Emerging therapeutic strategies in hypoxic-ischemic encephalopathy: a focus on cognitive outcomes.

Perinatal hypoxia-ischemia represents a significant risk to CNS development, leading to high mortality rates, diverse damages, and persistent neurological deficits. Despite advances in neonatal medicine in recent decades, the incidence of HIE remains substantial. Motor deficits can manifest early, while cognitive impairments may be diagnosed later, emphasizing the need for extended follow-up. This review aims to explore potential candidates for therapeutic interventions for hypoxic-ischemic encephalopathy (HIE), with a focus on cognitive deficits. We searched randomized clinical trials (RCT) that tested drug treatments for HIE and evaluated cognitive outcomes. The results included studies on erythropoietin, melatonin, magnesium sulfate, topiramate, and a combination of vitamin C and ibuprofen. Although there are several indications of the efficacy of these drugs among animal models, considering neuroprotective properties, the RCTs failed to provide complete effectiveness in the context of cognitive impairments derived from HIE. More robust RCTs are still needed to advance our knowledge and to establish standardized treatments for HIE.

Depressive-like behavior and impaired synaptic plasticity in the prefrontal cortex as later consequences of prenatal hypoxic-ischemic insult in rats.

Perinatal hypoxia-ischemia (HI) is a leading cause of morbidity and mortality among newborns. Infants with HI encephalopathy may experience lasting consequences, such as depression, in adulthood. In this study, we examined depressive-like behavior, neuronal population, and markers of monoaminergic and synaptic plasticity in the prefrontal cortex (PFC) of adolescent rats subjected to a prenatal HI model. Pregnant rats underwent a surgery in which uterine and ovarian blood flow was blocked for 45 min at E18 (HI procedure). Sham-operated subjects were also generated (SH procedure). Behavioral tests were conducted on male and female pups from P41 to P43, and animals were histologically processed or dissected for western blotting at P45. We found that the HI groups consumed less sucrose in the sucrose preference test and remained immobile for longer periods in the forced swim test. Additionally, we observed a significant reduction in neuronal density and PSD95 levels in the HI group, as well as a smaller number of synaptophysin-positive cells. Our results underscore the importance of this model in investigating the effects of HI-induced injuries, as it reproduces an increase in depressive-like behavior and suggests that the HI insult affects circuits involved in mood modulation.

Prenatal Systemic Hypoxia-Ischemia and Oligodendroglia Loss in Cerebellum.

Hypoxic-ischemic (HI) injury is an important cause of death and disabilities. Despite all improvements in neonatal care, the number of children who suffer some kind of injury during birth has remained stable in the last decade. A great number of studies have shown alterations in neural cells and many animal models have been proposed in the last 5 decades. Robinson et al. (2005) proposed an HI model in which the uterine arteries are temporarily clamped on the 18th gestation day. The findings were quite similar to the ones observed in postmortem studies. The white matter is clearly damaged, and a great amount of astrogliosis takes place both in the gray and white matters. Motor changes were also found but no data regarding the cerebellum, an important structure related to motor performance, was presented. Using this model, we have shown an increased level of iNOS at P0 and microgliosis and astrogliosis at P9, and astrogliosis at P23 (up to 4 weeks from the insult). NO is important in migration, maturation, and synaptic plasticity, but in exacerbated levels it may also contribute to cellular and tissue damage. We have also evaluated oligodendroglia development in the cerebellum. At P9 in HI animals, we found a decrease in the number of PDGFRα+ cells and an apparent delay in myelination, suggesting a failure in oligodendroglial progenitors migration/maturation and/or in the myelination process. These results point to an injury in cerebellar development that might help to explain the motor problems in HI.

Relapsing polychondritis in childhood: three case reports, comparison with adulthood disease and literature review.

Relapsing polychondritis (RP) is a rare autoimmune systemic disease, especially in childhood. To report three new pediatric RP cases, to provide a literature review and to compare with adulthood disease, retrospective data collection from three childhood RP cases was observed in a Brazilian Pediatric Rheumatology Division. A literature review based on a MEDLINE database search was performed. Arthritis and auricular chondritis were present in our three patients. Two cases presented with early and severe laryngotracheal chondritis, besides initial and symptomatic costochondritis. The other case developed prominent epiphyseal plate involvement. Two patients were refractory to corticosteroids and immunosuppressants and required the use of TNF-alpha inhibitors to improve the symptoms, while corticosteroids plus methotrexate induced remission in the other patient. The literature review showed 44 cases of pediatric-onset disease in English language. Arthritis and ear chondritis are the most common initial and cumulative manifestations of RP in children and adults. Nasal and laryngotracheobronchial chondritis are also common manifestations observed during follow-up in childhood. There is also an early severity of respiratory chondritis in childhood, requiring aggressive treatment with corticosteroids, immunosuppressants and biologic agents. The data presented by those 3 children, considered in conjunction with the data from the 44 published cases, may reflect some distinguishing childhood RP features, such as more severe and frequent respiratory tract involvement, symptomatic costochondritis and the atypical pattern of persistent and destructive arthritis with epiphyseal plate involvement. Response to immunosuppressants and biologic agents is anecdotal, but steroids remain the main drug during the flares.

Hereditary autoinflammatory syndromes: a Brazilian multicenter study.

OBJECTIVE: To evaluate the prevalence of genetic defects in clinically suspected autoinflammatory syndromes (AIS) in a Brazilian multicenter study. METHODS: The study included 102 patients with a clinical diagnosis of Cryopyrin Associated Periodic Syndromes (CAPS), TNF Receptor Associated Periodic Syndrome (TRAPS), Familial Mediterranean Fever (FMF), Mevalonate Kinase Deficiency (MKD) and Pediatric Granulomatous Arthritis (PGA). One of the five AIS-related genes (NLRP3, TNFRSF1A, MEFV, MVK and NOD2) was evaluated in each patient by direct DNA sequencing, based on the most probable clinical suspect. RESULTS: Clinical diagnoses of the 102 patients were: CAPS (n = 28), TRAPS (n = 31), FMF (n = 17), MKD (n = 17) and PGA (n = 9). Of them, 27/102 (26 %) had a confirmed genetic diagnosis: 6/28 (21 %) CAPS patients, 7/31 (23 %) TRAPS, 3/17 (18 %) FMF, 3/17 (18 %) MKD and 8/9 (89 %) PGA. CONCLUSION: We have found that approximately one third of the Brazilian patients with a clinical suspicion of AIS have a confirmed genetic diagnosis.

Adherence to methotrexate in juvenile idiopathic arthritis.

Non-adherence to treatments for chronic diseases may jeopardize patients' health, increase costs of care, and cause unnecessary clinic appointments and diagnostic studies, as well as additional treatments with potentially serious side effects. Little is known about adherence to methotrexate in pediatric rheumatology. Because this medication is commonly used in JIA, we assessed adherence among children receiving methotrexate in two countries. A total of 76 outpatients (M:F 21:55) with JIA seen in Rio de Janeiro (Brazil) and in Boston (US) taking methotrexate for >2 months were enrolled. Questionnaires were completed by the parents from both centers. Non-adherence was defined as omission of ≥3 prescribed doses in the previous 8 weeks. Patients' ages ranged from 1 to 17 years. Mean time on methotrexate was 20.5 months (±25). Overall rate of non-adherence was 18%. The rate of reported non-adherence was 8% in Boston and 24% in Rio de Janeiro (P = 0.012). The main reason for non-adherence in Boston was "child refused"; in Rio de Janeiro, the main reason was inability to obtain medication. Age had a negative association with adherence (P < 0.0001). Sex, time on methotrexate, route of administration, or concomitant use of other medications were not associated with adherence. Eighteen percent of children with JIA prescribed methotrexate were non-compliant. The difference in reasons for poor adherence between patients in Rio de Janeiro and Boston suggests that different strategies may be needed to improve adherence in these 2 settings. The rate of non-adherence warrants further investigation.