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The link between pain severity, depressive symptomatology and catastrophizing among women with endometriosis is still under-investigated. The aim of this study was to (i) evaluate differences in depressive symptomatology between women with and without endometriosis; (ii) investigate if pain severity is associated with depressive symptoms; and (iii) test if catastrophizing moderates the link between these two variables. A total of 172 women with a diagnosis of endometriosis and 62 healthy controls volunteered for this cross-sectional study. Depressive symptomatology, pain severity, and catastrophizing were assessed.Compared to healthy controls, women with endometriosis were more likely to score above the cutoff for depressive symptomatology, with 60.5% of the latter being classified as having a subthreshold depression or minor depression and 15.7% as having moderate or severe major depression. Pain severity was significantly associated with depressive symptoms even after controlling for several covariates. Finally, the moderation model suggested that among patients with endometriosis, the relationship between pain severity and depressive symptomatology depended on the level of catastrophizing, with this association being stronger for high levels of the moderator.Mental health practitioners working with women with endometriosis may consider those who report high levels of pain severity and of catastrophizing at high risk of depression and are advised to promote adaptive coping strategies among patients to foster a better adaptation to this chronic disease.

Literature about the impact of infertility and endometriosis on Quality of Life (QoL) is scarce and needs further investigation. Our aim was to deeply investigate the QoL of women with diagnoses of both endometriosis and infertility with failed Assisted Reproductive Treatments (ART). We conducted a concurrent mixed-method study composed of both quantitative and qualitative surveys. The quantitative survey included 22 women who completed the FertiQoL. The qualitative survey included 15 of them who provided written answers to open-ended questions aimed at deeply exploring their QoL. Data were initially analyzed separately and then combined in a meta-matrix. From the quantitative survey emerged that women at higher risk for low QoL were those who have experienced previous spontaneous miscarriages and that the domains of the FertiQoL related to fertility treatment (i.e. increased pain severity, disturbed daily life routine, and dissatisfaction with services) were the most critical. From the Interpretative Phenomenological Analysis (IPA) of qualitative survey, narrations about the physical, relational, social, emotional-cognitive, and behavioural impact of the diseases emerged. Mixed findings showed that the QoL of this population was scarce and that different levels (the inner world, the behaviours, the relational context, and the environmental context) are strictly connected and interact between them in influencing QoL. Multi-level preventive or supportive programs (with specific attention to pain experience, coping strategies, quality of services and governmental support) are required for this population.

Sixty women with a diagnosis of endometriosis (30 with low pain severity - LP; 30 with high pain severity - HP) were evaluated at study entry (T0) and after three months (T1). At T0 they were compared for different psychological dimensions to sixty-two age-paired healthy women (CG). HP group had significantly higher scores on depressive symptomatology, sexual distress, and catastrophizing than CG, and higher scores on worry traits than LP. Metacognitive beliefs predicted sexual distress at T1, over and above pain severity. Pain affects different domains of mental health in this population. Coping strategies, metacognitive beliefs, and worry traits may modulate pain experience and psychological distress.

In-depth study of the entire SARS-CoV-2 genome has uncovered many mutations, which have replaced the lineage that characterized the first wave of infections all around the world. In December 2020, the outbreak of variant of concern (VOC) 202012/01 (lineage B.1.1.7) in the United Kingdom defined a turning point during the pandemic, immediately posing a worldwide threat on the Covid-19 vaccination campaign. Here, we reported the evolution of B.1.1.7 lineage-related infections, analyzing samples collected from January 1st 2021, until April 15th 2021, in Friuli Venezia Giulia, a northeastern region of Italy. A cohort of 1508 nasopharyngeal swabs was analyzed by High Resolution Melting (HRM) and 479 randomly selected samples underwent Next Generation Sequencing analysis (NGS), uncovering a steady and continuous accumulation of B.1.1.7 lineage-related specimens, joined by sporadic cases of other known lineages (i.e. harboring the Spike glycoprotein p.E484K mutation). All the SARS-CoV-2 genome has been analyzed in order to highlight all the rare mutations that may eventually result in a new variant of interest. This work suggests that a thorough monitoring of the SARS-CoV-2 genome by NGS is essential to contain any new variant that could jeopardize all the efforts that have been made so far to resolve the emergence of the pandemic., Competing Interests: The authors have declared that no competing interests exist.

Hereditary spastic paraplegias (HSPs) include a group of neurodegenerative disorders characterized by slowly progressive spasticity and weakness of the lower extremities, caused by axon degeneration of corticospinal tracts. Spastic paraplegia type 4 (SPG4) is the most common autosomal dominant form of HSP and is caused by mutations in the SPAST gene. SPAST gene encodes for the protein spastin, a member of the ATPases Associated with a variety of cellular Activity (AAA) family.We describe a newly variant in SPAST gene, within an Italian family affected by pure HSP. In particular, we found a heterozygous intragenic microdeletion of 3T in exon 13 of SPG4 gene. The 3T deletion results in a mutated protein with a unique leucine residues deletion at the protein position 508, in the AAA ATPase domain. This variant is not registered in any public database either as rare normal variant nor as mutation in SPAST gene and the importance of this aminoacid is confirmed by the absolute conservation in multiple alignments with diverse species. We conclude that the novel SPAST gene variant identified is probably pathogenic and destabilizes the precise arrangement of the nucleotide binding domain, with a consequent loss-of-function of the mutated spastin protein.

Episodic ataxia type 2 (EA2) is a hereditary disorder characterized by paroxysmal attacks of ataxia, vertigo and nausea, due to mutations in the CACNA1A gene, which encodes for α1 subunit of the P/Q-type voltage-gated Ca 2+ channel (CaV2.1). Other manifestations may be associated to CACNA1A mutations, such as migraine and epilepsy. The correlation between episodic ataxia and epilepsy is often underestimated and misdiagnosed. Clinical presentation of EA2 varies among patients and within the same family, and the same genetic mutation can lead to different clinical phenotypes. We herewith describe an Italian family presenting with typical EA2 and, in two of the family members (patients II.3 and III.1), epileptic seizures. The sequencing revealed a heterozygous deletion of 6 nucleotides in exon 28 of CACNA1A gene, present in all affected patients. Evidence suggests that mutations of CACNA1A, conferring a loss/reduction of CaV2.1 function, lead to an increase of thalamocortical excitation that contributes to epileptiform discharges. Our description highlights intra-family variability of EA2 phenotype and suggests that mutations in the CACNA1A gene should be suspected in individuals with focal or generalized epilepsy, associated with a family history of episodic ataxia., (© 2021. Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: The impact of pain on quality of life and mental health of women with endometriosis is well known. However, the role that personality traits and coping strategies might have in influencing pain experience is still poorly understood and was the chief purpose of this study., Materials and Methods: We conducted a mixed-method sequential explanatory study, composed of a quantitative survey followed by qualitative interviews. The first quantitative phase included 162 women with endometriosis who completed a battery of validated questionnaires. After statistical analysis, a semistructured qualitative interview has been developed and conducted with 6 of them, in order to help explain findings obtained in the first phase. Thereafter, both analyses were combined in a metamatrix., Results: From the metamatrix, it emerged that acute pain experience, fear of its occurrence, its unpredictability, and control difficulties are the main concerns of women with endometriosis. Worry trait characteristics (ie, the need for control, anticipatory anxiety, intrusive worry thoughts) and maladaptive thoughts such as coping strategies (ie, self-blame, rumination, catastrophizing) were common in this sample and seem to indirectly affect pain experience. Indeed, the unsuccessful struggle in controlling pain reinforces negative thoughts/beliefs and feelings of powerlessness, leading, in turn, to psychological distress and higher pain experience., Discussion: From the study emerged a model of onset and maintenance of acute pain in women with endometriosis. Findings have clinical implications for the medical team and psychologists.

The aim of the study was to assess the predictive value of dyspareunia, general chronic pain, and metacognitive beliefs to sexual distress in a sample of women with endometriosis. Ninety-six women (mean age = 34.60 ± 6.44 years) with a diagnosis of endometriosis took part to this cross-sectional study. Sociodemographic and clinical data were collected by means of a structured ad hoc questionnaire. Metacognitive beliefs and sexual distress were assessed by means of the Metacognitions Questionnaire (MCQ30) and the Female Sexual Distress Scale-R (FSDS-r). General chronic pain intensity was collected by means of a Numeric Rating Scale. Data were subjected to Hierarchical logistic regression. We found high percentages of dyspareunia and sexual distress (i.e., 66% and 76%). Findings suggested that dyspareunia and chronic pain did not predict sexual distress, while negative beliefs about worries predicted sexual distress over and above them (p = .040, odd ratio 1.159). In the target population, metacognitive beliefs may have more influence on sexual distress than pain symptomatology.

Objective: To assess quality of life and psychological differences between infertile women with endometriosis and without endometriosis. To investigate predictive role of perfectionism, mindful awareness and beliefs about parenthood to quality of life in a sample of women with fertility problems., Methods: 43 infertile women (22 with endometriosis; 21 without endometriosis) who recurred to Assisted Reproductive Treatments (ARTs) in the last 12 months took part to this cross-sectional study. Sociodemographic and clinical data were collected by means of a structured ad hoc questionnaire. Fertility Quality of Life, Fertility Problem Inventory - Need of parenthood subscale, Obsessive Beliefs Questionnaire - Perfectionism subscale, and Cognitive and Affective Mindfulness Scale - Revised were used to assess target outcomes., Results: Any difference in quality of life and psychological condition was found between infertile women with and without endometriosis. Importance given to parenthood (beta = -.60, p < .001) and perfectionism (beta = -.30, p < .05) predicted quality of life related to fertility issues, independently of group., Conclusions: Infertility might elicit self-discrepancy between real-self (i.e. being infertile) and ideal-self (being fertile), which in turn has a negative impact on quality of life. Conclusions about the role of psychologist in ART's team are discussed., (Copyright © 2018 Elsevier B.V. All rights reserved.)

A comparison of the individual genomes within a species demonstrates that structural variation, including copy number variation (CNV), is a major contributor to phenotypic diversity and evolutionary adaptation. CNVs lead to the under/over-expression of a gene, according to the changes in the gene dosage, which account for the development of a number of genomic disorders. Thus, the development of efficient, rapid and accurate CNV screening is of fundamental importance. We report a method that enables the simultaneous determination of the copy numbers of several different targets as well as the discrimination among highly similar/almost identical targets that differ by only one single nucleotide variant, which establishes their copy numbers. The PCR co-amplification and single-base extension technologies are used to identify the copy number of a target sequence relative to a reference sequence of known genomic copy number in a given sample. This efficient and accurate quantification platform was successfully used to quantify the copy numbers of the primary spinal muscular atrophy-determining gene, SMN1, and the disease modifier gene, SMN2. The reliability, low-cost and potential for high-throughput make our method suitable for screening large populations as well as for use as a tool in clinical settings for genetic diagnosis/prognosis.

Mast cells (MCs) are innate immune cells that exert positive and negative immune modulatory functions capable to enhance or limit the intensity and/or duration of adaptive immune responses. Although MCs are crucial to regulate T cell immunity, their action in the pathogenesis of autoimmune diseases is still debated. Here we demonstrate that MCs play a crucial role in T1D pathogenesis so that their selective depletion in conditional MC knockout NOD mice protects them from the disease. MCs of diabetic NOD mice are overly inflammatory and secrete large amounts of IL-6 that favors differentiation of IL-17-secreting T cells at the site of autoimmunity. Moreover, while MCs of control mice acquire an IL-10+ phenotype upon interaction with FoxP3+ Treg cells, MCs of NOD mice do not undergo this tolerogenic differentiation. Our data indicate that overly inflammatory MCs unable to acquire a tolerogenic IL-10+ phenotype contribute to the pathogenesis of autoimmune T1D., (Copyright © 2016 Elsevier Inc. All rights reserved.)

It has been proven that both resting and activated mast cells (MCs) and basophils are able to induce a significant increase in proliferation and survival of naïve and activated B cells, and their differentiation into antibody-producing cells. The immunological context in which this regulation occurs is of particular interest and the idea that these innate cells induce antibody class switching and production is increasingly gaining ground. This direct role of MCs and basophils in acquired immunity requires cell to cell contact as well as soluble factors and exosomes. Here, we review our current understanding of the interaction between B cells and MCs or basophils as well as the evidence supporting B lymphocyte-MC/basophil crosstalk in pathological settings. Furthermore, we underline the obscure aspects of this interaction that could serve as important starting points for future research in the field of MC and basophil biology in the peculiar context of the connection between innate and adaptive immunity., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Splenic marginal zone lymphoma (SMZL) is a mature B-cell neoplasm characterized by rather indolent clinical course. However, nearly one third of patients experience a rapidly progressive disease with a dismal outcome. Despite the characterization of clone genetics and the recognition of deregulated immunologic stimulation in the pathogenesis of SMZL, little is known about microenvironment dynamics and their potential biological influence on disease outcome. Here we investigate the effect of stroma-intrinsic features on SMZL disease progression by focusing on the microenvironment of the bone marrow (BM), which represents an elective disease localization endorsing diagnostic and prognostic relevance. We show that the quality of the BM stromal meshwork of SMZL infiltrates correlates with time to progression. In particular, we describe the unfavorable prognostic influence of dense CD40 expression by BM stromal cells, which involves the contribution of CD40 ligand (CD40L)-expressing bystander mast cells infiltrating SMZL BM aggregates. The CD40/CD40L-assisted crosstalk between mesenchymal stromal cells and mast cells populating the SMZL microenvironment finds correlation in p53(-/-) mice developing SMZL and contributes to the engendering of detrimental proinflammatory conditions. Our study highlights a dynamic interaction, playing between nonneoplastic elements within the SMZL niche, toward disease progression.

The aryl hydrocarbon receptor (AhR) is a ligand-dependent transcription factor whose activity is modulated by xenobiotics as well as physiological ligands. These compounds may modulate inflammatory responses and contribute to the rising prevalence of allergic diseases observed in industrialized countries. Mast cells (MCs), located within tissues at the boundary of the external environment, represent a potential target of AhR ligands. In this study, we report that murine and human MCs constitutively express AhR, and its activation by the high-affinity ligand 6-formylindolo[3,2-b]carbazole (FICZ) determines a boost in degranulation. On the contrary, repeated exposure to FICZ inhibits MC degranulation. Accordingly, histamine release, in an in vivo passive systemic anaphylactic model, is exacerbated by a single dose and is attenuated by repetitive stimulation of AhR. FICZ-exposed MCs produce reactive oxygen species and IL-6 in response to cAMP-dependent signals. Moreover, AhR-activated MCs produce IL-17, a critical player in chronic inflammation and autoimmunity, suggesting a novel pathway for MC activation in the pathogenesis of these diseases. Indeed, histological analysis of patients with chronic obstructive pulmonary disease revealed an enrichment in AhR/IL-6 and AhR/IL-17 double-positive MCs within bronchial lamina propria. Thus, tissue-resident MCs could translate external chemical challenges through AhR by modulating allergic responses and contributing to the generation of inflammation-related diseases.

Mast cells (MCs) are currently recognized as effector cells in many settings of the immune response, including host defense, immune regulation, allergy, chronic inflammation, and autoimmune diseases. MC pleiotropic functions reflect their ability to secrete a wide spectrum of preformed or newly synthesized biologically active products with pro-inflammatory, anti-inflammatory and/or immunosuppressive properties, in response to multiple signals. Moreover, the modulation of MC effector phenotypes relies on the interaction of a wide variety of membrane molecules involved in cell-cell or cell-extracellular-matrix interaction. The delivery of co-stimulatory signals allows MC to specifically communicate with immune cells belonging to both innate and acquired immunity, as well as with non-immune tissue-specific cell types. This article reviews and discusses the evidence that MC membrane-expressed molecules play a central role in regulating MC priming and activation and in the modulation of innate and adaptive immune response not only against host injury, but also in peripheral tolerance and tumor-surveillance or -escape. The complex expression of MC surface molecules may be regarded as a measure of connectivity, with altered patterns of cell-cell interaction representing functionally distinct MC states. We will focalize our attention on roles and functions of recently discovered molecules involved in the cross-talk of MCs with other immune partners.

Background: The identification of reliable markers for diagnosis of breast cancer has been thoroughly addressed by metabolic profiling using nuclear magnetic resonance (NMR) spectroscopy or imaging. Several clear diagnostic indicators have emerged using either in vitro analysis of tissue extracts, ex vivo analysis of biopsies or in vivo direct spectral observations. Most of the breast cancer characteristic metabolites could be assayed by mass spectrometry (MS) to exploit the superior sensitivity of this technique and therefore reduce the traumatic impact of current biopsy procedures., Methods: Following extraction, aqueous metabolite mixtures were obtained that were submitted to liquid-chromatography, electrospray-ionization, mass spectrometry (LC/ESI-MS) analysis to estimate the content of choline (Cho) and its phosphorylated derivatives, phosphocholine (PCho) and glycerophosphocholine (GPCho). The determinations were performed using 10 samples from breast tissue biopsies, surgical specimens and one single sample of a hepatic metastasis. In addition, some measurements were also repeated using high-resolution ¹H NMR spectroscopy to complement the mass spectrometry results., Results: The contents of Cho, PCho and GPCho in breast tissue extracts were estimated by LC/ESI-MS based on standard compound calibration curves. Sharply increased ratios of phosphorylated-to-unphosphorylated metabolites, PCho/ Cho and (PCho+GPCho)/Cho, were observed in all tumor samples, although without discrimination between benign and malignant lesions, contrary to samples from healthy individuals and from those with fibrocystic disease., Conclusions: The assessment of breast cancer markers by LC/ESI-MS is feasible and diagnostically valuable. In addition to high sensitivity, the approach also shows a resolution advantage for assaying choline derivatives compared to NMR, and could complement the latter.

We describe a novel localization of C7 as a membrane-bound molecule on endothelial cells (ECs). Data obtained by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), Western blot analysis, Northern blot analysis, and mass spectrometry revealed that membrane-associated C7 (mC7) was indistinguishable from soluble C7 and was associated with vimentin on the cell surface. mC7 interacted with the other late complement components to form membrane-bound TCC (mTCC). Unlike the soluble SC5b-9, mTCC failed to stimulate ECs to express adhesion molecules, to secrete IL-8, and to induce albumin leakage through a monolayer of ECs, and more importantly protected ECs from the proinflammatory effect of SC5b-9. Our data disclose the possibility of a novel role of mC7 that acts as a trap for the late complement components to control excessive inflammation induced by SC5b-9.

Amyloidosis associated to hemodialysis is caused by persistently high beta(2)-microglobulin (beta(2)m) serum levels. beta(2)m is an intrinsically amyloidogenic protein whose capacity to assemble into amyloid fibrils in vitro and in vivo is concentration dependent; no beta(2)m genetic variant is known in the human population. We investigated the roles of two evolutionary conserved Trp residues in relation to beta(2)m structure, function and folding/misfolding by means of a combined biophysical and functional approach. We show that Trp60 plays a functional role in promoting the association of beta(2)m in class I major histocompatibility complex; it is exposed to the solvent at the apex of a protein loop in order to accomplish such function. The Trp60-->Gly mutation has a threefold effect: it stabilizes beta(2)m, inhibits beta(2)m amyloidogenic propensity and weakens the interaction with the class I major histocompatibility complex heavy chain. On the contrary, Trp95 is buried in the beta(2)m core; the Trp95-->Gly mutation destabilizes the protein, which is unfolded in solution, yielding nonfibrillar beta(2)m aggregates. Trp60 and Trp95 therefore play differential and complementary roles in beta(2)m, being relevant for function (Trp60) and for maintenance of a properly folded structure (Trp95) while affecting in distinct ways the intrinsic propensity of wild-type beta(2)m towards self-aggregation into amyloid fibrils.

CD40 is a member of the growing tumor necrosis factor receptor (TNF-R) family of molecules, and has been shown to play important roles in T cell-mediated B lymphocyte activation. Ligation of B cell CD40 by CD154 expressed on activated T cells stimulates B cell proliferation, differentiation, isotype switching, upregulation of surface molecules contributing to antigen presentation, development of the germinal center, and the humoral memory response. The present review will summarize recent literature data on the various CD40 signalling pathways, which involve both the TNF-R associated factors (TRAFs) and additional signalling proteins, and lead to activation of kinases and transcription factors.