop a model independent of NT-proBNP. Unsupervised k-means clustering classified participants into clusters. Transplant-free survival by cluster was examined using Kaplan-Meier and Cox proportional hazard regressions. Hazard by cluster was compared with NT-proBNP, Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL), and European Society of Cardiology and European Respiratory Society risk models alone and combined clinical and biomarker models., Results: The algorithm generated five clusters with good risk discrimination using six biomarkers, weight, height, and age at PAH diagnosis. In the test and validation cohorts, the biomarker model alone performed equivalent to REVEAL (area under the receiver operating characteristic curve, 0.74). Adding the biomarker model to the European Society of Cardiology and European Respiratory Society score and REVEAL score improved the European Society of Cardiology and European Respiratory Society score and REVEAL score. The best overall model was the biomarker model adjusted for NT-proBNP with the best C statistic, Akaike information criterion, and calibration for the adjusted model compared with either the biomarker or NT-proBNP model alone., Interpretation: In this study, a multibiomarker model alone was equivalent to current PAH clinical mortality risk prediction models and improved performance when combined and added to NT-proBNP. Clinical risk scores offer excellent predictive models, but require multiple tests; adding blood biomarkers to models can improve prediction or can enable more frequent, noninvasive monitoring of risk in PAH to support therapeutic decision-making., Competing Interests: Financial/Nonfinancial Disclosures None declared., (Copyright © 2024 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

The collective economic and environmental interest of the whole dairy sheep sector is to reduce feed costs and the negative impact of milk production on the environment. Thus, this study focused on the characterisation and genetic selection potential of feed efficiency in the Lacaune breed. Estimates for feed efficiency in dairy ewes are limited, mainly due to a lack of individual feed intake measurements in the sheepfold or in the pasture. We estimated the genetic parameters for two approximated (not entirely based on individual data) feed efficiency traits (lactation feed conversion ratio (LFCR) and residual energy intake (REI)) and daily milk yield (DMY) at different stages of lactation and throughout lactation. The accuracy of the efficiency traits was first evaluated on samples from Lacaune dairy ewes that were monitored individually, especially for their feed intake. Then, feed efficiency estimation methods were applied on eight commercial farms corresponding to 4 680 Lacaune dairy ewes over two milk lactations (30 854 records). Animals were collectively (for a large part of feed intake) or individually (for milk performance and dynamics of body fat reserves) monitored at different lactation stages. The heritabilities of LFCR and REI were estimated over lactations at 0.10 ± 0.01 and 0.11 ± 0.01, respectively. High genetic correlations were observed between the two efficiency traits and milk production traits, with a genetic correlation between LFCR and DMY of 0.74 ± 0.04 and between REI and DMY of -0.79 ± 0.04. A strong influence of environmental factors such as farm, year of milk production and lactation stage affected the genetic link between REI and milk production traits. Efficiency values observed in early lactation when animals were bred in the sheepfold were less genetically correlated with values obtained later in lactation when animals were grass-fed. However, individual characterisation of feed efficiency remains difficult due to the collective feeding context in dairy ewe farms., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

The main limitation for determining feed efficiency of freely grazing ruminants is measurement of daily individual feed intake. This paper describes an investigation that assessed a method for estimating intake of forage based on changes in BW of ewes. A total of 24 dry and non-pregnant Romane ewes (12 hoggets, HOG; mean±SD 51.8±2.8 kg BW; body condition score (BCS) 2.6±0.2; and 12 adults, ADU; 60.4±8.5 kg BW; BCS 2.7±0.8) were selected for the study and moved from their rangeland system to a confined pen with controlled conditions and equipped with individual automatic feeders. The experiment lasted for 28 days (21 days adaptation and 7 days feed intake measurement). Ewes were fed hay and trained to use the electronic feeders (one feeding station per ewe) in which actual daily intake (H intake24) was measured. The pens were designed to maximize movement of trained ewes through an automated Walk-over-Weighing device, by using water and mineral salts as attractants. Total individual intake of hay measured in the automatic feeder at each meal (H intake) was compared with indirect estimates of feed intake determined using differences in the BW of the ewes (∆BW) before and 1 h following morning and afternoon feeding at fixed times. The BW, BCS, H intake, H intake24, as well as plasma non-esterified fatty acids (NEFA), glucose and insulin profiles were determined. The BW was higher in ADU v. HOG but BCS was not affected by parity. The H intake24 was affected by day of experiment as a consequence of reduced availability and intake of water on one day. Plasma glucose, NEFA and insulin were not affected by parity or day of experiment. The H Intake was and ∆BW tended to be higher in the morning in HOG, whereas H intake was and ∆BW tended to be higher in ADU at the afternoon meal. Irrespective of parity or feeding time, there was very strong correlation (r 2=0.93) between H intake and ∆BW. This relationship confirms that our indirect method of estimating individual forage intake was reliable within the strictly controlled conditions of the present experiment. The method appears suitable for use in short-term intensive group feeding situations, and has potential to be further developed for longer-term forage intake studies, with a view to developing a method for freely grazing ruminants.

Polyethylene glycol (PEG) measured with NIRS is known to be a valuable faecal marker when used in indoor experiments. In order to verify whether it can be used at pasture, an experiment was conducted with two trials. In trial 1, six Romane breed adult dry ewes placed in metabolism cages were fed daily with natural, freshly cut rangeland from a fertilised or unfertilised paddock for 6 weeks. Three ewes did not receive PEG and the three others were dosed with 10 g of PEG in solution form once daily until the end of the experiment to measure in vivo dry matter digestibility and PEG recovery rate for each forage quality. At the same time (trial 2), 15 ewe lambs and 14 lactating adult ewes suckling one or two lambs were allowed to graze together on the same herbage as that cut for indoor ewes. All animals were initially equipped with faecal bags emptied twice daily for collecting total faeces, and eight ewe lambs and seven adults were dosed once daily with 10 g of PEG. Faecal grab samples were collected for 4 to 5 days for each forage quality grazed. Indoor trial 1 showed that PEG had no effect on dry matter intake (DMI) or on digestibility. PEG recovery rates measured on fertilised (77.7%) and unfertilised (82.1%) forage were not different (P>0.05). PEG recovery rates measured at pasture did not differ (P>0.05) between pasture quality and animal type with an average value of 68.9%. Faecal output measured with bags or estimated with PEG and calculated DMI were not different (P>0.05) when PEG recovery rate measured at pasture was used. Conversely, using indoor PEG recovery values, significantly (P<0.05) or tended to overestimate faecal output. In conclusion, PEG could be used as a faecal marker administered at a minimal dose of 1% of DMI with a recovery rate measured under pasture conditions for pasture intake measurements on a group of animals at the same physiological stage but not for individual measurements.

Effects of parity (primiparous, PRIM vs multiparous, MULT) and litter size (singletons, SING vs twins, TWIN) on metabolic profiles from 1 wk before lambing to the end of lactation were studied in 48 Lacaune dairy ewes reared in confinement during most of the year and grazed on improved pastures at the end of lactation (summer). Another group of 48 ewes was incorporated during the milking period (ie, from 1 wk after weaning), to measure the effects of milking frequency (1 vs 2 milkings per day) on intake, milk production and composition, and body energy usage. Thus, in a 2 × 2 × 2 factorial design, ewes (n = 96) were allocated to homogeneous groups according to body weight (BW) and body condition score (BCS) and were monitored from late pregnancy to late lactation as a function of parity (PRIM, n = 48; MULT, n = 48), litter size (LSi) (SING, n = 40; TWIN, n = 56) and daily milking frequency (FREQ; milked once, ONE; n = 48; or twice, TWO; n = 48). Individual BW, BCS, plasma metabolites, and metabolic hormones were measured regularly (ie, 9 consecutive sampling dates). The BW was higher in MULT but no differences because of LSi or FREQ were detected at the intra-parity group level. The BCS was higher in MULT and in ewes with SING throughout the experiment. The latter was related to the demands for body reserves mobilization, as expressed by higher nonesterified fatty acids and β-hydroxybutyrate concentrations in ewes with TWIN from late pregnancy to weaning (35 d postpartum) in both PRIM and MULT ewes. This was consistent with higher insulin in MULT and higher triiodothyronine, leptin and insulin-like growth factor 1 in ewes with SING during this period. Differences in energy balance because of FREQ were evident after interpretation of plasma nonesterified fatty acids, glucose, insulin, and leptin concentration during the milking period. At similar feed intakes, ewes in ONE were in positive balance with regard to TWO. Overall, clear effects of parity, LSi, physiological states, and FREQ on metabolic profiles were found because of differences in nutrient partitioning when combining these experimental factors. Without considering FREQ, changes in metabolic measures in milking period were marginal compared with the periparturient adjustments performed until weaning to compensate energy deficiencies., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Several external markers can be used for estimating total faecal output in view of assessing ruminant intake at pasture. Among them, ytterbium (Yb) has been used for many years in various conditions. Polyethylene glycol (PEG) is a promising external marker because it can be rapidly determined using near-infrared spectroscopy (NIRS). The study consisted of 24 adult lactating dairy ewes over three periods (P1, P2 and P3), fed with three different diets: P1, total mixed ration (TMR); P2, Italian ryegrass (IRG); and P3, pasture. After an adaptation period, the ewes were administered a daily dose of ytterbium oxide (0.35 g/day) and PEG (20 g/day) for 2 weeks. During the last week, the daily organic matter intake (OMIOBS) was measured. Faecal samples were collected at milking time (0800 and 1600 h) to determine marker content, using only samples collected in the morning (PEGm) or by averaging samples (Yb, PEGma). Faecal marker content made it possible to assess total faecal output, either using the two recovery rates for PEG (0.98 or 0.87) or not. The OMIOBS was assessed on the basis of total faeces estimated with Yb (OMIYb) or PEG (OMIPEG), and the digestibility was calculated on the basis of feed analysis. With total TMR (P1), the OMIPEG, corrected with recovery rate (OMIPEGm98) or not corrected (OMIPEGm) was 2.40 kg/day and 2.50 kg/day, respectively, and was not different (P>0.05) from OMIOBS (2.51 kg/day), whereas OMIYb was lower (2.14 kg/day) (P<0.001). With IRG (P2), OMIPEGm98 (1.67 kg/day), OMIPEGm87 (1.51 kg/day) and OMIYb (1.59 kg/day) were not different (P>0.05) from OMIOBS (1.57 kg/day). With pasture (P3), the OMIPEGm (1.54 kg/day) and OMIPEGm98 (1.48 kg/day) were not different (P>0.05) from the OMI assessed from the biomass measurement (1.52 kg/day). The OMIYb (1.36 kg/day) was lower (P<0.05) but not different from OMIPEGm98 and OMIPEGm87. Spearman's rank correlation between OMIOBS and other OMIs (predicted with Yb or PEG P1 and P2) showed that it is possible to rank animals using PEG when there is a sufficiently wide range of OMIOBS (1.65 to 2.8 kg/day in P1) but not within a narrower range (1.47 to 1.72 kg/day in P2). In conclusion, the present study confirms that PEG is a valuable external faecal marker, easy to prepare (solution), administer and determine (NIRS). It can be used to assess intake with numerous animals at pasture, but only for groups, and not to quantitatively estimate individual OMI.

In experiments based on ruminants' individual dry matter intake (DMI) assessment, several external markers can be used to estimate faecal output when total faeces collection is not possible. However, preparation of the markers to be administered and analytical procedures used for marker content determination are time-consuming thus strongly limiting the number of animals involved in the experiments. In this paper, polyethylene glycol (PEG, molecular weight 6000 da) was tested as a faecal marker. Four trials were conducted on dry, non-lactating ewes kept in digestibility crates that allowed individual measurements. The overall experiment was designed to assess the major factors that could lessen the effectiveness of this method, assuming that the use of grab samples of faeces is sufficient. Trial 1 was designed to test two levels of PEG (20 and 40 g/day) administered in two equal amounts. Trial 2 was designed to test the effect of either a single morning (0800 h) dose (20 g/day) or a twice daily administration (0800 and 1600 h) of the same fractionated dose. Trial 3 was designed to test a 20 g/day dose of PEG administered once daily to ewes fed with hays of different qualities: medium (MH) and low (LH). In trial 4, a lower dose of PEG (10 g/day) was administered once a day to ewes fed with fresh oat-vetch forage. It was demonstrated that PEG could be precisely estimated (average prediction error = 3.47 g/kg) with near-infrared reflectance spectroscopy (NIRS). On the basis of the four trials, it has been proved that PEG administration (20 and 40 g/day) did not significantly affect the DMI of ewes fed dry diets (trials 1, 2 and 3), whereas there was an unexpected increase of DMI for ewes fed exclusively with green feed (trial 4) without DM digestibility modification. Providing PEG as a single dose (0800 h) or split into two equal parts (0800 and 1600 h) did not alter the estimated DMI. Considering the interest of grab sampling, there were clear variations of PEG in faeces with higher concentrations observed at 0800 and 1600 h and lower concentrations at 1400 h. Consequently, with PEG (measured with NIRS) administered once and using the grab sampling procedure (morning collection), it is possible to estimate the DMI of dry feeds with good accuracy. For green feeds, more research is needed as the estimated results are still highly variable.

Maternal undernutrition during gestation can condition offspring adult health, with the periconceptional period pointed out as a key period. The aim of this study was to evaluate the effects of maternal periconceptional undernutrition on pregnancy and offspring growth performance in sheep. 52 Merinos d'Arles ewes were fed to requirements (control group, C), whereas 64 ewes received 50% of their dietary needs from -15 to +30 days post-conception (restricted group, R). Thereafter, both groups were fed according to needs. Maternal body weight (BW), body condition score (BCS) and Non Esterified Fatty Acids (NEFA), progesterone, leptin and cortisol plasma concentrations were monitored weekly during the restriction period and the following month, then monthly until weaning. Lambs were weighed weekly until weaning at 22 kg BW, then monthly. Plasma leptin was monitored monthly in lambs. The BW, BCS, and leptin concentrations were significantly decreased, whereas NEFA and cortisol concentrations were increased in R dams. Maximum progesterone concentration was higher in R ewes that had a high (10-25%) vs. low (0-10%) BW loss during restriction (27.9 ± 2.59 vs. 20.8 ± 2.00 ng/mL, P < 0.05). Overall, gestation was significantly longer in the R group (151.0 ± 0.3 vs. 149.4 ± 0.4 days, P < 0.001). There was no difference between groups for pregnancy rates, prolificacy, birth weight and lamb mortality, but the proportion of male lambs was significantly higher in the R group, only for singletons (16/26 vs. 9/26, P < 0.05). Lamb growth was not significantly modified by treatment. Leptin concentrations at birth were significantly lower in R vs. C males (6.15 ± 0.13 ng/mL vs. 7.42 ± 0.36 ng/mL, P < 0.05), whereas in females, leptin concentrations were significantly higher in R vs. C lambs at 4 mo of age (7.31 ± 0.27 ng/mL vs. 6.41 ± 0.29 ng/mL, P < 0.05). These results indicate that maternal periconceptional undernutrition in a hardy breed does not significantly affect lamb birth weight and growth rates, in contrast to previous reports in other breeds, suggesting that caution must be taken when extrapolating programming data between breeds and breeding conditions., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background: Pulmonary arterial hypertension (PAH) is a progressive disease which causes exercise limitation, heart failure, and death. Aspirin and simvastatin are highly effective and safe therapies for other cardiovascular diseases characterized by platelet activation and endothelial dysfunction, but have not been formally studied in PAH., Methods: ASA-STAT is a phase II, randomized, double-blind, placebo-controlled 2 × 2 factorial clinical trial of aspirin and simvastatin in patients with PAH. A total of 92 subjects were to be randomized to aspirin or aspirin placebo and simvastatin or simvastatin placebo. The primary outcome is the distance walked in 6 min at 6 months after randomization. Secondary measures include brachial artery flow-mediated dilation, circulating biomarkers of platelet and endothelial function, functional class, quality-of-life, and time to clinical end points. The incidence of adverse events will be compared between treatment groups. SCREENING AND ENROLLMENT: We screened a total of 712 individuals with PAH. Sixty-five subjects were enrolled when the trial was terminated for futility in reaching the primary end point for simvastatin., Conclusions: This study aims to determine whether aspirin or simvastatin have beneficial biologic or clinical effects in patients with PAH. The safety and side effects of these commonly prescribed cardiovascular drugs will also be assessed., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Bilateral paralysis of the diaphragm is either idiopathic or associated with several medical conditions, including trauma or thoracic surgery, viral infections, and neurologic congenital or degenerative disorders. We describe the case of a 36-year-old man with a history of neurofibromatosis who developed severe bilateral diaphragmatic paralysis from involvement of the phrenic nerve roots with neurofibromas. The patient manifested progressive exertional dyspnea and debilitating orthopnea requiring the use of noninvasive mechanical ventilation at night. A review of the literature reveals that neurofibromatosis is an unrecognized cause of diaphragmatic paralysis.

Objective: Alterations in maternal plasma arginine concentration accompany normal pregnancy. Nitric oxide is synthesized from L-arginine and influences fetal growth. We hypothesized that L-arginine would influence fetal growth and hypoxia-induced uricemia in a maternal hypoxia-induced fetal growth restriction model., Study Design: Fetal growth on day 21 of gestation was assessed in timed pregnant Wistar rats with or without exposure to maternal hypobaric hypoxia. Animals exposed to hypoxia received either no supplement or supplementation of drinking water with 0.2% L-arginine, 2% L-arginine, or 2% glycine. On day 21 of gestation, fetuses were delivered by hysterotomy and fetal and placental weights were obtained. Maternal and fetal plasma were assayed for uric acid as an index of tissue hypoxia. Xanthine oxidase and xanthine dehydrogenase, precursors of uric acid and reactive oxygen species, were assayed in maternal tissue. Results were analyzed by analysis of variance with correction for multiple comparisons., Results: Exposure of rats on normal diets to hypoxia resulted in a 30% reduction in fetal weights. L-Arginine, 2% or 0.2%, prevented the reduction in fetal weight (p < 0.0001). Isocaloric and isonitrogenous supplementation with glycine did not influence hypoxia-induced fetal growth restriction., Conclusion: L-Arginine, but not glycine, ameliorates maternal hypoxia-induced fetal growth restriction in the rat.

The enzyme system xanthine dehydrogenase (XD):xanthine oxidase, which generates the superoxide anion as a by-product of action on endogenous substrates, is believed to play a role in mediating pathophysiological changes through its contribution to total superoxide production. To aid with analysis of factors that regulate XD, we have developed a reverse transcription (RT)-coupled competitive quantitative polymerase chain reaction (PCR) assay which enables XD mRNA to be determined from small amounts of cultured cells where constitutive XD levels are low. A homologous insertion mutant of wild-type XD cDNA was prepared and used as an internal standard to normalize intersample PCR efficiency differences. XD mRNA levels determined by RT-PCR also were normalized to tubulin mRNA to compensate for RT differences and loading effects among samples. We report that XD mRNA levels, determined by RT-PCR, were increased twofold in hypoxic (3% oxygen) rat pulmonary microvascular endothelial cells relative to normoxic controls (20% oxygen). Conversely, XD mRNA was decreased threefold within 24 h under hyperoxic (95% oxygen) conditions. These data support the hypothesis that XD is regulated by oxygen tension in the pulmonary vasculature.