A rite of passage: The White Coat Ceremony for advanced practice registered nursing students.

ABSTRACT: Since 1993, when the Gold Foundation held its first White Coat Ceremony (WCC) to highlight humanism in medicine, many health professions have launched these ceremonies. In 2021, the University of Colorado College of Nursing hosted its first WCC. Postevent, a seven-question survey was sent to all faculty, staff, and student participants. The analytic question driving this program evaluation was as follows: "What is the significance of the White Coat Ceremony to APRN students?" Quantitative data from survey items were overwhelmingly positive; qualitative analysis of open-ended survey text reinforced the central WCC concept of Being/Becoming an APRN and elicited four themes: recognition, transition, symbolism, and connection. A detailed analysis of these themes is presented.

Development of a Prediction Model for Short-Term Remission of Patients with Crohn's Disease Treated with Anti-TNF Drugs.

Therapy with anti-tumor necrosis factor (TNF) has dramatically changed the natural history of Crohn's disease (CD). However, these drugs are not without adverse events, and up to 40% of patients could lose efficacy in the long term. We aimed to identify reliable markers of response to anti-TNF drugs in patients with CD. A consecutive cohort of 113 anti-TNF naive patients with CD was stratified according to clinical response as short-term remission (STR) or non-STR (NSTR) at 12 weeks of treatment. We compared the protein expression profiles of plasma samples in a subset of patients from both groups prior to anti-TNF therapy by SWATH proteomics. We identified 18 differentially expressed proteins (p ≤ 0.01, fold change ≥ 2.4) involved in the organization of the cytoskeleton and cell junction, hemostasis/platelet function, carbohydrate metabolism, and immune response as candidate biomarkers of STR. Among them, vinculin was one of the most deregulated proteins (p < 0.001), whose differential expression was confirmed by ELISA (p = 0.054). In the multivariate analysis, plasma vinculin levels along with basal CD Activity Index, corticosteroids induction, and bowel resection were factors predicting NSTR.

Patient and Provider Perceptions of COVID-19-Driven Telehealth Use From Nurse-Led Care Models in Rural, Frontier, and Urban Colorado Communities.

The purpose of this study was to characterize the patient and provider engagement in the sudden telehealth implementation that occurred with the onset of the COVID-19 pandemic. Patients and providers from 3 nurse-led models of care (federally qualified health centers, nurse midwifery practices, and the Nurse-Family partnership program) in Colorado were surveyed. Data from the Patient Attitude toward Telehealth survey and Provider Perceptions about Telehealth were collected. Patient respondents (n = 308) who resided primarily in rural or frontier communities were female, white, and Hispanic. Patients in urban areas used telehealth more frequently than in rural or frontier areas (P < .001). Rural/Frontier patients had significantly lower attitude scores than urban patients across each of 5 domains assessed. Telehealth modality differed across location (P < .023), with video calls, used more frequently by urban providers, and phone calls used by rural/frontier providers. Our data highlight differences in telehealth access and attitudes across rurality. These findings may contribute to future policy while addressing barriers to telehealth access and delivery.

Creating an academic-practice partnership in a primary care pediatric clinic.

There is increasing demand for primary care nationally, and advanced practice registered nurses are uniquely suited to meet this demand. Academic nursing programs are responding to this challenge by expanding graduate nurse practitioner (NP) programs, but they are limited by availability of student clinical placement sites and dedicated preceptors. We addressed these limitations by developing an academic-practice partnership between a College of Nursing pediatric nurse practitioner (PNP) program and a primary care clinic within an academic pediatric hospital. A novel PNP faculty role was developed with teaching, patient care, and clinical precepting responsibilities. This partnership increased access to pediatric primary care services within the local underserved community, increased the number of teaching faculty members and clinical preceptors, and expanded clinical education opportunities for PNP students.

Treating chronic pain and opioid misuse disorder among underserved populations in Colorado.

The increased use of prescription opioids has resulted in widespread misuse. As a result, more than 40,000 Americans lost their lives to opiate overdose in 2016 alone. These data have led to a national movement focused on appropriate opioid prescribing practices. The Centers for Disease Control and Prevention (CDC) developed its Guidelines for Prescribing Opioids for Chronic Pain (2017), a template for pain management and substance assessment in primary care. These CDC guidelines aim to prevent misuse/deaths and early identification of substance use disorders. Although the guidelines are appropriate for initiation of opioid therapy, they are not sufficient to manage patients who have already developed misuse disorders. Other modalities such as medication-assisted treatment (MAT) have been described as beneficial for patients with high risk for or who have an opioid misuse disorder. This article builds on the CDC's 2017 advisory document by applying it in praxis: first, non-opioid medication therapy options and nonmedication therapy options are explored; next, a case study is presented of an integrated primary care-managed patient who presented with both chronic pain and established opioid use disorder. Although the CDC guidelines were not followed in the patient's initial prescription opioid treatment regimen, those guidelines were used as a starting point for follow-up treatment, helping both to assess the patient's risk for opioid misuse disorder and to determine that MAT was an appropriate method of treatment.

Prevalencia de déficit de hierro sin anemia en la enfermedad inflamatoria intestinal y su impacto en la calidad de vida / Prevalence of iron deficiency without anaemia in inflammatory bowel disease and impact on health-related quality of life

Introducción: El déficit de hierro sin anemia asociada (DHSA) es un hallazgo frecuente en los pacientes no ingresados con enfermedad inflamatoria intestinal (EII), incluso en mayor proporción que la anemia. Sin embargo, no existen datos concluyentes de su presencia en nuestro medio ni del posible deterioro que conlleva en la calidad de vida relacionada con la salud (CVRS). Los objetivos de este trabajo fueron: establecer la prevalencia del DHSA, identificar posibles factores asociados y medir su impacto en la CVRS. Material y métodos: Se incluyeron 127 pacientes con EII, de manera consecutiva, en medio extrahospitalario en un estudio observacional, descriptivo, de corte transversal. Se definió DHSA como niveles de ferritina ≤30 ng/ml en ausencia de actividad inflamatoria o <100 ng/ml en su presencia, con índice de saturación de transferrina ≤16%, junto a niveles normales de hemoglobina. Se evaluó la CVRS mediante dos cuestionarios: CVEII-9 para los síntomas relacionados con EII, y FACIT-F para medir la presencia de fatiga, considerándola extrema ante una puntuación ≤ 30 puntos. Resultados: La prevalencia del DHSA fue del 37%. El sexo femenino (OR=2,9; p=0,015) y la presencia de actividad inflamatoria (OR=9,4; p=0,001) fueron las variables asociadas con su aparición. Los pacientes con DHSA presentaron cuestionarios de CVRS con menores puntuaciones de forma global; registrando una caída de 6,6 (p<0,001) y 4,3 (p=0,037) puntos en CVEII-9 y FACIT-F, respectivamente. Además, se observó un incremento en la presencia de fatiga extrema del 29,4%. Conclusión: La prevalencia de DHSA es considerable en los pacientes con EII en el ámbito extrahospitalario. Se asocia al sexo femenino y a la actividad inflamatoria, y supone un claro impacto negativo en la CVRS. Es necesaria una actitud más activa para el tratamiento de esta complicación (AU)

Introduction: Iron deficiency without anaemia (IDWA) is commonly found in outpatients with inflammatory bowel disease (IBD) in an even higher proportion than anaemia. However, its true prevalence and possible impact on health-related quality of life (HRQoL) are unknown. The objectives of this study were: to establish the prevalence of IDWA, identify possible associated factors and measure their impact on HRQoL. Material and methods: 127 patients with IBD in an outpatient setting were consecutively included in an observational, descriptive, cross-sectional study. IDWA was defined as ferritin levels of <100 ng/ml with inflammatory activity or ≤30 ng/ml without it, with transferrin saturation of ≤16%, and with normal haemoglobin levels. HRQoL was assessed using two questionnaires: the IBDQ-9 for symptoms related to IBD and the FACIT-F to measure the presence of fatigue. Fatigue was considered extreme with a score of ≤30 points. Results: The prevalence of IDWA was 37%. Variables associated with its occurrence were female gender (OR=2.9; p=.015) and the presence of inflammatory activity (OR=9.4; p=.001). Patients with IDWA presented HRQoL questionnaires with lower overall scores; decreases of 6.6 (p<.001) and 4.3 (p=.037) points in the IBDQ-9 and the FACIT-F were recorded, respectively. In addition, an increase of 29.4% in the presence of extreme fatigue was observed. Conclusion: The prevalence of IDWA is considerable in outpatients with IBD. IDWA is associated with female gender and inflammatory activity. It has a clear negative impact on HRQoL. A more active approach is needed to treat this complication (AU)

Prevalence of iron deficiency without anaemia in inflammatory bowel disease and impact on health-related quality of life. / Prevalencia de déficit de hierro sin anemia en la enfermedad inflamatoria intestinal y su impacto en la calidad de vida.

INTRODUCTION: Iron deficiency without anaemia (IDWA) is commonly found in outpatients with inflammatory bowel disease (IBD) in an even higher proportion than anaemia. However, its true prevalence and possible impact on health-related quality of life (HRQoL) are unknown. The objectives of this study were: to establish the prevalence of IDWA, identify possible associated factors and measure their impact on HRQoL. MATERIAL AND METHODS: 127 patients with IBD in an outpatient setting were consecutively included in an observational, descriptive, cross-sectional study. IDWA was defined as ferritin levels of <100 ng/ml with inflammatory activity or ≤30 ng/ml without it, with transferrin saturation of ≤16%, and with normal haemoglobin levels. HRQoL was assessed using two questionnaires: the IBDQ-9 for symptoms related to IBD and the FACIT-F to measure the presence of fatigue. Fatigue was considered extreme with a score of ≤30 points. RESULTS: The prevalence of IDWA was 37%. Variables associated with its occurrence were female gender (OR=2.9; p=.015) and the presence of inflammatory activity (OR=9.4; p=.001). Patients with IDWA presented HRQoL questionnaires with lower overall scores; decreases of 6.6 (p<.001) and 4.3 (p=.037) points in the IBDQ-9 and the FACIT-F were recorded, respectively. In addition, an increase of 29.4% in the presence of extreme fatigue was observed. CONCLUSION: The prevalence of IDWA is considerable in outpatients with IBD. IDWA is associated with female gender and inflammatory activity. It has a clear negative impact on HRQoL. A more active approach is needed to treat this complication.

Evolución tras el intercambio a infliximab biosimilar en pacientes con enfermedad inflamatoria intestinal en remisión clínica / Evolution after switching to biosimilar infliximab in inflammatory bowel disease patients in clinical remission

Introducción y objetivo: Infliximab biosimilar (CT-P13) ha sido aprobado para las mismas indicaciones que infliximab original (Remicade(R)); sin embargo, hay pocos datos clínicos sobre el intercambio en la enfermedad inflamatoria intestinal (EII). El objetivo del estudio fue evaluar la eficacia, la seguridad, el perfil de biodisponibilidad y los factores asociados a la recidiva tras el intercambio a infliximab biosimilar en pacientes con EII en remisión clínica. Material y métodos: Estudio observacional con pacientes con EII tratados con Remicade(R) durante al menos 6 meses y en remisión clínica durante al menos 3 meses, a los que se realizó el intercambio a infliximab biosimilar. Se evaluó la incidencia de recidiva, los efectos adversos y los cambios en la biodisponibilidad del fármaco (niveles y anticuerpos). Resultados: Se incluyeron 36 pacientes (63,9% EC), con una media de seguimiento de 8,4 meses (±3,5). El 13,9% presentaron recidiva clínica. El mayor tiempo de remisión clínica previo al intercambio (HR=0,54; IC 95%=0,29-0,98; p=0,04) y niveles de infliximab detectables en el momento del intercambio (HR=0,03; IC 95%=0,001-0,89; p=0,04) se asociaron a menor riesgo de recidiva. No hubo diferencias entre niveles de infliximab en el momento del intercambio y en las semanas 8 y 16 (p=0,94). El 8,3% presentaron algún efecto adverso, requiriendo suspensión del fármaco en un paciente por neumonía grave. Conclusión: El intercambio a infliximab biosimilar en una cohorte de vida real de pacientes con EII en remisión clínica no parece tener un impacto significativo en los resultados clínicos a corto plazo. Los factores asociados con la recidiva fueron similares a los esperados en pacientes que continúan con Remicade(R) (AU)

Background and aim: The biosimilar of infliximab (CT-P13) has been approved for the same indications held by the infliximab reference product (Remicade(R)); however, there are few clinical data on switching in inflammatory bowel disease (IBD). The aim of this study was to assess the efficacy, safety, bioavailability profile and factors associated with relapse after switching to biosimilar infliximab in IBD patients in clinical remission. Material and method: Observational study with IBD patients treated with Remicade(R) for at least 6 months and in clinical remission for at least 3 months who switched to infliximab biosimilar. The incidence of relapse, adverse effects and possible changes in drug bioavailability (trough level and antidrug antibodies) were evaluated. Results: Thirty six patients were included (63.9% CD) with a mean follow-up of 8.4 months (SD±3.5). The 13.9% had clinical relapse. The longer clinical remission time before switching (HR=0.54, 95% CI=0.29-0.98, P=.04) and detectable infliximab levels at the time of switching (HR=0.03, 95% CI=0.001-0.89, P=.04) were associated with a lower risk of relapse. No differences were found between infliximab levels at the time of switching and at weeks 8 and 16 (P=.94); 8.3% of the patients had some adverse event, requiring the suspension of biosimilar in one patient for severe pneumonia. Conclusion: Switching to biosimilar infliximab in a real-life cohort of IBD patients in clinical remission did not have a significant impact on short-term clinical outcomes. The factors associated with relapse were similar to those expected in patients continuing with Remicade(R) (AU)

Evolution after switching to biosimilar infliximab in inflammatory bowel disease patients in clinical remission. / Evolución tras el intercambio a infliximab biosimilar en pacientes con enfermedad inflamatoria intestinal en remisión clínica.

BACKGROUND AND AIM: The biosimilar of infliximab (CT-P13) has been approved for the same indications held by the infliximab reference product (Remicade®); however, there are few clinical data on switching in inflammatory bowel disease (IBD). The aim of this study was to assess the efficacy, safety, bioavailability profile and factors associated with relapse after switching to biosimilar infliximab in IBD patients in clinical remission. MATERIAL AND METHOD: Observational study with IBD patients treated with Remicade® for at least 6 months and in clinical remission for at least 3 months who switched to infliximab biosimilar. The incidence of relapse, adverse effects and possible changes in drug bioavailability (trough level and antidrug antibodies) were evaluated. RESULTS: Thirty six patients were included (63.9% CD) with a mean follow-up of 8.4 months (SD±3.5). The 13.9% had clinical relapse. The longer clinical remission time before switching (HR=0.54, 95% CI=0.29-0.98, P=.04) and detectable infliximab levels at the time of switching (HR=0.03, 95% CI=0.001-0.89, P=.04) were associated with a lower risk of relapse. No differences were found between infliximab levels at the time of switching and at weeks 8 and 16 (P=.94); 8.3% of the patients had some adverse event, requiring the suspension of biosimilar in one patient for severe pneumonia. CONCLUSION: Switching to biosimilar infliximab in a real-life cohort of IBD patients in clinical remission did not have a significant impact on short-term clinical outcomes. The factors associated with relapse were similar to those expected in patients continuing with Remicade®.

Virus-like attachment sites and plastic CpG islands:landmarks of diversity in plant Del retrotransposons.

Full-length Del elements from ten angiosperm genomes, 5 monocot and 5 dicot, were retrieved and putative attachment (att) sites were identified. In the 2432 Del elements, two types of U5 att sites and a single conserved type of U3 att site were identified. Retroviral att sites confer specificity to the integration process, different att sites types therefore implies lineage specificity. While some features are common to all Del elements, CpG island patterns within the LTRs were particular to lineage specific clusters. All eudicot copies grouped into one single clade while the monocots harbour a more diverse collection of elements. Furthermore, full-length Del elements and truncated copies were unevenly distributed amongst chromosomes. Elements of Del lineage are organized in plants into three clusters and each cluster is composed of elements with distinct LTR features. Our results suggest that the Del lineage efficiently amplified in the monocots and that one branch is probably a newly emerging sub-lineage. Finally, sequences in all groups are under purifying selection. These results show the LTR region is dynamic and important in the evolution of LTR-retrotransposons, we speculate that it is a trigger for retrotransposon diversification.

Glycogen synthase kinase 3 inhibition promotes adult hippocampal neurogenesis in vitro and in vivo.

Glycogen synthase kinase-3 (GSK-3) is a serine/threonine kinase originally identified as a regulator of glycogen metabolism but it also plays a pivotal role in numerous cellular functions, including differentiation, cell cycle regulation, and proliferation. The dentate gyrus of the hippocampus, together with the subventricular zone of the lateral ventricles, is one of the regions in which neurogenesis takes place in the adult brain. Here, using a chemical genetic approach that involves the use of several diverse inhibitors of GSK-3 as pharmacological tools, we show that inhibition of GSK-3 induces proliferation, migration, and differentiation of neural stem cells toward a neuronal phenotype in in vitro studies. Also, we demonstrate that inhibition of GSK-3 with the small molecule NP03112, called tideglusib, induces neurogenesis in the dentate gyrus of the hippocampus of adult rats. Taken together, our results suggest that GSK-3 should be considered as a new target molecule for modulating the production and integration of new neurons in the hippocampus as a treatment for neurodegenerative diseases or brain injury and, consequently, its inhibitors may represent new potential therapeutic drugs in neuroregenerative medicine.

Peroxisome proliferator-activated receptor γ ligands regulate neural stem cell proliferation and differentiation in vitro and in vivo.

Peroxisome proliferator-activated receptor gamma (PPARγ) belongs to a family of ligand-activated nuclear receptors and its ligands are known to control many physiological and pathological situations. Its role in the central nervous system has been under intense analysis during the last years. Here we show a novel function for PPARγ in controlling stem cell expansion in the adult mammalian brain. Adult rats treated with pioglitazone, a specific ligand of PPARγ, had elevated numbers of proliferating progenitor cells in the subventricular zone and the rostral migratory stream. Electron microscopy analysis also showed important changes in the subventricular zone ultrastructure of pioglitazone-treated animals including an increased number of migratory cell chains. These results were further confirmed in vitro. Neurosphere assays revealed significant increases in the number of neurosphere forming cells from pioglitazone- and rosiglitazone (two specific ligands of PPARγ receptor)-treated cultures that exhibited enhanced capacity for cell migration and differentiation. The effects of pioglitazone were blocked by the PPARγ receptor antagonists GW9662 and T0070907, suggesting that its effects are mediated by a mechanism dependent on PPARγ activation. These results indicate for the first time that activation of PPARγ receptor directly regulates proliferation, differentiation, and migration of neural stem cells in vivo.

Anticonvulsant and neuroprotective effects of the novel calcium antagonist NP04634 on kainic acid-induced seizures in rats.

Kainic acid (KA)-induced status epilepticus (SE) is a well-characterized model of excitotoxic neuronal injury. Excitotoxicity results from activation of specific glutamate receptors, with resultant elevation of intracellular Ca(2+). The CA1 and CA3 subregions of the hippocampus are especially vulnerable to KA, and this pattern of neuronal injury resembles that occurring in patients with temporal lobe epilepsy. Calcium plays an essential role in excitotoxicity, and accordingly calcium channel inhibitors have been shown to have protective effects in various experimental models of epilepsy and brain injury. Moreover, they also potentiate the antiseizure efficacy of conventional antiepileptic drugs. This study was undertaken to determine whether NP04634, a novel compound, reported as a non-L-type voltage-sensitive calcium channel (VSCC) inhibitor, could prevent the entrance in SE and the neuronal loss evoked by intraperitoneal injection of KA. Our results show that intragastrical administration of NP04634 reduced the percentage of rats that entered SE after KA injection, increased the latency of SE entry, and significantly reduced the mortality of rats that entered SE. Also, NP04634 prevented the loss of hippocampal CA1 and CA3 pyramidal neurons and reduced the gliosis induced by KA. These results point to a potential anticonvulsant and neuroprotective role for NP04634.

Síndrome de Wolf-Hirschhorn: reporte de un caso clínico y revisión de la literatura / Wolf-Hirschhorn syndrome: case report and literature review

El síndrome de Wolf-Hirschhorn es un trastorno cromosómico atribuible a una delección parcial del brazo corto del cromosoma 4 (4p-). Está caracterizado por hallazgos craneofaciales típicos en la infancia (“apariencia de guerrero griego” de la nariz, microcefalia, frente alta con glabela prominente, hipertelorismo, cejas muy arqueadas, filtrum corto, boca en carpa, y micrognatia, entre otros), retardo del crecimiento pre y postnatal, hipotonía y retardo del desarrollo. Los pacientes también pueden tener epilepsia y anormalidades que involucran otros órganos. El diagnóstico puede ser realizado por análisis citogenético convencional, el cual detecta la mayoría de los casos. El tratamiento incluye rehabilitación, terapia de lenguaje, drogas antiepilépticas cuando son necesarias, alimentación por gavaje o gastrostomía para las dificultades de la alimentación y terapia de soporte. Femenina de 10 meses de edad, quien presenta anomalías craneofaciales características, pie equinovaro bilateral, hipotonía, reflujo gastroesofágico, epilepsia, retardo del crecimiento y del desarrollo. El diagnóstico fue confirmado por detección de una delección de 4p que involucraba a la región crítica para este síndrome. Esta paciente recibe actualmente rehabilitación, medicación antirreflujo y ácido valproico. Esta condición debe ser reconocida por los pediatras, a fin de poder ofrecer un adecuado manejo a estos pacientes y sus familias.

Wolf-Hirschhorn Syndrome is a cromosomal disorder attributable to partial deletion of the short arm of chromosome 4(4p-). It is characterized by typical craneofacial features in infancy (“Greek warrior appearance” of the nose, microcephaly, high forehead with prominent glabella, hypertelorism, highly arched eyebrows, short philtrum, downturned mouth and micrognathia, among others), pre and postnatal growth retardation, hypotonia and developmental delay. Patients can also have epilepsy and abnormalities that involve other organs. Diagnosis can be made by conventional cytogenetic analysis which detects most of the cases. Treatment includes rehabilitation, speech therapy, antiepileptic drugs when necessary, gavage feeding or gastrostomy for feeding difficulties and standard management of other anomalies. 10 month-old female who presents characteristic craniofacial anomalies, clubfeet, hypotonia, gastroesofageal reflux, epilepsy, growth retardation and developmental delay. Diagnosis was confirmed by detection of a deletion of 4p that involved the critical region of the syndrome. This patient receives rehabilitation, antireflux medication and valproic acid. This condition must be recognized by pediatricians in order to offer adecuated management to these patients and their families.

CCAAT/enhancer binding protein beta deficiency provides cerebral protection following excitotoxic injury.

The CCAAT/enhancer-binding protein beta (C/EBPbeta, also known as CEBPB) was first identified as a regulator of differentiation and inflammatory processes in adipose tissue and liver. Although C/EBPbeta was initially implicated in synaptic plasticity, its function in the brain remains largely unknown. We have previously shown that C/EBPbeta regulates the expression of genes involved in inflammatory processes and brain injury. Here, we have demonstrated that the expression of C/EBPbeta is notably increased in the hippocampus in a murine model of excitotoxicity. Mice lacking C/EBPbeta showed a reduced inflammatory response after kainic acid injection, and exhibited a dramatic reduction in pyramidal cell loss in the CA1 and CA3 subfields of the hippocampus. These data reveal an essential function for C/EBPbeta in the pathways leading to excitotoxicity-mediated damage and suggest that inhibitors of this transcription factor should be evaluated as possible neuroprotective therapeutic agents.

NP031112, a thiadiazolidinone compound, prevents inflammation and neurodegeneration under excitotoxic conditions: potential therapeutic role in brain disorders.

Inflammation and neurodegeneration coexist in many acute damage and chronic CNS disorders (e.g., stroke, Alzheimer's disease, Parkinson's disease). A well characterized animal model of brain damage involves administration of kainic acid, which causes limbic seizure activity and subsequent neuronal death, especially in the CA1 and CA3 pyramidal cells and interneurons in the hilus of the hippocampus. Our previous work demonstrated a potent anti-inflammatory and neuroprotective effect of two thiadiazolidinones compounds, NP00111 (2,4-dibenzyl-[1,2,4]thiadiazolidine-3,5-dione) and NP01138 (2-ethyl-4-phenyl-[1,2,4]thiadiazolidine-3,5-dione), in primary cultures of cortical neurons, astrocytes, and microglia. Here, we show that injection of NP031112, a more potent thiadiazolidinone derivative, into the rat hippocampus dramatically reduces kainic acid-induced inflammation, as measured by edema formation using T2-weighted magnetic resonance imaging and glial activation and has a neuroprotective effect in the damaged areas of the hippocampus. Last, NP031112-induced neuroprotection, both in vitro and in vivo, was substantially attenuated by cotreatment with GW9662 (2-chloro-5-nitrobenzanilide), a known antagonist of the nuclear receptor peroxisome proliferator-activated receptor gamma, suggesting that the effects of NP031112 can be mediated through activation of this receptor. As such, these findings identify NP031112 as a potential therapeutic agent for the treatment of neurodegenerative disorders.

Regulation of inflammatory response in neural cells in vitro by thiadiazolidinones derivatives through peroxisome proliferator-activated receptor gamma activation.

In most neurodegenerative disorders, including multiple sclerosis, Parkinson disease, and Alzheimer disease, a massive neuronal cell death occurs as a consequence of an uncontrolled inflammatory response, where activated astrocytes and microglia and their cytotoxic agents play a crucial pathological role. Current treatments for these diseases are not effective. In the present study we investigate the effect of thiadiazolidinone derivatives, which have been recently suggested to play a role in neurodegenerative disorders. We have found that thiadiazolidinones are potent neuroprotector compounds. Thiadiazolidinones inhibited inflammatory activation of cultured brain astrocytes and microglia by diminishing lipopolysaccharide-induced interleukin 6, tumor necrosis factor alpha, inducible nitric-oxide synthase, and inducible cyclooxygenase type 2 expression. In addition, thiadiazolidinones inhibited tumor necrosis factor-alpha and nitric oxide production and, concomitantly, protected cortical neurons from cell death induced by the cell-free supernatant from activated microglia. The neuroprotective effects of thiadiazolidinones are completely inhibited by the peroxisome proliferator-activated receptor gamma antagonist GW9662. In contrast the glycogen synthase kinase 3beta inhibitor LiCl did not show any effect. These findings suggest that thiadiazolidinones potently attenuate lipopolysaccharide-induced neuroinflammation and reduces neuronal death by a mechanism dependent of peroxisome proliferator-activated receptor gamma activation.

The transcription factor early growth response factor-1 (EGR-1) promotes apoptosis of neuroblastoma cells.

Early growth response factor-1 (EGR-1) is an immediate early gene, which is rapidly activated in quiescent cells by mitogens or in postmitotic neurons after depolarization. EGR-1 has been involved in diverse biological functions such as cell growth, differentiation and apoptosis. Here we report that enforced expression of the EGR-1 gene induces apoptosis, as determined by flow cytometry and terminal deoxynucleotidyl transferase-mediated dUTP-fluorescein nick-end labelling (TUNEL) analysis, in murine Neuro2A cells. In accordance with this role of EGR-1 in cell death, antisense oligonucleotides increase cell viability in cells cultured in the absence of serum. This apoptotic activity of the EGR-1 appears to be mediated by p73, a member of the p53 family of proteins, since an increase in the amount of p73 is observed in clones stably expressing the EGR-1 protein. We also observed an increase in the transcriptional activity of the mdm2 promoter in cells overexpressing EGR-1, which is paralleled by a marked decrease in the levels of p53 protein, therefore excluding a role of this protein in mediating EGR-1-induced apoptosis. Our results suggest that EGR-1 is an important factor involved in neuronal apoptosis.