A liver immune rheostat regulates CD8 T cell immunity in chronic HBV infection.

Chronic hepatitis B virus (HBV) infection affects 300 million patients worldwide1,2, in whom virus-specific CD8 T cells by still ill-defined mechanisms lose their function and cannot eliminate HBV-infected hepatocytes3-7. Here we demonstrate that a liver immune rheostat renders virus-specific CD8 T cells refractory to activation and leads to their loss of effector functions. In preclinical models of persistent infection with hepatotropic viruses such as HBV, dysfunctional virus-specific CXCR6+ CD8 T cells accumulated in the liver and, as a characteristic hallmark, showed enhanced transcriptional activity of cAMP-responsive element modulator (CREM) distinct from T cell exhaustion. In patients with chronic hepatitis B, circulating and intrahepatic HBV-specific CXCR6+ CD8 T cells with enhanced CREM expression and transcriptional activity were detected at a frequency of 12-22% of HBV-specific CD8 T cells. Knocking out the inhibitory CREM/ICER isoform in T cells, however, failed to rescue T cell immunity. This indicates that CREM activity was a consequence, rather than the cause, of loss in T cell function, further supported by the observation of enhanced phosphorylation of protein kinase A (PKA) which is upstream of CREM. Indeed, we found that enhanced cAMP-PKA-signalling from increased T cell adenylyl cyclase activity augmented CREM activity and curbed T cell activation and effector function in persistent hepatic infection. Mechanistically, CD8 T cells recognizing their antigen on hepatocytes established close and extensive contact with liver sinusoidal endothelial cells, thereby enhancing adenylyl cyclase-cAMP-PKA signalling in T cells. In these hepatic CD8 T cells, which recognize their antigen on hepatocytes, phosphorylation of key signalling kinases of the T cell receptor signalling pathway was impaired, which rendered them refractory to activation. Thus, close contact with liver sinusoidal endothelial cells curbs the activation and effector function of HBV-specific CD8 T cells that target hepatocytes expressing viral antigens by means of the adenylyl cyclase-cAMP-PKA axis in an immune rheostat-like fashion.

PGE2 limits effector expansion of tumour-infiltrating stem-like CD8+ T cells.

Cancer-specific TCF1+ stem-like CD8+ T cells can drive protective anticancer immunity through expansion and effector cell differentiation1-4; however, this response is dysfunctional in tumours. Current cancer immunotherapies2,5-9 can promote anticancer responses through TCF1+ stem-like CD8+ T cells in some but not all patients. This variation points towards currently ill-defined mechanisms that limit TCF1+CD8+ T cell-mediated anticancer immunity. Here we demonstrate that tumour-derived prostaglandin E2 (PGE2) restricts the proliferative expansion and effector differentiation of TCF1+CD8+ T cells within tumours, which promotes cancer immune escape. PGE2 does not affect the priming of TCF1+CD8+ T cells in draining lymph nodes. PGE2 acts through EP2 and EP4 (EP2/EP4) receptor signalling in CD8+ T cells to limit the intratumoural generation of early and late effector T cell populations that originate from TCF1+ tumour-infiltrating CD8+ T lymphocytes (TILs). Ablation of EP2/EP4 signalling in cancer-specific CD8+ T cells rescues their expansion and effector differentiation within tumours and leads to tumour elimination in multiple mouse cancer models. Mechanistically, suppression of the interleukin-2 (IL-2) signalling pathway underlies the PGE2-mediated inhibition of TCF1+ TIL responses. Altogether, we uncover a key mechanism that restricts the IL-2 responsiveness of TCF1+ TILs and prevents anticancer T cell responses that originate from these cells. This study identifies the PGE2-EP2/EP4 axis as a molecular target to restore IL-2 responsiveness in anticancer TILs to achieve cancer immune control.

Evaluation of the technique of localization of the epidural space with the aid of a peripheral nerve stimulator and epidurographic, comparing two techniques for determining the infused volume, in rabbits (Oryctolagus Cuniculus).

Veterinary care for rabbits has been growing, and, consequently, the anesthetic and analgesic management of this species must be improved. The aim of the present study was to evaluate the technique of localization of the epidural space with the aid of a peripheral nerve stimulator and epidurographic, comparing two techniques for determining the infused volume in rabbits (Oryctolagus Cuniculus). In a prospective, randomized blinded study, six healthy New Zealand rabbits, adults, and weighing from 2.2 kg to 3.8 kg received two treatments, at 1 week intervals: 0.33 mL/kg (treatment I) or 0.05 mL per centimeter of the spine (treatment II) of ioexol epidurally. In both treatments, a peripheral nerve stimulator (2 Hz, 0.25 mA and 0.1 milliseconds) was used to determine the location of the epidural space. Latero-lateral and ventro-dorsal radiographs were taken after five (T5) and twenty-five minutes (T25) of iohexol administration. The epidural space was correctly accessed in 92% of attempts. Treatment I received a smaller volume of contrast than treatment II, 1.0 ± 0.2 mL versus 2.1 ± 0.1 mL (mean ± standard deviation), respectively (p = 0.007). At T5, the cranial progression of the contrast varied between L4 and L5 in treatment I, and L5 and T10 in treatment II. At T25, no contrast was observed in any rabbit. In conclusion, peripheral nerve stimulator aided in accessing the lumbosacral epidural space, and the administration of 0.05 mL per centimeter of the spine resulted in greater cranial progression of contrast.

A distinct stimulatory cDC1 subpopulation amplifies CD8+ T cell responses in tumors for protective anti-cancer immunity.

Type 1 conventional dendritic cells (cDC1) can support T cell responses within tumors but whether this determines protective versus ineffective anti-cancer immunity is poorly understood. Here, we use imaging-based deep learning to identify intratumoral cDC1-CD8+ T cell clustering as a unique feature of protective anti-cancer immunity. These clusters form selectively in stromal tumor regions and constitute niches in which cDC1 activate TCF1+ stem-like CD8+ T cells. We identify a distinct population of immunostimulatory CCR7neg cDC1 that produce CXCL9 to promote cluster formation and cross-present tumor antigens within these niches, which is required for intratumoral CD8+ T cell differentiation and expansion and promotes cancer immune control. Similarly, in human cancers, CCR7neg cDC1 interact with CD8+ T cells in clusters and are associated with patient survival. Our findings reveal an intratumoral phase of the anti-cancer T cell response orchestrated by tumor-residing cDC1 that determines protective versus ineffective immunity and could be exploited for cancer therapy.

Pyrimidine de novo synthesis inhibition selectively blocks effector but not memory T cell development.

Blocking pyrimidine de novo synthesis by inhibiting dihydroorotate dehydrogenase is used to treat autoimmunity and prevent expansion of rapidly dividing cell populations including activated T cells. Here we show memory T cell precursors are resistant to pyrimidine starvation. Although the treatment effectively blocked effector T cells, the number, function and transcriptional profile of memory T cells and their precursors were unaffected. This effect occurred in a narrow time window in the early T cell expansion phase when developing effector, but not memory precursor, T cells are vulnerable to pyrimidine starvation. This vulnerability stems from a higher proliferative rate of early effector T cells as well as lower pyrimidine synthesis capacity when compared with memory precursors. This differential sensitivity is a drug-targetable checkpoint that efficiently diminishes effector T cells without affecting the memory compartment. This cell fate checkpoint might therefore lead to new methods to safely manipulate effector T cell responses.

Secondary infections rejuvenate the intestinal CD103+ tissue-resident memory T cell pool.

Resident T lymphocytes (TRM) protect tissues during pathogen reexposure. Although TRM phenotype and restricted migratory pattern are established, we have a limited understanding of their response kinetics, stability, and turnover during reinfections. Such characterizations have been restricted by the absence of in vivo fate-mapping systems. We generated two mouse models, one to stably mark CD103+ T cells (a marker of TRM cells) and the other to specifically deplete CD103- T cells. Using these models, we observed that intestinal CD103+ T cells became activated during viral or bacterial reinfection, remained organ-confined, and retained their original phenotype but failed to reexpand. Instead, the population was largely rejuvenated by CD103+ T cells formed de novo during reinfections. This pattern remained unchanged upon deletion of antigen-specific circulating T cells, indicating that the lack of expansion was not due to competition with circulating subsets. Thus, although intestinal CD103+ resident T cells survived long term without antigen, they lacked the ability of classical memory T cells to reexpand. This indicated that CD103+ T cell populations could not autonomously maintain themselves. Instead, their numbers were sustained during reinfection via de novo formation from CD103- precursors. Moreover, in contrast to CD103- cells, which require antigen plus inflammation for their activation, CD103+ TRM became fully activated follwing exposure to inflammation alone. Together, our data indicate that primary CD103+ resident memory T cells lack secondary expansion potential and require CD103- precursors for their long-term maintenance.

'Stem-like' precursors are the fount to sustain persistent CD8+ T cell responses.

Virus-specific CD8+ T cells that differentiate in the context of resolved versus persisting infections exhibit divergent phenotypic and functional characteristics, which suggests that their differentiation trajectories are governed by distinct cellular dynamics, developmental pathways and molecular mechanisms. For acute infection, it is long known that antigen-specific T cell populations contain terminally differentiated effector T cells, known as short-lived effector T cells, and proliferation-competent and differentiation-competent memory precursor T cells. More recently, it was identified that a similar functional segregation occurs in chronic infections. A failure to generate proliferation-competent precursor cells in chronic infections and tumors results in the collapse of the T cell response. Thus, these precursor cells are major therapeutic and prophylactic targets of immune interventions. These observations suggest substantial commonality between T cell responses in acute and chronic infections but there are also critical differences. We are therefore reviewing the common features and peculiarities of precursor cells in acute infections, different types of persistent infection and cancer.

Human skin-resident host T cells can persist long term after allogeneic stem cell transplantation and maintain recirculation potential.

Tissue-resident memory T cells (TRM) have recently emerged as crucial cellular players for host defense in a wide variety of tissues and barrier sites. Insights into the maintenance and regulatory checkpoints of human TRM cells remain scarce, especially due to the difficulties associated with tracking T cells through time and space in humans. We therefore sought to identify and characterize skin-resident T cells in humans defined by their long-term in situ lodgment. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) preceded by myeloablative chemotherapy unmasked long-term sequestration of host T cell subsets in human skin despite complete donor T cell chimerism in the blood. Single-cell chimerism analysis paired with single-cell transcriptional profiling comprehensively characterized these bona fide long-term skin-resident T cells and revealed differential tissue maintenance for distinct T cell subsets, specific TRM cell markers such as galectin-3, but also tissue exit potential with retention of the transcriptomic TRM cell identity. Analysis of 26 allo-HSCT patients revealed profound interindividual variation in the tissue maintenance of host skin T cells. The long-term persistence of host skin T cells in a subset of these patients did not correlate with the development of chronic GvHD. Our data exemplify the power of exploiting a clinical situation as a proof of concept for the existence of bona fide human skin TRM cells and reveal long-term persistence of host T cells in a peripheral tissue but not in the circulation or bone marrow in a subset of allo-HSCT patients.

Morc3 silences endogenous retroviruses by enabling Daxx-mediated histone H3.3 incorporation.

Endogenous retroviruses (ERVs) comprise a significant portion of mammalian genomes. Although specific ERV loci feature regulatory roles for host gene expression, most ERV integrations are transcriptionally repressed by Setdb1-mediated H3K9me3 and DNA methylation. However, the protein network which regulates the deposition of these chromatin modifications is still incompletely understood. Here, we perform a genome-wide single guide RNA (sgRNA) screen for genes involved in ERV silencing and identify the GHKL ATPase protein Morc3 as a top-scoring hit. Morc3 knock-out (ko) cells display de-repression, reduced H3K9me3, and increased chromatin accessibility of distinct ERV families. We find that the Morc3 ATPase cycle and Morc3 SUMOylation are important for ERV chromatin regulation. Proteomic analyses reveal that Morc3 mutant proteins fail to interact with the histone H3.3 chaperone Daxx. This interaction depends on Morc3 SUMOylation and Daxx SUMO binding. Notably, in Morc3 ko cells, we observe strongly reduced histone H3.3 on Morc3 binding sites. Thus, our data demonstrate Morc3 as a critical regulator of Daxx-mediated histone H3.3 incorporation to ERV regions.

Determination of causal associations in occupational medicine and the medico-legal context: references and standards.

Causality is a transdisciplinary topic with the medical-legal field representing one of its most exciting aspects. Since medicine and law have different roots and objectives, this article provides references to support occupational physicians and medico-legal experts in the difficult task of establishing occupational causation. In addition to the traditional Bradford Hill criteria and Schilling's Classification, additional standards are provided to enhance critical assessment and contribute to the responsible use of the concept of causation in both the legal and medical-occupational fields.

Does oral salbutamol improve fatigue in multiple sclerosis? A pilot placebo-controlled study.

BACKGROUND: Because MS-related fatigue could be associated with enhanced proinflammatory cytokine production, drugs with immunomodulatories properties, such as salbutamol, may represent an alternative treatment. We aimed to evaluate the effect of salbutamol on MS-related fatigue. METHODS: Thirty patients with relapsing-remitting MS who were between 18 and 69 years old, and suffering from fatigue, were evaluated with the Fatigue Severity Scale (FSS) and the Brazilian version of the neurological fatigue index for multiple sclerosis (NFI/MS-BR). They received salbutamol 2 mg twice a day or a placebo in a pilot randomized, double-masked placebo-controlled trial. The primary outcome was the change in the FSS score at the end of 90 days. The secondary outcome was the efficacy, represented by changes in their scores on the NFI/MS-BR subdomains (in the same period) and the Expanded Disability Status Scale (EDSS) at the end of 90 days. RESULTS: Thirty subjects were allocated to receive either salbutamol (14) or a placebo (16). There was no superiority of salbutamol over the placebo in the FSS outcome at 30 (p ==0.498), 60 (p = 0.854) and 90 (p = 0.240) days. There was no a significant decrease in the proportion of patients with severe or moderate fatigue in the salbutamol group at the end of the follow-up. The scores on the NFI/MS-BR and its subscales did not improve significantly with treatment. No significant difference was observed in the EDSS outcome (p = 0.313). No serious adverse events were found. An increase in heart rate was evident in the salbutamol group only in the first 30 days, but without statistical significance in relation to placebo (p = 0.077). CONCLUSION: Treatment with salbutamol does not improve fatigue in patients with relapsing-remitting MS.

Salt generates antiinflammatory Th17 cells but amplifies pathogenicity in proinflammatory cytokine microenvironments.

Th cells integrate signals from their microenvironment to acquire distinct specialization programs for efficient clearance of diverse pathogens or for immunotolerance. Ionic signals have recently been demonstrated to affect T cell polarization and function. Sodium chloride (NaCl) was proposed to accumulate in peripheral tissues upon dietary intake and to promote autoimmunity via the Th17 cell axis. Here, we demonstrate that high-NaCl conditions induced a stable, pathogen-specific, antiinflammatory Th17 cell fate in human T cells in vitro. The p38/MAPK pathway, involving NFAT5 and SGK1, regulated FoxP3 and IL-17A expression in high-NaCl conditions. The NaCl-induced acquisition of an antiinflammatory Th17 cell fate was confirmed in vivo in an experimental autoimmune encephalomyelitis (EAE) mouse model, which demonstrated strongly reduced disease symptoms upon transfer of T cells polarized in high-NaCl conditions. However, NaCl was coopted to promote murine and human Th17 cell pathogenicity, if T cell stimulation occurred in a proinflammatory and TGF-ß-low cytokine microenvironment. Taken together, our findings reveal a context-dependent, dichotomous role for NaCl in shaping Th17 cell pathogenicity. NaCl might therefore prove beneficial for the treatment of chronic inflammatory diseases in combination with cytokine-blocking drugs.

Improving knowledge about permeability in membrane bioreactors through sensitivity analysis using artificial neural networks.

Membrane bioreactor (MBR) has been widely employed for industrial effluent treatment, as its higher efficiency in removing pollutants makes effluent reuse more feasible. However, membrane fouling remains as a limiting factor for its greater diffusion. This work performed a sensitivity analysis study to investigate the effects of analytical and operating variables on membrane permeability. The case study is a MBR treating oil refinery effluents. After the identification and validation of a predictive neural model for permeability, sensitivity analysis methods based on both connection weights and variable disturbances were used to quantify and rank the variables influence. A comprehensive analysis showed that Suspended solids and Days between cleanings exerted greater effects on permeability, whereas sludge filterability and sludge temperature were less significant. In sequence, a specific analysis revealed distinct dynamics in MBR operation given different solids concentrations. For instance, from higher solids concentrations, among all the evaluated parameters, only COD presented low significance to the permeability. This evidence suggests that permeability is more susceptible to variations when operating with higher concentrations of Suspended solids. The global result of this study contributes to more efficient MBR operations since distinct relations with permeability imply different effects on membrane fouling.

Meeting the Challenges of High-Dimensional Single-Cell Data Analysis in Immunology.

Recent advances in cytometry have radically altered the fate of single-cell proteomics by allowing a more accurate understanding of complex biological systems. Mass cytometry (CyTOF) provides simultaneous single-cell measurements that are crucial to understand cellular heterogeneity and identify novel cellular subsets. High-dimensional CyTOF data were traditionally analyzed by gating on bivariate dot plots, which are not only laborious given the quadratic increase of complexity with dimension but are also biased through manual gating. This review aims to discuss the impact of new analysis techniques for in-depths insights into the dynamics of immune regulation obtained from static snapshot data and to provide tools to immunologists to address the high dimensionality of their single-cell data.

Solid-state random microlasers fabricated via femtosecond laser writing.

Here we demonstrate resonant random lasing in Rhodamine B-doped polymeric microstructures fabricated by means of femtosecond laser writing via two-photon polymerization. To the best of our knowledge, this is the first demonstration of random lasing action in on-chip microdevices. Their feedback mechanism relies on diffuse reflections at the structure sidewall surfaces, which is known as spatially localized feedback since the scattering centers lie over the edges of the gain medium. By exciting the structures with a pulsed laser at 532 nm, a multimode emission with randomly distributed narrow peaks was observed, in accordance with the random nature of the feedback mechanism. Interestingly, their lasing threshold was found to be on the order of tens of nanojoules, which is comparable to what had been achieved for usual microcavities, thereby demonstrating the potentiality of these devices as solid-state lasers for integrated optics applications.

[A risk-based monitoring model for health care service institutions as a tool to protect health rights in Peru]. / Modelo de supervisión basado en el riesgo para instituciones prestadoras de servicios de salud como herramienta para la protección de los derechos en salud en Perú.

OBJECTIVES.: To describe the monitoring model of the Health Care Service Institutions (HCSI) of the National Health Authority (NHA) and assess the factors associated with risk-adjusted normative compliance (%RANC) within the Peruvian Health System (PHS). MATERIALS AND METHODS.: We carried out a case study of the experience of the NHA in the development and implementation of a monitoring program based on the ISO 31000-2009. With HCSI as the units of analysis, we calculated the %RANC (a scorein continuous scale ranging from 0 to 100) for comprehensive monitoring (CM) and for specific evaluations made from 2013 to 2015. A higher score in the %RANC means lower operational risk. Also, slope coefficients (ß) and their 95% confidence intervals (95% CI) were estimated using generalized linear models to estimate the association between %RANC as outcome, and health subsector, region, level of care and year, as explanatory variables. RESULTS.: The NHA made 1444 evaluations. For CM, only the Social Security Administration had higher %RANC than private centers (ß=7.7%; 95% CI 3.5 to 11.9). The HCSI of the coastal region (ß=-5.2, 95% CI -9.4 to -1.0), andean region (ß=-12.5; 95% CI -16.7 to -8.3) and jungle region (ß=-12.6, 95% CI% -17.7 to -7.6) had lower %RANC than those located in Lima Metropolitan area. %RANC was higher in 2015 than 2013 (ß=10.8; 95% CI 6.4 to 15.3). CONCLUSIONS.: The %RANC differs by health subsector, region and year of supervision. For CM, the HCSI in the Social Security Administration and in the Lima Metropolitan area had better scores, and scores improved over time. The implementation of actions aimed at improving %RANC in order to foster the full exercise of health rights in the PHS is suggested.

Modelo de supervisión basado en el riesgo para instituciones prestadoras de servicios de salud como herramienta para la protección de los derechos en salud en Perú / A risk-based monitoring model for health care service institutions as a tool to protect health rights in Peru

RESUMEN Objetivos. Describir el modelo de supervisión de las Instituciones Prestadoras de Servicios de Salud (IPRESS) de la Superintendencia Nacional de Salud (SUSALUD) y evaluar los factores asociados al porcentaje de cumplimiento normativo ajustado a riesgo (%CNAR) en las IPRESS del Sistema de Salud Peruano (SSP). Materiales y Métodos. Se realizó un estudio de caso sobre el desarrollo e implementación de un modelo de supervisión ajustado a riesgo basado en la norma ISO 31000-2009. Con la IPRESS como unidad de análisis, se calcularon los %CNAR (un puntaje continuo entre 0 a 100) de las supervisiones integrales (SI) y supervisiones selectivas efectuadas durante los años 2013 al 2015. Un mayor %CNAR implica un menor riesgo operacional. Se estimaron coeficientes β con IC95% mediante modelos lineales generalizados para valorar la asociación entre el %CNAR (variable de respuesta) y el subsector, la región, el nivel de complejidad y el año de supervisión (variables de exposición). Resultados. Se ejecutaron 1444 supervisiones. En las SI, solo la Seguridad Social en Salud (ESSALUD) tuvo mayor %CNAR que los centros privados [(β=7,7%;IC95%(3,5 a 11,9)]. Las IPRESS de la Costa [β=-5,2;IC95%(-9,4 a -1,0)], Sierra [β=-12,5;IC95%(-16,7 a -8,3)] y Selva [β=-12,6;IC95%(-17,7 a -7,6)] tuvieron menor %CNAR que aquellas ubicadas en Lima Metropolitana. El %CNAR fue superior en el año 2015 [β=10,8IC95%(6,4 a 15,3)] en relación al año 2013. Conclusiones. El %CNAR difiere por subsector, región y año de supervisión. En las SI las IPRESS supervisadas en ESSALUD, Lima Metropolitana y el año 2015, tuvieron mejores puntuaciones. Se sugiere la puesta en marcha de acciones orientadas a mejorar el %CNAR con el propósito de favorecer el ejercicio de los derechos en salud en el SSP.

ABSTRACT Objectives. To describe the monitoring model of the Health Care Service Institutions (HCSI) of the National Health Authority (NHA) and assess the factors associated with risk-adjusted normative compliance (%RANC) within the Peruvian Health System (PHS). Materials and Methods. We carried out a case study of the experience of the NHA in the development and implementation of a monitoring program based on the ISO 31000-2009. With HCSI as the units of analysis, we calculated the %RANC (a scorein continuous scale ranging from 0 to 100) for comprehensive monitoring (CM) and for specific evaluations made from 2013 to 2015. A higher score in the %RANC means lower operational risk. Also, slope coefficients (β) and their 95% confidence intervals (95% CI) were estimated using generalized linear models to estimate the association between %RANC as outcome, and health subsector, region, level of care and year, as explanatory variables. Results. The NHA made 1444 evaluations. For CM, only the Social Security Administration had higher %RANC than private centers (β=7.7%; 95% CI 3.5 to 11.9). The HCSI of the coastal region (β=-5.2, 95% CI -9.4 to -1.0), andean region (β=-12.5; 95% CI -16.7 to -8.3) and jungle region (β=-12.6, 95% CI% -17.7 to -7.6) had lower %RANC than those located in Lima Metropolitan area. %RANC was higher in 2015 than 2013 (β=10.8; 95% CI 6.4 to 15.3). Conclusions. The %RANC differs by health subsector, region and year of supervision. For CM, the HCSI in the Social Security Administration and in the Lima Metropolitan area had better scores, and scores improved over time. The implementation of actions aimed at improving %RANC in order to foster the full exercise of health rights in the PHS is suggested.

Retrotransposon derepression leads to activation of the unfolded protein response and apoptosis in pro-B cells.

The H3K9me3-specific histone methyltransferase Setdb1 impacts on transcriptional regulation by repressing both developmental genes and retrotransposons. How impaired retrotransposon silencing may lead to developmental phenotypes is currently unclear. Here, we show that loss of Setdb1 in pro-B cells completely abrogates B cell development. In pro-B cells, Setdb1 is dispensable for silencing of lineage-inappropriate developmental genes. Instead, we detect strong derepression of endogenous murine leukemia virus (MLV) copies. This activation coincides with an unusual change in chromatin structure, with only partial loss of H3K9me3 and unchanged DNA methylation, but strongly increased H3K4me3. Production of MLV proteins leads to activation of the unfolded protein response pathway and apoptosis. Thus, our data demonstrate that B cell development depends on the proper repression of retrotransposon sequences through Setdb1.

Single-Walled Carbon Nanotubes Functionalized with Carboxylic Acid for Fabricating Polymeric Composite Microstructures.

Carbon nanotube composites are promising materials for mechanical and electrical applications. However, methodologies to incorporate carbon nanotubes in polymeric matrices are on high demand, especially for fabricating devices in the micro-nanoscale. In this paper we show the fabrication of 3D polymeric microstructures with functionalized single-walled carbon nanotubes (SWCNT), by means of two-photon polymerization (2PP). We used a range of SWCNT concentrations (0.01-1 wt%) in the resin to fabricate the composite material. Scanning electron microscopy images show the fabricated microstructures surface quality. Raman spectroscopy was used to confirm the presence and evaluate the distribution of SWCNT in the microstructures. Atomic force microscopy was used to evaluate the mechanical properties of the fabricated microstructures.

Arthroscopic treatment for chronic lateral epicondylitis.

OBJECTIVE: To report the clinical and functional results from arthroscopic release of the short radial extensor of the carpus (SREC) in patients with chronic lateral epicondylitis that was refractory to conservative treatment. METHODS: Over the period from January 2012 to November 2013, 15 patients underwent arthroscopic treatment. The surgical technique used was the one described by Romeo and Cohen, based on anatomical studies on cadavers. The inclusion criteria were that the patients needed to present lateral epicondylitis and that conservative treatment (analgesics, anti-inflammatory agents, corticoid infiltration or physiotherapy) had failed over a period of more than six months. The patients were evaluated based on the elbow functional score of the Mayo Clinic, Nirschl's staging system and a visual analog scale (VAS) for pain. RESULTS: A total of 15 patients (9 men and 6 women) were included. The mean Mayo elbow functional score after the operation was 95 (ranging from 90 to 100). The pain VAS improved from a mean of 9.2 before the operation to 0.64 after the operation. On Nirschl's scale, the patients presented an improvement from a mean of 6.5 before the operation to approximately one. There were significant differences from before to after the surgery for the three functional scores used (p < 0.01). No correlations were observed using the Spearman test between the results and age, gender, length of time with symptoms before the operation or injury mechanism (p > 0.05). CONCLUSION: Arthroscopic treatment for lateral epicondylitis was shown to be a safe and effective therapeutic option when appropriately indicated and performed, in refractory cases of chronic lateral epicondylitis. It also allowed excellent viewing of the joint space for diagnosing and treating associated pathological conditions, with a minimally invasive procedure.

OBJETIVO: Relatar os resultados clínicos e funcionais da liberação artroscópica do extensor radial curto do carpo (ECRB) nos pacientes com epicondilite lateral crônica refratária ao tratamento conservador. MÉTODOS: No período compreendido entre janeiro de 2012 e novembro de 2013, 15 pacientes foram submetidos ao tratamento artroscópico. A técnica cirúrgica usada é a descrita por Romeo e Cohen, baseada em estudos anatômicos em cadáver. Os critérios de inclusão foram pacientes com epicondilite lateral nos quais o tratamento conservador (analgésicos, antiinflamatórios, infiltração de corticoides, fisioterapia) falhou por mais de seis meses. Os pacientes foram avaliados com base no escore funcional de cotovelo da Clinica Mayo, Sistema de Estágio de Nirschl e escala visual analógica de dor. RESULTADOS: Foram incluídos 15 pacientes, nove homens e seis mulheres. A média do escore funcional de cotovelo de Mayo pós-operatório foi de 95 (de 90 a 100). A EVS da dor teve uma melhoria média de 9,2 no pré-operatório para 0,64 no pós-operatório. Pela escala de Nirschl os pacientes apresentaram uma melhoria média de 6,5 no pré-operatório para aproximadamente um. Foi observada diferença significante entre pré e pós-cirúrgico nos três escores funcionais usados (p < 0,01). Não foram observadas correlações pelo teste de Spearman entre idade, gênero, tempo de sintomas pré-operatório, mecanismo de lesão com os resultados (p > 0,05). CONCLUSÃO: O tratamento artroscópico da epicondilite lateral mostra-se como uma opção terapêutica segura e eficaz quando indicado e feito de forma adequada nos casos refratários de epicondilite lateral crônica e permite ainda uma excelente visualização do espaço articular para diagnóstico e tratamento de patologias associadas com um procedimento minimamente invasivo.