Use of average volume-assured pressure support as a therapeutic option in patients with central sleep apnea syndrome.

PURPOSE: Central sleep apnea (CSA) syndrome commonly occurs with other medical conditions such as congestive heart failure, opiate use, and brainstem disorders. Various treatment modalities have been used with varied effectiveness in an attempt to improve ventilation and reduce the apnea-hypopnea index (AHI) in patients with CSA. This study evaluated whether or not a bilevel positive airway pressure mode of noninvasive ventilation, average volume-assured pressure support (AVAPS) is effective in treating CSA. METHODS: This was a retrospective review of patients with CSA who underwent AVAPS titration studies at our institution. We included patients with CSA with apnea-hypopnea index (events/hour) (AHI) ≥ 15, and examined the effectiveness of AVAPS in reducing AHI, improving oxygenation parameters, and improving sleep architecture. RESULTS: There were 12 patients, with mean age 62.8 ± 11.5 years, body mass index (BMI) 33.5 ± 4.7 kg/m2, 8 men, and Epworth Sleepiness Scale 9.3 ± 4.9. Five patients had CSA attributed to opiate use, 4 patients had CSA with Cheyne-Stokes respiration, and 3 patients had primary CSA. The only significant change from baseline PSG was AHI reduction with AVAPS: 63.3 ± 19.1 to 30.5 ± 30.3 (p < 0.003). In 5 patients (42%), AHI was reduced to < 15 with AVAPS use. Improvement in AHI was not related to gender, BMI, opiate use, or age. Defining response to therapy as AHI reduced to < 15, we found that lack of hypertension was the only significant predictor of response (p = 0.045). No significant changes in sleep architecture between the two studies were found. CONCLUSION: AVAPS is an effective mode of treating CSA in a significant proportion of patients. More studies are needed to confirm these findings and determine what factors are associated with response to therapy.

The Influence of Different Light Angles During Standardized Patient Photographic Assessment on the Aesthetic Perception of the Face.

BACKGROUND: 2D baseline and follow-up clinical images are potentially subject to inconsistency due to alteration of imaging parameters. However, no study to date has attempted to quantify the magnitude by which such images can be influenced. OBJECTIVE: The objective of the present study is to identify the magnitude by which images can be influenced by changing the imaging light angle. METHODS: This study is based on the evaluation of 2D frontal images of the face and included a total of 51 subjects of which n = 14 were males and n = 37 were females. Faces were photographed at 0°, 30°, and 60° light angle under identical and standardized conditions. Images were randomized and rated by 27 blinded raters for age, facial attractiveness, body mass index (BMI), temporal hollowing, lower cheek fullness, nasolabial sulcus severity, and jawline contour. RESULTS: Facial attractiveness decreased, facial unattractiveness increased and the evaluated BMI (based on facial assessment) increased statistically significantly at 60°. The assessment of regional facial scores, i.e., temporal hollowing, lower cheek fullness, and jawline contour, showed no statistically meaningful changes both at 30° and at 60° light angle. CONCLUSION: The results indicate that there might be an observed blind range in light angle (0°-30°) which does not influence facial assessment. Increasing the light angle past the threshold value to 60° might result in a statistically significant impact on facial perception which should be accounted for when documenting and/or presenting facial 2D images. LEVEL OF EVIDENCE V: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Differences in systemic and skin migrating-specific CD4 T cells in papular urticaria by flea bite.

BACKGROUND: Papular urticaria by flea bite is a chronic allergic condition in which clinical improvement may occur at the age of 7 years, thus representing a natural model of acquired immunologic tolerance in humans. The aim of this study was to characterize regulatory cells and specific responses to flea antigens of CD4(+) T lymphocytes expressing cutaneous migration markers in patients with papular urticaria caused by flea bite and with different disease evolution times. METHODS: Cell populations were characterized by flow cytometry in samples from patients and healthy controls. Specific cell stimulation was performed with a complete flea body extract. The Mann-Whitney U test was used for comparisons. RESULTS: Total dendritic cells were lower in patients than in healthy controls. No quantitative differences were found in CD4 regulatory T cells. CD4(+) T cells from patients produced more IL-4, lL-10, IL-17, and IFN-γ. Patients who experienced the onset of symptoms within the first 5 years of age showed a greater percentage of local (cutaneous lymphocyte antigen +) IL-4- and IL-17-producing cells, while patients who experienced the onset of symptoms after the age of 5 years had a higher percentage of systemic (cutaneous lymphocyte antigen -) IL-10-producing cells. CONCLUSION: Analysis of the cellular immune response against whole flea antigen in patients with papular urticaria by flea bites suggests a possible participation of inflammatory cytokines in the skin reaction (Th17) and a systemic control mechanism (IL-10). This pattern of cytokine production in patients could be a consequence of an impaired dendritic cell population.

A human astrocytoma cell line is highly susceptible to infection with Trypanosoma cruzi.

Astrocytes play a vital role in neuronal protection, homeostasis, vascular interchange and the local immune response. Some viruses and parasites can cross the blood-brain barrier and infect glia. Trypanosoma cruzi, the aetiological agent of Chagas disease, can seriously compromise the central nervous system, mainly in immune-suppressed individuals, but also during the acute phase of the infection. In this report, the infective capacity of T. cruzi in a human astrocyte tumour-derived cell line was studied. Astrocytes exposed to trypomastigotes (1:10 ratio) produced intracellular amastigotes and new trypomastigotes emerged by day 4 post-infection (p.i.). At day 6 p.i., 93% of the cells were infected. Using flow cytometry, changes were observed in both the expression of major histocompatibility complex class I and II molecules and the chemokine secretion pattern of astrocytes exposed to the parasite. Blocking the low-density lipoprotein receptor on astrocytes did not reduce parasite intracellular infection. Thus, T. cruzi can infect astrocytes and modulate the immune response during central nervous system infection.

Safety and efficacy of non-cemented femoral fixation in patients 75 years of age and older.

The aim of this study was to assess peri-operative complications, safety and efficacy of non-cemented femoral fixation in total hip arthroplasty (THA) as compared to cemented femoral fixation in the elderly population. Fifty-two matched pair analysis of patients with 75 years of age and older (104 patients), who underwent primary THA from June 1997 to December 2004, was performed based on age, sex, BMI, and Charnley classification. Mean age was 81 years (75-101) and the average follow up was 3.1 ± 2.9 years (1.2-6.4). There was no difference in peri-operative cardiopulmonary complications, pulmonary failures, deep venous thrombosis, pulmonary embolus, length of stay, or discharge deposition between the two groups. Non-cemented fixation is safe and effective in patients older than 75 years of age.

Extensible membrane nanotubules mediate attachment of Trypanosoma cruzi epimastigotes under flow.

Trypanosoma cruzi is the etiological agent of Chagas disease, an important cause of infectious chronic myocardiopathy in Latin America. The life cycle of the parasite involves two main hosts: a triatomine (arthropod hematophagous vector) and a mammal. Epimastigotes are flagellated forms inside the triatomine gut; they mature in its intestine into metacyclic trypomastigotes, the infective form for humans. Parasites attach despite the shear stress generated by fluid flow in the intestines of the host, but little is known about the mechanisms that stabilize attachment in these conditions. Here, we describe the effect of varying levels of shear stress on attached T. cruzi epimastigotes using a parallel plate flow chamber. When flow is applied, parasites are partially dragged but maintain a connection to the surface via ~40 nm wide filaments (nanotubules) and the activity of flagella is reduced. When flow stops, parasites return near their original position and flagellar motion resumes. Nanotubule elongation increases with increasing shear stress and is consistent with a model of membrane tether extension under force. Fluorescent probes used to confirm membrane composition also show micron-wide anchoring pads at the distal end of the nanotubules. Multiple tethering accounts for more resistance to large shear stresses and for reduced flagellar movement when flow is stopped. The formation of membrane nanotubules is a possible mechanism to enhance adherence to host cells under shear stress, favoring the continuity of the parasite´s life cycle.

Cross-reactive humoral and CD4+ T cell responses to Mu and Gamma SARS-CoV-2 variants in a Colombian population.

The SARS CoV-2 antibody and CD4+ T cell responses induced by natural infection and/or vaccination decline over time and cross-recognize other viral variants at different levels. However, there are few studies evaluating the levels and durability of the SARS CoV-2-specific antibody and CD4+ T cell response against the Mu, Gamma, and Delta variants. Here, we examined, in two ambispective cohorts of naturally-infected and/or vaccinated individuals, the titers of anti-RBD antibodies and the frequency of SARS-CoV-2-specific CD4+ T cells up to 6 months after the last antigen exposure. In naturally-infected individuals, the SARS-CoV-2 antibody response declined 6 months post-symptoms onset. However, the kinetic observed depended on the severity of the disease, since individuals who developed severe COVID-19 maintained the binding antibody titers. Also, there was detectable binding antibody cross-recognition for the Gamma, Mu, and Delta variants, but antibodies poorly neutralized Mu. COVID-19 vaccines induced an increase in antibody titers 15-30 days after receiving the second dose, but these levels decreased at 6 months. However, as expected, a third dose of the vaccine caused a rise in antibody titers. The dynamics of the antibody response upon vaccination depended on the previous SARS-CoV-2 exposure. Lower levels of vaccine-induced antibodies were associated with the development of breakthrough infections. Vaccination resulted in central memory spike-specific CD4+ T cell responses that cross-recognized peptides from the Gamma and Mu variants, and their duration also depended on previous SARS-CoV-2 exposure. In addition, we found cross-reactive CD4+ T cell responses in unexposed and unvaccinated individuals. These results have important implications for vaccine design for new SARS-CoV-2 variants of interest and concern.

Corrigendum: Cross-reactive humoral and CD4+ T cell responses to Mu and Gamma SARS-CoV-2 variants in a Colombian population.

[This corrects the article DOI: 10.3389/fimmu.2023.1241038.].

Chagasic patients are able to respond against a viral antigen from influenza virus.

BACKGROUND: Trypanosoma cruzi, the etiological agent of Chagas' disease, is an obligate intracellular parasite which induces a CD8+ T cell immune response with secretion of cytokines and release of cytotoxic granules. Although an immune-suppressive effect of T. cruzi on the acute phase of the disease has been described, little is known about the capacity of CD8+ T cell from chronic chagasic patients to respond to a non-T. cruzi microbial antigen. METHODS: In the present paper, the frequency, phenotype and the functional activity of the CD8+ T cells specific from Flu-MP*, an influenza virus epitope, were determined in 13 chagasic patients and 5 healthy donors. RESULTS: The results show that Flu-MP* peptide specific CD8+ T cells were found with similar frequencies in both groups. In addition, Flu-MP* specific CD8+ T cells were distributed in the early or intermediate/late differentiation stages without showing enrichment of a specific sub-population. The mentioned Flu-MP* specific CD8+ T cells from chagasic patients were predominately TEM (CCR7- CD62L-), producing IL-2, IFNγ, CD107a/b and perforin, and did not present significant differences when compared with those from healthy donors. CONCLUSIONS: Our results support the hypothesis that there is no CD8+ T cell nonspecific immune-suppression during chronic Chagas disease infection. Nonetheless, other viral antigens must be studied in order to confirm our findings.

Bicruciate retaining arthroplasty.

Total knee arthroplasty (TKA) is one of the most successful orthopaedic procedures with 10 to 20 year survivorships from multiple studies of greater than 95%. These success rates typically apply to patients over 70 years of age who may only want to return to activities of daily living. However, recently there is a demand by both senior citizens as well as young patients to have TKAs that return them to high activity levels and occasionally high performance sports. In this review, we will describe bicruciate retaining prostheses, including knowledge of their kinematics from fluoroscopic and gait studies, results of clinical studies, a summary of their potential advantages and disadvantages, anterior cruciate ligament viability at time of arthroplasty, considerations for implantation of these devices, and their role in the future of total knee arthroplasty.

Effectiveness and adherence to closed face shields in the prevention of COVID-19 transmission: a non-inferiority randomized controlled trial in a middle-income setting (COVPROSHIELD).

BACKGROUND: The use of respiratory devices can mitigate the spread of diseases such as COVID-19 in community settings. We aimed to determine the effectiveness of closed face shields with surgical face masks to prevent SARS-CoV-2 transmission in working adults during the COVID-19 pandemic in Bogotá, Colombia. METHODS: An open-label non-inferiority randomized controlled trial that randomly assigned participants to one of two groups: the intervention group was instructed to wear closed face shields with surgical face masks, and the active control group was instructed to wear only surgical face masks. The primary outcome was a positive reverse transcription polymerase chain reaction test, IgG/IgM antibody test for SARS-CoV-2 detection, or both during and at the end of the follow-up period of 21 days. The non-inferiority limit was established at - 5%. RESULTS: A total of 316 participants were randomized, 160 participants were assigned to the intervention group and 156 to the active control group. In total, 141 (88.1%) participants in the intervention group and 142 (91.0%) in the active control group completed the follow-up. PRIMARY OUTCOME: a positive SARS-CoV-2 test result was identified in one (0.71%) participant in the intervention group and three (2.1%) in the active control group. In the intention-to-treat analysis, the absolute risk difference was - 1.40% (95% CI [- 4.14%, 1.33%]), and in the per-protocol analysis, the risk difference was - 1.40% (95% CI [- 4.20, 1.40]), indicating non-inferiority of the closed face shield plus face mask (did not cross the non-inferiority limit). CONCLUSIONS: The use of closed face shields and surgical face masks was non-inferior to the surgical face mask alone in the prevention of SARS-CoV-2 infection in highly exposed groups. Settings with highly active viral transmission and conditions such as poor ventilation, crowding, and high mobility due to occupation may benefit from the combined use of masks and closed face shields to mitigate SARS-CoV-2 transmission. TRIAL REGISTRATION: ClinicalTrials.gov NCT04647305 . Registered on November 30, 2020.

CD8+ T Cell Response Quality Is Related to Parasite Control in an Animal Model of Single and Mixed Chronic Trypanosoma cruzi Infections.

Chagas disease (ChD) is a chronic infection caused by Trypanosoma cruzi. This highly diverse intracellular parasite is classified into seven genotypes or discrete typing units (DTUs) and they overlap in geographic ranges, vectors, and clinical characteristics. Although studies have suggested that ChD progression is due to a decline in the immune response quality, a direct relationship between T cell responses and disease outcome is still unclear. To investigate the relationship between parasite control and immune T cell responses, we used two distinct infection approaches in an animal model to explore the histological and parasitological outcomes and dissect the T cell responses in T. cruzi-infected mice. First, we performed single infection experiments with DA (TcI) or Y (TcII) T. cruzi strains to compare the infection outcomes and evaluate its relationship with the T cell response. Second, because infections with diverse T. cruzi genotypes can occur in naturally infected individuals, mice were infected with the Y or DA strain and subsequently reinfected with the Y strain. We found different infection outcomes in the two infection approaches used. The single chronic infection showed differences in the inflammatory infiltrate level, while mixed chronic infection by different T. cruzi DTUs showed dissimilarities in the parasite loads. Chronically infected mice with a low inflammatory infiltrate (DA-infected mice) or low parasitemia and parasitism (Y/Y-infected mice) showed increases in early-differentiated CD8+ T cells, a multifunctional T cell response and lower expression of inhibitory receptors on CD8+ T cells. In contrast, infected mice with a high inflammatory infiltrate (Y-infected mice) or high parasitemia and parasitism (DA/Y-infected mice) showed a CD8+ T cell response distinguished by an increase in late-differentiated cells, a monofunctional response, and enhanced expression of inhibitory receptors. Overall, our results demonstrated that the infection outcomes caused by single or mixed T. cruzi infection with different genotypes induce a differential immune CD8+ T cell response quality. These findings suggest that the CD8+ T cell response might dictate differences in the infection outcomes at the chronic T. cruzi stage. This study shows that the T cell response quality is related to parasite control during chronic T. cruzi infection.

Characterising the KMP-11 and HSP-70 recombinant antigens' humoral immune response profile in chagasic patients.

BACKGROUND: Antigen specificity and IgG subclass could be significant in the natural history of Chagas' disease. The relationship between the different stages of human Chagas' disease and the profiles of total IgG and its subclasses were thus analysed here; they were directed against a crude T. cruzi extract and three recombinant antigens: the T. cruzi kinetoplastid membrane protein-11 (rKMP-11), an internal fragment of the T. cruzi HSP-70 protein 192-433, and the entire Trypanosoma rangeli HSP-70 protein. METHODS: Seventeen Brazilian acute chagasic patients, 50 Colombian chronic chagasic patients (21 indeterminate and 29 cardiopathic patients) and 30 healthy individuals were included. Total IgG and its subtypes directed against the above-mentioned recombinant antigens were determined by ELISA tests. RESULTS: The T. cruzi KMP-11 and T. rangeli HSP-70 recombinant proteins were able to distinguish both acute from chronic chagasic patients and infected people from healthy individuals. Specific antibodies to T. cruzi crude antigen in acute patients came from IgG3 and IgG4 subclasses whereas IgG1 and IgG3 were the prevalent isotypes in indeterminate and chronic chagasic patients. By contrast, the specific prominent antibodies in all disease stages against T. cruzi KMP-11 and T. rangeli HSP-70 recombinant antigens were the IgG1 subclass. CONCLUSION: T. cruzi KMP-11 and the T. rangeli HSP-70 recombinant proteins may be explored together in the immunodiagnosis of Chagas' disease. Polarising the IgG1 subclass of the IgG response to T. cruzi KMP-11 and T. rangeli HSP-70 recombinant proteins could have important biological effects, taking into account that this is a complement fixing antibody.

Outcome analysis of surgery for Blount disease.

BACKGROUND: The purpose of this study was to evaluate the results of surgery for Blount disease using a patient-derived outcome assessment. Our hypothesis was that an outcome score that quantitates the patient's level of satisfaction should correlate with specific ranges of correction for those radiologic variables traditionally used to evaluate Blount disease. The surgeon's aim should be to realign abnormal preoperative geometry to achieve those ranges that have a significant correlation with good outcome. METHODS: Medical records from 2 hospitals (Barbados and Trinidad) were reviewed and patients who had surgery for Blount's from 1997 to 2005 were identified and recalled. Responders completed a Blount's Outcome Questionnaire, were examined clinically, and standing radiographs were taken. The questionnaire was designed by modifying the AAOS Pediatrics-Parent/Child Outcome Instrument. Linear regression was used to assess the predictive effect of selected radiographic measures on a visual analog pain score and satisfaction score calculated from the questionnaire. The model was adjusted for confounders: country, age at the time of study, sex, body mass index, and years postsurgery. Variables in the adjusted model achieving significance at P<0.05 were included in a multiple regression analysis. RESULTS: Fifty knees in 41 patients were included. The median satisfaction score was 93%. The metaphyseal-diaphyseal angle (MDA) and anatomical femoral-tibial angle (aFTA), both had a quadratic effect on the pain score (P<0.001). The predicted pain score was minimized at the MDA range of 0 to -10 degrees and at the aFTA range of 0 to +5 degrees. A significant effect on the satisfaction score was noted for MDA (P=0.02) and aFTA (P<0.001) with scores maximized at the MDA range of +5 to -5 degrees and at positive aFTA (valgus angulation). For women the satisfaction scores were lower and the pain scores higher. Overweight patients had higher pain scores. CONCLUSIONS: Results of this evaluation of the association between patient outcome scores (for pain and satisfaction) and postoperative clinical and radiologic variables support the recommendation that surgical correction should aim at producing an MDA score between -5 and +5 degrees and a valgus alignment with an aFTA score of 0 to 5 degrees. LEVEL OF EVIDENCE: Therapeutic study, investigating the results of treatment. Level III.

CD8+ T Cell Response to Trypanosoma cruzi Antigens during Chronic Chagas Disease.

Flow cytometry is a valuable technique in cellular immunology that allows evaluating effective parameters of the immune response associated with CD8+ T cells. During Chagas disease, infection caused by Trypanosoma cruzi parasite, similar to other intracellular infectious agents, antigen-specific CD8+ T cells are essential for controlling the infection. However, CD8+ T cell response is only partially effective in some chronic Chagas disease patients. Thus, characterization and phenotyping of T. cruzi-specific CD8+ T cells are of great importance during chronic Chagas disease.

An Animal Model of Acute and Chronic Chagas Disease With the Reticulotropic Y Strain of Trypanosoma cruzi That Depicts the Multifunctionality and Dysfunctionality of T Cells.

Chagas disease (ChD), a complex and persistent parasitosis caused by Trypanosoma cruzi, represents a natural model of chronic infection, in which some people exhibit cardiac or digestive complications that can result in death 20-40 years after the initial infection. Nonetheless, due to unknown mechanisms, some T. cruzi-infected individuals remain asymptomatic throughout their lives. Actually, no vaccine is available to prevent ChD, and treatments for chronic ChD patients are controversial. Chronically T. cruzi-infected individuals exhibit a deterioration of T cell function, an exhaustion state characterized by poor cytokine production and increased inhibitory receptor co-expression, suggesting that these changes are potentially related to ChD progression. Moreover, an effective anti-parasitic treatment appears to reverse this state and improve the T cell response. Taking into account these findings, the functionality state of T cells might provide a potential correlate of protection to detect individuals who will or will not develop the severe forms of ChD. Consequently, we investigated the T cell response, analyzed by flow cytometry with two multicolor immunofluorescence panels, to assess cytokines/cytotoxic molecules and the expression of inhibitory receptors, in a murine model of acute (10 and 30 days) and chronic (100 and 260 days) ChD, characterized by parasite persistence for up to 260 days post-infection and moderate inflammation of the colon and liver of T. cruzi-infected mice. Acute ChD induced a high antigen-specific multifunctional T cell response by producing IFN-γ, TNF-α, IL-2, granzyme B, and perforin; and a high frequency of T cells co-expressed 2B4, CD160, CTLA-4, and PD-1. In contrast, chronically infected mice with moderate inflammatory infiltrate in liver tissue exhibited monofunctional antigen-specific cells, high cytotoxic activity (granzyme B and perforin), and elevated levels of inhibitory receptors (predominantly CTLA-4 and PD-1) co-expressed on T cells. Taken together, these data support our previous results showing that similar to humans, the T. cruzi persistence in mice promotes the dysfunctionality of T cells, and these changes might correlate with ChD progression. Thus, these results constitute a model that will facilitate an in-depth search for immune markers and correlates of protection, as well as long-term studies of new immunotherapy strategies for ChD.

Impact of benznidazole treatment on the functional response of Trypanosoma cruzi antigen-specific CD4+CD8+ T cells in chronic Chagas disease patients.

BACKGROUND: Chagas disease is caused by Trypanosoma cruzi. The persistence of the parasite is associated with the disease chronicity and the impairment of the cellular immune response. It has been reported that the CD4+CD8+ T cell population expands in chronic Chagas disease patients. Few studies have focused on this subset of cells, and very little is known about the impact of antiparasitic treatment on this population. METHODOLOGY: Thirty-eight chronic Chagas disease patients (20 asymptomatic and 18 symptomatic) and twelve healthy controls were enrolled in this study. Peripheral blood mononuclear cells were stimulated with soluble T. cruzi antigens to analyze the production of cytokines and cytotoxic molecules by CD4+CD8+ T cells before and after benznidazole treatment. Additionally, expression and co-expression of five inhibitory receptors in these patients after treatment were studied using a multiparameter flow cytometry technique. PRINCIPAL FINDINGS: The frequency of CD4+CD8+ T cells was higher in chronic Chagas disease patients compared with healthy donors. Furthermore, a higher ratio of CD4+CD8low/CD4+CD8high subpopulations was observed in chronic Chagas disease patients than in healthy donors. Additionally, CD4+CD8+ T cells from these patients expressed and co-expressed higher levels of inhibitory receptors in direct proportion to the severity of the pathology. Benznidazole treatment reduced the frequency of CD4+CD8+ T cells and decreased the ratio of CD4+CD8low/CD4+CD8high subpopulations. The co-expression level of the inhibitory receptor was reduced after treatment simultaneously with the enhancement of the multifunctional capacity of CD4+CD8+ T cells. After treatment, an increase in the frequency of T. cruzi antigen-specific CD4+CD8+ T cells expressing IL-2 and TNF-α was also observed. CONCLUSIONS: CD4+CD8+ T cells could play an important role in the control of T. cruzi infection since they were able to produce effector molecules for parasite control. Benznidazole treatment partially reversed the exhaustion process caused by T. cruzi infection in these cells with an improvement in the functional response of the T. cruzi antigen-specific CD4+CD8+ T cells.

Expression of inhibitory receptors and polyfunctional responses of T cells are linked to the risk of congenital transmission of T. cruzi.

Congenital T. cruzi infections involve multiple factors in which complex interactions between the parasite and the immune system of pregnant women play important roles. In this study, we used an experimental murine model of chronic infection with T. cruzi to evaluate the changes in the expression of inhibitory receptors and the polyfunctionality of T cells during gestation and their association with congenital transmission rate of T. cruzi infection. The results showed that pregnant naïve mice had a higher percentage of CD4+ and CD8+ T cells that expressed inhibitory receptors than cells from non-pregnant naïve mice. However, in mice chronically infected with T. cruzi, gestation induced a significant decrease in the frequency of T cells that expressed or co-expressed inhibitory receptors, as well as an increase in the frequency of polyfunctional CD4+ and CD8+ T cells. This different behavior may be due to the breakdown in the infected mice of the gestation-induced immune homeostasis, probably to control the parasite load. Remarkably, it was observed that the mothers that transmitted the parasite had a higher frequency of T cells that expressed and co-expressed inhibitory receptors as well as a lower frequency of polyfunctional parasite-specific T cells than those that did not transmit it, even though the parasitemia load was similar in both groups. All together these data suggest that the maternal immune profile of the CD4+ and CD8+ T cells could be a determining factor in the congenital transmission of T. cruzi.

Promiscuous Recognition of a Trypanosoma cruzi CD8+ T Cell Epitope among HLA-A2, HLA-A24 and HLA-A1 Supertypes in Chagasic Patients.

BACKGROUND: TcTLE is a nonamer peptide from Trypanosoma cruzi KMP-11 protein that is conserved among different parasite strains and that is presented by different HLA-A molecules from the A2 supertype. Because peptides presented by several major histocompatibility complex (MHC) supertypes are potential targets for immunotherapy, the aim of this study was to determine whether MHC molecules other than the A2 supertype present the TcTLE peptide. METHODOLOGY/PRINCIPAL FINDINGS: From 36 HLA-A2-negative chagasic patients, the HLA-A genotypes of twenty-eight patients with CD8+ T cells that recognized the TcTLE peptide using tetramer (twenty) or functional (eight) assays, were determined. SSP-PCR was used to identify the A locus and the allelic variants. Flow cytometry was used to analyze the frequency of TcTLE-specific CD8+ T cells, and their functional activity (IFN-γ, TNFα, IL-2, perforin, granzyme and CD107a/b production) was induced by exposure to the TcTLE peptide. All patients tested had TcTLE-specific CD8+ T cells with frequencies ranging from 0.07-0.37%. Interestingly, seven of the twenty-eight patients had HLA-A homozygous alleles: A*24 (5 patients), A*23 (1 patient) and A*01 (1 patient), which belong to the A24 and A1 supertypes. In the remaining 21 patients with HLA-A heterozygous alleles, the most prominent alleles were A24 and A68. The most common allele sub-type was A*2402 (sixteen patients), which belongs to the A24 supertype, followed by A*6802 (six patients) from the A2 supertype. Additionally, the A*3002/A*3201 alleles from the A1 supertype were detected in one patient. All patients presented CD8+ T cells producing at least one cytokine after TcTLE peptide stimulation. CONCLUSION/SIGNIFICANCE: These results show that TcTLE is a promiscuous peptide that is presented by the A24 and A1 supertypes, in addition to the A2 supertype, suggesting its potential as a target for immunotherapy.

Enfermedad cerebrovascular en pacientes jóvenes: aspectos claves de la literatura / Cerebrovascular disease in young patients: key aspects of literature

RESUMEN La enfermedad cerebrovascular (ECV) es una patología con una alta tasa de morbimortalidad. Los adultos jóvenes, que se ubican entre las edades de 15 a 50 años, representan hasta el 15 % de los casos. Aparte de los factores de riesgo tradicionales, también se observan otros factores como: consumo de cannabis, cocaína y metanfetaminas. La ECV de origen isquémico sigue siendo el evento cerebrovascular más frecuente, sin embargo, el porcentaje del hemorrágico aumenta en comparación con el resto de la población adulta. Otras causas incluyen: malformaciones arteriovenosas, aneurismas, cardiopatía embolica, enfermedades autoinmunes, trombofilias, entre otras patologías. La clínica es muy variada, pudiendo cursar con síndrome piramidal caracterizado por hemiplejia o hemiparesia, alteraciones en la marcha, hiperreflexia, hipertonía e hipotrofia. Además, el paciente puede presentar afasia, crisis epilépticas y síndrome vestibular. Sin embargo, existen casos en los que no se evidencian factores de riesgo clásicos y el diagnóstico etiológico se vuelve un reto, haciendo necesario la realización de estudios más especializados en búsqueda de la patología de base desencadenante. El abordaje terapéutico siempre va a estar acompañado de la detección y el manejo de la causa desencadenante.

SUMMARY Cerebrovascular disease (CVD) is a pathology with a high morbidity and mortality rate. Young adults, who are between the ages of 15 and 50, account for up to 15 % of cases. Besides the traditional risk factors, other factors are also observed, such as: consumption of cannabis, cocaine and methamphetamines. CVD of ischemic origin continues to be the most frequent cerebrovascular event, however, the hemorrhagic percentage increases compared to the rest of the adult population. Other causes include: arterio-venous malformations, aneurysms, embolic heart disease, autoimmune diseases, thrombophilias, among other pathologies. The symptoms are very varied and can present with pyramidal syndrome characterized by hemiplegia or hemiparesis, gait disturbances, hyperreflexia, hypertonia and hypotrophy. In addition, the patient may present with aphasia, epileptic seizures, and vestibular syndrome. However, there are cases in which no classical risk factors and etiologic diagnosis is evident becomes a challenge, necessitating studies seeking more specialized pathology trigger base. The therapeutic approach will always be accompanied by the detection and management of the triggering cause.