The effect of improved modelling of plasma clearance in paediatric patients with expanded body spaces on estimation of the glomerular filtration rate.

The glomerular filtration rate (GFR) is used clinically to assess renal function. The most accurate estimation technique is tracer clearance where deterministic compartment pharmacokinetic models are most widely used. The aim of this study was to assess the viability of alternative pharmacokinetic models to describe tracer clearance, and in turn, measure GFR. This study was carried out on 126 clearance datasets obtained from 44 patients with large solid tumours; these were fitted to four pharmacokinetic models with superiority of model determined by Akaike Information Criteria. A fractal model was found to be superior to the best deterministic compartment model (70% of datasets, P < 0.0020) as was a gamma-distributed residence time model (93% of datasets, P < 0.0020); both models also gave greater mean weighted coefficients of determination than deterministic compartment models. These results suggest that gamma-distributed residence time and fractal models better describe tracer clearance than deterministic compartment models and therefore should allow more accurate estimation of GFR.

Human T-lymphotropic virus type 1 open reading frame I p12(I) is required for efficient viral infectivity in primary lymphocytes.

Human T-lymphotropic virus type 1 (HTLV-1) is a complex retrovirus encoding regulatory and accessory genes in four open reading frames (ORF I to IV) of the pX region. Emerging evidence indicates an important role for the pX ORF I-encoded accessory protein p12(I) in viral replication, but its contribution to viral pathogenesis remains to be defined. p12(I) is a conserved, membrane-associated protein containing four SH3-binding motifs (PXXP). Its interaction with the interleukin-2 (IL-2) receptor beta- and gamma-chains implies an involvement of p12(I) in intracellular signaling pathways. In addition, we have demonstrated that expression of pX ORF I p12(I) is essential for persistent infection in rabbits. In contrast, standard in vitro systems have thus far failed to demonstrate a contribution of p12(I) to viral infectivity and ultimately cellular transformation. In this study we developed multiple in vitro coculture assays to evaluate the role of p12(I) in viral infectivity in quiescent peripheral blood mononuclear cells to more accurately reflect the virus-cell interactions as they occur in vivo. Using these assays, we demonstrate a dramatic reduction in viral infectivity in quiescent T lymphocytes for a p12 mutant viral clone (ACH.p12) in comparison to the wild-type clone ACH. Moreover, addition of IL-2 and phytohemagglutinin during the infection completely rescued the ability of ACH.p12 to infect primary lymphocytes. When newly infected primary lymphocytes are used to passage virus, ACH.p12 also exhibited a reduced ability to productively infect activated lymphocytes. Our data are the first to demonstrate a functional role for pX ORF I in the infection of primary lymphocytes and suggest a role for p12(I) in activation of host cells during early stages of infection.

Human immunodeficiency virus type 1 Gag polyprotein multimerization requires the nucleocapsid domain and RNA and is promoted by the capsid-dimer interface and the basic region of matrix protein.

The human immunodeficiency virus type 1 (HIV-1) Gag polyprotein directs the formation of virions from productively infected cells. Many gag mutations disrupt virion assembly, but little is known about the biochemical effects of many of these mutations. Protein-protein interactions among Gag monomers are believed to be necessary for virion assembly, and data suggest that RNA may modify protein-protein interactions or even serve as a bridge linking Gag polyprotein monomers. To evaluate the primary sequence requirements for HIV-1 Gag homomeric interactions, a panel of HIV-1 Gag deletion mutants was expressed in bacteria and evaluated for the ability to associate with full-length Gag in vitro. The nucleocapsid protein, the major RNA-binding domain of Gag, exhibited activity comparable to that of the complete polyprotein. In the absence of the nucleocapsid protein, relatively weak activity was observed that was dependent upon both the capsid-dimer interface and basic residues within the matrix domain. The relevance of the in vitro findings was confirmed with an assay in which nonmyristylated mutant Gags were assessed for the ability to be incorporated into virions produced by wild-type Gag expressed in trans. Evidence of the importance of RNA for Gag-Gag interaction was provided by the demonstration that RNase impairs the Gag-Gag interaction and that HIV-1 Gag interacts efficiently with Gags encoded by distantly related retroviruses and with structurally unrelated RNA-binding proteins. These results are consistent with models in which Gag multimerization involves indirect contacts via an RNA bridge as well as direct protein-protein interactions.

Micturition detection switch.

Micturating renograms often need to be carried out on children, with whom difficulty may be experienced in synchronizing onset of micturition with camera and computer acquisition. A flow detection system has been developed which will automate these acquisitions, resulting in far fewer false starts or lost studies. The unit was developed specifically for the camera/computer system in our department (IGE 400T and DEC 11/34) but with only minor modifications would be suitable for interfacing to other equipment. It is a free standing unit which requires no modifications of the camera or computer circuitry apart from access to the remote start buttons.

A rate pressure product meter. A new module for use with the Simonsen & Weel System 8000 monitors.

A prototype rate pressure product module has been constructed for use with Simonsen and Weel Series 8000 monitors. The importance of method of display of rate pressure product is stressed.