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Biomedical subjects

J S Weissman

Publications and source records attributed to J S Weissman.

At least 55 records · Page 3Linked to original sources
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↗
PubMed1996

Characterization of the active intermediate of a GroEL-GroES-mediated protein folding reaction.

Recent studies of GroE-mediated protein folding indicate that substrate proteins are productively released from a cis ternary complex in which the nonnative substrate is sequestered within the GroEL channel underneath GroES. Here, we examine whether protein folding can occur in this space. Stopped-flow fluorescence anisotropy of a pyrene-rhodanese-GroEl complex indicates that addition of GroES and ATP (but not ADP) leads to a rapid change in substrate flexibility at GroEL. Strikingly, when GroES release is blocked by the use of either a nonhydrolyzable ATP analog or a single-ring GroEL mutant, substrates complete folding while remaining associated with chaperonin. We conclude that the cis ternary complex, in the presence of ATP, is the active state intermediate in the GroE-mediated folding reaction: folding is initiated in this state and for some substrates may be completed prior to the timed release of GroES triggered by ATP hydrolysis.

Adenosine Triphosphate↗
PubMed1996

The validity of self-reported health-care utilization by AIDS patients.

OBJECTIVES: To examine the validity of self-reported health-care utilization among persons with AIDS. DESIGN: A comparison of survey data with information collected from medical and financial records. METHODS: Personal interviews provided information on utilization within a 4-month period for inpatient admissions (n = 296), ambulatory visits (n = 284), and hours of homecare (n = 106). Risk group, socioeconomic characteristics, disease stage, functional status, memory, and respondent's recall ability were also measured. Reporting error was defined as the difference between self reports and medical/financial records. Variations among subgroups of patients were examined using t tests and multiple regression. To determine whether reporting errors affected analysis of utilization data, we compared coefficients from parallel utilization models using each data source to predict use/non-use and total utilization. RESULTS: Mean overall reporting errors were small and not significantly different from zero. Reporting errors were lowest for hospital admissions and highest for homecare. High utilizers underreported all types of services. The interviewer evaluation of recall was an independent and significant predictor of reporting errors for admissions and ambulatory visits. Reporting errors varied by selected subgroup characteristics, but the direction and significance of the error depended on the type of utilization measured. In the parallel utilization models, few differences appeared between models using self-reports and medical/financial records to identify correlates of use/non-use, but some differences between the models of total utilization were apparent. CONCLUSIONS: Self-reports of utilization by AIDS patients with a recall period of 4 months or less provide, on average, valid data for analytic purposes. However, caution should be applied to reports by high or low users or by respondents judged by interviewers to have major recall problems.

Acquired Immunodeficiency Syndrome↗
PubMed1996

The influence of health-related quality of life and social characteristics on hospital use by patients with AIDS in the Boston Health Study.

OBJECTIVES: The authors examine whether health-related quality of life (HRQL) and social factors were independent predictors of future hospital use for persons with acquired immunodeficiency syndrome (AIDS). METHODS: A panel of 305 patients with AIDS treated at three provider settings in the Boston, Massachusetts area were enrolled during 1990 and 1991. Data were collected at baseline study enrollment and again 4 months later. Patient interviews, hospital bills, and medical charts were used to measure hospital use (admissions and days during the 4 months after enrollment), sociodemographic characteristics (age, gender, race, education, insurance, homelessness, alcohol use, and AIDS risk factors), disease burden (patient severity and a three-level opportunistic diseases and complications score), HRQL (patient-reported symptoms, activities of daily living, neuropsychological status, and global health assessment), system of care, and use of prophylactic drugs. Logistic regression was used to estimate the odds of admission. Total days of hospital care by patients with at least one admission were analyzed using multiple linear regression. Clinical models of hospital use were developed first from the variables measuring disease burden and system of care. Models estimating the associations between hospital use and all other predictor variables measured at baseline then were estimated using stepwise techniques, controlling for variables in the core model. RESULTS: Patients were more likely than their reference groups to be hospitalized if they had serious opportunistic diseases (adjusted odds ratio [OR] = 2.7), had poorer neuropsychological status (OR = 1.9), were non-white (OR = 2.0), or were homeless (OR = 3.3) (all P < or = 0.05). Activities of daily living were associated moderately (OR = 1.3; P = 0.07). Only system of care and neuropsychological status predicted total hospital days. CONCLUSIONS: The results indicate that future hospital use by persons with AIDS may be influenced by social and other health-related factors in addition to the more clinically related characteristics that are recorded in a medical chart. It therefore may be appropriate to assess these factors when considering options for intervention or when comparing patterns of use among patient groups or settings.

Acquired Immunodeficiency Syndrome↗
PubMed1995

Mechanism of GroEL action: productive release of polypeptide from a sequestered position under GroES.

The chaperonin GroEL is a large, double-ring structure that, together with ATP and the cochaperonin GroES, assists protein folding in vivo. GroES forms an asymmetric complex with GroEL in which a single GroES ring binds one end of the GroEL cylinder. Cross-linking studies reveal that polypeptide binding occurs exclusively to the GroEL ring not occupied by GroES (trans). During the folding reaction, however, released GroES can rebind to the GroEL ring containing polypeptide (cis). The polypeptide is held tightly in a proteolytically protected environment in cis complexes, in the presence of ADP. Single turnover experiments with ornithine transcarbamylase reveal that polypeptide is productively released from the cis but not the trans complex. These observations suggest a two-step mechanism for GroEL-mediated folding. First, GroES displaces the polypeptide from its initial binding sites, sequestering it in the GroEL central cavity. Second, ATP hydrolysis induces release of GroES and productive release of polypeptide.

Animals↗
PubMed1995

Contribution of individual side-chains to the stability of BPTI examined by alanine-scanning mutagenesis.

Bovine pancreatic trypsin inhibitor (BPTI) serves as an important model system for the examination of almost all aspects of protein structure. Systematic studies of the effects of mutation on the thermodynamic stability of BPTI, however, have been limited by the extreme stability of the protein. A derivative of BPTI containing only the 5-55 disulfide bond, termed [5-55]Ala, has been shown previously to fold into a structure very similar to that of native BPTI and to be a functional trypsin inhibitor. [5-55]Ala undergoes a reversible thermal unfolding transition with a melting temperature of 39 degrees C, and is therefore well suited for stability studies. Using an alanine-scanning mutagenesis approach, we have examined the contribution to stability of each side-chain in the [5-55]Ala derivative of BPTI. These studies demonstrate the importance of the two hydrophobic cores composed largely of clusters of aromatic residues, as well as the internal hydrogen-bonding network, in stabilizing BPTI. Overall, there is a strong relationship between change in buried surface area and stability for both polar and hydrophobic residues, with proportionality constants of 50 and 20 cal/A2, respectively. None of the alanine substitutions substantially stabilized [5-55]Ala. Nonetheless, approximately 60% (28/46) of the alanine mutants were destabilized by less than 10 degrees C, suggesting that a form of BPTI with up to half of its residues being alanine could fold into a stable structure resembling the native one.

Alanine↗
PubMed1995

Satisfaction with ambulatory care of persons with AIDS: predictors of patient ratings of quality.

OBJECTIVE: To examine the relation of patient characteristics and site of care to the perception of ambulatory care quality by persons with AIDS (PWAs). DESIGN: Patient surveys and medical record review were used to determine PWAs' perceptions of their ambulatory care, self-perceived health status, primary care relationships, sociodemographic characteristics, and severity of illness. SETTING: A public-hospital HIV clinic, an academic group practice, and a staff-model health maintenance organization (HMO) that together care for 20% of all Massachusetts PWAs. PATIENTS: All active patients as of February 12, 1990, and all new AIDS patients at each of the three sites during the subsequent 13 months. MEASUREMENTS AND MAIN RESULTS: The primary outcome measure was a six-item scale of patient-rated quality of care (PRQC), a newly developed measure that combined patients' ratings of their physician care, nursing care, involvement in medical decisions, and overall quality of care. Multiple logistic regression was carried out with low PRQC (lowest quartile) as the dependent variable, to identify correlates of patient perceptions of poor quality. Patients who had a primary nurse were significantly less likely to have low PRQC scores (OR = 0.50, 95% CI = 0.26 to 0.97). Black patients and patients who used injection drugs were significantly more likely to rate their care in the lowest quartile (OR = 2.22, 95% CI = 1.04 to 4.78; and OR = 2.43, 95% CI = 1.13 to 5.23, respectively), as were those who had lower self-perceived health status, after controlling for confounders; no association was found by site or severity. CONCLUSIONS: These results show that primary nursing may be an important determinant of how PWAs rate the quality of their ambulatory care. Furthermore, PWAs who are black or who are injection drug users are less satisfied than are others with the quality of their ambulatory AIDS care.

Acquired Immunodeficiency Syndrome↗
PubMed1995

All roads lead to Rome? The multiple pathways of protein folding.

Recent studies have found that protein folding reactions often proceed through two or more kinetically distinct pathways. In at least some cases, the observed folding intermediates act as kinetic traps, slowing the rate at which folding is completed. These findings have important implications for understanding how proteins fold in vitro and in vivo.

Animals↗
PubMed1995

A kinetic explanation for the rearrangement pathway of BPTI folding.

Bovine pancreatic trypsin inhibitor (BPTI) does not fold by simple sequential formation of its native disulphide bonds. Instead, an initially formed intermediate, termed N', first rearranges to a more stable species in a slow process that requires substantial unfolding. We find that direct oxidation of N' is also inhibited by native structure which slows both the intermolecular step in oxidation--formation of a mixed disulphide bond with the oxidizing agent GSSG--as well as the subsequent intramolecular step. Folding does not occur appreciably by direct oxidation because the high GSSG concentrations required for efficient mixed disulphide formation cause N' to accumulate as a nonproductive, double-mixed disulphide species. The need to unfold previously acquired native structure, observed in the folding of BPTI, may be a common feature of disulphide-linked folding reactions.

Animals↗
PubMed1995

Costs of medical care and out-of-pocket expenditures for persons with AIDS in the Boston Health Study.

We examined the cost of health care and out-of-pocket medical expenditures for 189 persons with AIDS at three sites in Massachusetts: an HMO; a public hospital immunodeficiency clinic; and a group practice at a major teaching hospital. The mean cost of care during a four-month reference period was $9,093 +/- $12,683 (mean +/- standard deviation) per patient. Thirty-six percent of the cost was due to hospital care and 40% was due to home health care. Mean out-of-pocket expenditures were $429 +/- $991 (mean +/- standard deviation). Studies that focus on the cost of hospital care may seriously underestimate the medical costs of AIDS.

Acquired Immunodeficiency Syndrome↗
PubMed1994

GroEL-mediated protein folding proceeds by multiple rounds of binding and release of nonnative forms.

The chaperonin GroEL is a ribosome-sized double-ring structure that assists in folding a diverse set of polypeptides. We have examined the fate of a polypeptide during a chaperonin-mediated folding reaction. Strikingly, we find that, upon addition of ATP and the cochaperonin GroES, polypeptide is released rapidly from GroEL in a predominantly nonnative conformation that can be trapped by mutant forms of GroEL that are capable of binding but not releasing substrate. Released polypeptide undergoes kinetic partitioning: a fraction completes folding while the remainder is rebound rapidly by other GroEL molecules. Folding appears to occur in an all-or-none manner, as proteolysis and tryptophan fluorescence indicate that after rebinding, polypeptide has the same structure as in the original complex. These observations suggest that GroEL functions by carrying out multiple rounds of binding aggregation-prone or kinetically trapped intermediates, maintaining them in an unfolded state, and releasing them to attempt to fold in solution.

Bacterial Proteins↗