Serotonin, gastric emptying, and dyspepsia.
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Biomedical subjects
Publications and source records attributed to I Anderson.
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The ability of DNA to allosterically alter the conformation of the estrogen receptor's (ER) steroid binding domain was investigated. Using dissociation kinetics we observed that when DNA was bound to the DNA binding domain of the rat uterine ER the rate of estrogen dissociation from the steroid binding domain increased almost 2-fold. This change in the rate of estrogen dissociation depended on the concentration of DNA used and correlated with the thermodynamic binding affinities (Kd) of the ER for two different DNA sequences. We were unable to detect a DNA-induced change in the trypsin cleavage pattern of the amino terminal end of the ER. Using a whole cell dissociation kinetic assay with MCF-7 breast cancer cells we observed a 7-fold slower rate of estrogen dissociation from the ER within the cell than from the ER in vitro. This suggests that additional factors, other than DNA binding, may modify the steroid binding domain within the cell. We conclude that DNA can allosterically modulate the structure of the steroid binding domain of the ER, and we hypothesize that this conformational change may be necessary for the full transcriptional activity of the ER.
The localization of TGF-beta 1, -beta 2 and -beta 3 was studied in the growth plate, epiphysis and metaphysis of the tibiotarsus of three-week-old chicks. The different TGF-beta isoforms were localized to hypertrophic chondrocytes, chondroclasts, osteoblasts and osteoclasts using immunohistochemical staining analysis with specific TGF-beta antibodies. TGF-betas in osteoclasts and chondroclasts were restricted to those cells located on the respective matrices. TGF-beta 3 localization was mainly cytoplasmic in the transitional (early hypertrophic) chondrocytes, but nuclear staining was also detected in some proliferating chondrocytes. The cell-specific localization of these TGF-beta isoforms supports the hypothesis that TGF-beta has a role in the coupling of new bone formation to bone and cartilage matrix resorption during osteochondral development and suggests that TGF-beta may be a marker of chondrocyte differentiation. TGF-beta localization preceded a marked increase in type II collagen mRNA expression in transitional chondrocytes, suggesting a role for TGF-beta in the induction of synthesis of extracellular matrix.
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Intensive chemotherapy with autologous bone marrow transplantation is a promising approach for the treatment of breast cancer, provided that clonogenic tumor cells do not contaminate the patient's bone marrow. We have previously demonstrated that a combination of 4-hydroperoxycyclophosphamide (4-HC) and immunomagnetic purging (IMP) with monoclonal antibodies and microspheres could remove 4-5 logs of clonogenic breast cancer cells from a 10-fold excess of human bone marrow cells. In the present report we have evaluated an apparatus for separating tumor cells from a large volume of human marrow. This apparatus will permit preparation of large volumes of purged marrow for use in studies of intensive therapy with autologous marrow support. Bone marrow progenitor cell (CFU-GM) recovery following this IMP technique was 85% of the unpurged control, and suggests that marrow recovery following high dose systemic chemotherapy will not be adversely affected. A phase I study to evaluate marrow reconstitution following IMP is underway. Preliminary data suggest that this IMP method will not delay engraftment in breast cancer patients receiving high-dose chemotherapy and autologous bone marrow support, but further study is required.
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Intensive therapy with 5-fluorouracil (FU) and leucovorin (LV) has proved to be effective in the treatment of advanced colorectal cancer. The toxicity of this regimen has not been systematically evaluated. In the present study, 52 patients with advanced colorectal and refractory cancers received sequential 2-month cycles of weekly FU and high-dose LV and were monitored for toxicity as well as response in 103 cycles. Of 24 evaluable patients with colorectal cancer, 1 complete and 9 partial responses were seen (42%); 4 of 10 patients who had been refractory to conventional FU treatment responded to the FU/LV regimen. One partial response was observed among six patients with gastric carcinoma, and three minor responses were seen in five women with refractory breast cancer. A total of 24 patients (46%) completed the first cycle on schedule, although 7 subjects required a reduction in the dose of FU. The majority of patients required treatment breaks because of toxicity. Gastrointestinal toxicity proved to be dose-limiting on this schedule, necessitating FU dose modification and treatment of both diarrhea in 15 subjects and acute abdominal pain in 7 cases. No patient required a further treatment delay of FU dose adjustment. Myelosuppression was an uncommon complication on this regimen. Cutaneous toxicity was also prominent in this series of patients, with the hand-foot syndrome developing in 14 cases (27%); 11 subjects who developed this complication were treated with pyridoxine (150 mg daily), and all experienced improvement in their symptoms within 1 week. Partial and complete responses were observed in 41% of evaluable patients with colorectal cancer and in one of six evaluable patients with gastric carcinoma. We conclude that FU and high-dose LV can safely be given on a weekly basis, although acute gastrointestinal and cutaneous toxicity are common.
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We describe a patient in whom chronic leg ulceration was due to prolidase deficiency. The clinical features of this condition are described and we discuss the metabolic abnormality and the treatment regimes which have been employed. We also report the further finding of erosive cystitis, which we consider should be added to the list of clinical features of prolidase deficiency.
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Forty-three patients with factor XI deficiency detected by prolonged partial thromboplastin times were reviewed over an 11-year period. They were predominantly Ashkenazim--18 men and 25 women--ranging in age from 20 to 92 years. Thirteen patients had a history of bleeding, and eight had a family history of factor XI deficiency. Six patients with thyroid disease with four significant tumors were found for a 9% incidence of associated neoplasia. These consisted of two adenomas and two papillary-mixed cancers in two men distinguished by an aggressive course by virtue of extensive nodal disease, local recurrence, and systemic metastases in whom factor XI was profoundly decreased. It would appear that there is an undue association of factor XI deficiency and thyroid neoplasia suggestive of a shared genetic disturbance. These cases illustrate the benefit of routine preoperative coagulopathy screening by use of prothrombin time, partial thromboplastin time, and platelet counts. Factor XI deficiency is an infrequent cause of excessive bleeding, and the operative morbidity of surgical management of affected individuals can be avoided by the use of fresh-frozen plasma before and after surgery.
A laser controller that uses a fixed frequency clock and a digital rate-multiplying circuit to synchronize the triggering of a pulsed laser to the spinning of an analytical ultracentrifuge rotor has been designed. The circuit is simple, inexpensive, and virtually free of any adjustments. It tracks rotors undergoing full acceleration or deceleration. At constant rotor speed it provides triggering that is accurate and reproducible to better than 0.5 microseconds. The settings of this controller are independent of rotor speed over the full range of the ultracentrifuge.
A randomized clinical trial of once-weekly antenatal fetal heart rate monitoring in 539 high-risk patients could find no benefit of monitoring in terms of perinatal mortality, morbidity or Apgar score. The previously well-documented association between abnormal antenatal fetal heart rate traces and low Apgar score was confirmed. A detailed case review showed that in this population monitoring was irrelevant to almost all of the 13 perinatal deaths.
Toxoplasma gondii infection was established in sheep seven days (acute infection) or 28 days (chronic infection) before they were given enzootic abortion (EAE) vaccine alone or simultaneously with louping-ill (LI) vaccine. Uninfected controls received the same vaccination schedule. The serological response of acute toxoplasma-infected sheep to initial LI vaccination was significantly depressed but after revaccination four weeks later these sheep demonstrated a response equal to that of the revaccinated controls. Infected sheep also gave a significantly poorer response to EAE vaccine than control animals, the effect being more marked in those with chronic infection. Revaccination evoked no clear response in any group but on three of five sampling days antibody titres of controls were significantly higher than those of infected sheep.