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Contents: Emerging research suggests that the nitric oxide system may play a role in persistent breeding‐induced endometritis (PBIE) in the mare. Differences in uterine nitric oxide (NO) levels between mares susceptible or resistant to PBIE and a dose‐dependent inhibitory effect of NO on uterine contractility have been demonstrated. The objectives of this study were to investigate the difference in total nitric oxide synthase (NOS) activity of the endometrium between susceptible and resistant mares and the effect of a specific inducible nitric oxide synthase (iNOS) inhibitor on the endometrial NOS activity in vitro. Six susceptible and six resistant mares were selected based on preset criteria and the results of an intrauterine challenge with killed spermatozoa during oestrus. Endometrial biopsy samples were collected 24 hr post‐challenge and cultured at 37°C for 24 hr in L‐arginine supplemented minimum essential medium with or without a specific iNOS inhibitor (1,400 W dihydrochloride, 1 mM). The medium and the cultured endometrial tissue were collected after 24 hr of culture and assayed for NO and total protein, respectively. Total NO content of the medium, normalized to endometrial tissue wet weight or total protein, was used as a measure of endometrial NOS activity. Non‐parametric tests were applied for statistical analysis. Susceptible mares had significantly greater endometrial NOS activity than resistant mares. The iNOS inhibitor treatment significantly reduced NOS activity in endometrial samples derived from susceptible and resistant mares. These findings provide a basis for in vivo testing of specific iNOS inhibitors as preventative or therapeutic options for PBIE in mares. [ABSTRACT FROM AUTHOR]

Genetic sex in mammals is determined by the sex chromosomal composition of the zygote. The X and Y chromosomes are responsible for numerous factors that must work in close concert for the proper development of a healthy sexual phenotype. The role of androgens in case of XY chromosomal constitution is crucial for normal male sex differentiation. The intracellular androgenic action is mediated by the androgen receptor (AR), and its impaired function leads to a myriad of syndromes with severe clinical consequences, most notably androgen insensitivity syndrome and prostate cancer. In this paper, we investigated the possibility that an alteration of the equine AR gene explains a recently described familial XY, SRY + disorder of sex development. We uncovered a transition in the first nucleotide of the AR start codon (c.1A>G). To our knowledge, this represents the first causative AR mutation described in domestic animals. It is also a rarely observed mutation in eukaryotes and is unique among the >750 entries of the human androgen receptor mutation database. In addition, we found another quiet missense mutation in exon 1 (c.322C>T). Transcription of AR was confirmed by RT-PCR amplification of several exons. Translation of the full-length AR protein from the initiating GTG start codon was confirmed by Western blot using N- and C-terminal-specific antibodies. Two smaller peptides (25 and 14 amino acids long) were identified from the middle of exon 1 and across exons 5 and 6 by mass spectrometry. Based upon our experimental data and the supporting literature, it appears that the AR is expressed as a full-length protein and in a functional form, and the observed phenotype is the result of reduced AR protein expression levels. Copyright © 2011 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Data from the 1990 Youth Risk Behavior Survey were used to examine the interrelationship of drug use, sexual activity, and suicidal behavior in U.S. high school students. Findings indicated adolescents who engaged in substance use and/or sexual activity were more likely to experience suicide ideation and behavior than those who abstained from such activities. Data analysis revealed a significant and positive relationship between cocaine use and severity of outcomes of suicide attempts. Marijuana use and alcohol use were related to suicide behavior, but these relationships were not as strong as those noted for cocaine use. The study also revealed a positive relationship between frequency of sexual activity and attempted suicide, but could not determine whether such sexual activity was coerced, forced, or voluntary in nature. [ABSTRACT FROM AUTHOR]

Prostaglandins have many roles in the equine reproductive tract, including but not limited to luteolysis, luteal support, ovulation, transport through the uterine tube, uterine contraction, embryonic mobility, inflammation, and fibrosis. Altered secretion of inflammatory proteins are likely to disrupt the balance of endometrial function and could impair fertility. Our overall goal was to measure the expression of several prostaglandin- and inflammation-related genes in mares with different degrees of endometrial histological changes. Our hypothesis was that mares with neutrophilic and lymphocytic plasmocytic inflammation, fibrosis, or different biopsy grades would have altered concentrations of prostaglandin E2 (PGE2) and F2α (PGF2α), as well as altered expression of inflammation- and prostaglandin-related genes, compared to mares with minimal to no histological changes on biopsy evaluation. Forty-five endometrial biopsies from estrous mares were assessed by a reproductive pathologist for the degree of neutrophilic inflammation, lymphocytic and plasmocytic inflammation, and fibrosis, and a biopsy grade was assigned based on the Kenney-Doig system. A low-volume uterine lavage was collected from a subset of twenty-six mares prior to biopsy collection and was used to measure PGE2 and PGF2α concentrations via ELISA. Total RNA was extracted from biopsies and mRNA expression was evaluated for twenty-five genes of interest. A restricted maximum likelihood linear model was used to compare differences of mRNA expression, with a statistical significance set at P < 0.05. There was no difference in the abundance of PGE2 or PGF2α between any of the variables tested. Mares with endometrial biopsy grade I had lower expression of NF-kB, PTGS1 and HPGD compared to grade IIA or IIB (P < 0.05). Mares with neutrophilic inflammation had decreased expression of NF-kB, PTGS1, PTGER4, CBR1, mPGES2 and PTGIS compared to mares without inflammation. Mares with mild or minimal endometrial fibrosis had increased expression of mPGES2 and PTGIS, compared to mares with moderate endometrial fibrosis. In conclusion, several genes were identified to be differentially expressed in mares with histological changes compared to mares with no to minimal histological changes. The presence of inflammation and fibrosis may alter the concentration of prostaglandins in endometrial tissue, which could impair many of the uterine reproductive and immune functions during estrus, affecting early embryo survival., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Endometrial biopsy is required to diagnose mares with chronic endometritis and endometrial degenerative fibrosis. An increase in understanding of equine reproductive immunology could be utilised to create less-invasive, time-efficient diagnostic tools especially when evaluating mares for chronic endometritis., Objectives: To evaluate inflammatory cytokine and chemokine concentrations in uterine fluid samples collected by low-volume lavage (LVL) as a potential screening diagnostic biomarker for endometritis., Study Design: Prospective cross-sectional clinical study., Methods: Forty-six mares underwent a LVL and subsequently endometrial biopsy. Mares were split in three groups: healthy, acute endometritis, and chronic endometrial fibrosis (CEF) based on cytological and histological evaluation. A fluorescent bead-based multiplex assay for IFN-γ, IFN-α, IL-1β, IL-4, IL-10, IL-17, sCD14, TNF-α, CCL2, CCL3, CCL5 and CCL11 were carried out on the LVL fluid. The endometrial biopsy was utilised for histology and qPCR of IFN-γ, IL-1β, IL-6, IL-8, IL-17, TNF-α, CCL2 and CCL3 genes. Statistical analyses examined differences in inflammatory markers and predictive modelling for diseased endometrium., Results: Secreted concentrations of IFN-γ were lower in LVL fluid from reproductively healthy mares compared with acute endometritis (p = 0.04) and CEF (p = 0.006). Additionally, IL-17, IL-10, IL-1β, TNF-α, CCL2, CCL3, CCL5 and CCL11 were significantly increased (p ≤ 0.04) in LVL from CEF mares compared with healthy mares. Mares with CCL2 concentrations ≥550 pg/mL (14/14) had 100% probability of having CEF and/or acute endometritis. Healthy mares had lower relative abundance of IL-17 mRNA compared with mares in CEF group [median (interquartile rage) = 14.76 (13.3, 15.3) and 12.4 (10.54, 13.81)], respectively (p = 0.02)., Main Limitations: Limited sample size: larger numbers of mares with and without endometritis are required and reference intervals in LVL samples have to be established., Conclusions: Inflammatory chemokines and cytokines concentrations differed between healthy mares and mares with acute endometritis or CEF in LVL., (© 2024 EVJ Ltd.)

The seroprevalence and risk factors for exposure to Neospora caninum and Neospora hughesi in broodmares in Ontario were investigated. Sixty of the 219 (27.4%) study broodmares were seropositive for N. caninum and 65/219 (29.7%) for N. hughesi with cut-offs of ≥1:40 and ≥1:160, respectively. Thirty-one of 63 participating farms (49.2%) had at least 1 broodmare seropositive for N. caninum. Thirty-three of the 63 (52.4%) participating farms had at least 1 broodmare positive for N. hughesi. Risk factors for N. caninum included presence of farm dogs (OR = 6.70; 95% CI = 2.14-20.97; p = 0.001), and high stocking density (OR = 2.83; 95% CI = 1.27-6.30; p = 0.011). Presence of livestock, excluding cattle, was associated with reduced risk of exposure (OR = 0.17; 95% CI = 0.06-0.53; p = 0.002). The only risk factor for exposure to N. hughesi was feeding hay on the ground in the paddock (OR = 4.31; 95% CI = 1.65-11.22; p = 0.003). This study demonstrated widespread exposure to Neospora spp. in broodmares in Ontario., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024. Published by Elsevier B.V.)

Persistent breeding-induced endometritis (PBIE) is a major cause of infertility in mares. Endometrial inflammation that persists until embryonic descent ultimately results in early embryonic death. A poor endometrial biopsy grade (IIb or III) has been identified as a risk factor for PBIE. Intrauterine fluid accumulation (>2 cm in depth), pathologic endometrial edema, and elevated intrauterine neutrophil levels are all clinical features of PBIE. Commonly applied treatment options include uterine lavage and oxytocin therapy. N-acetyl cysteine (NAC), a mucolytic used to treat bacterial endometritis in mares, has anti-inflammatory properties and was investigated as a potential treatment for PBIE. A randomized, blinded, cross-over design clinical trial used NAC before breeding in PBIE-susceptible mares (n = 9). Intrauterine infusion of 3.3% NAC was performed 12 hours before insemination, and endometrial cytology and endometrial biopsy samples were obtained at 12 and 60 hours after insemination. Endometrial biopsies were evaluated for the degree of inflammation present. Clinical signs of endometrial edema and intrauterine fluid volumes were assessed by transrectal ultrasound at 12 and then every 24 hours after breeding. Data were analyzed using repeated measures analysis of variance and a Mann Whitney Wilcoxon Test. Treatment with NAC did not improve clinical signs in PBIE-affected mares. However, endometrial biopsies from mares treated with NAC displayed more diffuse and severe neutrophil infiltration than control cycles. Further research using a larger population of mares is required to evaluate the effects of NAC treatment on the endometrium of PBIE-susceptible mares., (Crown Copyright © 2020. Published by Elsevier Inc. All rights reserved.)

CASE DESCRIPTION 5 mares were evaluated because of reproductive complications following long-term (> 1 year) use of intrauterine glass marbles for estrus suppression. CLINICAL FINDINGS 3 mares had 1 intrauterine glass marble, and 2 mares had 2 intrauterine glass marbles. On examination, 2 mares had signs of chronic endometritis, and 3 had signs of pyometra. Marbles or glass shards adhered to the endometrium were identified by means of hysteroscopy in 3 of 5 mares. Five of 7 marbles had surface imperfections or were broken. TREATMENT AND OUTCOME All patients were treated with uterine lavage and intrauterine and systemic administration of antimicrobials chosen on the basis of results of bacterial culture and susceptibility testing. Two of 5 mares were treated with intrauterine Tris-EDTA. One mare underwent 3 unsuccessful embryo transfer procedures and was subsequently lost to follow-up. One mare was euthanized because of severe vaginal and cervical adhesions and chronic vaginal discharge. Three mares had no apparent signs of reproductive disease at the time of follow-up but were not rebred. CLINICAL RELEVANCE Results of the present small case series suggested that use of intrauterine glass marbles should be discouraged because of the potential for severe reproductive consequences.

Poor survival of cryopreservation by equine expanded blastocysts may involve low penetration of the embryonic capsule by cryoprotective agents (CPAs). This study characterized the permeation and accumulation rates of the CPAs ethylene glycol (EG) and glycerol (GLY) across isolated capsule in vitro, using a dual-chambered Valia-Chien permeation apparatus. Pieces of Days 14 to 18 ± 1 capsules separated media in the "donor" chamber containing either 1.5 M EG (n = 6), 0.74 M EG (n = 5), 0.87 M GLY (n = 7), or 0.15 M NaCl (saline, SAL) (n = 6), from the "recipient" chamber. Concentrations of CPA, determined by gas chromatography, allowed calculation of the capsule's apparent permeability (P(app)) to those CPAs. Permeation of capsule by 1.5 M EG was significantly more rapid than by 0.87 M GLY, or 0.74 M EG; permeation by both CPAs was significantly slower than by SAL. Accumulation of CPA in the recipient chamber depended more on initial donor chamber concentration, rather than type, of CPA. Accumulation rates for CPAs and SAL were linear only when capsule was present, demonstrating that their permeation through capsule was more complex than simple diffusion. Successful cryopreservation of equine expanded blastocysts has been previously linked to lengths of step-wise exposures to CPAs. Based on the present results, we inferred that alternative CPAs, more capable of permeating the capsule, or alternative methods of ensuring CPA entry into the cells, may also be required., (Copyright © 2011 Elsevier Inc. All rights reserved.)

We described the clinical, cytogenetic and molecular findings of 17 clinical equine cases presented for abnormal sexual development and infertility. Six horses with an enlarged clitoris had an XX, SRY-negative genotype, which displayed male-like behavior (adult individuals). Bilateral ovotestes were noted in 2 of those cases, while another case showed increased levels of circulating testosterone. Six horses with a female phenotype, including normal external genitalia, had an XY, SRY-negative genotype. These individuals had small gonads and an underdeveloped internal reproductive tract. Four horses with normal appearing external genitalia had an XY, SRY-positive genotype, 3 of them had hypoplastic testes and male-like behavior. In addition, one young filly with enlarged clitoris and hypoplastic testes had the same genotype but did not show male-like behavior due to her age. Three of these horses were related with 2 being siblings. These findings demonstrate the diversity of disorders of sexual development seen in the horse. Furthermore, they emphasize the need for further research to identify genes involved in abnormal sex determination and differentiation in the horse., (Copyright © 2010 S. Karger AG, Basel.)

People often prefer familiar stimuli, presumably because familiarity signals safety. This preference can occur with merely repeated old stimuli, but it is most robust with new but highly familiar prototypes of a known category (beauty-in-averageness effect). However, is familiarity always warm? Tuning accounts of mood hold that positive mood signals a safe environment, whereas negative mood signals an unsafe environment. Thus, the value of familiarity should depend on mood. We show that compared with a sad mood, a happy mood eliminates the preference for familiar stimuli, as shown in measures of self-reported liking and physiological measures of affect (electromyographic indicator of spontaneous smiling). The basic effect of exposure on preference and its modulation by mood were most robust for prototypes (category averages). All this occurs even though prototypes might be more familiar in a happy mood. We conclude that mood changes the hedonic implications of familiarity cues.

Background: Patients with hepatitis C virus (HCV) infection report a reduction in health status, but it is not known how they value their state of health. We assessed health utilities directly from patients with HCV infection., Methods: One hundred twenty-four patients with chronic HCV infection representing a cross section of disease severity were administered a disease-specific version of the Medical Outcomes Study 36-Item Short-Form Health Survey, the Beck Depression Inventory, and 3 direct health value measures, including the Rating Scale, Time Trade-off (TTO), and Standard Gamble (SG). Correlation among measures and factor analysis was performed., Results: The mean modified Medical Outcomes Study 36-Item Short-Form Health Survey scores were lower than normative population values, particularly on the Physical Component Summary scale. This scale was poorly correlated with the Rating Scale, TTO, and SG scores among HCV-infected subjects. The mean +/- SE TTO score was 0.83 +/- 0.02, and the mean +/- SE SG score was 0.79 +/- 0.02. The TTO and SG scores failed to show significant variability in relation to disease activity as determined by serum alanine aminotransferase level, histologic stage, and presence of decompensated liver disease. The Beck Depression Inventory was significantly inversely correlated with the TTO and SG., Conclusions: Although quality of life is compromised in patients with chronic HCV infection, patient-derived health utilities are not strongly associated with health status or clinical measures. Utility measures obtained from patients with HCV differ significantly from previous surrogate measures of health values. Such differences in utilities could affect decision analyses and cost-effectiveness analyses of treatment interventions for individuals with HCV infection.

Our objective was to determine the magnitude and direction of differences between adolescents with cystic fibrosis (CF) and their parents' reports of the adolescents' health-related quality of life (HRQOL) as measured by the adolescent and parent versions of the Child Health Questionnaire (CHQ). Sixty-two adolescents (mean age, 13.7 years; 46% female; mean forced expired volume in 1 sec, 73%) completed the 87-item adolescent form, and their parents (79% mothers; 77% working full or part time) completed the 50-item parent form of the CHQ during a routine clinic visit. For each scale, ANOVA was used to determine pairwise differences between adolescent and parent scale scores. For scales in which a significant parent-adolescent difference existed, ANCOVA was used to determine disease and demographic factors independently associated with differences in scores. Finally, responses for each pair were compared only on similarly worded items within each scale. For the full CHQ scales, adolescents rated their HRQOL significantly better than did their parents with regard to General Health (mean difference, 12.4 points), Role Function/Physical (mean difference, 9.0 points), Behavior (mean difference, 4.8 points), and Physical Function (mean difference, 4.0 points). No demographic or health factor was associated consistently with differences in parent-adolescent scores. When only similarly worded items were compared, adolescents still tended to rate their HRQOL better, but the difference was significant only for General Health (P = 0.0005), where adolescents rated themselves less susceptible to illness and less worried about their health than their parents. In conclusion, optimal measurement of adolescent HRQOL will likely require determining both parent and adolescent perceptions of HRQOL., (Copyright 2004 Wiley-Liss, Inc.)

Objective: To test the hypothesis that the likelihood of death or major morbidity is reduced for very low birth weight (VLBW; <1500 g) infants who are born at hospitals with subspecialty perinatal and neonatal care compared with other available birth sites., Methods: A population-based cohort study was conducted of all live births of 500 to 1499 g at the 19 hospitals in the greater Cincinnati region from September 1, 1995, through December 31, 1997 (N = 848). Primary outcome was the risk-adjusted, predischarge mortality or morbidity, including bronchopulmonary dysplasia, severe intracranial hemorrhage, severe retinopathy of prematurity, or necrotizing enterocolitis for VLBW infants who were born at subspecialty perinatal centers compared with those who were born at nonsubspecialty centers., Results: The odds of death or major morbidity for VLBW infants who are born at nonsubspecialty perinatal centers is twice that of infants who are born at subspecialty centers despite controlling for demographic (odds ratio [OR]: 2.64; 95% confidence interval [CI]: 1.7-4.2) and practice characteristics (OR: 1.96; 95% CI: 1.2-3.2). The effect of birth hospital type on death or major morbidity was greater for infants of 1000 to 1499 g birth weight (OR: 3.42; 95% CI: 2.0-6.1) than for infants of 500 to 999 g birth weight (OR: 2.1; 95% CI: 1.0-4.8)., Conclusion: The current study lends strong support to existing Academy of Pediatrics and American College of Obstetricians and Gynecologists recommendations that deliveries at <32 weeks' gestational age occur at subspecialty perinatal centers.

The beta(2)-adrenergic receptor (beta(2)AR) exists in multiple polymorphic forms with different characteristics. Their relevance to heart failure (HF) physiology is unknown. Cardiopulmonary exercise testing was performed on 232 compensated HF patients with a defined beta(2)AR genotype. Patients with the uncommon Ile164 polymorphism had a lower peak VO(2) (15.0+/-0.9 mL. kg(-1). min(-1)) than did patients with Thr164 (17.9+/-0.9 mL. kg(-1). min(-1), P<0.0001). The percentage achieved of predicted peak VO(2) was also lower in patients with Ile164 (62. 3+/-4.5% versus 71.5+/-5.1%, P=0.045). The relative risk of a patient having a VO(2)