Sign of Leser-Trélat Associated with Kaposi Sar-coma in an Immunocompetent Man.

A 68-year-old Latino man presented at our clinic with asymptomatic, indurated red nodules and macules of 2-month duration on the left arm, forearm, and palm (Figure 1). Performed punch biopsy presented characteristic -features of Kaposi sarcoma (KS). Immunohistochemistry was positive for human herpesvirus 8 (HHV8), a highly correlated viral marker, confirming the diagnosis of KS (Figure 2). He was referred to oncology for further management, where he was found to be fully immunocompetent with a negative assessment of human immunodefi-ciency virus (HIV). Computed tomography (CT) performed of his chest and abdomen revealed no involvement of internal organs.

Fractioned-pattern radiation mapping, Part I: modeling.

Here, we present a technique that predicts the radiation's distribution in any optical system. It is based on decomposing the emitting source power by assigning a fraction of the total power to each emitted ray. All kinds of power losses in the rays' optical paths are considered. Fractioned radiation patterns are created in the last optical system surface, each associated with a single ray. We refer to fractioned patterns as those that conform to a whole radiating pattern. Thus, the irradiance of the completely illuminated surface is calculated by adding the optical system's fractioned radiation maps. This method is non-zero étendue. The result presented here allows for predicting the radiation patterns accurately with a handful of equations and can help design any image and non-image-forming optical systems.

Fractioned-pattern radiation mapping, Part II: assessment.

In Part I, the authors proposed a theoretical background for predicting the radiation distribution in any optical system based on decomposing the emitting source power. Here, we describe the validity of this decomposition through a practical example that uses a radiating source and a single surface optical system. This source is calibrated in a metrology testbed that guarantees its traceability to the candela (cd), the International System (SI) base unit for luminous intensity I v. A second example, this time numerical, shows the method's performance in a multisurface optical system.

Recurrence After Atrial Fibrillation Ablation and Investigational Biomarkers of Cardiac Remodeling.

BACKGROUND: Recurrence after atrial fibrillation (AF) ablation remains common. We evaluated the association between recurrence and levels of biomarkers of cardiac remodeling, and their ability to improve recurrence prediction when added to a clinical prediction model. METHODS AND RESULTS: Blood samples collected before de novo catheter ablation were analyzed. Levels of bone morphogenetic protein-10, angiopoietin-2, fibroblast growth factor-23, insulin-like growth factor-binding protein-7, myosin-binding protein C3, growth differentiation factor-15, interleukin-6, N-terminal pro-brain natriuretic peptide, and high-sensitivity troponin T were measured. Recurrence was defined as ≥30 seconds of an atrial arrhythmia 3 to 12 months postablation. Multivariable logistic regression was performed using biomarker levels along with clinical covariates: APPLE score (Age >65 years, Persistent AF, imPaired eGFR [<60 ml/min/1.73m2], LA diameter ≥43 mm, EF <50%; which includes age, left atrial diameter, left ventricular ejection fraction, persistent atrial fibrillation, and estimated glomerular filtration rate), preablation rhythm, sex, height, body mass index, presence of an implanted continuous monitor, year of ablation, and additional linear ablation. A total of 1873 participants were included. A multivariable logistic regression showed an association between recurrence and levels of angiopoietin-2 (odds ratio, 1.08 [95% CI, 1.02-1.15], P=0.007) and interleukin-6 (odds ratio, 1.02 [95% CI, 1.003-1.03]; P=0.02). The area under the receiver operating characteristic curve of a model that only contained clinical predictors was 0.711. The addition of any of the 9 studied biomarkers to the predictive model did not result in a statistically significant improvement in the area under the receiver operating characteristic curve. CONCLUSIONS: Higher angiopoietin-2 and interleukin-6 levels were associated with recurrence after atrial fibrillation ablation in multivariable modeling. However, the addition of biomarkers to a clinical prediction model did not significantly improve recurrence prediction.

AMG 509 (Xaluritamig), an Anti-STEAP1 XmAb 2+1 T-cell Redirecting Immune Therapy with Avidity-Dependent Activity against Prostate Cancer.

The tumor-associated antigen STEAP1 is a potential therapeutic target that is expressed in most prostate tumors and at increased levels in metastatic castration-resistant prostate cancer (mCRPC). We developed a STEAP1-targeted XmAb 2+1 T-cell engager (TCE) molecule, AMG 509 (also designated xaluritamig), that is designed to redirect T cells to kill prostate cancer cells that express STEAP1. AMG 509 mediates potent T cell-dependent cytotoxicity of prostate cancer cell lines in vitro and promotes tumor regression in xenograft and syngeneic mouse models of prostate cancer in vivo. The avidity-driven activity of AMG 509 enables selectivity for tumor cells with high STEAP1 expression compared with normal cells. AMG 509 is the first STEAP1 TCE to advance to clinical testing, and we report a case study of a patient with mCRPC who achieved an objective response on AMG 509 treatment. SIGNIFICANCE: Immunotherapy in prostate cancer has met with limited success due to the immunosuppressive microenvironment and lack of tumor-specific targets. AMG 509 provides a targeted immunotherapy approach to engage a patient's T cells to kill STEAP1-expressing tumor cells and represents a new treatment option for mCRPC and potentially more broadly for prostate cancer. See related commentary by Hage Chehade et al., p. 20. See related article by Kelly et al., p. 76. This article is featured in Selected Articles from This Issue, p. 5.

Use of a Composed Simulator by Veterinarian Non-Experts in Minimally Invasive Surgery for Training and Acquisition of Surgical Skills for Laparoscopic Ovariectomy in Dogs.

This study aims to assess the acquisition of surgical skills for laparoscopic ovariectomy (LOE) in dogs by veterinary surgeons with no experience in minimally invasive surgery using the CALMA Veterinary Lap-trainer simulator (CVLTS) in an experimental and analytical setting. Veterinary surgeons with no experience in minimally invasive surgery (MIS) (experimental, n = 5), and MIS experts (experts, n = 3) were evaluated. Experimental and expert group participants watched an instructional video (initial time) before practicing the LOE on uterine tissues and ovaries freshly reconstituted after elective ovariohysterectomy (initial time evaluation). Then, the experimental group practiced five training sessions on the composite simulator with permanent feedback and then performed the LOE again (final time evaluation). Surgical performances in initial and final evaluations were video recorded and further evaluated by three external MIS experts using Global objective assessment of laparoscopic skills (GOALS) and LOE-specific rating scales (SRSs) in a double-blinded schedule. In addition, a hands movement assessment system (HMAS) attached to the back of the hands was used to quantitatively measure completion time, angularity, and movement smoothness. Data were analyzed with one-factor ANOVA and Tukey's contrast test. No statistically significant differences were found between the novice group's performance after training and the expert group's performance according to the GOALS (p < 0.01) and SRS (p < 0.05) scores. Moreover, the novices had significantly improved time, number of movements, and angularity in the final time compared with the initial time (p < 0.05), with no significant differences compared to the expert group (p > 0.05). LOE training using a composed simulator resulted in significantly improved laparoscopic skills and time, number, and angularity of movements data, providing evidence of the usefulness and reliability of CVLTS in training LOE.

Percepción de distancia central y periférica, en atletas del equipo nacional de tenis de mesa

El presente trabajo investiga sobre los estudios de percepción en atletas del equipo nacional de tenis de mesa. Tuvo como objetivo proponer ejercicios perceptivo-visuales para la mejora de la percepción de la distancia central y periférica en dicho equipo, a partir de la detección de las dificultades presentadas en el juego en los controles clasificatorios, 2019. La necesidad de realizar estudios que exploren la percepción de la distancia central y periférica en el ámbito de la psicología del deporte revela la importancia y actualidad del tema, por la contribución de este componente del sistema psicorregulador de las acciones motrices, al rendimiento de los atletas durante el proceso de entrenamiento y competencia. Se utilizaron métodos del nivel teórico como el análisis-síntesis y del nivel empírico la observación, la entrevista, la prueba de Vera y Saínz de la Torre para la determinación de la percepción de la distancia ajustada a las características específicas del tenis de mesa y el criterio de especialistas. Los principales resultados permitieron constatar un nivel inadecuado de desarrollo de la percepción de la distancia, en lo referente a los cálculos ópticos motriz, la visión central-periférica y los movimientos desequilibrados en los desplazamientos. Además, se aprecian dificultades en la coordinación y en las reacciones que afectan la precisión, potencia y colocación de los golpeos. Se elaboraron ejercicios perceptivo-visuales para la mejora de la percepción de la distancia central y periférica en el equipo nacional de tenis de mesa que fueron valoradas de muy adecuadas por los especialistas.

O presente trabalho investiga os estudos da percepção em atletas da seleção nacional de tênis de mesa. Teve como objetivo propor exercícios perceptivo-visuais para a melhoria da percepção da distância central e periférica nessa equipe, a partir da detecção das dificuldades apresentadas no jogo nos controles classificatórios de 2019. A necessidade de realizar estudos que explorem a percepção da distância central e periférica no campo da psicologia do esporte revela a importância e a atualidade do tema, devido à contribuição desse componente do sistema psicorregulatório das ações motoras para o desempenho dos atletas durante o processo de treinamento e competição. Foram utilizados métodos teóricos como análise-síntese e métodos empíricos como observação, entrevista, teste de Vera e Saínz de la Torre para a determinação da percepção da distância ajustada às características específicas do tênis de mesa e aos critérios dos especialistas. Os principais resultados mostraram um nível inadequado de desenvolvimento da percepção de distância, com relação a cálculos ópticos motores, visão centro-periférica e movimentos desequilibrados ao se movimentar. Além disso, há dificuldades na coordenação e nas reações que afetam a precisão, a potência e a colocação dos chutes. Exercícios perceptivo-visuais para a melhoria da percepção da distância central e periférica na equipe nacional de tênis de mesa foram elaborados e avaliados como muito adequados pelos especialistas.

This paper research perception studies in athletes from the national table tennis team. Its objective was to propose perceptual-visual exercises to improve the perception of central and peripheral distance in said team, based on the detection of the difficulties presented in the game in the qualifying controls, 2019. The need to carry out studies that explore the perception of central and peripheral distance in the field of sports psychology reveals the importance and topicality of the subject, due to the contribution of this component of the psychoregulatory system of motor actions, to the performance of athletes during the training and competition process. Theoretical level methods such as analysis-synthesis, as well as observation, interview and Vera and Saínz de la Torre test from the empirical level were used to determine the perception of distance adjusted to the specific characteristics of table tennis and tennis, also the specialist criteria method was used. The main results allowed to verify an inadequate level of development of the perception of distance, in relation to optical motor calculations, central-peripheral vision and unbalanced movements in displacements. In addition, there are difficulties in coordination and reactions that affect the precision, power and placement of the shots. Perceptual-visual exercises were developed to improve the perception of central and peripheral distance in the national table tennis team, which were valued as very adequate by specialists.

OncoVEXmGM-CSFexpands tumor antigen-specific CD8+ T-cell response in preclinical models.

BACKGROUND: Checkpoint inhibitors targeting cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) have demonstrated clinical efficacy in advanced melanoma, but only a subset of patients with inflamed tumors are responsive. Talimogene laherparepvec (T-VEC), a modified herpes simplex virus type 1 (HSV-1) expressing granulocyte-macrophage colony-stimulating factor (GM-CSF), is a first-in-class oncolytic immunotherapy approved for the treatment of melanoma and has been shown to inflame the tumor microenvironment. To evaluate the potential and mechanisms of T-VEC to elicit systemic antitumor immunity and overcome resistance to checkpoint inhibitors in murine tumor models, OncoVEXmGM-CSF was developed similarly to T-VEC, except the human GM-CSF transgene was replaced with murine GM-CSF. Previous work had demonstrated that OncoVEXmGM-CSF generated systemic antitumor immunity dependent on CD8+ T cells in an immune checkpoint-sensitive tumor cell model. METHODS: A novel B16F10 syngeneic tumor model with both HSV-1-permissive subcutaneous tumors and HSV-1-refractory experimental lung metastasis was used to study the local and systemic effects of OncoVEXmGM-CSF treatment alone or in combination with checkpoint inhibitors. RESULTS: Intratumoral injection of OncoVEXmGM-CSF in combination with an anti-CTLA-4 or anti-PD-1 blocking antibody led to increased tumor growth inhibition, a reduction in the number of lung metastases, and prolonged animal survival. OncoVEXmGM-CSF induced both neoantigen-specific and tumor antigen-specific T-cell responses. Furthermore, cured mice from the combination treatment of OncoVEXmGM-CSF and anti-CTLA-4 antibody rejected tumor rechallenges. CONCLUSIONS: These data support the concept that T-VEC and checkpoint inhibition may be an effective combination to treat patients with advanced melanoma.

Implementation of a Canine Ergonomic Abdominal Simulator for Training Basic Laparoscopic Skills in Veterinarians.

The validity of the CALMA Veterinary Lap-trainer simulator (CVLTS) for training basic veterinary laparoscopic skills was assessed and compared to a simple collapsible mobile box trainer. Ten veterinarian surgeons with no experience in laparoscopic surgery and four experts with at least two years of experience in minimally invasive surgery (MIS) were included. The training curriculum included object transfer, non-woven gauze cutting with curved scissors, and interrupted and continuous intracorporeal sutures, which were practiced on the CVLTS. The initial and final assessments were carried out in both the CVLTS and in a collapsible mobile simulator. These were video-recorded and evaluated by external experts using the Objective Structured Assessment of Technical Skills (OSATS) and a specific scale evaluation in a double-blinded schedule. The time, angular displacement, number, and movement smoothness were recorded using a hands movement assessment system (HMAS). Through a survey, the face validity and content were evaluated. The data were analyzed by a Pearson's proportions comparison or Mann Whitney U test and a bilateral Student's t-test. The experimental group OSATS, specific scores, and HMAS values, with the exception of the smoothness of movements, significantly improved after training, with no statistically significant differences compared to the expert group. No differences were found between the two simulators. The experts' and experimental participants' CVLTS mean score was 4.8. Our data support the CVLTS validations for laparoscopic surgery basic skills training.

Development and validation of a composed canine simulator for advanced veterinary laparoscopic training.

The development of innovative simulation models for veterinary laparoscopic surgery training is a priority today. This study aimed to describe a didactic simulation tool for the training of total laparoscopic gastropexy (TLG) with intracorporeal sutures in dogs. CALMA Veterinary Lap-trainer composite simulator (CLVTS) was developed from a plaster cast of 2 Great Dane canines mimicking the space and the correct position to carry out a TLG. After video instruction, 16 veterinarians with different degrees of experience in minimally invasive surgery (Experts, n = 6 and intermediates, n = 10) evaluated four sequential simulating TLG with intracorporeal suturing in the CLVTS. Subsequently, they completed an anonymous questionnaire analyzing the realism, usefulness, and educational quality of the simulator. The CLVTS showed a good preliminary acceptance (4.7/5) in terms of the usefulness and adequacy of the exercises that, in the participants' opinion, are appropriate and are related to the difficulty of the TLG. In addition, both experienced and intermediate surgeons gave high marks (4.5/5) to the feeling of realism, design, and practicality. There were no significant differences between the responses of the two groups. The results suggest that the CVLTS has both face and content validity. Where it can be practiced in a structured environment for the development of a total laparoscopic gastropexy with intracorporeal suture and without compromising patient safety, but still has some limitations of the scope of the study. Further studies are needed to establish the ability to assess or measure technical skills, including the degree of transferability to the actual surgical environment.

Characterization of an Anti-CD70 Half-Life Extended Bispecific T-Cell Engager (HLE-BiTE) and Associated On-Target Toxicity in Cynomolgus Monkeys.

Bispecific T-cell engager (BiTE) molecules have great potential to treat cancer. Nevertheless, dependent on the targeted tumor antigen, the mechanism of action that drives efficacy may also contribute to on-target/off-tumor toxicities. In this study, we characterize an anti-CD70 half-life extended BiTE molecule (termed N6P) which targets CD70, a TNF family protein detected in several cancers. First, the therapeutic potential of N6P was demonstrated using in vitro cytotoxicity assays and an orthotopic xenograft mouse study resulting in potent killing of CD70+ cancer cells. Next, in vitro characterization demonstrated specificity for CD70 and equipotent activity against human and cynomolgus monkey CD70+ cells. To understand the potential for on-target toxicity, a tissue expression analysis was performed and indicated CD70 is primarily restricted to lymphocytes in normal healthy tissues and cells. Therefore, no on-target toxicity was expected to be associated with N6P. However, in a repeat-dose toxicology study using cynomolgus monkeys, adverse N6P-mediated inflammation was identified in multiple tissues frequently involving the mesothelium and epithelium. Follow-up immunohistochemistry analysis revealed CD70 expression in mesothelial and epithelial cells in some tissues with N6P-mediated injury, but not in control tissues or those without injury. Collectively, the data indicate that for some target antigens such as CD70, BiTE molecules may exhibit activity in tissues with very low antigen expression or the antigen may be upregulated under stress enabling molecule activity. This work illustrates how a thorough understanding of expression and upregulation is needed to fully address putative liabilities associated with on-target/off-tumor activity of CD3 bispecific molecules.

Liver Metastasis Modulate Responses of Suppressive Macrophages and Exhausted T Cells to Immunotherapy Revealed by Single Cell Sequencing.

Liver metastasis is associated with immunotherapy resistance, although the underlying mechanisms remain incompletely understood. By applying single cell RNA-sequencing to a concurrent subcutaneous and liver tumor murine model to recapitulate liver metastases, it is identified that subsets within tumor-infiltrating exhausted CD8+ T (Tex) cells and immunosuppressive tumor-associated macrophages (TAMs) display opposite responses to concurrent liver tumors and anti-PD-1 treatment, suggesting a complex immune regulating network. Both angiogenic and interferon-reactive TAMs show increased frequencies in implanted liver tumors, and anti-PD-1 treatment further elevates the frequencies of angiogenic TAMs. Such TAMs frequencies negatively correlate with the proportions of cytotoxic T cell subsets. Further, expression of interferon-stimulated genes in TAMs is dramatically reduced under effective anti-PD-1 treatment, while such tendencies are diminished in mice with implanted liver tumors. Therefore, the study indicates that liver metastases could increase immunosuppressive TAMs frequencies and inhibit Tex responses to PD-1 blockade, resulting in compromised systemic antitumor immunity and limited immunotherapy efficacy.

AMG 757, a Half-Life Extended, DLL3-Targeted Bispecific T-Cell Engager, Shows High Potency and Sensitivity in Preclinical Models of Small-Cell Lung Cancer.

PURPOSE: Small-cell lung cancer (SCLC) is an aggressive neuroendocrine tumor with a high relapse rate, limited therapeutic options, and poor prognosis. We investigated the antitumor activity of AMG 757, a half-life extended bispecific T-cell engager molecule targeting delta-like ligand 3 (DLL3)-a target that is selectively expressed in SCLC tumors, but with minimal normal tissue expression. EXPERIMENTAL DESIGN: AMG 757 efficacy was evaluated in SCLC cell lines and in orthotopic and patient-derived xenograft (PDX) mouse SCLC models. Following AMG 757 administration, changes in tumor volume, pharmacodynamic changes in tumor-infiltrating T cells (TILs), and the spatial relationship between the appearance of TILs and tumor histology were examined. Tolerability was assessed in nonhuman primates (NHPs). RESULTS: AMG 757 showed potent and specific killing of even those SCLC cell lines with very low DLL3 expression (<1,000 molecules per cell). AMG 757 effectively engaged systemically administered human T cells, induced T-cell activation, and redirected T cells to lyse tumor cells to promote significant tumor regression and complete responses in PDX models of SCLC and in orthotopic models of established primary lung SCLC and metastatic liver lesions. AMG 757 was well tolerated with no AMG 757-related adverse findings up to the highest tested dose (4.5 mg/kg weekly) in NHP. AMG 757 exhibits an extended half-life in NHP, which is projected to enable intermittent administration in patients. CONCLUSIONS: AMG 757 has a compelling safety and efficacy profile in preclinical studies making it a viable option for targeting DLL3-expressing SCLC tumors in the clinical setting.

A nanoparticle vaccine that targets neoantigen peptides to lymphoid tissues elicits robust antitumor T cell responses.

Cancer vaccines using synthetic long peptides (SLP) targeting tumor antigens have been tested in the clinic but the outcomes have been unimpressive, perhaps because these peptides elicit predominantly CD4+ T cell responses. We hypothesized that enhanced delivery of peptide antigens to, and uptake in, secondary lymphoid tissues should elicit more robust CD8+ and CD4+ T cell responses and improved anti-tumor responses. Here, we have designed SLP-containing cationic lipoplexes (SLP-Lpx) that improve delivery of peptides to myeloid cells in the spleen and lymphatics. Using the G12D KRAS mutations as neoantigens, we found that vaccination of mice with naked synthetic peptides harboring the G12D mutation with CpG adjuvant stimulated mainly CD4+ T cell responses with limited tumor growth inhibition. On the other hand, immunization with SLP-Lpx stimulated both CD4+ and CD8+ T cells and suppressed tumor growth in a CD8+ T cell-dependent manner. Combination of the SLP-Lpx vaccines with a checkpoint inhibitor led to profound growth suppression of established tumors. These studies suggest that preferential targeting of peptides derived from neoantigens to the spleen via lipoplexes elicits potent CD4+ and CD8+ T cell responses that inhibit tumor growth.

Reflexiones en torno a la pertinencia de los procesos de formación e investigación en psicología clínica en la contemporaneidad / Reflections on the Relevance of the Training and Research Processes in Clinical Psychology in the Contemporary World

Resumen El cambio cultural asociado a la contemporaneidad ha traído consigo el debilitamiento de las instituciones disciplinares y la caída de los grandes metarrelatos y los valores absolutos como guías orientadoras de los sujetos. Concomitantemente, los marcos referenciales en los que la psicología clínica ha soportado la lectura e intervención de las problemáticas en salud mental son cuestionados en su vigencia y conveniencia para responder a ellas. Objetivo: analizar los procesos de formación e investigación de la psicología clínica para valorar su capacidad de responder a las problemáticas en salud mental en la contemporaneidad. Metodología: investigación de enfoque cualitativo, con perspectiva hermenéutica y técnicas de análisis documental y teoría fundamentada. Resultados: los procesos de formación en psicología clínica en EE. UU., Europa, Iberoamérica y Colombia en la contemporaneidad siguen el modelo de Boulder y sus variantes de Vail y Clinical Science, conservando las premisas ontológicas realistas y su dependencia del método clínico médico. Consecuentemente, los procesos investigativos se centran en la psicopatología y la psicoterapia, dejando rezagadas las reflexiones relativas a la contemporaneidad, las subjetividades y problemáticas emergentes de ella.

Abstract The cultural change associated with contemporaneity has brought with it the weakness of the disciplinary institutions and the decline of the great meta-narratives and absolute values as guides for the subjects. Concomitantly, the reference frameworks in which clinical psychology has supported the reading and intervention of mental health problems are questioned in their validity and convenience to respond to these issues. This situation confronts clinical psychology regarding the relevance of its training and research processes to understand and intervene the mental health problems in the contemporary context. Objective: analyze the training and research processes of clinical psychology to assess its ability to respond to contemporary mental health problems. Methodology: qualitative investigation, hermeneutic perspective and documentary analysis techniques and grounded theory. Results: the processes of training in clinical psychology in the US, Europe, Latin America and Colombia in the contemporary world follow Boulder model of and its variants of Vail and Clinical Science, preserving the realistic ontological premises and their dependence on the clinical medical method. Consequently, the research processes is focused on psychopathology and psychotherapy, leaving behind reflections related to contemporaneity, subjectivities and problems emerging from it. In conclusion, in order to increase its relevance, it is proposed to include reflections on contemporaneity and its emerging subjectivities in training and research processes in clinical psychology.

Glycan expression in chorionic villi from histocultures of women with early-onset preeclampsia: Immunomodulatory effects on peripheral natural killer cells.

New evidence suggests that glycan expression in placental cells of women with invasive disorders of pregnancy differs from that in normal pregnant women. Hypothesizing that modifications of glycan expression could account for the course of preeclampsia, we established placental villous histocultures and compared glycan expression in women with preeclampsia with that in normal pregnant women and also in syncytialized BeWo cells, and we tested the effect of glycan expression on the functional phenotypes of circulating natural killer (NK) cells. Histocultures of third-trimester placentae from women with preeclampsia and full-term placentae from healthy pregnant women and BeWo choriocarcinoma cells were assessed for the expression of terminal glycans by lectin-binding assays. Circulating NK cells from nonpregnant healthy donors were tested in vitro for their cytotoxic activity and intracellular cytokine content. Histocultures from women with preeclampsia expressed significantly more mannose than did those from healthy pregnant women. Both histocultures and BeWo cells expressed terminal fucose, mannose, sialic acid, and N -acetylgalactosamine, although mean fluorescence intensity (MFI) expression was lower in choriocarcinoma cells than in cells from histocultures. Cocultures of circulating NK cells with K562 target cells resulted in a dose-dependent cytotoxicity effect, but the use of BeWo cells as target reduced cytotoxic activity; this reduction was not affected by syncytialization. Histocultures of placental villous tissue of women with preeclampsia expressed high levels of terminal mannose. We proposethat placental glycans may modulate the functional activity of circulating NK cells in the context of systemic inflammatory response in preeclampsia.

Conduction Recovery After Cavotricuspid Isthmus Ablation When Performed With or Without Concomitant Atrial Fibrillation Ablation.

OBJECTIVES: This study sought to define the association between conduction recovery across the cavotricuspid isthmus (CTI) and typical atrial flutter (AFL) recurrence when CTI ablation is performed with pulmonary vein isolation (PVI) compared with a stand-alone procedure. BACKGROUND: CTI ablation is commonly performed at the same time as PVI to treat AFL or as an empiric therapy. Conduction recovery is a recognized problem after linear ablation in the left atrium (e.g., mitral isthmus ablation) and is proarrhythmic. Less is known about conduction recovery after CTI ablation and possible differences in outcomes when performed at the time of PVI compared with at the time of a stand-alone procedure. METHODS: Eligible participants who underwent stand-alone CTI ablation were compared with those who underwent a combined (CTI+PVI) procedure. CTI conduction recovery was assessed at the time of a second ablation. Conduction recovery across the CTI (primary outcome) and recurrence of typical AFL (secondary outcome) were studied using multivariable logistic regression. RESULTS: Among 295 eligible participants (median age: 64 years [interquartile range: 55 to 69 years]; 33% women), recovery was assessed in 232 and was more common after combined versus stand-alone CTI ablation (52% [72 of 139] vs. 13% [12 of 93]; p < 0.001). In multivariable analysis, CTI ablation performed as a combined procedure increased odds of CTI conduction recovery 7.8-fold (odds ratio: 7.8; 95% confidence interval: 3.3 to 18.3; p < 0.001) and clinical AFL recurrence 4.1-fold (odds ratio: 4.1; 95% confidence interval: 1.0 to 16.9; p = 0.049). CONCLUSIONS: CTI ablation performed at the time of atrial fibrillation ablation is associated with higher rates of conduction recovery and typical flutter recurrence.

Validation of Training and Acquisition of Surgical Skills in Veterinary Laparoscopic Surgery: A Review.

At present, veterinary laparoscopic surgery training is lacking in experiences that provide a controlled and safe environment where surgeons can practice specific techniques while receiving experts' feedback. Surgical skills acquired using simulators must be certified and transferable to the operating room. Most models for practicing laparoscopic skills in veterinary minimally invasive surgery are general task trainers and consist of boxes (simulators) designed for training human surgery. These simulators exhibit several limitations, including anatomic species and procedural differences, as well as general psychomotor training rather than in vivo skill recreation. In this paper, we review the existing methods of training, evaluation, and validation of technical skills in veterinary laparoscopic surgery. Content includes global and specific scales, and the conditions a structured curriculum should meet for improving the performance of novice surgeons during and after training. A focus on trainee-specific assessment and tailored-technical instruction should influence training programs. We provide a comprehensive analysis of current theories and concepts related to the evaluation and validation of simulators for training laparoscopic surgery in small animal surgery. We also highlight the need to develop new training models and complementary evaluation scales for the validation of training and acquisition of basic and advanced skills in veterinary laparoscopic surgery.

ASIC1a does not play a role in evoking the metabolic component of the exercise pressor reflex in a rat model of peripheral artery disease.

The role of the ASIC1a in evoking the exercise pressor reflex in rats with simulated peripheral artery disease is unknown. This prompted us to determine whether ASIC1a plays a role in evoking the exaggerated exercise pressor reflex in decerebrated rats with simulated peripheral artery disease. To simulate peripheral artery disease, we ligated the left femoral artery 72 h before the experiment. The right femoral artery was freely perfused and used as a control. To test our hypothesis, we measured the effect of injecting two ASIC1a blockers into the arterial supply of the triceps surae muscles with and without the femoral artery ligated on the reflex pressor responses to 1) static contraction of the triceps surae muscles, 2) calcaneal tendon stretch, and 3) intra-arterial injection of diprotonated phosphate (pH 6.0). We found that the ASIC1a blockers psalmotoxin-1 (200 ng/kg) and mambalgin-1 (6.5 µg/kg) decreased the pressor responses to static contraction as well as the peak pressor responses to injection of diprotonated phosphate when these responses were evoked from the freely perfused hindlimb. In contrast, ASIC1a blockers only decreased the peak pressor responses evoked by injection of diprotonated phosphate in the hindlimb circulation with simulated peripheral artery disease. This inhibitory effect was less than the one measured from the healthy hindlimb. Independently of the hindlimb of interest, ASIC1a blockers had no effect on the pressor responses to tendon stretch. Our results do not support the hypothesis that ASIC1a play a role in evoking the exercise pressor reflex arising from a hindlimb with simulated peripheral artery disease.NEW & NOTEWORTHY The role of ASIC1a in evoking the metabolic component of the exercise pressor reflex in peripheral artery disease is unknown. Using a within-rat experimental design, we found that the contribution of ASIC1a decreased in a rat model of peripheral artery disease. These results have key implications to help finding better treatments and improve morbidity, quality of life, and mortality in patients with peripheral artery disease.

ASIC1a plays a key role in evoking the metabolic component of the exercise pressor reflex in rats.

The role of the acid-sensing ion channel 1a (ASIC1a) in evoking the exercise pressor reflex is unknown, despite the fact that ASIC1a is opened by decreases in pH in the physiological range. This fact prompted us to test the hypothesis that ASIC1a plays an important role in evoking the exercise pressor reflex in decerebrated rats with freely perfused hindlimb muscles. To test this hypothesis, we measured the effect of injecting two ASIC1a blockers into the arterial supply of the triceps surae muscles on the reflex pressor responses to four maneuvers, namely 1) static contraction of the triceps surae muscles (i.e., the exercise pressor reflex), 2) calcaneal tendon stretch, 3) intra-arterial injection of lactic acid, and 4) intra-arterial injection of diprotonated phosphate. We found that the 2 ASIC1a blockers, psalmotoxin-1 (200 ng/kg) and mambalgin-1 (6.5 µg/kg), decreased the pressor responses to static contraction as well as the peak pressor responses to injection of lactic acid and diprotonated phosphate. In contrast, neither ASIC1a blocker had any effect on the pressor responses to tendon stretch. Importantly, we found that ASIC1a blockade significantly decreased the pressor response to static contraction after a latency of at least 8 s. Our results support the hypothesis that ASIC1a plays a key role in evoking the metabolic component of the exercise pressor reflex.NEW & NOTEWORTHY The role played by acid-sensing ion channel 1a (ASIC1a) in evoking the exercise pressor reflex remains unknown. In decerebrated rats with freely perfused femoral arteries, blocking ASIC1a with psalmotoxin-1 or mambalgin-1 significantly attenuated the pressor response to static contraction, lactic acid, and diprotonated phosphate injection but had no effect on the pressor response to stretch. We conclude that ASIC1a plays a key role in evoking the exercise pressor reflex by responding to contraction-induced metabolites, such as protons.