Valeria Ruggiero

Metabolomics analysis and modeling suggest a lysophosphocholines-PAF receptor interaction in fibromyalgia.

Fibromyalgia Syndrome (FMS) is a chronic disease characterized by widespread pain, and difficult to diagnose and treat. We analyzed the plasma metabolic profile of patients with FMS by using a metabolomics approach combining Liquid Chromatography-Quadrupole-Time Of Flight/Mass Spectrometry (LC-Q-TOF/MS) with multivariate statistical analysis, aiming to discriminate patients and controls. LC-Q-TOF/MS analysis of plasma (FMS patients: n = 22 and controls: n = 21) identified many lipid compounds, mainly lysophosphocholines (lysoPCs), phosphocholines and ceramides. Multivariate statistical analysis was performed to identify the discriminating metabolites. A protein docking and molecular dynamic (MD) study was then performed, using the most discriminating lysoPCs, to validate the binding to Platelet Activating Factor (1-alkyl-2-acetyl-sn-glycero-3-phosphocholine, PAF) Receptor (PAFr). Discriminating metabolites between FMS patients and controls were identified as 1-tetradecanoyl-sn-glycero-3-phosphocholine [PC(14∶0/0∶0)] and 1-hexadecanoyl-sn-glycero-3-phosphocholine [PC(16∶0/0∶0)]. MD and docking indicate that the ligands investigated have similar potentialities to activate the PAFr receptor. The application of a metabolomic approach discriminated FMS patients from controls, with an over-representation of PC(14∶0/0∶0) and PC(16∶0/0∶0) compounds in the metabolic profiles. These results and the modeling of metabolite-PAFr interaction, allowed us to hypothesize that lipids oxidative fragmentation might generate lysoPCs in abundance, that in turn will act as PAF-like bioactivators. Overall results suggest disease biomarkers and potential therapeutical targets for FMS.

The management of fibromyalgia from a psychosomatic perspective: an overview

Abstract Fibromyalgia (FM) is a central sensitization syndrome characterized by chronic widespread pain. FM is often comorbid with psychiatric disorders, as well as psychological distress that worsens the quality-of-life of people affected. The aim was to collect current evidence about the management of FM from a psychosomatic perspective. The literature was synthesized and summarized in a narrative format. The literature search was carried out in PubMed; review articles, meta-analysis, overview, and guidelines published in the last 10 years written in English were included. Five main topics (Diagnostic criteria of FM; Pathogenesis of chronic widespread pain in FM; Early stress and trauma as predisposing factors for central sensitization; FM and Psychiatric comorbidity; Implications for treatment) were pointed out and discussed. Much evidence underlies the importance of considering and treating the comorbidity of FM with psychiatric disorders and psychological factors that affect pain management. Validation of FM as a central sensitization syndrome by a clinician facilitates therapeutic strategies that involve patients as active participants in the pain management process, likely leading to improved outcomes.

A preliminary study on serum proteomics in fibromyalgia syndrome

Fibromyalgia syndrome (FMS) is a complex illness to diagnose and treat, which presents symptoms that may be part of, or overlap with other diseases or syndromes. The most widely used diagnostic criteria are those of the American College of Rheumatology [1]; no laboratory test has been validated for FMS diagnosis which remains primarily clinically based. Oxidative stress has been proposed as a relevant event in the pathogenesis of FMS with an increase of lipid peroxidation (LPO) [2] and a decrease in vitamin A and E concentrations [3]. Although the etiology of FMS remains unclear, genetic predisposition is likely to be an important factor and transmission is thought to be polygenic [4, 5]. If FMS is a multi-genetic disease then it could be hypothesized that differences exist in the type of proteins or protein expression levels in sera of FMS patients compared with healthy controls. Proteomic analysis is a powerful tool for the global evaluation of protein expression and plays a central role in clinical diagnosis and monitoring. Some studies [6] reported interesting proteomic analysis data with an overexpression of transaldolase and phosphoglicerate mutase I in salivary fluid of FMS patients and focused on the role of oxidative stress in the pathogenesis of the disease. The aim of this preliminary study was to evaluate, using two-dimensional gel electrophoresis (2-DE) and mass spectrometry (MS), changes in protein profiles of FMS patients with respect to control subjects to identify potential serum biomarkers useful for disease diagnosis and management. Sixteen females (52 ± 12 years) affected by FMS and 12 healthy females (48 ± 13 years) were enrolled; all patients fulfilled new ACR diagnostic criteria [1] (Table 1). The presence of a major clinical condition other than fibromyalgia was excluded by physical examination and routine blood and urine screening. No patients suffered of thyroid dysfunction. Psychiatric examination data of patients were reported in a previous study [7]. Study was approved from our Local Ethical Committee and informed consent was obtained from all subjects. Serum protein concentrations were quantified using the PlusOne 2D Quant Kit (GE Healthcare); first dimension isoelectric focusing (IEF) was carried out with 18 cm immobilized pH gradient strips of pH 3–10. The IPG strips were applied onto 10% acrylamide sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) slab gels (25.5 cm × 20.5 cm × 1.0 mm) and overlaid with a solution of 0.5% agarose with a trace of bromophenol blue. Gels were fixed, stained with Coomassie Brilliant Blue G-250 colloidal for 24 h and stored at room temperature. At least three sample replicates were performed. 2D data were processed with Progenesis SameSpots software, which computed multiplication fold, false discovery rate (FDR) q-value, p-values of all spots using one-way ANOVA analysis. A p-value < 0.05 was considered statistically significant; no difference has been found in protein expression according to patient therapy. After normalization, volume calculation and statistical analysis, same data differences were observed between *Corresponding author: Dr. Antonella Fais, Dipartimento di Scienze della Vita e dell’Ambiente, Università di Cagliari, 09042 Monserrato, Cagliari, Italy, Phone: +39 0706754506, Fax: +39 0706754523, E-mail: fais@unica.it Valeria Ruggiero and Enrico Cacace: Dipartimento di Scienze Mediche “Mario Aresu”, Università di Cagliari, Monserrato, Cagliari, Italy Benedetta Era, Marcella Corda and Stefania Utzeri: Dipartimento di Scienze della Vita e dell’Ambiente, Università di Cagliari, Monserrato, Cagliari, Italy Laura Molin: CNR-ISTM, Corso Stati Uniti 4, Padova, Italy

Purine metabolites in fibromyalgia syndrome

OBJECTIVE To evaluate serum purine metabolite concentrations in patients affected by fibromyalgia syndrome (FMS) and the relationships between their levels and FM clinical parameters. DESIGN AND METHODS Serum purine levels were quantified using LC/UV-vis in 22 fibromyalgic females (according to the American College of Rheumatology classification criteria) and 22 healthy females. RESULTS Significantly higher serum inosine, hypoxanthine and xanthine levels (p<0.001) and significantly lower serum adenosine (p<0.05) were detected in the FMS patients vs healthy controls. Our data show a negative correlation between adenosine and Fibromyalgia Impact Questionnaire (FIQ). CONCLUSIONS Study results suggest that purines, in particular adenosine and inosine, may be involved in pain transmission in fibromyalgia.

Tolerability of Tiaprofenic Acid in Patients with Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency

SummaryGlucose-6-phosphate dehydrogenase (G6PD) deficiency is an X-linked genetic disorder which can lead to acute haemolytic anaemia following ingestion of fava beans and the administration of certain drugs, mainly in subjects with bacterial or viral infections. It is common in the Mediterranean region and many variants are found in Sardinia. The aim of this study was to evaluate in vivo if treatment with tiaprofenic acid 600mg daily for 15 days would reduce erythrocyte GSH (reduced glutathione) concentrations and thus produce erythrocytolysis (assessed by evaluation of51Cr-labellederythrocyie survival) in subjects with G6PD deficiency. GSH concentrations were also evaluated in vitro after incubation of G6PD-deficient erythrocytes with increasing doses of tiaprofenic acid (20, 50, 100, 150 and 200 mg/L) and with acetylphenylhydrazine 5mg. The results obtained both in vitro and in vivo confirmed the absence of any oxidative action of tiaprofenic acid on the erythrocytes of G6PD-deficient subjects.

Free amino acids in fibromyalgia syndrome: relationship with clinical picture

Abstract The objectives of our study were to evaluate free amino acid (FAA) concentrations in the serum of patients affected by fibromyalgia syndrome (FMS) and to determine the relationships between FAA levels and FMS clinical parameters. Thus, serum amino acid concentrations were quantified (HPLC analysis) in 23 females with fibromyalgia (according to the American College of Rheumatology classification criteria) and 20 healthy females. The results showed significantly higher serum concentrations of aspartate, cysteine, glutamate, glycine, isoleucine, leucine, methionine, ornithine, phenylalanine, sarcosine, serine, taurine, tyrosine and valine in FMS patients vs. healthy controls. Patients with higher Fibromyalgia Impact Questionnaire (FIQ) scores showed increased levels of alanine, glutamine, isoleucine, leucine, phenylalanine, proline and valine. In conclusion, our results indicate an imbalance in some FAAs in FMS patients. Increased Glu is particularly interesting, as it could explain the deficit in monoaminergic transmission involved in pain.

Plasma phospholipase, γ-CEHC and antioxidant capacity in fibromyalgia

Recent studies have suggested a possible role of high levels of plasma lysophosphocholines (lysoPCs) in fibromyalgia syndrome (FMS). The aim of this study was to evaluate the content of plasma phospholipases (e.g., Platelet Activating Factor Acetyl Hydrolase [PAF‐AH], secretory Phospholipase A2 [sPLA2], Total Antioxidant Capacity [TAOC] and 2,7,8‐trimethyl‐2‐(2‐carboxyethyl)‐6‐hydroxy chroman [γ‐CEHC]) in FMS patients and their association with clinical status and quality of life.

The impact of fibromyalgia syndrome and the role of comorbidity with mood and post-traumatic stress disorder in worsening the quality of life

Background: The aim is to measure the association between fibromyalgia syndrome (FMS) and post-traumatic stress disorder (PTSD), mood and anxiety disorders using reliable psychiatric diagnoses according to Diagnostic and Statistical Manual of Mental Disorders (4th ed.; DSM-IV) and with a case–control design. Methods: Case–control study with cases (71 consecutive female patients with FMS) and controls (284 subjects without FMS), randomly drawn after a gender- and age-matching technique from the database of an epidemiological survey. Psychiatric diagnoses were conducted according to DSM-IV and carried out by clinical staff using a structured interview (Advanced Neuropsychiatric Tools and Assessment Schedule). QoL was measured by Short Form Health Survey (SF-12). Results: The lifetime prevalence of major depressive disorder (MDD; 43.7% vs 8.1%, p < .0001), bipolar disorder (BD; 21.1% vs 0.7%, p < .0001), PTSD (8.4% vs 1.4%, p < .0001) and panic disorder (28.2% vs 5.6%, p < .001) was higher in people with FMS than in controls. People with FMS showed a poorer QoL than controls on the SF-12 (26.43 ± 6.04 vs 37.45 ± 5.80, p < .0001). Those with comorbidity with MDD and BD showed a mean SF-12 score of 24.75 ± 6.31 versus 29.52 ± 4.84 (N = 25) of people with FMS without any mood disorder (p = .002). The attributable burden of FMS in worsening QoL was found comparable to that of serious chronic diseases such as multiple sclerosis. Conclusion: FMS is a disorder that ‘in itself’ can have a devastating impact on an individual’s life. The frequency of the association with major depressive and bipolar disorders increases the impact on the QoL of people with FMS. One of the causes of this association appears to be the extreme vulnerability to chronic stress that this disorder involves. The findings have important clinical significance: the physician must interpret in the right dimension and with dignity the suffering of the people with FMS.