Severity of intervertebral disc herniation regulates cytokine and chemokine levels in patients with chronic radicular back pain.

OBJECTIVE: The contributions of intervertebral disc disease and subject-specific covariates to systemic inflammation in low back pain are unknown. We examined the effects of symptomatic disc herniation (DH) and MRI herniation severity on serum cytokine levels in clinical subjects. DESIGN: Cytokine levels from lumbar DH subjects (N = 78) were compared to control subjects (N = 57) accounting for effects of DH, age, body mass index (BMI) and gender. Effect of DH severity on cytokine levels was analyzed on subsets of subjects with acute or chronic pain. Serum cytokines were also analyzed in a subset of patients between pre- and 3 months post-surgery. RESULTS: Cytokine levels were elevated in the serum of patients with symptomatic DH, and the covariates age, BMI and gender significantly contributed to levels of some cytokines. Severity of herniation was a significant contributor to pain intensity (VAS), serum levels of HMGB1, PDGFbb, and IL-9. The relationship between DH severity and cytokine levels was confirmed in subjects with chronic, but not acute symptoms. Serum levels of macrophage migration inhibitory factor (MIF) decreased, whereas levels of CCL3, CCL11, CXCL1, and CXCL10 were significantly elevated post surgery. CONCLUSIONS: This study is the first to show that DH severity is coordinately associated with changes in serum levels of inflammatory cytokines in chronic pain subjects. HMGB1, PDGFbb and IL-9 are novel mediators of increasing DH severity, indicative of cellular damage, neuro-inflammation and angiogenesis. Resolution of inflammation was observed with decrease in MIF post surgery. However, elevated chemokine levels indicate ongoing remodeling and wound healing at 3-month time point.

An up-to-date overview of sublingual sufentanil for the treatment of moderate to severe pain.

INTRODUCTION: Sufentanil is a selective µ-opioid agonist, used intravenously and intrathecally for moderate to severe acute pain. Sublingual sufentanil nanotablets have been developed; 15 mcg tablet for a patient-controlled analgesia device and 30-mcg tablet for a single-dose device administered by a healthcare professional. Dosing interval is a minimum of 20 min for a 15 mcg tablet and a treatment duration of up to 72 hours. The single 30-mcg nanotablet dosing interval is 1 hour. Mean plasma elimination half-life is 13 hours and bioavailability 47-57% after the first sublingual sufentanil tablet. AREAS COVERED: This review focuses on the effectiveness, safety, and feasibility of sublingual sufentanil 30-mcg single dose suspended by a healthcare professional for the management of moderate to severe acute pain. A few Phase 4 studies concerning the sublingual sufentanil tablet system containing 15-mcg nanotablets are also reviewed. EXPERT OPINION: Sufentanil sublingual 30-mcg nanotablets provide effective pain relief in various acute moderate to severe pain states. The safety profile of sublingual sufentanil 30 mcg is typical to opioids nausea, vomiting, and sedation being the most common ones. Sublingual sufentanil 30-mcg nanotablet has the potential for efficient moderate to severe pain management in supervised healthcare facilities.

A systematic review of the role of inflammatory biomarkers in acute, subacute and chronic non-specific low back pain.

BACKGROUND: Low back pain (LBP) is one of the greatest contributors to disability in the world and there is growing interest on the role of biomarkers in LBP. To purpose of this review was to analyze available evidence on the relationship between inflammatory biomarkers, clinical presentation, and outcomes in patients with acute, subacute and chronic non-specific low back pain (NSLBP). METHODS: A search was performed in Medline, Embase, Cinahl and Amed databases. Studies which measured levels of inflammatory biomarkers in participants with NSLBP were included. Two reviewers independently screened titles and abstracts, full-texts, and extracted data from included studies. Methodological quality was assessed using the Newcastle Ottawa Quality Assessment Scale. Level of evidence was assessed using the modified GRADE approach for prognostic studies. RESULTS: Seven primary studies were included in this review. All results assessed using the modified GRADE demonstrated low to very low quality evidence given the small number of studies and small sample. Three studies examined C-reactive protein (CRP), one of which found significantly higher CRP levels in an acute NSLBP group than in controls and an association between high pain intensity and elevated CRP. Three studies examined tumor necrosis factor alpha (TNF-α), two of which found elevated TNF-α in chronic NSLBP participants compared to controls. Two studies examined interleukin 6 (IL-6), none of which found a significant difference in IL-6 levels between NSLBP groups and controls. Two studies examined interleukin 1 beta (IL-ß), none of which found a significant difference in IL-ß levels between NSLBP groups and controls. CONCLUSIONS: This review found evidence of elevated CRP in individuals with acute NSLBP and elevated TNF-Α in individuals with chronic NSLBP. There are a limited number of high-quality studies evaluating similar patient groups and similar biomarkers, which limits the conclusion of this review.

Sex Differences in Interleukin-6 Responses Over Time Following Laboratory Pain Testing Among Patients With Knee Osteoarthritis.

Epidemiological studies suggest that women are not only at a higher risk for developing knee osteoarthritis (KOA), but also report greater symptom severity compared to men. One potential underlying mechanism of these sex differences may be exaggerated inflammatory responses to pain among women compared to men. The present study examined sex differences in interleukin-6 (IL-6) response over time following experimental pain testing. We hypothesized that women, when compared to men, would show greater IL-6 reactivity when exposed to acute pain in a human laboratory setting. Eighty-four participants (36 men and 48 women) with KOA scheduled for total knee arthroplasty underwent a quantitative sensory testing (QST) battery. A total of seven IL-6 measurements were taken, twice at baseline, once immediately after QST, and every 30 minutes up to 2 hours after QST. Consistent with our hypothesis, women, when compared to men, showed accelerated increases in IL-6 levels following laboratory-evoked pain, even after controlling for body mass index, marital status, clinical pain, evoked pain sensitivity, and situational pain catastrophizing. Given that KOA is a chronic condition, and individuals with KOA frequently experience pain, these sex differences in IL-6 reactivity may contribute to the maintenance and/or exacerbation of KOA symptoms. PERSPECTIVES: The present study demonstrates that women, when compared to men, exhibit greater IL-6 reactivity after exposure to laboratory-evoked pain. Such sex differences may explain the mechanisms underlying women's higher chronic pain risk and pain perception, as well as provide further insight in developing personalized pain interventions.

Diagnostic Value of D-dimer in Distinguishing between Spontaneous Subarachnoid Hemorrhage and Nontraumatic Acute Headache.

BACKGROUND: Spontaneous subarachnoid hemorrhage (SSAH) and nontraumatic acute headache patients presented with symptoms similar to headache. This study was to investigate the diagnostic value of D-dimer (DD) in distinguishing patients with SSAH from those with nontraumatic acute headache. METHODS: This retrospective study was performed and data were gathered from medical records of patients with acute headache symptoms from the Emergency Department and Neurology Clinics who were admitted to the Fourth Affiliated Hospital Zhejiang University School of Medicine between January 2015 and January 2019. Of the total 114 patients with headache symptoms enrolled in this study, 46 patients were diagnosed with SSAH (SAH group) and 68 cases with nontraumatic acute headache due to other causes (non-SAH group). The plasmatic levels of PT, INR, APTT, TT, FIB, and DD were compared between the two groups. Student's t-test of independent samples was adopted for comparing the mean between the two groups. Model discrimination was evaluated using the area under the receiver operating characteristic curve (AUC). Comparison of AUC was performed using the Z-test. RESULTS: There were no significant statistical differences of the PT, INR, TT and FIB (all p > 0.05). The APTT was significantly decreased in the SSAH group compared with non-SAH group, while DD was significantly increased (all p < 0.001); moreover, AUC in distinguishing patients with SSAH from those with nontraumatic acute headache was 0.721 (95% confidence interval (CI), 0.629 to 0.801) for APTT and 0.886 (95% CI, 0.813 to 0.938) for DD. There was a significant statistical difference (p < 0.01). Finally, the cutoff values were 25.2s in distinguishing patients with SSAH from those with nontraumatic acute headache (specificity 73.53% and sensitivity 60.87%) for APTT and 0.31 mg/L (specificity 83.82% and sensitivity 84.78%) for DD. CONCLUSIONS: As an easy-to-obtain and potential biomarker, DD could demonstrate more accurate and reliable diagnostic value than APTT in distinguishing between SSAH and nontraumatic acute headache.

Nonspecific Low Back Pain: Inflammatory Profiles of Patients With Acute and Chronic Pain.

BACKGROUND: The pathogenesis of low back pain (LBP) remains unclear. However, recent studies suggest that the inflammatory response may be inherent in spinal pain. The purpose of this study was to discern inflammatory profiles in patients with nonspecific acute and chronic LBP in relation to those in asymptomatic individuals. MATERIALS AND METHODS: Peripheral blood samples were obtained from asymptomatic controls and patients with nonspecific acute and chronic LBP reporting a minimum pain score of 3 on a 10-point Visual Analogue Scale (VAS). The levels of in vitro production of proinflammatory (tumor necrosis factor α [TNFα], interleukin [IL] 1ß, IL-6, IL-2, interferon γ) and anti-inflammatory (IL-1 receptor antagonist, soluble receptors of TNF2, and IL-10) mediators were determined by specific immunoassays. RESULTS: The mean VAS scores were comparable between the acute and chronic LBP patient groups. Compared with asymptomatic group, the production of TNFα, IL-1ß, IL-6 and their ratios to IL-10 levels were significantly elevated in both patient groups (P=0.0001 to 0.003). In acute LBP group, the ratio of IL-2:IL-10 was also significantly increased (P=0.02). In contrast, the production of interferon γ was significantly reduced compared with the other study groups (P=0.005 to 0.01), nevertheless, it was positively correlated (P=0.006) with pain scores. In chronic LBP patients, the production of TNFα, IL-1 receptor antagonist, and soluble receptors of TNF2 was significantly increased (P=0.001 to 0.03) in comparison with the control and acute LBP groups, and TNFα and IL-1ß levels were positively correlated (P<0.001) with VAS scores. CONCLUSIONS: The inflammatory profiles of patients with acute and chronic LBP are distinct. Nonetheless, in both patient groups, an imbalance between proinflammatory and anti-inflammatory mediator levels favors the production of proinflammatory components.

Progesterone relates to enhanced incisional acute pain and pinprick hyperalgesia in the luteal phase of female volunteers.

The role of sex hormones on postsurgical pain perception is basically unclear. Here, we studied the role of endogenous gonadal hormones for pain and hyperalgesia in human volunteers after experimental incision. A 4-mm incision was made in the volar forearm of 15 female volunteers both in the follicular and the luteal phase (random block design). Somatosensory profiles were assessed at baseline and 1 to 72 hours after incision by quantitative sensory testing, compared between both cycle phases, and related to individual plasma levels of gonadal hormones. Sensory testing at baseline revealed significantly lower pain thresholds (25 vs 46 mN, P < 0.005) and increased pain ratings to pinprick (0.96 vs 0.47, P < 0.0001) in the luteal phase; similarly, 1 hour after incision, pain intensity to incision (38 vs 21/100, P < 0.005), pinprick hyperalgesia by rating (P < 0.05), and area of secondary hyperalgesia (P < 0.001) were enhanced in the luteal phase. Multiple regression analysis revealed that pinprick pain sensitivity at baseline was significantly predicted by progesterone (partial r = 0.67, P < 0.001), follicle-stimulating hormone (FSH) (partial r = 0.61, P < 0.005), and negatively by testosterone (partial r = -0.44, P < 0.05). Likewise, incision-induced pain and pinprick hyperalgesia (rating and area) were significantly predicted by progesterone (partial r = 0.70, r = 0.46, and r = 0.47, respectively; P < 0.05-0.0001) and in part by FSH; the contribution of estrogen, however, was fully occluded by progesterone for all measures. In conclusion, pinprick pain and incision-induced pain and mechanical hyperalgesia were greater in the luteal phase and predicted by progesterone, suggesting a major role for progesterone. Other hormones involved are testosterone (protective) and in part FSH.

Serum zinc level during and after acute painful episodes in children with sickle cell anemia at the aminu kano teaching hospital, Kano, Northern Nigeria.

BACKGROUND: Acute painful crisis due to vaso-occlusive event is the leading cause of hospitalization in patients with sickle cell anemia (SCA). Zinc deficiency in children with SCA is associated with increased frequency and severity of acute painful events. We determined serum zinc level in children with SCA during acute painful crisis and compared the same with children with SCA who are in steady state and healthy non-sickle cell disease children. SUBJECTS AND METHODS: This was a descriptive longitudinal study, involving children with SCA age 6 months to 15 years at Aminu Kano Teaching Hospital, Kano, Northern Nigeria. Subjects were recruited into three groups, which consisted of SCA in acute painful crisis, SCA in steady state, and normal subjects with hemoglobin AA (HbAA). A total of 210 subjects were recruited, 70 subjects each for SCA in acute painful crisis, SCA in steady state, and HbAA groups, respectively. Serum zinc was analyzed with atomic absorption spectrophotometery. Serum zinc levels were repeated in children with SCA and acute painful crisis 4 weeks after resolution of painful events. RESULTS: The mean serum zinc level of SCA with acute painful crisis was higher than SCA in steady state, but the difference was not statistically significant (24.4 [11.0] and 23.4 [7.4]) µg/dL, respectively (t = 16.04, P = 0.54). While the HbAA control had significantly higher mean serum zinc level than SCA groups, both in acute painful and in steady state (F = 59.3, P = 0.001). Among children with SCA and acute painful crisis, repeat serum zinc level 4 weeks after resolution of acute painful events was significantly higher than during pain crisis (t = 64, P = 0.001). CONCLUSION: Zinc deficiency occurs in children with SCA and the deficiency is worsened by acute painful events Therefore, it is recommended that zinc level should be assessed and any deficiency treated. Supplementation of zinc should also be enhanced as this may reduce painful crisis in SCA.

[PROTECTIVE PROPERTIES OF DRUGS OF PLANT ORIGION IN ACUTE EMOTIONAL AND PAINFUL STRESS IN RATS].

The aim of the investigation was to study the protective properties of the herbal preparation - biotrite and tranquilizer diazepam under the modeling of emotional and painful stress in rats. Materials and methods. The experiment was conducted on 24 white male rats of 5 months of age. Animals (6 rats in the group) were kept on the standard diet of the vivarium: 1st group was intact; rats of the 2nd, 3rd and 4th groups were reproduced acute painful emotional stress for 3 hours. 60 minutes before the stress, rats received per os: the 2nd group - water, the 3rd group - diazepam in a dose of 1.25 mg / kg body weight of rats; 4th group - a preparation of biotrite in a dose of 50 mg / kg. Results and conclusion. The conducted studies demonstrated significant adaptive properties of the biotrite preparation, and the degree of their manifestations was higher than the stress-protective effects of diazepam.

ISSLS PRIZE IN CLINICAL SCIENCE 2018: longitudinal analysis of inflammatory, psychological, and sleep-related factors following an acute low back pain episode-the good, the bad, and the ugly.

STUDY DESIGN: Prospective longitudinal study. OBJECTIVE: To determine whether systemic cytokines and C-reactive protein (CRP) during an acute episode of low back pain (LBP) differ between individuals who did and did not recover by 6 months and to identify sub-groups based on patterns of inflammatory, psychological, and sleep features associated with recovery/non-recovery. Systemic inflammation is observed in chronic LBP and may contribute to the transition from acute to persistent LBP. Longitudinal studies are required to determine whether changes present early or develop over time. Psychological and/or sleep-related factors may be related. METHODS: Individuals within 2 weeks of onset of acute LBP (N = 109) and pain-free controls (N = 55) provided blood for assessment of CRP, tumor necrosis factor (TNF), interleukin-6 (IL-6) and interleukin-1ß, and completed questionnaires related to pain, disability, sleep, and psychological status. LBP participants repeated measurements at 6 months. Biomarkers were compared between LBP and control participants at baseline, and in longitudinal (baseline/6 months) analysis, between unrecovered (≥pain and disability), partially recovered (reduced pain and/or disability) and recovered (no pain and disability) participants at 6 months. We assessed baseline patterns of inflammatory, psychological, sleep, and pain data using hierarchical clustering and related the clusters to recovery (% change in pain) at 6 months. RESULTS: CRP was higher in acute LBP than controls at baseline. In LBP, baseline CRP was higher in the recovered than non-recovered groups. Conversely, TNF was higher at both time-points in the non-recovered than recovered groups. Two sub-groups were identified that associated with more ("inflammatory/poor sleep") or less ("high TNF/depression") recovery. CONCLUSIONS: This is the first evidence of a relationship between an "acute-phase" systemic inflammatory response and recovery at 6 months. High inflammation (CRP/IL-6) was associated with good recovery, but specific elevation of TNF, along with depressive symptoms, was associated with bad recovery. Depression and TNF may have a two-way relationship. These slides can be retrieved under Electronic Supplementary Material.

The glycation products before and after therapy for acute and chronic pain.

Pain increased the number of free radicals in the body. Previously, we studied changes mainly in oxygen and nitroxide free radicals and described these changes relative to the lipids and saccharides. In this article we focus on changes relative to proteins. Assessment of AGE products (advanced glycation end-products) was carried out by measuring fluorescence. Patients were divided into two groups: 15 patients with acute pain and 17 patients with chronic pain. Acute pain was associated with a variety of surgical procedures and patients were examined before and after surgical procedures. The group of patients with chronic pain suffered from various types of chronic pain, but mainly back pain. In patients with acute pain, total protein (TP) decreased after surgery, as did the level of AGE and the AGE/TP ratio. Nonetheless, post-operative pain increased. In patients with chronic pain, neither total protein, AGE, or AGE/TP changed, despite significant pain relief being reported after treatment. Changes in proteins, as biochemical markers, before and after pain treatment did not show any significant changes. In patients with acute pain, the recorded changes only lasted for 3-5 days after the operation. While in chronic pain, there were no significant changes at all. The assumption that changes in proteins, as biomarkers, would have the same importance as changes in lipids and saccharides was not proven.

Acute pain and peripheral sensitization following cautery disbudding in 1- and 4-week-old calves.

Acute pain and peripheral sensitization development after cautery disbudding was investigated in 33 calves administered preventive multimodal analgesia. The animals were assigned randomly to three groups: 1) Group SH (Control), undergoing sham disbudding at 1 and 4weeks of age; 2) Group ED (Early Disbudding), undergoing disbudding at 1week of age and sham disbudding at 4weeks of age; 3) Group LD (Late Disbudding), undergoing sham disbudding at 1week of age and disbudding at 4weeks of age. Physiological parameters (heart rate, respiratory rate, rectal temperature, invasive blood pressure, cortisol, ß-endorphin, interleukin-1ß, interleukin-6, tumor necrosis factor-α and haptoglobin plasmatic concentration), local variables (tactile sensitivity score, pressure pain thresholds and horn temperature), behavior and pain scores [multidimensional pain scale and visual analogue scale (VAS)] were assessed at baseline and at several pre-determined time points until 24h after disbudding. Tactile sensitivity score significantly and equally increased in both groups ED and LD and pressure pain thresholds significantly decreased in group LD until 24h after disbudding compared to group SH. Pain and VAS scores significantly and equally increased in both groups ED and LD until 24h after disbudding compared to group SH. No significant differences in physiological parameters, behavior and horn temperature were detected among groups. The present study suggests that acute pain and peripheral sensitization develop and do not differ in calves disbudded at 1week and 4weeks of age. Moreover, the use of physiological and behavioral parameters as sole indicators of acute pain might lead to improper conclusions and should be reassessed.

Circulating miR-23b-3p, miR-145-5p and miR-200b-3p are potential biomarkers to monitor acute pain associated with laminitis in horses.

Circulating microRNAs (miRNAs) are emerging as promising biomarkers for several disorders and related pain. In equine practice, acute laminitis is a common disease characterised by intense pain that severely compromises horse welfare. Recently, the Horse Grimace Scale (HGS), a facial expression-based pain coding system, was shown to be a valid welfare indicator to identify pain linked to acute laminitis. The present study aimed to: determine whether miRNAs can be used as biomarkers for acute pain in horses (Equus caballus) affected by laminitis; integrate miRNAs to their target genes and to categorise target genes for biological processes; gather additional evidence on concurrent validity of HGS by investigating how it correlates to miRNAs. Nine horses presenting acute laminitis with no prior treatment were recruited. As control group, nine healthy horses were further included in the experimental design. Samples were collected from horses with laminitis at admission before any treatment ('pre-treatment') and 7 days after routine laminitis treatment ('post-treatment'). The expression levels of nine circulating miRNAs, namely hsa-miR-532-3p, hsa-miR-219-5p, mmu-miR-134-5p, mmu-miR-124a-3p, hsa-miR-200b-3p, hsa-miR-146a-5p, hsa-miR-23b-3p, hsa-miR-145-5p and hsa-miR-181a-5p, were detected and assessed as potential biomarkers of pain by quantitative PCR using TaqMan® probes. The area under the receiver operating curve (AUC) was then used to evaluate the diagnostic performance of miRNAs. Molecular data were integrated with HGS scores assessed by one trained treatment and time point blind veterinarian. The comparative analysis demonstrated that the levels of miR-23b-3p (P=0.029), miR-145-5p (P=0.015) and miR-200b-3p (P=0.023) were significantly higher in pre-treatment and the AUCs were 0.854, 0.859 and 0.841, respectively. MiR-200b-3p decreased after routine laminitis treatment (P=0.043). Combining two miRNAs in a panel, namely miR-145-5p and miR-200b-3p, increased efficiency in distinguishing animals with acute pain from controls. In addition, deregulated miRNAs were positively correlated to HGS scores. Computational target prediction and functional enrichment identified common biological pathways between different miRNAs. In particular, the glutamatergic pathway was affected by all three miRNAs, suggesting a crucial role in the pathogenesis of pain. In conclusion, the dynamic expression of circulating miR-23b-3p, miR-145-5p and miR-200b-3p was detected in horses with acute laminitis and miRNAs can be considered potentially promising pain biomarkers. Further studies are needed in order to assess their relevancy in other painful conditions severely compromising horse welfare. An important implication would be the possibility to use them for the concurrent validation of non-invasive indicators of pain in horses.

Dipyrone (metamizole) markedly interferes with platelet inhibition by aspirin in patients with acute and chronic pain: A case-control study.

BACKGROUND: Nonopioid analgesic drugs may interfere with platelet inhibition by aspirin. Recent in vitro and clinical studies in patients with cardiovascular disease have suggested that this pharmacodynamic interaction may also occur with dipyrone, a nonopioid analgesic popular in Europe, Asia and South America. OBJECTIVE: Dipyrone is used extensively in acute and chronic pain. This study was undertaken to provide clinical data, so far missing, on its interactions in this group of patients. DESIGN: A case-control study. SETTING: Primary care in one European university hospital centre. PATIENTS: In total, 27 patients with stable cardiovascular, cerebrovascular or peripheral arterial disease and acute or chronic pain were identified and given dipyrone for at least 5 days in combination with low-dose aspirin. In total, 10 comparable patients on low-dose aspirin alone served as controls. MAIN OUTCOME MEASURES: Platelet-rich plasma was prepared to determine arachidonic acid-induced aggregation (aggregometry) and thromboxane formation (immunoassay). Platelet sensitivity to aspirin was examined in vitro. The presence of dipyrone (metabolites) in plasma was confirmed by HPLC. Additional in vitro measurements examined the aspirin/dipyrone interaction in healthy donors. RESULTS: Inhibition of aggregation was observed in only six of 27 patients receiving aspirin with dipyrone, with absence of complete inhibition by antiplatelet therapy showing in 78% of patients. In contrast, aggregation was completely inhibited in nine of 10 control patients (P < 0.001). Platelet thromboxane synthesis was higher in patients receiving dipyrone + aspirin compared with controls (387 ±â€Š89 vs. 7 ±â€Š1 ng ml, P < 0.001). Aspirin added in vitro failed to inhibit aggregation and thromboxane synthesis in platelet-rich plasma from dipyrone-treated patients. In vitro measurements with blood from healthy individuals confirmed that dipyrone dramatically reduces inhibition of platelet thromboxane synthesis by aspirin. CONCLUSIONS: Dipyrone given for 5 days or longer blunts platelet inhibition by low-dose aspirin in the majority of recipients. TRIAL REGISTRATION: German Clinical Trials Register: DRKS ID DRKS00000204. Universal Trial Number (UTN): U1111-1113-3946.

Clinical Evaluation Versus Undetectable High-Sensitivity Troponin for Assessment of Patients With Acute Chest Pain.

Decision-making in acute chest pain remains challenging despite normal (below ninety-ninth percentile) high-sensitivity troponin (hs-cTn). Some studies suggest that undetectable hs-cTn, far below the ninety-ninth percentile, might rule out acute coronary syndrome. We investigated clinical data in comparison to undetectable hs-cTnT. The study comprised 682 patients (November 2010 to September 2011) presenting at the emergency department with chest pain and normal hs-cTnT (<14 ng/l). The main end point was major adverse cardiac events (MACE: death, myocardial infarction, readmission for unstable angina, or revascularization) at a 4-year median follow-up; secondary end point was 30-day MACE. A clinical score was built by assigning points according to hazard ratios of the independent predictive variables: 1 point (male and effort-related pain) and 2 points (recurrent pain and prior ischemic heart disease). The negative predictive values of the clinical score and undetectable hs-cTnT (<5 ng/l), were tested. A total of 72 (10.6%) patients suffered long-term MACE. The C-statistics of the clinical score for long-term (0.75) and 30-day (0.88) MACE were higher than with the TIMI(Thrombolysis In Myocardial Infarction) risk (0.68, 0.77) or GRACE(Global Registry of Acute Coronary Events) (0.50, 0.47) scores. Likewise, the negative predictive values of score = 0 (97.5%, 100%) and ≤1 point (95.9%, 100%) were higher than using undetectable hs-cTnT (91.9%, 98.1%). Both clinical scores of 0 and ≤1 better classified patients at risk of MACE (p = 0.0001, log-rank test) than hs-cTnT <5 ng/l (p = 0.06). In conclusion, clinical data can guide decision-making and perform at least equally well as undetectable hs-cTnT, in patients presenting at the emergency department with chest pain and normal hs-cTnT.

Low Homoarginine Levels in the Prognosis of Patients With Acute Chest Pain.

BACKGROUND: The endogenous amino acid homoarginine predicts mortality in cerebro- and cardiovascular disease. The objective was to explore whether homoarginine is associated with atrial fibrillation (AF) and outcome in patients with acute chest pain. METHODS AND RESULTS: One thousand six hundred forty-nine patients with acute chest pain were consecutively enrolled in this study, of whom 589 were diagnosed acute coronary syndrome (ACS). On admission, plasma concentrations of homoarginine as well as brain natriuretic peptide (BNP), and high-sensitivity assayed troponin I (hsTnI) were determined along with electrocardiography (ECG) variables. During a median follow-up of 183 days, 60 major adverse cardiovascular events (MACEs; 3.8%), including all-cause death, myocardial infarction, or stroke, were registered in the overall study population and 43 MACEs (7.5%) in the ACS subgroup. Adjusted multivariable Cox regression analyses revealed that an increase of 1 SD of plasma log-transformed homoarginine (0.37) was associated with a hazard reduction of 26% (hazard ratio [HR], 0.74; 95% CI, 0.57-0.96) for incident MACE and likewise of 35% (HR, 0.65; 95% CI, 0.49-0.88) in ACS patients. In Kaplan-Meier survival curves, homoarginine was predictive for patients with high-sensitivity assayed troponin I (hsTnI) above 27 ng/L (P<0.05). Last, homoarginine was inversely associated with QTc duration (P<0.001) and prevalent AF (OR, 0.83; 95% CI, 0.71-0.95). CONCLUSION: Low plasma homoarginine was identified as a risk marker for incident MACEs in patients with acute chest pain, in particular, in those with elevated hsTnI. Impaired homoarginine was associated with prevalent AF. Further studies are needed to investigate the link to AF and evaluate homoarginine as a therapeutic option for these patients.

Substance P and Acute Pain in Patients Undergoing Orthopedic Surgery.

OBJECTIVE: There is a limited information about the role of Substance P (SP) in acute pain nociception following surgical stimulation in patients with a chronic inflammatory state not to mention the link between this neuropeptide level changes and intensity of pain. The goal of the research was to find the correlation between SP level changes and acute pain intensity in patients with rheumatoid arthritis undergoing elective orthopedic surgery. MATERIAL AND METHODS: Patients with rheumatoid arthritis (RA) were enrolled in the study. The correlation between acute pain intensity and concentration of SP in serum as well as in drainage fluid from postoperative wound was assessed in patients with RA who underwent Total Knee Replacement (TKA) under spinal anesthesia. RESULTS: In patients with RA a correlation between intensity of acute pain and serum SP was found postoperatively, whereas there was no correlation between intensity of acute pain and concentration of SP in drainage fluid. CONCLUSIONS: 1. The correlation between acute pain intensity and SP serum concentration was found postoperatively in patients with RA. 2. The correlation between acute pain intensity and SP concentration in drainage fluid was not found postoperatively in patients with RA.