Biomedical subjects

M J Myers

Publications and source records attributed to M J Myers.

At least 19 recordsLinked to original sources

PubMed1997

ECAT ART - a continuously rotating PET camera: performance characteristics, initial clinical studies, and installation considerations in a nuclear medicine department.

Advances in fully three-dimensional (3D) image reconstruction techniques have permitted the development of a commercial, rotating, partial ring, fully 3D positron emission tomographic (PET) scanner, the ECAT ART. The system has less than one-half the number of bismuth germanate detectors compared with a full ring scanner with the equivalent field of view, resulting in reduced capital cost. The performance characteristics, implications for installation in a nuclear medicine department, and clinical utility of the scanner are presented in this report. The sensitivity (20 cm diameterx20 cm long cylindrical phantom, no scatter correction) is 11400 cps.kBq-1.ml-1. This compares with 5800 and 40500 cps.kBq-1.ml-1 in 2D and 3D respectively for the equivalent full ring scanner (ECAT EXACT). With an energy window of 350-650 keV the maximum noise equivalent count (NEC) rate was 27 kcps at a radioactivity concentration of approximately 15 kBq.ml-1 in the cylinder. Spatial resolution is approximately 6 mm full width at half maximum on axis degrading to just under 8 mm at a distance of 20 cm off axis. Installation and use within the nuclear medicine department does not appreciably increase background levels of radiation on gamma cameras in adjacent rooms and the dose rate to an operator in the same room is 2 microSv. h-1 for a typical fluorine-18 fluorodeoxyglucose (18F-FDG) study with an initial injected activity of 370 MBq. The scanner has been used for clinical imaging with18F-FDG for neurological and oncological applications. Its novel use for imaging iron-52 transferrin for localising erythropoietic activity demonstrates its sensitivity and resolution advantages over a conventional dual-headed gamma camera. The ECAT ART provides a viable alternative to conventional full ring PET scanners without compromising the performance required for clinical PET imaging.

Equipment Design↗

PubMed1997

Leisure time physical activity and the 16-year risks of mortality from coronary heart disease and all-causes in the Multiple Risk Factor Intervention Trial (MRFIT).

PURPOSE: To examine the long-term association of leisure time physical activity (LTPA) and risk of death from coronary heart disease (CHD) and all-causes. METHODS: Data are from a prospective study of 12,138 middle-aged men at high risk for CHD participating in the MRFIT. Men were classified into deciles based on average min/d of LTPA reported at baseline, which were compared with cumulative CHD and all-cause mortality endpoints at the 16-year follow-up. RESULTS: Men in the least-active decile of LTPA who averaged 4.9 min/d of LTPA (range 0 to .9 min/d) had excess age-adjusted mortality rates of 29% and 22% for CHD and all-causes, respectively, as compared to those in combined deciles 2 to 4, who averaged 22.7 min/d of predominantly light and moderate LTPA (range 10-36 min/d). No further decrement in mortality rates was noted in those in the higher declines of LTPA. These associations remained significant (P < 0.05) after proportional hazards adjustments for additional possible confounding variables. CONCLUSION: These data suggest that a relatively small amount (10 to 36 min/d) of daily moderate intensity LTPA can significantly reduce premature mortality, particularly from CHD, in middle-aged and older men at high risk for CHD.

Adult↗

PubMed1997

Effects of an endotoxin challenge on growth performance, carcass accretion rates, and serum hormone and metabolite concentrations in control pigs and those treated with recombinant porcine somatotropin.

Barrows were restrictively fed starting at 20 kg BW to determine the effects of endotoxin on growth performance of control and somatotropin-treated pigs. The following treatments were used: 1) daily i.m. vehicle injection until 55 kg BW; 2) daily i.m. injections of 100 micrograms of recombinant porcine somatotropin (pST)/kg BW, until 55 kg; 3) i.v. saline injections for 7 d consecutively starting at 60 kg BW; 4) i.v. injections of 1 microgram of bacterial lipopolysaccharide (LPS)/kg BW for 7 d starting at 60 kg BW; and 5) the combined LPS+pST treatment, with pST injections from 20 kg through the 7 d of LPS treatment. Pigs evaluated for LPS effects were fed to 60 kg anticipating a weight loss. Pigs were bled at 0800 and 1100 at 55 kg and on d 7 of LPS treatment. Rectal temperatures were taken on d 7. Treatment with pST increased ADG by 13 to 20% and improved feed:gain by 17 to 23% before LPS treatment. During the 7 d of LPS injections, ADG and feed:gain did not differ, although feed efficiency was impaired and variable. Rectal temperatures at 1100 were progressively increased: control < LPS < LPS-pST (P < .01). Protein accretion was improved 27% by pST treatment, and lipid accretion was decreased 45% before LPS. Lipid stores decreased (P < .01) after LPS treatment in the pST-treated pigs. Lipopolysaccharide treatment and(or) decreased feed intake reduced the hyperinsulinemia and hyperglycemia (P < .01) associated with pST treatment. These results indicate that LPS induced a simulated septicemia and that the effects were not negated by pST treatment. The observed hyperthermia was additive, possibly due to increased lean body mass induced by pST combined with the pyrogenic effect of LPS.

Animals↗

PubMed1997

Effect of growth hormone or chromium picolinate on swine metabolism and inflammatory cytokine production after endotoxin challenge exposure.

OBJECTIVE: To determine whether recombinant porcine somatotropin (PST) or chromium picolinate (CrP) affected cytokine production and metabolism in swine after endotoxin challenge exposure. ANIMALS: 20 Poland China X Landrace pigs, 5/group. PROCEDURE: Pigs were given CrP-supplemented feed at body weight of 20 kg; PST treatment began at 60 kg, and both treatments continued through body weight of 90 kg. At 90 kg, pigs were challenge exposed with 20 micrograms of lipopolysaccharide (LPS)/kg of body weight. Blood samples were obtained at various times through 24 hours after LPS challenge exposure. RESULTS: In all pigs not given PST, glucose concentration decreased 2 to 4 hours after LPS. In PST-treated pigs, blood glucose concentration was decreased at 6 to 8 hours after LPS. Plasma insulin concentration paralleled changes in glucose concentration. Nonesterified fatty acid concentration was high 2 to 24 hours after LPS in pigs not given PST and at 6 to 24 h in PST-treated pigs. Plasma urea nitrogen concentration was high at 6 to 24 hours after LPS in pigs not given PST. The urea nitrogen values in PST-treated pigs were lower at all times. Serum aspartate transaminase activity was high 6 to 24 hours after LPS in pigs not given PST, whereas PST treatment prevented the increase in this enzyme activity. In untreated (PST) pigs, plasma bilirubin (total and direct) concentrations were high 4 to 8 hours after LPS and returned to normal at 24 hours. The PST- and CrP-treated pigs maintained normal plasma bilirubin concentrations. Interleukin 6 activity was unaffected by CrP and PST treatments. Treatment with CrP and PST decreased the tumor necrosis factor alpha response to LPS, compared with that in control pigs. CONCLUSIONS: PST, and to a lesser extent CrP, provide protection against the adverse metabolic effects of LPS-induced septic shock.

Analysis of Variance↗

PubMed1996

Assessment of two devices for measuring tympanic membrane temperature in swine, dairy cattle, and dairy calves.

OBJECTIVE: To compare tympanic membrane temperature readings obtained with 2 commercially available devices with rectal temperature readings obtained with a standard mercury thermometer in dairy cattle, dairy calves, and swine. DESIGN: Clinical trial. ANIMALS: 6 Holstein calves (approx 6 months old), 6 Holstein cattle (approx 4 years old), and 5 Landrace-Poland China swine. PROCEDURE: Tympanic membrane temperatures were measured, and results were compared with rectal temperatures obtained with a standard mercury thermometer. Tympanic membrane temperatures were obtained before and after insertion of the rectal thermometer. Temperature readings in swine were obtained following passive restraint in a cage-like device or restraint using a snare to assess the effect of stress on tympanic membrane temperature. RESULTS: Tympanic membrane temperature readings from both devices were lower than those obtained using a rectal thermometer for all animals. Repeated measurement of tympanic membrane temperature of individual cattle resulted in consistent readings for both devices. CLINICAL IMPLICATIONS: Because all animals were visibly healthy, results suggest that tympanic membrane temperature readings obtained with either device may be an adequate assessment of health status.

Animals↗

PubMed1996

Computational methods in radionuclide dosimetry.

The various approaches in radionuclide dosimetry depend on the size and spatial relation of the sources and targets considered in conjunction with the emission range of the radionuclide used. We present some of the frequently reported computational techniques on the basis of the source/target size. For whole organs, or for sources of targets bigger than some centimetres, the acknowledged standard was introduced 30 years ago by the MIRD committee and is still being updated. That approach, based on the absorbed fraction concept, is mainly used for radioprotection purposes but has been updated to take into account the dosimetric challenge raised by therapeutic use of vectored radiopharmaceuticals. At this level, the most important computational effort is in the field of photon dosimetry. On the millimetre scale, photons can often be disregarded, and beta or electron dosimetry is generally reported. Heterogeneities at this level are mainly above the cell level, involving groups of cell or a part of an organ. The dose distribution pattern is often calculated by generalizing a point source dose distribution, but direct calculation by Monte Carlo techniques is also frequently reported because it allows media of inhomogeneous density to be considered. At the cell level, alpha and electron (low-range beta or Auger) are the predominant emissions examined. Heterogeneities in the dose distribution are taken into account, mainly to determine the mean dose at the nucleus. At the DNA level, Auger electrons or alpha-particles are considered from a microdosimetric point of view. These studies are often connected with radiobiological experiments on radionuclide toxicity.

Beta Particles↗

PubMed1995

Non-invasive measurement of microvascular permeability to a small solute in man: validation of the technique.

1. The purpose of the study was to evaluate a non-invasive technique for measurement of microvascular permeability to a small hydrophilic solute. 2. The technique measures the clearance of 99mTc-labelled diethylenetriaminepenta-acetic acid (99mTc-DTPA) from plasma into interstitial fluid in a limb after intravenous injection and uses a scintillation probe and a technique of graphical analysis called the Patlak plot, the uptake constant of which reflects 99mTc-DTPA transfer from plasma to interstitial fluid. Using deconvolution analysis, the retention function in the limb of intravenous 99mTc-DTPA was also measured. 3. The clearance values given by these two analytical techniques were compared with clearance from the same vascular bed after bolus femoral intra-arterial injection of 99mTc-DTPA. 4. Sixteen patients undergoing routine diagnostic arteriography were studied: six received sequential femoral intra-arterial injections of 99mTc-labelled human serum albumin (HSA) and 99mTc-DTPA, two received sequential intra-arterial and intravenous injections of 99mTc-HSA and eight received sequential intra-arterial and intravenous injections of 99mTc-DTPA. Tissue uptake and clearance were recorded from the limb with a scintillation probe and plasma clearance by arterial blood sampling. Tracer recirculation was addressed using a second scintillation probe over the contralateral limb. 5. After intra-arterial injection, 99mTc-HSA clearance was monoexponential, reflecting intravascular transit, and was completed by 2-5 min in seven subjects and in about 10 min in one. The corresponding 99mTc-DTPA clearance curves in the six subjects who also received intra-arterial DTPA were biexponential, analysis of which yielded a 99mTc-DTPA extraction fraction of about 0.6. By comparison with 99mTc-HSA clearance, the first exponential clearly corresponded to intravascular transit of unextracted 99mTc-DTPA. 6. In the eight patients given sequential intra-arterial and intravenous injections of 99mTc-DTPA, the second exponential recorded after intra-arterial injection, representing 99mTc-DTPA clearance from the interstitial fluid, agreed well with (a) the Patlak uptake constant recorded over the limb after intravenous injection, representing clearance from plasma into the interstitial fluid and (b) the retention function of 99mTc-DTPA in a limb calculated by deconvolution analysis. The mean clearance following intra-arterial injection (expressed in relation to extracellular fluid volume) was 9.6 (SD 2.4) ml min-1 100 ml-1, while the corresponding mean clearance after intravenous injection was 8.8 (2.1) ml min-1 100 ml-1 calculated by Patlak analysis and 10.5 (2.7) ml min-1 100 ml-1 by deconvolution analysis.(ABSTRACT TRUNCATED AT 400 WORDS)

Capillary Permeability↗

PubMed1995

Oxytetracycline-mediated alteration of murine immunocompetence.

The immunomodulatory effect of oxytetracycline (OTC) on murine splenic lymphocytes (MSL), peritoneal exudate macrophage (PEM) functions and antibody production was examined. In vivo exposure to OTC slightly delayed initiation of antibody formation during the primary response. However, OTC exposure had no effect on either the peak time of antibody response or peak antibody titer. OTC also had no significant effect on the secondary antibody response. Mitogen-induced proliferation of MSL cocultured with OTC and pokeweed mitogen, phytohemagglutinin or concanavalin was equivocal. However, allogeneic stimulation of MSL was inhibited at 100 micrograms/ml OTC. There was also a decrease in the number of cells recovered. OTC had no effect on lymphocyte cytotoxicity in cells cultured in vitro. OTC inhibited the cytotoxic response of Corynebacterium parvum-elicited PEM at 10 micrograms/ml (effector:target of 10:1). Low levels of OTC (1-10 micrograms/ml) augmented the cytotoxic response (effector:target of 5:1). The effect of OTC on induction of PEM cytotoxicity was assessed by coculturing thioglycollate-elicited (TG) PEM in vitro with IFN-gamma and endotoxin along with 0-100 micrograms/ml OTC. Induction of cytotoxicity was inhibited at 0.5 microgram/ml. The effect of OTC on TG-PEM antimicrobial activity was assessed by measuring reduction of nitroblue tetrazolium (NBT) and cytochrome C. OTC inhibited the reduction of NBT at 500 micrograms/ml following PMA stimulation of TG-PEM. OTC had no effect on either NBT or cytochrome C reduction following stimulation with opsonized zymosan. These results demonstrate that OTC-mediated immunosuppression is a multifaceted event, with differing sensitivities both between immune cells and between different pathways within the same cell.

Adjuvants, Immunologic↗

PubMed1995

Effect of recombinant growth hormone and chromium picolinate on cytokine production and growth performance in swine.

The effect of dietary chromium picolinate (CrP) and recombinant porcine growth hormone, somatotropin (rPST) administration on growth performance and cytokine production in Landrace-Poland China gilts was determined using a 2 by 2 treatment array. Treatments were: (1) control (basal diet), (2) CrP-supplemented diet (basal diet + 300 micrograms Cr3+/kg diet as CrP), (3) rPST (100 pg/kg body weight/day), and (4) rPST+CrP. CrP-supplemented diets were fed beginning at 20 kg body weight through 90 kg. Administration of rPST was begun at 60 kg weight and continued through 90 kg. All rPST treated pigs demonstrated improvements in growth performance versus controls. Pigs given CrP-supplemented diets showed no differences in growth performance. At 90 kg, pigs were challenged with endotoxin (lipopolysaccharide, 0.2 microgram/kg i.v.). Blood samples were collected at 0, 1, and 3 h postchallenge. Plasma IL-6 levels increased from 23 U/ml at time 0 to 1,927 U/ml at 3 h for control swine. Swine from the CrP treatment group had IL-6 levels of 8,130 U/ml at 3 h post-LPS. There were no differences in plasma IL-6 from pigs in the rPST and rPST+CrP treatment groups compared to the controls. Endotoxin challenge had no effect on either blood glucose levels or induction of TNF-alpha in any treatment group. PBMC from CrP-treated animals produced more IL-2 than peripheral blood mononuclear cells from all other groups.

Animals↗

PubMed1995

The effect of inhalation of platelet-activating factor on the pulmonary clearance of 99mTc-DTPA aerosol.

Platelet-activating factor (PAF) is a short-acting, lipid-soluble autocoid, inhalation of which causes an immediate pulmonary vascular sequestration of granulocytes and a peripheral neutropenia. We investigated the effect of PAF inhalation on the pulmonary clearance rate of inhaled 99mTc-DTPA in order to test the hypothesis that the pulmonary sequestration of granulocytes results in acute lung injury. In nine normal nonsmoking adults, the rate of clearance of DTPA, corrected for background activity, was 1.5 (SD 0.7) %/min over the first 10 min after inhalation. Inhalation of 4.8 micrograms PAF abruptly increased the clearance rate to a mean value of 2.3 (1.4) %/min (p < 0.05). No increase in clearance was observed in four nonsmoking subjects who inhaled vehicle only. The mean overall increase after PAF was 87% of the baseline clearance, significantly different (p < 0.05) from the corresponding change in the control group, which was -17%. After PAF, the clearance rate returned to baseline values within 10 min in all subjects. In all subjects who inhaled PAF, but in none who inhaled vehicle, there was an immediate neutropenia of 51 (SD 25) % of the baseline value (p < 0.01). This neutropenia persisted longer than the corresponding accelerated DTPA clearance and was still 74 (36) % of the baseline value at 10 min. Furthermore, there was no correlation between the increase in DTPA clearance induced by PAF inhalation and the decrease in peripheral blood granulocyte count. We conclude that PAF inhalation results in an increase in pulmonary DTPA clearance, probably not mediated by pulmonary vascular granulocyte sequestration.

Administration, Inhalation↗

PubMed1995

The use of xenon-133 for measurement of blood flow through systemic arteriovenous malformations before and after therapeutic embolization.

Embolization is increasingly used to treat systemic arteriovenous (AV) shunts although its success, as judged by either angiographic or clinical means, is difficult to quantify. The aim of the study was to quantify blood flow through AV shunts with 133Xe, which, because of its relatively long transit time through peripheral tissues, behaves like microspheres. Following arterial injection, 133Xe entering an AV shunt rapidly arrives in the lung and can be quantified with a scintillation probe. In 17 patients with systemic AV shunts, the reduction in shunt flow following therapeutic embolization was quantified in the angiography theatre by comparing the initial count rates in the lung, recorded by probe, following injection of identical quantities of 133Xe into a supplying artery before and after embolization. By comparing the lung counts with those given by an intravenous injection of 133Xe, the fraction of flow at the catheter tip entering the shunt was also quantified. Tissue perfusion in the vascular territory distal to the shunt was measured at the same time by recording the clearance of non-shunted 133Xe with a second probe over the extremity. Control injections of 133Xe were given in the contralateral limb in order to assess 133Xe transit in the absence of shunting and to compare tissue perfusion between the two sides. Shunt flow ranged from 40% to 100% (of that at the tip of the catheter) (n = 14), while the reduction in shunt flow following embolization ranged from 15% to 96% (n = 19). Tissue perfusion distal to the shunt and in the contralateral limb was about 5 ml 100 ml-1 min-1. Contrast medium had no consistent effect on tissue perfusion in either limb, or on shunt flow. There was no difference in peripheral perfusion between the abnormal and control sides, nor any significant difference in perfusion in the distal tissue on the abnormal side before and after embolization. There was, however, a consistent increase in the fraction of the injected 133Xe delivered to the distal tissue after embolization (median increase 93%, p < 0.001). The technique is relatively simple and merits further development as a means of continuous quantification of systemic AV shunt flow in the angiography theatre at the time of embolization.

Adult↗

PubMed1995

Granulocyte margination in bone marrow: comparison with margination in the spleen and liver.

The kinetics of radiolabelled granulocytes in the reticuloendothelial system were studied in order to evaluate granulocyte margination in bone marrow. A total of 34 patients took part in a two-part study. In the first part, bone marrow uptake of indium-111-labelled granulocytes was retrospectively analysed in early (3-h) and late (24-h) images in 26 patients, 13 with bronchiectasis and 13 with enclosed abdominal abscesses. The ratios between early and late counts from the bone marrow, spleen, liver and inflammatory lesion were used to quantify granulocyte margination in bone marrow, postulating that if the lesion to bone marrow ratio at 24 h exceeds the value at 3 h, then the "excess" bone marrow counts on the early images would represent margination. In the second part, this suggestion was prospectively tested using Rutland-Patlak graphical and deconvolution analysis of dynamic data, acquired in 8 patients undergoing routine scanning with technetium-99m HMPAO-labelled granulocytes. In the first part of the study, it appeared that the bone marrow is a regional site of granulocyte margination, like the spleen, with at least one-half of the 3-h marrow signal arising from marginated granulocytes, compared with about two-thirds from the spleen. In the second part, it was found that the gradient of the Patlak plot, based on spleen and marrow, continuously decreased, consistent with bi-directional movement of cells between these organs and the blood. Granulocyte pooling in the marrow was confirmed with deconvolution analysis, which generated biphasic retention functions for marrow and spleen. These curves were also consistent with two-way granulocyte exchange, and gave mean cell transit times in both organs of about 12 min and probabilities of extraction on each pass of 5-10%. We conclude that granulocytes marginate in bone marrow to an extent similar to that in the spleen.

Abdominal Abscess↗

PubMed1995

Endotoxin and interferon-gamma differentially regulate the transcriptional levels of proto-oncogenes and cytokine genes during the differentiation of colony-stimulating factor type-1-derived macrophages.

The expression of cytokine genes for interleukin-1 (IL-1) (alpha and beta) and tumour necrosis factor-alpha (TNF-alpha), along with the proto-oncogenes c-fos, c-fms and c-myc, was examined by nuclear run-off and Northern blot analysis during in vitro differentiation of colony-stimulating factor type-1 (CSF-1)-derived bone marrow macrophages (BMDM). Constitutive transcription of c-myc was maximal on day 3 and decreased with differentiation. Constitutive transcription of c-fms and c-fos was similar at all times examined. In contrast, the steady-state mRNA levels were maximal on day 5 for c-myc and day 7 for c-fms and c-fos. Thirty minutes after endotoxin (lipopolysaccharide; LPS) stimulation, there was a rapid increase in run-off transcription rates for c-myc in day 3-day 9 BMDM, with maximal levels observed in day 7 BMDM. c-fms transcription was maximally induced within 1 hr by LPS in day 3 and day 5 BMDM. LPS induced transcription of c-fos to equivalent levels in day 3-day 9 BMDM. LPS stimulation augmented steady-state mRNA levels for c-myc, c-fms and c-fos. Maximal induction of c-myc was observed in day 3 BMDM. c-fos and c-fms were both maximally induced in day 5 and day 7 BMDM. Interferon-gamma (IFN-gamma) had no effect on transcription of the proto-oncogenes examined. In contrast to the proto-oncogenes, peak levels of run-off transcription for IL-1 alpha and IL-1 beta genes were observed 1-2 hr after LPS stimulation for day 3, day 5 and day 7 BMDM. The kinetics of LPS-induced steady-state mRNA accumulation of IL-1 alpha and IL-1 beta were similar to the kinetics of run-off transcription. Constitutive transcription of TNF-alpha was observed on all days of differentiation. LPS and IFN-gamma both enhanced run-off transcription of the TNF-alpha gene; however, LPS had a more pronounced effect. The kinetics of induction of TNF-alpha transcription paralleled the kinetics of steady-state TNF-alpha mRNA accumulation. IFN-gamma resulted in secretion of TNF-alpha in day 5, day 7, and day 9 BMDM after 4-8 hr of stimulation. Day 3 BMDM had little, if any, secreted TNF-alpha activity.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1995

In vitro modulation of bovine blood neutrophils and mononuclear cells by oxytetracycline.

The effect of oxytetracycline (OTC) on bovine blood mononuclear cells and neutrophil functions was examined in vitro. Neutrophil functions tested include respiratory burst, peroxidase, and antibacterial activities. Neutrophils were treated with OTC (10 to 1,500 micrograms/ml) before exposure to either opsonized zymosan or bacteria. A dose-response inhibition of antibacterial activity to high concentrations of OTC (500 to 1,000 micrograms/ml) was observed. Beginning at a concentration of 15 micrograms/ml, OTC treatment of neutrophil lysates resulted in decreased peroxidase activity. A dose response was not observed. In contrast, respiratory burst, measured by nitroblue tetrazolium dye reduction, increased after OTC exposure, but only at high concentrations (500 and 1,000 micrograms/ml) of OTC. Mitogen-induced proliferation of blood mononuclear cells cocultured with OTC and concanavalin A, phytohemagglutinin-P, or pokeweed mitogen was inhibited at an OTC concentration of 100 micrograms/ml at 48 and 72 hours of culture. These results indicate that blood mononuclear cells are more sensitive to the inhibitory effects of OTC than are neutrophils. Furthermore, the OTC-mediated inhibition of neutrophil antimicrobial activity is inversely related to the increase in nitroblue tetrazolium reduction. This suggests that OTC is uncoupling the hexose monophosphate shunt from production of secreted oxygen radicals. These results also suggest that the peroxidase enzyme system has a large biological reserve capacity.

Animals↗

PubMed1994

Induction of hepatic acute-phase protein transcripts: differential effects of acute and subchronic dimethylnitrosamine exposure in vivo.

Inflammatory responses are accompanied by increased expression of hepatocyte-derived proteins collectively known as acute phase reactants (APR). B6C3F1 female mice were exposed intraperitoneally every 24 hr to either vehicle (PBS) or DMN (5 mg/kg) for up to six exposures. Following a single treatment (acute), liver tissues were collected at 3, 6, 12, and 24 hr post-exposure. The same collection scheme was repeated following the fourth and sixth exposures (subchronic). Total cellular RNA was isolated and Northern blot analyses were performed using 3'-end radiolabeled oligonucleotides specific for serum amyloid A (SAA), serum amyloid P (SAP), and albumin (ALB). SAA transcripts were detected 3 hr after acute DMN exposure, peaked at 6 hr, and rapidly declined to vehicle control levels by 12 hr. No SAA transcripts were observed in vehicle-treated controls. In contrast, SAP transcripts were constitutively expressed in both vehicle and DMN-treated groups throughout the acute exposure period. However, at 3 and 6 hr after DMN exposure, elevated levels of SAP transcripts were observed before returning to control levels at 12 and 24 hr. Expression of albumin transcripts decreased rapidly following acute DMN exposure and remained suppressed throughout the first 24-hr period measured. Serum levels of complement component-3 (C3) increased 2 hr after a single DMN exposure, whereas decreases in serum albumin levels were first observed at 24 hr post-exposure. After four exposures to DMN, SAA transcripts were detected at all time periods measured. Similarly, SAP transcripts in livers of DMN-exposed animals were consistently elevated above vehicle controls. Results after six exposures to DMN were similar, with SAA and SAP transcripts elevated at all time points tested. By comparison, repeated vehicle exposures resulted in a stress-related transient expression of SAA and SAP transcripts. Thus, acute and subchronic DMN exposure resulted in differential APR transcript expression and may serve as useful biomarkers following chemical exposure.

Acute-Phase Proteins↗

PubMed1994

Aryl hydrocarbon (Ah) receptor-independent induction of Cyp1a2 gene expression by acenaphthylene and related compounds in B6C3F1 mice.

Treatment of B6C3F1 mice with acenaphthylene, acenaphthene, fluorene, phenanthrene, anthracene and dibenzofuran resulted in induction of hepatic microsomal methoxyresorufin O-deethylase (MROD) activity. Acenaphthylene was the most potent inducer of MROD, a Cyp1a2-dependent activity, and was utilized as a prototypical inducer for this group of tricyclic hydrocarbons. Acenaphthylene (300 mg/kg) caused a > 80-fold induction of hepatic microsomal MROD activity; no induction was observed in kidney or lung. Analysis of induced hepatic microsomes with antibodies to Cyp1a1 and Cyp1a2 showed that acenaphthylene induced immunoreactive Cyp1a2 but not Cyp1a1 proteins and subsequent mRNA analysis confirmed with a cDNA probe for Cyp1a1 and Cyp1a2 that acenaphthylene induced Cyp1a2 but not Cyp1a1 mRNA. Results from nuclear run-on experiments using hepatic nuclei showed that acenaphthylene caused an approximately 4-fold increase in the rate of Cyp1a2 gene transcription in B6C3F1 mice. Results of competitive binding studies indicated that the tricyclic hydrocarbons did not competitively displace [3H]2,3,7,8-tetrachlorodibenzo-p-dioxin or [3H]benzo[a]pyrene from the mouse hepatic cytosolic aryl hydrocarbon (Ah) receptor or 4S carcinogen binding protein respectively. The data indicate that acenaphthylene and related tricyclic hydrocarbons induce Cyp1a2 gene expression in B6C3F1 mice via an Ah receptor-independent pathway. Thus, tricyclic hydrocarbons induce Cyp1a2 without the co-induction of Cyp1a1 and therefore these relatively non-toxic compounds can be used to further probe the role of Cyp1a2 in the metabolism and metabolic activation of diverse chemical carcinogens.

Acenaphthenes↗

PubMed1994

Effect of a new oral somatostatin analog (SDZ CO 611) on gastric emptying, mouth to cecum transit time, and pancreatic and gut hormone release in normal male subjects.

Sixteen healthy male volunteers participated in a randomized, double blind, parallel groups study. Subjects received either 1 or 5 mg SDZ CO 611 (a new, orally active somatostatin analog) twice daily over a 14-day period and acted as their own controls. Gastric emptying of 99mTc and mouth to cecum transit time, as measured by the breath hydrogen technique, after a mixed meal containing lactulose and 99mTc-diethylenetriaminepentaacetate, were assessed once before, twice during, and once after the period of study medication. Gastric emptying of 99mTc was significantly accelerated by the higher dose of SDZ CO 611, whereas mouth to cecum transit time was prolonged by the drug in a dose-dependent manner. Both doses of SDZ CO 611 led to suppression of the fasting level and postprandial release of several gastrointestinal and pancreatic hormones. This effect was more marked in those subjects taking 10 mg/day of the study medication. Motilin and pancreatic polypeptide were the most sensitive to the inhibitory actions of the analog. Glucose tolerance was significantly impaired by the 10-mg dose of the drug. We conclude that this new, orally active derivative of somatostatin is as effective on the gastrointestinal tract as the sc somatostatin analog octreotide. It would, therefore, be a useful advance in the treatment of gastroenteropancreatic tumors.

Administration, Oral↗

PubMed1993

Uncoupling the correlates of locomotor costs: a factorial approach.

Although the metabolic cost of running has been found to vary systematically with running speed and body mass in animals, no mechanistic model of cost determination has been widely accepted. Because two suggested cost determinants--mechanical power output and the rate of force application--covary with running speed when gait (stride frequency) is unconstrained, examining the influence of each factor on cost has been problematic. We experimentally uncoupled the usual relationships between three readily manipulated cost correlates--speed, stride frequency, and mass distribution--to study the determinants of the cost of running in humans along a section of the cost response surface. Two levels of each cost correlate were used in a factorial design in which subjects ran at all eight combinations of factor levels while rate of oxygen consumption (VO2), mechanical power, and contact time were measured as response variables. Contact time and mechanical power were measured from high-speed cinefilm. Mechanical power accounted for 88%, and contact time (rate of force application) 57%, of speed-related VO2 variation. Variation in cost produced by changes in stride frequency and mass distribution were largely explained by mechanical power. Contact time was not significantly correlated with overall variation in VO2, while mechanical power output explained 80% of that variation. For the range of conditions tested, we conclude that the mechanical power derived from muscular contractions is an important determinant of the cost of running. While we have shown that the rate at which muscles shorten is not the sole determinant of the cost of running, the extent to which this factor influences cost remains unclear.

Analysis of Variance↗