A mouse model of sensory neuropathy induced by a long course of monomethyl-auristatin E treatment.

Antibody-drug conjugates (ADCs) are anticancer drugs consisting of a monoclonal antibody, targeting selective tumor antigens, to which has been frequently associated a highly potent cytotoxic agent, the monomethyl auristatin E (MMAE) using a chemical linker. MMAE is a tubulin polymerization inhibitor derived from dolastin-10. These MMAE-ADCs are responsible for peripheral nerve toxicities. Our objective was to develop and characterize a mouse model of MMAE-induced peripheral neuropathy induced by free MMAE injections. MMAE was injected in Swiss mice at 50 µg/kg i.p. every other day for 7 weeks. Assessments of motor and sensory nerve functions were performed once a week on MMAE and Vehicle-treated mice. Sciatic nerve and paw skin were removed at the end of experiment for subsequent immunofluorescence and morphological analysis. MMAE did not affect motor coordination, muscular strength and heat nociception, but significantly induced tactile allodynia in MMAE-treated mice compared with Vehicle-treated mice from day 35 to day 49. MMAE significantly reduced myelinated and unmyelinated axon densities in sciatic nerves and led to a loss of intraepidermal nerve fiber in paw skin. In summary, long course of low dose of MMAE induced a peripheral sensory neuropathy associated with nerve degeneration, without general state alteration. This model may represent a ready accessible tool to screen neuroprotective strategies in the context of peripheral neuropathies induced by MMAE-ADCs.

Candesartan restores pressure-induced vasodilation and prevents skin pressure ulcer formation in diabetic mice.

BACKGROUND: Angiotensin II type 1 receptor (AT1R) blockers have beneficial effects on neurovascular complications in diabetes and in organ's protection against ischemic episodes. The present study examines whether the AT1R blocker candesartan (1) has a beneficial effect on diabetes-induced alteration of pressure-induced vasodilation (PIV, a cutaneous physiological neurovascular mechanism which could delay the occurrence of tissue ischemia), and (2) could be protective against skin pressure ulcer formation. METHODS: Male Swiss mice aged 5-6 weeks were randomly assigned to four experimental groups. In two groups, diabetes was induced by a single intraperitoneal injection of streptozotocin (STZ, 200 mg.kg(-1)). After 6 weeks, control and STZ mice received either no treatment or candesartan (1 mg/kg-daily in drinking water) during 2 weeks. At the end of treatment (8 weeks of diabetes duration), C-fiber mediated nociception threshold, endothelium-dependent vasodilation and PIV were assessed. Pressure ulcers (PUs) were then induced by pinching the dorsal skin between two magnetic plates for three hours. Skin ulcer area development was assessed during three days, and histological examination of the depth of the skin lesion was performed at day three. RESULTS: After 8 weeks of diabetes, the skin neurovascular functions (C-fiber nociception, endothelium-dependent vasodilation and PIV) were markedly altered in STZ-treated mice, but were fully restored by treatment with candesartan. Whereas in diabetes mice exposure of the skin to pressure induced wide and deep necrotic lesions, treatment with candersartan restored their ability to resist to pressure-induced ulceration as efficiently as the control mice. CONCLUSION: Candesartan decreases the vulnerability to pressure-induced ulceration and restores skin neurovascular functions in mice with STZ-induced established diabetes.

Erythropoietin, a novel repurposed drug: an innovative treatment for wound healing in patients with diabetes mellitus.

Developing a new drug is expensive: the cost of going from bench to bedside is about $US1 billion. Therefore, the repurposing of an approved drug is potentially rewarding because it expands the drug's existing therapeutic profile and preempts additional development costs. As the safety profile of a repurposed drug is already well known, any new investigations could then focus on its efficacy and other therapeutic benefits. Recombinant erythropoietin (EPO) is a potential candidate for repurposing because the results of numerous studies have shown that systemic and topical EPO is therapeutically beneficial when it is administered to healthy and diabetic animals with acute and chronic skin wounds and burns. Moreover, the molecular mechanisms of EPO's actions have been elucidated: EPO acts on those nonhematopoietic cells which are involved in the innate immune response where it promotes cellular proliferation and differentiation, exerts its cytoprotective actions, and inhibits apoptosis. In this review, the mechanism of EPO's action in skin wound healing is reviewed, and its potential for treating acute and chronic skin wounds and stimulating tissue regeneration in diabetic patients is discussed.

Netazepide, an Antagonist of Cholecystokinin Type 2 Receptor, Prevents Vincristine-Induced Sensory Neuropathy in Mice.

Among the vinca-alkaloid class, vincristine is a potent chemotherapeutic agent with significant neurotoxic effects and is employed to address a wide spectrum of cancer types. Recently, the therapeutic potential of the cholecystokinin type 2 receptor (CCK2R) as a target for vincristine-induced peripheral neuropathy (VIPN) was demonstrated. In this study, the impact of preventive CCK2R blockade using netazepide (Trio Medicines Ltd., London, UK) was investigated in a mouse model of vincristine-induced peripheral neuropathy. Netazepide is a highly selective CCK2R antagonist under development for the treatment of patients with gastric neuroendocrine tumors caused by hypergastrinemia secondary to chronic autoimmune atrophic gastritis. Vincristine-induced peripheral neuropathy was induced by intraperitoneal injections of vincristine at 100 µg/kg/d for 7 days (D0 to D7). Netazepide (2 mg/kg/d or 5 mg/kg/d, per os) was administered one day before vincristine treatment until D7. Vincristine induced a high tactile allodynia from D1 to D7. VIPN was characterized by dorsal root ganglion neuron (DRG) and intraepidermal nerve fiber (IENF) loss, and enlargement and loss of myelinated axons in the sciatic nerve. Netazepide completely prevented the painful symptoms and nerve injuries induced by vincristine. In conclusion, the fact that netazepide protected against vincristine-induced peripheral neuropathy in a mouse model strongly supports the assessment of its therapeutic potential in patients receiving such chemotherapy.

[Interest of a short educational intervention coordinated by community pharmacists for elderly type 2 diabetes patients in a rural area]. / Intérêt d'une séance éducative « flash ¼ coordonnée par des pharmaciens d'officine pour des patients âgés diabétiques de type 2 en milieu rural.

The number of elderly people with type 2 diabetes (T2D) is increasing worldwide. Community pharmacies, thanks to their proximity, provide more easy access to therapeutic education for rural patients. Populations living in isolated areas require specific educational resources related to their condition. The aim of this project was to perform a short (FLASH) educational intervention, coordinated by community pharmacists, and then evaluate the impact of this intervention on patient knowledge of their disease. The study was performed in Issoudun, a rural French town of approximately 10,000 inhabitants. Educational priorities were defined and the project was presented to health authorities and local health professionals. Pharmacies in Issoudun recruited patients, either alone or accompanied by their caregivers. The educational intervention lasted 2h and focused on 4 teaching objectives: knowledge concerning diabetes, diabetic complications and how to monitor them; how to react to hypoglycemia; understanding treatments; and understanding glycated hemoglobin. The impact of this educational intervention was assessed using a questionnaire delivered before the intervention, immediately after, and after 6months. Forty-five patients aged 71±6years with T2D duration of 14±6years were recruited over 6months. Some false beliefs were identified before the intervention. The educational session led to a significant improvement in the percentage of correct answers (before: 60.3%±7.5, after: 99%±0.4, P=0.0002) and at 6months (99.5%±0.3, P=0.0002) compared with the patients' initial knowledge. Almost all false beliefs were corrected by the intervention and patients were able to recall the mechanism of action of their drugs, with the help of a "key and lock" schematic. This short FLASH educational intervention, coordinated by community pharmacists, showed that the model was both interesting to patients and effective. This method could be expanded to other rural communities and medical deserts.

Neuroprotective Effect of Polyvalent Immunoglobulins on Mouse Models of Chemotherapy-Induced Peripheral Neuropathy.

The occurrence of neuropathic pain in chemotherapy-induced peripheral neuropathy (CIPN) is a major dose-limiting effect of many commonly-used anticancer agents. Polyvalent human immunoglobulins (hIg), used in the treatment of several peripheral neuropathies, may alleviate neuropathic pain. The aim of this project was to investigate the preventive effect of hIg in two mouse models of CIPN, induced by vincristine (VCR, 100 µg/kg/d) and oxaliplatin (OXP, 6 mg/kg/3d). Human Ig were administered one day before the first injection of chemotherapy. The onset of CIPN and effects of hIg were assessed via functional tests and morphological analyses of sensory nerves. To evaluate the effect of hIg on chemotherapy cytotoxicity, viability assays were performed using hIg (0 to 12 mg/mL) combined with anticancer agents on human cancer cell lines. The preventive treatment with hIg alleviated tactile hypersensitivity and nerve injuries induced by VCR. It also alleviated tactile/cold hypersensitivities and nerve injuries induced by OXP. Treatment with hIg did not affect the cytotoxicity of either chemotherapy. Furthermore, in combination with VCR, hIg potentiated chemo-induced cell death. In conclusion, hIg is a promising therapy to prevent the onset of CIPN and potentiate chemotherapy effect on cancer, reinforcing the interest in hIg in the management of CIPN.

[TRPV1 in neuropathic pain: from animal models to therapeutical prospects]. / TRPV1 dans les neuropathies douloureuses - Des modèles animaux aux perspectives thérapeutiques.

Since its cloning in 1997, functional and structural studies of TRPV1 have led to an improvement in our understanding of the mechanisms that underlie the transduction of noxious thermal and mechanical stimuli by sensory neurons. Because of its role in inflammatory processes and nociceptive pathways, TRPV1 has become an important target for neuropathic pain relief. Models of painful small-fiber sensory neuropathy were developed and several laboratories have progressed in the conception of TRPV1 agonists and antagonists. Patch and cream containing capsaicin, the most famous TRPV1 agonist, are commercialized to relieve neuropathic pain. Others agonists and TRPV1 antagonists are tested in clinical trials and new agents, "TRPV1 modulators", with fewer side effects are currently developed in experimental studies.

Exploring Serum Biomarkers for Neuropathic Pain in Rat Models of Chemotherapy-Induced Peripheral Neuropathy: A Comparative Pilot Study with Oxaliplatin, Paclitaxel, Bortezomib, and Vincristine.

Blood biomarkers, including neurofilament light chain (NfL), have garnered attention as potential indicators for chemotherapy-induced peripheral neuropathy (CIPN), a dose-limiting adverse effect of neurotoxic anticancer drugs. However, no blood biomarker has been established for routine application or translational research. This pilot study aimed to evaluate a limited panel of blood biomarkers in rat models of CIPN and their correlations with neuropathic pain. CIPN models were induced through repeated injections of oxaliplatin, paclitaxel, bortezomib, and vincristine. Electronic von Frey testing was used to assess tactile allodynia. Post anticancer injections, serum concentrations of 31 proteins were measured. Allodynia thresholds decreased in anticancer-treated animals compared to controls. No consistent modifications were observed in the biomarkers across CIPN models. The most noteworthy biomarkers with increased concentrations in at least two CIPN models were NfL (paclitaxel, vincristine), MCP-1, and RANTES (oxaliplatin, vincristine). Vincristine-treated animals exhibited strong correlations between LIX, MCP-1, NfL, and VEGF concentrations and tactile allodynia thresholds. No single biomarker can be recommended as a unique indicator of CIPN-related pain. Because of the study limitations (single dose of each anticancer drug, young animals, and single time measurement of biomarkers), further investigations are necessary to define the kinetics, specificities, and sensitivities of MCP-1, RANTES, and NfL.

Drug repurposing: From the discovery of a useful pharmacological effect to making the treatment available to the patient.

The repurposing of a medicine already on the market to a new indication could be an opportunity to respond rapidly to a therapeutic need not yet covered, particularly in the context of rare and neglected diseases, or health emergencies. However, at each stage, difficulties may arise that will prevent the repurposed drug from being provided to patients. Beyond fortuity or a systematic strategy to detect a useful pharmacological effect, the implementation of the preclinical and clinical stages is sometimes complicated by the difficulty of accessing the molecule and its pharmaceutical data. Furthermore, relevant clinical results will not always be sufficient to ensure that a marketing authorisation is obtained or that patients receive satisfactory care. In addition to describing these various obstacles, the round table provided an opportunity to put forward recommendations for overcoming them, in particular the creation of a public-private partnership structure with sufficient funding to be able to offer individualised support for projects up to and including the marketing application.

Renin-Angiotensin-System Inhibitors for the Prevention of Chemotherapy-Induced Peripheral Neuropathy: OncoToxSRA, a Preliminary Cohort Study.

Chemotherapy-induced peripheral neuropathy (CIPN) is a frequent and dose-limiting adverse side effect of treatment. CIPN affects the oncological prognosis of patients, as well as their quality of life. To date, no specific pharmacological therapy has demonstrated effectiveness in preventing CIPN. Accumulating preclinical evidence suggests that renin-angiotensin system (RAS) inhibitors may have neuroprotective effects. One hundred and twenty patients were included in this observational study and were followed from the beginning of their neurotoxic chemotherapy schedule until their final assessment, at least one month after its cessation. The National Cancer Institute's common toxicity criteria 4.0 (NCI-CTC 4.0) were used to grade the severity of adverse events. Follow-ups also included electrochemical skin conductance and scales for pain, quality of life and disability. Among patients receiving a platinum-based regimen, the mean grade of sensory neuropathy (NCI-CTC 4.0) was significantly lower in the RAS inhibitor group after the end of their anticancer treatment schedule. Because of the observational design of the study, patients in the RAS inhibitor group cumulated comorbidities at risk of developing CIPN. Randomized controlled trials in platinum-based regimens would be worth conducting in the future to confirm the neuroprotective potential of RAS inhibitors during chemotherapy.

Neuroprotective Effect of Ramipril Is Mediated by AT2 in a Mouse MODEL of Paclitaxel-Induced Peripheral Neuropathy.

Paclitaxel (PTX)-induced peripheral neuropathy (PIPN) induces numerous symptoms affecting patient quality of life, leading to decreased doses or even to cessation of anticancer therapy. Previous studies have reported that a widely used drug, ramipril, improves neuroprotection in several rodent models of peripheral neuropathy. The protective role of the angiotensin II type 2 receptor (AT2) in the central and peripheral nervous systems is well-established. Here, we evaluate the effects of ramipril in the prevention of PIPN and the involvement of AT2 in this effect. Paclitaxel was administered in wild type or AT2-deficient mice on alternate days for 8 days, at a cumulative dose of 8 mg/kg (2 mg/kg per injection). Ramipril, PD123319 (an AT2 antagonist), or a combination of both were administered one day before PTX administration, and daily for the next twenty days. PTX-administered mice developed mechanical allodynia and showed a loss of sensory nerve fibers. Ramipril prevented the functional and morphological alterations in PTX mice. The preventive effect of ramipril against tactile allodynia was completely absent in AT2-deficient mice and was counteracted by PD123319 administration in wild type mice. Our work highlights the potential of ramipril as a novel preventive treatment for PIPN, and points to the involvement of AT2 in the neuroprotective role of ramipril in PIPN.

Alternative to animal experimentation in pharmacology teaching: Development and validation of an equivalent digital learning tool.

Regarding animal experiments in pharmacology teaching, ethical considerations led us to examine an alternative approach to the use of living animals. This study aimed to assess whether digital tools could replace live animal experiments in terms of motivation and knowledge acquisition. The study was carried out with students enrolled in the 5th year of the industry/research stream at the Faculty of Pharmacy of the University of Limoges. The participants were randomly assigned to groups of traditional or digital teaching methods, with the common theme of the class being the effect of a diuretic agent (furosemide) in rats. The scenario and learning objectives were identical for the two groups. Before the class and after randomization, the acceptance of the digital educational material was assessed with a scale, which predicts the acceptability of users according to individual dimensions and social representations, followed by the assessment of the motivation by a situational motivation scale (SIMS) for both groups. After the class, the students' motivation was assessed by a questionnaire based on Deci and Ryan's self-determination theory. In the end, the participants were evaluated for homogeneity, based on general knowledge of renal pharmacology, and for knowledge acquisition concerning specific knowledge related to this teaching session. This study revealed a good acceptance of the digital tool and a good motivation toward the digital method among all the students. It found the two teaching methods (digital and traditional) to be equivalent in terms of motivation and knowledge acquisition. In our study, digital pedagogical tools as an alternative to live animals did not affect students' motivation and knowledge acquisition.

Blockade of Cholecystokinin Type 2 Receptors Prevents the Onset of Vincristine-Induced Neuropathy in Mice.

Vincristine (VCR) is responsible for the onset of the VCR-induced peripheral neuropathy (VIPN), associated with neuropathic pain. Several reports have strongly linked the cholecystokinin type 2 receptor (CCK2R) to nociceptive modulation. Thus, our aim was to evaluate the effect of CCK2R blockade on the onset of VIPN, as well as its interaction on VCR anticancer efficacy. VCR was administrated in mice for 8 days (100 µg/kg/d, i.p.). Transcriptomic analysis of the dorsal root ganglia (DRG) was performed at day 7 in VCR and control mice. Proglumide (30 mg/kg/d), a CCK1R and CCK2R antagonist, and Ly225910 (1 mg/kg/d), a selective CCK2R antagonist, were administrated one day before and during VCR treatment. Tactile sensitivity was assessed during treatments. Immunofluorescence and morphological analyses were performed on the skin, DRG and sciatic nerve at day 7. The cytotoxicity of VCR in combination with proglumide/Ly225910 was evaluated in human cancer cell lines. Cck2r was highly upregulated in the DRG of VCR mice. Proglumide accelerated the recovery of normal sensitivity, while Ly225910 totally prevented the onset of allodynia and nerve injuries induced by VCR. Proglumide or Ly225910 in combination with VCR did not affect the cytotoxicity of VCR. Targeting CCK2R could therefore be an effective strategy to prevent the onset of VIPN.

Low-magnitude whole body vibration with resistive exercise as a countermeasure against cardiovascular deconditioning after 60 days of head-down bed rest.

Whole body vibration with resistive exercise is a promising countermeasure against some weightlessness-induced dysfunctions. Our objective was to study whether the combination of low-magnitude whole body vibration with a resistive exercise can prevent the cardiovascular deconditioning induced by a nonstrict 60-day head-down bed rest (Earth Star International Bed Rest Experiment Project). Fourteen healthy men participated in this study. We recorded electrocardiograms and blood pressure waves by means of a noninvasive beat-by-beat measurement system (Cardiospace, integrated by Centre National d'Etudes Spatiales and Astronaut Center of China) during an orthostatic test (20 min of 75-degree head-up tilt test) before and immediately after bed rest. We estimated heart rate, blood pressure, cardiac output, stroke volume, total peripheral resistance, baroreflex sensitivity, and heart rate variability. Low-magnitude whole body vibration with resistive exercise prevented an increase of the sympathetic index (reflecting the sympathovagal balance of cardiac autonomic control) and limited the decrease of the spontaneous baroreflex sensitivity induced by 60 days of head-down bed rest. However, this countermeasure had very little effect on cardiac hemodynamics and did not improve the orthostatic tolerance. This combined countermeasure did not efficiently prevent orthostatic intolerance but prevents changes in the autonomic nervous system associated with cardiovascular deconditioning. The underlying mechanisms remain hypothetical but might involve cutaneous and muscular mechanoreceptors.

An overview of ongoing clinical trials assessing pharmacological therapeutic strategies to manage chemotherapy-induced peripheral neuropathy, based on preclinical studies in rodent models.

Chemotherapy-induced peripheral neuropathy (CIPN) is a major dose-limiting side effect induced by a variety of chemotherapeutic agents. Symptoms are mainly sensory: pain, tingling, numbness, and temperature sensitivity. They may require the tapering of chemotherapy regimens or even their cessation; thus, the prevention/treatment of CIPN is critical to increase effectiveness of cancer treatment. However, CIPN management is mainly based on conventional neuropathic pain treatments, with poor clinical efficacy. Therefore, significant effort is made to identify new pharmacological targets to prevent/treat CIPN. Animal modeling is a key component in predicting human response to drugs and in understanding the pathophysiological mechanisms underlying CIPN. In fact, studies performed in rodents highlighted several pharmacological targets to treat/prevent CIPN. This review provides updated information about ongoing clinical trials testing drugs for the management of CIPN and presents some of their proof-of-concept studies conducted in rodent models. The presented drugs target oxidative stress, renin-angiotensin system, glutamatergic neurotransmission, sphingolipid metabolism, neuronal uptake transporters, nicotinamide adenine dinucleotide metabolism, endocannabinoid system, transient receptor potential channels, and serotoninergic receptors. As some clinical trials focus on the effect of the drugs on pain, others evaluate their efficacy by assessing general neuropathy. Moreover, based on studies conducted in rodent models, it remains unclear if some of the tested drugs act in an antinociceptive fashion or have neuroprotective properties. Thus, further investigations are needed to understand their mechanism of action, as well as a global standardization of the methods used to assess efficacy of new therapeutic strategies in the treatment of CIPN.

The Cholecystokinin Type 2 Receptor, a Pharmacological Target for Pain Management.

Over the past decades, accumulating evidence has demonstrated a pivotal role of cholecystokinin type 2 receptor (CCK2R) in pain modulation. The established role of CCK2R activation in directly facilitating nociception has led to the development of several CCK2R antagonists, which have been shown to successfully alleviate pain in several rodent models of pain. However, the outcomes of clinical trials are more modest since they have not demonstrated the expected biological effect obtained in animals. Such discordances of results between preclinical and clinical studies suggest reconsidering our knowledge about the molecular basis of the pharmacology and functioning of CCK2R. This review focuses on the cellular localization of CCK2R specifically in the sensory nervous system and discusses in further detail the molecular mechanisms and signal transduction pathways involved in controlling pain perception. We then provide a comprehensive overview of the most successful compounds targeting CCK2R and report recent advances in pharmacological strategies used to achieve CCK2R modulation. We purposely distinguish between CCK2R benefits obtained in preclinical models and outcomes in clinical trials with different pain etiologies. Lastly, we emphasize the biological and clinical relevance of CCK2R as a promising target for the development of new treatments for pain management.

Ramipril Alleviates Oxaliplatin-Induced Acute Pain Syndrome in Mice.

Oxaliplatin is a key drug for colorectal cancer that causes OXP-induced peripheral neuropathy, a dose-limiting effect characterized by cold and tactile hyperesthesia. The relationship between the sensory nervous system and modulation of the renin-angiotensin system has been described, focusing on pain and neurodegeneration in several animal models. We assessed the effect of the RAS modulator, ramipril, an angiotensin converting-enzyme inhibitor in a mouse model of OXP-induced acute pain syndrome. OXP was administered in Swiss mice at a cumulative dose of 15 mg/kg (3 x 5 mg/kg/3 days, i.p.). RAM was administered i.p. every day from 24 h before the first OXP injection until the end of the experiments. We evaluated OIAS development and treatment effects by sensorimotor tests, intraepidermal nerve fiber and dorsal root ganglia-neuron immunohistochemical analyses, and sciatic nerve ultrastructural analysis. OXP-treated mice showed tactile allodynia and cold hypersensitivity, without motor impairment and evidence of nerve degeneration. RAM prevented cold sensitivity and improved recovery of normal tactile sensitivity in OXP-treated mice. Our finding that RAM alleviates OXP-induced pain is a step towards evaluating its therapeutic potential in patients receiving OXP treatment.

The Angiotensin II Type 2 Receptor, a Target for Protection and Regeneration of the Peripheral Nervous System?

Preclinical evidence, accumulated over the past decade, indicates that the angiotensin II type 2 receptor (AT2R) stimulation exerts significant neuroprotective effects in various animal models of neuronal injury, notably in the central nervous system. While the atypical G protein-coupled receptor superfamily nature of AT2R and its related signaling are still under investigation, pharmacological studies have shown that stimulation of AT2R leads to neuritogenesis in vitro and in vivo. In this review, we focus on the potential neuroprotective and neuroregenerative roles of AT2R specifically in the peripheral nervous system (PNS). The first section describes the evidence for AT2R expression in the PNS and highlights current controversies concerning the cellular distribution of the receptor. The second section focuses on AT2R signaling implicated in neuronal survival and in neurite outgrowth. The following sections review the relatively few preclinical studies highlighting the putative neuroprotective and neuroregenerative effects of AT2R stimulation in the context of peripheral neuropathy.

Enforced physical inactivity increases endothelial microparticle levels in healthy volunteers.

A sedentary lifestyle has adverse effects on the cardiovascular system, including impaired endothelial functions. Subjecting healthy men to 7 days of dry immersion (DI) presented a unique opportunity to analyze the specific effects of enhanced inactivity on the endothelium. We investigated endothelial properties before, during, and after 7 days of DI involving eight subjects. Microcirculatory functions were assessed with laser Doppler in the skin of the calf. We studied basal blood flow and endothelium-dependent and -independent vasodilation. We also measured plasma levels of microparticles, a sign of cellular dysfunction, and soluble endothelial factors, reflecting the endothelial state. Basal flow and endothelium-dependent vasodilation were reduced by DI (22 + or - 4 vs. 15 + or - 2 arbitrary units and 29 + or - 6% vs. 12 + or - 6%, respectively, P < 0.05), and this was accompanied by an increase in circulating endothelial microparticles (EMPs), which was significant on day 3 (42 + or - 8 vs. 65 + or - 10 EMPs/microl, P < 0.05), whereas microparticles from other cell origins remained unchanged. Plasma soluble VEGF decreased significantly during DI, whereas VEGF receptor 1 and soluble CD62E were unchanged, indicating that the increase in EMPs was associated with a change in antiapoptotic tone rather than endothelial activation. Our study showed that extreme physical inactivity in humans induced by 7 days of DI causes microvascular impairment with a disturbance of endothelial functions, associated with a selective increase in EMPs. Microcirculatory endothelial dysfunction might contribute to cardiovascular deconditioning as well as to hypodynamia-associated pathologies. In conclusion, the endothelium should be the focus of special care in situations of acute limitation of physical activity.

Skin and Nerve Neovascularization in POEMS Syndrome: Insights From a Small Cohort.

Polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, skin changes (POEMS) syndrome is a rare systemic disorder linked to plasma cell dyscrasia and is related to elevation of vascular endothelial growth factor (VEGF). Diagnosis is still challenging and pathophysiology unclear. Because VEGF drives neovascularization, we investigated skin and nerve vascularization in 6 patients with POEMS syndrome compared with 5 control groups of polyneuropathies and healthy subjects (n = 104) from the University Hospital of Limoges between 2009 and 2018. We evaluated loss of small and large fibers in these patients. Skin and nerve vascularization were quantified manually on immunofluorescence using vessel staining (anti-α-SMA antibody). Dermal vascularization was significantly higher in POEMS syndrome than in other groups, but unrelated to loss of small fibers and VEGF. Perineurial vascularization was higher in POEMS syndrome than in healthy controls, and was related to loss of large fibers and VEGF level. Our study highlights the existence of neovascularization in skin of patients with this rare disorder. These data suggest that skin neovascularization could be an additional biomarker to help in the diagnosis and understanding of POEMS syndrome. Moreover, nerve neovascularization, driven by VEGF overexpression, may play a role in the pathophysiology of large fiber loss in this condition.