An IFN-beta-albumin fusion protein that displays improved pharmacokinetic and pharmacodynamic properties in nonhuman primates.

The long half-life and stability of human serum albumin (HSA) make it an attractive candidate for fusion to short-lived therapeutic proteins. Albuferon (Human Genome Sciences [HGS], Inc., Rockville, MD) beta is a novel recombinant protein derived from a gene fusion of interferon-beta (IFN-beta ) and HSA. In vitro, Albuferon beta displays antiviral and antiproliferative activities and triggers the IFN-stimulated response element (ISRE) signal transduction pathway. Array analysis of 5694 independent genes in Daudi-treated cells revealed that Albuferon beta and IFN-beta induce the expression of an identical set of 30 genes, including 9 previously not identified. In rhesus monkeys administered a dose of 50 microg/kg intravenously (i.v.) or subcutaneously (s.c.) or 300 microg/kg s.c., Albuferon beta demonstrated favorable pharmacokinetic properties. Subcutaneous bioavailability was 87%, plasma clearance at 4.7-5.7 ml/h/kg was approximately 140-fold lower than that of IFN-beta, and the terminal half-life was 36-40 h compared with 8 h for IFN-beta. Importantly, Albuferon beta induced sustained increases in serum neopterin levels and 2',5' mRNA expression. At a molar dose equivalent to one-half the dose of IFN-beta, Albuferon beta elicited comparable neopterin responses and significantly higher 2',5'-OAS mRNA levels in rhesus monkeys. The enhanced in vivo pharmacologic properties of IFN-beta when fused to serum albumin suggest a clinical opportunity for improved IFN-beta therapy.     

MR imaging features in hypothalamic hamartoma: a report of three cases and review of literature

Hypothalamic hamartomas are rare tumours of particular interest because of their unusual symptoms. Three cases of hypothalamic hamartomas are reported in children, who presented with precocious puberty and gelastic seizures.     

Wegener's granulomatosis. Immunomicroscopic and ultrastructural study of four cases

Four cases of Wegener's granulomatosis involving lung are reported in which immunomicroscopy demonstrated that the parenchymal and vascular infiltrates were composed primarily of T cells and monocytes. No IgG, IgA, IgM, or C3 was identified in pulmonary vessels or alveolar septa. Ultrastructural studies failed to demonstrate dense deposits in alveolar septal capillaries or interstitium. These findings indicate that a cellular immune mechanism is active in these forms of pulmonary vasculitis and that immune complex deposition does not play a role.     

The control of chloride conductance in rat parotid isolated acinar cells investigated by photorelease of caged compounds

The control of Cl^– conductance in rat parotid isolated acinar cells was studied by combined use of whole-cell recording and flash photolysis techniques. Cells were voltage-clamped either at a membrane potential of –40 mV or stepped between –85 mV and 0 mV. Bath-applied carbachol and noradrenaline evoked Cl^– current at –85 mV and K⁺ current at 0 mV. Similar current activations resulted from the photolytic release of either inositol trisphosphate (InsP ₃) or Ca²⁺ by a brief near-UV flash. The peak amplitudes of the Cl^– conductance (at –85 mV), measured relative to the K⁺ conductance (at 0 mV), evoked by application of carbachol, noradrenaline or direct manipulation of cytosolic free calcium ([Ca²⁺]_i), were very similar, being 0.56±0.09 (mean±SEM,n=9), 0.52 ± 0.01 (n=7) and 0.46±0.06 (n=7). In contrast, the relative amplitude of the Cl^– conductance evoked by InsP₃ was much larger: 1.49±0.24 (n=9). Neither bath application of isoprenaline nor photolysis of caged cAMP induced any detectable membrane current. The most probable interpretation of these results is that the observed activation of Cl^– conductance by agonists can be explained by the elevation of [Ca²⁺]_i alone. In addition, the present results provide further support for the previously reported suggestion that the Cl^– channels and the Ca²⁺-release sites are co-localised [10].     

Diffusion of oxygen and carbon dioxide through blood flowing in a channel

The numerical solutions of diffusion equations have been obtained for the cases of oxygen and carbon dioxide diffusing through blood flowing between two porous parallel planes. It is assumed that at the entrance to the channel the concentration profiles are uniform and the velocity profile is fully developed. The rheological characteristics of blood are described by the Casson equation. The computations have been made employing the explicit finite-difference forward-marching procedure. The results have been obtained for a wide range of yield numbers, inlet partial pressures, pH, membrane resistances and haemoglobin concentrations.     

Adult-onset type II citrullinemia and idiopathic neonatal hepatitis caused by citrin deficiency: involvement of the aspartate glutamate carrier for urea synthesis and maintenance of the urea cycle

Citrin is a mitochondrial aspartate glutamate carrier primarily expressed in the liver, heart, and kidney. We found that adult-onset type II citrullinemia is caused by mutations in the SLC25A13 gene that encodes for citrin. In this report, we describe the frequency of SLC25A13 mutations, the roles of citrin as a member of the urea cycle and as a member of the malate-aspartate shuttle, the relationship between its functions and symptoms of citrin deficiency, and therapeutic issues.     

Identification and characterization of human pulmonary dendritic cells

Dendritic cells (DC) are specialized antigen-presenting cells, linking innate and adaptive immune responses, and thus play an important role in immunologically mediated diseases, including pulmonary diseases such as asthma and respiratory viral infections. Although much is known about the characteristics of lung DC in animal models, very few data concerning human lung DC are available. The goal of our study was to identify and characterize dendritic cells in human lung by preparing single-cell suspensions from surgical resection specimens and subsequent labeling with the recently developed blood dendritic cell antigen (BDCA) markers. A straightforward isolation procedure was developed to avoid phenotypical and functional changes induced by extensive purification methods. In this way, human lung DC were directly identified without the need for an additional adherence step for further purification. For the first time, we demonstrate the presence of three previously unidentified DC subsets in human lung digests: myeloid DC type 1 (BDCA1+/HLA-DR+), myeloid DC type 2 (BDCA3+/HLA-DR+), and plasmacytoid DC (BDCA2+/CD123+). The presence of CD1a+ DC in the human lung was confirmed. The identification and characterization of different human pulmonary DC subtypes is of great importance for the future development of DC-based immunotherapies.     

Strategies to improve the signal and noise performance of active matrix, flat-panel imagers for diagnostic x-ray applications

A theoretical investigation of factors limiting the detective quantum efficiency (DQE) of active matrix flat-panel imagers (AMFPIs), and of methods to overcome these limitations, is reported. At the higher exposure levels associated with radiography, the present generation of AMFPIs is capable of exhibiting DQE performance equivalent, or superior, to that of existing film-screen and computed radiography systems. However, at exposure levels commonly encountered in fluoroscopy, AMFPIs exhibit significantly reduced DQE and this problem is accentuated at higher spatial frequencies. The problem applies both to AMFPIs that rely on indirect detection as well as direct detection of the incident radiation. This reduced performance derives from the relatively large magnitude of the square of the total additive noise compared to the system gain for existing AMFPIs. In order to circumvent these restrictions, a variety of strategies to decrease additive noise and enhance system gain are proposed. Additive noise could be reduced through improved preamplifier, pixel and array design, including the incorporation of compensation lines to sample external line noise. System gain could be enhanced through the use of continuous photodiodes, pixel amplifiers, or higher gain x-ray converters such as lead iodide. The feasibility of these and other strategies is discussed and potential improvements to DQE performance are quantified through a theoretical investigation of a variety of hypothetical 200 microm pitch designs. At low exposures, such improvements could greatly increase the magnitude of the low spatial frequency component of the DQE, rendering it practically independent of exposure while simultaneously reducing the falloff in DQE at higher spatial frequencies. Furthermore, such noise reduction and gain enhancement could lead to the development of AMFPIs with high DQE performance which are capable of providing both high resolution radiographic images, at approximately 100 microm pixel resolution, as well as variable resolution fluoroscopic images at 30 fps.     

Successful management of spontaneous pneumothorax during general anaesthesia in a patient with eosinophilia

A 10-year-old male patient posted for left elbow arthrolysis developed pneumothorax during general anaesthesia. He had history of upper respiratory tract infection and high eosinophil count, which remained high in spite of treatment. In such patients, it is advisable to use steroid pre-operatively & intraoperatively to produce transient eosinopenia so that complications of eosinophilia are avoided.