Pathologic quiz case. Syncytial variant nodular sclerosing Hodgkin disease.
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Adult↗
Biomedical subjects
D L Morgan
Publications and source records attributed to D L Morgan.
Automaticity and the myth of personal agency.
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Automatism↗
Fluorescent tissue site-selective lanthanide chelate, Tb-PCTMB for enhanced imaging of cancer.
In-vivo and in-vitro investigations indicate that a newly developed polyazamacrocyclic chelate of Tb(III) has superior properties for use as an abnormal tissue marker. In addition to tissue selectivity, this molecule is unique because of its low toxicity, attractive fluorescent properties, rapid pharmokinetics, and relatively high water solubility. The complex Tb-3,6,9-tris(methylene phosphonic acid n-butyl ester)-3,6,9,15-tetraazabicyclo[9.3.1]-pentadeca-1(15),11,13 -triene (Tb-PCTMB) has also been shown to exhibit strongly shifted emission (delta lambda--280 nm), moving the detection frequency away from autofluorescence backgrounds, and good quantum efficiencies (phi = 0.51), providing high brightness. Fluorescence imaging was used to quantify Tb-PCTMB at the picomolar level in tissues and to show the significant difference in affinity for the chelate by adenocarcinoma cells HT-29 versus normal epithelial cells (IEC-6). Topical application, or lavage introduction, under endoscopy was used to instill a millimolar aqueous solution of Tb-PCTMB into a dimethylhydrizene-treated Sprague Dawley rat large intestine containing a suspect growth. Subsequent in vitro fluorescence detection and standard histological evaluation confirmed enhanced uptake by adenocarcinoma tissue. Semiquantitative signal interrogation was employed to show the potential for using Tb-PCTMB as a contrast enhancement marker for disease detection.
Animals↗
Genetic deletion of p21WAF1 enhances papilloma formation but not malignant conversion in experimental mouse skin carcinogenesis.
Tumor suppression by p53 is believed to reside in its ability to regulate gene transcription, including up-regulation of p21WAF1. In p53(-/-) mice, chemical- or oncogene-induced skin tumors undergo accelerated malignant conversion. To determine the contribution of the p21WAF1 gene product to epidermal carcinogenesis, animals +/+, +/-, and -/- for a null mutation in the p21WAF1 gene were treated once with 25 nmol 7,12-dimethylbenz[a]anthracene, followed by 5 microg of TPA two times/week for 20 weeks. Papilloma frequency was higher in the p21WAF1-deficient mice. However, the frequency of malignant conversion was similar among all three genotypes. After TPA treatment, all genotypes developed epidermal hyperplasia, although the labeling index was lower in p21WAF1 (-/-) epidermis compared with p21WAF1 (+/+). Furthermore, the expression of differentiation markers was the same across genotypes in untreated or TPA-treated epidermis. Similar frequencies of malignant conversion were also observed in an in vitro assay. Thus, p21WAF1 suppresses early stages of papilloma formation but not malignant progression in mouse skin carcinogenesis, and decreased levels of p21WAF1 do not account for the enhanced malignant conversion of p53 null epidermal tumors.
9,10-Dimethyl-1,2-benzanthracene↗
Specific inhibitors of platelet-derived growth factor or epidermal growth factor receptor tyrosine kinase reduce pulmonary fibrosis in rats.
The proliferation of myofibroblasts is a central feature of pulmonary fibrosis. In this study we have used tyrosine kinase inhibitors of the tyrphostin class to specifically block autophosphorylation of the platelet-derived growth factor receptor (PDGF-R) or epidermal growth factor receptor (EGF-R). AG1296 specifically inhibited autophosphorylation of PDGF-R and blocked PDGF-stimulated [3H]thymidine uptake by rat lung myofibroblasts in vitro. AG1478 was demonstrated as a selective blocker of EGF-R autophosphorylation and inhibited EGF-stimulated DNA synthesis in vitro. In a rat model of pulmonary fibrosis caused by intratracheal instillation of vanadium pentoxide (V2O5), intraperitoneal delivery of 50 mg/kg AG1296 or AG1478 in dimethylsulfoxide 1 hour before V2O5 instillation and again 2 days after instillation reduced the number of epithelial and mesenchymal cells incorporating bromodeoxyuridine (Brdu) by approximately 50% at 3 and 6 days after instillation. V2O5 instillation increased lung hydroxyproline fivefold 15 days after instillation, and AG1296 was more than 90% effective in preventing the increase in hydroxyproline, whereas AG1478 caused a 50% to 60% decrease in V2O5-stimulated hydroxyproline accumulation. These data provide evidence that PDGF and EGF receptor ligands are potent mitogens for collagen-producing mesenchymal cells during pulmonary fibrogenesis, and targeting tyrosine kinase receptors could offer a strategy for the treatment of fibrotic lung diseases.
Animals↗
Do cross-bridges contribute to the tension during stretch of passive muscle?
The tension rise during stretch of passive skeletal muscle is biphasic, with an initial steep rise, followed by a subsequent more gradual change. The initial rise has been interpreted as being due to the presence of numbers of long-term, stable cross-bridges in resting muscle fibres. A point of weakness with the cross-bridge interpretation is that the initial stiffness reaches its peak value at muscle lengths beyond the optimum for myofilament overlap. To explain this result it has been suggested that despite the reduced overlap at longer lengths, the closer interfilament spacing and a higher sensitivity of the myofilaments to Ca2+ allows more stable cross-bridges to form. Recently the stretch responses of passive muscle have been re-examined and it has been suggested that it is not necessary to invoke cross-bridge mechanisms at all. Explanations based on a viscous resistance to interfilament sliding and mechanical properties of the elastic filaments, the gap filaments, were thought to adequately account for the observed tension changes. However, an important property of passive muscle, the dependence of stretch responses on the immediate history of contraction and length changes, thixotropy, cannot be explained simply in terms of viscous and viscoelastic properties. The review discusses the cross-bridge interpretation of muscle thixotropy and the relationship of passive stiffness to filament resting tension and latency relaxation. It is proposed that cross-bridges can exist in three states; one, responsible for the resting stiffness, requires resting levels of calcium. When, during activation, calcium levels rise, cross-bridges enter a low-force, high-stiffness state, signalled by latency relaxation, before they move to the third, force-generating state. It is concluded that, compared with viscoelastic models, a cross-bridge-based explanation of passive muscle properties is better able to accommodate the currently known facts although, as new information becomes available, this view may need to be revised.
Actin Cytoskeleton↗
Diagnosing dementia: perspectives of primary care physicians.
As few as 50% of dementia cases are diagnosed by physicians. This study investigated how primary care physicians assess patients for dementia and identified barriers to dementia diagnosis in the primary care setting. Seventy-eight physicians in three geographic areas participated in 18 focus groups. Barriers identified included: (a) the failure to recognize and respond to symptoms of dementia; (b) a perceived lack of need to determine a specific diagnosis; (c) limited time; and (d) negative attitudes toward the importance of assessment and diagnosis. These barriers keep physicians from diagnosing dementia and, consequently, from offering concrete help for patients experiencing symptoms of dementia or for the families who care for them.
Aged↗
Characterization of inhaled alpha-methylstyrene vapor toxicity for B6C3F1 mice and F344 rats.
alpha-Methylstyrene (AMS) is a chemical intermediate used in the synthesis of specialty polymers and copolymers. Inhalation studies of AMS were conducted because of the lack of toxicity data and the structural similarity of AMS to styrene, a toxic and potentially carcinogenic chemical. Male and female B6C3F1 mice were exposed to 0, 600, 800, or 1000 ppm AMS 6 h/day, 5 days/week, for 12 days. After 1 exposure, 21% (5/24) of female mice were found dead in the 1000-ppm group, 56% (10/18) in the 800-ppm group, and 6% (1/18) in the 600-ppm concentration group. After 12 exposures, relative liver weights were significantly increased and relative spleen weights were significantly decreased in both male and female mice at all concentrations. No microscopic treatment-related lesions were observed. A decrease in hepatic glutathione (GSH) was associated with AMS exposure for 1 and 5 days. Male and female F344 rats were exposed to 0, 600 or 1000 ppm AMS for 12 days. No mortality or sedation occurred in AMS-exposed rats. Relative liver weights were significantly increased in both males and females after 12 exposures to 600 or 1000 ppm. An increased hyaline droplet accumulation was detected in male rats in both concentration groups; no significant microscopic lesions were observed in other tissues examined. Exposure of male and female F344 rats and male NBR rats to 0, 125, 250 or 500 ppm AMS, 6 h/day for 9 days resulted in increased accumulation of hyaline droplets in the renal tubules of male F344 rats in the 250 and 500 ppm concentration groups. Although AMS and styrene are structurally very similar, AMS was considerably less toxic for mice and more toxic for male rats than styrene.
Administration, Inhalation↗
Characterization of hepatocellular resistance and susceptibility to styrene toxicity in B6C3F1 mice.
Short-term inhalation exposure of B6C3F1 mice to styrene causes necrosis of centrilobular (CL) hepatocytes. However, in spite of continued exposure, the necrotic parenchyma is rapidly regenerated, indicating resistance by regenerated cells to styrene toxicity. These studies were conducted to test the hypothesis that resistance to repeated styrene exposure is due to sustained cell proliferation, with production of hepatocytes that have reduced metabolic capacity. Male mice were exposed to air or 500 ppm styrene (6 h/day); hepatotoxicity was evaluated by microscopic examination, serum liver enzyme levels, and bromodeoxyuridine (BrdU)-labeling index (LI). Metabolism was assessed by measurement of blood styrene and styrene oxide. Both single and repeated exposures to styrene resulted in mortality by Day 2; in mice that survived, there was CL necrosis with elevated BrdU LI at Day 6, and complete restoration of the necrotic parenchyma by Day 15. The BrdU LI in mice given a single exposure had returned to control levels by Day 15. Re-exposure of these mice on Day 15 resulted in additional mortality and hepatocellular necrosis, indicating that regenerated CL cells were again susceptible to the cytolethal effect of styrene following a 14-day recovery. However, in mice repeatedly exposed to styrene for 14 days, the BrdU LI remained significantly increased on Day 15, with preferential labeling of CL hepatocytes with enlarged nuclei (karyomegaly). If repeated exposures were followed by a 10-day recovery period, CL karyomegaly persisted, but the BrdU LI returned to control level and CL hepatocytes became susceptible again to styrene toxicity as demonstrated by additional mortality and acute necrosis after a challenge exposure. These findings indicated a requirement for continued styrene exposure and DNA synthesis in order to maintain this resistant phenotype. Analyses of proliferating-cell nuclear-antigen (PCNA) labeling were conducted to further characterize the cell cycle kinetics of these hepatocytes. The proportion of cells in S-phase was increased by repeated exposure. However, PCNA analysis also revealed an even larger increase in the G1 cell compartment with repeated exposures, without a concurrent increase in G2 phase or in mitotic cell numbers. These data indicate that resistance to styrene-induced necrosis under conditions of repeated exposure is not due to sustained cell turnover and production of new, metabolically inactive cells, but rather is due to some other, as yet unknown, protective phenotype of the regenerated cells.
Administration, Inhalation↗
Exposure of C57BL/6 mice to carbon disulfide induces early lesions of atherosclerosis and enhances arterial fatty deposits induced by a high fat diet.
Even though atherosclerotic cardiovascular disease (ACVD) is the number one cause of death in the United States, the effects of environmental toxicants on this process are less well studied than the effects of chemicals on the second leading cause of death, cancer. There is considerable epidemiological evidence that workers exposed to carbon disulfide (CS2) have increased rates of ACVD, and there is conflicting evidence of the atherogenic potential of CS2 from animal studies. Chemical modification, such as oxidation of low-density lipoproteins (LDL), is tightly associated with increased LDL uptake by macrophages and the development of arterial fatty streaks. CS2 has been previously demonstrated to modify several proteins in vitro including LDL, and others in vivo through derivatization and covalent cross-linking. To investigate both the capacity of CS2 to induce arterial fatty deposits by itself, and its ability to enhance the rate of fatty deposit formation induced by a western style, high fat diet, groups of 20 female C57BL/6 mice were exposed to 0, 50, 500, or 800 ppm CS2 by inhalation. Half the animals in each group were placed on an atherogenic high fat diet and half on a control diet (NIH-07). Animals were sacrificed after 1, 4, 8, 12, 16, or 20 weeks of exposure, and the rates of fatty deposit formation under the aortic valve leaflets were evaluated. Exposure of mice on the control diet to 500 and 800 ppm CS2 induced a small but significant increase in the rate of fatty deposit formation over non-exposed controls. A more striking result was observed in the animals on the high fat diet. There was marked enhancement of the rate of fatty deposit formation in mice exposed to 500 and 800 ppm over the animals on the high fat diet alone. In addition, there was a small but significant enhancement in mice exposed to 50 ppm over the rate of fatty deposit formation induced by the high fat diet alone. Analysis of erythrocyte spectrin for protein cross-linking revealed a dose-dependent formation of alpha- and beta-heterodimers in animals on both diets. These data demonstrate that CS2 is atherogenic at high concentrations, but more importantly, suggest that, in conjunction with other risk factors, CS2 at relatively low concentrations can enhance atherogenesis.
Administration, Inhalation↗
A new strategy for controlling the level of activation in artificially stimulated muscle.
Distributed stimulation of slow skeletal muscle has previously been used to produce smooth tetanic contractions at low stimulus rates. This involved distributed or interleaved stimulation of portions of the muscle with near equal tension contributions. Extending this to fast and mixed muscle encounters difficulties in getting and maintaining equal twitch responses for the portions. This need has now been circumvented by using distributed stimulation with unequal interpulse intervals. Described here is a microprocessor-based eight channel distributed muscle stimulator that can adjust stimulation timing to produce an optimally smooth tension over a range of stimulus rates even when the portions are unequal. This design is based on modeling results. Distributed stimulation experiments performed on skeletal muscle show that this method can be used to achieve smooth tension at physiological stimulus rates, which should reduce fatigue. This has important implications in functional neuromuscular stimulation (FNS) as well as in enabling experiments to be conducted to characterize the biomechanical behavior of partially activated fast and mixed muscle.
Animals↗
Early events in stretch-induced muscle damage.
Unaccustomed exercise involving stretch of active muscle at long length causes an immediate loss of tension-generating capacity, a shift of optimum length, and changes in excitation-contraction coupling. Eventually, fiber damage may be observed, resulting in pain and tenderness. The subject of this review is the early stage in this process, particularly the cause of the immediate drop in tension. There is strong evidence pointing to sarcomere length instabilities and nonuniformities as important contributors to these changes. The evidence includes the influence of initial length, electron microscopy of rapidly fixed active fibers, the shift in optimum length in single fibers, and the effects of training on sacomere numbers. Experiments using Ca(2+)-sensitive dyes clearly show changes in excitiation-contraction coupling, but cross-species comparisons indicate that these are not always able to explain the consequences seen. We conclude that sarcomere length instabilities provide the most comprehensive explanation of the early consequences of eccentric exercise.
Animals↗
Damage to human muscle from eccentric exercise after training with concentric exercise.
1. It is known that a period of eccentric exercise provides protection against damage to muscle from subsequent eccentric exercise. Here we ask, does concentric exercise do the opposite, make muscle more prone to damage? 2. The triceps surae muscle group of one leg in each of eight human subjects was subjected to 30 min of concentric exercise per day, for 5 days. At the end of the training period there was a small but significant increase in passive torque in the exercised muscle (P < 0.05), with no changes in the untrained muscle. 3. After a single period of eccentric exercise, angle-torque curves for muscles of both legs shifted in the direction of longer muscle lengths, suggestive of an increase in series compliance. The shift in the concentrically trained muscle was significantly greater over the first 48 h post-exercise (P < 0. 05). 4. The volume of the trained leg increased significantly more than the untrained leg for five subjects over 72 h post-exercise (P < 0.05). Peak torque fell, passive stiffness increased and both muscles became sore, but with no significant differences between the two legs. 5. It is concluded that a period of concentric exercise increases the susceptibility of muscle to changes associated with the damage from eccentric exercise.
Adult↗
The effect of length on the relationship between tension and intracellular [Ca2+] in intact frog skeletal muscle fibres.
1. The relationship between tension and intracellular calcium concentration ([Ca2+]i) in intact frog skeletal muscle fibres was determined at two fibre lengths, corresponding to mean sarcomere lengths (SL) of 2.2 and 2.9 micron. Tension and [Ca2+]i were recorded during the slow decline of tension following stimulation in the presence of cyclopiazonic acid (CPA), a sarcoplasmic reticulum Ca2+-uptake pump inhibitor. [Ca2+]i was estimated by injecting the K+ salt form of the fluorescent dye fura-2 into the fibres. Experimental temperature was 3.0 C. 2. At a SL of 2.2 micron, where thick and thin filaments fully overlap, the [Ca2+]i corresponding to 50 % tension generation ([Ca2+]50) was 1.09 +/- 0.02 microM (mean +/- S.E.M., n = 61 contractions). At a SL of 2.9 micron, where overlap is approximately 50 %, the [Ca2+]50 was significantly lower, 0.69 +/- 0. 02 microM (n = 22 contractions). This is in agreement with previous results from skinned fibres. 3. The relationship between tension and [Ca2+]i was very steep, as reported previously from experiments at a SL of 2.2 micron in which the membrane permeant acetoxymethyl ester form of fura-2 was used. The fall in tension from 90 to 10 % occurred in 0.12 +/- 0.01 pCa units (mean +/- S.E.M., n = 61) for a SL of 2.2 micron and 0.17 +/- 0.01 pCa units (n = 22) for a SL of 2.9 micron, corresponding to Hill coefficients of 15.4 and 10.9, respectively. 4. We conclude that the increase in sensitivity of tension to [Ca2+] that occurs in skinned skeletal muscle fibres upon stretch also occurs in intact fibres, that the steepness of the relation between tension and [Ca2+]i in intact fibres reported previously cannot be attributed to the use of the acetoxymethyl ester form of fura-2 to report [Ca2+]i, and that the steepness decreases as myofilament overlap decreases.
Animals↗
Topical retinoic acid reduces skin papilloma formation but resistant papillomas are at high risk for malignant conversion.
Retinoic acid (RA) was topically applied to the skin of Sencar mice during the promotion phase of specific tumor induction protocols that produce papillomas at low (12-O-tetradecanoylphorbol-13-acetate promoted, TPA) or high (mezerein-promoted) risk for premalignant progression and malignant conversion. RA consistently reduced the yield of papillomas and carcinomas in both protocols, but the frequency of malignant conversion in papillomas that emerged during RA treatment was not reduced. When TPA was reapplied after cessation of RA treatment, the number of papillomas increased 2-fold, suggesting that RA had not eliminated initiated cells. In vitro, RA prevented the emergence of transformed keratinocytes in an assay that mimics malignant conversion, suggesting that RA can suppress conversion if applied during the stage of premalignant progression. Examination of tumor markers at weeks 14 and 22 of the tumor-induction experiments in vivo indicated that papillomas evolving during RA treatment exhibited a phenotype of high progression risk, even in the TPA-promoted groups. In the majority of these tumors, the alpha6beta4 integrin and retinoid X receptor alpha transcripts were detected suprabasally, indicating an advanced state of premalignant progression. RA-treated tumors also expressed higher levels of transcripts for transforming growth factor (TGF)-beta1 and localized TGF-beta1 peptide in the basal portions of the tumor fronds. Because up-regulated expression of TGF-beta1 suppresses papilloma formation, these studies suggest a mechanism whereby RA can prevent papilloma eruption via a TGF-beta intermediate, but papillomas resistant to RA may have altered TGF-beta signaling and progress to carcinomas at an increased frequency.
Administration, Topical↗
Cooperation of p53 loss of function and v-Ha-ras in transformation of mouse keratinocyte cell lines.
We previously demonstrated that after transduction with the v-Ha-ras oncogene and grafting onto nude mouse hosts, primary epidermal keratinocytes with a null mutation in the p53 gene form tumors with increased growth rates and predisposition to malignant conversion relative to p53 wild-type keratinocytes (Weinberg WC, et al., Cancer Res 54:5584-5592, 1994). To further explore the cooperation between p53 loss of function and activation of the ras oncogene, cell lines were established from the normal epidermises of newborn and adult p53-null mice, and parallel subclones were reconstituted with the p53val135 temperature-sensitive mutant. Reconstituted lines C, G, N, and V demonstrated functional p53 transcriptional activator activity at the wild-type-permissive temperature of 32 degrees C, compared with the hygromycin-selected control line X and parental p53-null lines NHK4 and AK1b. Hygromycin-selected subclones, but not the parental lines, made normal skin in vivo; all cell lines made carcinomas after introduction of v-Ha-ras, independent of p53 status. These cell lines were compared in vitro at 32 degrees C to maximize the amount of p53val135 in the wild-type conformation. Expression of v-Ha-ras did not consistently alter p53-mediated transcriptional activity, suggesting tat ras acts downstream or independently of p53. No correlation was observed between p53-mediated transcriptional activity and in vitro growth rates, colony formation after exposure to ultraviolet light, or suppression by normal neighboring keratinocytes. However, keratinocyte cell lines devoid of p53 and expressing v-Ha-ras formed colonies in soft agar; this was blocked at 32 degrees C in all cell lines reconstituted with p53val135. These keratinocyte lines provide a model for exploring the role of p53 and the interaction of p53 and ras in keratinocyte transformation.
Animals↗
Chronic eosinophilic leukemia and hypereosinophilic syndromes. Proposal for classification, literature review, and report of a case with a unique chromosomal abnormality.
The idiopathic hypereosinophilic syndromes (HES) are rare hematologic disorders characterized by persistent eosinophilia with organ involvement that encompass a wide spectrum of clinical and hematological disease states. We propose a classification scheme to further delineate these patients, and present a case of a 45-year-old male with persistent eosinophilia, severe tissue and hematologic involvement, and trisomy 15. Although multiple cytogenetic abnormalities have been associated with hypereosinophilic syndromes, this is the first reported case where trisomy 15 is the sole chromosomal abnormality.
Adult↗
Characterization of a valine-lysine thiourea cross-link on rat globin produced by carbon disulfide or N,N-diethyldithiocarbamate in vivo.
Previous in vivo studies have supported protein cross-linking by CS2 as both a mechanism of neurotoxicity and a potential biomarker of effect through the detection of a structure responsible for CS2-mediated protein cross-linking, namely, lysine-lysine thiourea. In this study, the structure of a previously uncharacterized stable protein cross-link produced by CS2 in vivo involving lysine and the N-terminal valine of globin has been determined. Rats were exposed to 50, 500, and 800 ppm CS2 for 2, 4, 8, and 13 weeks by inhalation or to 3 mmol/kg N,N-diethyldithiocarbamate administered orally on alternating days for 8 and 16 weeks. Acid hydrolysis, using 6 N HCl, of globin from control and exposed rats caused cyclization of the valine-lysine thiourea cross-link in treated rats to isopropyl norleucyl thiohydantoin. The hydrolysate was separated by size-exclusion chromatography, and the fraction that coeluted with the synthetic deuterated isopropyl norleucyl thiohydantoin internal standard was derivatized with 3-[4'-(ethylene-N,N, N-trimethylamino)phenyl]-2-isothiocyanate and analyzed by liquid chromatography/tandem mass spectrometry using selected reaction monitoring detection. Derivatized isopropyl norleucyl thiohydantoin obtained from CS2-treated rats displayed a cumulative dose response and was detectable at the lowest exposure (50 ppm, 2 weeks) at levels of approximately 50 pmol/g of globin. N, N-Diethyldithiocarbamate-treated rats, but not controls, also contained a CS2-generated valine-lysine thiourea cross-link on globin. In vitro incubation of human hemoglobin with either CS2 or N, N-diethyldithiocarbamate also resulted in the formation of CS2-generated valine-lysine thiourea. These observations demonstrate the potential of thiourea cross-linking involving a free amino terminus and epsilon-amino groups of lysine to accumulate in a long-lived globular protein and suggest that cross-linking of globin may provide a specific dosimeter of internal exposure for CS2 capable of assessing exposure over subchronic periods.
Animals↗