Cotinine in the serum, saliva, and urine of nonsmokers, passive smokers, and active smokers.

Cotinine was measured in the serum, saliva, and urine of nonsmokers, passive smokers, and active smokers. Serum and saliva could not discriminate between nonsmokers and passive smokers. Mean urine cotinine was higher in passive smokers than nonsmokers but there was a great deal of intersubject overlap. Cotinine in all body fluids could separate active smokers from the other two groups. Among smokers, light smokers had lower levels than heavier smokers.     

A phase I clinical and pharmacokinetic study of the topoisomerase I inhibitor topotecan (SK&F 104864) given as an intravenous bolus every 21 days.

Topotecan (SK&F 104864) is a novel antitumor agent whose mechanism of action is inhibition of the DNA unwinding protein topoisomerase I. An analog of camptothecin, topotecan was designed to be more water soluble in an effort to decrease the severe and sporadic toxicities experienced during phase I/II trials of the parent compound. In this phase I clinical and pharmacological trial, topotecan was given as a bolus intravenous (i.v.) infusion over 30 min every 21 days. A total of 42 patients entered the study, receiving doses ranging from 2.5 to 22.5 mg/m2. The maximum tolerated dose (MTD) of topotecan given in this schedule was 22.5 mg/m2. Myelosuppression, primarily neutropenia, was dose-limiting. The extent of prior therapy did not predict for more severe neutropenia. Non-hematologic toxicities were mild and included low-grade to moderate fever, nausea, vomiting, alopecia, diarrhea and skin rashes. There were no objective partial or complete responses, although there was a suggestion of antitumor activity in three patients. Topotecan undergoes pH-dependent hydrolysis of the lactone ring; only the closed, lactone form is active. The lactone form predominated during infusion, with hydrolysis occurring rapidly following the end of infusion. There were linear relationships between dose administered and peak plasma lactone concentrations as well as AUC lactone to AUC total. The lactone was rapidly cleared from plasma with a total body clearance of 25.7 (+/- 6.7) l/h/m2. The plasma lactone concentration declined rapidly with a harmonic mean terminal half-life of 3.4 (+/- 1.1)h. Lactone hydrolysis and renal excretion were the major routes of elimination.(ABSTRACT TRUNCATED AT 250 WORDS)     

The Butajira rural health project in Ethiopia: mortality pattern of the under fives.

A total of 492 deaths of children below 5 years of age were registered during a 2-year period of demographic surveillance in a rural population of Ethiopia, where an epidemiologic study base population of 28,780 individuals was established in 1987. Data were collected by lay-reporters using a verbal autopsy method. The under-five cumulative mortality rate was 209 per 1000 children. When sub-divided into infants and children 1-4 years, the respective yearly mortality rates were 101 and 32.3 per 1000. There were considerable variations within the district by Peasants' Associations. Rural Lowlands experienced the highest mortality rates, especially for children 1-4 years. Mortality trends over a 2-year period indicate a significant increase for the child population, but not for infants. Similar trends were observed for boys and girls although the rates for boys were generally higher especially during infancy. More deaths occurred in the months of April, June, and July, and October and November indicating two peak seasons in both years. More deaths occurred in Peasant's Associations that were furthest from the health centre. Major probable causes of death were acute respiratory infections, measles, and diarrhoea. It is concluded that even in rural areas of a developing country it is possible to collect from mothers the much needed and valid fertility and mortality data through epidemiological surveillance by using lay-reporters.     

Cardiac metabolism: A technical spectrum of modalities including positron emission tomography,single-photon emission computed tomography,and magnetic resonance spectroscopy

Noninvasive techniques for the assessment of cardiac metabolism are important for the detection of potentially salvageable tissue in jeopardized areas of the myocardium. The correct identification of hibernating and stunned myocardium in patients with severely depressed cardiac function can have vital therapeutic consequences for the patient. Changes in myocardial fatty acid and glucose metabolism during acute and prolonged ischemia can be traced by positron-emitting or gamma-emitting radiopharmaceuticals. Alternatively,³¹P-labeled magnetic resonance spectroscopy can be used for the assessment of high-energy phosphate metabolism. It is not yet clear which modality will emerge as the most useful in the clinical setting. Positron emission tomography (PET) that uses combinations of flow tracers and metabolic tracers offers unique opportunities for quantification and high-resolution static and rapid dynamic studies. Currently, assessment of glucose metabolism with¹⁸F-fluorodeoxyglucose is regarded as the gold standard for myocardial viability and prediction of improvement of impaired contractile function after revascularization. However, preserved oxidative metabolism may be required for potential functional improvement, and therefore assessment of residual oxidative metabolism by¹¹C-labeled acetate PET may prove to be more accurate than¹⁸F-fluorodeoxyglucose PET, which reflects both anaerobic and oxidative metabolism. Moreover, because fatty acids are metabolized only aerobically, they are excellent candidates for the clinical assessment of myocardial viability and prediction of functional improvement after revascularization. Especially derivatives of fatty acids that are not metabolized but accumulate in the myocyte are attractive for myocardial imaging. Examples are¹²³I-beta-methyl-p-iodophenyl pentadecanoic acid and 15-(o-¹²³I-phenyl)-pentadecanoic acid. These tracers can be detected by planar scintigraphy and single-photon emission computed tomography, which are more economical and widely available than PET. In addition, 511 keV collimators have been developed recently, making the detection of positron emitters by planar scintigraphy and single-photon emission computed tomography feasible. The experience with³¹P-labeled magnetic resonance spectroscopy in humans is still limited. With current magnetic resonance spectroscopic techniques, insufficient spatial resolution is achieved for clinical purposes, but the possibility of serial measurements to monitor rapid changes of phosphate-containing molecules in time makes magnetic resonance spectroscopy very valuable for the research of myocardial metabolism.     

In vitro evaluation of ablation parameters of normal and fibrous aorta using smooth excimer laser coronary angioplasty

A modified exeimer laser energy delivery system was used to irradiate 100 segments of normal and fibrous aorta in vitro. The laser beam was scanned into 8 fiber bundles consisting of 50 fibers each resulting in a reduction of the applied pulse energy. The total repetition rate was increased to 150 Hz in order to keep the repetition rate per fiber bundle close to 20 Hz and to minimize thermal injury. The results demonstrate that effective ablation (etch rate per 8 pulses > 2.0 μm) occurred at an energy fluency of 50 mJ/mm² in both normal and fibrous aorta. Tissue damage (carbonization, tissue separation, fissures, cracks, and vacuolization) was in a range of 100 ± 28 to 152 ± 30 μm for normal aorta and in a range of 57 ± 35 to 110 ± 39 μm for fibrous aorta. We conclude that effective ablation of normal and fibrous human aorta can be achieved by the application of smooth excimer laser coronary angioplasty. This improvement of excimer laser technology may result in a reduction of shock wave- and cavitation-induced damage leading to a reduction of tissue injury. However, this awaits further in vitro and in vivo confirmation. © 1993 Wiley-Liss, Inc.     

PET examination of [11C]NNC 687 and [11C]NNC 756 as new radioligands for the D1-dopamine receptor

The benzazepines NNC 687 and NNC 756 have in animal studies been described as selective D₁-dopamine receptor antagonists. Both compounds have been labeled with¹¹C for examination by positron emission tomography (PET). In the present study central receptor binding was studied in monkeys and healthy men. After IV injection of both radioligands in Cynomolgus monkeys radioactivity accumulated markedly in the striatum, a region with a high density of D₁-dopamine receptors. This striatal uptake was displaced by high doses of the selective D₁-antagonist SCH 23390 (2 mg/kg) but not by the 5HT₂-antagonist ketanserin (1.5 mg/kg) or the selective D₂-antagonist raclopride (3 mg/kg). The cortical uptake after injection of [¹¹C]NNC 687 was not reduced in displacement experiments with ketanserin. The cortical uptake of [¹¹C]NNC 756 was reduced in displacement and protection experiments with ketanserin by 24–28% (1.5 mg/kg), whereas no reduction could be demonstrated on striatal uptake. In healthy males both compounds accumulated markedly in the striatum. For [¹¹C]NNC 687 the ratio of radioactivity in the putamen to cerebellum was about 1.5. For [¹¹C]NNC 756 the ratio was about 5. This ratio of 5 for [¹¹C]NNC 756 is the highest obtained so far for PET radioligands for the D₁-dopamine receptor.     

Immature corn as a source of niacin for rats

The variability in the concentration and biological availability of niacin in corn was investigated. Plots of both sweet and field corn were harvested at different stages. In rat growth assays for available niacin, grains harvested at the immature, "milky" stage and then dried gave values of 88 and 74 micrograms/g, respectively. These values were in contrast to the low growth assay values of 18 and 16 micrograms/g for grain harvested at maturity, and even higher than the value of approximately 56 micrograms/g obtained for each immature corn in both the Association of Official Analytical Chemists procedure of chemical analysis and a standard microbiological procedure. However, when the milky grains were precooked at neutral pH, the values from these procedures were higher and agreed with the biological assay results. It is suggested that, during the initial alkaline digestion used for these two procedures, a proportion of the niacin in NAD, the major form of niacin in milky corn, degrades. However, when the materials are first cooked at neutral pH, nicotinamide is released without loss, and the pyridine ring is then stable. The traditional American Indian practice of roasting and drying "green corn" apparently provided a valuable source of niacin.     

Quantitative thallium-201 scintigraphy after dipyridamole infusion combined with low level exercise in healthy volunteers

To establish test specific normal limits for quantitative analysis of uptake and washout of ²⁰¹Tl after dipyridamole infusion combined with low level exercise, 20 healthy volunteers were studied with low likelihood of coronary artery disease (CAD) assessed by a stepwise probability analysis based on age, sex, symptoms, resting electrocardiogram, and exercise electrocardiography. Likelihood of CAD in these volunteers was calculated as 1%. After dipyridamole infusion combined with low level exercise, one volunteer complained of headache; no other side effects were observed. There were no chest pain complaints. Maximal hemodynamic changes were achieved during the 6th and 7th min of the test. No ST segment depression was recorded. Visual analysis of the ²⁰¹Tl scintigrams was normal in all volunteers. Mean regional washout at 4 h was 44.37%±2.11%. The regional washout in the 70° LAO view (46.65%±1.10%) was significantly higher than in the anterior and 30° LAO views (43.44%±1.50% and 43.02%±1.45%, respectively). Profiles of uptake and washout of ²⁰¹Tl were different after dipyridamole infusion combined with low level exercise as compared to maximal exercise. Thus, in quantitative analysis of ²⁰¹Tl scintigraphy after dipyridamole infusion in conjunction with low level exercise as applied in the present study, it is mandatory to use normal limits of uptake and washout of ²⁰¹Tl derived from healthy volunteers who underwent the same combined protocol.     

Characterization of Anticapsular Monoclonal Antibodies That Regulate Activation of the Complement System by the Cryptococcus neoformans Capsule

Incubation of the encapsulated yeast Cryptococcus neoformans in human serum leads to alternative pathway-mediated deposition of C3 fragments in the capsule. We examined the ability of monoclonal antibodies (MAbs) specific for different epitopes of the major capsular polysaccharide to alter the kinetics for classical and alternative pathway-mediated deposition of C3 onto a serotype A strain. We studied MAbs reactive with capsular serotypes A, B, C, and D (MAb group II); serotypes A, B, and D (MAb group III); and serotypes A and D (MAb group IV). The MAb groupings are based on antibody variable region usage which determines the antibody molecular structure. When both the classical and alternative pathways were operative, group II MAbs induced early classical pathway-mediated binding of C3 but reduced the overall rate of C3 accumulation and the amount of bound C3. Group III MAbs closely mimicked the effects of group II MAbs but exhibited reduced support of early classical pathway-facilitated accumulation of C3. Depending on the antibody isotype, group IV MAbs slightly or markedly enhanced early binding of C3 but had no effect on either the rate of C3 accumulation or the amount of bound C3. When the classical pathway was blocked, group II and III MAbs markedly suppressed C3 binding that normally would have occurred via the alternative pathway. In contrast, MAbs of group IV had no effect on alternative pathway-mediated C3 binding. These results indicate that anticapsular antibodies with different epitope specificities may have distinct regulatory effects on activation and binding of C3.Cryptococcus neoformans is the etiological agent of cryptococcal meningitis, a life-threatening infection of particular importance in patients with deficiencies in cellular immunity, most notably patients with the AIDS. The yeast is surrounded by a polysaccharide capsule that is composed primarily of glucuronoxylomannan (GXM), which has a linear (1→3)-α-d-mannopyranan backbone bearing β-d-xylopyranosyl, β-d-glucopyranosyluronic acid, and O-acetyl substituents (3, 9, 54). The cryptococcal capsule occurs as four major serotypes (A, B, C, and D) and is an essential virulence factor for the yeast.One of the most striking features of the cryptococcal capsule is its ability to activate the alternative complement pathway. Incubation of encapsulated cryptococci in normal human serum (NHS) leads to the deposition of 10⁷ to 10⁸ C3 fragments on the yeast (28, 56). The C3 is deposited at the surface and throughout the capsule (30). Available evidence indicates that the amount of anti-GXM antibodies found in NHS is not sufficient to initiate the classical pathway (24); consequently, activation and binding of C3 to the cryptococcal capsule are mediated entirely by the alternative complement pathway (29, 30, 55). One of the hallmark features of alternative pathway deposition of C3 onto encapsulated cryptococci is a delay of 5 to 8 min before readily detectable amounts of C3 are found on yeast cells incubated in NHS (29, 55). Once past the initial lag, C3 fragments rapidly accumulate on the yeast cells as incubation proceeds for an additional 10 min.Recently, there has been interest in antibody-mediated resistance to cryptococcosis. Monoclonal antibodies (MAbs) have been proposed for treatment of cryptococcosis (7), and immunization with GXM-protein conjugates has been suggested for prevention of cryptococcosis (6, 12, 13). However, it is becoming increasingly clear that anti-GXM MAbs may have distinct specificities and biological activities. Anti-GXM MAbs which differ in (i) reactivities with GXM of the four major serotypes (2), (ii) apparent binding sites in the cryptococcal capsule (32, 37), and (iii) abilities to provide protection in a murine model of cryptococcosis (32, 37) have been described. Some differences in biological activity are related to differences in the epitope specificities of the various MAbs (32, 37).One means by which antibodies could enhance resistance to cryptococcosis is through accelerated deposition of opsonic C3 fragments via the action of the classical pathway. Such an acceleration would reduce or eliminate the 5- to 8-min lag that occurs during alternative pathway-mediated deposition of C3 fragments. The objectives of our study were to evaluate the effects of anti-GXM MAbs on the kinetics and sites for deposition of C3 fragments into the cryptococcal capsule. We examined several well-characterized antibodies that differed in the epitope specificity of the MAbs. The results showed that MAbs with different isotypes and epitope specificities had distinctly different effects on activation and binding of C3 via the classical and alternative pathways; many antibodies markedly suppressed C3 binding, some antibodies accelerated C3 binding, and other antibodies had little or no effect.