William Stewart Halsted: letters to a young female admirer.

OBJECTIVE: To present the first new information in the past 25 years concerning the life of Dr. William Stewart Halsted. This paper reports on recently discovered personal correspondence of Dr. Halsted, beginning at age 66, to a young lady, Elizabeth Blanchard Randall, 40 years his junior. SUMMARY BACKGROUND DATA: Dr. William Stewart Halsted is generally considered the most important and influential surgeon that this country has produced. During his Hopkins days in Baltimore (1886-1922) he was rather reclusive, and little is known of his personal life. He was married but had no children. Several biographies written by Halsted's contemporaries constitute the bulk of what is known about Halsted's personal life. METHODS: All extant letters from Dr. Halsted to Miss Randall were reviewed. Archival materials were consulted to understand the context for this friendship. The correspondence between Halsted and Randall took place during a 3-year period, although their acquaintance was probably long-standing. RESULTS: The letters reveal Dr. Halsted and Miss Randall's great and warm affection for each other, despite their 40-year age difference. The letters have a playful nature absent in Halsted's other correspondence. This relationship has not been previously noted. CONCLUSIONS: Late in Halsted's life, he developed a warm and affectionate relationship with a young lady 40 years his junior, as revealed in Halsted's correspondence. Halsted's warm, personal, and playful letters are in stark contrast to his biographers' portrayals of him as a more serious and reclusive person.

Weight control in the physician's office.

BACKGROUND: Lifestyle changes involving diet, behavior, and physical activity are the cornerstone of successful weight control. Incorporating meal replacements (1-2 per day) into traditional lifestyle interventions may offer an additional strategy for overweight patients in the primary care setting. METHODS: One hundred thirteen overweight premenopausal women (mean +/- SD age, 40.4 +/- 5.5 years; weight, 82 +/- 10 kg; and body mass index, 30 +/- 3 kg/m(2)) participated in a 1-year weight-reduction study consisting of 26 sessions. The women were randomly assigned to 3 different traditional lifestyle-based groups: (1) dietitian-led group intervention (1 hour per session), (2) dietitian-led group intervention incorporating meal replacements (1 hour per session), or (3) primary care office intervention incorporating meal replacements with individual physician and nurse visits (10-15 minutes per visit). RESULTS: For the 74 subjects (65%) completing 1 year, the primary care office intervention using meal replacements was as effective as the traditional dietitian-led group intervention not using meal replacements (mean +/- SD weight loss, 4.3% +/- 6.5% vs 4.1% +/- 6.4%, respectively). Comparison of the dietitian-led groups showed that women using meal replacements maintained a significantly greater weight loss (9.1% +/- 8.9% vs 4.1% +/- 6.4%) (P =.03). Analysis across groups showed that weight loss of 5% to 10% was associated with significant (P =.01) reduction in percentage of body fat, body mass index, waist circumference, resting energy expenditure, insulin level, total cholesterol level, and low-density lipoprotein cholesterol level. Weight loss of 10% or greater was associated with additional significant (P =.05) improvements in blood pressure and triglyceride level. CONCLUSIONS: A traditional lifestyle intervention using meal replacements can be effective for weight control and reduction in risk of chronic disease in the physician's office setting as well as in the dietitian-led group setting.

Financial performance and participation in Medicaid and Medi-Cal managed care.

This article assesses the participation and the financial performance of licensed health maintenance organization (HMOs) in the Medicaid market. The study found that participation by Medicaid Dominant plans has more than doubled from 11 percent in 1992 to 23 percent in 1998 while Medicaid membership in Commercial Dominant plans declined from 71 percent in 1994 to 51 percent in 1998. Both participating and non-participating plans incurred operating losses in 1998. Medi-Cal participating plans had higher operating margins than Medicaid participating plans throughout the United States. Interviews with key informants express concern about competence in program management, rate adequacy, decline in Medicaid enrollment, and turbulence forces of managed care market on Medicaid programs.

Setting the target for a better cervical screening test: characteristics of a cost-effective test for cervical neoplasia screening.

OBJECTIVE: To determine the potential effects on costs and outcomes of changes in sensitivity and specificity with new screening methods for cervical cancer. METHODS: Using a Markov model of the natural history of cervical cancer, we estimated the effects of sensitivity, specificity, and screening frequency on cost-effectiveness. Our estimates of conventional Papanicolaou test sensitivity of 51% and specificity of 97% were obtained from a meta-analysis. We estimated the effect of reducing false-negative rates from 40-90% and increasing false-positive rates by up to 20%, independently and jointly. We varied the marginal cost of improving sensitivity from $0 to $15. RESULTS: When specificity was held constant, increasing sensitivity of the Papanicolaou test increased life expectancy and costs. When sensitivity was held constant, decreasing specificity of the Papanicolaou test increased costs, an effect that was more dramatic at more frequent intervals. Decreased specificity had a substantial effect on cost-effectiveness estimates of improved Papanicolaou test sensitivity. Most of those effects are related to the cost of evaluation and treatment of low-grade lesions. CONCLUSION: Policies or technologies that increased sensitivity of cervical cytologic screening increased overall costs, even if the cost of the technology was identical to that of conventional Papanicolaou smears. These effects appear to be caused by relatively high prevalence of low-grade lesions and are magnified at frequent screening intervals. Efficient cervical cancer screening requires methods with greater ability to detect lesions that are most likely to become cancerous.

Factors affecting progress of Australian and international students in a problem-based learning medical course.

CONTEXT: Research on the factors affecting progress in medical schools has typically focused on mainstream (non-Indigenous Australian, non-international) students in traditional, didactic programmes. These results may not be applicable to students, particularly those from culturally diverse backgrounds, undertaking problem-based learning courses. OBJECTIVE: This study used qualitative methodology to explore and compare factors affecting progress for mainstream Australian students (non-Indigenous Australian, non-international) and international students (full fee-paying students who had relocated countries to study) in a problem-based learning medical course. Intervention strategies were devised on the basis of the participants' experiences. METHODS: Six focus group discussions were conducted (three with mainstream Australian and three with international participants). Transcripts of these discussions were coded and analysed independently by two researchers and discussed until consensus was attained. RESULTS: Participants identified both positive and negative experiences related to the course structure, which were consistent with previous findings. The participants' experiences demonstrated a relationship between sense of 'belongingness' to the medical school community, participation in learning opportunities and progress through the course. CONCLUSIONS: The results suggest that interventions aimed at reducing barriers to progress need to promote students' confidence, motivation and subsequent participation in course learning opportunities. These results have application to other problem-based learning courses particularly those which face the challenge of providing an optimal learning environment for students from diverse backgrounds.

Insurers' views of the partnership for long-term care.

The Partnership for Long-Term Care was established in 1986 to demonstrate the feasibility of implementing public-private collaborations to offer affordable long-term care insurance products to a broad range of individuals. A fall 1996 survey of long-term care insurers indicates that those who participate are major players in the market and that most plan to continue their participation. Insurers were motivated to participate because the Partnership provided an opportunity to contribute to "good" public policy, market a product with a state seal of approval, and potentially increase their market share. While the survey did reveal dissatisfaction with some aspects of the Partnership, it also demonstrated that it is possible to develop a working partnership between states and insurers despite the need for compromise.

Factors important in the purchase of partnership long-term care insurance.

OBJECTIVE: To understand the factors important in the purchase of long-term care insurance through the Robert Wood Johnson Foundation Partnership for Long-Term Care. DATA SOURCES: Information on the Partnership programs, telephone surveys, data on Partnership purchasers, and random sample frames. STUDY DESIGN: Logistic regression analysis is used to examine characteristics associated with the purchase of a Partnership insurance policy. Independent variables are health status, demographic and financial characteristics, knowledge, and attitudes. DATA COLLECTION: A telephone survey of Partnership purchasers and a random sample of the population in each Partnership state were conducted. Survey questions included health status, opinions about long-term care and long-term care insurance, financial planning, demographic characteristics, and income and assets. PRINCIPAL FINDINGS: Important in the purchase of a Partnership policy were variables associated with education and knowledge about long-term care. Other important factors include attitudes and health status. Partnership purchase is associated with higher income and asset levels up to a point, with the effect plateauing and decreasing at the highest income and asset levels. CONCLUSIONS: Improved education and knowledge are important in increasing long-term care insurance purchase. Attitudes about having a caregiver, and about the government's role in paying for long-term care as well as the potential purchaser's willingness to consider nursing home care affect policy purchase. Also associated with Partnership policy purchase are better health and middle income and asset levels.

Utilization of services in Arizona's capitated Medicaid program for long-term care beneficiaries.

The Arizona Long-Term Care System (ALTCS), Arizona's Medicaid program for long-term care (LTC) beneficiaries, capitates contractors to provide a full range of acute and LTC services to financially-eligible beneficiaries determined to be at risk of institutionalization. This article compares the acute care utilization experience of LTC beneficiaries in ALTCS with those in a fee-for-service (FFS) Medicaid program, linking data from both the Medicare and the Medicaid program files. Patterns of use observed in Arizona seem more consistent with a managed care environment than those observed in the FFS comparison. Rates of acute care utilization observed for both the capitated and the FFS program should be of interest to States considering incorporating LTC beneficiaries into their Medicaid managed care program.

Plasma protein binding of phenylacetate and phenylbutyrate, two novel antineoplastic agents.

Phenylacetate and phenylbutyrate, two novel inducers of tumor cytostasis and differentiation, are currently in clinical trials for the treatment of cancer in adults. The purpose of our study was to evaluate the plasma protein-binding characteristics of phenylacetate and phenylbutyrate in the plasma of normal volunteers and that of patients with cancer. Drug plasma protein-binding analysis was examined using three separate devices: a micropartition system and two equilibrium dialysis systems, all of which exhibited similar results. Phenylacetate and phenylbutyrate concentrations were determined by high-performance liquid chromatography. Both drugs exhibited concentration-dependent binding. Our results showed sodium phenylacetate to have a higher free fraction than sodium phenylbutyrate at corresponding concentrations (> 0.442 +/- 0.008 and > 0.188 +/- 0.001, respectively). Plasma pH did not greatly affect protein binding of either drug. As albumin concentration decreased, an increase in free fraction of both drugs was observed, however alpha 1-acid glyco-protein showed no change in free fraction as its concentration increased. Patients with cancer with lower levels of albumin showed an increase in free fraction with both phenylacetate and phenylbutyrate. When phenylacetate and phenylbutyrate were added together in plasma, the free fraction of phenylacetate increased, whereas the phenylbutyrate free fraction slightly decreased. We conclude that phenylacetate and phenylbutyrate have high free fractions that change with varying albumin levels and when both phenylacetate and phenylbutyrate are present together in plasma.

Why talk about mental states? The significance of children's conversations with friends, siblings, and mothers.

Natural language data from 38 47-month-olds recorded at home in unstructured observations were analyzed and comparisons made of characteristics of mental state term use in child-friend, child-sibling, and child-mother dyads. Significantly more references to mental states were made by the children in conversations with siblings and friends than with mothers. Frequent use of mental state terms by both partners was related to cooperative interaction in both child-friend and child-sibling dyads and several associations were found with measures of language fluency, gender, and maternal education, although these varied across the 2 dyads. Children's use of mental state terms in conversations with siblings and friends was correlated with their performance on two false belief measures. Results highlight the importance of extending investigations into the social implications of the development of children's "theories of mind."

Severe thrombocytopenia in patients treated with suramin: evidence for an immune mechanism in one.

Although suramin has long been used to treat human trypanosomiasis, recent clinical trials have tested its efficacy against the acquired immunodeficiency syndrome (AIDS) and various malignancies. Thromobocytopenia was observed in early trials with suramin in AIDS, but has been uncommon in patients treated for solid tumors. Here we describe 5 patients out of a total of 67 (7%) who developed severe thrombocytopenia while receiving suramin as part of a phase II clinical trial for metastatic prostate carcinoma refractory to hormonal therapy. IgG purified from one patient's plasma caused suramin-dependent platelet aggregation. There was also evidence of crossreactivity between suramin and heparin in this system. An immune mechanism, however, could not be documented in the other cases, suggesting that multiple mechanisms may be responsible for severe thrombocytopenia in this patient population.

The in-vitro response of 4 antisteroid receptor agents on the hormone-responsive prostate-cancer cell-line lncap.

Previous reports indicate that flutamide withdrawal is associated with PSA declines and tumor shrinkage in selected patients with 'hormone-refractory' prostate cancer. Though the mechanisms underlying this effect are not clear, investigators have hypothesized that these effects are mediated by mutant androgen receptors recognizing hydroxy-flutamide as an androgenic agonist. Such receptors have been well described in the human prostate cancer cell line LNCaP. Despite the finding that the androgen receptor of LNCaP aberrantly recognizes a variety of steroids, including estrogen and progesterone, as androgenic agonists, there are no studies which examine the effect of estrogen antagonists and progesterone antagonist on baseline and androgen-stimulated LNCaP growth. In this report, LNCaP cells were cultured in phenol red-free media using charcoal-stripped sera. As previously reported, flutamide enhanced LNCaP growth and bicalutamide inhibited androgen-stimulated LNCaP proliferation. Neither tamoxifen nor RU486 influenced LNCaP growth (either in the presence or absence of exogenous androgens). From these data we conclude that antagonists of estrogen and progesterone action have no anti-proliferative effect on LNCaP cells and that the mutant androgen receptor expressed in these cells is quite restrictive in the recognition of compounds with antagonistic activity. The clinical implications of these findings are discussed.

In vitro antitumor effect of hydroxyurea on hormone-refractory prostate cancer cells and its potentiation by phenylbutyrate.

Previous clinical trials have suggested that hydroxyurea may possess some activity against prostate cancer. The in vitro antiproliferative activity of hydroxyurea was evaluated in three hormone-refractory prostate cancer cell lines, PC-3, DU-145 and PC-3M. Fifty-percent inhibition of growth in all three cell lines required prolonged (120 h) exposure to hydroxyurea at a concentration of approximately 100 microM. Using pharmacokinetic data obtained during the course of a clinical trial of hydroxyurea, we simulated a dosing regimen that would sustain plasma drug concentrations above 100 microM for 120 h (1 g loading dose, followed by 500 mg every 6 h for 5 days in a 70 kg man). Since this dosing regimen is likely to generate an unacceptable degree of myelosuppression, in vitro combination studies were conducted with hydroxyurea and phenylbutyrate, a new differentiating agent with no myelosuppressive effects. These studies resulted in a reduction of the hydroxyurea concentration necessary for 50% growth inhibition (50 microM of hydroxyurea plus 0.5 mM of phenylbutyrate). A regimen designed to achieve that hydroxyurea concentration (400 mg loading dose, followed by 200 mg every 6 h for 5 days) should be clinically achievable. Based on these results, this combination deserves further evaluation in patients with stage D prostate cancer.

A phase I and pharmacokinetic study of intravenous phenylacetate in patients with cancer.

Phenylacetate has recently been shown to suppress tumor growth and promote differentiation in experimental models. A phase I trial of phenylacetate was conducted in 17 patients with advanced solid tumors. Each patient received a single i.v. bolus dose followed by a 14-day continuous i.v. infusion of the drug. Twenty-one cycles of therapy were administered at four dose levels, achieved by increasing the rate of the continuous i.v. infusion. Phenylacetate displayed nonlinear pharmacokinetics [Km = 105.1 +/- 44.5 (SD) microgram/ml, Vmax = 24.1 +/- 5.2 mg/kg/h and Vd = 19.2 +/- 3.3 L]. There was also evidence for induction of drug clearance. Ninety-nine % of phenylacetate elimination was accounted for by conversion to phenylacetylglutamine, which was excreted in the urine. Continuous i.v. infusion rates resulting in serum phenylacetate concentrations exceeding Km often resulted in rapid drug accumulation and dose-limiting toxicity, which consisted of reversible central nervous system depression, preceded by emesis. Three of nine patients with metastatic, hormone-refractory prostate cancer maintained stable prostatic specific antigen levels for more than 2 months; another had less bone pain. One of six patients with glioblastoma multiforme, whose steroid dosage has remained unchanged for the duration of therapy, has sustained functional improvement for more than 9 months. The use of adaptive control with feedback for the dosing of each patient enabled us to safely maintain stable phenylacetate concentrations up to the range of 200-300 micrograms/ml, which resulted in clinical improvement in some patients with advanced disease.

Managed Medicaid cost savings: the Arizona experience.

This paper reports on estimated cost savings for acute care beneficiaries in the Arizona Health Care Cost Containment System (AHCCCS) over its first nine years of operation, fiscal years 1983-1991. AHCCCS has similar eligibility and service coverage as a traditional Medicaid program has but capitates health plans to provide medical services to beneficiaries. The results indicate that the program yielded $100 million in savings over estimates of what a traditional Medicaid program would have cost in Arizona. In addition, AHCCCS experienced a smaller rate of increase in program expenditures over time, so that cost savings have increased as the program has matured.

Monitoring access following Medicare price changes: physician perspective.

In this article, the author examines changes in Medicare beneficiaries' access to services following the Omnibus Budget Reconciliation Act of 1987 "overpriced" procedure price reductions from the physician perspective. Three measures of physician availability remained essentially constant: number of physicians treating beneficiaries or performing overpriced procedures; average Medicare caseload; and average share of a physician's Medicare practice comprised of those who are poor and not white. Physician practice characteristics were examined and provided evidence of continuing participation in Medicare: Average Medicare revenue increased 10 percent, and average volume of all services increased. However, physicians with the largest fee reductions or who were the most financially dependent on the procedures did not change overpriced procedure volume.