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Three methods of determining digoxin population pharmacokinetic parameters were compared for their abilities to predict 118 measured serum digoxin concentrations (SDCs) in 49 patients. NONMEM software (version IV) was used to generate a residual and a weighted residual for each measured-concentration-predicted-concentration pair. Prediction error analysis was done by a maximum likelihood technique that accounted for several within-patient measures. Data analysis also included graphic observation of weighted residuals (WRES) and calculation of the mean WRES and median absolute prediction error. A further parallel analysis was also carried out on subpopulations with and without concurrent quinidine and congestive heart failure (CHF). Method III was without bias in all subpopulations studied and had the smallest WRES in all populations. Method I was without bias in the overall population, however, it underpredicted SDCs in patients receiving quinidine and in those with CHF. Method II underpredicted SDCs in the overall population, those receiving quinidine, and in patients without CHF. There were no between-method differences in precision as assessed by absolute prediction error.

This study investigates immobilisation of murine IgG in various ELISA procedures. Monoclonal murine IgG isotypes and polyclonal IgG from sera were studied. Similar binding curves to plastic were found for all four individual murine IgG isotypes. Single isotypes displayed different affinities for both protein A and protein G, in particular IgG1 was poorly and IgG3 strongly bound to both of these proteins. When mixtures of the isotypes were bound to either plastic, protein A or protein G, competition was observed in which IgG3 was dominant. Paradoxically, studies on the binding rates of single isotypes direct to plastic revealed that IgG3 had the slowest binding rate. Heating of bound IgGs resulted in significant but isotypically non-selective losses from the plates. The data demonstrate that despite obtaining equivalent individual IgG isotype binding curves, mixtures of IgG isotypes behave very differently, with competition for binding occurring even on plastic. The IgG isotype levels of murine sera were measured for individual mice, and the capture efficiency of each IgG isotype by protein A determined at different serum dilutions. Comparisons were made between the observed capture levels of IgG isotypes and their known serum levels. At all dilutions tested, greater than expected binding of IgG3, IgG2b and IgG2a was observed. At a serum dilution of 1/100 the binding of these three isotypes was increased 16-, 2.9- and 0.4-fold, respectively. These increases were balanced by a decrease in IgG1 binding which was the most prevalent serum IgG isotype. The results described above suggest that capture techniques are biased and unlikely to provide a coating of IgG isotypes that accurately reflects that of the serum. This bias is derived from the specificity of the individual isotypes for either protein A or protein G, and the errors further compounded by direct competition between isotypes whatever the capture surface. Induced coalescence of IgG3 may explain the latter observations.

The molecular mechanisms by which human cancer cells spread to bone are largely unexplored. The process likely involves cell adhesion molecules (CAMs) that are responsible for homophilic and heterophilic cell-cell interactions. One relevant CAM may be the calcium-dependent transmembrane glycoprotein E-cadherin. To investigate the involvement of E-cadherin in breast cancer metastasis to bone, we used an in vivo model in which osteolytic bone metastases preferentially occur after injections of cancer cells directly into the arterial circulation through the left ventricle of the hearts of nude mice. We have found that E-cadherin-negative human breast cancer cells MDA-MB-231 (MDA-231) develop radiographically detectable multiple osteolytic bone metastases and cachexia in this model. However, MDA-231 breast cancer cells that were transfected with E-cadherin cDNA showed a dramatically impaired capacity to form osteolytic metastases and induce cachexia. Histological and histomorphometrical analyses of bones of mice bearing mock-transfected MDA-231 revealed aggressive metastatic tumor, whereas metastatic tumor burden was significantly decreased in the bones of mice bearing E-cadherin-expressing MDA-231. Nude mice bearing E-cadherin-transfected MDA-231 breast cancer cells survived longer than mice bearing mock-transfected MDA-231 breast cancer cells. Anchorage-dependent and -independent growth in culture and tumor enlargement in the mammary fat pad of nude mice were unchanged between mock-transfected and E-cadherin-expressing MDA-231, suggesting that these differences in metastatic behavior are not due to an impairment of cell growth and tumor-igenicity. Our results show the suppressive effects of E-cadherin expression on bone metastasis by circulating breast cancer cells and suggest that the modulation of expression of this CAM may reduce the destructive effects of breast cancer cells on bone.

Inhaled nitric oxide (NO) has been shown to be a selective pulmonary vasodilator in certain patients with primary pulmonary hypertension (PPH).The purpose of this study was to design and test a system for delivery of NO to awaken, ambulatory patients with PPH and to evaluate this system in the home setting.The ambulatory delivery system consisted of a tank of 80 ppm of NO (balance N2), a modified gas-pulsing device, and nasal cannulas. The pulsing device was set to deliver NO for 0.1 s at the beginning of each inspiration.Using this system, eight patients with PPH were studied with pulmonary artery catheters in place. Inhalation of NO led to significant reductions in both mean pulmonary arterial pressure (PAPm) (51 +/-12 to 43 +/- 10 mm Hg; p=0.001) and pulmonary vascular resistance (PVR) (790 +/- 285 to 620 +/- 208 dyne x s x cm-5; p=0.01). Three of the eight patients had both greater than 20% and greater than 30% decreases in PAPm and PVR, respectively. No exhaled NO or N02 was detectable in any of the eight patients. One patient was discharged home from the hospital on a regimen of inhaled NO. At 9 months, no adverse effects were noted and the system was working well.Pulsed delivery of inhaled NO to ambulatory patients with PPH, via nasal prongs, is feasible and, in some patients, leads to significant improvement in pulmonary hypertension. Inhaled 09NO, therefore, may have a role in the long-term treatment of patients with PPH.

A major stimulus to research on grape flavour has been wine production, because grape varietal flavour is a primary determinant of wine style, quality and price. This emphasis on winegrape varietal flavour contrasts with the flavour requirements of grapes destined for drying or the table market, for which the concentrations of sugars and acids are of prime importance. The flavour of dried grapes is also strongly influenced by Maillard chemistry, and because this topic has been reviewed extensively (Vernin and Parkanyi 1982; Waller and Feather 1983) it will not be treated in the present work. The specific flavour attributes of table grapes have attracted little attention (Webb 1981) although floral characteristics would doubtless be appreciated and information about winegrape flavour is of relevance to this topic.

During pregnancy there is a dramatic reduction in the serum levels of agalactosyl IgG (G0IgG) in both normal women and those with rheumatoid arthritis. In order to determine if a similar reduction in G0IgG were apparent in fetal serum, a comparison of the galactose content of IgG from nine paired samples of umbilical vein or fetal blood and peripheral maternal serum, at gestational ages ranging from 16-41 weeks was performed. The full-term maternal IgG samples were highly galactosylated, so confirming previous observations of reduced G0IgG levels during pregnancy. In addition every paired sample of fetal IgG had a higher level of galactosylation than the corresponding maternal IgG. Therefore, during pregnancy there is both a reduced biosynthesis of the G0IgG glycoform by the mother, and a restriction of its transport across the placenta. The ratio of estimated G0IgG in fetal and maternal serum was found to be related to changes in IgG transport, and in particular the active transport of IgG1 across the placenta during gestation. Our data suggest that the placental IgG transport mechanism is either carbohydrate independent by discriminating for IgG1, or is carbohydrate dependent selecting for highly galactosylated IgG glycoforms. This study emphasizes the need for further investigations on the biological function of G0IgG in normal physiological states, in addition to disease states, such as juvenile and adult rheumatoid arthritis, where elevated G0IgG levels correlate with disease activity.

Summary Airway maintenance and protection during anaesthesia and recovery provided by the reinforced laryngeal mask airway was compared with the sequential use of a tracheal tube followed by the Guedel airway in 66 patients having anaesthesia for nasal surgery. One patient was withdrawn from the laryngeal mask group because the airway was difficult to position. All patients had an oropharyngeal pack inserted and Moffett's solution instilled into the nasal cavities. At the end of surgery the nasal cavities were packed. During operation airway maintenance was good and airway protection was equally effective in both groups. Contamination of the lower airway occurred in only five patients. During recovery from anaesthesia the laryngeal mask and Guedel airway were well tolerated by most patients, but only the mask laryngeal provided an unobstructed airway in all patients. The laryngeal mask protects the larynx from contamination during and after operation until the return of the patient's own protective reflexes.

Genetic and environmental factors are thought to contribute to either the initial susceptibility to synovitis or persistence of joint disease in patients with rheumatoid arthritis. The genetic component of the disease probably accounts for no more than 12–15% of the whole, only one-third to one-half of this component can be accounted for by genes encoded within the HLA complex which may influence disease severity rather than susceptibility (1). At present the recognition of specific HLA markers for more aggressive forms of the disease has not yet been translated into any form of successful therapy. Further, therapies aimed at CD4+ T-cells have not been successful, as also predicted from lack of amelioration of arthritis in AIDS patients. Clearly other risk factors need to be established in order for new therapeutic strategies to be developed.

Soft-tissue sarcoma is a rare diagnosis in general and more so in the foot. The author has seen two in the last 9 years, both of which were fatal. As podiatry becomes more and more an accepted primary care specialty, our index of suspicion needs to increase and our diagnostic procedures need to be aggressive. The incidence of primary and secondary cancerous lesions in the foot and ankle are increasing.

The rat and human forms of the T-cell surface glycoprotein CD4 share a common glycosylation site at the Asn270/271 position but differ with respect to the locations of the second glycosylation sites at Asn159 (rat) and Asn300 (human). The glycosylation of soluble recombinant forms of human and rat CD4 (sCD4) expressed in Chinese hamster ovary cells has been characterized. The most obvious differences between the rat and human sCD4 oligosaccharides were the greater abundance of oligomannose and hybrid oligosaccharides on rat sCD4 and the presence of oligosaccharides carrying a terminal alpha-galactose residue on human sCD4. This is the first report of the occurrence of alpha-galactose residues on a glycoprotein expressed in Chinese hamster ovary cells. Comparison of mutant rat sCD4 molecules with single glycosylation sites and glycopeptides indicated that site-specific and independent processing occurred at each glycosylation site. The glycosylation at the conserved site at Asn270 of rat sCD4 was identical to that seen for the equivalent site in human sCD4, and the oligomannose and hybrid structures were restricted to the nonconserved site at Asn159 in rat sCD4. However, there was more oligosaccharide processing at this site in a truncated form of rat sCD4 consisting of the two NH2-terminal domains. These results indicate that not only the local three-dimensional structure but also domain interactions can influence the processing at individual glycosylation sites.

The mechanisms by which tumor cells metastasize to bone are not well understood. We have investigated the role of the basement membrane glycoprotein, laminin, in bone metastasis, since antagonists to laminin have been shown to inhibit the formation of lung metastases. We studied the formation of osteolytic metastases caused by a human tumor which is known to cause osteolysis and hypercalcemia in nude mice. We found that tumor-bearing nude mice developed hypercalcemia, cachexia, and characteristic osteolytic lesions throughout the skeleton after injection of this human melanoma cell line (A375) into the left ventricle. When we gave injections to nude mice with A375 cells which had been exposed to C(YIGSR)3-NH2, a laminin-derived synthetic peptide containing three linear sequences of YIGSR with an amino-terminal cysteine which competes with laminin for its receptor, we found a decrease in the formation of detectable osteolytic bone metastases. The tumor cells were incubated with the antagonist and then inoculated into nude mice which were administered the antagonist i.p. Hypercalcemia and cachexia were also decreased in tumor-bearing mice treated with the laminin antagonist. In contrast, laminin itself increased the number of osteolytic bone metastases, as has been shown for other tumor cells. These data suggest that laminin plays a role in the formation of osteolytic bone metastases in this model and that laminin antagonists may be useful in the prevention of bone metastases in some human tumors.

The intermediate lobe of the pituitary (IL) is a promising model system for the study of dopaminergic neurotransmission. We sought to characterize the release of dopamine (DA) from the IL using electrochemical methods which provide increased spatial and temporal resolution compared to the superfusion techniques which had previously been employed to study this system. After pretreatment with monoamine oxidase (MAO) inhibitors, we were able to routinely measure DA overflow after 30-sec, 9-Hz electrical stimulation of the pituitary stalk. This effect was blocked by tetrodotoxin and Cd++ ions confirming that it was due to synaptic activation. Intracellular recording from the postsynaptic cells (melanotrophs) showed a postsynaptic hyperpolarization with a time course that was identical to that of DA overflow. Overflow was increased and prolonged by agents that inhibited DA uptake (nomifensine, mazindol or cocaine) and increased but not prolonged by a D2 antagonist (sulpiride), presumably acting via presynaptic autoreceptors. The DA precursor 3,4-dihydroxyphenylalanine also increased DA overflow gradually over a 45-min time period. In view of reports of possible colocalization of DA and gamma-aminobutyric acid in IL, we determined the possible effects of GABAergic agents on DA release. Neither agonists (muscimol or baclofen) nor antagonists (bicuculline or 2-hydroxysaclofen) had any effect on DA overflow. By using the MAOA-specific inhibitor clorgyline and the MAOB-specific inhibitor deprenyl we were able to confirm that the MAOA form of the enzyme is involved in DA metabolism in this preparation.

The effects that finite resolution and choice of apodisation function have on Fourier transform (FT) Raman spectra are illustrated by the 839 cm-1 ((nu) 1) and 914 cm-1 ((nu) 3) bands of KMnO4. FT-Raman spectra were recorded at 0.5, 2, 4, 8, and 16 cm-1 resolution using boxcar, Norton-Beer (medium) and triangular apodisation functions at each resolution. The results show that the dramatic changes in bandshape that occur as the ratio (resolution/true full width at half height of band) increases is strongly dependent on the choice of the apodisation function.

The development of a range of subcomponents and a common integration technology for preparing InP based OEICs for subscriber access systems is described. The development of suitable packaging techniques for incorporating these devices in transceiver modules is also discussed. OEICs are seen as an advantageous route for achieving the type of high functionality devices that are required in these systems, offering the potential of low cost and high reliability. Device functionalities include lasers, waveguides, broad and narrow band WDM, power monitoring, and signal detection. To this end, we have prepared OEICs incorporating DFB and DBR lasers, waveguides, process tolerant couplers, wavelength duplexers, add-drop narrow band WDM components, optical filters, and monitor diodes. Laser-waveguide integration is achieved by a butt coupled approach using low pressure MOVPE. The process is designed to be high yielding and is suitable for high volume OEIC fabrication in future manufacture. OEICs so far developed include those incorporating lasers with wavelength duplexers for 1300/1530 nm bidirectional links, lasers with wavelength duplexers and an additional coupler for bidirectional telephony (1300 nm) and broadband (1530 nm) services, and lasers with narrow band WDM components providing add-drop optical multiplexing facilities.

Raman spectroscopic studies have been carried out on a rhenium/alumina catalyst, active in metathesis reactions. Raman data comparing the state of the rhenium on the fresh catlyst (freshly activated and following air exposure), and on catalyst promoted with tetramethyltin are presented.The ammonium perrhenate impregnated alumina catalyst precursor contains a tetrahedral oxidic rhenium species in a hydrated state. When the precursor is activated, a reduction in the number of attached hydroxyl groups and a distortion of the tetrahedral rhenium moiety occurs. The extent of hydration of the rhenium phase is therefore an important parameter determining metathesis activity. There is no evidence for the presence of a surface rhenium heptoxide phase.An extra Raman band at 777 cm–1, observed following tetramethyltin promotion, is attributed to a Re–Sn vibration. This Re–Sn interaction may be responsible for the observed promotional effect.

During the first year of the program, basic materials growth experiments were carried out in order to develop the necessary capability of the growth of quantum well lasers by Atmospheric Pressure MOVPE (AP-MOVPE). In the latter part of the program, this technology was transferred to a Low Pressure MOVPE (LP-MOVPE) reactor which demonstrated superior materials and interface qualities with respect to structures prepared by AP-MOVPE. By correlating SIMS data and Hall analysis, conditions were determined for the growth of high quality and abrupt p-doped and n-doped InP of known carrier concentration. In this way p-doped InP over the range mid 10 to the 17th power /cc to 2 x 10 to the 18th power/cc could be grown, with carrier concentrations extended up to 10 to the 19th power/cc for p++ InGaAs contact layers. Quantum well laser structures were grown and tested. Keywords: Quantum well, Indium phosphide heterostructures.