Cytotoxicity of 2-aldo- and 2-ketopyridine-N(4)-substituted thiosemicarbazones and mode of action in human Tmolt4 cells.

The 2-aldo- and 2-ketopyridine-N(4)-substituted thiosemicarbazones and their copper complexes demonstrated potent cytotoxic activity against a series of murine and human suspended cultured tumor cells. Selected compounds were active against the growth of cultured cells from solid human tumors, i.e. Mck-7 breast effusion, lung A549 and lung MB-9812, bone SOS-2 and clear cell Caki renal tumor. In Tmolt4 T cell leukemia cells the compounds inhibited the syntheses of DNA, RNA and protein over 60 min at 25 to 100 microM. Multiple target sites in nucleic acid metabolism were suppressed by the agents, i.e. DNA polymerase alpha, ribonucleoside reductase, dihydrofolate reductase, de novo purine synthesis, thymidylate synthetase and nucleoside kinases. The total effects of the agents on DNA metabolism led to the reduction of deoxyribonucleotide pools as well as DNA fragmentation.

Targeting of human Tmolt4 leukemic type II IMP dehydrogenase by cyclic imide related derivatives.

2,3-Dihydrophthalazine-1,4-diones, indazolones, 3-imino-1-oxoisodolines, homophthalimides, napthalidimides, diphenamides, and 6,7-dihydro-5H-dibenz[c,e]azepines proved to be potent inhibitors of the activity of human Tmolt4 T cell leukemia Type II IMP dehydrogenase (IMPDH). This inhibition was competitive, yielding Ki values in the range of 1.96 to 48.9 microM. The inhibition of Type II IMPDH correlated positively with the inhibition of the growth of Tmolt4 cells, the syntheses of DNA and purine, and the activity of crude IMPDH. The Type II IMPDH isoform is found in rapidly proliferating cells. The isoform present in normal resting cells, Type I IMPDH, was elevated by the compounds at 100 microM. In addition, Compound 5 significantly increased the Type I enzyme activity in a concentration and time dependent manner. The selectivity of these derivatives towards Type II IMPDH will allow for the separation of cellular effects, which should reduce clinical toxicity when treating with antimetabolite IMPDH inhibitors.

Hypercalcemia during the osteogenic phase after rat marrow ablation coincides with increased bone resorption assessed by the NTx marker.

Marrow ablation is a model of bone turnover in which the excavated tibial intramedullary cavity is rapidly and reproducibly filled by osteoblasts with new woven bone (days 6-8), which is then rapidly resorbed by osteoclasts (days 10-15). We showed previously (Magnuson et al., 1997) that marrow ablation induces a dramatic hypercalcemia and hypercalciuria in rats that unexpectedly peaked at the time of maximal osteogenesis and continued throughout the subsequent resorption phase. Based upon the amount of calcium mobilized and a peak of urinary hydroxyproline, we suggested that the hypercalcemia and hypercalciuria were due to increased systemic osteoclastic bone resorption induced by marrow ablation. We now apply a new enzyme-linked immunosorbent assay for rodent alpha(2)(I) N-telopeptide (NTx), a marker of bone resorption, to the marrow ablation model to demonstrate that excretion of NTx parallels that of calcium release in the operated control group. Specifically, maximal NTx/creatinine excretion coincides with the onset of hypercalcemia on days 7-8. A peak of NTx was also observed in methylprednisolone- and deflazacort-treated ablated animals. Analyses for urinary free deoxypyridinoline crosslink failed to detect a significant ablation-induced change in excretion. Interleukin 6 activity was increased in all operated control and glucocorticoid-treated groups after marrow ablation, whereas serum parathyroid hormone remained at presurgical levels in operated controls throughout the 15-day study period. The NTx results confirm that bilateral tibial marrow ablation induces a burst of extratibial bone resorption and hypercalcemia 7-8 days later. We have estimated that the osteogenic phase of the ablation model deposits 40 mg of calcium as hydroxyapatite crystals within the intramedullary cavity on days 6-8; this represents 33%-50% of the total blood calcium content of a young rat. We hypothesize that the size and rapidity of this demand for ionized calcium is met through an extratibial bone resorption pathway of osteoclast formation and activation that anticipates and fulfills this need, and that is initiated at the time of marrow ablation.

Cytotoxicity of rhenium(I) alkoxo and hydroxo carbonyl complexes in murine and human tumor cells.

The rhenium(I) alkoxo/hydroxo carbonyl complexes were shown to be very potent in suspended tumor cell lines in suppressing growth but were more selective in inhibiting the growth of cultures from solid tumors. Their mode of action in L1210 lymphoid leukemia cells indicated that they were not alkylating agents but interfered with nucleic acid metabolism at multiple enzyme sites, e.g. dihydrofolate reductase, PRPP-amido transferase, thymidine kinase, with DNA strand scission after 60 min incubation. These compounds did not function mechanistically exclusively as cisplatin derivatives causing intrastrand linkages of DNA but rather they mimicked the metal complexes of aminecarboxyboranes, furan oximes, N-substituted thiosemicarbazones, trifluoromethyl borons and ferratricarbadecarbanyl complexes acting as antimetabolites.

Characteristics of radiology groups and of diagnostic radiologists and radiation oncologists in different types of practices.

PURPOSE: To describe the characteristics of U.S. radiology groups and of radiologists in different types of practices in 1995. MATERIALS AND METHODS: A survey was distributed to 3,024 radiologists; the response rate was 75%. Responses were weighted to represent all U.S. groups or radiologists. RESULTS: There were 3,285 groups; 340 were academic, and 356 were multispecialty. Fifty percent of groups had two to four members; 39% of radiologists were in groups with fewer than eight members, and 8% were solo practitioners. Seventy percent of all radiologists were in practices owned entirely by physicians in the practice, and 80% of these were themselves owners. Eight percent of radiologists were in government-owned practices, and 15% (primarily academic) were in privately-owned practices in which all physicians were employees. Sixty-nine percent of academic diagnostic radiologists worked primarily in one field, but this was true of only 22% of those in nonacademic groups. Solo diagnostic practitioners also typically had a broad practice but excluded high-cost modalities. Radiologists in nonacademic groups averaged more vacation days (30 d/yr) than academic (19 d/yr) or solo (12 d/yr) practitioners. Solo and locum tenens practitioners were relatively old; academic radiologists, relatively young. CONCLUSION: Through 1995, average group size has grown slowly. There are important differences among practice types, especially between academic and nonacademic practices.

Women in the radiology profession: data from a 1995 national survey.

OBJECTIVE: This report provides an in-depth picture of similarities and differences in the professional and practice characteristics of women and men who are radiologists in the United States, with specific attention to whether gender differences are less pronounced among younger radiologists. MATERIALS AND METHODS: Data were taken from a national stratified random sample survey of radiologists. The response rate was 75%. The 1731 men and 294 women responding included diagnostic radiologists, radiation oncologists, and radiology-related nuclear medicine specialists. RESULTS: Seven percent of respondents who completed their radiology residency before 1970 were women, compared with 9% in 1970-1979, 19% in 1980-1989, and 27% in 1990-1995. Gender differences were smaller among posttraining radiologists younger than 40 years old than among those 40 years old or older for the following questions: when the respondent decided to specialize in radiology, whether the respondent is a subspecialist within diagnostic radiology, whether the respondent's practice is primarily academic, whether the practice is privately owned, and whether the respondent is a practice owner (partner, shareholder). Women who were residents and fellows more frequently indicated problems with unwanted sexual attention occurring in the past 2 years than did women who were not in training positions. However, posttraining women were more likely to have encountered discrimination in salary, hiring, or promotion at some time in their careers. CONCLUSION: Women's professional roles in radiology are changing slowly. A narrowing gender gap among younger radiologists on some professional and practice characteristics may indicate a further diminishing of gender differences in radiology in the future. It may also reflect greater gender equality at earlier rather than later stages of one's career.

Hiring by radiology groups in 1996.

PURPOSE: To determine the hiring activity of radiology groups in 1996. MATERIALS AND METHODS: A survey was mailed to a stratified, random sample of 794 radiology groups in autumn 1996. The response rate was 78%. Responses were weighted to be representative of all of the approximately 3,300 groups in the United States. Findings were compared with those of previous, similar surveys. RESULTS: In the 12 months before the survey, groups sought to hire 1,732 +/- 155 (+/- 1 standard error) diagnostic radiologists and radiation oncologists; 788 +/- 105 of these positions were to fill expansion positions, 562 +/- 86 were replacements for persons who had left the profession, and 382 +/- 78 were replacements for persons who moved to other radiology positions. During the year, an additional 500 +/- 119 positions were vacated that groups did not seek to refill. Groups succeeded in hiring 1,438 +/- 143 radiologists. The percentage of available positions that were filled did not differ across fields. Managed health care reduced the probability a group was expanding but did not otherwise affect hiring activity. CONCLUSION: The 1991-1995 decline in hiring has ceased and perhaps even reversed. There were approximately as many positions available in 1996 as were needed by graduates, although there may have been a small shortfall.

The employment market for 1996 diagnostic radiology and radiation oncology graduates: training program directors' point of view.

OBJECTIVE: In light of concerns about the job market, we describe the employment situation for 1996 graduates and the status and plans of training programs. MATERIALS AND METHODS: In April-May 1996, and in a December follow-up, we surveyed all radiation oncology residency directors and a 50% random sample of diagnostic radiology residency directors about the employment situation of their 1996 residency and fellowship graduates and about their programs. One hundred percent of those surveyed responded. We compared findings with similar 1995 surveys. Differences were assessed with t tests, with a p value less than or equal to .05 as the test of significance. RESULTS: Unemployment 6 months after graduation was 0.8% for diagnostic fellows and less for other categories. Approximately 91% of graduates had positions that reasonably matched their training and personal employment goals. Our survey showed that programs have reduced beginning residency slots by 6% in diagnostic radiology and 4% in radiation oncology over the last 3 years. Program directors plan additional reductions of 3% and 29%, respectively, for total reductions in diagnostic radiology of 9% and in radiation oncology of 33%. Many observers were dismayed because of the low percentage of available slots that filled in the 1996 National Resident Matching Program. However, as in previous years, by late April to mid May 1996, more than 92% of beginning-year residency slots were filled. CONCLUSION: Unemployment continues to be low. "Soft" indicators such as the percentage of graduates with unsuitable positions show no deterioration. However, if major surpluses of diagnostic radiologists or radiation oncologists are pending, both the reductions in program size and the failure to fill all available slots are, to date, too minor to offer significant relief. Given the small size of actual reductions so far, the reported plans for large reductions of radiation oncologists seem questionable.

Graduates speak: the employment experience of 1995 graduates of diagnostic radiology and radiation oncology training programs.

PURPOSE: To determine the initial employment experience of 1995 graduates of radiology programs. MATERIALS AND METHODS: A questionnaire was mailed to all graduates of radiation oncology programs and to a stratified, random sample of 600 graduates of diagnostic radiology programs. The final response rate was 66%. RESULTS: After graduation, 4%-10% of graduates worked for a period as locum tenens, worked in a job unrelated to radiology, or were unemployed. Immediate postgraduation unemployment was 2%-5%; 7-12 months later, it was less than 0.5%. Median actual salary was approximately equal to median expected salary. Radiation oncology fellowship graduates often had poorer outcomes. Almost half of the graduates with posttraining employment had a job with at least one characteristic regarded as unfavorable by some commentators (most commonly, undesirable location or no opportunity to become a partner), and at least one-fifth had and disliked such a characteristic. Geographic constraints, including the need to find employment for a spouse or companion, did not adversely affect employment outcome. CONCLUSION: Eventual unemployment was low, and starting salaries have not collapsed. Generally, the implications of job characteristics are best assessed by monitoring trends, but the prevalence of non-partnership track employment may well have increased.

Profile of U.S. radiologists at middecade: overview of findings from the 1995 survey of radiologists.

PURPOSE: To profile the demographic, professional, and practice characteristics of diagnostic radiologists and radiation oncologists in the United States. MATERIALS AND METHODS: Questionnaires mailed to a national stratified random sample of 3,024 diagnostic radiologists, radiation oncologists, and nuclear medicine specialists yielded a 75% response rate. Weighted data reflect what responses would be if all radiologists had been surveyed and had responded. RESULTS: Among professionally active, posttraining radiologists in 1995, 14% were women; 12% were radiation oncologists, 62% diagnostic generalists, and 26% diagnostic subspecialists; 92% were board certified in radiology; 48% had postresidency fellowship training; 69% were in a position where practice ownership was a potential, and of these, 80% were practice owners. Enjoyment of work was less the greater the perceived effect of managed care on a radiologists practice, but average work satisfaction was unchanged from 1990. Among radiologists aged 55 years or older, the percentage who were retired was unchanged from 1990. Average hours worked by professionally active radiologists aged 65 years or older increased since 1990. CONCLUSION: Despite the spread of managed care and other trends that affect radiologists, surprisingly, few changes were evident in the demographic or professional characteristics of U.S. radiologists in 1995 compared with 1990.

Construction of a Bayesian network for mammographic diagnosis of breast cancer.

Bayesian networks use the techniques of probability theory to reason under uncertainty, and have become an important formalism for medical decision support systems. We describe the development and validation of a Bayesian network (MammoNet) to assist in mammographic diagnosis of breast cancer. MammoNet integrates five patient-history features, two physical findings, and 15 mammographic features extracted by experienced radiologists to determine the probability of malignancy. We outline the methods and issues in the system's design, implementation, and evaluation. Bayesian networks provide a potentially useful tool for mammographic decision support.

The demand side of the job market for diagnostic radiologists and radiation oncologists: hiring by physician groups in 1995.

OBJECTIVE: The American College of Radiology sought to assess the hiring activities of radiology groups in 1995, the 1995 employment market for diagnostic radiologists and radiation oncologists, and changes in the employment market since 1991. MATERIALS AND METHODS: We mailed surveys about recruitment and hiring to a stratified random sample of 600 radiology groups in the United States; 85% responded. The responses were weighted to show what they would have been if all of the approximately 3150 radiology groups in the United States had answered the survey. The findings were compared with similar surveys conducted in 1994 and 1991. RESULTS: In 1995, 31% (+/- 1% [SE]) of radiology groups actively recruited diagnostic radiologists or radiation oncologists, seeking to fill 1423 (+/- 119) openings. These figures represent a progressive decline from the 50% of groups recruiting and 2255 positions offered in 1991. In 1995, radiology groups filled 85% of available positions, compared with 76% in 1994 and 71% in 1991. In 1995, positions available because of expansion of radiology groups numbered 613 (+/- 73), considerably fewer than the estimated 720-position increase that takes place each year in the number of posttraining diagnostic radiologist and radiation oncologists in practice. In 1995, general diagnostic radiology accounted for approximately 48% of the full time-equivalent radiologists sought; radiation oncology, 11%; and the diagnostic subspecialties, 41%. We found few statistically significant differences among specialty and subspecialty fields in the percentage of available positions filled. Private, nonacademic groups offered 77% of their positions on a partnership track basis. Groups strongly affected by managed care recruited fewer radiologists and offered fewer expansion positions than similar groups that were less affected by managed care. However, managed care did not influence whether positions were offered on a partnership basis. CONCLUSION: Available positions continued to decline, and the shortfall of expansion positions relative to the annual growth in the workforce may generate serious employment problems. Managed care is having a negative effect on employment opportunities for radiologists. Gaining employment remains about equally difficult, regardless of field. The approximately 200 positions that remained unfilled at the end of the 1995 hiring season did not result from a mismatch between radiologists' skills and the qualifications that radiology groups were seeking.

The employment market for 1995 graduates of diagnostic radiology and radiation oncology training.

OBJECTIVE: Despite widespread concern that a major surplus of non-primary-care physicians is developing, little nonanecdotal information has been available. Therefore, we developed and applied a methodology for appraising the situation of new graduates. Graduates should be particularly vulnerable because, unlike seasoned physicians. they all must find employment. MATERIALS AND METHODS: In April-May 1995, and in a December follow-up, we surveyed diagnostic radiology and radiation oncology training program directors about the status of their 1995 residency and fellowship graduates, their programs, and the employment market. More than 90% responded. We compared findings with similar 1994 surveys. Differences were assessed with t tests or multiple regression analyses, with a p value of less than or equal to .05 as the test of significance. RESULTS: Directors reported unemployment 6 months after graduation was 0.6% (+/- 0.3%) for diagnostic radiology fellows and less for others. They said approximately 90% of graduates had positions reasonably matching their training and personal employment goals. Reported unemployment rates and percentages of graduates in desired positions did not differ from 1994. However, training directors generally were more pessimistic in 1995, overwhelmingly reporting the employment market was more difficult than in recent years. Few statistically significant differences among subgroups--including diagnostic subspecialties--were found. Net planned changes in program size will generate reductions of at most a few percent in the annual number of graduates, and more than 98% of beginning year residency slots were filled. CONCLUSION: Unemployment was remarkably low. Also, surprisingly, even "soft" indicators such as undesired positions or difficulties during the process of employment search (i.e., in April-May) did not show deterioration. Projections of pending physician surpluses may be exaggerated. Given our findings, program directors' growing pessimism is puzzling. This pessimism has not called forth sizable cuts in program size and, if major surpluses are pending, neither reductions in program size nor failure to fill all available slots offer significant relief, at least to date. The employment market is about equally good (or equally difficult) across diagnostic subspecialties. The absence of regional differences indicates graduates are effectively reaching beyond the locality where they trained in their employment search.

The sex ratio of American radiologists: comparison and implications by age, subspecialty, and type of practice.

OBJECTIVE: The purpose of this paper is to present results related to two questions regarding changes in the sex ratio of American radiologists. Do men and women in radiology have different patterns of subspecialization, postresidency training, board certification, or practice characteristics? Do differences in patterns between the sexes imply that the number of radiologists required in the future will change with a changing sex ratio of radiologists? MATERIALS AND METHODS: A survey questionnaire was mailed to a stratified random sample of 2804 radiologists, radiation oncologists, and nuclear medicine specialists drawn from the American Medical Association Physician Masterfile. The survey achieved a response rate of 69%. Stratification criteria included sex, age, and subspecialty. The survey questions included age, sex, subspecialty, training status, board certification, type of practice, principal work activity, source of income, hours worked, and amount of time away from the practice. Data analysis used descriptive statistics, ordinary least squares regression, and logit analysis. Weighting assured that results represent all radiologists. RESULTS: Only 13% of active radiologists who have finished training are women. The percentage varies with age; 6% of radiologists 45 years old or older; 22% of those 35-44 years old, and 23% of those younger than 35 years old were women. Differences in the sex ratio were not associated with differences in board certification or postresidency fellowships, but subspecialization differed by sex. Women were more likely than men to be salaried, to work part-time, to be engaged in teaching, and to work in an office rather than in a hospital. Differences in the sex ratio had little impact on estimates of the number of radiologists that will be needed in the future. CONCLUSION: Female radiologists have subspecialization and practice characteristics different from those of male radiologists. The increasing percentage of women in the profession will have little effect on the number of radiologists and radiation oncologists needed.