Effect of Conservative Rehabilitation Interventions on Health-Related Quality of Life in Women with Upper Limb Lymphedema Secondary to Breast Cancer: A Systematic Review.

Breast cancer-related lymphedema (BCRL) of the upper limb is a very common condition in women undergoing breast cancer treatment; it can cause considerable alterations in the daily life of patients and a decrease in their health-related quality of life (HRQoL). Currently, there are many conservative therapies that try to palliate the symptoms, but the results are still controversial and there are still no globally accepted treatments. The purpose of this article is to determine the effect, according to the current available evidence, on HRQoL of different conservative interventions in the rehabilitation of BCRL in the upper limb in women. Eighteen articles that compared the effects of standard treatments, such as manual lymphatic drainage-based decongestive therapy or compression measures, and other newer treatments, including new technologies and other types of treatment programs, were reviewed. According to the results of this review, the most recommended modality for the improvement of HRQoL would be a complex decongestive technique without manual lymphatic drainage. Although there are clinical trials that have demonstrated the effectiveness of various treatments, the results of the positive effects on HRQoL remain highly controversial. There is a need to continue to develop studies to help guide therapeutic decisions that can promote HRQoL in women affected by upper limb BCRL.

Validity and reliability of the Berlin questionnaire for the detection of moderate or severe obstructive sleep apnea in patients aged 40 years or older detected from primary care.

Background: The obstructive sleep apnea syndrome (OSA) is a highly prevalent condition. In Spain and other countries, only 5%-9% of patients with OSA have been diagnosed and treated. The lack of accessibility to diagnosis is considered the main cause of this situation through easy-to-use screening instruments, it is necessary to check their validity and reliability in the context where they are to be used. Objective: To validate the Spanish translation of the Berlin questionnaire for screening for moderate or severe OSA in patients aged 40 years or more detected in primary care. Methods: A descriptive observational study, with a first qualitative phase of transcultural adaptation to Spanish using the translation-back-translation method. Setting: primary care level of the Spanish National Health System. A total of 255 patients recruited from 7 healthcare centers completed the study. The Berlin questionnaire was administered to the recruited patients, and subsequently, a respiratory polygraphy was performed to confirm the diagnosis of OSA. The concurrent criterion validity of the questionnaire and its reliability in terms of internal consistency and reproducibility (intra-observer agreement) were analyzed. Results: The patients' mean age was 54.76 years (SD: 6.57; 95% CI: 53.53-54.99), and 54.12% were men (95% CI: 47.96-60.27). We found that 61.57% (95% CI: 55.57-67.57) presented OSA (apnea-hypopnea index-AHI >5), and 45.5% (95% CI: 17.05-57.92) presented moderate or severe (AHI >15) OSA. The Berlin questionnaire, with a cut-off point of 4.5, showed a sensitivity of 76.77% (95% CI: 67.94-85.59), a specificity of 74.49% (95% CI: 65.35-83.63), a positive predictive value of 75.25% (95% CI: 66.34-84.16), a negative predictive value of 76.04% (95% CI: 66.98-85.10), and an area under the curve of 0.786 (95% CI: 0.721-0.851). Cronbach's alpha coefficient was 0.730 (95% CI: 0.668-0.784), and the Kappa index was 0.739 (95% CI, 0.384-1.000). Conclusion: The Spanish adaptation of the Berlin questionnaire has good validity and reliability as a test for the diagnostic screening of moderate or severe OSA in patients aged 40 years or older. The findings of our study confirm that primary care physicians should use such screening tools to predict OSA.

The usefulness of the Spanish version of the STOP-Bang questionnaire for screening for moderate or severe sleep apnea syndrome in primary care.

Rationale: Sleep apnea-hypopnea syndrome (OSA) is a highly prevalent disease and has been related to cardiovascular diseases and occupational and traffic accidents. Currently, it is estimated that there is a significant underdiagnosis of OSA, mainly due to the difficulty accessing the tests for that purpose. Objective: To determine the usefulness of the Spanish version of the STOP-Bang questionnaire (SBQ) for screening for moderate or severe OSA in the adult population attending primary care. Methods: A descriptive observational multicenter study was conducted. Through an opportunistic search, (patients over 18 years old), were recruited in seven primary care centers. The SBQ was applied to them and home respiratory polygraphy (HRP) was subsequently performed to confirm the diagnosis of OSA. The criterion validity of the SBQ was analyzed, comparing the score obtained by the SBQ with the apnea-hypopnea index (AHI) obtained by RP, establishing the diagnosis of OSA for an AHI>5. The reliability of the questionnaire was evaluated. Results: A total of 255 subjects, 54.1% men, with a mean age of 54.76 ± 10 years, were recruited in the study. The results showed that 61.57% (95% Confidence Interval: 55.57-67.57) of the subjects presented OSA, presenting 22.75% (17.57-57.92) a mild OSA (530) (11.54-20.62). The Kuder and Richardson coefficient was 0.623 (0.335-0.788) and Cohen's Kappa coefficient was 0.871 (0.520-1.00; p < 0.001). For moderate/severe OSA screening (AHI>15) the SBQ obtained an ROC curve of 0.769 (0.704-0.833) that with an optimal cutoff of 3, achieved a sensitivity of 84.85% (77.28-92.42) and a specificity of 55.10% (44.74-65.46). Conclusions: The SBQ is very effective for detecting moderate/severe OSA. Its psychometric properties are similar to those obtained in studies on other populations. Because of its ease of use, the SBQ is a very useful tool for primary health care professionals.

Profibrotic Role of Inducible Heat Shock Protein 90α Isoform in Systemic Sclerosis.

Systemic sclerosis (SSc) is an autoimmune disease that affects skin and multiple internal organs. TGF-ß, a central trigger of cutaneous fibrosis, activates fibroblasts with the involvement of the stress-inducible chaperone heat shock protein 90 isoform α (Hsp90α). Available evidence supports overexpression and secretion of Hsp90α as a feature in profibrotic pathological conditions. The aim of this work is to investigate the expression and function of Hsp90α in experimental models of skin fibrosis such as human fibroblasts, C57BL/6 mice, and in human SSc. For this purpose, we generated a new experimental model based on doxorubicin administration with improved characteristics with respect to the bleomycin model. We visualized disease progression in vivo by fluorescence imaging. In this work, we obtained Hsp90α mRNA overexpression in human skin fibroblasts, in bleomycin- and doxorubicin-induced mouse fibrotic skin, and in lungs of bleomycin- and doxorubicin-treated mice. Hsp90α-deficient mice showed significantly decreased skin thickness compared with wild-type mice in both animal models. In SSc patients, serum Hsp90α levels were increased in patients with lung involvement and in patients with the diffuse form of SSc (dSSc) compared with patients with the limited form of SSc. The serum Hsp90α levels of patients dSSc were correlated with the Rodnan score and the forced vital capacity variable. These results provide new supportive evidence of the contribution of the Hsp90α isoform in the development of skin fibrosis. In SSc, these results indicated that higher serum levels were associated with dSSc and lung fibrosis.

Activity-Oriented Antiedema Proprioceptive Therapy (TAPA) for Shoulder Mobility Improvement in Women with Upper Limb Lymphedema Secondary to Breast Cancer: A Multicenter Controlled Clinical Trial.

BACKGROUND: Lymphedema, secondary to breast cancer (BCRL), is the abnormal accumulation of protein-rich fluid in the interstitium caused by a malfunction of the lymphatic system. It causes swelling, deficiencies in upper limb functions and structures, sensory pain and emotional alterations, which have a chronic course and affect the upper limb's functionality. This study aims to verify the efficacy and efficiency in the upper limb´s functionality of a protocolized experimental approach based on occupational therapy, TAPA (activity-oriented proprioceptive antiedema therapy), in the rehabilitation of BCRL in stages I and II, comparing it with the conservative treatment considered as the standard, complex decongestive therapy (CDT), through a multicenter randomized clinical trial. METHODS: a randomized and prospective clinical trial was conducted with experimental and control groups. Women diagnosed with BCRL belonging to institutions in Córdoba and Aragon (Spain) participated. Sociodemographic variables and those related to the functionality of the affected upper limb were evaluated before and after the intervention. RESULTS: The results showed statistically significant differences in the analysis of covariance performed for the variable joint balance of the shoulder´s external rotation (p = 0.045) that could be attributed to the intervention performed; however, the effect size was minimal (η2 ≤ 0.080). In the rest of the variables, no significant differences were found. CONCLUSIONS: TAPA may be an alternative to the conservative treatment of women with BCRL. It was shown to be just as effective for volume reduction and activity performance as CDT but more effective in improving external rotation in shoulder joint balance.

Impact of Activity-Oriented Propioceptive Antiedema Therapy on the Health-Related Quality of Life of Women with Upper-Limb Lymphedema Secondary to Breast Cancer-A Randomized Clinical Trial.

BACKGROUND: Alterations derived from lymphedema in the upper-limb secondary to breast cancer-related lymphedema (BCRL) decrease the health-related quality of life (HRQoL), but there is limited evidence of the impact of the different interventions on it. The aim of this research was to compare the effect of conventional treatment with another treatment based on Activity-Oriented Antiedema Proprioceptive Therapy (TAPA) on HRQoL in women diagnosed with BCRL. METHODS: A prospective clinical study was designed with two parallel arms. The study population consisted of women diagnosed with BCRL in stage I and II, belonging to different institutions in Córdoba and Aragon, Spain. Sociodemographic and HRQoL-related variables, pain, tightness, heaviness and functionality were obtained before and after treatments. RESULTS: 51 women participated in the study, 25 received the conventional treatment and 26 the TAPA, with a mean age of 59.24 ± 9.55 years. HRQoL was significantly related to upper-limb function and pain on the participants' affected side. In addition, covariance analysis (ANCOVA) showed that the TAPA treatment interfered less in the performance of activities of daily life and produced significant improvements in the social dimension of HRQoL. CONCLUSIONS: the non-use of compressive elements in the rehabilitative treatment of the BCRL that is proposed with TAPA improves aspects such as self-image and participation in social and recreational activities.

Osteogenic capacity of mesenchymal stem cells from patients with osteoporotic hip fractures in vivo.

PURPOSE: Human mesenchymal stem cells (MSCs) have the ability to differentiate into bone-forming osteoblasts. The aim of this study was to elucidate if MSCs from patients with OP show a senescent phenotype and explore their bone-forming ability in vivo. MATERIALS AND METHODS: MSCs from patients with OP and controls with osteoarthritis (OA) were implanted into the subcutaneous tissue of immunodeficient mice for histological analysis and expression of human genes by RT-PCR. The expression of senescence-associated phenotype (SASP) genes, as well as p16, p21, and galactosidase, was studied in cultures of MSCs. RESULTS: In vivo bone formation was evaluated in 103 implants (47 OP, 56 OA). New bone was observed in 45% of the implants with OP cells and 46% of those with OA cells (p = 0.99). The expression of several bone-related genes (collagen, osteocalcin, alkaline phosphatase, sialoprotein) was also similar in both groups. There were no differences between groups in SASP gene expression, p16, and p21 expression, or in senescence-associated galactosidase activity. CONCLUSION: Senescence markers and the osteogenic capacity in vivo of MSCs from patients with OP are not inferior to that of cells from controls of similar age with OA. This supports the interest of future studies to evaluate the potential use of autologous MSCs from OP patients in bone regeneration procedures.

Efficacy and efficiency of a new therapeutic approach based on activity-oriented proprioceptive antiedema therapy (TAPA) for edema reduction and improved occupational performance in the rehabilitation of breast cancer-related arm lymphedema in women: a controlled, randomized clinical trial.

BACKGROUND: Breast cancer (BC) is a major public health issue. More than one out of five women treated for breast cancer will develop lymphedema in an upper extremity. Current evidence advocates transdisciplinary oncological rehabilitation. Therefore, research in this area is necessary since limited consensus having been reached with regard to the basic essential components of this rehabilitation. Consensus has, however, been reached on the use of decongestive lymphedema therapy (DLT), but due to a lack of tests, the necessary dosages are unknown and its level is moderately strong. This study attempts to verify both the efficacy of activity-oriented proprioceptive antiedema therapy (TAPA), as compared to conventional treatments such as DLT or Complex Physical Therapy (CPT), as well as its efficiency in terms of cost-effectiveness, for patients affected by breast cancer-related arm lymphedema. METHODS: Controlled, randomized clinical trial with dual stratification, two parallel arms, longitudinal and single blind. 64 women with breast cancer-related arm lymphedema will take part in the study. The experimental group intervention will be the same for stage I and II, and will consist of neuro-dynamic exercises oriented to the activity, proprioceptive neuromuscular facilitation activities and proprioceptive anti-edema bandaging. The control group intervention, depending on the stage, will consist of preventive measures, skin care and exercise-prescribed training in the lymphedema workshop as well as compression garments (Stage I) or conservative Complex Decongestive Therapy treatment (skin care, multi-layer bandaging, manual lymphatic drainage and massage therapy) (Stage II). RESULTS: Sociodemographic and clinical variables will be collected for the measurement of edema volume and ADL performance. Statistical analysis will be performed on intent to treat. DISCUSSION: It has been recommended that patient training be added to DLT, as well as a re-designing of patient lifestyles and the promotion of health-related aspects. In addition, clinical trials should be undertaken to assess neural mobilization techniques and proprioceptive neuromuscular facilitation should be included in the therapy. Cohesive bandaging will also be performed as an early form of pressotherapy. The proposed study combines all of these aspects in order to increased comfort and promote the participation of individuals with lymphedema in everyday situations. LIMITATIONS: The authors have proposed the assessment of the experimental treatment for stages I and II. One possible limitation is the lack of awareness of whether or not this treatment would be effective for other stages as well as the concern for proper hand cleansing during use of bandages, given the current COVID-19 pandemic situation. TRIAL REGISTRATION: This trial was registered in ClinicalTrials.gov ( NCT03762044 ). Date of registration: 23 November 2018. Prospectively Registered.

Therapeutic Effects of Anti-Bone Morphogenetic Protein and Activin Membrane-Bound Inhibitor Treatment in Psoriasis and Arthritis.

OBJECTIVE: The transforming growth factor ß (TGFß) inhibitor BAMBI (bone morphogenetic protein and activin membrane-bound inhibitor) has been shown to control differentiation of CD4+ T lymphocytes into either tolerogenic Treg cells or pathogenic Th17 cells, through the regulation of TGFß and interleukin-2 (IL-2) signaling strength. The present study was undertaken to explore the potential beneficial effects of this strategy of pharmacologic inhibition using novel anti-BAMBI monoclonal antibodies (mAb) in different experimental murine models of chronic skin and joint inflammatory/autoimmune disease. METHODS: Development of Saccharomyces cerevisiae mannan-induced psoriatic arthritis (MIP) (n = 18-30 mice per group), imiquimod-induced skin psoriasis (n = 20-30 mice per group), or type II collagen-induced arthritis (CIA) (n = 13-16 mice per group) was analyzed in a total of 2-5 different experiments with either wild-type (WT) or BAMBI-deficient B10.RIII mice that were left untreated or treated with mAb B101.37 (mouse IgG1 anti-BAMBI), a mouse IgG1 anti-TNP isotype control, anti-CD25, or anti-TGFß mAb. RESULTS: Treatment of normal mice with IgG1 anti-BAMBI mAb clone B101.37 led to expansion of Treg cells in vivo, and had both preventive and therapeutic effects in mice with MIP (each P < 0.05 versus controls). The conferred protection against disease progression was found to be mediated by Treg cells, which controlled the activation and expansion of pathogenic IL-17-producing cells, and was dependent on the level of TGFß activity. Furthermore, treatment with B101.37 mAb blocked both the development of skin psoriasis induced by imiquimod and the development of CIA in mice (each P < 0.05 versus controls). Finally, pharmacologic inhibition of BAMBI with the IgM anti-BAMBI mAb B143.14 also potentiated the suppressive activity of Treg cells in vitro (P < 0.001 versus controls). CONCLUSION: These results in murine models identify BAMBI as a promising new therapeutic target for chronic inflammatory diseases and other pathologic conditions modulated by Treg cells.

Multifaceted effects of soluble human CD6 in experimental cancer models.

BACKGROUND: CD6 is a lymphocyte surface co-receptor physically associated with the T-cell receptor (TCR)/CD3 complex at the center of the immunological synapse. There, CD6 assists in cell-to-cell contact stabilization and modulation of activation/differentiation events through interaction with CD166/ALCAM (activated leukocyte cell adhesion molecule), its main reported ligand. While accumulating evidence is attracting new interest on targeting CD6 for therapeutic purposes in autoimmune disorders, little is known on its potential in cancer. In an attempt to elucidate the in vivo relevance of blocking CD6-mediated interactions in health and disease, we explored the consequences of expressing high circulating levels of a soluble form CD6 (sCD6) as a decoy receptor. METHODS: High sCD6 serum levels were achieved by using transgenic C57BL/6 mice expressing human sCD6 under the control of lymphoid-specific transcriptional elements (shCD6LckEµTg) or wild type either transduced with hepatotropic adeno-associated virus coding for mouse sCD6 or undergoing repeated infusions of recombinant human sCD6 protein. Characterization of sCD6-induced changes was performed by ex vivo flow cytometry and functional analyses of mouse lymphoid organ cells. The in vivo relevance of those changes was explored by challenging mice with subcutaneous or metastatic tumors induced by syngeneic cancer cells of different lineage origins. RESULTS: Through a combination of in vitro and in vivo studies, we show that circulating sCD6 expression induces defective regulatory T cell (Treg) generation and function, decreased CD166/ALCAM-mediated tumor cell proliferation/migration and impaired galectin-induced T-cell apoptosis, supporting the fact that sCD6 modulates antitumor lymphocyte effector function and tumorigenesis. Accordingly, sCD6 expression in vivo resulted in delayed subcutaneous tumor growth and/or reduced metastasis on challenge of mice with syngeneic cancer cells. CONCLUSIONS: Evidence is provided for the disruption of CD6 receptor-ligand interactions as a feasible immunomodulatory approach in cancer.

Anti-IL17 treatment ameliorates Down syndrome phenotypes in mice.

Down syndrome (DS) is characterized by structural and functional anomalies that are present prenatally and that lead to intellectual disabilities. Later in life, the cognitive abilities of DS individuals progressively deteriorate due to the development of Alzheimer's disease (AD)-associated neuropathology (i.e., ß-amyloid (Aß) plaques, neurofibrillary tangles (NFTs), neurodegeneration, synaptic pathology, neuroinflammation and increased oxidative stress). Increasing evidence has shown that among these pathological processes, neuroinflammation plays a predominant role in AD etiopathology. In AD mouse models, increased neuroinflammation appears earlier than Aß plaques and NFTs, and in DS and AD models, neuroinflammation exacerbates the levels of soluble and insoluble Aß species, favoring neurodegeneration. The Ts65Dn (TS) mouse, the most commonly used murine model of DS, recapitulates many alterations present in both DS and AD individuals, including enhanced neuroinflammation. In this study, we observed an altered neuroinflammatory milieu in the hippocampus of the TS mouse model. Pro-inflammatory mediators that were elevated in the hippocampus of this model included pro-inflammatory cytokine IL17A, which has a fundamental role in mediating brain damage in neuroinflammatory processes. Here, we analyzed the ability of an anti-IL17A antibody to reduce the neuropathological alterations that are present in TS mice during early neurodevelopmental stages (i.e., hippocampal neurogenesis and hypocellularity) or that are aggravated in later-life stages (i.e., cognitive abilities, cholinergic neuronal loss and increased cellular senescence, APP expression, Aß peptide expression and neuroinflammation). Administration of anti-IL17 for 5 months, starting at the age of 7 months, partially improved the cognitive abilities of the TS mice, reduced the expression of several pro-inflammatory cytokines and the density of activated microglia and normalized the APP and Aß1-42 levels in the hippocampi of the TS mice. These results suggest that IL17-mediated neuroinflammation is involved in several AD phenotypes in TS mice and provide a new therapeutic target to reduce these pathological characteristics.

Impact of Positive Pressure Treatment of the Airway on Health-Related Quality of Life in Elderly Patients With Obstructive Sleep Apnea.

BACKGROUND: Obstructive sleep apnea (OSA) is a chronic illness that increases in prevalence with age. Treatment includes continuous positive airway pressure (CPAP) devices. Studies about the use of CPAP in the elderly are scarce. The main objective of this study is to determine whether CPAP contributes to improvement in health-related quality of life (HRQL) in elderly patients with OSA. METHOD: This was a prospective, pre-/postintervention assessment of a cohort of patients ≥65 years of age with OSA diagnosis by polysomnography who were being treated with CPAP and were physically independent and had good cognitive status. We determined HRQL before and after 3 months of CPAP treatment using the Short Form-36 Health Survey (SF-36, a 36-item, patient-reported survey) and Sleep Apnea Quality of Life Index (SAQLI). The effect of CPAP on daytime sleepiness was assessed with the Epworth Sleepiness Scale (ESS). RESULTS: Of the 103 participants with a mean age of 71.5 ± 4.19 years, 66% were male. After 3 months of therapy, the mean CPAP usage was 6.3 ± 1.41 hr/day. The effectiveness of CPAP in controlling the OSA was demonstrated (mean difference pre- and posttherapy: 34.30 ± 18.52 events/hr, p < .001). Postintervention, the categories of the SF-36 improved meaningfully ( p < .001). Moreover, all categories of SAQLI improved ( p < .001) with the exception of "symptoms" ( p = .073). ESS scores also improved significantly (difference = 5.2 ± 4.47, p < .001) postintervention. CONCLUSION: Therapy with CPAP in elderly patients with OSA helps improve their HRQL and reduces daytime sleepiness.

CD6 modulates thymocyte selection and peripheral T cell homeostasis.

The CD6 glycoprotein is a lymphocyte surface receptor putatively involved in T cell development and activation. CD6 facilitates adhesion between T cells and antigen-presenting cells through its interaction with CD166/ALCAM (activated leukocyte cell adhesion molecule), and physically associates with the T cell receptor (TCR) at the center of the immunological synapse. However, its precise role during thymocyte development and peripheral T cell immune responses remains to be defined. Here, we analyze the in vivo consequences of CD6 deficiency. CD6(-/-) thymi showed a reduction in both CD4(+) and CD8(+) single-positive subsets, and double-positive thymocytes exhibited increased Ca(2+) mobilization to TCR cross-linking in vitro. Bone marrow chimera experiments revealed a T cell-autonomous selective disadvantage of CD6(-/-) T cells during development. The analysis of TCR-transgenic mice (OT-I and Marilyn) confirmed that abnormal T cell selection events occur in the absence of CD6. CD6(-/-) mice displayed increased frequencies of antigen-experienced peripheral T cells generated under certain levels of TCR signal strength or co-stimulation, such as effector/memory (CD4(+)TEM and CD8(+)TCM) and regulatory (T reg) T cells. The suppressive activity of CD6(-/-) T reg cells was diminished, and CD6(-/-) mice presented an exacerbated autoimmune response to collagen. Collectively, these data indicate that CD6 modulates the threshold for thymocyte selection and the generation and/or function of several peripheral T cell subpopulations, including T reg cells.

Selective Impairment of TH17-Differentiation and Protection against Autoimmune Arthritis after Overexpression of BCL2A1 in T Lymphocytes.

The inhibition of apoptotic cell death in T cells through the dysregulated expression of BCL2 family members has been associated with the protection against the development of different autoimmune diseases. However, multiple mechanisms were proposed to be responsible for such protective effect. The purpose of this study was to explore the effect of the T-cell overexpression of BCL2A1, an anti-apoptotic BCL2 family member without an effect on cell cycle progression, in the development of collagen-induced arthritis. Our results demonstrated an attenuated development of arthritis in these transgenic mice. The protective effect was unrelated to the suppressive activity of regulatory T cells but it was associated with a defective activation of p38 mitogen-activated protein kinase in CD4+ cells after in vitro TCR stimulation. In addition, the in vitro and in vivo TH17 differentiation were impaired in BCL2A1 transgenic mice. Taken together, we demonstrated here a previously unknown role for BCL2A1 controlling the activation of CD4+ cells and their differentiation into pathogenic proinflammatory TH17 cells and identified BCL2A1 as a potential target in the control of autoimmune/inflammatory diseases.

Bone Morphogenetic Protein and Activin Membrane-Bound Inhibitor, a Transforming Growth Factor ß Rheostat That Controls Murine Treg Cell/Th17 Cell Differentiation and the Development of Autoimmune Arthritis by Reducing Interleukin-2 Signaling.

OBJECTIVE: Transforming growth factor ß (TGFß) plays a prominent role in the establishment of immunologic tolerance, and mice lacking TGFß1 die of multiorgan inflammation early in life. TGFß controls the differentiation of CD4+ lymphocytes into Treg cells or proinflammatory Th17 cells. Although this dual capacity is modulated by the presence of additional cytokines around the activated cells, TGFß also dissociates Th17/Treg cell differentiation in a dose-dependent manner by mechanisms still unknown. The purpose of this study was to explore the contribution of bone morphogenetic protein and activin membrane-bound inhibitor (BAMBI) to the modulation of TGFß activity during the differentiation of CD4+ cells and in the control of immunologic tolerance in mice with collagen-induced arthritis (CIA). METHODS: The in vitro and in vivo Treg cell and Th17 cell differentiation and the development of CIA were compared in wild-type mice and BAMBI-deficient mice. RESULTS: BAMBI was induced after activation by TGFß and fixed the appropriate intensity level of TGFß signaling in CD4+ cells. Its deficiency protected mice against the development of CIA by a Treg cell- and TGFß-dependent mechanism. Mechanistically, BAMBI was found to regulate CD25 expression and interleukin-2 (IL-2) signaling in Treg cells and in IL-2- and/or TGFß-activated CD4+ cells and modulated Treg cell and Th17 cell differentiation both in vitro and in vivo. CONCLUSION: Taken together, the results indicate that BAMBI is a component of a rheostat-like mechanism that, through the control of TGFß and IL-2 signaling strength, regulates the differentiation of CD4+ lymphocytes and the development of autoimmune arthritis.

Distinct serum proteome profiles associated with collagen-induced arthritis and complete Freund's adjuvant-induced inflammation in CD38⁻/⁻ mice: The discriminative power of protein species or proteoforms.

Collagen-type-II-induced arthritis (CIA) is an autoimmune disease, which involves a complex host systemic response including inflammatory and autoimmune reactions. CIA is milder in CD38(-/-) than in wild-type (WT) mice. ProteoMiner-equalized serum samples were subjected to 2D-DiGE and MS-MALDI-TOF/TOF analyses to identify proteins that changed in their relative abundances in CD38(-/-) versus WT mice either with arthritis (CIA(+) ), with no arthritis (CIA(-) ), or with inflammation (complete Freund's adjuvant (CFA)-treated mice). Multivariate analyses revealed that a multiprotein signature (n = 28) was able to discriminate CIA(+) from CIA(-) mice, and WT from CD38(-/-) mice within each condition. Likewise, a distinct multiprotein signature (n = 16) was identified which differentiated CIA(+) CD38(-/-) mice from CIA(+) WT mice, and lastly, a third multiprotein signature (n = 18) indicated that CD38(-/-) and WT mice could be segregated in response to CFA treatment. Further analyses showed that the discriminative power to distinguish these groups was reached at protein species level and not at the protein level. Hence, the need to identify and quantify proteins at protein species level to better correlate proteome changes with disease processes. It is crucial for plasma proteomics at the low-abundance protein species level to apply the ProteoMiner enrichment. All MS data have been deposited in the ProteomeXchange with identifiers PXD001788, PXD001799 and PXD002071 (http://proteomecentral.proteomexchange.org/dataset/PXD001788, http://proteomecentral.proteomexchange.org/dataset/PXD001799 and http://proteomecentral.proteomexchange.org/dataset/PXD002071).

Transgenic expression of soluble human CD5 enhances experimentally-induced autoimmune and anti-tumoral immune responses.

CD5 is a lymphoid-specific transmembrane glycoprotein constitutively expressed on thymocytes and mature T and B1a lymphocytes. Current data support the view that CD5 is a negative regulator of antigen-specific receptor-mediated signaling in these cells, and that this would likely be achieved through interaction with CD5 ligand/s (CD5L) of still undefined nature expressed on immune or accessory cells. To determine the functional consequence of loss of CD5/CD5L interaction in vivo, a new transgenic mouse line was generated (shCD5EµTg), expressing a circulating soluble form of human CD5 (shCD5) as a decoy to impair membrane-bound CD5 function. These shCD5EµTg mice showed an enhanced response to autologous antigens, as deduced from the presentation of more severe forms of experimentally inducible autoimmune disease (collagen-induced arthritis, CIA; and experimental autoimmune encephalitis, EAE), as well as an increased anti-tumoral response in non-orthotopic cancer models (B16 melanoma). This enhancement of the immune response was in agreement with the finding of significantly reduced proportions of spleen and lymph node Treg cells (CD4+CD25+FoxP3+), and of peritoneal IL-10-producing and CD5+ B cells, as well as an increased proportion of spleen NKT cells in shCD5EµTg mice. Similar changes in lymphocyte subpopulations were observed in wild-type mice following repeated administration of exogenous recombinant shCD5 protein. These data reveal the relevant role played by CD5/CD5L interactions on the homeostasis of some functionally relevant lymphocyte subpopulations and the modulation of immune responses to autologous antigens.

p27(Kip1) inhibits systemic autoimmunity through the control of Treg cell activity and differentiation.

OBJECTIVE: Despite the importance of Treg cells in the maintenance of immunologic tolerance, the mechanisms that control their generation and activity are unknown. Since the cell cycle inhibitor p27(Kip1) (p27) was involved in T cell anergy, we undertook this study to explore its role in both Treg cell processes. METHODS: The development of type II collagen-induced arthritis (CIA) and lupus-like abnormalities was compared between transgenic mice overexpressing human Bcl-2 in T cells (BCL2-TgT mice) and nontransgenic mice that were deficient or not deficient in p27. The contribution of Treg cells to disease evolution was also explored. Finally, the in vitro activity of Treg cells and their differentiation from naive CD4+ cells was compared between these strains of mice. RESULTS: BCL2-TgT mice were protected against CIA by a Treg cell-dependent mechanism. In association with this protection, the overexpression of Bcl-2 in T cells enhanced the differentiation and activity of Treg cells. Both Bcl-2 effects were independent of its antiapoptotic activity but dependent on its capacity to induce the expression of p27 that augmented the strength of transforming growth factor ß (TGFß) signaling in T cells. Accordingly, down-modulation of p27 expression in BCL2-TgT mice promoted CIA. In addition, p27 deficiency in aged C57BL/6 mice reduced the number and activity of Treg cells and induced the development of mild lupus-like abnormalities. CONCLUSION: Our results point to p27 as a critical regulator of Treg cell differentiation and function through the positive modulation of TGFß signaling strength in T cells.

Aportaciones de la medicina forense a la investigación de la conducta suicida / Contributions of forensic medicine to research of suicidal behaviour

El suicidio es la principal causa de muerte violenta en España, por delante de los accidentes de tráfico, y se estima que cada año se suicidan cerca de 3.500 personas. Los factores de riesgo identificados de la conducta suicida se basan, principalmente, en estudios de intentos de suicidio. La centralización de las autopsias en los Institutos de Medicina Legal facilita la homogenización del método de trabajo y la consistencia de los resultados a nivel práctico-judicial y de investigación. La medicina forense debe proyectarse en la investigación en general y de la conducta suicida en particular, en colaboración con otros equipos de investigación. La investigación debe efectuarse según la normativa ética y administrativa vigente y ser aprobada por el Comité Ético de referencia. Con respecto a la investigación de los factores de riesgo del suicidio, el reclutamiento de casos y controles, la obtención de muestras biológicas, la colaboración en la realización de autopsias psicológicas y los estudios epidemiológicos, son aportaciones esenciales de la medicina forense(AU)

In Spain, suicide is the leading cause of violent death, ahead of motor vehicle accidents, with about 3,500 people dying by this mean in Spain. The risk factors identified are primarily based on studies of suicide attempts. The centralization of autopsies in the Institutes of Legal Medicine allows the homogenization of working methods and the consistency of results for both research and legal purposes. Forensics should focus on medical research in general and on suicidal behaviour in particular, in collaboration with other research teams. Research must be conducted according to existing ethical and administrative legislation. All must be approved by the Ethics Committee of reference. With regard to the investigation of risk factors for suicide, forensics are essential in the recruitment of cases and controls-obtaining biological samples, collaborating in conducting psychological autopsies and epidemiological studies(AU)