Extracardiac 18F-florbetapir imaging in patients with systemic amyloidosis: more than hearts and minds.

PURPOSE: 18F-Florbetapir has been reported to show cardiac uptake in patients with systemic light-chain amyloidosis (AL). This study systematically assessed uptake of 18F-florbetapir in patients with proven systemic amyloidosis at sites outside the heart. METHODS: Seventeen patients with proven cardiac amyloidosis underwent 18F-florbetapir PET/CT imaging, 15 with AL and 2 with transthyretin amyloidosis (ATTR). Three patients had repeat scans. All patients had protocolized assessment at the UK National Amyloidosis Centre including imaging with 123I-serum amyloid P component (SAP). 18F-Florbetapir images were assessed for areas of increased tracer accumulation and time-uptake curves in terms of standardized uptake values (SUVmean) were produced. RESULTS: All 17 patients showed 18F-florbetapir uptake at one or more extracardiac sites. Uptake was seen in the spleen in 6 patients (35%; 6 of 9, 67%, with splenic involvement on 123I-SAP scintigraphy), in the fat in 11 (65%), in the tongue in 8 (47%), in the parotids in 8 (47%), in the masticatory muscles in 7 (41%), in the lungs in 3 (18%), and in the kidney in 2 (12%) on the late half-body images. The 18F-florbetapir spleen retention index (SRI) was calculated. SRI >0.045 had 100% sensitivity/sensitivity (in relation to 123I-SAP splenic uptake, the current standard) in detecting splenic amyloid on dynamic imaging and a sensitivity of 66.7% and a specificity of 100% on the late half-body images. Intense lung uptake was seen in three patients, one of whom had lung interstitial infiltration suggestive of amyloid deposition on previous high-resolution CT. Repeat imaging showed a stable appearance in all three patients suggesting no early impact of treatment response. CONCLUSION: 18F-Florbetapir PET/CT is a promising tool for the detection of extracardiac sites of amyloid deposition. The combination of uptake in the heart and uptake in the spleen on 18F-florbetapir PET/CT, a hallmark of AL, suggests that this tracer holds promise as a screening tool for AL.

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.

A quantitative analysis of the intranasal delivery of topical nasal drugs to the middle meatus: spray versus drop administration.

The delivery of nasal drugs specifically to the middle meatus is of critical importance in the medical treatment of rhinosinusitis. In this respect, topical nasal drug administration by drops has generally been perceived to be superior to nasal sprays, although there is a lack of evidence to support this notion. This study aims to compare the intranasal delivery of nasal sprays and drops to the middle meatus in vivo, using a novel quantitative method. A surgical patty was placed in the middle meatus. Radio-labelled topical nasal drops and aqueous sprays were administered in a standardized fashion in normal volunteers (10 nasal cavities). The subsequent absorption of administered radio-labelled saline on the patty was measured using a gamma counter. A randomized prospective crossover design was used for the study. The mean percentage (range) of absorbed administered saline on the swab was 8.7 (0.3-39.5) and 9.7 (0.03-20.4) for the spray and drop administration techniques respectively (p = 0.8). Thus, there is wide variation in the delivery of topical nasal drugs and the perceived superiority of nasal drop administration, in terms of delivery to the middle meatus, may be incorrect.

Effect of radial artery harvesting on tissue perfusion and function of the hand.

This study was designed to measure the degree to which hand and forearm blood flow is reduced following harvesting of the radial artery in myocardial revascularization surgery and determine whether there is an effect on hand function. Twenty patients who had the radial artery used for myocardial revascularization underwent bilateral blood flow assessment of hands and forearms using Technetium-99m human serum albumin and clinical evaluation of hand function. Mean tissue perfusion in ml/100 ml/min +/- SD was as follows: donor hand 21.9 +/- 5.6, non-donor hand 25.5 +/- 6.1 (P = 0.00043), donor arm (hand and forearm) 17.5 +/- 3.7 and non-donor arm (hand and forearm) 21 +/- 5.1 (P = 0.000681). No clinical evidence of hand claudication was detected. This study suggests that removal of the radial artery reduces the tissue perfusion of the hand and forearm but does not affect hand function in the short term. The use of radial artery grafts in patients at risk of developing peripheral vascular disease should be carefully considered

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.

Improvement of nebulised antibiotic delivery in cystic fibrosis.

AIM: To investigate deposition patterns and to assess the delivery rate of two nebuliser systems in children with cystic fibrosis (CF). METHODS: Thirty three children with CF on regular treatment with nebulised antibiotics had radioisotope scans performed using technetium-99m labelled aerosol antibiotic generated by a Ventstream nebuliser (median mass diameter (MMD), 3.3 microm; delivery rate, 0. 075 ml/min) under conditions similar to their routine home practice. The inhomogeneity of the images was scored on a 1-10 rating scale (a low score indicating even distribution of the antibiotic), and stomach deposition was measured as a percentage of overall deposition. Twenty patients had a repeat scan using an Optimist nebuliser (MMD, 1.8 microm; delivery rate, 0.02 ml/min). RESULTS: The mean inhomogeneity scores were 5.4 in the Ventstream group and 3. 5 in the Optimist group. Mean stomach deposition was 17.3% in the 33 patients using the Ventstream nebuliser. There was an inverse relation between height and stomach deposition (r = 0.69). In the 20 patients who had both nebulisers, the mean percentages of stomach deposition for the Ventstream and Optimist nebulisers were 11.8% and 1.6%, respectively. The Ventstream nebuliser delivered antibiotic at an average 2.8 times faster rate than the Optimist nebuliser. IMPLICATIONS: A smaller particle size results in a more homogenous distribution of the antibiotic in the lungs with decreased stomach deposition. This should not be seen as a recommendation to use the Optimist nebuliser because more antibiotic was delivered to most parts of the lung with the Ventstream because of its increased delivery rate.

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.