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Louis, Alexandre, Charlotte Pröpper, Yann Savina, Corentin Tanne, Guy Duperrex, Paul Robach, Pascal Zellner, Stéphane Doutreleau, Jean-Michel Boulet, Alain Frey, Fabien Pillard, Cristina Pistea, Mathias Poussel, Thomas Thuet, Jean-Paul Richalet, and François Lecoq-Jammes. The impact of COVID-19 on the response to hypoxia. High Alt Med Biol . 24:321-328, 2023. Background: Severe high-altitude illness (SHAI) and coronavirus disease 2019 (COVID-19), while differing in most aspects of pathophysiology, both involve respiratory capacity. We examined the long-term impact of COVID-19 on response to hypoxia in individuals free of symptoms but having tested positive during the pandemic. The need for recommendations for such individuals planning a stay at high altitude are discussed. Methods: This multicenter study recruited participants from the multiSHAI cohort, all of whom had previously undergone a hypoxic exercise test. These participants were classified into two groups depending on whether they had since suffered mild-to-moderate COVID-19 (COVID+) or not (Control) and then asked to retake the test. Primary outcomes were: desaturation induced by hypoxia at exercise (ΔSpE), hypoxic cardiac response at exercise, hypoxic ventilatory response at exercise, and SHAI risk score. Results: A total of 68 participants retook the test, 36 classified in the COVID+ group. Analyses of primary outcomes showed no significant differences between groups. However, the COVID+ group showed significantly increased ventilation (VE) parameters during both hypoxic ( p  = 0.003) and normoxic exercise ( p  = 0.007). However, only the VE/oxygen consumption relationship during hypoxic exercise was significantly different. Conclusion: This study demonstrates no negative impact of COVID-19 on response to hypoxia as evaluated by the Richalet test. Clinical Trial Registration: NTC number: NCT05167357.

Purpose: A decision tree based on a clinicophysiological score (severe high-altitude illness (SHAI) score) has been developed to detect subjects susceptible to SHAI. We aimed to validate this decision tree, to rationalize the prescription of acetazolamide (ACZ), and to specify the rule for a progressive acclimatization., Methods: Data were obtained from 641 subjects in 15 European medical centers before and during a sojourn at high altitude. Depending on the value of the SHAI score, advice was given and ACZ was eventually prescribed. The outcome was the occurrence of SHAI at high altitude as a function of the SHAI score, ACZ prescription, and use and fulfillment of the acclimatization rule., Results: The occurrence of SHAI was 22.6%, similar to what was observed 18 yr before (23.7%), whereas life-threatening forms of SHAI (high-altitude pulmonary and cerebral edema) were less frequent (2.6%-0.8%, P = 0.007). The negative predictive value of the decision tree based was 81%, suggesting that the procedure is efficient to detect subjects who will not suffer from SHAI, therefore limiting the use of ACZ. The maximal daily altitude gain that limits the occurrence of SHAI was established at 400 m. The occurrence of SHAI was reduced from 27% to 12% when the recommendations for ACZ use and 400-m daily altitude gain were respected (P < 0.001)., Conclusions: This multicenter study confirmed the interest of the SHAI score in predicting the individual risk for SHAI. The conditions for an optimized acclimatization (400-m rule) were also specified, and we proposed a rational decision tree for the prescription of ACZ, adapted to each individual tolerance to hypoxia., (Copyright © 2020 by the American College of Sports Medicine.)

Two new strains of Sphingomonas elodea (designated as PHP1 and PBAD1) were tested for toxicity and pathogenicity in healthy Sprague-Dawley CD(®) IGS rats in separate studies. In each study, twelve rats/sex were administered ≥10(8) viable cells/rat by oral gavage, and four untreated rats/sex served as controls. Blood, feces, and selected organs/tissues collected at various times over the course of the 22 day study were evaluated for the presence of PHP1 or PBAD1 (depending on the study) by a validated method, to determine the potential for survival, propagation, or infectivity of PHP1 and PBAD1 cells in the rat. No mortalities, test substance-related changes in clinical or macroscopic findings, body weight or body weight gain were observed in treated animals compared with controls, indicating a lack of toxicity. PHP1 or PBAD1 were not detected in the tissue, fecal or fluid samples collected from treated animals. Therefore, neither PHP1 nor PBAD1 were pathogenic or acutely toxic under the conditions of the studies., (Copyright © 2016. Published by Elsevier Inc.)

We identify an autosomal mutation in the CSF3R gene in a family with a chronic neutrophilia. This T617N mutation energetically favors dimerization of the granulocyte colony-stimulating factor (G-CSF) receptor transmembrane domain, and thus, strongly promotes constitutive activation of the receptor and hypersensitivity to G-CSF for proliferation and differentiation, which ultimately leads to chronic neutrophilia. Mutant hematopoietic stem cells yield a myeloproliferative-like disorder in xenotransplantation and syngenic mouse bone marrow engraftment assays. The survey of 12 affected individuals during three generations indicates that only one patient had a myelodysplastic syndrome. Our data thus indicate that mutations in the CSF3R gene can be responsible for hereditary neutrophilia mimicking a myeloproliferative disorder.

Changes in bone mineral density (BMD) are associated with clinical neuropathies. Following nerve injury in the rat, there is a loss of BMD, which may be related to nerve injury or reduced mechanical loading. The purpose of this study was to investigate if altered mechanical loading is solely responsible for the observed loss of BMD in neuropathic pain models. In addition, we sought to study the action of chronic bisphosphonate treatment on both neuropathy-induced osteopenia and pain. We therefore had two hypotheses: firstly, that nerve injuries can have variable effects on hind limb bone loss in rats which are not attributable to differences in the extent of hind limb disuse and, secondly, that bisphosphonate treatment can reverse bone loss in a rat mononeuropathy model, and this is not attributable to bisphosphonate effects on nociception or hind paw unweighting. Male Sprague-Dawley rats were subject to chronic constriction injury (CCI), partial sciatic nerve ligation (PSN) or L5 + L6 spinal nerve ligation (SNL). Loss of BMD, defined as a numerically lower BMD as compared to control animals, was extreme following CCI (maximum ipsilateral/contralateral difference of 0.023 +/- 0.011); BMD loss following either PSN or SNL in the rat was subtle (0.010 +/- 0.002 and 0.013 +/- 0.012 g/cm2, respectively), significant only at early time points and had resolved by 7 weeks post-surgery. Chronic bisphosphonate treatment significantly inhibited CCI-induced osteopenia in the rat without inhibiting the reduction in weight-bearing tactile allodynia or mechanical hyperalgesia. Loss of BMD is observed in rats in a variety of neuropathic pain models. Lack of correlation between neuropathy-induced bone loss and weight bearing demonstrates that the bone loss is not simply a function of reduced mechanical loading and suggests that altered bone-nerve signaling is involved. Furthermore, chronic bisphosphonate treatment inhibits neuropathy-induced osteopenia without affecting behavioral measurements of neuropathic pain. This indicates that osteopenia is not directly related to neuropathic pain behaviors.

Several recent reports have demonstrated a role for selective cannabinoid CB2 receptor agonists in pain modulation, showing both analgesic and antihyperalgesic activities. While the mechanism of action is poorly understood, it has been postulated that these effects may be indirect, involving release of endogenous opioids. We have previously reported that administration of the selective cannabinoid CB2 receptor agonist GW405833 (2,3-dichloro-phenyl)-[5-methoxy-2-methyl-3-(2-morpholin-4-yl-ethyl)-indol-1-yl]-methanone) to rats elicits potent and efficacious antihyperalgesic effects against neuropathic and inflammatory pain and, at high dose (100 mg/kg), is analgesic and ataxic [Valenzano, K.J., Tafesse, L., Lee, G., Harrison, J.E., Boulet, J., Gottshall, S.L., Mark, L., Pearson, M.S., Miller, W., Shan, S., Rabadi, L., Rotstheyn, Y., Chaffer, S.M., Turchin, P.I., Elsemore, D.A., Toth, M., Koetzner, L., Whiteside, G.T., 2005. Pharmacological and pharmacokinetic characterization of the cannabinoid receptor 2 agonist, GW405833, utilizing rodent models of acute and chronic pain, anxiety, ataxia and catalepsy. Neuropharmacology 48, 658-672]. In the current study, we confirm these properties using mouse models and investigate the role of cannabinoid CB2 receptors using knockout animals. Furthermore, we provide evidence that the antinociceptive properties of GW405833 are opioid independent. GW405833 elicited robust antihyperalgesic effects in mouse models of inflammatory (Freund's complete adjuvant) and neuropathic (Seltzer) pain. In contrast, GW405833 showed no antihyperalgesic activity against Freund's complete adjuvant-mediated inflammatory pain in cannabinoid CB2 receptor knockout mice. As in rats, high-dose GW405833 (100 mg/kg) showed both analgesic and sedative activities in wild-type mice, activities that were also apparent in cannabinoid CB2 receptor knockout mice. In rats, neither the antihyperalgesic effect in the Freund's complete adjuvant model nor the analgesic effects in tail flick and hot plate assays were inhibited by pre-treatment with the non-selective opioid receptor antagonist, naltrexone. These data demonstrate that the antihyperalgesic effects of GW405833 are mediated via the cannabinoid CB2 receptor, whereas the analgesic and sedative effects are not. Furthermore, these data suggest that the mechanism of action for GW405833 does not depend on the release of endogenous opioids.

The role of opioid receptors located in the central nervous system (CNS) and peripheral nervous system in inflammatory pain is well established. In contrast, although it is has been shown that mu agonists can reduce other manifestations of inflammation, such as edema, the mechanism of action remains unclear. In this study, we have activated mu receptors located centrally, those located peripherally, and those located both centrally and peripherally and compared the effects on pain and edema using the rat carrageenan model of acute inflammation. Activation of mu receptors located only in the periphery, by administration of the peripheralized mu agonist [8-(3,3-diphenyl-propyl)-4-oxo-1-phenyl-1,3,8-triaza-spiro[4.5]dec-3-yl]-acetic acid (DiPOA) or local administration of morphine, resulted in antihyperalgesia (30 mg/kg DiPOA, 83% inhibition; 100 microg/rat morphine, 75% inhibition) without affecting edema. In contrast, activation of both central and peripheral mu receptors using systemically administered morphine resulted in antihyperalgesia (1 mg/kg, 80% inhibition) and inhibition of edema (10 mg/kg, 54% inhibition). Finally, activation of only receptors located in the CNS, by central administration of DiPOA or systemic administration of morphine after block of only the peripheral mu receptors using q-naltrexone, resulted in a significant reduction in edema. Our findings confirm the role of peripheral mu receptors in the pathology of pain associated with acute inflammation and argue against the involvement of these receptors in edema formation. Furthermore, our data demonstrate that activation of mu receptors in the brain inhibits carrageenan-induced edema and suggest that the antiedematous effect of morphine is due to action at central receptors alone.

To date, two cannabinoid receptors have been identified, CB1 and CB2. Activation of these receptors with non-selective cannabinoid receptor agonists reduces pain sensitivity in animals and humans. However, activation of CB1 receptors is also associated with central side effects, including ataxia and catalepsy. More recently, a role for selective CB2 agonists in pain modification has been demonstrated. GW405833, a selective CB2 agonist, was recently reported to partially reverse the inflammation and hyperalgesia in a rat model of acute inflammation. In the current report, we extend the characterization and therapeutic potential of this compound. For the first time, we show that GW405833 selectively binds both rat and human CB2 receptors with high affinity, where it acts as a partial agonist (approximately 50% reduction of forskolin-mediated cAMP production compared to the full cannabinoid agonist, CP55,940). We also report for the first time that intraperitoneal administration of GW405833 (0.3-100 mg/kg) to rats shows linear, dose-dependent increases in plasma levels and substantial penetration into the central nervous system. In addition, GW405833 (up to 30 mg/kg) elicits potent and efficacious antihyperalgesic effects in rodent models of neuropathic, incisional and chronic inflammatory pain, the first description of this compound in these models. In contrast, analgesia, sedation and catalepsy were not observed in this dose range, but were apparent at 100 mg/kg. Additionally, GW405833 was not antihyperalgesic against chronic inflammatory pain in CB2 knockout mice. These data support the tenet that selective CB2 receptor agonists have the potential to treat pain without eliciting the centrally-mediated side effects associated with non-selective cannabinoid agonists, and highlight the utility of GW405833 for the investigation of CB2 physiology.

Osteoarthritis (OA) is an age-related joint disease characterized by degeneration of articular cartilage and is associated with chronic pain. Although several experimental models of OA have been employed to investigate the underlying etiologies of the disease, there has been relatively little investigation into development of animal models of OA to study the pain associated with the condition. In the present study, we investigated OA induced by injection of either iodoacetate or papain into the knee joint of rats, and assessed the joint degeneration with radiographic analyses and measured pain behavior using hind limb weight bearing. We found that injection of iodoacetate, but not papain, resulted in a chronic joint degeneration as measured by decreased bone mineral content and bone mineral density, necrosis of articular cartilage and osteophyte formation. These pathological changes were associated with pain that manifested as time- and concentration-dependent alterations in hind limb weight bearing. These alterations in hind limb weight bearing were reversed with morphine, but were not significantly affected by acute administration of either indomethacin or celecoxib. However, administration of 30 mg/kg celecoxib twice daily for 10 days resulted in a significant restoration of hind limb weight bearing. We conclude that the iodoacetate model of OA is a relevant animal model to study pain associated with OA, and can be used to test potential therapeutic agents.

Objectives: Using a standardized prescription sheet we attempted to improve requests for serum tumor markers in a general hospital., Methods: Over two 35-day periods before and one year after defining a local prescription consensus and introducing a new prescription sheet, we counted the number of orders for five tumor markers (CEA, CA 19-9, CA 15-3, CA 125, alpha FP) and determined their compliance to the defined prescription protocol., Results: Between the two study periods, the number of prescriptions for the designated tumor markers fell by 24%, from 153 requests in 94 patients to 123 requests in 99 patients, despite a 6% increase in the number of admissions. There was a significant reduction in the number of serum markers orders per prescription (from 1.6 to 1.2) although the distribution by tumor marker remained unchanged. Compliance to the prescription protocol improved, rising from 65 to 87% in units where the pre-protocol compliance rate was below 80%. The rate of compliance was not correlated with correct completion of the new prescription sheet (91% vs 86% respectively). The 6-month cost-savings was estimated at 31,104 FF using the general French nomenclature for laboratory tests. Direct cost reduction was estimated at 5,688 FF., Conclusion: Long-lasting improvement of serum tumor marker prescriptions can be achieved in a general hospital. Obtaining a local consensus implicating all prescribing units seems more important than a change in the presentation of the prescription sheet.

Objective: To assess whether postprandial dietary thermogenesis contributes to weight loss during HIV infection., Methods: The thermogenic response to a test meal (15 kcal/kg) was evaluated with indirect calorimetry in 16 HIV-infected patients in a stable condition and compared with a control group. Patients were compared according to AIDS (n = 8) or non-AIDS (n = 8) status and to body weight loss (WL; n = 9) or no loss (NL; n = 7). Indirect calorimetry was performed after fasting 6 h and during 5 h after the test meal., Results: Maximum value of energy expenditure was reached later in the WL group than in the control and NL group (200 versus 30 min, respectively). Energy expenditure returned to the initial value 300 min after the test meal (last measurement) in the control group but remained elevated in the patient group. Energy expenditure after food intake was more elevated in HIV-infected patients than in controls, especially in patients with detectable clinical change in their nutritional status (0.96 versus 0.72 kcal/kg body weight)., Conclusion: Both kinetics and quantitative aspect of dietary thermogenesis are modified during HIV infection and the different variations are dependent on the extent of body weight loss.