Citations

AbstractIntroductionThe situation generated in the health system by the COVID‐19 pandemic has provoked a crisis involving the necessity to cancel non‐urgent and oncologic activity in the operating room and in day‐to‐day practice. As the situation continues, the need to reinstate attention for patients with chronic pain grows. The restoration of this activity has to begin with on‐site appointments and possible surgical procedures. On‐site clinical activity has to guarantee the safety of patients and health workers.ObjectivesThe objective of this review was to evaluate how to manage activity in pain units, considering the scenario generated by the pandemic and the implications of chronic pain on the immune system and proposed pharmacological and interventional therapies.MethodsBesides the established general recommendations (physical distance, surgical masks, gloves, etc.), we established specific recommendations that will allow patient treatment and relieve the disruption of the immune response. It is important to highlight the use of opioids with the least influence in the immune system. Further, individualized corticoid use, risk assessment, reduced immune suppression, and dose adjustment should take patient needs into account. In this scenario, we highlight the use of radiofrequency and neuromodulation therapies, techniques that do not interfere with the immune response.ConclusionsWe describe procedures to implement these recommendations for individual clinical situations, the therapeutic possibilities and safety guidelines for each center, and government recommendations during the COVID‐19 pandemic.

AbstractSuppression of the insulin‐like growth factor‐1 (IGF‐1) signaling pathway reduces age‐related disorders and increases lifespan across species, making the IGF‐1 pathway a key regulator of aging. Previous in vitro intervertebral disc cell studies have reported the pro‐anabolic effect of exogenously adding IGF‐1 on matrix production. However, the overall effects of suppressing IGF‐1 signaling on age‐related intervertebral disc degeneration (IDD) is not known. Here, the effects of suppressing IGF‐1 signaling on age‐related IDD in vivo were examined using PAPPA−/− mice. These are animals with targeted deletion of pregnancy‐associated plasma protein A (PAPPA), the major protease that cleaves inhibitory IGF binding proteins that control bioavailability of IGF‐1 for cell signaling. Compared to age‐matched wild‐type (Wt) littermates, reduced levels of matrix proteoglycan (PG) and aggrecan were seen in discs of 23‐month old PAPPA−/− mice. Decreased aggrecanolysis and expression of two key catabolic markers, matrix metalloproteinase‐3 and a disintegrin and metalloproteinase with thrombospondin motifs‐4, were also observed in discs of old PAPPA−/− mice compared to Wt littermates. Suppressing IGF‐1 signaling has been implicated to shift cellular metabolism toward maintenance rather than growth and decreasing cellular senescence. Along this line, discs of old PAPPA−/− mice also exhibited lower cellular senescence, assessed by p53 and lamin B1 markers. Collectively, the data reveal complex regulation of disc matrix homeostasis by PAPPA/IGF‐1 signaling during chronologic aging, that is, reduced IGF‐1 bioavailability confers the benefit of decreasing disc cellular senescence and matrix catabolism but also the disadvantage of decreasing disc PG matrix anabolism. This pathway requires further mechanistic elucidation before IGF‐1 could be considered as a therapeutic growth factor for treating IDD.

Abstract Introduction: Anti-thyroid Drugs (ATD) have become the most frequently used treatment for Graves’ disease (GD) in the United States. However, the response to this therapy is variable. Factors that predict biochemically responsive vs. biochemically persistent disease remain unknown. Identifying predictors of disease poorly responsive to ATD can help guide treatment decision making, follow up planning and prognosis. Methods: From a database of patients with GD treated with ATD and receiving care at an academic medical center between 2009–2019, we selected adults with incident GD treated with ≥14 days of ATD. Results: 172 patients (from a database of 730 patients with GD on ATD) were sampled for the purpose of this pilot and 97 of these met inclusion criteria. Patients had a median age of 50 (18–90); female, 70.1%; never smokers, 64.9%; median goiter size of 40 g (15–100); and median TRAb on presentation of 8.1 mIU/L (1.0- 60). Graves’ orbitopathy (GO) was present in 13.4% at baseline. Patients (100%) were started on methimazole at a median dose of 20 mg (2.5–60). The median time from presentation until biochemical improvement (defined as the first instance of FT4 ≤1.7 ng/dL) was 120.9 days (18–1525), and to biochemical euthyroidism (normal TSH & FT4) was 251 days (41–1259) including a median of 3 (0–17) dose adjustments. In a univariate analysis, response to ATD was divided into two groups; biochemically responsive and biochemically persistent disease (based on reaching biochemical improvement in ≤6 months, or >6 months respectively). Biochemically persistent disease was more common in those with GO at presentation (38.5% vs.11.1%) (p .024). There was a trend towards greater prevalence of biochemically persistent disease in those with TRAb ≥ 8.0 mIU/L (46.2% vs. 27.8%) (p .204), and goiter estimated 30 grams or above by physical examination (30.8% vs. 19.4%) (p .460). Biochemically responsive disease was associated with higher frequency of hypothyroidism during treatment (p .047). Conclusion: Our preliminary results illustrate the spectrum of response to ATD and predictors of biochemically persistent disease. We aim to expand this analysis utilizing a large database. As use of ATD increases, clinicians and patients can apply this data to estimate response to therapy, and identify patients that may require more aggressive therapy, thereby tailoring management plans.

Abstract Context SDHB mutations are found in an increasing number of neoplasms, most notably in paragangliomas and pheochromocytomas (PPGLs). SDHB-PPGLs are slow-growing tumors, but ∼50% of them may develop metastasis. The molecular basis of metastasis in these tumors is a long-standing and unresolved problem. Thus, a better understanding of the biology of metastasis is needed. Objective This study aimed to identify gene methylation changes relevant for metastatic SDHB-PPGLs. Design We performed genome-wide profiling of DNA methylation in diverse clinical and genetic PPGL subtypes, and validated protocadherin γ-C3 (PCDHGC3) gene promoter methylation in metastatic SDHB-PPGLs. Results We define an epigenetic landscape specific for metastatic SDHB-PPGLs. DNA methylation levels were found significantly higher in metastatic SDHB-PPGLs than in SDHB-PPGLs without metastases. One such change included long-range de novo methylation of the PCDHA, PCDHB, and PCDHG gene clusters. High levels of PCDHGC3 promoter methylation were validated in primary metastatic SDHB-PPGLs, it was found amplified in the corresponding metastases, and it was significantly correlated with PCDHGC3 reduced expression. Interestingly, this epigenetic alteration could be detected in primary tumors that developed metastasis several years later. We also show that PCDHGC3 down regulation engages metastasis-initiating capabilities by promoting cell proliferation, migration, and invasion. Conclusions Our data provide a map of the DNA methylome episignature specific to an SDHB-mutated cancer and establish PCDHGC3 as a putative suppressor gene and a potential biomarker to identify patients with SDHB-mutated cancer at high risk of metastasis who might benefit from future targeted therapies.

Objectives: We compared the magnitude and direction of associations between forgiveness and pain, mental and physical health, quality of life, and anger in a sample of fibromyalgia syndrome (FM) participants and healthy controls. In addition, we compared FM and controls on mean levels of these variables. Materials and Methods: A total of 173 individuals with FM and 81 controls completed this study. FM participants and controls were residents of Germany recruited with the support of the German Fibromyalgia Patient Association and several self-help groups. FM participants and controls were about 53 years of age, mostly married (70%), Christians (81%), with levels of education ranging from 9 to 13+ years. All participants completed assessments of forgiveness, pain, health, quality of life, and anger. Results: Analyses revealed that FM participants reported higher pain and anger and poorer health and quality of life. FM participants also reported lower levels of both forgiveness of self and others. Size and direction of associations of forgiveness with pain, health, quality of life, and anger in were not significantly different between healthy individuals and individuals with FM. Discussion: Forgiveness of self and others is beneficially associated with pain, health, quality of life, and anger in FM participants at levels that are of similar size and direction as in healthy controls. However, FM participants manifest lower levels of forgiveness of self and others. Therapeutic promotion of forgiveness as a psychosocial coping strategy may help patients with FM to better manage psychological and physical symptoms, thereby enhancing well-being.

Abstract Thrombospondin-1 (TSP) is a transiently expressed matricellular protein known to promote chemotaxis of leukocytes to inflammatory sites. However, TSP and its receptor CD36 are abundantly expressed in chronically inflamed tissues such as the rheumatoid synovium. Here, we show that TSP provides the costimulatory signal that is necessary for the activation of autoreactive T cells. Data presented reveal that TSP-mediated costimulation is achieved through its independent interaction with CD36 on APCs and with CD47 on T cells. We propose that a CD47-TSP-CD36 trimolecular complex is a novel costimulatory pathway that significantly decreases the threshold of T cell activation. Consistent with the paradigm that lesions in rheumatoid synovitis are sites of antigenic recognition, the characteristic focal expression of TSP on APCs such as macrophages and fibroblast-like synoviocytes suggest a central role of TSP in the expansion of tissue-infiltrating T cells.

Abstract CD4+CD28null T cells are oligoclonal lymphocytes rarely found in healthy individuals younger than 40 yr, but are found in high frequencies in elderly individuals and in patients with chronic inflammatory diseases. Contrary to paradigm, they are functionally active and persist over many years. Such clonogenic potential and longevity suggest altered responses to apoptosis-inducing signals. In this study, we show that CD4+CD28null T cells are protected from undergoing activation-induced cell death. Whereas CD28+ T cells underwent Fas-mediated apoptosis upon cross-linking of CD3, CD28null T cells were highly resistant. CD28null T cells were found to progress through the cell cycle, and cells at all stages of the cell cycle were resistant to apoptosis, unlike their CD28+ counterparts. Neither the activation-induced up-regulation of the IL-2R α-chain (CD25) nor the addition of exogenous IL-2 renders them susceptible to Fas-mediated apoptosis. These properties of CD28null T cells were related to high levels of Fas-associated death domain-like IL-1-converting enzyme-like inhibitory protein, an inhibitor of Fas signaling that is normally degraded in T cells following activation in the presence of IL-2. Consistent with previous data showing protection of CD28null cells from spontaneous cell death, the present studies unequivocally show dysregulation of apoptotic pathways in CD4+CD28null T cells that favor their clonal outgrowth and maintenance in vivo.

Abstract The ability to mount protective immune responses depends on the diversity of T cells. T cell diversity may be compromised by the declining thymic output of new T cells. The aging process imposes a threat to diversity, because thymic function deteriorates. In this study we have examined the relationship between thymic production, homeostatic T cell proliferation and TCR β-chain diversity in young (∼25 years), middle-aged (∼60 years), and elderly adults (∼75 years). TCR excision circles (TREC) as a marker of thymic output exponentially decreased by >95% between 25 and 60 years of age. The frequency of Ki67+ cycling CD4 T cells remained steady, and surprisingly, the diversity of the naive CD4 T cell repertoire was maintained at ∼2 × 107 different TCR β-chains. After the age of 70 years, TRECs only slightly declined, but homeostatic proliferation doubled. The diversity of the T cell pool drastically contracted to 200,000 TCR β-chains. Also, the phenotypic distinction between naive and memory CD4 T cells became fuzzy. The collapse in CD4 T cell diversity during the seventh and eighth decades indicates substantial T cell loss and implies that therapeutic measures to improve vaccine responses will have to include strategies for T cell replenishment.

Abstract To evaluate the disease-modulating role of HLA-DR2 and DR3 molecules, which have been associated with systemic lupus erythematosus, a humanized mouse model was examined. HLA-DR2 (DRB1*1502)- and DR3 (DRB1*0301)-transgenic mice were backcrossed to the New Zealand Mixed 2410 (NZM 2410, H2z) strain. Seventh generation DR2 and DR3 transgene-positive animals along with their transgene-negative littermates and the parental strain NZM2410 were monitored for proteinuria, azotemia, autoantibody production, development of nephritis, and mortality. The results showed no significant differences in proteinuria, azotemia, or mortality between the backcrosses with and without HLA-DR2 or HLA-DR3. However, the genetic analysis of different backcrosses showed that heterozygosity at the endogenous H2-E locus (Ez/Eb) was strongly linked with acceleration of lupus nephritis in both HLA-DR2 and HLA-DR3 transgenics. More importantly, the presence of the HLA-DR2, but not the HLA-DR3, transgene significantly enhanced the production of anti-dsDNA, but not anti-ssDNA, anti-histone-dsDNA complex, or anti-histone, Abs. In contrast, neither HLA-DR2 nor HLA-DR3 influenced the development of glomerulonephritis or the degree of immune complex deposition. Moreover, nephritic kidneys from mice with and without HLA-DR2 or HLA-DR3 transgenes showed similar patterns of cytokine expression. Collectively, these findings provide molecular evidence that the association of HLA-DR2 or HLA-DR3 with lupus susceptibility is related to the type of autoantibody rather than to disease mortality. The use of a humanized mouse model provides a way of dissecting the roles of human MHC genes in systemic lupus erythematosus pathogenesis.

Abstract Fibroblast-like synoviocytes (FLS) from patients with rheumatoid arthritis elicit spontaneous proliferation of autologous T cells in an HLA-DR and CD47 costimulation-dependent manner. T cell costimulation through CD47 is attributed to specific interaction with thrombospondin-1 (TSP1), a CD47 ligand displayed on FLS. CD47 binding by FLS has broad biological impact that includes adhesion and the triggering of specific costimulatory signals. TSP1+ FLS are highly adhesive to T cells and support their aggregation and growth in situ. Long-term cultures of T cells and FLS form heterotypic foci that are amenable to propagation without exogenous growth factors. T cell adhesion and aggregate formation on TSP1+ FLS substrates are inhibited by CD47-binding peptides. In contrast, FLS from arthroscopy controls lack adhesive or T cell growth-promoting activities. CD47 stimulation transduces a costimulatory signal different from that of CD28, producing a gene expression profile that included induction of ferritin L chain, a component of the inflammatory response. Ferritin L chain augments CD3-induced proliferation of T cells. Collectively, these results demonstrate the active role of FLS in the recruitment, activation, and expansion of T cells in a CD47-dependent manner. Because TSP1 is abundantly expressed in the rheumatoid synovium, CD47-TSP1 interaction is proposed to be a key component of an FLS/T cell regulatory circuit that perpetuates the inflammatory process in the rheumatoid joint.