PubMed Health⌕ Search

Biomedical subjects

J S Weissman

Publications and source records attributed to J S Weissman.

At least 19 recordsLinked to original sources
PubMed2000

Molecular basis of a yeast prion species barrier.

The yeast [PSI+] factor is inherited by a prion mechanism involving self-propagating Sup35p aggregates. We find that Sup35p prion function is conserved among distantly related yeasts. As with mammalian prions, a species barrier inhibits prion induction between Sup35p from different yeast species. This barrier is faithfully reproduced in vitro where, remarkably, ongoing polymerization of one Sup35p species does not affect conversion of another. Chimeric analysis identifies a short domain sufficient to allow foreign Sup35p to cross this barrier. These observations argue that the species barrier results from specificity in the growing aggregate, mediated by a well-defined epitope on the amyloid surface and, together with our identification of a novel yeast prion domain, show that multiple prion-based heritable states can propagate independently within one cell.

Amyloidosis↗
PubMed1999

The effect of patients' preferences on racial differences in access to renal transplantation.

BACKGROUND: In the United States, black patients undergo renal transplantation less often than white patients, but few studies have directly assessed the association between race and patients' preferences with respect to transplantation. METHODS: To assess preferences with respect to transplantation and experiences with medical care, we interviewed 1392 (82.9 percent) of 1679 eligible patients with end-stage renal disease (age range, 18 to 54 years) approximately 10 months after they had begun maintenance treatment with dialysis. Participants were selected from a stratified random sample of patients undergoing dialysis in four regions of the United States (Alabama, southern California, Michigan, and the mid-Atlantic region of Maryland, Virginia, and the District of Columbia) in 1996 and 1997. Patients were followed until March 1999. RESULTS: The interviews were conducted with 384 black women, 354 white women, 337 black men, and 317 white men. Black patients were less likely than white patients to want a transplant (76.3 percent of black women reported such a preference, vs. 79.3 percent of white women, and 80.7 percent of black men vs. 85.5 percent of white men), and they were less likely to be very certain about this preference (58.3 percent vs. 65.3 percent and 64.1 percent vs. 75.7 percent, respectively; P<0.01 for each comparison with both sexes combined). However, much larger differences were evident in rates of referral for evaluation at a transplantation center (50.4 percent for black women vs. 70.5 percent for white women, and 53.9 percent for black men vs. 76.2 percent for white men; P<0.001 for each comparison) and placement on a waiting list or transplantation within 18 months after the start of dialysis therapy (31.3 percent for black women vs. 56.5 percent for white women, and 35.3 percent for black men vs. 60.6 percent for white men; P<0.001). These racial differences remained significant after adjustment for patients' preferences and expectations about transplantation, sociodemographic characteristics, the type of dialysis facility, perceptions of care, health status, the cause of renal failure, and the presence or absence of coexisting illnesses. CONCLUSIONS: In the United States, the preferences and expectations with respect to renal transplantation among patients with end-stage renal disease differ according to race. These differences, however, explain only a small fraction of the substantial racial differences in access to transplantation. Physicians should ensure that black patients who desire renal transplantation are fully informed about it and are referred for evaluation.

Adult↗
PubMed1999

Academic health centers on the front lines: survival strategies in highly competitive markets.

The authors describe approaches that five academic health centers (AHCs) have taken to reduce costs, enhance quality, or improve their market positions since the onset of price competition and managed care. The five AHCs, all on the West Coast, were selected for study because they (1) are located in markets that had been highly competitive for the longest time; (2) are committed to all the major missions of AHCs; and (3) own or substantially control their major clinical teaching facilities. The study findings reflect the status of the five AHCs during the fall of 1998. Although some findings may no longer be current (especially in light of ongoing implementation of the Balanced Budget Act of 1997), they still provide insights into the options and opportunities available to many AHCs in highly competitive markets. The authors report on the institutions' financial viability (positive), levels of government support (advantageous), and competition from other AHCs (modest). They outline the study AHCs' survival strategies in three broad areas: increasing revenues via exploiting market niches, reducing costs, and reorganizing to improve internal governance and decision making. They also report how marketplace competition and the strategies the AHCs used to confront it have affected the AHCs' missions. The authors summarize the outstanding lessons that all AHCs can learn from the experiences of the AHCs studied, although adding that AHCs in other parts of the country should use caution in looking to the West Coast AHCs for answers.

Academic Medical Centers↗
PubMed1999

Hospital readmissions and quality of care.

BACKGROUND: Readmission rates are often proposed as markers for quality of care. However, a consistent link between readmissions and quality has not been established. OBJECTIVE: To test the relation of readmission to quality and the utility of readmissions as hospital quality measures. SUBJECTS: One thousand, seven hundred and fifty-eight Medicare patients hospitalized in four states between 1991 to 1992 with pneumonia or congestive heart failure (CHF). DESIGN: Case control. MEASURES: Related adverse readmissions (RARs), defined as readmissions that indicate potentially sub-optimal care during initial hospitalization, were identified from administrative data using readmission diagnoses and intervening time periods designated by physician panels. We used linear regression to estimate the association between implicit and explicit quality measures and readmission status (RARs, non-RAR readmissions, and nonreadmissions), adjusting for severity. We tested whether RARs were associated with inferior care and performed simulations to determine whether RARs discriminated between hospitals on the basis of quality. RESULTS: Compared with nonreadmitted pneumonia patients, patients with RARs had lower adjusted quality measured both by explicit (0.25 standardized units, P = 0.004) and implicit methods (0.17, P = 0.047). Adjusted differences for CHF patients were 0.17 (P = 0.048) and 0.20 (P = 0.017), respectively. In some analyses, patients with non-RAR readmissions also experienced lower quality. However, rates of inferior quality care did not differ significantly by readmission status, and simulations identified no meaningful relationship between RARs and hospital quality of care. CONCLUSIONS: RARs are statistically associated with lower quality of care. However, neither RARs nor other readmissions appear to be useful tools for identifying patients who experience inferior care or for comparing quality among hospitals.

Aged↗
PubMed1999

Quality of care by race and gender for congestive heart failure and pneumonia.

BACKGROUND: Variations in the rates of major procedures by race and gender are well described, but few studies have assessed the quality of care by race and gender for basic hospital services. OBJECTIVE: To assess quality of care by race and gender. RESEARCH DESIGN: Retrospective review of medical records. SUBJECTS: Stratified random sample of 2,175 Medicare beneficiaries hospitalized for congestive heart failure or pneumonia in Illinois, New York, and Pennsylvania during 1991 and 1992. MEASURES: Explicit process criteria and implicit review by physicians. RESULTS: In adjusted analyses, black patients with congestive heart failure or pneumonia received lower quality of care overall than other patients with these conditions by both explicit process criteria and implicit review (P < 0.05). On explicit measures, overall quality of care did not differ by gender for either condition, but significant differences were noted on explicit subscales. Women received worse cognitive care than men from physicians for both conditions, better cognitive care from nurses for pneumonia, and better therapeutic care for congestive heart failure (P < 0.05). Women received worse quality of care than men by implicit review (P = 0.03) for congestive heart failure but not pneumonia. CONCLUSIONS: Consistent racial differences in quality of care persist in basic hospital services for two common medical conditions. Physicians, nurses, and policy makers should strive to eliminate these differences. Gender differences in quality of care are less pronounced and may vary by condition and type of provider or service.

Black or African American↗
PubMed1999

Termination from Medicaid: how does it affect access, continuity of care, and willingness to purchase insurance?

Welfare reform has raised fears that Medicaid recipients will lose coverage, yet efforts to insure the poor via waiver programs may fall short. A telephone sample of 351 enrolled and terminated members of a Medicaid managed care plan based in community health centers were asked about insurance status, source of care, willingness to purchase new insurance, and access. Of terminated families, 78 percent had one member without insurance, 93 percent retained a regular source of care (vs. 96 percent enrolled), and 86 percent retained the same source as before losing coverage. Only 11 percent of uninsured respondents were willing to pay $200 per month and 57 percent to pay $50 per month for replacement coverage, and they were more likely to report problems getting prescription medications and obtaining treatment for serious symptoms and to go without care because of the expense. Access to care is diminished for those who lose Medicaid coverage, even for persons attending community health centers.

Adult↗
PubMed1998

GroEL-GroES-mediated protein folding requires an intact central cavity.

The chaperonin GroEL is an oligomeric double ring structure that, together with the cochaperonin GroES, assists protein folding. Biochemical analyses indicate that folding occurs in a cis ternary complex in which substrate is sequestered within the GroEL central cavity underneath GroES. Recently, however, studies of GroEL "minichaperones" containing only the apical substrate binding subdomain have questioned the functional importance of substrate encapsulation within GroEL-GroES complexes. Minichaperones were reported to assist folding despite the fact that they are monomeric and therefore cannot form a central cavity. Here we compare directly the folding activity of minichaperones with that of the full GroEL-GroES system. In agreement with earlier studies, minichaperones assist folding of some proteins. However, this effect is observed only under conditions where substantial spontaneous folding is also observed and is indistinguishable from that resulting from addition of the nonchaperone protein alpha-casein. By contrast, the full GroE system efficiently promotes folding of several substrates under conditions where essentially no spontaneous folding is observed. These data argue that the full GroEL folding activity requires the intact GroEL-GroES complex, and in light of previous studies, underscore the importance of substrate encapsulation for providing a folding environment distinct from the bulk solution.

Base Sequence↗
PubMed1998

A critical role for amino-terminal glutamine/asparagine repeats in the formation and propagation of a yeast prion.

The yeast [PSI+] factor propagates by a prion-like mechanism involving self-replicating Sup35p amyloids. We identified multiple Sup35p mutants that either are poorly recruited into, or cause curing of, wildtype amyloids in vivo. In vitro, these mutants showed markedly decreased rates of amyloid formation, strongly supporting the protein-only prion hypothesis. Kinetic analysis suggests that the prion state replicates by accelerating slow conformational changes rather than by providing stable nuclei. Strikingly, our mutations map exclusively within a short glutamine/asparagine-rich region of Sup35p, and all but one occur at polar residues. Even after replacement of this region with polyglutamine, Sup35p retains its ability to form amyloids. These and other considerations suggest similarities between the prion-like propagation of [PSI+] and polyglutamine-mediated pathogenesis of several neurodegenerative diseases.

Amino Acid Sequence↗
PubMed1998

Costs and outcomes of AIDS care: comparing a health maintenance organization with fee-for-service systems in the Boston Health Study.

OBJECTIVE: A 4-month observational cohort study was performed to compare the performance of one health maintenance organization (HMO) with two fee-for-service (FFS) systems in Boston, Massachusetts in treating 255 patients with AIDS. MAIN OUTCOME MEASURES: Total 4-month costs; cost subcomponents, including inpatient, outpatient, home care, and zidovudine costs; functional status (difficulties with activities of daily living); and satisfaction with care. RESULTS: Compared with FFS patients, HMO patients were better educated, more often white, less often on Medicaid, and more often reported homosexual or bisexual behaviors as HIV risk factors (all factors, p = .001). Both groups had similar duration of AIDS, baseline hemoglobin levels, and leukocyte counts. Total 4-month costs at the HMO were significantly lower than those in the FFS settings ($4799 U.S. versus $8540 U.S.; p = .013), as were outpatient costs ($1131 U.S. versus $1614 U.S.; p = .001), after adjustment for sociodemographic factors, baseline functioning, main HIV risk factor, and other clinical variables. Adjusted physical functioning (p = .32) and patient satisfaction (p = .82). were similar between systems. CONCLUSIONS: The HMO had significantly lower total costs without any observable decrement in functional outcomes or patient satisfaction. The largest component of these cost savings came from reduced spending on inpatient care, but the HMO also spent less on outpatient and home care. Better coordination of care at the HMO may have been responsible for these lower costs.

Acquired Immunodeficiency Syndrome↗
PubMed1998

Ero1p: a novel and ubiquitous protein with an essential role in oxidative protein folding in the endoplasmic reticulum.

The structure of many proteins entering the secretory pathway is dependent on stabilization by disulfide bonds. To support disulfide-linked folding, the endoplasmic reticulum (ER) must maintain a strongly oxidizing environment compared to the highly reduced environment of the cytosol. We report here the identification and characterization of Ero1p, a novel and essential ER-resident protein. Mutations in Ero1p cause extreme sensitivity to the reducing agent DTT, whereas overexpression confers DTT resistance. Strikingly, compromised Ero1p function results in ER retention of disulfide-stabilized proteins in a reduced, nonnative form, while not affecting structural maturation of a disulfide-free protein. We conclude that there exists a specific cellular redox machinery required for disulfide-linked protein folding in the ER and that Ero1p is an essential component of this machinery.

Animals↗
PubMed1997

Relationship between market competition and the activities and attitudes of medical school faculty.

CONTEXT: Growth in health care market competition and the concomitant increasing dependence of academic health centers on clinical revenues may require medical school faculty to increase patient care activity, perhaps at the expense of research and teaching. However, the relationship between health care market competitiveness and the activities and attitudes of medical school faculty has not been established. OBJECTIVE: To examine the relationship between market competitiveness and the activities and attitudes of medical school faculty members. DESIGN: Mailed survey of 3394 life-science faculty in the 50 universities that received the most funding from the National Institutes of Health in 1993. SETTING: Medical schools in research-intensive universities. PARTICIPANTS: A total of 2167 faculty responded to the survey (response rate, 64%). We analyzed the responses of 1671 medical school research faculty located in markets of differing health care competitiveness, ranging from least competitive (stage 1) to most competitive (stage 4) markets. MAIN OUTCOME MEASURES: The number of publications in refereed journals in the last 3 years, the average number of hours per week of teaching contact, whether faculty in clinical departments had patient care responsibilities, and measures of departmental community, cooperation, and conflict. RESULTS: Clinical researchers in stage 1 and 2 markets published more scientific articles than those in stage 3 markets (14.5 vs 12.6, P=.04) or in stage 4 markets (14.5 vs 12.0, P=.03). Among 96 young faculty (professional age-<10 years) in clinical departments, 11 (44%) of those in stage 1 and 2 markets had patient care duties compared with 32 (56.1%) of young faculty members in stage 3 markets (P=.04) and 12 (85.7%) of those in stage 4 markets (P=.01). The percentage of senior faculty in clinical departments (n=691) with patient care responsibilities did not differ significantly by market stage. Compared with faculty in less competitive markets, faculty in stage 4 markets perceived lower levels of departmental cooperation and higher levels of conflict. CONCLUSIONS: Increased competitiveness of health care markets seems to hinder the capacity of academic health centers to conduct clinical research and to foster the careers of young clinical faculty.

Academic Medical Centers↗
PubMed1997

The Boston AIDS Survival Score (BASS): a multidimensional AIDS severity instrument.

OBJECTIVES: This study developed a new acquired immunodeficiency syndrome (AIDS) severity system by including diagnostic, physiological, functional, and sociodemographic factors predictive of survival. METHODS: Three-hundred five persons with AIDS in Boston were interviewed; their medical records were reviewed and vital status ascertained. RESULTS: Overall median (+/- SD) survival for the cohort from the first interview until death was 560 +/- 14.4 days. The best model for predicting survival, the Boston AIDS Survival Score, included the Justice score (stage 2 relative hazard [RH] = 1.25, 95% confidence interval [CI] = 0.80, 1.96; stage 3 RH = 1.76, 95% CI = 1.15, 2.70), a newly developed opportunistic disease score (Boston Opportunistic Disease Survival Score; stage 2 RH = 1.35, 95% CI = 0.90, 2.02; stage 3 RH = 2.10, 95% CI = 1.38, 3.18), and measures of activities of daily living (any intermediate limitations, RH = 1.84, 95% CI = 1.05, 3.21; any basic limitations, RH = 2.60, 95% CI = 1.44, 4.69). This model had substantially greater predictive power (R2 = .17, C statistic = .68) than the Justice score alone (R2 = .09, C statistic = .61). CONCLUSIONS: Incorporating data on clinically important events and functional status into a physiologically based system can improve the prediction of survival with AIDS.

Acquired Immunodeficiency Syndrome↗
PubMed1996

Release of both native and non-native proteins from a cis-only GroEL ternary complex.

Protein folding by the double-ring chaperonin GroEL is initiated in cis ternary complexes, in which polypeptide is sequestered in the central channel of a GroEL ring, capped by the co-chaperonin GroES. The cis ternary complex is dissociated (half-life of approximately 15 s) by trans-sided ATP hydrolysis, which triggers release of GroES. For the substrate protein rhodanese, only approximately 15% of cis-localized molecules attain their native form before hydrolysis. A major question concerning the GroEL mechanism is whether both native and non-native forms are released from the cis complex. Here we address this question using a 'cis-only' mixed-ring GroEL complex that binds polypeptide and GroES on only one of its two rings. This complex mediates refolding of rhodanese but, as with wild-type GroEL, renaturation is quenched by addition of mutant GroEL 'traps', which bind but do not release polypeptide substrate. This indicates that non-native forms are released from the cis complex. Quenching of refolding by traps was also observed under physiological conditions, both in undiluted Xenopus oocyte extract and in intact oocytes. We conclude that release of non-native forms from GroEL in vivo allows a kinetic partitioning among various chaperones and proteolytic components, which determines both the conformation and lifetime of a protein.

Adenosine Diphosphate↗