The Vagus Nerve Regulates Immunometabolic Homeostasis in the Ovine Fetus near Term: The Impact on Terminal Ileum.

BACKGROUND: Glucosensing elements are widely distributed throughout the body and relay information about circulating glucose levels to the brain via the vagus nerve. However, while anatomical wiring has been established, little is known about the physiological role of the vagus nerve in glucosensing. The contribution of the vagus nerve to inflammation in the fetus is poorly understood. Increased glucose levels and inflammation act synergistically when causing organ injury, but their interplay remains incompletely understood. We hypothesized that vagotomy (Vx) will trigger a rise in systemic glucose levels and this will be enhanced during systemic and organ-specific inflammation. Efferent vagus nerve stimulation (VNS) should reverse this phenotype. METHODS: Near-term fetal sheep (n = 57) were surgically prepared using vascular catheters and ECG electrodes as the control and treatment groups (lipopolysaccharide (LPS), Vx + LPS, Vx + LPS + selective efferent VNS). The experiment was started 72 h postoperatively to allow for post-surgical recovery. Inflammation was induced with LPS bolus intravenously (LPS group, 400 ng/fetus/day for 2 days; n = 23). For the Vx + LPS group (n = 11), a bilateral cervical vagotomy was performed during surgery; of these n = 5 received double the LPS dose, LPS800. The Vx + LPS + efferent VNS group (n = 8) received cervical VNS probes bilaterally distal from Vx in eight animals. Efferent VNS was administered for 20 min on days 1 and 2 +/10 min around the LPS bolus. Fetal arterial blood samples were drawn on each postoperative day of recovery (-72 h, -48 h, and -24 h) as well as at the baseline and seven selected time points (3-54 h) to profile inflammation (ELISA IL-6, pg/mL), insulin (ELISA), blood gas, and metabolism (glucose). At 54 h post-LPS, a necropsy was performed, and the terminal ileum macrophages' CD11c (M1 phenotype) immunofluorescence was quantified to detect inflammation. The results are reported for p < 0.05 and for Spearman R2 > 0.1. The results are presented as the median (IQR). RESULTS: Across the treatment groups, blood gas and cardiovascular changes indicated mild septicemia. At 3 h in the LPS group, IL-6 peaked. That peak was decreased in the Vx + LPS400 group and doubled in the Vx + LPS800 group. The efferent VNS sped up the reduction in the inflammatory response profile over 54 h. The M1 macrophage activity was increased in the LPS and Vx + LPS800 groups only. The glucose and insulin concentrations in the Vx + LPS group were, respectively, 1.3-fold (throughout the experiment) and 2.3-fold higher vs. control (at 3 h). The efferent VNS normalized the glucose concentrations. CONCLUSIONS: The complete withdrawal of vagal innervation resulted in a 72-h delayed onset of a sustained increase in glucose for at least 54 h and intermittent hyperinsulinemia. Under the conditions of moderate fetal inflammation, this was related to higher levels of gut inflammation. The efferent VNS reduced the systemic inflammatory response as well as restored both the concentrations of glucose and the degree of terminal ileum inflammation, but not the insulin concentrations. Supporting our hypothesis, these findings revealed a novel regulatory, hormetic, role of the vagus nerve in the immunometabolic response to endotoxin in near-term fetuses.

Management of heavy menstrual bleeding in women with bleeding disorders in a tertiary care center.

Background: Heavy menstrual bleeding (HMB) affects a significant number of women with bleeding disorders and has a negative impact on their quality of life. Objective: This retrospective study examined the management of patients with inherited bleeding disorders who used medical treatments, alone or in combination, for HMB. Methods: Chart review was performed on women attending the Women with Bleeding Disorders Clinic in Kingston, Ontario, between 2005 and 2017. Data collected included patient demographics, the reason for presentation and diagnosis, medical history, treatments, and patient satisfaction. Results: One hundred nine women were included in this cohort. Of these, only 74 (68%) were satisfied with medical management, and only 18 (17%) with first-line therapy. Treatments included combined contraceptives (oral pill, transdermal patch, and vaginal ring), progesterone-only pills, tranexamic acid, 52-mg levonorgestrel intrauterine system (LIUS), depomedroxyprogesterone acetate, and desmopressin, either alone or in combination. Satisfactory control of HMB occurred most often with the LIUS. Conclusion: In this cohort, managed in a tertiary care Women with Bleeding Disorders Clinic, only 68% of patients had successful control of HMB with medical treatment, and a minority were satisfied with first-line therapy. These data clearly highlight the need for additional research, including treatment approaches and novel therapies for this population.

How are Canadian cannabis dispensaries counselling breastfeeding consumers?

Objectives: This study aimed to identify recommendations given to breastfeeding individuals by Canadian cannabis dispensary employees, since the legalization of recreational cannabis in 2018. Methods: This was a nationwide cross-sectional study conducted from November 2020 to January 2021. A mystery caller approach was used to identify recommendations given to breastfeeding individuals seeking a product for "relaxation." This study was modelled on similar studies which assessed recommendations given to pregnant women looking for cannabis products to manage nausea and vomiting (Vastis V, Shea AK, Vincent S, Metz TD. 275: Are canadian cannabis dispensaries counselling pregnant women appropriately? Am. J. Obstet. Gynecol. 2020;222: S187.(Abst). Lusero I, Paltrow LM, Rosenbloom N. Recommendations from cannabis dispensaries about first-trimester cannabis use Obstet Gynecol 2018;132:781-2.). The primary outcome was the recommendation of a cannabis product. Secondary outcomes included stated benefits of cannabis, recommended discussion with health care provider, length of call, rationale for recommendation, and reported source of information on which the recommendation was based. Results: The majority (79.4%) of employees of the 714 Canadian dispensaries contacted recommended against a cannabis product for "relaxation" while breastfeeding. The recommendations from dispensary employees were often (80%) provided without a specific reason, whereas a minority referenced published research (2%) and opinion (17.6%). Cannabis products were rarely (3.3%) classified as safe in breastfeeding. Approximately 76.6% of dispensary employees recommended contacting a health care provider, while 2.4% recommended against. Conclusions: Although a high proportion of dispensary employees recommended against using a cannabis product during lactation, there were still 20.6% that did recommend use, which contrasts the current public health guidelines and is not supported by the paediatric and obstetric societies. These findings highlight the need for further education about the safety of cannabis products while breastfeeding.

Recording and manipulation of vagus nerve electrical activity in chronically instrumented unanesthetized near term fetal sheep.

BACKGROUND: The chronically instrumented pregnant sheep has been used as a model of human fetal development and responses to pathophysiologic stimuli. This is due to the unique amenability of the unanesthetized fetal sheep to the surgical placement and maintenance of catheters and electrodes, allowing repetitive blood sampling, substance injection, recording of bioelectrical activity, application of electric stimulation, and in vivo organ imaging. Recently, there has been growing interest in the pleiotropic effects of vagus nerve stimulation (VNS) on various organ systems such as innate immunity and inflammation, and metabolism. There is no approach to study this in utero and corresponding physiological understanding is scarce. NEW METHOD: Based on our previous presentation of a stable chronically instrumented unanesthetized fetal sheep model, here we describe the surgical instrumentation procedure allowing successful implantation of a cervical uni- or bilateral VNS probe with or without vagotomy. RESULTS: In a cohort of 68 animals, we present the changes in blood gas, metabolic, and inflammatory markers during the postoperative period. We detail the design of a VNS probe which also allows recording from the fetal nerve. We also present an example of fetal vagus electroneurogram (VENG) recorded from the VNS probe and an analytical approach to the data. COMPARISON WITH EXISTING METHODS: This method represents the first implementation of fetal VENG/VNS in a large pregnant mammalian organism. CONCLUSIONS: This study describes a new surgical procedure allowing to record and manipulate chronically fetal vagus nerve activity in an animal model of human pregnancy.

Instrumentation of Near-term Fetal Sheep for Multivariate Chronic Non-anesthetized Recordings.

The chronically instrumented pregnant sheep has been used as a model of human fetal development and responses to pathophysiologic stimuli such as endotoxins, bacteria, umbilical cord occlusions, hypoxia and various pharmacological treatments. The life-saving clinical practices of glucocorticoid treatment in fetuses at risk of premature birth and the therapeutic hypothermia have been developed in this model. This is due to the unique amenability of the non-anesthetized fetal sheep to the surgical placement and maintenance of catheters and electrodes, allowing repetitive blood sampling, substance injection, recording of bioelectrical activity, application of electric stimulation and in vivo organ imaging. Here we describe the surgical instrumentation procedure required to achieve a stable chronically instrumented non-anesthetized fetal sheep model including characterization of the post-operative recovery from blood gas, metabolic and inflammation standpoints.

Effect of maternal ketoacidosis on the ovine fetus.

Ketoacidosis during pregnancy carries significant risk of intrauterine fetal demise, but little is known about the impact of ketoacids on the ovine fetus. We report a case series of maternal ketoacidosis in ewes. Maternal ketoacidosis may result in biochemical and acid-base fetal abnormalities associated with changes in feto-placental unit perfusion.

Effet de l'acidocétose maternelle sur un fœtus ovin. L'acidocétose durant la gestation comporte un risque important de mortalité intra-utérine du fœtus, mais on connaît peu de choses à propos de l'impact des acides cétoniques sur le fœtus ovin. Nous signalons une série de cas d'acidocétose maternelle chez les brebis. L'acidocétose maternelle peut provoquer des anomalies biochimiques et acides avec des changements dans la perfusion de l'unité fœto-placentaire.(Traduit par Isabelle Vallières).