Induced prostaglandin release alters steroid concentrations but not pregnancy survival in cows.

Embryonic mortality (EM) is a major factor limiting reproductive efficiency in cattle, and despite negative connotations related to reproductive performance, prostaglandin F2α (PGF2α) is capable of being released by the uterus by Day 30 of gestation. Therefore, the objective was to evaluate differences in PGF2α release after an oxytocin challenge between cows with high circulating concentrations of pregnancy-associated glycoproteins (PAGs) vs low PAG because of the association of increased PAG concentrations with pregnancy success. At Day 30 of gestation, pregnant cows were divided into oxytocin treatment (OT; n = 13) and control (CON; n = 12) groups. Treatment cows were further subdivided by circulating PAG concentration (high PAG, n = 7; and low PAG, n = 6). Blood samples were collected every 30 min beginning 1 h before oxytocin administration and continuing for 4 h. Prostaglandin F2α metabolite (PGFM), progesterone, estradiol-17ß (E2), and PAG concentrations were quantified. The peak concentration of PGFM occurred 2 h after oxytocin injection in treatment animals and returned to baseline levels by 4 h. No correlations were observed between PAG and PGFM, progesterone, or E2 concentrations (P > 0.05). There was no difference in initial or final PGFM concentrations between groups (P > 0.05). Progesterone and E2 concentrations decreased in cows after treatment of oxytocin (P < 0.05); however, only progesterone returned to basal concentrations by the end of the sampling period. In summary, cows with high vs low PAG concentrations at Day 30 of gestation have a similar PGFM response to oxytocin challenge.

Incidence and treatment of positive pelvic sidewall lymph nodes in patients with rectal cancer.

AIM: The involvement of pelvic sidewall (PSW) lymph nodes in rectal cancer is a marker of locally advanced disease and poor prognosis. Eastern countries generally advocate lateral lymph node dissection (LLND) over the Western approach of neoadjuvant chemoradiotherapy and more limited surgery. The aim of this study was to evaluate how these advanced cancers were treated in three UK Health Boards. METHODOLOGY: This was a retrospective review of three colorectal multidisciplinary team meetings from 2008 to 2016. All patients with rectal cancer and suspicious PSW lymph nodes on pretreatment MRI were included. RESULTS: There were 153 (6.2%) patients who met the inclusion criteria from a total of 2461 diagnosed rectal cancers. There was significant variability between the three centres with surgical intervention ranging from 59.2% to 84.4%, P = 0.015. There were 81 patients who had neoadjuvant chemoradiotherapy prior to surgery; of these 67 (82.7%) still had positive PSW nodes on the restaging MRI, but only 13 (19.4%) had LLND. There was no difference in local recurrence (15.3% vs 11.8%, P = 0.66), 5-year overall survival (69.2% vs 80.1%, P = 0.16) or 5-year disease-free survival (69.2% vs 79.4%, P = 0.72) between patients having LLND and those receiving standard neoadjuvant treatment followed by total mesorectal excision surgery. CONCLUSIONS: This study has demonstrated that rectal cancer patients with PSW positive nodal disease have advanced disease, mostly of the lower rectum, and receive a highly heterogeneous spectrum of therapies, even within a relatively small geographical area. Greater accuracy in our preoperative staging is needed to select those patients who will benefit from LLND surgery.

Pregnancy rates to fixed-time AI in Bos indicus-influenced beef cows using PGF2α with (Bee Synch I) or without (Bee Synch II) GnRH at the onset of the 5-day CO-Synch + CIDR protocol.

Objectives were to 1) characterize fixed-time AI (FTAI) pregnancy rates using the 5-Day CO-Synch + CIDR protocol in mature, suckled Bos indicus-influenced beef cows, 2) compare FTAI pregnancy rates in the latter to a modified version (5-Day Bee Synch + CIDR; Bee Synch I) that included treatment with prostaglandin F2α (PGF2α) at CIDR insertion on Day 0, and 3) test the hypothesis that elimination of both GnRH-1 at the onset of synchronization and the double dose of PGF on Day 5 (Bee Synch II) would not reduce FTAI pregnancy rates compared to Bee Synch I. For Experiment 1-trial 1, Brahman x Hereford (F-1) cows (n = 168) at least 40 d postpartum (PP; r = 40-92 d) at the time of CIDR insertion were administered the 5-Day CO-Synch + CIDR protocol with FTAI at 72 h after CIDR removal. Pregnancy rates to FTAI averaged 34.9 ± 1.9%. In Experiment 1-trial 2, fall- and spring-breeding Brahman x Hereford (F-1) beef cows (n = 269) were stratified by days PP and assigned randomly to receive either the 5-Day CO-Synch + CIDR (n = 136) or Bee Synch I (n = 133) protocol, with FTAI at 66 h after CIDR removal. Pregnancy rate to FTAI was greater (P < 0.05) in Bee Synch I (52.6 ± 0.9%) than in the 5-Day CO-Synch + CIDR procedure (40.4 ± 5.7%). For Experiment 2, 422 mature Braford, Brangus, Nelore x Brahman, and Brahman crossbred cows (Bos indicus proportion unknown) at 4 locations were treated with Bee Synch I, with FTAI at 66 h. Overall FTAI pregnancy rate averaged 51.7 ±â€¯2.1%. Finally, from 2013 through spring 2018, we used a switchback design using fall- and spring-breeding herds to compare Bee Synch I (402 observations) to Bee Synch II (393 observations). Overall frequency of detected estrus at 66 h using ESTROTECT™ breeding indicator patches was 57.2 ±â€¯2.4%, conception rates of those detected in estrus was 64.4 ±â€¯3.5%, and FTAI pregnancy rates averaged 52.3 ±â€¯2.4%, none of which differed between treatments. Moreover, pregnancy rates to FTAI in both treatments did not differ in cows synchronized between 40 and 80 d PP but increased after 80 d PP (P < 0.05). Bee Synch II, which eliminates GnRH-1 and the double dose of PGF2α on Day 5, results in FTAI pregnancy rates essentially identical to Bee Synch I but reduces synchronization costs and avoids the need for off-label (double dose PGF2α) drug use.

Ovarian follicular and luteal characteristics in Bos indicus-influenced beef cows using prostaglandin F2α with or without GnRH at the onset of the 5-day CO-Synch + controlled internal drug release (CIDR) protocol.

A modification of the standard 5-day CO-Synch + CIDR procedure (5-day Bee Synch + CIDR; Bee Synch), developed for use in Bos indicus-influenced cows, utilizes the addition of prostaglandin F2α (PGF) on Day 0 of the protocol to eliminate mature corpora lutea (CL) and fixed-time AI (FTAI) at 66 h. Objectives were to test the hypothesis that elimination of GnRH on Day 0 (GnRH-1) does not impact significantly the synchronized development of a dominant follicle for presumptive FTAI. Seventy-one estrous cycling Brangus and Brahman x Hereford suckled cows were used in two replicates (35-36/replicate). Following stratification, cows were assigned randomly to a 2 × 3 factorial arrangement of treatments involving two truncated (no FTAI or GnRH-2) versions of Bee Synch (Bee Synch It and IIt), each begun 3, 7, and 10 days post-ovulation. Cows in Bee Synch It received 100 µg GnRH (GnRH-1), 25 mg PGF, and a CIDR on Day 0, whereas cows assigned to Bee Synch IIt received the same treatment but without GnRH-1. All cows received 50 mg PGF on Day 5 at CIDR removal. Synchronized new follicular wave emergence (NFWE; days 1-4) was observed in 68.6 and 38.9% of Bee Synch It and IIt, respectively (P = 0.01). This increased to 93.3% and 72.2%, respectively, if days 0-4 were considered. Inclusion of GnRH at CIDR insertion improved synchronized NFWE but size of the largest follicle at 66 h, the normal time of FTAI, did not differ due to treatment or day of the estrous cycle.

The Association of Coloproctology of Great Britain and Ireland consensus guidelines in surgery for inflammatory bowel disease.

AIM: There is a requirement of an expansive and up to date review of surgical management of inflammatory bowel disease (IBD) that can dovetail with the medical guidelines produced by the British Society of Gastroenterology. METHODS: Surgeons who are members of the ACPGBI with a recognised interest in IBD were invited to contribute various sections of the guidelines. They were directed to produce a procedure based document using literature searches that were systematic, comprehensible, transparent and reproducible. Levels of evidence were graded. An editorial board was convened to ensure consistency of style, presentation and quality. Each author was asked to provide a set of recommendations which were evidence based and unambiguous. These recommendations were submitted to the whole guideline group and scored. They were then refined and submitted to a second vote. Only those that achieved >80% consensus at level 5 (strongly agree) or level 4 (agree) after 2 votes were included in the guidelines. RESULTS: All aspects of surgical care for IBD have been included along with 157 recommendations for management. CONCLUSION: These guidelines provide an up to date and evidence based summary of the current surgical knowledge in the management of IBD and will serve as a useful practical text for clinicians performing this type of surgery.

Appendiceal mucocoele with midgut malrotation.

Introduction Malrotation of the midgut and appendiceal mucocoele are both extremely rare pathological conditions in adults. To our knowledge, there are only two reported cases in the English literature with a combination of both conditions. Case History A 65-year-old man presented with a 10-day history of upper abdominal pain associated with abdominal bloating and weight loss. He was otherwise fit and healthy with no significant past medical history. On examination, his abdomen was soft with tenderness and palpable fullness over the left upper quadrant. The initial blood test, chest x-ray and abdominal x-ray demonstrated no significant abnormality. Computed tomography showed a 17cm x 8cm x 6cm elongated cystic mass with possible malrotation of the intestines. Histopathology showed a low grade mucinous tumour of the appendix. At 12 months following surgery, there was no evidence of recurrence or postoperative complications and the patient was discharged from the care of the colorectal team. Conclusions We report a patient with a combination of two rare conditions. This case illustrates how a combination of pathologies can present a challenge to the unwary general surgeon.

Nutritional Programming of Accelerated Puberty in Heifers: Involvement of Pro-Opiomelanocortin Neurones in the Arcuate Nucleus.

The timing of puberty and subsequent fertility in female mammals are dependent on the integration of metabolic signals by the hypothalamus. Pro-opiomelanocortin (POMC) neurones in the arcuate nucleus (ARC) comprise a critical metabolic-sensing pathway controlling the reproductive neuroendocrine axis. α-Melanocyte-stimulating hormone (αMSH), a product of the POMC gene, has excitatory effects on gonadotrophin-releasing hormone (GnRH) neurones and fibres containing αMSH project to GnRH and kisspeptin neurones. Because kisspeptin is a potent stimulator of GnRH release, αMSH may also stimulate GnRH secretion indirectly via kisspeptin neurones. In the present work, we report studies conducted in young female cattle (heifers) aiming to determine whether increased nutrient intake during the juvenile period (4-8 months of age), a strategy previously shown to advance puberty, alters POMC and KISS1 mRNA expression, as well as αMSH close contacts on GnRH and kisspeptin neurones. In Experiment 1, POMC mRNA expression, detected by in situ hybridisation, was greater (P < 0.05) in the ARC in heifers that gained 1 kg/day of body weight (high-gain, HG; n = 6) compared to heifers that gained 0.5 kg/day (low-gain, LG; n = 5). The number of KISS1-expressing cells in the middle ARC was reduced (P < 0.05) in HG compared to LG heifers. In Experiment 2, double-immunofluorescence showed limited αMSH-positive close contacts on GnRH neurones, and the magnitude of these inputs was not influenced by nutritional status. Conversely, a large number of kisspeptin-immunoreactive cells in the ARC were observed in close proximity to αMSH-containing varicosities. Furthermore, HG heifers (n = 5) exhibited a greater (P < 0.05) percentage of kisspeptin neurones in direct apposition to αMSH fibres and an increased (P < 0.05) number of αMSH close contacts per kisspeptin cell compared to LG heifers (n = 6). These results indicate that the POMC-kisspeptin pathway may be important in mediating the nutritional acceleration of puberty in heifers.

Reproduction Symposium: hypothalamic neuropeptides and the nutritional programming of puberty in heifers.

Nutrition during the juvenile period has a major impact on timing reproductive maturity in heifers. Restricted growth delays puberty, whereas elevated BW gain advances the onset of puberty. The initiation of high-frequency episodic release of GnRH and, consequently, LH during the peripubertal period is crucial for maturation of the reproductive axis and establishment of normal estrous cycles. Nutritional signals are perceived by metabolic-sensing cells in the hypothalamus, which interact with estradiol-receptive neurons to regulate the secretory activity of GnRH neurons. The orexigenic peptide, neuropeptide Y (NPY), and the anorexigenic peptide derived from the proopiomelanocortin (POMC) gene, melanocyte-stimulating hormone α (αMSH), are believed to be major afferent pathways that transmit inhibitory (NPY) and excitatory (αMSH) inputs to GnRH neurons. The neuropeptide kisspeptin is considered a major stimulator of GnRH secretion and has been shown to mediate estradiol's effect on GnRH neuronal activity. Kisspeptin may also integrate the neuronal pathways mediating the metabolic and gonadal steroid hormone control of gonadotropin secretion. Recent studies in our laboratories indicate that functional and structural changes in the pathways involving NPY, POMC, and kisspeptin neurons occur in response to high rates of BW gain during the juvenile period in heifers. Changes include regulation of expression in NPY, POMC, and KISS1 and plasticity in the neuronal projections to GnRH neurons and within the neuronal network comprising these cells. Moreover, an intricate pattern of differential gene expression in the arcuate nucleus of the hypothalamus occurs in response to feeding high concentrate diets that promote elevated BW gain. Genes involved include those controlling feeding intake and cell metabolism, neuronal growth and remodeling, and synaptic transmission. Characterizing the cellular pathways and molecular networks involved in the mechanisms that control the timing of pubertal onset will assist in improving existing strategies and facilitate the development of novel approaches to program puberty in heifers. These include the use of diets that elevate BW gain during strategic periods of prepubertal development.

Pharmacologic application of native GnRH in the winter anovulatory mare, I: frequency of reversion to the anovulatory state following ovulation induction and cessation of treatment.

The continuous, subcutaneous infusion of native GnRH into seasonally anovulatory mares stimulates the synthesis and secretion of LH without pituitary refractoriness, offering opportunities to markedly accelerate the timing of ovulation within the operational breeding season. Herein, we tested the hypothesis that ovarian cycles induced in winter anovulatory mares using continuous administration of native GnRH for 28 days, beginning in either early February or early March (North America) would not revert to an anovulatory state after treatment withdrawal. Anovulatory mares received sham pumps (control) or native GnRH (100 µg/h) for 28 days beginning from February 2 or 3 (GnRH-Feb) or March 2 or 3 (GnRH-Mar). Mean concentrations of LH were five- to seven-fold greater during February in the GnRH-Feb group compared with control and GnRH-Mar groups through February and ending on March 2 or 3. However, concentrations of LH returned to the winter baseline within 3 to 11 days after pump removal and all GnRH-Feb mares failed to remain cyclic after treatment withdrawal. Correspondingly, during March, concentrations of LH in the GnRH-Mar group were greater (P < 0.001) than in the control and GnRH-Feb groups during the 28-day treatment period. Follicular growth and frequency of ovulation (6/10 GnRH-Feb; 9/10 GnRH-Mar, 1/11 controls, respectively) were greater (P < 0.01) in GnRH-treated mares. Ovulatory cycles continued in five of nine GnRH-Mar mares that ovulated, with interovulatory intervals of 15 to 24 days; whereas, three of nine mares had extended (33-42 days) interovulatory intervals and one of nine mares had a persistent CL after cessation of treatment. In summary, continuous administration of native GnRH for 28 days, beginning in early February or March, elevated circulating LH adequately to stimulate follicular growth and ovulation up to 60 days earlier than in untreated controls. However, if continuous, subcutaneous infusion of GnRH is selected as the only pharmacologic or managerial intervention, and mares are not pregnant, treatment must be continued at least until the end of March. This will improve the likelihood of a normal interovulatory interval after treatment withdrawal.

Pharmacologic application of native GnRH in the winter anovulatory mare, II: accelerating the timing of pregnancy.

Onset of the winter anovulatory period in mares is associated with a marked diminution in adenohypophyseal synthesis and release of LH. Native GnRH, unlike its synthetic agonists, stimulates the synthesis and secretion of LH in mares without pituitary refractoriness. Herein we tested the hypotheses that (1) the average Julian day of pregnancy can be accelerated by up to 2 months in winter anovulatory mares treated continuously with native GnRH beginning on February 1 and (2) mares will sustain luteal function and pregnancy after treatment withdrawal. Forty-two winter anovulatory mares were stratified by age, body condition score, and size of the largest follicle across two locations in a randomized design and assigned to one of three groups (n = 14 per group): (1) CONTROL: untreated, (2) GnRH-14: GnRH delivered subcutaneously in saline at a rate of 100 µg/h for 8 weeks (February 1-March 29) using four consecutive 14-day pumps (Alzet 2ML2), or (3) GnRH-28: GnRH delivered as in (2), but using two 28-day pumps (Alzet 2ML4). On development of a 35-mm follicle and expression of estrus, mares were bred the following day and treated with hCG. Pregnancies were confirmed using transrectal ultrasonography on Days 14, 24, 33, and 45, with blood samples collected to assess luteal function. Mares treated with GnRH (GnRH-14 and GnRH-28) did not differ reproductively in their responses and data were pooled for statistical comparisons. Mares treated with GnRH exhibited marked increases (P ≤ 0.04) in the frequency of development of a 35-mm follicle, submission rate for live cover and/or artificial insemination, ovulation, and pregnancy compared with control mares on treatment Day 56 (March 29). Interval to the first 35-mm follicle was 51.8 ± 4.9 and 19.3 ± 3.5 days (least square mean ± standard error of the mean) for control and GnRH-treated mares, respectively. Interval to pregnancy was 65.3 ± 6.7 and 28.6 ± 4.8 days (least square mean ± standard error of the mean) for control and GnRH-treated mares, respectively, excluding one GnRH-14 mare that failed to become pregnant over four cycles. By the end of the treatment period (March 29), only 21% of control mares were pregnant compared with 79% of GnRH-treated mares. Furthermore, mean serum concentrations of progesterone were similar to (GnRH-28; P = 0.26) or greater than (GnRH-14; P = 0.01) that of control mares from Day 0 to 46 postbreeding. Data illustrate that continuous administration of native GnRH is a highly efficient option for managing seasonal anovulation in mares and could be effectively used in the breeding industry if a user-friendly delivery option were available.

Variability in management of T1 colorectal cancer in Wales.

INTRODUCTION: The management of T1 colorectal cancer is controversial. Surgical resection should offer cure in the majority of patients and can stage lymph nodes accurately. Nevertheless, there can be significant associated morbidity and it potentially risks overtreating the patient. Endoscopic/local excision has significantly reduced morbidity but risks undertreating undetected metastatic lymph nodes, thereby compromising oncological outcomes. The aim of this study was to review the practice across Wales over a two-year period. METHODS: Data on T1 tumours for the period of 2009-2011 were collected from the Cancer Network Information System Cymru. RESULTS: A total of 161 patients were diagnosed as having T1 colorectal cancer (without prior neoadjuvant treatment). The median age was 68 years (range: 14-91 years) and 66% of the patients were male. Forty-eight (30%) of these tumours were screen detected. There were 112 colonic and 49 rectal tumours. Ninety-five patients with colonic tumours (85%) underwent major surgical resections, 51% of which were laparoscopic. Forty patients with rectal cancers (82%) underwent major surgical resection and 45% of these procedures were laparoscopic. The rest of the patients underwent local excision in the form of endoscopic polypectomy or transanal resection. CONCLUSIONS: This study demonstrates that there is no consensus in the management of T1 disease across Wales. With the advent of screening and the development of more sophisticated endoscopic techniques, the decision of how to treat T1 colorectal cancer will become a more regular challenge for the colorectal multidisciplinary team. The treatment needs standardisation. For now, however, this balance of risk will need to be made on an individual patient basis.

Systematic review and meta-analysis of histopathological factors influencing the risk of lymph node metastasis in early colorectal cancer.

AIM: Lymph node (LN) metastases are present in up to 17% of early colorectal cancers (pT1). Identification of associated histopathological factors would enable counselling of patients regarding this risk. METHOD: Pubmed and Embase were employed utilizing the terms 'early colorectal cancer', 'lymph node metastasis', 'submucosal invasion', 'lymphovascular invasion', 'tumour budding' and 'histological differentiation'. Analysis was performed using REVIEW MANAGER 5.1. RESULTS: Twenty-three cohort studies including 4510 patients were analysed. There was a significantly higher risk of LN metastasis with a depth of submucosal invasion > 1 mm than with lesser degrees of penetration (OR 3.87, 95% CI 1.50-10.00, P = 0.005). Lymphovascular invasion was significantly associated with LN metastasis (OR 4.81, 95% CI 3.14-7.37, P < 0.00001). Poorly differentiated tumours had a higher risk of LN metastasis compared with well or moderately differentiated tumours (OR 5.60, 95% CI 2.90-10.82, P < 0.00001). Tumour budding was found to be significantly associated with LN metastasis (OR 7.74, 95% CI 4.47-13.39, P < 0.001). CONCLUSION: Meta-analysis of the current literature demonstrates that in early colorectal cancer a depth of submucosal invasion by the primary tumour of > 1 mm, lymphovascular invasion, poor differentiation and tumour budding are significantly associated with LN metastasis.