Pediatric problematic severe asthma: Recent advances in management

Problematic severe asthma remains a significant challenge to manage, accounting for the majority of healthcare utilization among children with asthma. The heterogeneity is recognized and the clinical phenotypes of “difficult-to-treat” asthma (DA) and “severe therapy-resistant asthma” (STRA) help to guide management. Recent evidence supports molecular distinctions between these phenotypes and shows poor correlations between peripheral and airway markers of inflammation, especially in STRA. Airway neutrophils in the context of childhood severe asthma have been explored, but their role in disease causation, protection, or as bystanders remain unknown, and thus, treatment implications are unclear. Several novel management strategies, including once-daily maintenance therapy, single-device maintenance and reliever therapy, and novel biological treatments are being increasingly used for DA and STRA. However, pediatric data for efficacy of novel treatments is scarce, and when available, is restricted to adolescents. The aim of this review is to highlight recent advances in objective biomarkers that aid stratification and management of childhood severe asthma and to highlight gaps in pediatric evidence. Specifically, the urgent need for efficacy studies to improve the management of problematic severe asthma in children younger than 12 years.     

Acceptability of orodispersible films for delivery of medicines to infants and preschool children

Orodispersible films (ODFs) possess potential to facilitate oral drug delivery to children; however, documentation of their acceptability in this age group is lacking. This study is the first to explore the initial perceptions, acceptability and ease of use of ODFs for infants and preschool children, and their caregivers through observed administration of the type of dosage form. Placebo ODFs were administered to children stratified into aged 6 to 12?months, 1?year, 2?years, 3?years, 4?years and 5?years old and into those with an acute illness or long-term stable condition in hospital setting. Acceptability of the dosage form and end-user views were assessed by (a) direct observation of administration, (b) questionnaires to caregivers and nurses, and (c) age-adapted questionnaires for children aged 3?years and over. The majority of children (78%) aged 3?years and over gave the ODF a positive rating both on verbal and non-verbal scales. Despite little prior experience, 78% of caregivers expressed positive opinion about ODFs before administration. After the ODFs were taken, 79% of infant caregivers and 86% caregivers of preschool children positively rated their child’s acceptance of the ODF. The intraclass correlation coefficient value was 0.92 showing good agreement between ratings of caregivers and nurses. ODFs showed a high degree of acceptability among young children and their caregivers. If drug loading permits, pharmaceutical companies should consider developing pediatric medicines in this format. The methodology described here is useful in assessing the acceptability of active ODF preparations and other dosage forms to children.     

Pyroglutamylated RFamide peptide 43 stimulates the hypothalamic-pituitary-gonadal axis via gonadotropin-releasing hormone in rats

Although it is established that other members of the RFamide family stimulate the hypothalamic-pituitary-gonadal axis, the influence of the novel pyroglutamylated RFamide peptide 43 (QRFP43) is not known. We show intracerebroventricular (icv) administration of QRFP43 (2 nmol) to male rats increased plasma LH and FSH levels at 40 min after injection. icv administration of 3 nmol QRFP43 did not affect food intake in ad-libitum-fed male rats. The icv administration of 2 nmol QRFP43 did not significantly influence behavior in male rats. Intraperitoneal administration of doses up to 1200 nmol/kg QRFP43 in male rats did not significantly influence circulating gonadotropin or sex steroid levels. In vitro, QRFP43 stimulated GnRH release from hypothalamic explants from male rats and from GT1-7 cells. Pretreatment with a GnRH receptor antagonist, cetrorelix, blocked the increase in plasma LH levels after icv administration of QRFP43 (2 nmol). These results suggest that icv QRFP43 activates the hypothalamic-pituitary-gonadal axis via GnRH.     

Impaired glucocorticoid receptor function evolves in aberrant physiological responses to bacterial endotoxin

The consequences of glucocorticoid receptor (GR) dysfunction for neuroimmunoendocrine responses to an inflammatory challenge were studied in transgenic mice expressing antisense RNA directed against the GR [GR-impaired (GR-i) mice]. Mice were implanted intraperitoneally with a biotelemetry transmitter to monitor body temperature and locomotion. GR-i mice showed decreased locomotion and body temperature during the dark phase of the diurnal cycle. Intraperitoneal administration of saline caused a rapid increase in body temperature in control mice, which was terminated within 90 min. In GR-i mice, however, body temperature remained elevated for about 6 h. Intraperitoneal injection of endotoxin (10 μg/mouse) produced a biphasic fever in control mice. However, in endotoxin-injected GR-i mice, body temperature was not significantly different from their saline-injected controls during the first 6 h. Body temperature then increased and remained elevated during the night period. Both strains showed hypolocomotion after endotoxin. In a second experiment, mice were injected intraperitoneally with saline or endotoxin and killed after 1, 3, 6 or 24 h. In GR-i mice, endotoxin caused an augmented rise in plasma ACTH, but not in corticosterone levels. The endotoxin-induced increase in serum levels of interleukin-1β and interleukin-6 was not different between the strains. However, whereas in control mice tumour necrosis factor-α levels were below detection at the time points studied, substantial levels of this cytokine were found in the serum of GR-i mice 1 h after endotoxin administration. It may be concluded that life-long impairment of GR evolves in aberrant physiological and humoral responses to an acute inflammatory challenge. These findings expand our understanding about the neuroendocrine and physiological disturbances associated with stress-related disorders.     

Chromosome 13 workshop report

Evidence was presented that provided support for linkage in a relatively broad telomeric region of chromosome 13. A significant overlap for positive markers linked to both bipolar disorder and schizophrenia occurred in this area. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 88:260–262, 1999. © 1999 Wiley-Liss, Inc.     

Impact of gout on in-hospital outcomes of acute coronary syndrome-related hospitalizations and revascularizations: Insights from the national inpatient sample

BACKGROUND Previous studies have established a role of gout in predicting risk and prognosis of cardiovascular diseases. However, large-scale data on the impact of gout on inpatient outcomes of acute coronary syndrome(ACS)-related hospitalizations and post-revascularization is inadequate.AIM To evaluate the impact of gout on in-hospital outcomes of ACS hospitalizations,subsequent healthcare burden and predictors of post-revascularization inpatient mortality.METHODS We used the national inpatient sample(2010-2014) to identify the ACS and goutrelated hospitalizations, relevant comorbidities, revascularization and postrevascularization outcomes using the ICD-9 CM codes. A multivariable analysis was performed to evaluate the predictors of post-revascularization in-hospital mortality.RESULTS We identified 3144744 ACS-related hospitalizations, of which 105198(3.35%) also had gout. The ACS-gout cohort were more often older white males with a higher prevalence of comorbidities. Coronary artery bypass grafting was required more often in the ACS-gout cohort. Post-revascularization complications including cardiac(3.2% vs 2.9%), respiratory(3.5% vs 2.9%), and hemorrhage(3.1% vs 2.7%)were higher whereas all-cause mortality was lower(2.2% vs 3.0%) in the ACSgout cohort(P 0.001). An older age(OR 15.63, CI: 5.51-44.39), non-elective admissions(OR 2.00, CI: 1.44-2.79), lower household income(OR 1.44, CI: 1.17-1.78), and comorbid conditions predicted higher mortality in ACS-gout cohort undergoing revascularization(P 0.001). Odds of post-revascularization inhospital mortality were lower in Hispanics(OR 0.45, CI: 0.31-0.67) and Asians(OR 0.65, CI: 0.45-0.94) as compared to white(P 0.001). However, postoperative complications significantly raised mortality odds. Mean length of stay,transfer to other facilities, and hospital charges were higher in the ACS-gout cohort.CONCLUSION Although gout was not independently associated with an increased risk of postrevascularization in-hospital mortality in ACS, it did increase postrevascularization complications.     

Are isofurans and neuroprostanes increased after subarachnoid hemorrhage and traumatic brain injury?

Current diagnostic tools to assess neurological injury after aneurysmal subarachnoid hemorrhage (aSAH) and traumatic brain injury (TBI) have poor discriminatory abilities. Free radicals are associated with the pathophysiology of secondary damage after brain trauma. We examined cerebrospinal fluid (CSF) lipid markers of oxidative stress, isofurans (IsoFs), F(4)-neuroprostanes (F(4)-NeuroPs), and F(2)-isoprostanes (F(2)-IsoPs), in two case-controlled studies in patients with aSAH or severe TBI. Patients with aSAH (n=18) or TBI (n=18) were age and gender matched with separate control groups. CSF samples were collected from patients within 24?h of the injury. CSF IsoFs and F(4)-NeuroPs were increased in aSAH patients compared with their controls. In TBI patients, IsoFs and F(4)-NeuroPs were increased compared with their controls. F(2)-IsoPs were increased in aSAH patients, but not in TBI patients, compared with their respective controls. CSF IsoFs and F(4)-NeuroPs are consistently increased after a catastrophic central nervous system injury. These results suggest their measurement may enhance the management of unconscious patients in neurological care.