Jairo Alberto Dussán-Sarria

Higher serum S100B and BDNF levels are correlated with a lower pressure-pain threshold in fibromyalgia

BackgroundFibromyalgia (FM) is conceptualized as a central sensitization (CS) condition, that presents high serum brain-derived neurotrophic factor (BDNF) and neuroglia activation. Although the S100B protein regulates neuroglia functions, it has been traditionally used as a proxy of central nervous system damage. However, neither BDNF nor S100B association with the clinical picture of FM has been elucidated. To explore their association with the pressure-pain threshold (PPT) in FM, we performed a cross-sectional study, including 56 females with confirmed FM aged 18–65 years. Linear regression models were used to adjust for potential confounding factors between serum BDNF, S100B and PPT.ResultsSerum BDNF and S100B were correlated (Spearman’s Rho = 0.29). Serum BDNF (log) and S100B (log) were correlated with the PPT (log) (Partial η2 = 0.129, P = 0.012 for the BDNF (log), and Partial η2 = 0.105, P = 0.025 for the S100B (log)). Serum BDNF (log) was inversely associated with PPT (log) (β = -1.01, SE = 0.41), age (β = -0.02, SE = 0.15) and obsessive compulsive disorder (β = -0.36, SE = 0.15), while serum S100B (log) was inversely associated with PPT (log) (β = -1.38, SE = 0.50), only.ConclusionsBoth neuroglia key mediators in the CS process were inversely correlated with the PPT. Serum assessment of BDNF and S100B deserve further study to determine its potential as a proxy for the CS spectrum in FM.

Neuroplastic Effects of Transcranial Direct Current Stimulation on Painful Symptoms Reduction in Chronic Hepatitis C: A Phase II Randomized, Double Blind, Sham Controlled Trial

Introduction: Pegylated Interferon Alpha (Peg-IFN) in combination with other drugs is the standard treatment for chronic hepatitis C infection (HCV) and is related to severe painful symptoms. The aim of this study was access the efficacy of transcranial direct current stimulation (tDCS) in controlling the painful symptoms related to Peg-IFN side effects. Materials and Methods: In this phase II double-blind trial, twenty eight (n = 28) HCV subjects were randomized to receive either 5 consecutive days of active tDCS (n = 14) or sham (n = 14) during 5 consecutive days with anodal stimulation over the primary motor cortex region using 2 mA for 20 min. The primary outcomes were visual analogue scale (VAS) pain and brain-derived neurotrophic factor (BDNF) serum levels. Secondary outcomes were the pressure-pain threshold (PPT), the Brazilian Profile of Chronic Pain: Screen (B-PCP:S), and drug analgesics use. Results: tDCS reduced the VAS scores (P < 0.003), with a mean pain drop of 56% (p < 0.001). Furthermore, tDCS was able to enhance BDNF levels (p < 0.01). The mean increase was 37.48% in the active group. Finally, tDCS raised PPT (p < 0.001) and reduced the B-PCP:S scores and analgesic use (p < 0.05). Conclusions: Five sessions of tDCS were effective in reducing the painful symptoms in HCV patients undergoing Peg-IFN treatment. These findings support the efficacy of tDCS as a promising therapeutic tool to improve the tolerance of the side effects related to the use of Peg-IFN. Future larger studies (phase III and IV trials) are needed to confirm the clinical use of the therapeutic effects of tDCS in such condition. Trial registration: Brazilian Human Health Regulator for Research with the approval number CAAE 07802012.0.0000.5327.

Motor Cortex Excitability and BDNF Levels in Chronic Musculoskeletal Pain According to Structural Pathology.

The central sensitization syndrome (CSS) encompasses disorders with overlapping symptoms in a structural pathology spectrum ranging from persistent nociception [e.g., osteoarthritis (OA)] to an absence of tissue injuries such as the one presented in fibromyalgia (FM) and myofascial pain syndrome (MPS). First, we hypothesized that these syndromes present differences in their cortical excitability parameters assessed by transcranial magnetic stimulation (TMS), namely motor evoked potential (MEP), cortical silent period (CSP), short intracortical inhibition (SICI) and short intracortical facilitation (SICF). Second, considering that the presence of tissue injury could be detected by serum neurotrophins, we hypothesized that the spectrum of structural pathology (i.e., from persistent nociception like in OA, to the absence of tissue injury like in FM and MPS), could be detected by differential efficiency of their descending pain inhibitory system, as assessed by the conditioned pain modulation (CPM) paradigm. Third, we explored whether brain-derived neurotrophic factor (BDNF) had an influence on the relationship between motor cortex excitability and structural pathology. This cross-sectional study pooled baseline data from three randomized clinical trials. We included females (n = 114), aged 19–65 years old with disability by chronic pain syndromes (CPS): FM (n = 19), MPS (n = 54), OA (n = 27) and healthy subjects (n = 14). We assessed the serum BDNF, the motor cortex excitability by parameters the TMS measures and the change on numerical pain scale [NPS (0–10)] during CPM-task. The adjusted mean (SD) on the SICI observed in the absence of tissue injury was 56.36% lower than with persistent nociceptive input [0.31(0.18) vs. 0.55 (0.32)], respectively. The BDNF was inversely correlated with the SICI and with the change on NPS (0–10)during CPM-task. These findings suggest greater disinhibition in the motor cortex and the descending pain inhibitory system in FM and MPS than in OA and healthy subjects. Likewise, the inter-hemispheric disinhibition as well as the dysfunction in the descending pain modulatory system is higher in chronic pain without tissue injury compared to a structural lesion. In addition, they suggest that a greater level of serum BDNF may be involved in the processes that mediate the disinhibition of motor cortex excitability, as well as the function of descending inhibitory pain modulation system, independently of the physiopathology mechanism of musculoskeletal pain syndromes.

Repetitive Transcranial Magnetic Stimulation for Fibromyalgia: Systematic Review and Meta‐Analysis

Fibromyalgia (FM) is a prevalent chronic pain syndrome with few effective therapeutic options available. Repetitive transcranial magnetic stimulation (rTMS) is an emerging therapeutic alternative for this condition; however, results have been mixed.

Clinical Value of Serum Neuroplasticity Mediators in Identifying the Central Sensitivity Syndrome in Patients With Chronic Pain With and Without Structural Pathology.

Background and Objectives:Central sensitivity syndrome (CSS) encompasses disorders with overlapping symptoms in a spectrum of structural pathology from persistent somatic nociception (eg, osteoarthritis) to absence of tissue injury such as in fibromyalgia, chronic tension-type headache, and myofascial pain syndrome. Likewise, the spectrum of the neuroplasticity mediators associated with CSS might present a pattern of clinical utility. Methods:We studied the brain-derived neurotrophic factor (BDNF), tumor necrosis factor-&agr; (TNF-&agr;), and interleukins 6 (IL-6) and IL-10 in female patients with CSS absent of structural pathology (chronic tension-type headache [n=30], myofascial pain syndrome [n=29], fibromyalgia [n=22]); with CSS due to persistent somatic/visceral nociception (osteoarthritis [n=27] and endometriosis [n=32]); and in pain-free controls (n=37). Results:Patients with CSS absent of structural pathology presented higher serum TNF-&agr; (28.61±12.74 pg/mL) and BDNF (49.87±31.86 ng/mL) than those with persistent somatic/visceral nociception (TNF-&agr;=17.35±7.38 pg/mL; BDNF=20.44±8.30 ng/mL) and controls (TNF-&agr;=21.41±5.74 pg/mL, BDNF=14.09±11.80 ng/mL). Moreover, CSS patients absent of structural pathology presented lower IL levels. Receiver operator characteristics analysis showed the ability of BDNF to screen CSS (irrespective of the presence of structural pathology) from controls (cutoff=13.31 ng/mL, area under the curve [AUC]=0.86, sensitivity=95.06%, specificity=56.76%); and its ability to identify persistent nociception in CSS patients when experiencing moderate-severe depressive symptoms (AUC=0.81; cutoff=42.83 ng/mL, sensitivity=56.80%, specificity=100%). When the level of pain measured on the visual analog scale was <5 and moderate-severe depressive symptoms were observed TNF-&agr; discriminated structural pathology in the chronic pain conditions (AUC=0.97; cutoff=22.11 pg/mL, sensitivity=90%, specificity=91.3%). Conclusion:Neuroplasticity mediators could play a role as screening tools for pain clinicians, and as validation of the complex and diffuse symptoms of these patients.

Neonatal hypoxic-ischemic encephalopathy reduces c-Fos activation in the rat hippocampus: evidence of a long-lasting effect.

The effect of neonatal hypoxic–ischemic encephalopathy (HIE) on maturation of nociceptive pathways has been sparsely explored. To investigate whether neonatal HIE alters neuronal activity, nociceptive behavior, and serum neuroplasticity mediators (brain‐derived neurotrophic factor [BDNF] and tumor necrosis factor‐α [TNF]) in the short, medium, and long term. Neonate male Wistar rats were randomized to receive a brain insult that could be either ischemic (left carotid artery ligation [LCAL]), hypoxic (8% oxygen chamber), hypoxic–ischemic (LCAL and hypoxic chamber), sham‐ischemic, or sham‐hypoxic. Neuronal activity (c‐Fos activation at region CA1 and dentate gyrus of the hippocampus), nociceptive behavior (von Frey, tail‐flick, and hot‐plate tests), neuroplasticity mediators (BDNF, TNF), and a cellular injury marker (lactase dehydrogenase [LDH]) were assessed in blood serum 14, 30, and 60 days after birth. Neonatal HIE persistently reduced c‐Fos activation in the ipsilateral hippocampal region CA1; however, contralateral c‐Fos reduction appeared only 7 weeks after the event. Neonatal HIE acutely reduced the paw withdrawal threshold (von Frey test), but this returned to normal by the 30th postnatal day. Hypoxia reduced serum LDH levels. Serum neuroplasticity mediators increased with age, and neonatal HIE did not affect their ontogeny. Neonatal HIE‐induced reduction in neuronal activity occurs acutely in the ipsilateral hippocampal region CA1 and persists for at least 60 days, but the contralateral effect of the insult is delayed. Alterations in the nociceptive response are acute and self‐limited. Serum neuroplasticity mediators increase with age, and remain unaffected by HIE.

Preditores de mortalidade intra‐hospitalar em pacientes submetidos a cirurgias não eletivas em um hospital universitário: uma coorte prospectiva

INTRODUCTION Morbidity and mortality associated with urgent or emergency surgeries are high compared to elective procedures. Perioperative risk scores identify the non-elective character as an independent factor of complications and death. The present study aims to characterize the population undergoing non-elective surgeries at the Hospital de Clínicas de Porto Alegre and identify the clinical and surgical factors associated with death within 30 days postoperatively. METHODOLOGY A prospective cohort study of 187 patients undergoing elective surgeries between April and May 2014 at the Hospital de Clínicas, Porto Alegre. Patient-related data, pre-operative risk situations, and surgical information were evaluated. Death in 30 days was the primary outcome measured. RESULTS The mean age of the sample was 48.5 years, and 84.4% of the subjects had comorbidities. The primary endpoint was observed in 14.4% of the cases, with exploratory laparotomy being the procedure with the highest mortality (47.7%). After multivariate logistic regression, age (odds ratio [OR] 1.0360, p <0.05), anemia (OR 3.961, p <0.05), acute or chronic renal insufficiency (OR 6.075, p <0.05), sepsis (OR 7.027, p <0.05), and patient-related risk factors for mortality, in addition to the large surgery category (OR 7.502, p <0.05) were identified. CONCLUSION The high mortality rate found may reflect the high complexity of the institutions patients. Knowing the profile of the patients assisted helps in the definition of management priorities, suggesting the need to create specific care lines for groups identified as high risk in order to reduce perioperative complications and deaths.

Higher Cortical Facilitation and Serum BDNF Are Associated with Increased Sensitivity to Heat Pain and Reduced Endogenous Pain Inhibition in Healthy Males

Background Although the brain-derived neurotrophic factor (BDNF) has been intensively investigated in animal models of chronic pain, its role in human pain processing is less understood. Objective To study the neurophysiology of BDNF modulation on acute experimental pain, we performed a cross-sectional study. Methods We recruited 20 healthy male volunteers (19-40 years old) and assessed their serum BDNF levels, quantitative sensory testing, and cortical excitability parameters using transcranial magnetic stimulation. Results Linear regression models demonstrated that the BDNF (β = -5.245, P = 0.034) and intracortical facilitation (β = -3.311, P = 0.034) were inversely correlated with heat pain threshold (adjusted R2 = 44.26). The BDNF (β = -3.719, P ≤ 0.001) was also inversely correlated with conditioned pain modulation (adjusted R2 = 56.8). Conclusions Our findings indicate that higher serum BDNF and intracortical facilitation of the primary motor cortex are associated with increased sensitivity to heat pain and high serum BDNF with reduced pain inhibition during noxious heterotopic stimulation.

Comparison of pain burden and psychological factors in Brazilian women living with HIV and chronic neuropathic or nociceptive pain: An exploratory study

Psychological factors including pain catastrophizing and resilience associate with adjustment and quality of life in people living with chronic pain. Nevertheless, their presentation among females living with HIV and chronic pain has been poorly studied. Given that chronic pain in those living with HIV might occur due to different mechanisms (nociceptive or neuropathic), we hypothesize that the associated psychological states could also differ between these groups. We aimed to compare pain frequency and interference, psychological factors and sleep quality between females living with chronic nociceptive or neuropathic pain. Also, we explored correlations between psychological factors, pain severity and interference in females living with HIV and chronic pain. We performed a cross sectional study assessing females living with HIV and chronic pain, and compared it with a female HIV-positive, pain-free control sample in Brazil. To discriminate the most likely underlying mechanism for the chronic pain, we applied the Leeds Assessment for Neuropathic Signs and Symptoms (LANSS). Forty-nine females living with HIV and chronic pain were assessed, and divided in control (n = 12), nociceptive (n = 10) and neuropathic pain (n = 27) groups. Using validated scales, their pain catastrophizing, resilience, depression, anxiety and sleep disorders were assessed between May 2014 and August 2015. Compared to controls, females living with HIV and neuropathic chronic pain had higher pain frequency (p<0.001), interference on activities (p = 0.002), interference with emotions (p<0.001), catastrophizing (p<0.001), depression (p = 0.015), and lower resilience (p = 0.011). Catastrophizing was also significantly correlated to the burden of chronic pain. The type of chronic pain in females living with HIV should raise concerns regarding significant burden in psychological states in this population (particularly neuropathic pain). Using scales such as the LANSS to identify the type of choric pain, could be of use to address relevant issues for the patients, and to propose tailored therapies.

Caffeine teratogenicity in rats: morphological characterization and hypothesized mechanisms

Caffeine consumption during pregnancy has been shown in the scientific literature to be associated with teratogenicity such as low birth weight, fetal malformations, and miscarriage. However, the morphological alterations of the offspring of dams exposed during pregnancy have not been consistently described, and the mechanisms why they occur remain elusive. Thus, we aimed to characterize the offspring malformations induced by moderate and high doses of caffeine during pregnancy. Dams were divided into three groups: control, moderate (0.3 g/L), and high dose (1.0 g/L) of caffeine, which was provided in the drinking water beginning on gestational day 1 and continuing throughout the entire gestation. At moderate doses, only one of the dams had stillborn pups, although no macroscopic malformations were observed. High doses of caffeine induced significantly more malformations ( P <0.001) and early death (before P4). The malformations observed were related to fetal development and cardiovascular alterations, namely bruises, macrocephaly with short limbs, abnormal development (or absence) of head structures and limbs, labial malformations, hydrops fetalis, and poor placental formation. We discussed the proposed mechanisms by which caffeine might induce these phenotypes, which may involve down-regulation of adenosine A1 receptors, and increased mothers’ catecholamines. Our findings further confirm the evidence of the teratogenic effects of high doses of caffeine administered during pregnancy. These findings support the recommendation to avoid caffeine exposure during pregnancy. Keywords: Caffeine; offspring; teratogenicity; pregnancy; hydrops; cardiovascular alterations