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Background: "Ricominciare" is a single-center, prospective, pre-/post-intervention pilot study aimed at verifying the feasibility and safety of the ARC Intellicare (ARC) system (an artificial intelligence-powered and inertial motion unit-based mobile platform) in the home rehabilitation of people with disabilities due to respiratory or neurological diseases., Methods: People with Parkinson's disease (pwPD) or post-COVID-19 condition (COV19) and an indication for exercise or home rehabilitation to optimize motor and respiratory function were enrolled. They underwent training for ARC usage and received an ARC unit to be used independently at home for 4 weeks, for 45 min 5 days/week sessions of respiratory and motor patient-tailored rehabilitation. ARC allows for exercise monitoring thanks to data from five IMU sensors, processed by an AI proprietary library to provide (i) patients with real-time feedback and (ii) therapists with information on patient adherence to the prescribed therapy. Usability (System Usability Scale, SUS), adherence, and adverse events were primary study outcomes. Modified Barthel Index (mBI), Barthel Dyspnea Index (BaDI), 2-Minute Walking Test (2MWT), Brief Fatigue Inventory (BFI), Beck Depression or Anxiety Inventory (BDI, BAI), and quality of life (EQ-5D) were also monitored pre- and post-treatment., Results: A total of 21 out of 23 eligible patients were enrolled and completed the study: 11 COV19 and 10 pwPD. The mean total SUS score was 77/100. The median patients' adherence to exercise prescriptions was 80%. Clinical outcome measures (BaDI, 2MWT distance, BFI; BAI, BDI, and EQ-5D) improved significantly; no side effects were reported., Conclusion: ARC is usable and safe for home rehabilitation. Preliminary data suggest promising results on the effectiveness in subjects with post-COVID condition or Parkinson's disease.

Background: This proof of concept study was aimed at characterizing novel salivary biomarkers specific for different subsets in primary Sjögren's syndrome (pSS) in order to improve patients' profiling., Methods: pSS patients were stratified in three subgroups according to both (a) focus score in the minor salivary gland biopsies (i.e. intensity of immune cell infiltration in the tissue) and (b) unstimulated salivary flow rate. Healthy volunteers were included as controls. A nano-HPLC-SWATH-MS approach was used for the analysis of saliva proteome of different subsets., Results: We found 203 differentially expressed proteins in pSS patients with respect to controls with evident differences in the expression of normal constituents of the human salivary proteome (i.e. prolactin-inducible protein, proline-rich proteins, cystatins) and several mediators of inflammatory processes. The comparative analysis of the pSS phenotypes unrevealed 63 proteins that were shared and specifically modulated in the three subsets of pSS patients converging on several inflammatory pathways. Among them S100A protein appeared of particular interest merging on IL-12 signaling and being significantly influenced by either salivary flow impairment or intensity of immune cell infiltration in the tissue., Conclusions: Constellations of proteins, including S100A proteins, characterize different pSS subsets reflecting either salivary gland dysfunction or inflammation. Salivary proteomics may foster future research projects ultimately aimed at developing personalized treatments for pSS patients., Competing Interests: Competing interestsThe authors declare that they have no competing interests.

Objectives: Salivary cystatin S is a defence protein mainly produced by submandibular glands and involved in innate oral immunity. This study aimed to verify whether cystatin S was diversely expressed in different disease subsets of primary Sjogren's syndrome (pSS) patients, defined on the basis of salivary flow [unstimulated salivary flow rate (USFR)], minor salivary gland (MSG) focus score and submandibular gland ultrasonography abnormalities. We also evaluated miR-126 and miR-335-5p expression in MSG biopsies to verify whether an aberrant regulation of cystatin S at the glandular level may influence its salivary expression., Methods: Forty pSS patients and 20 sex- and age-matched healthy volunteers were included. Salivary cystatin S levels were assessed by western blot analysis using a stain-free technology. The expression of miR-126, miR-335-5p and cystatin S was assessed by quantitative PCR in 15 MSG biopsies differing for USFR and MSG focus score., Results: We found that salivary cystatin S was significantly decreased in pSS patients vs healthy volunteers ( P = 0.000), especially in those with hyposalivation. A positive correlation was observed between cystatin S and USFR ( r = 0.75, P = 0.01). Salivary cystatin S was also significantly reduced in patients with a submandibular gland ultrasonography score ⩾2. The expression levels of miR-126 and miR-335-5P increased in inverse proportion with USFR. The mRNA of cystatin S did not change significantly, suggesting post-transcriptional regulation., Conclusion: Cystatin S emerged as a promising biomarker for pSS, strongly correlated with glandular dysfunction. An upregulation of miR-126 and miR-335-5P might be implicated in its expression., (© The Author 2017. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com)

Background: Systemic sclerosis (SSc) is an autoimmune disease characterized by progressive fibrosis of the skin and the internal organs. In a previous work we suggested a correlation between levels of salivary psoriasin (S100A7) and pulmonary involvement in SSc patients. The goals of this study are to determine the distribution characteristics of psoriasin in whole saliva (WS) of SSc and healthy donor populations and define its predictive value on diffusion capacity of carbon monoxide (DLCO), along with others clinical parameters., Methods: Salivary level of psoriasin was determined by ELISA kit in 134 SSc patients, 63 Raynaud syndrome patients, 40 patients affected by other connective diseases (non-case) and 74 healthy control subjects., Results: A significant increase of salivary psoriasin was observed in SSc patients when compared with other healthy and pathological controls. Moreover, we confirmed the efficacy of salivary psoriasin to correlate with DLCO in a large cohort of SSc patients., Conclusions: Overall our results suggest a rapid, non invasive and low costing method which can help clinicians in the evaluation of SSc pulmonary involvement.

Objectives: Recently, convincing data have been published on the value of salivary gland ultrasonography (SGUS) in differentiating primary SS from non-immune-mediated sicca syndrome. Limited data are available regarding the diagnostic accuracy of SGUS in distinguishing SS from other rheumatic diseases. The purpose of this study was to assess the usefulness of SGUS in distinguishing patients with SS from those with xerostomia and/or xerophthalmia and a diagnosis of stable UCTD., Methods: This cross-sectional study consecutively enrolled 150 patients either diagnosed with SS (as established by the American-European Consensus Group criteria) or affected by UCTD but not SS. Parotid and submandibular glands on both sides were assessed for size, parenchymal echogenicity and inhomogeneity by means of SGUS, which was performed by a radiologist blinded to the diagnosis. Echostructural alterations of the salivary glands were graded from 0 to 3 (cut-off >2)., Results: This study included 109 patients: 55 with SS and 54 with UCTD. Patients with SS showed a higher SGUS score in comparison with those with UCTD [mean 2.2 (s.d. 1.8) vs 0.2 (s.d. 0.5), P < 0.0001]. The SGUS cut-off >2 showed a sensitivity of 65%, a specificity of 96%, a positive predictive value of 95% and a negative predictive value of 73% for SS diagnosis. A significant correlation was also found between the SGUS score and the minor salivary gland biopsy/focus score (r = 0.484, P < 0.0001)., Conclusion: This study confirmed the good sensitivity and the high specificity of SGUS in differentiating SS from other CTDs., (© The Author 2015. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Introduction: Recently, a great interest has arisen for salivary gland ultrasonography (SGUS) as a valuable tool for the assessment of major salivary gland involvement in primary Sjögren's syndrome (pSS. The aims of this study were to test the accuracy of SGUS for the early detection of pSSand to compare the diagnostic performance of SGUS with minor salivary gland biopsy (MSGB) and unstimulated salivary flow (USFR) in this context., Method: Patients with suspected pSS and symptoms duration of ≤5 years were consecutively enrolled in this study. The diagnosis of pSS was made according to the AECG criteria. SGUS was performed by two radiologists blinded to the diagnosis and a previously reported ultrasound scoring system (De Vita et al. 1992, cut-off ≥ 1) was used to grade the echostructure alterations of the salivary glands. Statistical analysis was performed using SPSS v16., Results: This study included 50 pSS patients and 57 controls with no-SS sicca symptoms. The mean(SD) age of the pSS group was lower than non-SS group (47(13) vs 53(12)yrs, p = 0.006). No further differences between the two groups were observed. Patients with pSS showed a significantly higher SGUS score in comparison with controls (mean(SD) = 2.1(1.8) vs 0.0(0.4), p = 0.000). The SGUS cut-off ≥ 1 showed a sensitivity (SE) of 66 %, a specificity (SP) of 98 %, a positive predictive value (PPV) of 97 % and a negative predictive value (NPV) of 73 % for pSS diagnosis. The SGUS score correlated also with patients' MSGB/FS and USFR., Conclusions: This study confirmed the good performance of SGUS for the early non-invasive diagnosis of pSS. Further research in larger international cohort of patients is mandatory in order to assess the role of SGUS in the diagnostic algorithm of pSS.

Fibromyalgia (FM) syndrome is a chronic disease with unknown etiology, characterised by widespread pain and fatigue. Moreover, several patients manifest non-specific symptoms such as sleep disturbances, mood disorders, and neurocognitive impairment. We have reviewed the literature of the past year to underline the progress of research in the fields of etiopathogenesis, therapies and assessment, considering articles published between November 2012 and November 2013.

Objectives: To investigate the influence of psychiatric comorbidity on sexual satisfaction in premenopausal and postmenopausal female affected by fibro-myalgia (FM)., Methods: We enrolled 100 FM females and 40 age-matched healthy females. Psychiatric diagnoses were carried out using the Structured Clinical Interview for DSM-IV Axis I Disorders-Patient Edition; sexual satisfaction was evaluated using the Index of Sexual Satisfaction (ISS), clinical assessment included the Fibromyalgia Impact Questionnaire (FIQ), tender point (TP) count and pain evaluation by means of a visual analogue scale (VAS)., Results: The data were analysed according to the presence and absence of psychiatric comorbidity in FM patients (all FM, only FM, FM with a lifetime psychiatric disorder, FM with a current psychiatric disorder). FM patients with a current psychiatric comorbidity (n=24) showed ISS values significantly higher (41.5±17.5) with respect to patients with only FM (n=45) (27.3±17.4, p<0.05) and healthy controls (24.1±12.8, p<0.01). The FIQ values of patients with current psychiatric comorbidity were significantly higher (68.4±13.5) compared to the values of patients with only FM (55.7±17.9) (p<0.05). No differences were found between VAS pain or the number of TP of the three groups of patients., Conclusions: Our results suggest that psychiatric comorbidity has more influence on the sexual satisfaction of FM patients than the presence of the rheumatic disease itself. Because the ISS gives an indication of the relationship with partners, this finding suggests that emotional aspects may play a crucial role in sexual behavior, in particular in those FM patients with current psychiatric comorbidity.

Background: Chronic Fatigue Syndrome (CFS) is a severe, systemic illness characterized by persistent, debilitating and medically unexplained fatigue. The etiology and pathophysiology of CFS remains obscure, and diagnosis is formulated through the patient's history and exclusion of other medical causes. Thereby, the availability of biomarkers for CFS could be useful for clinical research. In the present study, we used a proteomic approach to evaluate the global changes in the salivary profile in a couple of monozygotic twins who were discordant for CFS. The aim was to evaluate differences of salivary protein expression in the CFS patient in respect to his healthy twin., Methods: Saliva samples were submitted to two-dimensional electrophoresis (2DE). The gels were stained with Sypro, and a comparison between CFS subject and the healthy one was performed by the software Progenesis Same Spot including the Analysis of variance (ANOVA test). The proteins spot found with a ≥2-fold spot quantity change and p<0.05 were identified by Nano-liquid chromatography electrospray ionization tandem mass spectrometry. To validate the expression changes found with 2DE of 5 proteins (14-3-3 protein zeta/delta, cyclophilin A, Cystatin-C, Protein S100-A7, and zinc-alpha-2-glycoprotein), we used the western blot analysis. Moreover, proteins differentially expressed were functionally analyzed using the Ingenuity Pathways Analysis software with the aim to determine the predominant canonical pathways and the interaction network involved., Results: The analysis of the protein profiles allowed us to find 13 proteins with a different expression in CFS in respect to control. Nine spots were up-regulated in CFS and 4 down-regulated. These proteins belong to different functional classes, such as inflammatory response, immune system and metabolism. In particular, as shown by the pathway analysis, the network built with our proteins highlights the involvement of inflammatory response in CFS pathogenesis., Conclusions: This study shows the presence of differentially expressed proteins in the saliva of the couple of monozygotic twins discordant for CFS, probably related to the disease. Consequently, we believe the proteomic approach could be useful both to define a panel of potential diagnostic biomarkers and to shed new light on the comprehension of the pathogenetic pathways of CFS.

Background: Gross cystic disease fluid protein-15(GCDFP-15)/prolactin-inducible protein (PIP) is a secretory acinar glycoprotein of 14 KDa which we have recently described as significantly lower in salivary samples of patients with primary Sjögren's syndrome (pSS) in comparison to healthy volunteers by proteomic analysis., Aims of the Study: (1) to validate our previous data on the decrease of GCDFP-15/PIP protein in a larger number of subjects with pSS (2) to integrate the proteomic results with complementary immunoassays in order better clarify the pathophysiological relevance of GCDFP-15/PIP in pSS exocrinopathy (3) to assess both the glandular expression of the GCDFP-15/PIP and the levels of glandular GCDFP-15/PIP mRNA in the patients' minor salivary gland (MSG) biopsies in order to verify whether the observed reduction of GCDFP-15/PIP in saliva may be related to a decrease in the protein production., Patients and Methods: A total of 123 salivary samples from patients affected by pSS, no-SS sicca syndrome and sex- age-matched healthy volunteers were analyzed by different proteomic techniques (SELDI-TOF-MS, 2DE, MALDI-TOF-MS). The expression of GCDFP-15/PIP was then validated by western blot analysis. Real Time PCR and immunohistochemistry for GCDFP-15/PIP in the minor salivary glands (MSG) biopsies were then carried out., Results: By using complementary proteomic analysis we found that a putative peak of 16547 m/z was among the best independent biomarkers for pSS able to discriminate between patients and healthy controls with a sensitivity of 96 % and a specificity of 70%, with a global cross validated error of 29%. We identified the peak as the GCDFP-15/PIP protein and verified that the intensity of GCDFP-15/PIP was significantly lower in pSS patients when compared to both no-SS sicca subjects and healthy controls (p<0.0001). GCDFP-15/PIP expression also correlated with both the salivary flow rate (r=0.312, p=0.023) and MSG biopsies focus score (r=-0.377, p=0.04). Finally, immunohistochemistry confirmed that GCDFP-15/PIP staining was faint in mucus acini and Real Time PCR showed that GCDFP-15/PIP mRNA was significantly lower in pSS patients when compared to both no-SS sicca subjects and healthy controls (p=0.023) thus supporting the hypothesis that the observed reduction of GCDFP-15/PIP in pSS saliva may be related to a decrease in the protein production., Conclusion: In this study by different complementary-omic techniques we confirmed the potential role of GCDFP-15/PIP as a novel biomarker for pSS. This finding might also be functionally important as GCDFP-15/PIP has previously been shown to bind to Aquaporin 5 (AQP5), a salivary gland water channel, critical to saliva formation that is known to be downregulated in pSS. It is likely that exploring the GCDFP-15/PIP/AQP5 axis will help better understand the mechanism of salivary gland dysfunction in pSS.

Fibromyalgia is a common syndrome characterised by widespread pain and a constellation of other symptoms and overlapping conditions that contribute to complicate the diagnosis, the assessment and the treatment. Furthermore, the etiological causes for the moment only consist of assumptions, and the underlying pathogenetic mechanisms still remain to be clarified. For the above-mentioned reasons, with the present review we sought to provide an overview of the literature on fibromyalgia from both the pre-clinical and clinical studies indexed in PubMed during the last year, classifying original articles and reviews into etiopathogenesis, assessment and therapy.

Introduction: A growing interest has arisen in salivary proteomics as a tool for the identification of biomarkers for primary Sjögren's syndrome (pSS). Nonetheless, only a limited number of preclinical validation studies have been performed, limiting the possibility of translating proteomic results into clinical practice. The primary aim of this study was to refine the diagnostic power of a panel of candidate salivary biomarkers described in pSS with respect to both healthy volunteers and pathological controls. We also explored the pathogenetic function of the detected putative biomarkers both in the local exocrinopathy and in the systemic inflammatory processes of SS., Methods: One hundred and eighty patients were included in the study overall. In the first "exploratory phase", we enrolled 40 females with pSS, 40 sex- and age-matched healthy volunteers, 10 patients with sicca non-SS and 15 secondary SS (sSS) patients. The testing cohort of the second "challenge phase" of the study was represented by 75 unselected, consecutive subjects: 19 pSS, 21 healthy volunteers, 10 sicca non-SS and 25 sSS patients. Salivary proteomic analysis was performed combining two-dimensional electrophoresis (2DE) and matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry (MALDI-TOF-MS). Western blot (WB) analysis and enzyme-linked immunosorbent assay (ELISA) were employed to validate 2DE results. Ingenuity Pathway Analysis (IPA) Knowledge base was adopted to associate candidate biomarkers in a signalling pathogenetic network., Results: A total of 28, 6, 7 and 12 protein spots were found to be significantly different in pSS samples with respect to healthy volunteers, non-SS sicca syndrome, SSc-sSS and rheumatoid arthritis-sSS, leading to the identification of 15 differently expressed proteins. Among them, α-amylases precursor, carbonic anhydrase VI, β-2 microglobulin, glyceraldehydes-3-phosphate dehydrogenase (G3PDH), epidermal fatty acid binding protein (E-FABP) and immunoglobulin k light chain (IGK-light chain) apparently showed the most significant differences in pSS when compared to healthy volunteers and non-SS pathological controls. On the other hand, as expected, pSS and sSS salivary profiles shared a great number of similarities., Conclusions: This study demonstrated that salivary fluid might represent a novel ideal milieu for the detection of a diagnostic panel of candidate biomarkers for pSS, and to gain an insight into the pathogenetic processes underlying glandular and systemic autoimmune disorders.

Objectives: To evaluate the role of spasmophilia (SP) in fibromyalgia syndrome (FM)., Methods: Three hundred and fourteen patients (280 F, 34 M) with a diagnosis of FM or FM and spasmophilia (FM+SP) were recruited. Clinical assessment of patients and controls included the Questionnaires FIQ, HAQ and the tender point (TP) count. Life-time or ongoing psychiatric aspects were evaluated by trained psychiatrists by means of the classic scales: Structured Clinical Interview (SCID) for DSM-IV. The following analysis were evaluated: cytokine (IL1, IL2, IL6, IL8, IL10), TNF-α, cortisol, GH, ACTH, IGF1, 5HT, intracellular Mg, plasma calcium p(Ca), PTH, (25(OH)D) and thyroid functionality. Some typical symptoms were investigated., Results: Eighty-one patients resulted positive for spamophilia (FM+SP), while 233 resulted negative for spasmophilia (FM). The mean TP number resulted higher in the FM group (15.33±3.88) with respect to FM+SP (12.88±6.17, p=0.016), while FIQ and HAQ did not differ between the two studied groups. FM patients exhibited a higher frequency of psychiatric disorders with respect to FM+SP patients (72% FM vs. 49% FM+SP, p<0.01). In particular the frequency of depression was 65.5% FM vs. 35% FM+SP (p<0.01)., Conclusions: The presence of spasmophilia seems to influence psychiatric comorbidity which was less prevalent in FM+SP patients. FM is indeed characterised by an abnormal sensory processing of pain that seems to result from a combination of interactions between neurotransmitters, stress, hormones and the nervous system; spasmophilia would seem to be more linked to a dysfunction at the neuromuscular level.

In the last few years, many attempts have been carried out for the research of specific biological biomarkers in fibromyalgia (FM) since, so far, no laboratory tests have been appropriately validated for the diagnosis and the prognostic stratification of the disease. In our study for the first time, we carried out a proteomic analysis of the whole saliva of FM patients in order to evaluate salivary biomarkers. Twenty-two FM patients with all fulfilling the American College of Rheumathology diagnostic criteria for FM and 26 sex-and age-matched healthy subjects were enrolled in the study. Proteomic analysis was performed by combining 2-DE and MALDI-TOF-MS. The most relevant observation which emerged from the data analysis was the exclusive and significant over-expression of transaldolase and phosphoglycerate mutase I. These findings were validated by Western blot analysis and the total optical density confirmed the significant up-regulation of transaldolase and phosphoglycerate mutase I in FM samples with respect to healthy subjects. It was noteworthy that seven further salivary proteins resulted differentially expressed, namely: calgranulin A, calgranulin C, cyclophilin A, profilin 1, Rho GDP-dissociation inhibitor 2, proteasome subunit-α-type-2 and haptoglobin-related protein precursor. These preliminary results demonstrated the utility of salivary proteomic analysis in the identification of salivary biomarkers in FM patients and in clarifying some of the pathogenetic aspects of the disease., (Copyright © 2009 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)