Lipid mediators in glaucoma: Unraveling their diverse roles and untapped therapeutic potential.

Glaucoma is a complex neurodegenerative disease characterized by optic nerve damage and visual field loss, and remains a leading cause of irreversible blindness. Elevated intraocular pressure (IOP) is a critical risk factor that requires effective management. Emerging research underscores dual roles of bioactive lipid mediators in both IOP regulation, and the modulation of neurodegeneration and neuroinflammation in glaucoma. Bioactive lipids, encompassing eicosanoids, specialized pro-resolving mediators (SPMs), sphingolipids, and endocannabinoids, have emerged as crucial players in these processes, orchestrating inflammation and diverse effects on aqueous humor dynamics and tissue remodeling. Perturbations in these lipid mediators contribute to retinal ganglion cell loss, vascular dysfunction, oxidative stress, and neuroinflammation. Glaucoma management primarily targets IOP reduction via pharmacological agents and surgical interventions, with prostaglandin analogues at the forefront. Intriguingly, additional lipid mediators offer promise in attenuating inflammation and providing neuroprotection. Here we explore these pathways to shed light on their intricate roles, and to unveil novel therapeutic avenues for glaucoma management.

Blastocyst-induced changes in the bovine endometrial transcriptome.

The objectives of this study were (i) to determine whether blastocyst-induced responses in endometrial explants were detectable after 6- or 24-h co-culture in vitro; (ii) to test if direct contact is required between embryos and the endometrial surface in order to stimulate endometrial gene expression; (iii) to establish the number of blastocysts required to elicit a detectable endometrial response; (iv) to investigate if upregulation of five interferon-stimulated genes (ISGs) in the endometrium was specific to the blastocyst stage and (v) to test if alterations in endometrial gene expression can be induced by blastocyst-conditioned medium. Exposure of endometrial explants to Day 8 blastocysts in vitro for 6 or 24 h induced the expression of ISGs (MX1, MX2, OAS1, ISG15, RSAD2); expression of IFNAR1, IFNAR2, NFKB1, IL1B, STAT1, LGALS3BP, LGALS9, HPGD, PTGES, ITGB1, AKR1C4, AMD1 and AQP4 was not affected. Culture of explants in the presence of more than five blastocysts was sufficient to induce the effect, with maximum expression of ISGs occurring in the presence of 20 blastocysts. This effect was exclusive to blastocyst stage embryos; oocytes, 2-cell embryos or Day 5 morulae did not alter the relative abundance of any of the transcripts examined. Direct contact between blastocysts and the endometrial surface was not required in order to alter the abundance of these transcripts and blastocyst-conditioned medium alone was sufficient to stimulate a response. Results support the notion that local embryo-maternal interaction may occur as early as Day 8 of pregnancy in cattle.

Effect of human chorionic gonadotrophin administration 2 days after insemination on progesterone concentration and pregnancy per artificial insemination in lactating dairy cows.

The aim of this study was to examine the effect of a single administration of human chorionic gonadotrophin (hCG) during the establishment of the corpus luteum (CL) on progesterone (P4) concentration and pregnancy per artificial insemination (P/AI) in lactating dairy cows. Postpartum spring-calving lactating dairy cows (n = 800; mean ± SD days in milk and parity were 78.5 ± 16.7 and 2.3 ± 0.8, respectively) on 3 farms were enrolled on the study. All cows underwent the same fixed-time AI (FTAI) protocol involving a 7-d progesterone-releasing intravaginal device with gonadotrophin-releasing hormone (GnRH) administration at device insertion, prostaglandin at device removal followed by GnRH 56 h later, and AI 16 h after the second GnRH injection. Cows were blocked on days postpartum, body condition score, and parity and randomly assigned to receive either 3,000 IU of hCG 2 d after FTAI or no further treatment (control). Blood samples were collected on d 7 and 14 postestrus by coccygeal venipuncture on a subset of 204 cows to measure serum P4 concentration, and pregnancy was diagnosed by ultrasonography approximately 30 and 70 d after FTAI. Administration of hCG caused an increase in circulating P4 concentrations compared with the control treatment on d 7 (+22.2%) and d 14 (+25.7%). The P/AI at 30 d after FTAI was affected by treatment, farm, body condition score, and calving to service interval. Overall, administration of hCG decreased P/AI (46.3% vs. 55.1% for the control). Among cows that did not become pregnant following AI, a greater proportion of control cows exhibited a short repeat interval (≤17 d) compared with cows treated with hCG (8.6% vs. 2.8%, respectively). In addition, the percentages of cows pregnant at d 21 (59.6% vs. 52.0%) and d 42 (78.3% vs. 71.9%) were greater in control than in hCG-treated cows. The overall incidence of embryo loss was 10.7% and was not affected by treatment. There was a tendency for an interaction between treatment and CL status at synchronization protocol initiation for both P4 concentration and P/AI. In conclusion, administration of hCG 2 d after FTAI increased circulating P4 concentrations. Unexpectedly, cows treated with hCG had lower fertility; however, this negative effect on fertility was manifested primarily in cows lacking a CL at the onset of the synchronization protocol.

Short communication: Glucose infusion into early postpartum cows defines an upper physiological set point for blood glucose and causes rapid and reversible changes in blood hormones and metabolites.

Low blood glucose concentrations after calving are associated with infertility in postpartum dairy cows perhaps because glucose is a master regulator of hormones and metabolites that control reproductive processes. The hypothesis was that low blood glucose postpartum is caused by inadequate glucose entry rate relative to whole-body demand as opposed to the alternative possibility that postpartum cows have a lower regulatory set point for blood glucose. Eight early postpartum (10 to 25 d) dairy cows (5 Holstein and 3 Guernsey) were jugular catheterized. During the first 24 h, cows were infused with physiological saline at 83.3 mL/h. After 24 h, the infusion solution was switched to 50% dextrose that was infused at a rate of 41.7 mL/h (total daily glucose dose=500 g). On d 3 and d 4, the rate of glucose infusion was increased to 83.3 mL/h (daily dose=1,000 g) and 125 mL/h (daily dose=1,500 g), respectively. On d 5, physiological saline was infused at 83.3 mL/h. Blood was sampled hourly through a second jugular catheter (contralateral side) and analyzed for glucose, nonesterified fatty acids, ß-hydroxybutyrate, insulin-like growth factor 1, and insulin. Blood glucose concentrations on d 1 (saline infusion) averaged 53.4±1.7 mg/dL. Blood glucose concentrations increased on d 2 when cows were infused with 500 g/d and increased further on d 3 when cows were infused with 1,000g of glucose/d. Increasing the infusion rate to 1,500 g/d on d 4 did not cause a further increase in blood glucose concentrations. Based on a segmented regression analysis, the upper physiological set point for blood glucose was 72.1 mg/dL. Both insulin and insulin-like growth factor 1 concentrations increased in response to glucose infusion and decreased when cows were infused with saline on d 5. Serum nonesterified fatty acids and ß-hydroxybutyrate concentrations decreased in response to glucose infusion and rebounded upward on d 5 (saline infusion). In conclusion, early postpartum cows had circulating blood glucose concentrations that were well below the upper set point defined in this study (72.1 mg/dL). Infusing approximately 1,000 g of glucose daily increased blood glucose to the physiological set point and rapidly changed the hormonal and metabolic profile that typifies postpartum cows. The inability of the early postpartum cow to achieve an adequate entry rate for glucose relative to whole-body demand is a possible mechanism that links postpartum physiology and nutrition to reproduction in dairy cows.

Reproduction in grazing dairy cows treated with 14-day controlled internal drug release for presynchronization before timed artificial insemination compared with artificial insemination after observed estrus.

Progesterone-releasing (controlled internal drug release, CIDR) devices inserted for 14 d are used to presynchronize the estrous cycle for timed artificial insemination (TAI) in beef heifers (14-d CIDR-PGF(2α) program). The objective was to test a similar program in dairy cows by measuring first-service conception rates (FSCR), pregnancy rates after 2 AI, and time to pregnancy compared with a control (AI after observed estrus). Postpartum cows (Holstein, Jersey, or crossbred; n=1,363) from 4 grazing dairy farms were assigned to 1 of 2 programs: 14dCIDR_TAI [CIDR in for 14 d, CIDR out, PGF(2α) injection at 19 d after CIDR removal, GnRH injection 56 h later, and then TAI 16 h later; n=737] or control [AI after observed estrus; reproductive program with PGF(2α) (cycling cows) and CIDR (noncycling cows) to synchronize estrus with the start of the breeding season; n=626]. Body condition was scored (1 to 5; thin to fat) at the start of the trial. The interval from the start of the breeding period (final PGF(2α) injection of either program) to first AI was shorter for 14dCIDR_TAI compared with the control (3.0±0.2 vs. 5.3±0.2 d; mean ± SEM) but 14dCIDR_TAI cows had lesser FSCR than controls (48 vs. 61%). Farm affected FSCR (50, 51, 67, and 58% for farms 1 to 4). The BCS affected FSCR (50, 55, and 62% for BCS=2, 2.5, and 3, respectively). Cows that either calved the year before (carryover) or that calved early in the calving season had greater FSCR than cows that calved later in the calving season (55, 61, and 42%, respectively). The percentage of cows pregnant to AI (first and second inseminations within 31-d breeding season) was similar for 14dCIDR_TAI and control (64 vs. 70%) cows, but farm (64, 62, 80, and 69%) and time of calving (70, 76, and 56%: carryover, early, and late, respectively) affected the percentage. Survival analyses showed an initial advantage for 14dCIDR_TAI (more cows inseminated and more pregnancies achieved early in the breeding season) that was not maintained over time. Conclusions were that the 14dCIDR_TAI program achieved acceptable FSCR (48%) and overall AI pregnancy rates (64%), but did not surpass a control program that used AI after observed estrus (61 and 70%, respectively).

Short communication: presynchronization for timed artificial insemination in grazing dairy cows by using progesterone for 14 days with or without prostaglandin F2α at the time of progesterone withdrawal.

Progesterone-containing devices can be inserted intravaginally for 14 d to presynchronize the estrous cycle for timed artificial insemination (TAI) in beef heifers ("14-day CIDR-PG" or "Show-Me-Synch" program). The progesterone treatment is effective for presynchronization because cattle develop a persistent dominant follicle during treatment that ovulates within 3 d after progesterone removal. The subsequent estrous cycle can be effectively used for a TAI program. Some cattle will retain a functional corpus luteum (CL) for the entire 14-d treatment period and will not be synchronized effectively because the interval to ovulation depends on the lifespan of their existing CL. The objective was to test the effect of a luteolytic dose of PGF(2α) at progesterone removal for improving synchrony of estrus after treatment and increasing conception rate to a subsequent TAI in dairy cows. Postpartum cows (n = 1,021) from 2 grazing dairy herds were assigned to 1 of 2 presynchronization programs that used a controlled internal drug releasing (CIDR) device containing progesterone: 14dCIDR (CIDR in, 14 d, CIDR out; n = 523) or 14dCIDR+PGF(2α) (CIDR in, 14 d, CIDR out, and PGF(2α); n = 498). Cows were body condition scored (BCS; 1 to 5, thin to fat) and tail painted at CIDR removal. Paint score (PS) was recorded after CIDR removal [PS = 0 (all paint removed, indication of estrus), PS = 3 (paint partially removed), or PS = 5 (no paint removed; indication of no estrus)]. At 19 d after CIDR removal, all cows were treated with PGF(2α), 56 h later treated with GnRH, and then 16 h later were TAI. Treating cows with PGF(2α) at CIDR removal increased the percentage with PS = 0 within 5 d (58.1% vs. 68.9%; 14dCIDR vs. 14dCIDR+PGF(2α)). We found no effect of treatment, however, on conception rate at TAI (41.1% vs. 43.6%; respectively). The TAI conception rate increased with increasing BCS and was greater for cows that had PS = 0 within 5 d after CIDR removal. In summary, treating cows with PGF(2α) at CIDR removal increased the percentage of cows with all tail paint removed but did not increase percentage of pregnant cows after TAI.

Hot topic: Successful fixed-time insemination within 21 d after first insemination by combining chemical pregnancy diagnosis on d 18 with a rapid resynchronization program.

Cattle that are not pregnant to first fixed-time artificial insemination (TAI) may be resynchronized for a second TAI if they are found nonpregnant at pregnancy diagnosis. The specific interval between first and second TAI ranges from 4 to 8 wk. The selected interval depends on the available method of pregnancy diagnosis and the efficiency of the resynchronization program. The objective of this experiment was to evaluate a pregnancy diagnosis and resynchronization system that achieved a 21-d interval between TAI. This 21-d interval approximates the natural return-to-service interval. It also enables resynchronization to be implemented within the same estrous cycle in which cattle are first inseminated. Holstein heifers were randomly assigned to a 21-d resynchronization program (21d_resynch; n = 40) or a control group in which estrus was observed for the purpose of re-insemination (control; n = 29). The 21d_resynch heifers were diagnosed for pregnancy on d 18 after a TAI (d 0) by using predetermined cut-off values for 2'-5' oligoadenylate synthetase 1 (Oas1) gene expression in leukocytes and plasma progesterone concentration. Heifers that were not pregnant to first TAI had greater expression of Oas1 at the time of PGF(2α) (d -3) than pregnant heifers, but this relationship was reversed on d 18 after TAI: the heifers that were pregnant to first TAI had almost 5-fold greater expression of Oas1 compared with nonpregnant heifers. Nonpregnant heifers in the 21d_resynch group were injected with a luteolytic dose of PGF(2α) on d 19 and were injected with GnRH on d 21 and submitted to TAI. The pregnancy per AI after first insemination was similar for 21d_resynch (50.0%; pregnancy diagnosis on d 18) and control (51.7%; pregnancy diagnosis on d 27). Likewise, no difference was detected in second insemination pregnancy per AI for 21d_resynch (36.8%; nonpregnant heifers TAI on d 21) and control (35.7%; nonpregnant heifers inseminated at return to estrus or after nonpregnant diagnosis on d 27). The interval between first and second insemination was shorter for 21d_resynch compared with control (21.0 ± 0 and 27.5 ± 2.1 d). The conclusion is that a TAI resynchronization can be programmed within 21 d of previous TAI when a d 18 pregnancy test and a rapid resynchronization are used.

A new, safety-oriented, integrated drug administration and automated anesthesia record system.

UNLABELLED: Medication errors are an important cause of patient morbidity and mortality and excessive costs, including in anesthesia. Conventional methods of injectable drug administration in anesthesia make little use of technology to support manual checking and are idiosyncratic and relatively error prone. Similarly, conventional anesthesia records are handwritten, time-consuming to make, and often unreliable. There are automated record systems, but they do not provide support for checking drugs. Therefore, by using a multifaceted approach based on established principles of systems design and human factors psychology, we have developed a system that includes trays that promote a well-organized anesthetic workspace, color- and bar-coded labeling of syringes, and automatic visual and auditory verification of the syringe labels by computer just before each drug administration. In addition, documentation of drugs administered and a traditional anesthetic case record are generated automatically. The system has been successfully deployed for 25 mo and has been used by 35 anesthesiologists in 1148 diverse cases, including cardiopulmonary bypass procedures, heart and lung transplants, and orthopedic and otorhinolaryngologic operations. It is in daily use in a tertiary teaching center and in a private hospital. IMPLICATIONS: Traditional methods of drug administration and record keeping in anesthesia are relatively error prone. By using sound principles of systems design and human factors psychology, we have designed and deployed a system with the aim of improving patient safety by facilitating correct drug administration and accurate anesthesia record making.

Commissioning conferences: a consultative approach to purchasing.

In 1991 the South East London Health Authority developed a process called 'commissioning conferences' to help them purchase services. The first commissioning conference was used to produce a specification of service for people with diabetes mellitus. For this, 120 local people and 15 independent experts were consulted in a structured way.