Inhibition of IL-1ß release from macrophages targeted with necrosulfonamide-loaded porous nanoparticles.

Inflammation is required for protective responses against pathogens and is thus essential for survival, but sustained inflammation can lead to diseases, such as atherosclerosis and cancer. Two important mediators of inflammation are the cytokines IL-1ß and IL-18, which are produced by myeloid cells of the immune system, including macrophages. These cytokines are released into the extracellular space through pores formed in the plasma membrane by the oligomerized protein gasdermin D (GSDMD). Necrosulfonamide (NSA) was recently identified as an effective GSDMD inhibitor and represents a promising therapeutic agent in GSDMD-dependent inflammatory diseases. Here, we targeted NSA to both mouse and human macrophages by using three different types of porous nanoparticles (NP), i.e. mesoporous silica (MSN), porous crosslinked cyclodextrin carriers (CD-NP), and a mesoporous magnesium-phosphate carrier (MPC-NP), all displaying high loading capacities for this hydrophobic drug. Cellular uptake and intracellular NSA delivery were tracked in time-lapse experiments by live-cell, high-throughput fluorescence microscopy, demonstrating rapid nanoparticle uptake and effective targeted delivery of NSA to phagocytic cells. Notably, a strong cytostatic effect was observed when a macrophage cell line was exposed to free NSA. In contrast, cell growth was much less affected when NSA was delivered via the nanoparticle carriers. Utilizing NSA-loaded nanoparticles, a successful concentration-dependent suppression of IL-1ß secretion from freshly differentiated primary murine and human macrophages was observed. Functional assays showed the strongest suppressive effect on human macrophages when using CD-NP for NSA delivery, followed by MSN-NP. In contrast, MPC-NP completely blocked the metabolic activity in macrophages when loaded with NSA. This study demonstrates the potential of porous nanoparticles for the effective delivery of hydrophobic drugs to macrophages in order to suppress inflammatory responses.

Young children with a minor traumatic head injury: clinical observation or CT scan?

Currently, in young children with minor traumatic head injuries (MTHI) classified as intermediate risk (IR), PECARN recommends clinical observation over computer tomography (CT) scan depending on provider comfort, although both options being possible. In this study, we describe clinicians' choice and which factors were associated with this decision. This was a planned sub-study of a prospective multicenter observational study that enrolled 1006 children younger than 18 years with MTHI who presented to six emergency departments in The Netherlands. Of those, 280 children classified as IR group fulfilling one or more minor criteria, leaving the clinician with the choice between clinical observation and a CT scan. In our cohort, 228/280 (81%) children were admitted for clinical observation, 15/280 (5.4%) received a CT scan, 6/280 (2.1%) received a CT scan and were admitted for observation, and 31/280 (11%) children were discharged from the emergency department without any intervention. Three objective factors were associated with a CT scan, namely age above 2 years, the presence of any loss of consciousness (LOC), and presentation on weekend days. CONCLUSION: In children with MTHI in an IR group, clinicians prefer clinical observation above performing a CT scan. Older age, day of presentation, and any loss of consciousness are factors associated with a CT scan. WHAT IS KNOWN: • Clinical decision rules have been developed in the management of children of different risk groups with minor traumatic head injury (MTHI). • According to the Dutch national, clinical decision rules in children under 6 years of age up to 50% of children classify as intermediate risk (IR) and clinicians may choose between clinical observation and computed tomography (CT). WHAT IS NEW: • In this IR group, clinical observation is chosen in 81% children with MTHI. • In the subgroup where clinicians performed a CT scan, children were older and presented more frequently on a weekend day, and more frequently consciousness was lost.

The interleukin-1 cytokine family members: Role in cancer pathogenesis and potential therapeutic applications in cancer immunotherapy.

The interleukin-1 (IL-1) family is one of the first described cytokine families and consists of eight cytokines (IL-1ß, IL-1α, IL-18, IL-33, IL-36α, IL-36ß, IL-36γ and IL-37) and three receptor antagonists (IL-1Ra, IL-36Ra and IL-38). The family members are known to play an essential role in inflammation. The importance of inflammation in cancer has been well established in the past decades. This review sets out to give an overview of the role of each IL-1 family member in cancer pathogenesis and show their potential as potential anticancer drug candidates. First, the molecular structure is described. Next, both the pro- and anti-tumoral properties are highlighted. Additionally, a critical interpretation of current literature is given. To conclude, the IL-1 family is a toolbox with a collection of powerful tools that can be considered as potential drugs or drug targets.

Multi-centre study found that strict adherence to guidelines led to computed tomography scans being overused in children with minor head injuries.

AIM: Our primary aim was to calculate the head computed tomography (CT) scan rate in children with a minor head injury (MHI) when the Dutch National guidelines were followed in clinical practice. The secondary aim was to determine the incidence of CT abnormalities and the guideline predictors associated with traumatic abnormalities. METHODS: We performed a multi-centre, prospective observational cross-sectional study in the emergency departments of six hospitals in The Netherlands between 1 April 2015 and 31 December 2016. RESULTS: Data on 1002 patients were studied and 69% of cases complied with the guidelines. The overall CT rate was 44% and the incidence of traumatic abnormal CT findings was 13%. CT scans were performed in 19% of children under two years of age, 48% of children between two and five years and 63% of children aged six years or more. Multivariate regression analysis for all age categories showed that CT abnormalities were predicted by a Glasgow Coma Scale of less than 15, suspicion of a basal skull fracture, vomiting and scalp haematomas or external lesions of the skull. CONCLUSION: Strict adherence to the Dutch national guidelines resulted in CT overuse. New guidelines are needed to safely reduce CT scan indications.

Serum hepcidin in infants born after 32 to 37 wk of gestational age.

BACKGROUND: Preterm infants are at risk of iron deficiency (ID). Hepcidin has been suggested as a good additional indicator of ID in preterm infants, next to ferritin. METHODS: In a prospective observational study, we analyzed serum hepcidin in 111 infants born after 32+0 to 36+6 wk gestational age during the first 4 mo of life. RESULTS: Hepcidin concentrations decreased during the first 4 mo of life, and concentrations were lower in infants with ID compared to those without ID. Infants who developed ID at the age of 4 mo had already significantly lower levels of hepcidin at 1.5 mo of age, while ferritin was already significantly lower at the age of 1 wk. CONCLUSION: Hepcidin concentrations of late preterm infants decrease during the first 4 mo of life. This decrease, which parallels a decrease of ferritin concentration, we interpret as a physiological response, aiming to increase iron availability. Hepcidin concentrations are lower in infants with ID compared with those without ID, with a notable change already observed at 1.5 mo of age. Hepcidin can be used as an early marker of ID, although an additive value of hepcidin over ferritin in the diagnosis of ID is not present.

[Cardiorespiratory events after first immunization in premature infants: a prospective cohort study]. / Cardiorespiratoire verstoringen na 1e vaccinatie bij prematuur geboren kinderen: een prospectief cohortonderzoek.

OBJECTIVE: To investigate whether all preterm infants born before 33 weeks of gestation need cardiorespiratory monitoring due to the risk of cardiorespiratory disturbances following their first vaccination at 2 months of age. DESIGN: A prospective observational cohort study. METHOD: During a period lasting a little over a year, all preterm infants who were being cared for at the neonatal ward of Medical Centre Alkmaar because they had been born before 33 weeks of gestation received their first immunization at the age of 2 months and were subsequently monitored. Infants who had already been discharged by that time were readmitted for this purpose. RESULTS: In this cohort of 41 premature infants whose mean gestational age was 30.8 weeks (SD: 1.9), 10 of these had a mild decrease in oxygen saturation or bradycardia; three developed a moderate cardiorespiratory event requiring tactile stimulation. The incidence of disturbances was higher in younger and lower-weight infants and those who had experienced more severe morbidity during the neonatal phase. Moderate disturbances only occurred in the infants who had not yet been discharged from hospital after birth. CONCLUSION: It is recommended that still-hospitalized premature infants receive their first immunizations under cardiorespiratory monitoring, as events were observed during a period of 0-24 hours thereafter. In premature infants who had already been discharged - mainly because they were less premature or dysmature - immunization without cardiorespiratory monitoring appeared to be safe. Further research is needed for substantiating this strategy.

The effect of oxandrolone on voice frequency in growth hormone-treated girls with Turner syndrome.

OBJECTIVES/HYPOTHESIS: Oxandrolone (Ox) increases height gain but may also cause voice deepening in growth hormone (GH)-treated girls with Turner syndrome (TS). We assessed the effect of Ox on objective and subjective speaking voice frequency in GH-treated girls with TS. STUDY DESIGN: A multicenter, randomized, placebo (Pl)-controlled, double-blind study was conducted. METHODS: One hundred thirty-three patients were included and treated with GH (1.33 mg/m2/d) from baseline, combined with Pl or Ox in a low (0.03 mg/kg/d) or conventional (0.06 mg/kg/d) dose from the age of 8 years and estrogens from the age of 12 years. Yearly from starting Ox/Pl until 6 months after discontinuing GH+Ox/Pl, voices were recorded and questionnaires were completed. RESULTS: At start, mean (±standard deviation [SD]) voice frequency SD score (SDS) was high for age (1.0±1.2, P<0.001) but normal for height. Compared with GH+Pl, voices tended to lower on GH+Ox 0.03 (P=0.09) and significantly lowered on GH+Ox 0.06 (P=0.007). At the last measurement, voice frequency SDS was still relatively high in GH+Pl group (0.6±0.7, P=0.002) but similar to healthy girls in both GH+Ox groups. Voice frequency became lower than -2 SDS in one patient (3%) on GH+Ox 0.03 and three patients (11%) on GH+Ox 0.06. The percentage of patients reporting subjective voice deepening was similar between the dosage groups. CONCLUSIONS: Untreated girls with TS have relatively high-pitched voices. The addition of Ox to GH decreases voice frequency in a dose-dependent way. Although most voice frequencies remain within the normal range, they may occasionally become lower than -2 SDS, especially on GH+Ox 0.06 mg/kg/d.

[Thrombocytopenia in two newborn babies. Unexpected serious complications in full-term babies]. / Trombocytopenie bij twee pasgeborenen: onverwacht ernstige complicaties bij aterme neonaten.

Thrombocytopenia usually has a moderate course in full-term babies. Here, however, we describe two newborns with serious complications due to neonatal alloimmune thrombocytopenia. One patient was transferred to the paediatrician because of pallor, a swelling on the head and petechiae. He had a subgaleal hemorrhage. Following a platelet transfusion he made a complete recovery. The other presented with thrombocytopenia and petechiae and was treated with intravenous immunoglobulin. Several days later the patient started vomiting. Cranial ultrasound showed hydrocephalus most probably arising from an intraventricular haemorrhage following the thrombocytopenia, for which he received a ventriculoperitoneal drain. After this he made a successful recovery. Although neonatal alloimmune thrombocytopenia is a rare condition it can have serious consequences for the newborn and for subsequent pregnancies. It is important that treatment be started early and that cranial ultrasound always be performed.

Screening rules for growth to detect celiac disease: a case-control simulation study.

BACKGROUND: It is generally assumed that most patients with celiac disease (CD) have a slowed growth in terms of length (or height) and weight. However, the effectiveness of slowed growth as a tool for identifying children with CD is unknown. Our aim is to study the diagnostic efficiency of several growth criteria used to detect CD children. METHODS: A case-control simulation study was carried out. Longitudinal length and weight measurements from birth to 2.5 years of age were used from three groups of CD patients (n = 134) (one group diagnosed by screening, two groups with clinical manifestations), and a reference group obtained from the Social Medical Survey of Children Attending Child Health Clinics (SMOCC) cohort (n = 2,151) in The Netherlands. The main outcome measures were sensitivity, specificity and positive predictive value (PPV) for each criterion. RESULTS: Body mass index (BMI) performed best for the groups with clinical manifestations. Thirty percent of the CD children with clinical manifestations and two percent of the reference children had a BMI Standard Deviation Score (SDS) less than -1.5 and a decrease in BMI SDS of at least -2.5 (PPV = 0.85%). The growth criteria did not discriminate between the screened CD group and the reference group. CONCLUSION: For the CD children with clinical manifestations, the most sensitive growth parameter is a decrease in BMI SDS. BMI is a better predictor than weight, and much better than length or height. Toddlers with CD detected by screening grow normally at this stage of the disease.

Catch-up growth: definition, mechanisms, and models.

Catch-up growth is characterized by height velocity above the limits of normal for age for at least 1 year after a transient period of growth inhibition; it can be complete or incomplete. Although catch-up growth can be expressed in terms of height velocity, the change in height standard deviation score is more appropriate. Catch-up growth is difficult to distinguish from the pubertal growth spurt. The increased growth rate following intrauterine growth retardation is usually called catch-up growth, although it does not meet all the criteria. It is not possible to know whether catch-up growth is complete for an individual child, but if final height is within the target range, it can be considered that catch-up growth has probably been complete. In groups of patients, complete catch-up growth is expected to result in a mean final height close to the mean target height. Increased growth velocity due to growth hormone (GH) therapy is accurately called catch-up growth in children with GH deficiency but should be called growth enhancement in children with other disorders. Two hypotheses have been proposed to explain the mechanism of catch-up growth: the neuroendocrine hypothesis, for which no persuasive experimental data have been produced, and the growth plate hypothesis, which cannot explain the increased growth rate observed in human catch-up growth.