An assessment of the safety of pediatric ibuprofen. A practitioner-based randomized clinical trial

OBJECTIVE: To test the hypothesis that ibuprofen increases the risk of hospitalization for gastrointestinal bleeding, renal failure, or anaphylaxis among febrile children. DESIGN: Randomized double-blind acetaminophen-controlled trial. SETTING: Outpatient pediatric and family medicine practices. PATIENTS: A total of 84,192 children. INTERVENTION: Patients were randomly assigned to receive 12 mg/kg of acetaminophen, 5 mg/kg of ibuprofen, or 10 mg/kg of ibuprofen. MAIN OUTCOME MEASURES: Hospitalizations for acute gastrointestinal bleeding, acute renal failure, and anaphylaxis. RESULTS: A total of 277 patients (0.3%) were unavailable for follow-up. Overall, 795 participants (1%) were hospitalized, primarily for infectious diseases; hospitalization rates did not differ according to treatment group. Four children had diagnoses of acute, nonmajor gastrointestinal bleeding (two in each ibuprofen dosage group); among ibuprofen-treated children, the observed risk of gastrointestinal bleeding, 7.2 per 100,000 (95% confidence interval, 2 to 18 per 100,000), was not significantly different from the risk among acetaminophen-treated children (P = .31). There were no hospitalizations for acute renal failure or anaphylaxis; the upper 95% confidence bound for the risk of either of these outcomes was 5.4 per 100,000 ibuprofen-treated children. Among a number of other possibly serious adverse drug events, low white blood cell count was marginally associated with ibuprofen treatment. Because this association was observed in the setting of multiple comparisons and white blood cell counts may have been low before treatment, causation is unclear. CONCLUSIONS: The risk of hospitalization for gastrointestinal bleeding, renal failure, or anaphylaxis was not increased following short-term use of ibuprofen in children. These data, however, provide no information on the risks of less severe outcomes or the risks of prolonged ibuprofen use.     

Generation of constitutively active recombinant caspases-3 and -6 by rearrangement of their subunits

Caspases play a major role in the transduction of the apoptotic signal and execution of apoptosis in mammalian cells. Ectopic overexpression of the short prodomain caspases-3 and -6 precursors in mammalian cells does not induce apoptosis. This is due to their inability to undergo autocatalytic processing/activation and suggests that they depend on the long prodomain caspases for activation. To investigate directly the apoptotic activity of these two caspases in vivo, we engineered constitutively active recombinant caspases-3 and -6 precursors. This was achieved by making contiguous precursor caspases-3 and -6 molecules, which have their small subunits preceding their large subunits. Unlike their wild type counterparts, these recombinant molecules were capable of autocatalytic processing in an in vitro translation reaction, suggesting that they are catalytically active. They were also capable of autoprocessing and inducing apoptosis in vivo independent of the upstream caspases. Furthermore, their autocatalytic and apoptotic activities were inhibited by the pancaspase inhibitor z-VAD-fluoromethylketone, but not by CrmA or Bcl-2, thus directly demonstrating that the targets of inhibition of apoptosis by CrmA and Bcl-2 are upstream of caspases-3 and -6. Since caspases-3 and -6 are the most downstream executioners of apoptosis, the constitutively active versions of these caspases could be used at very low concentrations in gene therapy model systems to induce apoptosis in target tissues or tumors.     

Adenosine acts by A1 receptors to stimulate release of prolactin from anterior-pituitaries in vitro

Adenosine has been identified in the anterior pituitary gland and is secreted from cultured folliculostellate (FS) cells. To determine whether adenosine controls the secretion of anterior pituitary hormones in vitro, adenosine was incubated with anterior pituitaries. It stimulated prolactin (PRL) release at the lowest concentration used (10(-10) M); the stimulation peaked at 10(-8) M with a threefold increase in release and declined to minimal stimulation at 10(-4) and 10(-3) M. Follicle-stimulating hormone release was maximally inhibited at 10(-8) M, whereas luteinizing hormone release was not significantly inhibited. Two selective A1 adenosine receptor antagonists (10(-7) or 10(-5) M) had no effect on basal PRL release, but either antagonist completely blocked the response to the most effective concentration of adenosine (10(-8) M). In contrast, a highly specific A2 receptor antagonist (10(-7) or 10(-5) M) had no effect on basal PRL release or the stimulation of PRL release induced by adenosine (10(-8) M). We conclude that adenosine acts to stimulate PRL release in vitro by activating A1 receptors. Since the A1 receptors decrease intracellular-free calcium, this would decrease the activation of nitric oxide synthase in the FS cells, resulting in decreased release of nitric oxide (NO). NO inhibits PRL release by activating guanylate cyclase that synthesizes cGMP from GTP; cGMP concentrations increase in the lactotrophs leading to inhibition of PRL release. In the case of adenosine, NO release from the FS cells decreases, resulting in decreased concentrations of NO in the lactotrophs, consequent decreased cGMP formation, and resultant increased PRL release.     

Prenatal diagnosis of a fetal head and neck neoplasm: differential diagnosis, management, and histology

A fetal head and neck malignancy was prenatally diagnosed. The parents allowed the fetus to die during labour, due to the poor prognosis. We discuss the corresponding pathology findings, differential diagnosis, and management of this rare entity. Prenatal diagnosis of fetal neoplasms theoretically improves outcome, although this was not true in our case.     

Internal validity of attention deficit hyperactivity disorder, oppositional defiant disorder, and overt conduct disorder symptoms in young children: implications from teacher ratings for a dimensional approach to symptom validity

A software system for interactive manipulation of three-dimensional data has been developed, based on the Open Inventor tool kit. The primary use of this software system is in the segmentation of tomographic reconstructions of subcellular structures. To this end, the reconstruction is represented by volume rendering and displayed in stereo. A three-dimensional cursor with adjustable shape and size is used to define and isolate regions of interest inside the volume, based on the user's expert knowledge. Once isolated, the region of interest can be conveniently analyzed and displayed.     

Anaesthesia and the broken hearted. 170th annual oration: Royal Victoria Hospital, Belfast 2nd October 1997

Endoscopic evaluation of the patient with lung metastases takes on many forms depending upon the extent of disease and the intent of treatment, be that curative or palliative. Thorascopy, and occasionally mediastinoscopy, may be helpful in assessing operability in patients with extensive disease on a preoperative computed tomography scan. However, when in doubt, exploration is always indicated in the young, good risk patient. Palliative efforts usually concern airway obstruction and malignant effects. A variety of technologies, including laser, brachytherapy, and endoluminal stents, helps manage symptomatic bronchial or tracheal lesions.