Programmed cell death ligand 1 expression associated with subtypes of post-transplant lymphoproliferative disorder among pediatric kidney transplant recipients.

BACKGROUND: Programmed cell death ligand 1 (PD-L1) expression on tumor cells engages the PD-1 receptor on T cells, inhibiting anti-tumor responses. PD-L1 has been detected in cases of post-transplant lymphoproliferative disorder (PTLD) but reports are limited. Here we examine PD-L1 expression and evaluate for clinical correlations. METHODS: Twenty-one cases of PTLD were identified among pediatric kidney transplant recipients at our institution from February 1996 to April 2017. Using paraffin-embedded tissue biopsies, we examined 21 primary tumors for expression using PD-L1 monoclonal antibody performed with PAX5 as a double stain. We scored expression of PD-L1 on lesional B-cells as a percentage of positive cells. Clinical course and outcome were obtained from retrospective chart review. RESULTS: Applying revised 2017 WHO PTLD classification showed five non-destructive, nine polymorphic, and seven monomorphic cases. Average PD-L1 expression based upon PTLD subtype was: non-destructive 11%, polymorphic 43%, and monomorphic 73% (p = .01). Two patients transferred shortly after diagnosis, five received chemotherapy, and three died from PTLD. Among the fatalities, all showed monomorphic PTLD and 90% of lesional B-cells expressed PD-L1. CONCLUSION: In this case series, significant differences in PD-L1 expression were seen among different subtypes, and monomorphic PTLD demonstrated the highest expression. Study of a larger cohort is needed, and if the correlation of PD-L1 expression and PTLD subtype is confirmed, this may highlight the potential utility of checkpoint inhibitor therapy in cases of severe or refractory disease among kidney transplant recipient in whom the risk of allograft loss is acceptable given the option of chronic dialysis.

Tissue expander-stimulated lengthening of arteries for the treatment of midaortic syndrome in children.

BACKGROUND: Midaortic syndrome (MAS) is a rare condition characterized by stenosis of the abdominal aorta. Patients with disease refractory to medical management will usually require either endovascular therapy or surgery with use of prosthetic graft material for bypass or patch angioplasty. We report our early experience with a novel approach using a tissue expander (TE) to lengthen the normal native arteries in children with MAS, allowing primary aortic repair without the need for prosthetic graft material. METHODS: We conducted a retrospective review of patients with MAS undergoing the TE-stimulated lengthening of arteries (TESLA) procedure at our institution from 2010 to 2014. Data are presented as mean (range). RESULTS: Five patients aged 4.8 years (3-8 years) underwent the TESLA procedure. Stages of this procedure include the following: stage I, insertion of retroaortic TE; stage II, serial TE injections; and stage III, final repair with excision of aortic stenosis and primary end-to-end aortic anastomosis. Stage II was completed in 4 months (1-9 months) with 12 (7-20) TE injections. Goal lengthening was achieved in all patients. Stage III could not be completed in one patient because of extreme aortic inflammation, which precluded safe excision of the aortic stenosis and required use of a prosthetic bypass graft. The other four patients completed stage III with two (one to three) additional vessels also requiring reconstruction (renal or mesenteric arteries). At 3.2 years (1-6 years) of follow-up, all patients are doing well. CONCLUSIONS: The TESLA procedure allows surgical correction of MAS without the need for prosthetic grafts in young children who are still growing.

Contaminación del aire y vulnerabilidad de individuos expuestos: un caso de estudio para el centro de Medellín / Air pollution and vulnerability of exposed individuals: the case of downtown Medellín

La presencia de problemas respiratorios en zonas con alta contaminación se relaciona con factores como la exposición, la susceptibilidad y la capacidad de respuesta por parte de los individuos. OBJETIVO: presentar evidencia estadística de cómo la probabilidad de presentar un síntoma o enfermedad está relacionado con la exposición, la susceptibilidad y la respuesta social de individuos expuestos a la contaminación por material particulado. METODOLOGIA: se emplea información única de una encuesta a 1.000 individuos expuestos en el centro de Medellín para realizar un análisis descriptivo y modelos de respuesta binaria probit. Se analizaron 27 modelos para las siguientes variables dependientes: presenta un síntoma o enfermedad (EMF), presenta un síntoma (LEVE) y presenta una enfermedad (GRAVE). RESULTADOS: se evidencia que la exposición es una variable clave en la presencia de problemas respiratorios (vulnerabilidad), pero que los individuos expuestos pueden presentar problemas en salud debido no solo a la contaminación per se, sino a condiciones personales y sociales implícitas.

The presence of respiratory problems in high level pollution areas is linked to factors such as exposure, susceptibility, and social coping. OBJECTIVE:o present statistical evidence regarding the relationship between the probability of experiencing symptoms or contracting a respiratory disease and factors such as exposure to pollution, susceptibility, and social coping among people inhabiting areas with particulate matter pollution. METHODOLOGY: The study used unique information collected from a survey conducted on 1000 people in downtown Medellin who were exposed to this problem. This information was used to perform a descriptive statistic analysis and to build 27 PROBIT models. The dependent variables were: the patient has a symptom or disease -EMF-, the patient has a symptom -LEVE-, and the patient has a respiratory disease -GRAVE-. Results: The results evidence that exposure is a key variable affecting the presence of respiratory symptoms or diseases (vulnerability); however, exposed individuals may also experience health problems not only due to air pollution per se, but also to implicit personal and social conditions.

Chronic nicotine exposure inhibits estrogen-mediated synaptic functions in hippocampus of female rats.

Nicotine, the addictive agent in cigarettes, reduces circulating estradiol-17ß (E2) and inhibits E2-mediated intracellular signaling in hippocampus of female rats. In hippocampus, E2-signaling regulates synaptic plasticity by phosphorylation of the N-methyl-D-aspartic acid receptor subunit NR2B and cyclic-AMP response element binding protein (pCREB). Therefore, we hypothesized that chronic nicotine exposure induces synaptic dysfunction in hippocampus of female rats. Female rats were exposed to nicotine or saline for 16 days followed by electrophysiological analysis of hippocampus. Briefly, population measurements of excitatory post-synaptic field potentials (fEPSPs) were recorded from stratum radiatum of the CA1 hippocampal slice subfield. A strict software-controlled protocol was used which recorded 30 min of baseline data (stimulation rate of 1/min), a paired-pulse stimulation sequence followed by tetanic stimulation, and 1h of post-tetanus recording. EPSP amplitude and the initial EPSP slope were measured off-line. We then investigated by Western blot analysis the effects of nicotine on hippocampal estrogen receptor-beta (ER-ß), NR2B and pCREB. The results demonstrated significantly decreased post-tetanic potentiation and paired-pulse facilitation at the 40, and 80 ms interval in nicotine-exposed rats compared to the saline group. Western blot analysis revealed that nicotine decreased protein levels of ER-ß, NR2B, and pCREB. We also confirmed the role of E2 in regulating NR2B and pCREB phosphorylation by performing Western blots in hippocapmal tissue obtained from E2-treated ovariectomized rats. In conclusion, chronic nicotine exposure attenuates short-term synaptic plasticity, and the observed synaptic defects might be a consequence of loss of estradiol-17ß-signaling. However, determining the exact molecular mechanisms of chronic nicotine exposure on synaptic plasticity specific to the female brain require further investigation.

Synergistic inhibitory effect of nicotine plus oral contraceptive on mitochondrial complex-IV is mediated by estrogen receptor-ß in female rats.

Chronic nicotine and oral contraceptive (NOC) exposure caused significant loss of hippocampal membrane-bound estrogen receptor-beta (ER-ß) in female rats compared with exposure to nicotine alone. Mitochondrial ER-ß regulates estrogen-mediated mitochondrial structure and function; therefore, investigating the impact of NOC on mitochondrial ER-ß and its function could help delineate the harmful synergism between nicotine and OC. In this study, we tested the hypothesis that NOC-induced loss of mitochondrial ER-ß alters the oxidative phosphorylation system protein levels and mitochondrial respiratory function. This hypothesis was tested in hippocampal mitochondria isolated from female rats exposed to saline, nicotine, OC or NOC for 16 days. NOC decreased the mitochondrial ER-ß protein levels and reduced oxygen consumption and complex IV (CIV) activity by 34% and 26% compared with saline- or nicotine-administered groups, respectively. We also observed significantly low protein levels of all mitochondrial-encoded CIV subunits after NOC as compared with the nicotine or saline groups. Similarly, the silencing of ER-ß reduced the phosphorylation of cyclic-AMP response element binding protein, and also reduced levels of CIV mitochondrial-encoded subunits after estrogen stimulation. Overall, these results suggest that mitochondrial ER-ß loss is responsible for mitochondrial malfunction after NOC.