Kisspeptin Signalling in the Hypothalamic Arcuate Nucleus Regulates GnRH Pulse Generator Frequency in the Rat

Kisspeptin and its G protein-coupled receptor (GPR) 54 are essential for activation of the hypothalamo-pituitary-gonadal axis. In the rat, the kisspeptin neurons critical for gonadotropin secretion are located in the hypothalamic arcuate (ARC) and anteroventral periventricular (AVPV) nuclei. As the ARC is known to be the site of the gonadotropin-releasing hormone (GnRH) pulse generator we explored whether kisspeptin-GPR54 signalling in the ARC regulates GnRH pulses.We examined the effects of kisspeptin-10 or a selective kisspeptin antagonist administration intra-ARC or intra-medial preoptic area (mPOA), (which includes the AVPV), on pulsatile luteinizing hormone (LH) secretion in the rat. Ovariectomized rats with subcutaneous 17β-estradiol capsules were chronically implanted with bilateral intra-ARC or intra-mPOA cannulae, or intra-cerebroventricular (icv) cannulae and intravenous catheters. Blood samples were collected every 5 min for 5–8 h for LH measurement. After 2 h of control blood sampling, kisspeptin-10 or kisspeptin antagonist was administered via pre-implanted cannulae. Intranuclear administration of kisspeptin-10 resulted in a dose-dependent increase in circulating levels of LH lasting approximately 1 h, before recovering to a normal pulsatile pattern of circulating LH. Both icv and intra-ARC administration of kisspeptin antagonist suppressed LH pulse frequency profoundly. However, intra-mPOA administration of kisspeptin antagonist did not affect pulsatile LH secretion.These data are the first to identify the arcuate nucleus as a key site for kisspeptin modulation of LH pulse frequency, supporting the notion that kisspeptin-GPR54 signalling in this region of the mediobasal hypothalamus is a critical neural component of the hypothalamic GnRH pulse generator

The Use of Mechanical Bowel Preparation and Oral Antibiotic Prophylaxis in Elective Colorectal Surgery: A Call for Change in Practice

Elective colorectal surgery is associated with one of the highest rates of surgical site infections (SSIs), which result in prolonged length of stay, morbidity, and mortality for these patients and have a significant financial burden to healthcare systems. In an effort to reduce the frequency of SSI rates associated with colorectal surgery, the 2018 World Health Organisation (WHO) guidelines recommend the routine use of mechanical bowel preparation (MBP) and oral antibiotic prophylaxis (OAP) in adult patients undergoing elective colorectal surgery. However, this recommendation remains a topic of debate internationally. The National Institute of Clinical Excellence (NICE) guidelines, last revised in 2019, recommend against the routine use of MBP and do not address the issue of OAP. In this communication, we reviewed the current guidelines and examined the most recent evidence from randomised-control trials (RCTs) and meta-analyses on the effect of MBP and OAP on SSI rates since the 2019 NICE guideline review. This recent evidence clearly demonstrated an SSI-risk-reduction benefit with the additional use of OAP and the combination of MBP and OAP in this group of patients, and we therefore highlight the need for change of the current NICE guidelines

Colorectal Cancer and the Obese Patient: A Call for Guidelines

The link between obesity and colorectal cancer has been well established. The worldwide rise in obesity rates in the past 40 years means that we are dealing with increasing numbers of obese patients with colorectal cancer. We aimed to review the existing guidelines and make recommendations specific to this group of patients. Upon comparing the current NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ®), the guidelines from the European Society of Medical Oncology (ESMO) and the guidelines of the Japanese Society for Cancer of the Colon and Rectum (JSCCR), we observed that these did not take into consideration the needs of obese patients. We proceeded to make specific recommendations with regards to the diagnostic work-up, surgical pathways, minimally invasive technique, perioperative treatment, post-operative surveillance, and management of metastatic disease in this group of patients. Our review highlights the need for modification of the existing guidelines to account for the needs of this patient cohort. A multidisciplinary approach, including principles used by bariatric surgeons, should be the way forward to reach consensus in the management of this group of patients

Laparoscopic Management of Acute Small Bowel Obstruction in Non-Selected Patients: A 10-Year Experience

The laparoscopic approach to the management of small bowel obstruction (SBO) has been associated with reduced length of hospital stay, complications, and mortality. The laparoscopy-first approach has been limited to highly selective cases to date. In this retrospective observational study, we report our 10-year experience and outcomes within a dedicated Emergency Surgery unit that adopted a non-selective approach in the laparoscopic management of SBO. The surgical approach to all patients that underwent surgery for SBO by an experienced Emergency Surgeon, over a period of 10 years, was divided into two groups of open surgery (OS) or laparoscopy-first (LF). Outcomes included length of stay, complications, mortality, readmission rates and reasons for conversion. Data were reviewed to identify patterns of learning. A total of 189 patients were included in the study. A total of 81.5% were managed with an LF approach. Of these, 25.3% required conversion. LF patients had a similar length of stay, lower 30-day readmission rates and wound complications. Reasons for conversion included need for bowel resection, perforation, and malignancy. Our study had a high intention-to-treat LF population and identified major indications for conversion. As our laparoscopic experience increased, conversion rates substantially reduced. We propose that a LF approach is feasible and can benefit from training within dedicated Emergency Surgery teams

Anastomotic Leak in Ovarian Cancer Cytoreduction Surgery: A Systematic Review and Meta-Analysis

Introduction: Anastomotic leaks (AL) following ovarian cytoreduction surgery could be detrimental, leading to significant delays in commencing adjuvant chemotherapy, prolonged hospital stays and increased morbidity. The aim of this study was to investigate risk factors associated with anastomotic leaks after ovarian cytoreduction surgery. Material and methods: The MEDLINE (via PubMed), Cochrane Library, EMBASE and Scopus bibliographical databases were searched. Original clinical studies investigating risk factors for AL in ovarian cytoreduction surgery were included. Results: Eighteen studies with non-overlapping populations reporting on patients undergoing cytoreduction surgery for ovarian cancer (n = 4622, including 344 cases complicated by AL) were included in our analysis. Patients undergoing ovarian cytoreduction surgery complicated by AL had a significantly higher rate of 30-day mortality but no difference in 60-day mortality. Multiple bowel resections were associated with an increased risk of postoperative AL, while no association was observed with body mass index (BMI), American Society of Anesthesiologists (ASA) score, age, smoking, operative approach (primary versus interval cytoreductive, stapled versus hand-sewn anastomoses and formation of diverting stoma), neoadjuvant chemotherapy and use of hyperthermic intraperitoneal chemotherapy (HIPEC). Discussion: Multiple bowel resections were the only clinical risk factor associated with increased risk for AL after bowel surgery in the ovarian cancer population. The increased 30-day mortality rate in patients undergoing ovarian cytoreduction complicated by AL highlights the need to minimize the number of bowel resections in this population. Further studies are required to clarify any association between neoadjuvant chemotherapy and decreased AL rates

Effect of intra-arcuate nucleus (ARC) and intra-medial preoptic area (mPOA) administration of kisspeptin-10 (KP) on LH secretion.

<p>Representative examples illustrating the effects of intra-ARC infusion of (A) 400 nl aCSF or (B) 100 pmol KP in ovariectomized 17βestradiol-replaced rats. C, Summary showing the effect of KP on LH secretion, calculated by comparing the mean area of under LH profile 2 h before with 1 h after its administration. Representative examples illustrating the effects of intra-mPOA infusion of (D) 400 nl aCSF or (E) 100 pmol KP in ovariectomized 17βestradiol-replaced rats. F, Summary showing the effect of intra-mPOA KP on LH secretion. LH secretion was dramatically increased immediately after KP treatment in both nuclei, which lasted about 1 h in most experimental animals. *P<0.05 versus aCSF control group at the same time point. ^#P<0.05 versus 10 pmol KP treatment group at the same time point; N = 5–7 per group.</p

Effect of intracerebroventricular (icv), intra-medial preoptic area (mPOA) or intra-arcuate nucleus (ARC) administration of kisspeptin antagonist, peptide 234 (Kiss-antag), on LH pulse amplitude (ng/mg) in ovariectomized 17β-estradiol-replaced rats.

<p>*2 rats continued to show LH pulses during kisspeptin antagonist infusion<b>/</b>not significant from baseline value (P = 0.28).</p><p>LH pulse amplitude (Mean ± SEM) is indicated before, during and post administration of antagonist or artificial cerebrospinal fluid (aCSF).</p

Effect of intracerebroventricular (icv) administration of kisspeptin antagonist (Kiss-antag) on LH pulse frequency.

<p>Representative examples illustrating the effects of continuous icv infusion of (A) aCSF (4 µl/h for 3 h) or (B and C) Kiss-antag (2.5 nmol/h for 3 h) in ovariectomized 17βestradiol-replaced rats. Pulsatile LH secretion was either completely suppressed during the period of Kiss-antag infusion (B) or LH pulse interval was significantly prolonged by Kiss-antag (C). D, Summary showing the inhibitory effect of Kiss-antag on pulsatile LH secretion. ^†P<0.001 versus aCSF control group at the same time point. ^#P<0.001 versus Kiss-antag treated group during the time of infusion; N = 5–6 per group. *LH pulse.</p

Schematic illustration of the intra-cerebral microinjection sites.

<p>Bilateral cannulae were positioned in the medial preoptic area (mPOA) at bregma −0.26 mm or the hypothalamic arcuate nucleus (ARC) at bregma −3.30 mm according to the rat brain atlas of Paxinos and Watson (19). Closed triangles represent the location of the cannulae tips. Ac, anterior commissure; 3v, third cerebral ventricle.</p

Effect of intra-arcuate nucleus (ARC) administration of kisspeptin antagonist (Kiss-antag) on pulsatile LH secretion.

<p>Representative examples illustrating the effects of intra-ARC injection of (A) of 500 nl aCSF (3 injections at 30 min intervals), (B) 10 pmol Kiss-antag (3 injections at 30 min intervals) or (C) 50 pmol Kiss-antag (3 injections at 30 min intervals) in ovariectomized 17βestradiol-replaced rats. D, Summary showing the inhibitory effect of Kiss-antag on LH pulse frequency. *P<0.05 versus aCSF control group at the same time point. ^#P<0.001 versus Kiss-antag (10 pmol ×3) at the same time point; N = 5–6 per group.</p