Relationship of objective street quality attributes with youth physical activity: findings from the Healthy Communities Study.

BACKGROUND: Residential environments may significantly influence youth physical activity (PA). However, few studies have examined detailed street quality attributes via observational audits in relation to context-specific PA among youth. OBJECTIVES: The objective of this study was to explore whether the overall quality of street environments, as well as specific attributes, was associated with neighbourhood-based and street-based PA within a national sample of youth in the Healthy Communities Study. METHODS: Data were collected from 4616 youth from 130 communities across the USA. Youth PA in the neighbourhood and on the participant's street was captured using 7-d recall interviews. Windshield survey observational audits documented five street quality variables: burned, boarded up or abandoned residential units, litter, overall condition of residences, street type and presence of sidewalks in good condition. RESULTS: Youth with no litter on their street reported significantly lower neighbourhood-based PA and youth living on a side street, cul-de-sac, dead-end or one-way street reported greater neighbourhood-based PA. No significant associations were detected for the overall street quality index or with street-based PA. CONCLUSIONS: Specific street quality attributes may be associated with youth PA. Further research and collaboration between diverse disciplines and agencies should focus on understanding and improving street quality to promote youth PA and health.

Further characterization of an adenosine-containing modification of vaccinia virus proteins.

Three vaccinia virus (VV) core proteins which become labeled when virus is grown in the presence of radiolabeled adenosine or orthophosphate were identified as the major viral core proteins 4A, 4B, and 25K on the basis of comigration with [35S]methionine-labeled viral proteins and immunoprecipitation with monospecific polyclonal antisera. Boronate affinity chromatography and HPLC analysis suggested that a cis-diol-containing adenosine compound is present on this set of viral proteins. The replication of VV in tissue culture cells was prevented by the ADP-ribosylation inhibitors nicotinamide (NIC), 3-aminobenzamide (3-AB), and meta-iodobenzylguanidine (MIBG). None of these compounds significantly affected viral DNA synthesis at lower drug concentrations, although at higher concentrations of the three drugs a reduction in viral DNA synthesis was evident. Total VV protein synthesis also decreased at higher inhibitor levels, and the proteolytic processing of the major virion core proteins was greatly diminished as well. The three inhibitors also affected labeling of viral core proteins and cellular histone proteins by [8-14C]adenosine. In addition, mature, infectious virus particles were not formed in the presence of either 60 mM NIC or 3-AB, or 0.6 mM MIBG. These results provide evidence that the major VV core proteins are subject to modification by an adenosine compound, and suggest the possibility that this modification might represent ADP-ribosylation.

Cell type-dependent and -independent control of HER-2/neu translation.

Overexpression of the HER-2 oncogene occurs in a variety of human tumors, including 25-30% of breast carcinomas, and has been associated with an adverse prognosis. Amplification of the HER-2 gene is frequently detected in tumors, but by itself may not fully account for HER-2 overexpression since transcriptional and post-transcriptional mechanisms also regulate HER-2 protein synthesis. Our studies reveal that the efficiency of HER-2 translation differs between primary and transformed cells. In primary human fibroblasts and human mammary epithelial cells, the HER-2 mRNA is associated with monosome and small polysome fractions. In contrast, in BT474 and MCF-7 human breast cancer cell lines and in COS-7 cells the mRNA co-sedimented with larger polysomes, indicating that it is more efficiently translated in these transformed cells. Northern analysis revealed no detectable mRNA size difference, and nuclease S1 protection and sequence analyses showed no differences between the HER-2 transcript leader in primary cells compared to transformed human cells. The transcript leader in all cell types contains a short upstream open reading frame that is also conserved in other mammalian species. Transient transfection assays revealed that the HER-2 transcript leader repressed downstream translation approximately five-fold in both primary and transformed cells and mutation of the upstream initiation codon alleviated most of the inhibitory effect. These results indicate that HER2 expression is translationally controlled both by a short upstream open reading frame that represses HER-2 translation in a cell type-independent manner, and by a distinct cell type-dependent mechanism that increases translational efficiency of HER-2 in transformed cells.

Canadian multicenter azidothymidine trial: AZT pharmacokinetics.

The study objective was to describe the pharmacokinetics of azidothymidine (AZT) in a large population of early, asymptomatic human immunodeficiency virus (HIV)-infected individuals. The study design was a multicenter, prospective, descriptive single-dose pharmacokinetic study. Each of 66 fasting, male, HIV-infected homosexuals older than 18 years of age and in CDC classifications II, III, and IVC2 received a single 400-mg oral dose of AZT with subsequent pharmacokinetic measurements performed during an 8-h period for AZT and its major metabolite, glucuronylazidothymidine (GAZT). Results were obtained in 65 patients (36 smokers, 29 nonsmokers), of whom 3 were noted to have hepatic dysfunction. In those with normal hepatic function, the following parameters were described: AZT, area under the curve (AUC) +/- SD, 9.9 +/- 5.7 microM.h, maximum concentration (Cmax) +/- SD, 7.3 +/- 4.7 microM; time to maximum concentration (Tmax) +/- SD, 0.93 +/- 0.42 h, and half-life (t1/2) +/- SD, 1.0 +/- 0.8 h. Corresponding values for GAZT were: AUC +/- SD 35.7 +/- 10.3 microM.h, Cmax +/- SD 21.3 +/- 7.3 microM, Tmax +/- SD 1.2 +/- 0.50 h, t1/2 +/- SD 0.98 +/- 0.62 h, No significant differences were found in comparisons of study site, CDC classification of disease, smokers versus nonsmokers, and in patients with hepatic dysfunction, although a higher AUC and earlier Cmax for AZT was noted in the latter group. It is concluded that AZT pharmacokinetics are similar in patients with early asymptomatic HIV disease when compared with previous reports in patients with later disease.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparison of morning versus evening dosing with a new once-daily oral theophylline formulation.

A double-blind, cross-over comparison of morning (8 A.M.) versus evening (10 P.M.) dosing regimens with a new once-daily oral theophylline (Uniphyl, Purdue Frederick) was performed. The comparison was based upon steady-state theophylline pharmacokinetics, spirometric measurements over 24 hours, the patients' quantitative reporting of asthmatic symptoms, and medication side effects. No statistically significant differences were observed in any theophylline parameter between the dosing regimens. Evening dosing, but not morning dosing, resulted in a significant attenuation of the early morning dip in pulmonary function. The morning severity of wheezing, chest tightness, and shortness of breath was significantly reduced after evening dosing. Overall no difference in the incidence of symptoms was noted. No significant differences in side effects were noted. Evening dosing with Uniphyl produced a significant improvement in morning pulmonary function, and this benefit was subjectively noted by the patients. No decline in this benefit was noted later in the day. Evening dosing with Uniphyl clearly is superior to morning dosing.

Inhibition of vaccinia virus replication by nicotinamide: evidence for ADP-ribosylation of viral proteins.

Replication of vaccinia virus (VV) in monolayers of BSC40 cells was inhibited 99.9% in the presence of 60 mM nicotinamide (NIC), a competitive inhibitor of ADP-ribosylation reactions. Dot-blot hybridization analysis of infected cell extracts utilizing a VV DNA-specific probe indicated that the drug had only minimal effects on viral DNA synthesis. SDS-polyacrylamide gel electrophoresis of newly synthesized VV proteins pulse-labeled at early (2 h) or late (8 h) times post-infection revealed that although the full spectrum of expected viral polypeptides was evident, quantitative differences in the levels of expression of a distinct subset of viral proteins were observed in the presence of the drug. Velocity sedimentation of virus-infected cell lysates established that no mature particles were assembled in drug treated cells. Additional evidence suggesting that VV morphogenesis was abortive in the presence of NIC was obtained by pulse-chase labeling experiments that demonstrated that the two VV major late core polypeptide precursors P94 and P65, whose proteolytic processing to VP62 and VP60 is intimately associated with viral assembly, were not cleaved in the presence of NIC. Interestingly, growth of VV in the presence of [3H]adenosine resulted in the metabolic labeling of eight proteins that were associated with purified virions. These proteins co-migrated with proteins labeled with [3H]adenosine that were present in extracts of VV-infected, but not uninfected, cells. These analyses also revealed that the [3H]adenosine-labeling of a subset of cellular proteins (MW 18-20 kDa, possibly histones) was increased 4-fold by VV infection. The observed induction of either increased synthesis or hyper-modification of these 18-20 kDa proteins was inhibited by NIC. These results are discussed with respect to whether one or more VV polypeptides are subject to obligatory ADP-ribosylation modification reactions in order to attain their active configuration, and if so, whether the enzymes catalyzing these reactions are specified by the virus or host cell.

Feasibility of recanalization of human coronary arteries using high-intensity ultrasound.

To investigate the feasibility of ultrasonic recanalization of obstructed human coronary arteries in vitro, high-intensity ultrasound was applied to 16 coronary arteries obtained at autopsy, using a prototype instrument enabling insonification through a catheter tip. It was a 119 cm long, 0.95 mm thick wire in an 8Fr catheter connected to an external ultrasonic transformer and power generator. A 5 MHz phased-array 2-dimensional echocardiography instrument was used to determine minimal luminal diameter and percent diameter narrowing before and after ultrasound application. The ultrasonic energy was delivered at 21.5 kHz and with a 52 +/- 19 micrometer average amplitude of tip displacement. The mean percent luminal diameter narrowing, flow rate and mean pressure gradient before ultrasound exposure were 74 +/- 11%, 97 +/- 61 ml/min, and 92 +/- 18 mm Hg, respectively. After recanalization, the mean percent luminal diameter narrowing decreased to 45 +/- 17% (p < 0.001), the mean flow rate increased to 84 +/- 92 ml/min (p < 0.001), and the mean pressure gradient was reduced to 45 +/- 24 mm Hg (p < 0.001). Of the debris particles, 95% had a diameter < 9 microns (range 5 to 12). Arterial perforation occurred in 5 of 16 arteries (31%) and all 5 occurred due to stiff wire manipulation and without ultrasound application. Mechanical fracture of the wire occurred in 8 cases (50%). No signs of thermal injury were found on histology. Thus, ultrasonic recanalization of human coronary arteries in vitro is feasible. It may reduce obstruction and improve blood flow. Debris sizes are sufficiently small to minimize the hazard of peripheral embolization.

The effects of hyperthermia and ionizing radiation in normal and ataxia telangiectasia human fibroblast lines.

The effects of 45 degrees C hyperthermia and gamma radiation have been studied in three normal human fibroblast lines (GM38, GM730, WI38) and compared to the effects in two lines derived from patients with the hereditary disease ataxia telangiectasia (AT3BI, AT5BI). All lines, both normal and gamma-sensitive AT, showed a similar resistance to killing by heat alone, suggesting that the defect responsible for the increased radiation sensitivity in AT lines does not confer increased heat sensitivity. Shouldered survival curves were obtained in each case indicating the ability to accumulate sublethal heat damage. All normal and AT cell lines exhibited increased resistance to the lethal effects of heat in response to a thermal stress, indicating that the defect that causes radiosensitivity in AT cell lines does not prevent the induction of thermotolerance. Heat (45 degrees C, 30 min) was shown to increase the sensitivity of the normal cell lines to killing by gamma radiation. The thermal enhancement ratios obtained ranged from about 2.5 to 3.0. The same heat treatment, however, produced very little increase in the radiation sensitivity of the AT cells. Thermal enhancement ratios of about 1.2 were obtained in these lines. We hypothesize that, in normal cells, this heat treatment inactivates the process which is already defective in AT lines, and that this process may be required for the proper rejoining of double-strand breaks produced during the repair of other radiation-induced lesions.

Sensitivity of hyperthermia-treated human cells to killing by ultraviolet or gamma radiation.

Human xeroderma pigmentosum (XP) or Fanconi anemia (FA) fibroblasts displayed shouldered 45 degrees C heat survival curves not significantly different from normal fibroblasts, a result similar to that previously found for ataxia telangiectasia (AT) cells, indicating heat resistance is not linked to either uv or low-LET ionizing radiation resistance. Hyperthermia (45 degrees C) sensitized normal and XP fibroblasts to killing by gamma radiation but failed to sensitize the cells to the lethal effects of 254 nm uv radiation. Thermal inhibition of repair of ionizing radiation lesions but not uv-induced lesions appears to contribute synergistically to cell death. The thermal enhancement ratio (TER) for the synergistic interaction of hyperthermia (45 degrees C, 30 min) and gamma radiation was significantly lower in one FA and two strains (TER = 1.7-1.8) than that reported previously for three normal strains (TER = 2.5-3.0). These XP and FA strains may be more gamma sensitive than normal human fibroblasts. Since hyperthermia treatment only slightly increases the gamma-radiation sensitivity of ataxia telangiectasia (AT) fibroblasts compared to normal strains, it is possible that the degree of thermal enhancement attainable reflects the genetically inherent ionizing radiation repair capacity of the cells. The data indicate that both repair inhibition and particular lesion types are required for lethal synergism between heat and radiation. We therefore postulate that the transient thermal inhibition of repair results in the conversion of gamma-induced lesions to irrepairable lethal damage, while uv-type damage can remain unaltered during this period.

A test for increased lethality in land snails exposed to 60 Hz magnetic fields.

A recent report suggested that exposures of land snails to 0.1 mT, 60 Hz magnetic fields for periods of 48-120 h increase mortality levels by 2-10 times. In direct experimental tests, we were unable to confirm this effect.

Urea kinetics varies in Jamaican women and men in relation to adiposity, lean body mass and protein intake.

OBJECTIVE: We have measured urea kinetics in normal adult men and women of different body composition to determine whether adiposity is associated with differences in the rate of urea production or endogenous urea hydrolysis. DESIGN: Urea kinetics were determined from the excretion of [15N15N]urea in urine over a period of 48 h following a single oral dose of [15N15N]urea, in nine lean and nine obese women and in seven light and seven heavy males while they were consuming their habitual diets. Urinary 5-L-oxoproline was measured as an index of glycine metabolic status. SETTING: The studies were carried out in the research ward of the Tropical Metabolism Research Unit, University of the West Indies. RESULTS: Successful studies were completed in eight obese and five lean women and in six heavy and five light men. When compared with lean women, in obese women the rate of urea production and hydrolysis was significantly greater and this difference could not be accounted for by the greater fat-free mass alone, and was in part associated directly with the increase in fat mass. The rate of urea production and hydrolysis was greater in heavy men than in light men, a difference which was attributed to an increase in dietary protein. In obese women and heavy men there was a significantly higher rate of excretion of 5-L-oxoproline in urine when compared with lean women and lean men respectively. CONCLUSION: This paper highlights the difficulty in identifying an appropriate reference with which to express results in people of different body composition. In obese women urea production and the hydrolysis of urea are increased, in part related to the increased fat-free mass, but also related to the increased fat mass itself. In obese women and men on high protein diets the greater rate of hydrolysis urea may be a reflection of an increased demand for the synthesis of non-essential amino acids, especially glycine.

Effects of ultrasound on Drosophila--IV. Pulsed exposures of eggs.

Drosophila larvae are damaged by exposures to low temporal average intensity pulsed ultrasound with peak intensities of 10-20W/cm2 (2 MHz). Eggs of the same organism are affected by exposures to 3W/cm2 c.w. ultrasound. This experiment shows that eggs become sensitive to high peak intensity (50-100 W/cm2) pulsed ultrasound only shortly before hatching. At this age the larvae have formed and have taken air into the respiratory system. This observation supports the postulate that the sites of action of the ultrasound are the small stabilized gas bodies within the organisms.

Effects of pulsed ultrasound on the frog heart: III. The radiation force mechanism.

Earlier studies have shown that a single, millisecond duration pulse of ultrasound delivered to the frog heart in vivo during systole can produce a reduction in the developed aortic pressure, while a pulse delivered during diastole can produce a premature ventricular contraction. The threshold for these effects is 5-10 MPa with a 5-ms pulse. Since cardiac tissues respond to mechanical stimulation, the objective of this study was to investigate acoustic radiation force as a possible mechanism for the observed effects of ultrasound on the frog heart. In two experiments, the radiation force exerted on the heart was varied by varying the ultrasonic frequency and the acoustic beam width. Results of these studies indicated that the rate of occurrence of the reduced aortic pressure effect was directly correlated with the magnitude of the radiation force exerted on the heart. A third experiment tested the radiation force mechanism directly by placing an acoustic reflector on the frog heart. The acoustic reflector maximized the radiation force delivered to the heart, but eliminated direct interaction of the ultrasound with the heart and experimentally eliminated heating and cavitation as mechanisms of action. The reduced aortic pressure effect was observed with the reflector on the heart, indicating that radiation force is capable of producing this effect. No premature ventricular contractions were observed with the acoustic reflector over the heart, suggesting that another property of the exposure may be responsible for this bioeffect.

Thresholds for premature contractions in murine hearts exposed to pulsed ultrasound.

A single pulse of high intensity ultrasound can produce either a premature ventricular contraction or a reduction in the aortic pressure in frog hearts. The objective of this study was to determine whether similar ultrasound exposures can produce premature contractions in the mammalian heart. The cardiac activity of murine hearts in vivo was monitored noninvasively using electrocardiography and plethysmography. Each ultrasound exposure was a single pulse of ultrasound, several milliseconds in duration, delivered to the murine heart during diastole. The thresholds for producing a premature contraction with a 5-ms ultrasound pulse at 1.2 MHz was approximately 2 MPa peak positive pressure. The occurrence of premature contractions decreased as the duration of the ultrasound pulse decreased. These results found with the mammalian heart are similar to those reported earlier for the frog heart. No damage to cardiac tissue was observed grossly, although significant hemorrhage occurred to adjacent lung tissue.

The sensitivity of Drosophila larvae to continuous-wave ultrasound.

The threshold for killing of freshly hatched Drosophila larvae exposed to continuous-wave (CW) ultrasound shows a minimum at approximately 0.3 MHz. This suggests that the stiffness of the material surrounding the gas bodies in the organism is comparable to water. From this, it is apparent that the gas bodies in three-day-old larvae that we have used in earlier studies are far larger than resonance size at the frequencies (1-5 MHz) used. Yet, these larvae were killed by short exposures to low-temporal-average-intensity pulsed ultrasound with peak intensities of the order of 10 W/cm2. Hence, it appears that "large" bubbles cannot be ignored in considerations of the biological effects of pulsed ultrasound and lithotripsy.

Timing of exposures in ultrasonic hemorrhage of murine lung.

Pressure thresholds for lung hemorrhage by exposure to low-temporal-average-intensity, pulsed ultrasound are of the order of 1 MPa. Earlier evidence suggested that ultrasound modifies the tissue over short periods of time in such a way that the nonthermal action of ultrasound is enhanced. Measurements of thresholds (1) for hemorrhage and (2) for penetration of the hemorrhage through the murine lung in which a given "on-time" was presented to the tissue over periods of time up to 3 min support the hypothesis.

Hemorrhage in murine fetuses exposed to pulsed ultrasound.

In the late-gestation fetal mouse, exposure to piezoelectric lithotripter fields at amplitudes < 1 MPa produced hemorrhages in tissues near developing bone, such as the head and limbs. This study was undertaken to determine if exposure to pulsed ultrasound at diagnostic frequencies produces similar hemorrhages in the late-gestation fetal mouse. On the 18th day of gestation, fetal mice were exposed in utero to pulsed ultrasound with a 10-micros pulse duration and 100-Hz pulse repetition frequency for a total exposure duration of 3 min. Hemorrhages occurred most often to the developing fetal head. At 1.2 MHz, a threshold for hemorrhage to the fetal head was determined at positive exposure pressures of approximately 4 MPa and corresponding negative pressures of approximately 2.5 MPa. The threshold increased with at least the first power of frequency.