Impact of homeostatic body hydration status, evaluated by hemodynamic measures, on different pain sensitization paths to a chronic pain syndrome.

Contrasting findings on the mechanisms of chronic pain and hypertension development render the current conventional evidence of a negative relationship between blood pressure (BP) and pain severity insufficient for developing personalized treatments. In this interdisciplinary study, patients with fibromyalgia (FM) exhibiting clinically normal or elevated BP, alongside healthy participants were assessed. Different pain sensitization responses were evaluated using a dynamic 'slowly repeated evoked pain' (SREP) measure, as well as static pain pressure threshold and tolerance measures. Cardiovascular responses to clino-orthostatic (lying-standing) challenges were also examined as acute re- and de-hydration events, challenging cardiovascular and cerebrovascular homeostasis. These challenges involve compensating effects from various cardiac preload or afterload mechanisms associated with different homeostatic body hydration statuses. Additionally, hair cortisol concentration was considered as a factor with an impact on chronic hydration statuses. Pain windup (SREP) and lower pain threshold in FM patients were found to be related to BP rise during clinostatic (lying) rehydration or orthostatic (standing) dehydration events, respectively. These events were determined by acute systemic vasoconstriction (i.e., cardiac afterload response) overcompensating for clinostatic or orthostatic cardiac preload under-responses (low cardiac output or stroke volume). Lower pain tolerance was associated with tonic blood pressure reduction, determined by permanent hypovolemia (low stroke volume) decompensated by permanent systemic vasodilation. In conclusion, the body hydration status profiles assessed by (re)activity of systemic vascular resistance and effective blood volume-related measures can help predict the risk and intensity of different pain sensitization components in chronic pain syndrome, facilitating a more personalized management approach.

The Role of Depressive Disorders in Autonomic Cardiovascular Dysregulation in Fibromyalgia.

OBJECTIVE: Previous research revealed aberrances in autonomic cardiovascular regulation in fibromyalgia, which may be relevant to symptoms genesis and the increased risk of cardiovascular disorders in individuals with fibromyalgia. This study investigated the role of comorbid depression in autonomic cardiovascular dysregulations in fibromyalgia. METHODS: Cardiovascular recordings were obtained in 53 participants with fibromyalgia who also had depression ( n = 27), in participants with fibromyalgia without depression ( n = 26), and in 29 healthy controls, at rest and during a cold pressor test and an arithmetic task. Assessed parameters included interbeat interval, blood pressure, heart rate variability, baroreflex sensitivity, stroke volume, preejection period, left ventricular ejection time, Heather index, and total peripheral resistance. RESULTS: Participants with both fibromyalgia and depression displayed lower tonic interbeat interval, baroreflex sensitivity, and heart rate variability compared with participants with fibromyalgia without depression and controls ( p values < .012, d values = 0.71-1.06). Participants with fibromyalgia but without depression did not differ from controls in these variables. Moreover, participants with fibromyalgia who also had depression, but not those without depression, exhibited lower Heather index, stroke volume, and left ventricular ejection time compared with controls ( p values < .013, d values = 0.62-0.78). No group differences arose for preejection period or total peripheral resistance. Stress reactivity was reduced in participants with fibromyalgia, independently of depression, for diastolic blood pressure, interbeat interval, left ventricular ejection time, and heart rate variability, than in controls. CONCLUSIONS: The role of depression in the autonomic dysregulation in fibromyalgia involves chronotropic cardiac control rather than adrenergic influences on contractility and vascular tone. Blunted cardiovascular reactivity may be ascribable to pathological factors inherent to fibromyalgia. These results underline the importance of diagnostics and treatment of comorbid depressive disorders in the management of fibromyalgia.

Blunted short-term autonomic cardiovascular reactivity to orthostatic and clinostatic challenges in fibromyalgia as an indicator of the severity of chronic pain.

Fibromyalgia is a long-term pain disorder that has been related to autonomic dysfunctions and reduced cardiovascular reactivity. We aimed to assess the dynamic short-term cardiovascular responses to postural changes in fibromyalgia. Thirty-eight women with fibromyalgia and thirty-six healthy women underwent the "Chronic Pain Autonomic Stress Test". Electrocardiogram, blood pressure and impedance cardiography were continuously recorded during active standing and lying down. Second-by-second values were derived over the first 30 s of each posture. Lower reactivity during the beginning of each position was observed in fibromyalgia sufferers compared to healthy women, with smaller responses seen during stand up in heart rate, blood pressure, cardiac output, total peripheral resistance, and pre-ejection period, and smaller changes during lying down in heart rate, cardiac output and total peripheral resistance. The magnitude of the autonomic adjustments to postural changes was inversely associated with the severity of clinical pain. These findings indicate an early impaired autonomic cardiovascular response to orthostatic and clinostatic challenges in fibromyalgia, suggesting less autonomic flexibility and adaptability to situational demands and challenges. Short-term second-by-second cardiovascular measures may be useful in the clinical assessment of fibromyalgia.

The cardiac, vasomotor, and myocardial branches of the baroreflex in fibromyalgia: Associations with pain, affective impairments, sleep problems, and fatigue.

This study investigated the cardiac, vasomotor, and myocardial branches of the baroreflex in fibromyalgia using the spontaneous sequence method. Systolic blood pressure (SBP), interbeat interval (IBI), stroke volume (SV), pre-ejection period (PEP), and total peripheral resistance (TPR) were continuously recorded in 40 fibromyalgia patients and 30 healthy individuals during a cold pressor test and a mental arithmetic task. Sequences of covariation between SBP and IBI (cardiac branch), SV and PEP (myocardial branch), and TPR (vasomotor branch) were identified. Baroreflex sensitivity (BRS) was represented by the slope of the regression line between values in the sequences; baroreflex effectiveness (BEI) was indexed by the proportion of progressive SBP changes that elicited reflex responses. Patients exhibited lower BRS in the three branches, lower BEI in the cardiac and vasomotor branches, and reduced reactivity in cardiac BRS and BEI, SBP, IBI, SV, and PEP. Moreover, BRS and BEI were inversely related to clinical pain, cold pressor pain, depression, trait anxiety, sleep problems, and fatigue. Reduced function of the three baroreflex branches implies diminished resources for autonomic inotropic, chronotropic, and vascular regulation in fibromyalgia. Blunted stress reactivity indicates a limited capacity for autonomic cardiovascular adjustment to situational requirements. The associations of BRS and BEI with pain perception may reflect the antinociceptive effects arising from baroreceptor afferents, where reduced baroreflex function may contribute to the hyperalgesia characterizing fibromyalgia. The associations with affective impairments, sleep problems, and fatigue suggest that baroreflex dysfunctions are also involved in the secondary symptoms of the disorder.

El trabajo en una planta de hospitalización / Work at a Hopital Ward

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Cytokine treatment optimises the immunotherapeutic effects of umbilical cord-derived MSC for treatment of inflammatory liver disease.

BACKGROUND: Mesenchymal stromal cells (MSC) possess immunomodulatory properties and low immunogenicity, both crucial properties for their development into an effective cellular immunotherapy. They have shown benefit in clinical trials targeting liver diseases; however the efficacy of MSC therapy will benefit from improvement of the immunomodulatory and immunogenic properties of MSC. METHODS: MSC derived from human umbilical cords (ucMSC) were treated for 3 days in vitro with various inflammatory factors, interleukins, vitamins and serum deprivation. Their immunogenicity and immunomodulatory capacity were examined by gene-expression analysis, surface-marker expressions, IDO activity, PGE2 secretion and inhibition of T cell proliferation and IFNγ production. Furthermore, their activation of NK cell cytotoxicity was investigated via CD107a expression on NK cells. The immunomodulatory capacity, biodistribution and survival of pre-treated ucMSC were investigated in a CCl4-induced liver disease mouse model. In addition, capacity of pre-treated MSC to ameliorate liver inflammation was examined in an ex vivo liver inflammation co-culture model. RESULTS: IFN-γ and a multiple cytokine cocktail (MC) consisting of IFN-γ, TGFß and retinoic acid upregulated the expression of immunomodulatory factor PD-L1 and IDO activity. Subsequently, both treatments enhanced the capacity of ucMSC to inhibit CD4 and CD8 T cell proliferation and IFN-γ production. The susceptibility of ucMSC for NK cell lysis was decreased by IFN-ß, TGFß and MC treatment. In vivo, no immunomodulation was observed by the ucMSC. Four hours after intravenous infusion in mice with CCl4-induced inflammatory liver injury, the majority of ucMSC were trapped in the lungs. Rapid clearance of ucMSC(VitB6), ucMSC(Starv + VitB6) and ucMSC(MC) and altered bio-distribution of ucMSC(TGFß) compared to untreated ucMSC was observed. In the ex vivo co-culture system with inflammatory liver slices ucMSC(MC) showed significantly enhanced modulatory capacity compared to untreated ucMSC. CONCLUSIONS: The present study demonstrates the responsiveness of ucMSC to in vitro optimisation treatment. The observed improvements in immunomodulatory capacity as well as immunogenicity after MC treatment may improve the efficacy of ucMSC as immunotherapy targeted towards liver inflammation.

Obstructive sleep apnoea syndrome, endothelial function and markers of endothelialization. Changes after CPAP.

STUDY OBJECTIVES: This study tries to assess the endothelial function in vivo using flow-mediated dilatation (FMD) and several biomarkers of endothelium formation/restoration and damage in patients with obstructive sleep apnoea (OSA) syndrome at baseline and after three months with CPAP therapy. DESIGN: Observational study, before and after CPAP therapy. SETTING AND PATIENTS: We studied 30 patients with apnoea/hypopnoea index (AHI) >15/h that were compared with themselves after three months of CPAP therapy. FMD was assessed non-invasively in vivo using the Laser-Doppler flowmetry. Circulating cell-free DNA (cf-DNA) and microparticles (MPs) were measured as markers of endothelial damage and the vascular endothelial growth factor (VEGF) was determined as a marker of endothelial restoration process. MEASUREMENTS AND RESULTS: After three month with CPAP, FMD significantly increased (1072.26 ± 483.21 vs. 1604.38 ± 915.69 PU, p< 0.005) cf-DNA and MPs significantly decreased (187.93 ± 115.81 vs. 121.28 ± 78.98 pg/ml, p<0.01, and 69.60 ± 62.60 vs. 39.82 ± 22.14 U/µL, p<0.05, respectively) and VEGF levels increased (585.02 ± 246.06 vs. 641.11 ± 212.69 pg/ml, p<0.05). These changes were higher in patients with more severe disease. There was a relationship between markers of damage (r = -0.53, p<0.005) but not between markers of damage and restoration, thus suggesting that both types of markers should be measured together. CONCLUSIONS: CPAP therapy improves FMD. This improvement may be related to an increase of endothelial restoration process and a decrease of endothelial damage.