Past, present and future of gestational trophoblastic diseases.
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Antimetabolites, Antineoplastic↗
Biomedical subjects
J L Lewis
Publications and source records attributed to J L Lewis.
In vivo forces during remodeling of a two-segment anterior cruciate ligament graft in a goat model.
An existing goat model was used to measure in vivo graft forces during walking, to determine if the forces set at surgery change over time under the same external load and if the forces in the graft during in vivo function can be dictated by the forces set at surgery. The anterior cruciate ligament was reconstructed in 12 goats with use of a composite graft consisting of a bone-patellar tendon-bone autograft and a synthetic augmentation segment. The forces in the graft segments were established intraoperatively by a force-setting technique. In five animals, the tendon segment was set to carry 90% of the total graft force, and in the seven other animals, the augmentation segment was set to carry 90% of the total force. The total graft force was the same in all animals. Graft forces due to anterior tibial loads of 67 N were measured before and after fixation and 6 weeks after surgery with the use of buckle transducers mounted extra-articularly over the anterior tibia. They were also measured during straight, level walking at 6 weeks. The forces changed significantly from just after surgery to 6 weeks later, such that the initially set load-sharing was eliminated by 6 weeks. At 6 weeks, a relatively smooth gait had been achieved, and the maximum total graft force in each animal during walking averaged 35 N and was of similar magnitude to forces generated by the anterior tibial loads of 67 N with the animal anesthetized. After fixation, forces in the tendon graft segments were significantly different between the group with high set forces and that with low set forces. At 6 weeks, when functional joint loads were approaching normal levels, the graft segment forces for the two groups were not significantly different. Load-sharing between tendon and augmentation segment and load in the tendon segment at 6 weeks could not be dictated at surgery.
Animals↗
Local staging of prostate cancer with 0.2 T body coil MRI.
This study was undertaken to evaluate the accuracy of low field strength body coil MRI in the staging of clinically localized prostate cancer. Fifty-three patients with prostate cancer were examined on a 0.2 T body coil system before undergoing radical prostatectomy. Of the 20 cases with unconfined stage T3 disease on histology, 12 were correctly staged, whilst three cases were overstaged by MRI. (Accuracy 79.2%, sensitivity 60%, and specificity 90.9%.) The accuracy, sensitivity and specificity for the detection of capsular penetration were 77.3%, 55% and 90.9%, respectively, whilst those for seminal vesical invasion were 94.3%, 83.3% and 95.7%, respectively. It is concluded that a high level of staging accuracy, comparable to that obtained in some published studies using high field strength endorectal coil MRI, can be obtained using 0.2 T body coil MRI.
Aged↗
Management of high-risk gestational trophoblastic disease--the Memorial Hospital experience.
Thirty-two patients with high-risk gestational trophoblastic disease (GTD), defined as metastases to the brain or liver (regardless of hCG level or duration of disease) or prior unsuccessful chemotherapy are reviewed. In this classification, an antecedent term pregnancy is not considered to be an independent high-risk factor. Initial chemotherapy in 15 (46.8%) patients consisted of methotrexate, actinomycin D, and chlorambucil (MAC), actinomycin D alone in seven (21.8%), etoposide, methotrexate, actinomycin D, cytoxan on covin (EMACO) EMACO in three (9.4%), ITMA (hydroxyurea, vincristine, methotrexate, folinic acid, cyclophosphamide, actinomycin D, adriamycin, and melphalan) in three (9.4%). The remaining patients were treated with actinomycin D and 6-mercaptopurine (1), CHAMOCA (1), carboplatin and Taxol (1), and methotrexate (1). All patients with brain metastases were treated with cranial radiotherapy. Overall complete remission was achieved in 14 of 32 (43.7%) patients. Five of 9 (55.5%) patients whose disease followed a term pregnancy survived compared to nine of 23 (39.1%) patients whose disease followed other types of pregnancies. The data analyzed according to the clinical classification of 'high-risk' indicates that an overall survival rate of 70% was achieved. The Memorial Hospital classification therefore identifies patients who need primary chemotherapy more aggressive than MAC and similar to the WHO scoring system is a better predictor of survival than the clinical classification.
Journal Article↗
Benzo[a]pyrene at an environmentally relevant dose is slowly absorbed by, and extensively metabolized in, tracheal epithelium.
While tobacco smoke has been conclusively identified as a lung carcinogen, there is much debate over which smoke constituent(s) are primarily responsible for its carcinogenicity. Previous studies in our laboratory suggested that highly lipophilic carcinogens are slowly absorbed in the thicker epithelium of the conducting airways, potentially allowing for substantial local metabolism. The bioactivation of polycyclic aromatic hydrocarbons in airway epithelium may, hence, be important in tobacco smoke-induced carcinogenesis. In the present study, the hypothesis of slow absorption and substantial local metabolic activation of highly lipophilic carcinogen in airway epithelium was tested in dogs. A single dose of tritiated benzo[a]pyrene (BaP) dissolved in a saline/phospholipid suspension was instilled in the trachea, just anterior to the carina. At intervals of a few minutes up to 30 min over a 3-h period, blood samples were drawn from the azygous vein, which drains the area around the point of instillation, and from the systemic circulation. Tissue samples were taken at the end of the experiment. The concentration of BaP with depth into the tracheal mucosa was determined with autoradiography. BaP was slowly absorbed into the trachea with a half-time of approximately 73 min, which is consistent with diffusion-limited passage through the epithelium and lead to local doses in the tracheal epithelium that were more than a 1000-fold those of other tissues. The long retention of BaP in the epithelium provided the local metabolizing enzymes with high substrate levels over a long period, resulting in extensive metabolism. At 3 h after the exposure, 23% of the BaP-equivalent activity remained in the tracheal mucosa. Of this fraction, 13% was parent compound, 28% was organic extractable, 31% was water-soluble, and 28-7% of the instilled dose was bound to tracheal tissues. These results explain the tendency of highly lipophilic carcinogens, such as BaP, to induce tumors at the site of entry and, furthermore, indicate that the highly lipophilic components of tobacco smoke and polluted air may be the most important contributors to lung tumors of the conducting airways.
Absorption↗
An isotope-dilution gas chromatography-mass spectrometry method for trace analysis of xylene metabolites in tissues.
A gas chromatography-mass spectrometry (GC-MS) method using isotope dilution was developed to measure trace levels of xylene metabolites in brain tissues. The primary metabolites of xylene are dimethylphenol (DMP), methylbenzyl alcohol (MBA), toluic acid (TA), and methylhippuric acid (MHA). The internal standard was a mixture of deuterated DMP-d3, TA-d7, and MHA-d7. DMP-d3 was commercially available and was used as the internal standard for both DMP and MBA. TA-d7 and MHA-d7 were biosynthesized by administering xylene-d10 to rats and collecting their urine. Based on the noise peaks in 10 blank samples, the on-column limits of quantitation (mean +10 SD of noise peaks) were approximately 305, 1220, 545, and 386 pg for DMP, MBA, TA, and MHA, respectively. Analyte detection and recovery tests from brain tissues of control rats were conducted by spiking the tissues with 32 nmol/g of each analyte, together with the deuterated metabolites. The tissues were homogenized, extracted with ethyl acetate, and derivatized by trimethylsilylation. One microliter of the sample was injected into the GC-MS. The recoveries of the analytes were 104 +/- 8%, 80 +/- 9%, 93 +/- 10%, and 92 +/- 11% (mean +/- SD, n = 7) for DMP, MBA, TA, and MHA, respectively. The tissue preparation efficiency, which was indicated by absolute recoveries of internal standards, was approximately 33% for DMP, MBA, and TA and approximately 80% for MHA. No metabolites were detected in untreated control tissues. This simple and sensitive method to simultaneously detect major xylene metabolites in brain tissues could also be used for the analysis of blood and urine samples from workers to monitor p-xylene exposure.
Animals↗
Psychopathologic risk factors for intentional and nonintentional injury.
OBJECTIVE: Trauma has a high rate of recurrence, suggesting that some people are more injury-prone than others. This study was performed to evaluate some of the psychological and social factors that might influence the likelihood of traumatic injury. METHODS: A case-control study was conducted to evaluate the relationship between selected psychosocial factors and traumatic injury. At a Level I trauma center, victims of intentional trauma (excluding attempted suicide), victims of nonintentional trauma, and patients undergoing elective surgery were interviewed by a person blinded to the purposes of the study. They were given an intelligence test and underwent a structured interview, yielding psychiatric diagnostic categories established in the third edition of the Diagnostic and Statistical Manual of Mental Disorders, Revised (DSM-III-R). RESULTS: Trauma patients were younger than elective surgery patients (p < 0.01) and were more likely to be men (p < 0.01). Victims of intentional injury had a higher probability of alcohol use (p < 0.01) and admitted illicit drug use (p < 0.001) than either nonintentional injury victims or elective surgery patients. Victims of intentional injury were more likely to be unemployed than those in the other two groups (p < 0.02), whereas elective surgery patients were more likely to be retired (p < 0.05) or to be disabled (p < 0.0001). The average intelligence score was slightly above the median in the nonintentional trauma group and in the control group (55th percentile and 54th percentile, respectively), compared with a mean intelligence score equivalent to the 35th percentile in the victims of intentional trauma (p < 0.001). Thirty percent of elective surgery patients met diagnostic criteria for at least one category of psychopathology, compared with 50% of nonintentional trauma patients, and 63% of intentional trauma patients (p < 0.01, trauma vs. elective surgery). Logistic regression analysis identified six variables that were independently associated with an increased tendency to be a victim of trauma: younger age, lower intelligence, antisocial personality, mental retardation, depression, and low income. CONCLUSIONS: Victims of trauma, both nonintentional, and especially intentional, have a high incidence of psychopathology. Victims of intentional trauma have significantly lower intelligence scores than either nonintentional injury or elective surgery patients. The high incidence of unemployment, alcohol abuse, and illicit drug use in victims of intentional injury might provide several opportunities for trauma prevention programs. Underlying psychological disorders will have to be addressed to reduce the likelihood of becoming a victim of trauma.
Accident Proneness↗
Stromal cells negatively regulate primitive haemopoietic progenitor cell activation via a phosphatidylinositol-anchored cell adhesion/signalling mechanism.
We have tested the effect of stromal cells on the proliferation in long- and short-term cultures of primitive (Thy-1+, CD34+, CD33-, CD38- , HLA-DR , adherent in vitro and quiescent in vivo) progenitors in normal human bone marrow. These primitive cells produce granulocyte-macrophage colony-forming cells (CFU-GM) that are measured in secondary clonogenic assays. Addition of stromal cells to normal adherent haemopoietic progenitor cells reduced CFU-GM production by 80% (P =0.0002) after 1 week of incubation. In long-term culture (LTC), in the presence of stroma. the normal adherent cells did not produce significant numbers of CFU-GM until 3-4 weeks later which suggests that stromal cells reduce the probability of quiescent cell activation. This effect could not be attributed to soluble inhibitory factors and was specific to stroma grown with, rather than without, methylprednisolone. It was blocked by heparanase (H'ase) II treatment of stromal cells, by phosphatidylinositol-specific phospholipase C (PI-PLC) treatment of progenitor cells, by antibody blocking of beta1 integrin molecules or by exposure to glucose/N-acetyl-D-glucosamine/alpha-methyl-D-mannoside, but not by exposure to galactose or fructose. Moreover, these interventions enabled the progenitor cells to respond to stimulatory factors in the culture supernatant. We interpret these results as support for a model involving primitive progenitor cell binding to stroma by PI-CAM/HS, beta1 integrin activation via lectin-like interactions and the transduction of signals which reduce the ability of primitive cells to respond to ambient stimulators. This model provides a mechanism for the maintenance of the quiescent state of stem cells by adhesion to stromal cells.
Cell Communication↗
Intraoperative force-setting did not improve the mechanical properties of an augmented bone-tendon-bone anterior cruciate ligament graft in a goat model.
It has been hypothesized that load affects the mechanical properties of an anterior cruciate ligament graft while it remodels. The goal of this study was to use an existing goat model to evaluate the effect of intraoperative set force on the postoperative mechanical properties of an autograft that had been augmented with a synthetic segment. The following questions were addressed. Do augmented autografts set with a high force intraoperatively have improved structural and material graft properties and lower anterior-posterior knee laxity at 3 months after surgery, compared with autografts set with a low intraoperative force? How do the structural and material properties of these implanted autografts compare with the mechanical properties of an intact anterior cruciate ligament or an unimplanted control autograft? The anterior cruciate ligament was reconstructed in seven goats with use of a composite graft consisting of a bone-patellar tendon-bone autograft and a synthetic augmentation device. A force-setting technique was used intraoperatively to establish the load-sharing between the autograft and augmentation segments such that the autograft carried either a high (16.5 N in four animals) or low (1.5 N in three animals) level of force, while the total force in the composite graft remained constant. Tensile testing was performed at 3 months after surgery to determine the material and structural properties of the autograft, the intact anterior cruciate ligament from the normal contralateral knee, and a control bone-patellar tendon-bone graft of similar size that was harvested from the contralateral knee at the time of necropsy and had never been implanted in the joint. The structural and material properties of the autografts initially set to high or low loads at surgery were not significantly different after 3 months of implantation. The strength and stiffness of the implanted tendons were an average of 24 and 20% of the strength and stiffness of the normal anterior cruciate ligament and 31 and 62% of the control tendons, respectively. Intraoperative set force in an augmented anterior cruciate ligament graft at the levels chosen in this study did not significantly affect weakening of the autograft at 3 months.
Animals↗
Treatment of resistant gestational choriocarcinoma with taxol: a report of two cases.
Two patients with resistant gestational choriocarcinoma were treated w with Taxol after extensive prior chemotherapy including EMACO and platinum-based salvage chemotherapy. Both patients showed significant responses to Taxol. One patient relapsed in the brain and liver after treatment and died. Taxol was combined with carboplatin in the other patient who achieved sustained clinical and hormonal remission after craniotomy and excision of resistant disease in the brain.
Adult↗
Expression of A, B, and H blood group antigens in epithelial ovarian cancer: relationship to tumor grade and patient survival.
The expression of A, B, and H blood group antigens in epithelial ovarian cancer was evaluated in 137 patients with advanced disease by staining frozen sections with specific monoclonal antibodies using an indirect immunoperoxidase method. Expression of blood group antigens was observed in a proportion of ovarian carcinomas and in some areas of ovarian surface epithelium. Forty-eight percent of the tumors tested from 130 blood group A, B, or 0 individuals showed no expression of the appropriate blood group antigen, 32% had heterogeneous antigen expression, and 20% had strong expression. In the 7 blood group AB patients studied, no expression, heterogeneous expression of both antigens, or absence of one, but not the other antigen, was observed. No tumor showed A, B, or H antigen expression that was not compatible with the patient's blood group type. Histologic Grade 3 tumors showed absence of blood group antigen expression more often than did Grade 2 tumors. The presence or absence of A, B, or H antigen expression did not correlate with survival in this group of patients. This is in contrast to studies in other epithelial tumor types in which the normal epithelium synthesizes blood group antigens and loss of ABH antigen expression is observed in the corresponding tumors.
Aged↗
A molecular anatomical analysis of mosaic trisomy 16.
A one-month-old child presenting with an aortic coarctation was found to have a left single transverse palmar crease and proportionate growth delay on physical examination, prompting a peripheral blood chromosome analysis. This showed a mosaic trisomy of chromosome 16, subsequently observed to decrease with the passage of time. As her phenotype was relatively benign, further analysis was performed to define more precisely the extent of her mosaicism given the supposedly lethal nature of the aneuploid cell line. Fluorescence in situ hybridisation and CA repeat polymorphism studies demonstrated the aneuploidy in multiple tissues, including the structurally affected aorta. Molecular analysis showed both maternal chromosomes 16 to be present in the trisomic cells, but maternal heterodisomy was not present in the diploid cells. Given the increasing number of individuals described with aneuploid mosaicism, we suggest that the study of multiple tissues is a necessary approach, the eventual goal being the appreciation of the relationship between the characteristics of a somatic mosaicism and the phenotype it imparts.
Alleles↗
Determination of spinal facet joint loads from extra articular strains--a theoretical validation.
Loads on the facet joints of the lumbar spine may play a role in low back pain. Abnormal loading of the facets, either primarily or as a consequence of disc degeneration, may accelerate their degeneration. Study of these phenomena is difficult, since here are few methods for a direct measure of facet forces occurring in vivo. The authors developed a method for the direct measure of facet forces in a canine animal model of spine disease using strain gages. The method used empirical calibration of the strain gages, which was used to reduce experimental strain output to facet force during function. In this Technical Note, a theoretical model is formulated, solved and validated which gives a theoretical basis for the data reduction method. The facet is modeled as a cantilevered plate and deformations, as function of applied normal load, solved for using a finite difference method. The model is validated by comparison with two experiments with strain-gaged facets. Results from the model show that a minimum of three strain gages is required to determine uniquely the location and magnitude of an applied load to the facet, and that at least two gages should be placed in the region where the cranial articular process joins the pedicle with the gage axis parallel to that of the process. Plate surface strains were found to be insensitive to changes in the area of the applied loads, for a given resultant force magnitude. The method may be useful in other applications in which resultant force magnitude and location need to be measured on plate-like structures.
Algorithms↗
Abnormal kinetics of colony formation by erythroid burst-forming units (BFU-E) in chronic myeloid leukaemia.
We have investigated the kinetics of colony formation by progenitor cells in chronic myeloid leukaemia (CML) using erythroid burst-forming units (BFU-E) as a model system. For this, we scored the numbers of subcolonies produced by individual BFU-E in cultures of normal marrow and blood cells and in cultures of CML blood cells. The formation of an erythroid burst consisting of a single subcolony was taken as evidence for immediate terminal differentiation; the formation of multiple subcolonies was taken as evidence for commitment to terminal differentiation only after several cell generations. Therefore the probability of differentiation can be obtained by scoring the numbers of subcolonies in individual erythroid bursts. We found that the probability of differentiation is decreased (P = 0.0004) and the number of subcolonies increased (P = 0.01) in CML BFU-E compared with normal BFU-E. The cellularity of the BFU-E was also increased in CML. Using the probabilities of differentiation and renewal obtained from the BFU-E cultures the results fitted the predictions of a stochastic branching model. These results indicate that (a) commitment to terminal erythroid differentiation occurs over several cell generations in populations of BFU-E, (b) the probability of commitment to terminal differentiation (PD) within a particular population of BFU-E, remains a constant independent of the number of cell generations involved, (c) PD is lower during burst formation by CML BFU-E than by normal BFU-E, and (d) commitment to terminal differentiation occurs over more cell generations in CML burst formation than in normal burst formation. Therefore a reduced probability of differentiation may be a primary defect and could explain the expansion of the erythroid progenitor cell compartment in CML.
Bone Marrow↗
Evaluation of "discordant maturation' in chronic myeloid leukaemia using cultures of primitive progenitor cells and their production of clonogenic progeny (CFU-GM).
The 'discordant maturation hypothesis' proposes that the most mature proliferating cells in chronic-phase chronic myeloid leukaemia (CML) are responsible for the expansion of the Ph-positive population. To evaluate this hypothesis we used a delta assay for primitive haemopoietic cells (P delta assay for P delta cells) which allows investigation of the kinetics of granulocyte-macrophage progenitor (CFU-GM) production. The frequencies of these primitive (P delta) cells were similar in CML blood (14.5/10(5) mononuclear cells), CML marrow (17.3/10(5)) and normal marrow (11.6/10(5)) The average frequency in normal blood is only 0.58/10(6). The absolute numbers of P delta cells in CML patients are therefore greatly increased. The average numbers of CFU-GM produced by individual P delta cells were reduced in CML blood (8.1) and marrow (11.6) compared with normal marrow (28.5). This is consistent with a reduced probability of differentiation at the single cell level in CML. Although the absolute number of CFU-GM produced by individual CML P delta cells was subnormal there was a relative increase in the number of day 7 CFU-GM compared with the number of day 14 and 21 CFU-GM, which agrees with the 'discordant maturation hypothesis'. This bias towards day 7 colony formation could reflect accelerated maturation by the CFU-GM produced by P delta cells or, alternatively, the production of CFU-GM with shorter than normal maturation pathways. Overall, these results suggest that discordant maturation does not by itself account for myeloid expansion in CML. It is more likely that myeloid expansion in CML is due mainly to an increase in the number of primitive haemopoietic progenitor cells.
Bone Marrow↗
Fracture of articular cartilage.
Crack formation and propagation is a significant element of the degeneration process in articular cartilage. In order to understand this process, and separate the relative importance of structural overload and material failure, methods for measuring the fracture toughness of cartilage are needed. In this paper, two such methods are described and used to measure fracture properties of cartilage from the canine patella. A modified single edge notch (MSEN) specimen was used to measure J, and a trouser tear test was used to measure T, both measures of fracture toughness with units of kN/m. A pseudo-elastic modulus was also obtained from the MSEN test. Several potential error sources were examined, and results for the MSEN test compared with another method for measuring the fracture parameter for urethane rubber. Good agreement was found. The two test methods were used to measure properties of cartilage from the patellae of 12 canines: 4-9 specimens from each of 12 patellae, with 5 right-left pairs were tested. Values of J ranged from 0.14-1.2 kN/m. J values correlated with T and were an average of 1.7 times larger than T. A variety of failure responses was seen in the MSEN tests, consequently a grade of 0 to 3 was assigned to each test, where 0 represented a brittle-like crack with minimal opening and 3 represented plastic flow with no crack formation. The initial cracks in 12/82 specimens did not propagate and were assigned to grade 3. The method for reducing data in the MSEN test assumed pseudo-elastic response and could not be used for the grade 3 specimens. Stiffness did not correlate with J. Neither J nor T was statistically different between right-left pairs, but varied between animals. The test methods appear useful for providing a quantitative measure of fracture toughness for cartilage and other soft materials.
Animals↗
Effect of chronic exposure to ultraviolet radiation and photoreactivation on life span and tumor development in the marsupial Monodelphis domestica.
The effect of exposure to chronic ultraviolet (UV) radiation on life span was examined in Monodelphis domestica, which is capable of photoreactivation repair of UV-radiation-induced pyrimidine dimers. Shaved Monodelphis were exposed to 500 J/m2 UV radiation, 500 J/m2 UV radiation then 90 min of photoreactivating light (PRL), or 90 min of PRL three times weekly for 104 weeks. Opossums were weighed weekly; samples for serum chemistry and hematology testing were obtained periodically. Complete postmortem examinations revealed a primary cause of death for each opossum. Meaningful differences among the groups in weight gain, serum chemistry values or hematology values were not seen. Significant life-shortening due to UV-radiation exposure was found for females but not males. Photoreactivation prolonged life only in the females exposed to UV radiation. Exposure to UV radiation was not associated with accelerated development of degenerative disease. Significant treatment-related mortality occurred in both male and female opossums exposed to UV radiation. Photoreactivation reduced the relative risk of skin tumors but not eye tumors in Monodelphis exposed to UV radiation. Eye and skin tumors were less likely to be a cause of death in UV-radiation-exposed opossums subsequently exposed to PRL than in opossums exposed to UV radiation alone. Females exposed only to UV radiation had an increased risk of skin tumor development relative to males.
Animals↗
Phenotype and progeny of primitive adherent human hematopoietic progenitors.
Hematopoietic progenitor cells can be classified as plastic- and stroma-adherent (P+S+), stroma-adherent (P-S+) and non-adherent (P-S-). Both P+S+ and P-S+ populations are detected in delta (delta) culture systems where they produce non-adherent (P-S-) granulocyte-macrophage colony-forming cells (CFU-GM) and erythroid burst-forming units (BFU-E). Here we demonstrate that the plastic-adherent progenitor cells (P delta cells) comprise 5-10 percent of the CD34+, population in adult human marrow. Moreover, they do not express CD3 or CD22 and 88 percent of them are CD38-, 88 percent are CD33- and 74 percent are HLA-DR-. Production of CFU-GM by purified plastic-adherent CD34+, adherent cells was 60 percent of the number produced by recombined CD34+, and CD34- fractions. We have shown also that the plastic-adherent P+S+ cells are the precursors of the stroma-adherent P-S+ cells (S delta cells), day 21 cobblestone-area forming cells (CAFC) and cells capable of sustained hematopoiesis in a modified long-term bone marrow culture system. These observations support the primitive nature of P delta cells and establish a phenotypic sequence of plastic and stroma adherence through stroma adherence to non-adherence in hematopoietic cell development. To further investigate the relationship between P delta cells, S delta cells and long-term culture-initiating cells (LTCIC), we cultured whole mononuclear cell tractions and plastic-adherent cell-depleted mononuclear cell fractions in long-term culture and in the S delta assay. The results indicated the P delta cells were inhibited in the presence of stromal cells.
ADP-ribosyl Cyclase↗