Ultrasound attenuation imaging: a reproducible alternative for the noninvasive quantitative assessment of hepatic steatosis in children.

BACKGROUND: Pediatric hepatic steatosis is a global public health concern, as an increasing number of children are affected by this condition. Liver biopsy is the gold standard diagnostic method; however, this procedure is invasive. Magnetic resonance imaging (MRI)-derived proton density fat fraction has been accepted as an alternative to biopsy. However, this method is limited by cost and availability. Ultrasound (US) attenuation imaging is an upcoming tool for noninvasive quantitative assessment of hepatic steatosis in children. A limited number of publications have focused on US attenuation imaging and the stages of hepatic steatosis in children. OBJECTIVE: To analyze the usefulness of ultrasound attenuation imaging for the diagnosis and quantification of hepatic steatosis in children. MATERIAL AND METHODS: Between July and November 2021, 174 patients were included and divided into two groups: group 1, patients with risk factors for steatosis (n = 147), and group 2, patients without risk factors for steatosis (n = 27). In all cases, age, sex, weight, body mass index (BMI), and BMI percentile were determined. B-mode US (two observers) and US attenuation imaging with attenuation coefficient acquisition (two independent sessions, two different observers) were performed in both groups. Steatosis was classified into four grades (0: absent, 1: mild, 2: moderate and 3: severe) using B-mode US. Attenuation coefficient acquisition was correlated with steatosis score according to Spearman's correlation. Attenuation coefficient acquisition measurements' interobserver agreement was assessed using intraclass correlation coefficients (ICC). RESULTS: All attenuation coefficient acquisition measurements were satisfactory without technical failures. The median values for group 1 for the first session were 0.64 (0.57-0.69) dB/cm/MHz and 0.64 (0.60-0.70) dB/cm/MHz for the second session. The median values for group 2 for the first session were 0.54 (0.51-0.56) dB/cm/MHz and 0.54 (0.51-0.56) dB/cm/MHz for the second. The average attenuation coefficient acquisition was 0.65 (0.59-0.69) dB/cm/MHz for group 1 and 0.54 (0.52-0.56) dB/cm/MHz for group 2. There was excellent interobserver agreement at 0.94 (95% CI 0.92-0.96). There was substantial agreement between both observers (κ = 0.77, with a P < 0.001). There was a positive correlation between ultrasound attenuation imaging and B-mode scores for both observers (r = 0.87, P < 0.001 for observer 1; r = 0.86, P < 0.001 for observer 2). Attenuation coefficient acquisition median values were significantly different for each steatosis grade (P < 0.001). In the assessment of steatosis by B-mode US, the agreement between the two observers was moderate (κ = 0.49 and κ = 0.55, respectively, with a P < 0.001 in both cases). CONCLUSION: US attenuation imaging is a promising tool for the diagnosis and follow-up of pediatric steatosis, which provides a more repeatable form of classification, especially at low levels of steatosis detectable in B-mode US.

Ventana cortical anterior para extracción de vástago en revisión de artroplastia total de cadera: una alternativa a la osteotomía trocantérica extendida / Anterior cortical window for stem extraction in total hip arthroplasty revision: an alternative to extended trochanteric osteotomy

Total hip arthroplasty (THA) is a safe and effective procedure in patients with end-stage ostheoarthritis. In the last years the indication for THA is increasingly in younger patients, associated with rising of life expectancy, this imply an increase in revision surgeries for various causes such as: aseptic loosening, fractures and infections. In this context and in view of the need to replace the femoral component, alternatives to the classic extended trochanteric osteotomy (ETO) arise, such as the anterior cortical window (ACW), which allows the rate of complications to be reduced with excellent results. We present the case of a 51-year-old patient who sustained one episode of dislocation, who required revision surgery due to aseptic loosenig, where the ACW was used for the extraction of the stem. In addition, a review of the literature was made to show advantages and complications regarding ETO.

Resultados de distracción para el cuidado en oncología pediátrica desde la evidencia de enfermería: revisión integrativa / Distraction results for pediatric oncology care from nursing evidence: integrative review

Introducción: El cáncer pediátrico provoca un cambio radical en el entorno externo e interno del niño o adolescente afectando su desarrollo y crecimiento. Objetivo: Sintetizar los hallazgos de estudios de Enfermería que publicaron resultados en la salud física, psicológica, social e inmunitaria mediante el uso de estrategias de distracción para el cuidado. Metodología: Revisión integrativa de literatura, cualitativa de alcance descriptivo y retrospectivo fundamentada en parámetros establecidos por Whittemore y Knafl con cinco etapas. Criterios de inclusión: artículos científicos con resultados en salud física, psicológica, social e inmunitaria mediante uso de la distracción desde enfermería a población pediátrica con diagnóstico oncológico, publicados en 15 bases de datos científicas, idiomas: inglés, portugués y español, entre los años 2011-2020, con nivel de evidencia según Lobiondo Nivel I, II y III, estudios con asignación al azar, con grupo control independiente y separado, basados en evaluación critica del Instituto Joanna Briggs. Resultados: Las estrategias de distracción usadas en niños y adolescentes con diagnóstico oncológico incluyeron: ejercicio, juego, masaje, música y terapias complementarias realizadas en diferentes escenarios que obtuvieron resultados significativos en la salud física, psicológica, social e inmunitaria. Conclusiones: Con el uso de la distracción en el ámbito hospitalario o no hospitalario se logran beneficios en la salud demostrando ser intervención innovadora e importante para el cuidado de enfermería en población pediátrica oncológica. (AU)

Introduction: Pediatric cancer causes a radical change in the external and internal environment of the child or adolescent affecting their development and growth. Objective: To synthesize the findings of nursing studies that published results in physical, psychological, social and immune health through the use of distraction strategies for care. Methodology: Integrative literature review, qualitative descriptive and retrospective based on parameters established by Whittemore and Knafl with five stages. Inclusion criteria: scientific articles with results in physical, psychological, social and immune health through the use of distraction from nursing to pediatric population with oncological diagnosis, published in 15 scientific databases, languages: English, Portuguese and Spanish, between the years 2011-2020, with level of evidence according to Lobiondo Level I, II and III, randomized studies, with independent and separate control group, based on critical evaluation of the Joanna Briggs Institute. Results: The distraction strategies used in children and adolescents with oncological diagnosis included: exercise, play, massage, music and complementary therapies performed in different scenarios that obtained significant results in physical, psychological, social and immune health.Conclusions: With the use of distraction in the hospital or non-hospital setting, health benefits are achieved, proving to be an innovative and important intervention for nursing care in the pediatric oncological population. (AU)

Pharmacological characterization of a novel peptide inhibitor of the Keap1-Nrf2 protein-protein interaction.

LAS200813 is a novel bicyclic lipopeptide that activates Nrf2 by binding to Keap1, thereby antagonising the Keap1-Nrf2 protein-protein interaction. In this work we report the pharmacological characterization of LAS200813 in Nrf2-dependent translational preclinical models. LAS200813 binds to Keap1 with high affinity (IC50: 0.73 nM) and is able to induce the translocation of Nrf2 to the nucleus. Furthermore, LAS200813 increases the expression of Nrf2 target genes in human bronchial epithelial cells (EC50 of 96 and 70 nM for srxn1 and nqo1, respectively). Similarly, the intratracheal administration of LAS200813 to rats increases the expression of Nrf2-dependent genes in lung tissue, an effect that lasts for a few hours. Moreover, in cells exposed to cigarette smoke, LAS200813 shows an antioxidant effect by increasing the production of glutathione and prevents cellular apoptosis. In conclusion, the results described herein demonstrate that LAS200813 is a potent non-electrophilic Nrf2-activating peptide designed to be administered by inhaled route which may be a potential therapeutic strategy for respiratory diseases driven by oxidative stress.

Influence of Obstructive Sleep Apnea on Systemic Inflammation in Pregnancy.

Background: Obstructive sleep apnea (OSA) is prevalent in pregnancy and it is associated with adverse pregnancy-related outcomes such as gestational diabetes, pre-eclampsia, and low birth weight. Maternal systemic inflammation is proposed to be one of the main intermediate mechanisms. However, the effects of OSA on systemic inflammation are unknown in normal pregnancy. Methods: Women in the 3rd trimester underwent hospital polysomnography to evaluate whether OSA increases systemic inflammation in normal pregnancy and its potential association with adverse fetal outcomes. OSA was defined as an apnea-hypopnea index (AHI) of ≥ 5 h-1. Plasma cytokines levels (TNF-α, IL-1ß, IL-6, IL-8, and IL-10) were determined by multiple immunoassays. Results: We included 11 patients with OSA and 22 women with AHI < 5 h-1, who were homogeneous in age, and body mass index (BMI). Women with OSA had significant higher levels of TNF-α, IL-1ß, IL-8, and IL-10. We found significant correlations between AHI during REM and TNF-α (r = 0.40), IL-1ß (r = 0.36), IL-6 (r = 0.52), IL-8 (r = 0.43), between obstructive apnea index and TNF-α (r = 0.46) and between AHI and IL-1ß (r = 0.43). We also found that CT90% was related to IL-8 (r = 0.37). There were no significant differences in neonatal characteristics; however, we found inverse correlations between TNF-α and IL-8 with birth weight (both r = -0.48), while IL-8 showed a significant inverse relationship with neonatal gestational age (r = -0.48). Conclusions: OSA in our normal pregnancy population was associated with higher systemic inflammation, which was related to obstructive events, especially during REM sleep. Moreover, systemic inflammation was inversely correlated with neonatal birth weight and age.

Inequality and psychological well-being in times of COVID-19: evidence from Spain.

Using two novel online surveys collected in May and November 2020, we study the consequences of the COVID-19 pandemic on Spanish households. We document a large and negative effect on household income. By May 2020, the average individual lived in a household that had lost 16% of their pre-pandemic monthly income. Furthermore, this drop was highly unequal: while households in the richest quintile lost 6.8% of their income, those in the poorest quintile lost 27%. We also document that the pandemic deepened the gender-income gap: on average, women experienced a three-percentage point larger income loss than men. While this is consistent with previous findings in the literature, in this paper we document that this effect is driven by women from middle-income households with kids. Finally, we provide evidence that Spanish individuals experienced moderate declines in their levels of psychological well-being. This effect is not different for individuals living in rich or poor households, but the reasons behind well-being losses do differ: richer individuals are more concerned about loss of contact with dear ones, while low-income individuals are more likely to mention loss of income and employment as a key source of emotional distress.

Red cell distribution width: a new tool for the severity prediction of sleep apnoea syndrome in children.

INTRODUCTION: Red cell distribution width (RDW) is a parameter included in the complete blood count which informs about the size of the circulating red blood cell population and its distribution. In adults, an increase in RDW was shown to be associated both with obstructive sleep apnoea (OSA) and with an increase in cardiovascular mortality. The aim of this study was to determine whether RDW is a potential biomarker for screening children with moderate-severe OSA. METHODS: An observational study in snoring patients was performed. All patients underwent a sleep study and were classified either as simple snorers (apnoea-hypopnoea index (AHI) <1 event·h-1) or as patients with OSA (mild AHI ≥1 to <5 events·h-1; moderate-severe AHI ≥5 events·h-1). Blood analyses (complete blood count and C-reactive protein) were performed for every individual. RESULTS: A total of 175 individuals were recruited. The mean age was 8.3±3.6 years. Correlation studies between RDW and several sleep-related parameters showed negative significant associations with minimum oxygen saturation, and positive significant associations with oxygen desaturation index (≥3% and ≥4%), AHI and the arousal index. A predictive model for paediatric severe OSA (AHI ≥5 events·h-1) was found based on mean corpuscular haemoglobin concentration (MCHC) <34.9 g·dL-1 and RDW >13.1% values, adjusting for body mass index z-score and age (area under the curve 0.657; p=0.004). In addition, differences were found in eosinophil count and C-reactive protein concentrations among the three subgroups. CONCLUSIONS: In children, RDW stands out as a biomarker associated with the severity of OSA. The use of RDW and MCHC could be a simple but useful tool for the severity prediction of paediatric OSA in snoring patients.

Discovery of a Novel Inhaled PI3Kδ Inhibitor for the Treatment of Respiratory Diseases.

Oral PI3Kδ inhibitors such as Idelalisib and Duvelisib have shown efficacy as anticancer agents and Idelalisib has been approved for the treatment of three B-cell cancers. However, Idelalisib has a black box warning on its product label regarding the risks of fatal and serious toxicities including hepatic toxicity, severe diarrhea, colitis, pneumonitis, infections, and intestinal perforation. Some of these side effects are mechanism-related and could hinder the development of Idelalisib for less severe conditions. For respiratory diseases, compounds administered by inhalation are delivered directly to the site of action and may improve the therapeutic index of a drug, minimizing undesired side effects. This work describes the discovery and optimization of inhaled PI3Kδ inhibitors intended for the treatment of severe asthma and COPD. Once the potency was in the desired range, efforts were focused on identifying the particular physicochemical properties that could translate into better lung retention. This medicinal chemistry exercise led to the identification of LAS195319 as a candidate for clinical development.

Compromiso de conciencia secundario a intoxicación por litio: reporte de un caso / Commitment of conscience secondary to lithium intoxication: case report

INTRODUCCIÓN: La intoxicación por litio (IL) es potencialmente grave. Destacan manifestaciones neurológicas, tales como deterioro cognitivo, síndrome cerebeloso y compromiso de conciencia (CC). En la literatura se han descrito secuelas permanentes secundarias a la IL, siendo importante el manejo precoz para prevenir una evolución tórpida de este cuadro. PRESENTACIÓN DEL CASO: Paciente de sexo femenino de 77 años con antecedentes de Trastorno Afectivo Bipolar (TAB), en tratamiento con Litio, inició cuadro de 5 días de evolución caracterizado por bradipsiquia, compromiso del estado general (CEG) y disminución de fuerza en extremidades inferiores. Evaluada por Neurología, se descartó patología cerebrovascular e infecciosa intercurrente, se midió litemia que resultó alterada. Se diagnosticó CC secundario a IL. Se indicó suspensión de fármaco y manejo de balance hidroelectrolítico. Evolucionó con daño neurológico de pronóstico incierto y fue dada de alta por Neurología. DISCUSIÓN: La intoxicación por litio debe sospecharse en cualquier paciente con alteración del estado de conciencia basal, que sea usuario de este medicamento. Pacientes que presentan IL requieren hospitalización para manejo de fluidos y electrolitos, monitorizando función renal y litemia. A nivel del sistema nervioso central (SNC) la IL puede dejar secuelas irreversibles, por lo que se recomienda un seguimiento regular de aquellos pacientes que sean usuarios de este medicamento, para evitar un deterioro clínico secundario a una intoxicación.

INTRODUCTION: (LI) can be potentially serious. Includes neurological manifestations such as cognitive impairment, cerebellar syndrome and compromise of consciousness (CC). In the literature have been described permanent sequelae secondary to intoxication by this drug, early management is important to prevent an undesirable evolution of this medical condition. CASE REPORT: 77-year-old female patient with a history of Bipolar Affective Disorder, under treatment with Lithium, began a 5-day history of bradypsychia, compromise of the general state and decrease strength in lower extremities. Evaluated by Neurology, ruled out cerebrovascular and infectious pathologies. Plasmatic lithium levels were obtained in altered range. CC secondary to LI was diagnosed. Drug suspension, fluid and electrolyte balance management were indicated. She evolved with neurological damage of uncertain prognosis and discharged from hospital. DISCUSSION: LI should be suspected in any patient with altered baseline consciousness, who is a user of this medication. Patients requires admission for fluid and electrolyte management, monitoring of renal function and plasmatic lithium levels. At the level of the central nervous system (CNS) IL can leave irreversible sequels, so it is recommended a regular monitoring of patients who are users of this drug, to avoid clinical deterioration secondary to intoxication.

Discovery of a Potent, Selective, and Orally Available PI3Kδ Inhibitor for the Treatment of Inflammatory Diseases.

The delta isoform of the phosphatidylinositol 3-kinase (PI3Kδ) has been shown to have an essential role in specific immune cell functions and thus represents a potential therapeutic target for autoimmune and inflammatory diseases. Herein, the optimization of a series of pyrrolotriazinones as potent and selective PI3Kδ inhibitors is described. The main challenge of the optimization process was to identify an orally available compound with a good pharmacokinetic profile in preclinical species that predicted a suitable dosing regimen in humans. Structure-activity relationships and structure-property relationships are discussed. This medicinal chemistry exercise led to the identification of LAS191954 as a candidate for clinical development.

Pharmacological characterization of CRTh2 antagonist LAS191859: Long receptor residence time translates into long-lasting in vivo efficacy.

The chemoattractant receptor-homologous molecule expressed on T-helper type 2 cells (CRTh2) is a G protein-coupled receptor expressed on the leukocytes most closely associated with asthma and allergy like eosinophils, mast cells, Th2-lymphocytes and basophils. At present it is clear that CRTh2 mediates most prostaglandin D2 (PGD2) pro-inflammatory effects and as a result antagonists for this receptor have reached asthma clinical studies showing a trend of lung function improvement. The challenge remains to identify compounds with improved clinical efficacy when administered once a day. Herein we described the pharmacological profile of LAS191859, a novel, potent and selective CRTh2 antagonist. In vitro evidence in GTPγS binding studies indicate that LAS191859 is a CRTh2 antagonist with activity in the low nanomolar range. This potency is also maintained in cellular assays performed with human eosinophils and whole blood. The main differentiation of LAS191859 vs other CRTh2 antagonists is in its receptor binding kinetics. LAS191859 has a residence time half-life of 21h at CRTh2 that translates into a long-lasting in vivo efficacy that is independent of plasma levels. We believe that the strategy behind this compound will allow optimal efficacy and posology for chronic asthma treatment.

Role of Polycomb RYBP in Maintaining the B-1-to-B-2 B-Cell Lineage Switch in Adult Hematopoiesis.

Polycomb chromatin modifiers regulate hematopoietic pluripotent stem and progenitor cell self-renewal and expansion. Polycomb complex redundancy and biochemical heterogeneity complicate the unraveling of the functional contributions of distinct components. We have studied the hematopoietic activity of RYBP, a direct interactor and proposed modulator of RING1A/RING1B-dependent histone H2A monoubiquitylation (H2AUb). Using a mouse model to conditionally inactivate Rybp in adult hematopoiesis, we have found that RYBP deletion results in a reversion of B-1-to-B-2 B-cell progenitor ratios, i.e., of the innate (predominantly fetal) to acquired (mostly adult) immunity precursors. Increased numbers of B-1 progenitors correlated with a loss of pre-proB cells, the B-2 progenitors. RYBP-deficient stem and progenitor cell populations (LKS) and isolated common lymphoid progenitors (CLP) gave rise to increased numbers of B-1 progenitors in vitro. Rybp inactivation, however, did not result in changes of global H2AUb and did not interact genetically with Ring1A or Ring1B deletions. These results show that a sustained regulation of the B-1-to-B-2 switch is needed throughout adult life and that RYBP plays an important role in keeping B-2 dominance, most likely independently of its Polycomb affiliation.

Polycomb RING1A- and RING1B-dependent histone H2A monoubiquitylation at pericentromeric regions promotes S-phase progression.

The functions of polycomb products extend beyond their well-known activity as transcriptional regulators to include genome duplication processes. Polycomb activities during DNA replication and DNA damage repair are unclear, particularly without induced replicative stress. We have used a cellular model of conditionally inactive polycomb E3 ligases (RING1A and RING1B), which monoubiquitylate lysine 119 of histone H2A (H2AK119Ub), to examine DNA replication in unperturbed cells. We identify slow elongation and fork stalling during DNA replication that is associated with the accumulation of mid and late S-phase cells. Signs of replicative stress and colocalisation of double-strand breaks with chromocenters, the sites of coalesced pericentromeric heterocromatic (PCH) domains, were enriched in cells at mid S-phase, the stage at which PCH is replicated. Altered replication was rescued by targeted monoubiquitylation of PCH through methyl-CpG binding domain protein 1. The acute senescence associated with the depletion of RING1 proteins, which is mediated by p21 (also known as CDKN1A) upregulation, could be uncoupled from a response to DNA damage. These findings link cell proliferation and the polycomb proteins RING1A and RING1B to S-phase progression through a specific function in PCH replication.

Comparison of energy expenditure, body composition, metabolic disorders, and energy intake between obese children with a history of craniopharyngioma and children with multifactorial obesity.

UNLABELLED: Craniopharyngioma is a histologically benign brain malformation with a fundamental role in satiety modulation, causing obesity in up to 52% of patients. AIM: To evaluate cardiovascular risk factors, body composition, resting energy expenditure (REE), and energy intake in craniopharyngioma patients and to compare the data with those from children with multifactorial obesity. POPULATION: All obese children and adolescents who underwent craniopharyngioma resection and a control group of children with multifactorial obesity in follow-up between May 2012 and April 2013. MATERIALS AND METHODS: Anthropometric measurements, bioelectrical impedance, indirect calorimetry, energy intake, homeostatic model assessment insulin resistance (HOMA-IR), and dyslipidemia were evaluated. RESULTS: Twenty-three patients with craniopharyngioma and 43 controls were included. Children with craniopharyngioma-related obesity had a lower fat-free mass percentage (62.4 vs. 67.5; p=0.01) and a higher fat mass percentage (37.5 vs. 32.5; p=0.01) compared to those with multifactorial obesity. A positive association was found between %REE and %fat-free mass in subjects with multifactorial obesity (68±1% in normal REE vs. 62.6±1% in low REE; p=0.04), but not in craniopharyngioma patients (62±2.7 in normal REE vs. 61.2±1.8% in low REE; p=0.8). No differences were found in metabolic involvement or energy intake. CONCLUSIONS: REE was lower in craniopharyngioma patients compared to children with multifactorial obesity regardless of the amount of fat-free mass, suggesting that other factors may be responsible for the lower REE.

Association between insulin resistance and risk of complications in children and adolescents with type 1 diabetes.

BACKGROUND: It has been hypothesized that insulin resistance may be involved in the development of type 1 diabetes complications and early diagnosis would be important for their prevention. Our aim was to study insulin resistance in our population of children with type 1 diabetes and to identify associated early risk factors for micro- and macrovascular complications. METHODS: A descriptive, cross-sectional study was conducted including 150 children with type 1 diabetes. Anthropometric, bioelectric impedance, carotid Doppler ultrasonography, electromyography, and conduction velocity studies were performed. Baseline plasma glucose, lipid profile, uric acid, plasma thyrotropin, glycosylated hemoglobin A1C, and microalbuminuria were assessed. More insulin-resistant patients were defined as those having an estimated glucose disposal rate (eGDR) value below the first quartile. RESULTS: Clinically manifest microvascular complications were not found in any of the patients. More insulin-resistant patients had a greater sub scapular fold thickness, a higher incidence of obesity (12% vs. 1.7% p 0.007), higher fructosamine levels (496 vs. 403 p<0.00019, and a higher incidence of altered lipid metabolism (70% vs. 39% p 0.0007). CONCLUSION: In the subgroup of patients with lower eGDR there were more children with lipid disorders, obesity, and worse diabetic control, which, if not corrected, may lead to development of micro- and macrovascular complications.

Structure-activity relationships (SAR) and structure-kinetic relationships (SKR) of bicyclic heteroaromatic acetic acids as potent CRTh2 antagonists I.

A knowledge-based design strategy led to the discovery of several new series of potent and orally bioavailable CRTh2 antagonists where a bicyclic heteroaromatic ring serves as the central core. Structure-kinetic relationships (SKR) opened up the possibility of long receptor residence times.

Structure-activity relationships (SAR) and structure-kinetic relationships (SKR) of bicyclic heteroaromatic acetic acids as potent CRTh2 antagonists II: lead optimization.

Extensive structure-activity relationship (SAR) and structure-kinetic relationship (SKR) studies in the bicyclic heteroaromatic series of CRTh2 antagonists led to the identification of several molecules that possessed both excellent binding and cellular potencies along with long receptor residence times. A small substituent in the bicyclic core provided an order of magnitude jump in dissociation half-lives. Selected optimized compounds demonstrated suitable pharmacokinetic profiles.

Structure-activity relationships (SAR) and structure-kinetic relationships (SKR) of bicyclic heteroaromatic acetic acids as potent CRTh2 antagonists III: the role of a hydrogen-bond acceptor in long receptor residence times.

The correct positioning and orientation of an hydrogen bond acceptor (HBA) in the tail portion of the biaryl series of CRTh2 antagonists is a requirement for long receptor residence time. The HBA in combination with a small steric substituent in the core section (R(core) ≠ H) gives access to compounds with dissociation half-lives of ⩾ 24h.

2-(1H-Pyrazol-1-yl)acetic acids as chemoattractant receptor-homologous molecule expressed on Th2 lymphocytes (CRTh2) antagonists.

In this manuscript, the synthesis and biological activity of a series of pyrazole acetic acid derivatives as CRTh2 antagonists is presented. Biological evaluation in vitro revealed that the pyrazole core showed in several cases a different structure-activity relationship (SAR) to that of related indole acetic acid. A potent series of ortho-sulfonyl benzyl substituents was found, from which compounds 27 and 63 were advanced to in vivo profiling.

Haga su diagnóstico / Make your diagnosis

El diagnóstico es: síndrome megavejiga-microcolon-hipoperistaltismo intestinal: SMMHI