The effects of 1,25-dihydroxycholecalciferol (1,25-(OH)2D3), parathyroid hormone (PTH), and L-thy... more The effects of 1,25-dihydroxycholecalciferol (1,25-(OH)2D3), parathyroid hormone (PTH), and L-thyroxine (T4) on trabecular bone remodeling were evaluated by histomorphometric methods in adult female beagle dogs. Intravenous 1,25-(OH)2D3 (1.25 micrograms/day in equally divided doses) was administered intermittently for 6 days and withdrawn 14 days for three complete cycles. PTH was administered intravenously (2.5 U/kg/day) in divided doses 6 hours apart for 60 days. Thyroxine was given orally (1.0 mg/kg/day) in divided doses for a similar interval. Static and dynamic changes were evaluated using tetracycline and DCAF (2,4 BIS) N, N', Di (carboxymethyl) (amino methyl fluorescein) in vivo double labeling of bone from the iliac crest taken before treatment and after 60 days. The intermittent administration of 1,25-(OH)2D3 stimulated the bone resorption rate and depressed the formation rate. 1,25-(OH)2D3 increased trabecular resorption surfaces; osteoid surface, volume, and thickness; mineralization lag time; and osteoblast number but decreased the bone volume. Multiple small daily doses of PTH resulted in an overall negative balance in trabecular bone. This was associated with an increased trabecular surface-to-volume ratio, bone resorption and formation rates, active forming surfaces, osteoid volume and surface, life span of bone forming and resorbing sites, and the number of osteoclast nuclei. Thyroxine appeared to increase bone mass by enhancing the switch-over from the resorptive to the formative phase of remodeling. Coupling between osteoid apposition and mineralization was increased by recruiting more forming sites and prolonging their life span. Thyroxine increased bone resorption and formation rates, trabecular bone volume and balance, number of osteoclast nuclei, and life span of bone forming sites. The osteoid seam thickness and mineralization lag time were decreased. The present study demonstrated that 1,25-(OH)2D3, PTH, and thyroxine at the dose and schedule used, markedly altered stimulators of remodeling in trabecular bone of adult dogs.
Prostaglandins Leukotrienes and Essential Fatty Acids, Nov 1, 1990
Prostaglandins of the E series, primarily E2 and E1, have the greatest activity in bone. Followin... more Prostaglandins of the E series, primarily E2 and E1, have the greatest activity in bone. Following discovery of their potent ability to stimulate bone resorption in vitro, clinical investigations have placed prostaglandins at sites of localized bone resorption associated with inflammatory or space occupying lesions in vivo. These studies have shown that prostaglandin production at such sites may be increased by cytokines such as interleukin-1 but the mechanisms by which prostaglandins stimulate bone resorption are not yet known. Observation of periosteal bone formation in patients given, pharmacological doses of prostaglandin has led to investigation of its bone forming activity. Young, growing rats have increased metaphyseal bone formation and this is accompanied by increased periosteal and endocortical bone formation in older animals. In the mature animals there is a generalized activation of remodelling with increased formation in the remodeling cycle. This is also seen in oophorectomized rats and results in repletion of the lost bone in this model of osteoporosis. In animal models of localized disuse osteopenia, prostaglandins are found to be elevated at the site of bone loss and prostaglandin inhibitors at least partially protect against the exaggerated resorption that occurs. This is also seen in models of orthodontic tooth movement, periodontitis and osteomyelitis. Prostaglandin synthesis inhibitors have been shown to delay healing of bone and this has led to limitations on their use clinically in some situations. Exogenously administered prostaglandins have been found to enhance periosteal callus formation, but healing is not uniformly enhanced. Prostaglandins have also been associated with hypercalcemia in certain animal tumors that model human hypercalcemia of malignancy but are probably most important in this condition as mediators in the localized resorption of bone at tumor sites. These in vivo studies have shown that prostaglandins are involved with increases in both bone formation and bone resorption. In vitro studies have shown that prostaglandins stimulate osteoblasts as well as osteoclastic bone resorption but understanding these effects under in vivo conditions will require further investigation.
The INHAND (International Harmonization of Nomenclature and Diagnostic Criteria for Lesions in Ra... more The INHAND (International Harmonization of Nomenclature and Diagnostic Criteria for Lesions in Rats and Mice) Project (www.toxpath.org/inhand.asp) is an initiative of the Societies of Toxicological Pathology from Europe (ESTP), Great Britain (BSTP), Japan (JSTP) and North America (STP) to develop an internationally accepted nomenclature for proliferative and nonproliferative lesions in laboratory animals. The purpose of this publication is to provide a standardized nomenclature for classifying microscopic lesions observed in the skeletal tissues and teeth of laboratory rats and mice, with color photomicrographs illustrating examples of many common lesions. The standardized nomenclature presented in this document is also available on the internet (http://www.goreni.org/). Sources of material were databases from government, academic and industrial laboratories throughout the world.
Histopathologic evaluation and peer review using digital whole-slide images (WSIs) is a relativel... more Histopathologic evaluation and peer review using digital whole-slide images (WSIs) is a relatively new medium for assessing nonclinical toxicology studies in Good Laboratory Practice (GLP) environments. To better understand the present and future use of digital pathology in nonclinical toxicology studies, the Society of Toxicologic Pathology (STP) formed a working group to survey STP members with the goal of creating recommendations for implementation. The survey was administered in December 2019, immediately before the COVID-19 pandemic, and the results suggested that the use of digital histopathology for routine GLP histopathology assessment was not widespread. Subsequently, in follow-up correspondence during the pandemic, many responding institutions either began investigating or adopting digital WSI systems to reduce employee exposure to COVID-19. Therefore, the working group presents the survey results as a pre-pandemic baseline data set. Recommendations for use of WSI systems ...
Elevated tissue lactate concentrations typically found in tumors can be measured by in vivo nucle... more Elevated tissue lactate concentrations typically found in tumors can be measured by in vivo nuclear magnetic resonance (NMR) spectroscopy. In this study, lactate turnover in rat C6 glioma was determined from in vivo 1H NMR measurements of [3-13C]lactate buildup during steady-state hyperglycemia with [1-13C]glucose. With this tumor model, a narrow range of values was observed for the first-order rate constant that describes lactate efflux, k2 = 0.043 +/- 0.007 (n = 12) SD min-1. For individual animals, the standard error in k2 was small (< 18%), which indicated that the NMR data fit the kinetic model well. Lactate measurements before and after infusing [1-13C]glucose showed that the majority of the tumor lactate pool was metabolically active. Signals from 13C-labeled glutamate in tumors were at least 10-fold smaller than the [3-13C]lactate signal, whereas spectra of the contralateral hemispheres revealed the expected labeling of [4-13C]glutamate, as well as [2-13C] and [3-13C]glut...
The effects of intermittent low doses (1.25 mug daily, administered intravenously for 6 days and ... more The effects of intermittent low doses (1.25 mug daily, administered intravenously for 6 days and withdrawn for 14 days for 3 complete cycles) of 1,25-dihydroxycholecalciferol (1,25-[OH](2)D(3)) on cortical bone were determined and compared in ribs with steady state and regionally accelerated remodeling in adult intact female dogs. The bone changes were analyzed by dynamic bone histomorphometric methods, using tetracycline and DCAF (2,4 BIS) N, N' di (carboxymethyl) (amino methyl fluorescein) in vivo double labeling of bones before treatment and after 60 days of intermittent 1,25-(OH)(2)D(3) administration. Serum calcium and phosphorus levels increased during 1,25-(OH)(2)D(3) administration. Urinary hydroxyproline excretion increased during the first interval of 1,25-(OH)(2)D(3) administration but was not changed significantly during the last two intervals. In normal cortical bone (11th rib) following the administration of 1,25-(OH)(2)D(3) there was a marked decrease in the activ...
Drug-induced vascular injury (DIVI) is a recurrent challenge in the development of novel pharmace... more Drug-induced vascular injury (DIVI) is a recurrent challenge in the development of novel pharmaceutical agents. Although DIVI in laboratory animal species has been well characterized for vasoactive small molecules, there is little available information regarding DIVI associated with biotherapeutics such as peptides/proteins or antibodies. Because of the uncertainty about whether DIVI in preclinical studies is predictive of effects in humans and the lack of robust biomarkers of DIVI, preclinical DIVI findings can cause considerable delays in or even halt development of promising new drugs. This review discusses standard terminology, characteristics, and mechanisms of DIVI associated with biotherapeutics. Guidance and points to consider for the toxicologist and pathologist facing preclinical cases of biotherapeutic-related DIVI are outlined, and examples of regulatory feedback for each of the mechanistic types of DIVI are included to provide insight into risk assessment.
Increased capacity for glycolytic metabolism is a well-known characteristic of neoplastic cells. ... more Increased capacity for glycolytic metabolism is a well-known characteristic of neoplastic cells. Because lactic acid is the end product of glycolysis, in vivo MRS measurements of tumor lactate concentration ([lac],) may provide valuable information about tumor metabolism, which will aid the development of therapies and the clinical diagnosis and treatment of tumors. In the present study, several hemodynamic and histologic parameters were evaluated with respect to their influence on [lac],. Pronounced differences in [lac], in two distinct populations of tumors suggested a putative perfusion threshold. Above this threshold, [lac], was independent of hemodynamic and histologic factors including tumor blood flow (measured using MRS and the method of D,O washout), extent of necrosis and inflammatory cell infiltrate. Thus, for most tumors, [lac], was not determined by any one single factor such as hypoxia, venous clearance, glucose supply, extent of necrosis or degree of inflammatory cell infiltrate. Rather, [lac], may be equilibrated, at least in part, by an interplay of forces involving hemodynamics and substrate supply. In general, the data are consistent with the hypothesis that elevated lactate in most tumors is related to the high glycolytic activity of adequately perfused, viable neoplastic cells.
Nonlinvasive evaluation of skeletal tissue, particularly certain site6 that tend to be predispose... more Nonlinvasive evaluation of skeletal tissue, particularly certain site6 that tend to be predisposed to disease, is critical in understandlng the pathogenesis, progression, and successf ul treatment of various diseases like osteoporosis, rheumatoid arthritis, and osteoarthritis. Although several noninvasive techniques are currently available to evaluate skeletal tissues, they all have critical Ilmltations. We report here a systematic study to compare the morphological changes (overall profile and tlssue architecture) in the proximal tibiae and coccygeal vertebrae oi a young growing rat and an older retired female bm-r rat using 2-and 3-dimensional MR (magnetic resonance) microscopy and histology. We have obtained MR microimages of intact rat tibiae and vettebrae with resolution upto 24 24 250 pm and have found exmilent correlations between MR microscopy results and histological asiessment.
The potential adverse biologic effects of sub chronic (cumulatively 10 weeks) exposure to a high ... more The potential adverse biologic effects of sub chronic (cumulatively 10 weeks) exposure to a high magnetic field (9.4 T) were evaluated in young adult male and female Fischer rats as well as in their progeny. Biologic end points in adult rats included changes in daily clinical observations; spatial memory tests; weekly heart rates, body weights, food and water consumption, and the feed efficiency ratio; terminal hematologic, blood biochemical and urinary parameter changes; gross pathologic findings; and major organ weights. In offspring, biologic end points included the gestation period, number of live births, number of pups, ratio of male to female pups/litter; postnatal time period of eye opening; birth and weekly body weights, behavioral changes, central nervous system responses, as well as hematologic, blood biochemistry, and urinary parameter changes; and gross pathologic findings. Findings from this study showed that there were no adverse biologic effects in male and female adult rats or their progeny that could be attributed to 10-week exposure to a 9.4-T static magnetic field.
The secretory response to 16, 16-dimethyl prostaglandin E 2 (DMPG) administered orally in 4 diffe... more The secretory response to 16, 16-dimethyl prostaglandin E 2 (DMPG) administered orally in 4 different dosages and to placebo was evaluated in healthy volunteers over a 2-hr period. During stimulation of gastric secretion by histamine, DMPG at the highest dosage (1.5 /J.g per kg) reduced volume by 47% and acid output by 79%. Pepsin concentration was not affected. At the same dose, DMPG inhibited basal secretion by 54% and 99% for volume and acid output, respectively. There were no side effects secondary to DMPG administration, which indicates that this compound may be useful in treating peptic ulcer disease. Prostaglandins are 20-carbon fatty acids which are synthesized from essential fatty acid precursors in man. These ubiquitous pharmacologically potent compounds affect a variety of biological functions and may play a role in some pathological states. One pharmacological action common to some prostaglandins is their inhibitory effect on gastric acid secretion. The efficacy of prostaglandins E,. E 2. and A, as antisecretory compounds against both pharmacological and physiological stimu
Toxicologic pathology is transitioning from analog to digital methods. This transition seems inev... more Toxicologic pathology is transitioning from analog to digital methods. This transition seems inevitable due to a host of ongoing social and medical technological forces. Of these, artificial intelligence (AI) and in particular machine learning (ML) are globally disruptive, rapidly growing sectors of technology whose impact on the long-established field of histopathology is quickly being realized. The development of increasing numbers of algorithms, peering ever deeper into the histopathological space, has demonstrated to the scientific community that AI pathology platforms are now poised to truly impact the future of precision and personalized medicine. However, as with all great technological advances, there are implementation and adoption challenges. This review aims to define common and relevant AI and ML terminology, describe data generation and interpretation, outline current and potential future business cases, discuss validation and regulatory hurdles, and most importantly, p...
1986) describing the effects of prostaglandin E-I and E-2 on bone remodeling during healing in be... more 1986) describing the effects of prostaglandin E-I and E-2 on bone remodeling during healing in beagle dogs is informative and of scientific interest. However, the authors did not correctly describe my own contribution to that study. Dr. J. Babcock of the Upjohn Company approved the appropriation of company funds to support the study, upon the recommendation of the Project Bone Team. The study was originally conceived as a collaborative effort between myself, the Upjohn Company, and R. W. Norridin of Colorado State University. My personal contribution to the study concerned the (optimal) dosages, vehicles, routes, and duration of treatment used, which were based on the results of three previous (in-house) Upjohn studies in beagle dogs. These studies included (1) a 30-day I.V. PG E-1 study in normal intact beagle dogs (conducted by J. Lund and evaluated and interpreted by me); (2) a 3-month oral PG E-2 study in normal, intact, adult beagle dogs (conducted, evaluated, and interpreted by me); and (3) an oral PG E-2/Fracture study in adult beagle dogs (conducted, evaluated, and interpreted by me). Results of studies 1 and 2 were presented orally in August 1982 at the Sun Valley Bone Workshop, and in November 1982 at the Orthopaedic Specialty Session of the 33rd Annual Meeting of the American College of Veterinary Pathologists. Study 3 was presented orally in August 1983 at the Sun Valley Bone Workshop, and in December 1983 at the Orthopaedic Specialty Session of the 34th Annual Meeting of the American College of Veterinary Pathologists. Abstracts of these three studies were published in the proceedings of the 1982 [1] and 1983 [2] Annual Meeting of the American College of Veterinary Pathologists.
... specimens were not performed in the study. The purpose of this present study was to examine t... more ... specimens were not performed in the study. The purpose of this present study was to examine the pathological skeletal changes associated with the intraosseous infusion of sodium bicarbonate in swine. Moreover, the physiological effects of this ...
The effects of 1,25-dihydroxycholecalciferol (1,25-(OH)2D3), parathyroid hormone (PTH), and L-thy... more The effects of 1,25-dihydroxycholecalciferol (1,25-(OH)2D3), parathyroid hormone (PTH), and L-thyroxine (T4) on trabecular bone remodeling were evaluated by histomorphometric methods in adult female beagle dogs. Intravenous 1,25-(OH)2D3 (1.25 micrograms/day in equally divided doses) was administered intermittently for 6 days and withdrawn 14 days for three complete cycles. PTH was administered intravenously (2.5 U/kg/day) in divided doses 6 hours apart for 60 days. Thyroxine was given orally (1.0 mg/kg/day) in divided doses for a similar interval. Static and dynamic changes were evaluated using tetracycline and DCAF (2,4 BIS) N, N', Di (carboxymethyl) (amino methyl fluorescein) in vivo double labeling of bone from the iliac crest taken before treatment and after 60 days. The intermittent administration of 1,25-(OH)2D3 stimulated the bone resorption rate and depressed the formation rate. 1,25-(OH)2D3 increased trabecular resorption surfaces; osteoid surface, volume, and thickness; mineralization lag time; and osteoblast number but decreased the bone volume. Multiple small daily doses of PTH resulted in an overall negative balance in trabecular bone. This was associated with an increased trabecular surface-to-volume ratio, bone resorption and formation rates, active forming surfaces, osteoid volume and surface, life span of bone forming and resorbing sites, and the number of osteoclast nuclei. Thyroxine appeared to increase bone mass by enhancing the switch-over from the resorptive to the formative phase of remodeling. Coupling between osteoid apposition and mineralization was increased by recruiting more forming sites and prolonging their life span. Thyroxine increased bone resorption and formation rates, trabecular bone volume and balance, number of osteoclast nuclei, and life span of bone forming sites. The osteoid seam thickness and mineralization lag time were decreased. The present study demonstrated that 1,25-(OH)2D3, PTH, and thyroxine at the dose and schedule used, markedly altered stimulators of remodeling in trabecular bone of adult dogs.
Prostaglandins Leukotrienes and Essential Fatty Acids, Nov 1, 1990
Prostaglandins of the E series, primarily E2 and E1, have the greatest activity in bone. Followin... more Prostaglandins of the E series, primarily E2 and E1, have the greatest activity in bone. Following discovery of their potent ability to stimulate bone resorption in vitro, clinical investigations have placed prostaglandins at sites of localized bone resorption associated with inflammatory or space occupying lesions in vivo. These studies have shown that prostaglandin production at such sites may be increased by cytokines such as interleukin-1 but the mechanisms by which prostaglandins stimulate bone resorption are not yet known. Observation of periosteal bone formation in patients given, pharmacological doses of prostaglandin has led to investigation of its bone forming activity. Young, growing rats have increased metaphyseal bone formation and this is accompanied by increased periosteal and endocortical bone formation in older animals. In the mature animals there is a generalized activation of remodelling with increased formation in the remodeling cycle. This is also seen in oophorectomized rats and results in repletion of the lost bone in this model of osteoporosis. In animal models of localized disuse osteopenia, prostaglandins are found to be elevated at the site of bone loss and prostaglandin inhibitors at least partially protect against the exaggerated resorption that occurs. This is also seen in models of orthodontic tooth movement, periodontitis and osteomyelitis. Prostaglandin synthesis inhibitors have been shown to delay healing of bone and this has led to limitations on their use clinically in some situations. Exogenously administered prostaglandins have been found to enhance periosteal callus formation, but healing is not uniformly enhanced. Prostaglandins have also been associated with hypercalcemia in certain animal tumors that model human hypercalcemia of malignancy but are probably most important in this condition as mediators in the localized resorption of bone at tumor sites. These in vivo studies have shown that prostaglandins are involved with increases in both bone formation and bone resorption. In vitro studies have shown that prostaglandins stimulate osteoblasts as well as osteoclastic bone resorption but understanding these effects under in vivo conditions will require further investigation.
The INHAND (International Harmonization of Nomenclature and Diagnostic Criteria for Lesions in Ra... more The INHAND (International Harmonization of Nomenclature and Diagnostic Criteria for Lesions in Rats and Mice) Project (www.toxpath.org/inhand.asp) is an initiative of the Societies of Toxicological Pathology from Europe (ESTP), Great Britain (BSTP), Japan (JSTP) and North America (STP) to develop an internationally accepted nomenclature for proliferative and nonproliferative lesions in laboratory animals. The purpose of this publication is to provide a standardized nomenclature for classifying microscopic lesions observed in the skeletal tissues and teeth of laboratory rats and mice, with color photomicrographs illustrating examples of many common lesions. The standardized nomenclature presented in this document is also available on the internet (http://www.goreni.org/). Sources of material were databases from government, academic and industrial laboratories throughout the world.
Histopathologic evaluation and peer review using digital whole-slide images (WSIs) is a relativel... more Histopathologic evaluation and peer review using digital whole-slide images (WSIs) is a relatively new medium for assessing nonclinical toxicology studies in Good Laboratory Practice (GLP) environments. To better understand the present and future use of digital pathology in nonclinical toxicology studies, the Society of Toxicologic Pathology (STP) formed a working group to survey STP members with the goal of creating recommendations for implementation. The survey was administered in December 2019, immediately before the COVID-19 pandemic, and the results suggested that the use of digital histopathology for routine GLP histopathology assessment was not widespread. Subsequently, in follow-up correspondence during the pandemic, many responding institutions either began investigating or adopting digital WSI systems to reduce employee exposure to COVID-19. Therefore, the working group presents the survey results as a pre-pandemic baseline data set. Recommendations for use of WSI systems ...
Elevated tissue lactate concentrations typically found in tumors can be measured by in vivo nucle... more Elevated tissue lactate concentrations typically found in tumors can be measured by in vivo nuclear magnetic resonance (NMR) spectroscopy. In this study, lactate turnover in rat C6 glioma was determined from in vivo 1H NMR measurements of [3-13C]lactate buildup during steady-state hyperglycemia with [1-13C]glucose. With this tumor model, a narrow range of values was observed for the first-order rate constant that describes lactate efflux, k2 = 0.043 +/- 0.007 (n = 12) SD min-1. For individual animals, the standard error in k2 was small (< 18%), which indicated that the NMR data fit the kinetic model well. Lactate measurements before and after infusing [1-13C]glucose showed that the majority of the tumor lactate pool was metabolically active. Signals from 13C-labeled glutamate in tumors were at least 10-fold smaller than the [3-13C]lactate signal, whereas spectra of the contralateral hemispheres revealed the expected labeling of [4-13C]glutamate, as well as [2-13C] and [3-13C]glut...
The effects of intermittent low doses (1.25 mug daily, administered intravenously for 6 days and ... more The effects of intermittent low doses (1.25 mug daily, administered intravenously for 6 days and withdrawn for 14 days for 3 complete cycles) of 1,25-dihydroxycholecalciferol (1,25-[OH](2)D(3)) on cortical bone were determined and compared in ribs with steady state and regionally accelerated remodeling in adult intact female dogs. The bone changes were analyzed by dynamic bone histomorphometric methods, using tetracycline and DCAF (2,4 BIS) N, N' di (carboxymethyl) (amino methyl fluorescein) in vivo double labeling of bones before treatment and after 60 days of intermittent 1,25-(OH)(2)D(3) administration. Serum calcium and phosphorus levels increased during 1,25-(OH)(2)D(3) administration. Urinary hydroxyproline excretion increased during the first interval of 1,25-(OH)(2)D(3) administration but was not changed significantly during the last two intervals. In normal cortical bone (11th rib) following the administration of 1,25-(OH)(2)D(3) there was a marked decrease in the activ...
Drug-induced vascular injury (DIVI) is a recurrent challenge in the development of novel pharmace... more Drug-induced vascular injury (DIVI) is a recurrent challenge in the development of novel pharmaceutical agents. Although DIVI in laboratory animal species has been well characterized for vasoactive small molecules, there is little available information regarding DIVI associated with biotherapeutics such as peptides/proteins or antibodies. Because of the uncertainty about whether DIVI in preclinical studies is predictive of effects in humans and the lack of robust biomarkers of DIVI, preclinical DIVI findings can cause considerable delays in or even halt development of promising new drugs. This review discusses standard terminology, characteristics, and mechanisms of DIVI associated with biotherapeutics. Guidance and points to consider for the toxicologist and pathologist facing preclinical cases of biotherapeutic-related DIVI are outlined, and examples of regulatory feedback for each of the mechanistic types of DIVI are included to provide insight into risk assessment.
Increased capacity for glycolytic metabolism is a well-known characteristic of neoplastic cells. ... more Increased capacity for glycolytic metabolism is a well-known characteristic of neoplastic cells. Because lactic acid is the end product of glycolysis, in vivo MRS measurements of tumor lactate concentration ([lac],) may provide valuable information about tumor metabolism, which will aid the development of therapies and the clinical diagnosis and treatment of tumors. In the present study, several hemodynamic and histologic parameters were evaluated with respect to their influence on [lac],. Pronounced differences in [lac], in two distinct populations of tumors suggested a putative perfusion threshold. Above this threshold, [lac], was independent of hemodynamic and histologic factors including tumor blood flow (measured using MRS and the method of D,O washout), extent of necrosis and inflammatory cell infiltrate. Thus, for most tumors, [lac], was not determined by any one single factor such as hypoxia, venous clearance, glucose supply, extent of necrosis or degree of inflammatory cell infiltrate. Rather, [lac], may be equilibrated, at least in part, by an interplay of forces involving hemodynamics and substrate supply. In general, the data are consistent with the hypothesis that elevated lactate in most tumors is related to the high glycolytic activity of adequately perfused, viable neoplastic cells.
Nonlinvasive evaluation of skeletal tissue, particularly certain site6 that tend to be predispose... more Nonlinvasive evaluation of skeletal tissue, particularly certain site6 that tend to be predisposed to disease, is critical in understandlng the pathogenesis, progression, and successf ul treatment of various diseases like osteoporosis, rheumatoid arthritis, and osteoarthritis. Although several noninvasive techniques are currently available to evaluate skeletal tissues, they all have critical Ilmltations. We report here a systematic study to compare the morphological changes (overall profile and tlssue architecture) in the proximal tibiae and coccygeal vertebrae oi a young growing rat and an older retired female bm-r rat using 2-and 3-dimensional MR (magnetic resonance) microscopy and histology. We have obtained MR microimages of intact rat tibiae and vettebrae with resolution upto 24 24 250 pm and have found exmilent correlations between MR microscopy results and histological asiessment.
The potential adverse biologic effects of sub chronic (cumulatively 10 weeks) exposure to a high ... more The potential adverse biologic effects of sub chronic (cumulatively 10 weeks) exposure to a high magnetic field (9.4 T) were evaluated in young adult male and female Fischer rats as well as in their progeny. Biologic end points in adult rats included changes in daily clinical observations; spatial memory tests; weekly heart rates, body weights, food and water consumption, and the feed efficiency ratio; terminal hematologic, blood biochemical and urinary parameter changes; gross pathologic findings; and major organ weights. In offspring, biologic end points included the gestation period, number of live births, number of pups, ratio of male to female pups/litter; postnatal time period of eye opening; birth and weekly body weights, behavioral changes, central nervous system responses, as well as hematologic, blood biochemistry, and urinary parameter changes; and gross pathologic findings. Findings from this study showed that there were no adverse biologic effects in male and female adult rats or their progeny that could be attributed to 10-week exposure to a 9.4-T static magnetic field.
The secretory response to 16, 16-dimethyl prostaglandin E 2 (DMPG) administered orally in 4 diffe... more The secretory response to 16, 16-dimethyl prostaglandin E 2 (DMPG) administered orally in 4 different dosages and to placebo was evaluated in healthy volunteers over a 2-hr period. During stimulation of gastric secretion by histamine, DMPG at the highest dosage (1.5 /J.g per kg) reduced volume by 47% and acid output by 79%. Pepsin concentration was not affected. At the same dose, DMPG inhibited basal secretion by 54% and 99% for volume and acid output, respectively. There were no side effects secondary to DMPG administration, which indicates that this compound may be useful in treating peptic ulcer disease. Prostaglandins are 20-carbon fatty acids which are synthesized from essential fatty acid precursors in man. These ubiquitous pharmacologically potent compounds affect a variety of biological functions and may play a role in some pathological states. One pharmacological action common to some prostaglandins is their inhibitory effect on gastric acid secretion. The efficacy of prostaglandins E,. E 2. and A, as antisecretory compounds against both pharmacological and physiological stimu
Toxicologic pathology is transitioning from analog to digital methods. This transition seems inev... more Toxicologic pathology is transitioning from analog to digital methods. This transition seems inevitable due to a host of ongoing social and medical technological forces. Of these, artificial intelligence (AI) and in particular machine learning (ML) are globally disruptive, rapidly growing sectors of technology whose impact on the long-established field of histopathology is quickly being realized. The development of increasing numbers of algorithms, peering ever deeper into the histopathological space, has demonstrated to the scientific community that AI pathology platforms are now poised to truly impact the future of precision and personalized medicine. However, as with all great technological advances, there are implementation and adoption challenges. This review aims to define common and relevant AI and ML terminology, describe data generation and interpretation, outline current and potential future business cases, discuss validation and regulatory hurdles, and most importantly, p...
1986) describing the effects of prostaglandin E-I and E-2 on bone remodeling during healing in be... more 1986) describing the effects of prostaglandin E-I and E-2 on bone remodeling during healing in beagle dogs is informative and of scientific interest. However, the authors did not correctly describe my own contribution to that study. Dr. J. Babcock of the Upjohn Company approved the appropriation of company funds to support the study, upon the recommendation of the Project Bone Team. The study was originally conceived as a collaborative effort between myself, the Upjohn Company, and R. W. Norridin of Colorado State University. My personal contribution to the study concerned the (optimal) dosages, vehicles, routes, and duration of treatment used, which were based on the results of three previous (in-house) Upjohn studies in beagle dogs. These studies included (1) a 30-day I.V. PG E-1 study in normal intact beagle dogs (conducted by J. Lund and evaluated and interpreted by me); (2) a 3-month oral PG E-2 study in normal, intact, adult beagle dogs (conducted, evaluated, and interpreted by me); and (3) an oral PG E-2/Fracture study in adult beagle dogs (conducted, evaluated, and interpreted by me). Results of studies 1 and 2 were presented orally in August 1982 at the Sun Valley Bone Workshop, and in November 1982 at the Orthopaedic Specialty Session of the 33rd Annual Meeting of the American College of Veterinary Pathologists. Study 3 was presented orally in August 1983 at the Sun Valley Bone Workshop, and in December 1983 at the Orthopaedic Specialty Session of the 34th Annual Meeting of the American College of Veterinary Pathologists. Abstracts of these three studies were published in the proceedings of the 1982 [1] and 1983 [2] Annual Meeting of the American College of Veterinary Pathologists.
... specimens were not performed in the study. The purpose of this present study was to examine t... more ... specimens were not performed in the study. The purpose of this present study was to examine the pathological skeletal changes associated with the intraosseous infusion of sodium bicarbonate in swine. Moreover, the physiological effects of this ...
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