SignificanceThe transition from placental to lung-based oxygen supply at mammalian birth involves an obligatory period of asphyxia, which is further aggravated by complications during delivery. This oxygen deprivation is a major threat to the fetal brain, and, under such conditions, hormonal and cardiovascular mechanisms are activated to enhance brain perfusion. Our work now demonstrates an intrinsic mechanism in the fetal brain whereby vasopressin activates hippocampal interneurons, leading to desynchronization and suppression of neuronal network activity in species (rat and guinea pig) that are born at widely different stages of brain maturation. Silencing of synchronous neuronal activity by vasopressin is expected to decrease neuronal energy demand and prevent maladaptive synaptic plasticity, thus acting as a pan-mammalian neuroprotective mechanism during birth.

Objective Birth asphyxia (BA) is often associated with seizures that may exacerbate the ensuing hypoxic–ischemic encephalopathy. In rodent models of BA, exposure to hypoxia is used to evoke seizures, that commence already during the insult. This is in stark contrast to clinical BA, in which seizures are typically seen upon recovery. Here, we introduce a term‐equivalent rat model of BA, in which seizures are triggered after exposure to asphyxia. Methods Postnatal day 11–12 male rat pups were exposed to steady asphyxia (15 min; air containing 5% O2 + 20% CO2) or to intermittent asphyxia (30 min; three 5 + 5‐min cycles of 9% and 5% O2 at 20% CO2). Cortical activity and electrographic seizures were recorded in freely behaving animals. Simultaneous electrode measurements of intracortical pH, Po2, and local field potentials (LFPs) were made under urethane anesthesia. Results Both protocols decreased blood pH to <7.0 and brain pH from 7.3 to 6.7 and led to a fall in base excess by 20 mmol·L–1. Electrographic seizures with convulsions spanning the entire Racine scale were triggered after intermittent but not steady asphyxia. In the presence of 20% CO2, brain Po2 was only transiently affected by 9% ambient O2 but fell below detection level during the steps to 5% O2, and LFP activity was nearly abolished. Post‐asphyxia seizures were strongly suppressed when brain pH recovery was slowed down by 5% CO2. Significance The rate of brain pH recovery has a strong influence on post‐asphyxia seizure propensity. The recurring hypoxic episodes during intermittent asphyxia promote neuronal excitability, which leads to seizures only after the suppressing effect of the hypercapnic acidosis is relieved. The present rodent model of BA is to our best knowledge the first one in which, consistent with clinical BA, behavioral and electrographic seizures are triggered after and not during the BA‐mimicking insult.

Birth asphyxia (BA) is a pathologic condition that arises from severe perinatal hypoxia and hypercapnia.Recovery following BA is often associated with seizures which may exacerbate the ensuing hypoxicischemic encephalopathy (HIE). Drugs used to treat post-BA seizures are often ineffective and there are concerns over their safety. Therefore, novel seizure-suppressing therapies are urgently needed. Most rodent models of BA-induced seizures are based on exposing neonatal rats or mice to hypoxia (or hypoxiaischemia), and overlook the fact that the hypercapnic acidosis linked to asphyxia has brain-sparing effects by suppressing neuronal excitability and enhancing cerebral blood flow. Thus, the aim of the present study was to investigate the dependence of asphyxia-induced seizures on brain pH and oxygen (Po 2 ) levels in a rodent model of term BA based on postnatal day 11-12 rat pups. Cortical activity and electrographic seizures were recorded in freely-behaving animals using epidural electrodes. Simultaneous measurements of cortical local field potentials as well as intracortical pH and Po 2 were made using microelectrodes and microsensors in urethane-anesthesized animals. The pups were exposed either to steady asphyxia (duration 15 min; with ambient air containing 5 % O 2 plus 20 % CO 2 ) or to intermittent asphyxia (30 min; with repetitive 5 min steps from 9 % to 5 % O 2 at constant 20 % CO 2 ). Both protocols led to acidemia (blood pH <7.0) coupled to a fall in base excess by 20 mmol/l, and to a large increase in plasma copeptin (from 0.2 nM to about 5 nM), a biomarker of BA. Brain pH decreased from 7.3 to 6.7 by the end of intermittent asphyxia.Brain Po 2 was only transiently affected by 9% ambient O 2 , but it fell below the level of detection with steps to 5 % O 2 , during which neuronal activity was near-abolished. The Po 2 steps to 9% were associated with a moderate increase in pH (0.12 units) and a slight recovery (~10 % of baseline) in ongoing neuronal activity.Behavioral seizures spanning the entire Racine scale were triggered after intermittent but not steady asphyxia, and they were tightly associated with neocortical electrographic seizures. The seizures were strongly suppressed when the post-asphyxia brain pH recovery was slowed down by a low level (5 %) of ambient CO 2 . The post-asphyxia overshoot in brain Po 2 (from 30 to 85 mmHg) had no discernible effect on neuronal activity. Our data suggest that the recurring hypoxic episodes during intermittent asphyxia promote neuronal excitability, which becomes established as hyperexcitability and seizures once the suppressing effect of the hypercapnic acidosis is relieved. The present rodent model of BA is to our best knowledge the first one where, consistent with the clinical picture of BA, robust behavioral and electrographic seizures are triggered after and not during the asphyxic insult. HIGHLIGHTS Experimental asphyxia induced severe acidemia and abolished most cortical activity. Cortical activity during asphyxia was closely linked with changes in brai...

Mammalian birth is accompanied by a period of obligatory asphyxia, which consists of hypoxia (drop in blood O2 levels) and hypercapnia (elevation of blood CO2 levels). Prolonged, complicated birth can extend the asphyxic period, leading to a pathophysiological situation, and in humans, to the diagnosis of clinical birth asphyxia, the main cause of hypoxic-ischemic encephalopathy (HIE). The neuroendocrine component of birth asphyxia, in particular the increase in circulating levels of arginine vasopressin (AVP), has been extensively studied in humans. Here we show for the first time that normal rat birth is also accompanied by an AVP surge, and that the fetal AVP surge is further enhanced in a model of birth asphyxia, based on exposing 6-day old rat pups to a gas mixture containing 4% O2 and 20% CO2 for 45 min. Instead of AVP, which is highly unstable with a short plasma half-life, we measured the levels of copeptin, the C-terminal part of prepro-AVP that is biochemically much more stable. In our animal model, the bulk of AVP/copeptin release occurred at the beginning of asphyxia (mean 7.8 nM after 15 min of asphyxia), but some release was still ongoing even 90 min after the end of the 45 min experimental asphyxia (mean 1.2 nM). Notably, the highest copeptin levels were measured after hypoxia alone (mean 14.1 nM at 45 min), whereas copeptin levels were low during hypercapnia alone (mean 2.7 nM at 45 min), indicating that the hypoxia component of asphyxia is responsible for the increase in AVP/copeptin release. Alternating the O2 level between 5 and 9% (CO2 at 20%) with 5 min intervals to mimic intermittent asphyxia during prolonged labor resulted in a slower but quantitatively similar rise in copeptin (peak of 8.3 nM at 30 min). Finally, we demonstrate that our rat model satisfies the standard acid-base criteria for birth asphyxia diagnosis, namely a drop in blood pH below 7.0 and the formation of a negative base excess exceeding −11.2 mmol/l. The mechanistic insights from our work validate the use of the present rodent model in preclinical work on birth asphyxia.

Background Osteoarthritis (OA) is a leading cause of disability and pain especially among older adults, but it is also known to affect working age individuals, often leading to reduced productivity and increased healthcare usage. The aim of this study was to determine the burden of hip and knee OA in Finnish occupational healthcare. Methods This was a retrospective registry study utilizing the electronic medical records of the largest private and occupational healthcare provider in Finland. All consented patients with hip or knee OA were identified. A subcohort of occupational healthcare (OCH) patients was then compared to an age- and gender-matched control group without OA. Patient demographics including comorbidities were determined and healthcare contacts, medication prescriptions, and sick leaves were compared between the two groups. The study period was from January 1st, 2012 to April 30th, 2020. Results 51,068 patients with hip or knee OA were identified (all OA cohort) and 35,109 of these formed the occupational healthcare subcohort. Most of the OA patients were female and belonged to the age group 50–59 years. The point prevalence of hip/knee OA at the end of the study period was 5.6% for the occupational healthcare subcohort. OA patients had 2.2 times more healthcare contacts and 2.8 times more overall sick leave days compared to the age- and gender-matched control cohort. Etoricoxib was the most commonly prescribed medication at OA-related visits (21.8% of patients). Opioids were prescribed to 10.6% of patients at OA-related visits and the most prescribed opioid was a combination of codeine and paracetamol (4.8% of patients). 5054 OA patients (14.4%) had a contraindication for non-steroidal anti-inflammatory drugs (NSAIDs). Conclusions This retrospective registry study utilizing real-world data provides new evidence on the disease burden of hip or knee osteoarthritis from the electronic medical records of Finnish occupational healthcare customers. OA patients had more comorbidities, more healthcare contacts, more sick leave days, and more analgesic prescriptions compared to an age- and gender-matched control cohort without OA.