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Biomedical subjects

N B Smith

Publications and source records attributed to N B Smith.

At least 19 recordsLinked to original sources
PubMed2001

Metabolism of DHEA by cytochromes P450 in rat and human liver microsomal fractions.

Administration of dehydroepiandrosterone (DHEA) to rodents produces many unique biological responses, some of which may be due to metabolism of DHEA to more biologically active products. In the current study, DHEA metabolism was studied using human and rat liver microsomal fractions. In both species, DHEA was extensively metabolized to multiple products; formation of these products was potently inhibited in both species by miconazole, demonstrating a principal role for cytochrome P450. In the rat, use of P450 form-selective inhibitors suggested the participation of P4501A and 3A forms in DHEA metabolism. Human liver samples displayed interindividual differences in that one of five subjects metabolized DHEA to a much greater extent than the others. This difference correlated with the level of P4503A activity present in the human liver samples. For one subject, troleandomycin inhibited hepatic microsomal metabolism of DHEA by 78%, compared to 81% inhibition by miconazole, suggesting the importance of P4503A in these reactions. Form-selective inhibitors of P4502D6 and P4502E1 had a modest inhibitory effect, suggesting that these forms may also contribute to metabolism of DHEA in humans. Metabolites identified by LC-MS in both species included 16alpha-hydroxy-DHEA, 7alpha-hydroxy-DHEA, and 7-oxo-DHEA. While 16alpha-hydroxy-DHEA appeared to be the major metabolite produced in rat, the major metabolite produced in humans was a mono-hydroxylated DHEA species, whose position of hydroxylation is unknown.

Adult↗
PubMed2000

Docosahexaenoic acid reverses cyclosporin A-induced changes in membrane structure and function.

The use of a fish oil vehicle for cyclosporin A (CsA) can decrease the toxic effects of CsA but the mechanism is unclear. Here we examine the mechanism by which docosahexaenoic acid (DHA), a fish oil-derived polyunsaturated fatty acid, can alter the toxic effects of CsA on mouse organ function, endothelial macromolecular permeability, and membrane bilayer function. Mice given CsA and fish oil showed increased liver toxicity, kidney toxicity, incorporation of DHA, and evidence of oxidized fatty acids compared to control animals. We hypothesized that the toxic effects of CsA were primarily a result of membrane perturbation, which could be decreased if DHA were not oxidized. The presence of CsA (10 mol%) alone increased dipalmitoylphosphatidylcholine membrane permeability by seven fold over control (no CsA, no DHA). However, if non-oxidized DHA (15 mol%) and CsA were added to the membrane, the permeability returned to control levels. Interestingly, if the DHA was oxidized, the antagonistic effect of DHA on CsA was completely lost. While CsA alone increased endothelial permeability to albumin, the combination of non-oxidized DHA and CsA had no effect on endothelial macromolecular permeability. However the combination of oxidized DHA and CsA was no different than the effects of CsA only. CsA increased the fluorescence anisotropy of DPH in the liquid crystalline state of DPPC, while DHA decreased fluorescence anisotropy. However the combination of CsA and DHA was no different than DHA alone. We conclude that non-oxidized DHA can reverse the membrane perturbing effects of CsA, and the increases in endothelial macromolecular permeability, which may explain how fish oil is capable of decreasing the toxicity of CsA.

Animals↗
PubMed2000

Estimation of ascitic fluid volume using 99Tcm labelled macroaggregated albumin.

We have assessed the usefulness of a radionuclide dilution method for estimation of ascitic fluid volume. 99Tc(m) macroaggregated albumin (10 MBq) was injected into the peritoneal fluid. Multiple samples were taken using a trocath peritoneal dialysis catheter over a 4-h period. Blood samples were taken at the same time and a 4-h urine collection was made during the study. At 4 h a controlled drainage of ascitic fluid, followed by suction drainage, was used and a total drained volume measured. For comparison, peritoneal volumes were measured from the radioactivity of peritoneal fluid activity samples using dilution techniques. The estimated peritoneal fluid volume using the radionuclide method was consistently higher than the drained volume. This was attributed to either a lack of uniform distribution of the activity in the peritoneal cavity by 4 h or early breakdown and absorption of activity from the peritoneal cavity. In two patients it was not possible to measure a volume due to poor distribution of the radionuclide in the peritoneal fluid. We found that in our group of patients the radionuclide dilution is of little value in estimating the peritoneal fluid volume.

Adult↗
PubMed1999

Transrectal ultrasound applicator for prostate heating monitored using MRI thermometry.

PURPOSE: For potential localized hyperthermia treatment of tumors within the prostate, an ultrasound applicator consisting entirely of nonmagnetic materials for use with magnetic resonance imaging (MRI) has been developed and tested on muscle tissue ex vivo and in vivo. METHODS AND MATERIALS: A partial-cylindrical intracavitary transducer consisting of 16 elements in a 4 x 4 pattern was constructed. It produced a radially propagating acoustic pressure field. Each element of this array (1.5 x 0.75 cm), operating at 1.5 MHz, could be separately powered to produce a desired energy deposition pattern within a target volume. Spatial and temporal temperature elevations were determined using the temperature-dependent proton resonant frequency (PRF) shift and phase subtraction of MR images acquired during ultrasonic heating. Four rabbits were exposed to the ultrasound to raise the local tissue temperature to 45 degrees C for 25 minutes. Six experiments compared thermocouple temperature results to PRF shift temperature results. RESULTS: The tests showed that the multi-element ultrasound applicator was MRI-compatible and allowed imaging during sonication. The induced temperature distribution could be controlled by monitoring the RF power to each transducer element. Therapeutic temperature elevations were easily achieved in vivo at power levels that were about 16% of the maximum system power. From the six thermocouple experiments, comparison between the thermocouple temperature and the PRF temperature yielded an average error of 0.34+/-0.36 degrees C. CONCLUSIONS: The MRI-compatible intracavitary applicator and driving system was able to control the ultrasound field and temperature pattern in vivo. MRI thermometry using the PRF shift can provide adequate temperature accuracy and stability for controlling the temperature distribution.

Animals↗
PubMed1999

In vivo demonstration of noninvasive thermal surgery of the liver and kidney using an ultrasonic phased array.

A 256-element, continuous-wave ultrasonic phased array has been used to thermally coagulate deep-seated liver and kidney tissue. The array elements were formed on a 1-3 piezocomposite bowl with a 10-cm radius of curvature and 12-cm diameter. The 0.65 x 0.65 cm2 projection elements were driven at 1.1 MHz by a custom-built amplifier system. A series of in vivo porcine experiments demonstrated the ability to coagulate liver and kidney tissue using the large-scale phased array. The temperature response of the treatment was guided and monitored using magnetic resonance (MR) images. Focal lesion volumes greater than 0.5 cm3 in kidney and 2 cm3 in liver were formed from a single 20-s sonication.

Animals↗
PubMed1998

The feasibility of using focused ultrasound for transmyocardial revascularization.

Transmyocardial laser revascularization (TMR) is used for improving the blood supply to damaged myocardium due to advanced heart disease. We hypothesize that focused ultrasound can be used to generate channels through the cardiac muscle by vaporizing the tissue at the focal spot. The purpose of this study was to evaluate the effects of varying the ultrasound exposure parameters (frequency, amplitude, pulse period, duty cycle, focal depth and exposure time) on the vaporized tissue size and to determine the feasibility of using ultrasound for creating cavities and/or channels in the left ventricular wall for transmyocardial revascularization. Based on in vitro experiments using bovine myocardium, the experiments indicate that a 1 mm diameter channel could be created by using, for example, a focused transducer with a diameter of 10 cm and a radius of curvature of 8 cm operating at a frequency of 2.52 MHz. The required spatial peak intensity during the 0.5-s sonications was found to be 2300 W/cm2 with a pulse repetition period of 40 ms and a 50% duty cycle. These parameters have been used to create cavities during in vivo tests using canine myocardium. The results demonstrated that ultrasound could be used to create small channels through myocardium. The most important potential for ultrasound is its ability to generate these channels completely noninvasively.

Animals↗
PubMed1996

Behavioral effects of prenatal exposure to pulsed-wave ultrasound in unanesthetized rats.

The present experiment examined the developmental neurotoxicity of pulsed-wave (pw) ultrasound in rats, using an exposure system designed to eliminate restraint or anesthesia from the exposure conditions. Pregnant Sprague-Dawley CD rats trained to remain immobile in a water-filled ultrasound exposure tank were scanned with 3-MHz pw ultrasound at spatial peak temporal average intensities (ISPTA) of 0, 2, 20, or 30 W/cm2 on embryonic days 4-20 for approximately 10 min/day. The data showed that such insonation produced no adverse effects on maternal weight gain or reproductive outcome, nor on the postnatal growth or survival of the offspring. No exposure-related alterations in behavioral development were observed in the offspring of rats scanned with pw ultrasound during gestation. In addition, there was no consistent evidence of an ultrasound-associated change in the adult offspring behaviors tested; i.e., no treatment effects were found on measures of locomotor activity, water maze learning, and acoustic startle reactivity. An effect on tactile startle was observed on some trials in the low exposure group male offspring, but this effect was neither dose dependent nor consistent with any other finding. Overall, these results indicate that the neurobehavioral development of rats was not altered by prenatal exposure to pw ultrasound at ISPTA levels of up to 30 W/cm2.

Animals↗
PubMed1995

Scintigraphic measurement of ileocaecal transit in irritable bowel syndrome and chronic idiopathic constipation.

This study investigated the hypothesis that some features of functional gastrointestinal disorders may be associated with abnormalities of ileocaecal transit by measuring ileocaecal transit using a scintigraphic technique in 43 patients with chronic constipation, 20 patients with irritable bowel syndrome (IBS), and 18 control subjects. Subjects ingested enteric coated capsules, which delivered 111-indium radionuclide to the distal ileum. Gammacamera images were acquired at hourly intervals until caecal filling was complete. Ileocaecal transit was defined as the time between peak scintigraphic activity in the terminal ileum and peak activity in the caecum. The mean (SD) ileocaecal transit of 103 (50) minutes in patients with IBS was significantly faster than that in control subjects (mean (SD) ileocaecal transit 174 (78) minutes, p < 0.002). There were no significant differences in ileocaecal transit between patients with chronic idiopathic constipation and the control subjects, or between patients with constipation predominant and diarrhoea predominant IBS. This study developed a practical scintigraphic method of measuring ileocaecal transit. The rapid ileocaecal transit in both the constipation and diarrhoea predominant forms of IBS suggests that bloating may not after all result from delayed ileal emptying.

Adult↗
PubMed1994

Teratologic evaluation of rats prenatally exposed to pulsed-wave ultrasound.

While there are no known risks associated with diagnostic ultrasound, uncertainty about the safety of prenatal ultrasound exposure remains. The purpose of the present experiment was to evaluate the teratogenic potential of pulsed-wave (pw) ultrasound in rats, in the absence of maternal anesthesia or restraint. Pregnant CD rats, trained to remain immobile in a water-filled ultrasound exposure tank, were scanned with 3-MHz pw ultrasound at levels of 0, 2, 20 or 30 W/cm2 ISPTA (spatial peak, temporal average intensity) on gestational days 4-19 for approximately 10 min/day. Examination of fetuses on E20 revealed no increase in skeletal or visceral malformations in groups exposed to pw ultrasound in utero. The number of implantations/dam was significantly increased in all pw ultrasound exposure groups compared to sham-exposed animals and, in a possibly related finding, resorptions were increased in the two highest exposure groups. Although significantly increased compared to controls, resorption frequencies in these groups were low (< 10%). No exposure-related changes in fetal weights were observed in offspring of rats scanned with pw ultrasound during gestation. The results indicate that, under the conditions described, no overt embryotoxicity is associated with gestational exposure to pw ultrasound intensities of up to 30 W/cm2.

Animals↗
PubMed1994

Behavioral teratologic effects of prenatal exposure to continuous-wave ultrasound in unanesthetized rats.

While there are no known risks associated with diagnostic ultrasound, uncertainty about the safety of prenatal ultrasound exposure remains. The purpose of the present experiment was to evaluate the behavioral teratogenic potential of continuous-wave (cw) ultrasound in rats, in the absence of maternal anesthesia or restraint. Pregnant CD rats, trained to remain immobile in a water-filled ultrasound exposure tank, were scanned with 3 MHz cw ultrasound at levels of 0, 2, 10, 20, or 30 W/cm2 ISPTA (spatial peak, temporal average intensity) on gestational days 4-20 for approximately 10 min/day. Offspring were examined postnatally for survival, growth, physical landmarks of development, behavioral development, and the adult functions of locomotor activity, learning and memory, and startle reactivity. No effects of prenatal ultrasound were found on maternal characteristics, offspring survival or growth, physical or behavioral landmarks of development, or adult tests of passive avoidance or startle. Effects at the highest intensity were obtained on corner and side locomotor activity and in a multiple-T water maze on measures of errors of commission and time spent finding the goal. The results showed that prenatal cw ultrasound in rats can induce effects on some postnatal neurobehavioral functions at high exposure intensities (30 W/cm2), but at lower intensities (2-20 W/cm2) no consistent evidence of neurobehavioral effects was observed.

Animals↗
PubMed1994

Simplified method for the measurement of segmental colonic transit time.

Segmental colonic transit has been measured in 101 patients. Two MBq of 111Indium absorbed on resin pellets and encapsulated in an enteric coated capsule was given at 7 00 am. Hourly images during the first day, and three images during each subsequent day were acquired for up to three days. Using all scan and patient data the scans were categorised in one of the five patterns of colonic transit: normal, rapid, right delay, left delay, or generalised delay. The geometric centres and per cent activity at each time point was compared between the five groups of colonic transit patients to find the best time for imaging and so to distinguish the five groups. During the first day, early images did not help in diagnosis of patterns of transit, however, in the later images (six hours onwards after the ingestion of the activity) the rapid transit groups could be identified. Images at 27 and 51 hours were both required to distinguish all five groups of patients from each other. Only in the 'normal' transit patients was there some excretion of the activity during the course of the second day, otherwise there was no difference in the images taken in the course of a day (second or third day). A simplified protocol requires a minimum of three images to distinguish all five patterns of colonic transit. The activity should be ingested in the morning (7 00 am) and the first image taken at the end of the working day (8-10 hours after ingestion), the second image on the morning of the second day, and the third image during the course of the third day. This simple protocol would provide all the clinically relevant information necessary for correct classification of the colonic transit.

Adolescent↗
PubMed1993

Scintigraphic defecography: quantitative and dynamic assessment of anorectal function.

PURPOSE: Conventional assessment of anorectal function with defecating videoproctography is semiquantitative and the high radiation exposure precludes prolonged or repeated testing. The aim of this study was to develop a dynamic scintigraphic method of assessing anorectal function. METHODS: Fourteen patients with fecal incontinence, 18 patients with chronic constipation, and 8 control subjects were assessed by scintigraphic defecography. This involves introduction of a technetium-99m-radiolabeled artificial stool into the rectum of the subject and acquisition of gamma camera images during evacuation. RESULTS: Mean evacuation rate was 2.8 percent/second in incontinent patients and 0.9 percent/second in constipated patients (P < 0.001). The mean anorectal angles were 136 degrees and 133 degrees, respectively. There were 18 cases of pelvic floor descent and 6 rectoceles. Scintigraphic defecography provides quantitative information on rectal evacuation. Anorectal angle and pelvic floor movement can be examined. The radiation dose to pelvic organs is significantly less than with videoproctography. CONCLUSION: We believe that scintigraphic defecography is the investigation of choice for objective and dynamic assessment of anorectal function.

Adult↗