Biomedical subjects

G Oster

Publications and source records attributed to G Oster.

At least 37 records · Page 2Linked to original sources

PubMed2000

The mechanochemistry of V-ATPase proton pumps.

The vacuolar H(+)-ATPases (V-ATPases) are a universal class of proton pumps that are structurally similar to the F-ATPases. Both protein families are characterized by a membrane-bound segment (V(o), F(o)) responsible for the translocation of protons, and a soluble portion, (V(1), F(1)), which supplies the energy for translocation by hydrolyzing ATP. Here we present a mechanochemical model for the functioning of the V(o) ion pump that is consistent with the known structural features and biochemistry. The model reproduces a variety of experimental measurements of performance and provides a unified view of the many mechanisms of intracellular pH regulation.

Adenosine Triphosphate↗

PubMed2000

Why is the mechanical efficiency of F(1)-ATPase so high?

The experimentally measured mechanical efficiency of the F(1)-ATPase under viscous loading is nearly 100%, far higher than any other hydrolysis-driven molecular motor (Yasuda et al., 1998). Here we give a molecular explanation for this remarkable property.

Biomechanical Phenomena↗

PubMed2000

Effect of protein shape on multibody interactions between membrane inclusions.

The elastic interaction of membrane inclusions provides one of the simplest physical realizations of multibody forces. Here we show how the cross-sectional shape of the inclusion greatly changes the character of the interaction, and illustrates a pattern formation mechanism. The formalism provides a transparent framework for modeling bilayer-inclusion boundary effects on the multibody interaction.

Biophysical Phenomena↗

PubMed2000

Use of rhDNase therapy and costs of respiratory-related care in patients with cystic fibrosis.

OBJECTIVE: To assess the relationship between level of use of recombinant deoxyribonuclease I (rhDNase) therapy and costs of respiratory-related care in patients with cystic fibrosis. DESIGN: Retrospective, cohort study using healthcare claims data from a large New England health insurer. PATIENTS: All cystic fibrosis patients five years of age and older who began therapy with rhDNase in 1994 (the year it was first marketed in the US). Healthcare claims were compiled for six months prior to first receipt of rhDNase (pretreatment) and for 30 months subsequently (follow-up). Patients were stratified according to their level of rhDNase use during follow-up, based on whether it was above or below the median number of therapy days for the sample. MAIN OUTCOME MEASURES: Costs of rhDNase, all antibiotics, and all respiratory-related outpatient (physician, home health, hospital outpatient) and inpatient care were included. All costs were expressed on an annualized basis. RESULTS: Twenty-four patients with cystic fibrosis who began treatment with rhDNase in 1994 met all entry criteria; the median number of therapy days over a 30-month period was 355. Among patients with low (i.e., below the median) rhDNase use (n = 12), mean +/- SD annualized costs of respiratory-related care increased by almost $17,000 between pretreatment and follow-up, from $29,251 +/- $37,919 to $46,109 +/- $40,944. Among high-use patients (n = 12), costs decreased by approximately $2500, from $37,178 +/- $48,476 to $34,592 +/- $22,591. The change in both groups was accounted for primarily by a change in the number of respiratory-related hospitalizations. CONCLUSIONS: Prolonged use of rhDNase may reduce costs of respiratory-related care in patients with cystic fibrosis; further study is required, however, to confirm these findings.

Adolescent↗

PubMed2000

The clinical and economic burden of obesity in a managed care setting.

OBJECTIVE: To estimate the clinical and economic burden of obesity in a managed care setting. STUDY DESIGN: Prevalence-based cost-of-illness evaluation using modeling techniques and data from secondary sources. PATIENTS AND METHODS: The health and economic burden of obesity was estimated for a hypothetical health plan with 1 million members between the ages of 35 and 84 years, based on projections of the numbers of cases of 8 diseases for which obesity is an established risk factor (coronary heart disease, hypertension, hypercholesterolemia, gallbladder disease, stroke, type 2 diabetes, osteoarthritis of the knee, and endometrial cancer), obesity-attributable "etiologic fractions," and estimates of associated medical care costs. Our analysis was based on data from a variety of secondary sources, including a large managed care plan in the Pacific Northwest region of the United States. RESULTS: In a population of 1 million persons aged 35 to 84 years, it was estimated that obesity would account for approximately 132,900 cases of hypertension (45% of all cases), 58,500 cases of type 2 diabetes (85%), 51,500 cases of hypercholesterolemia (18%), and 16,500 cases of coronary heart disease (35%). Healthcare costs attributable to obesity were estimated to total $345.9 million annually (or 41% of the total for the 8 diseases of interest). CONCLUSION: The clinical and economic burden of obesity in a managed care setting is substantial.

Adult↗

PubMed2000

Childhood vaccination against pneumococcal otitis media and pneumonia: an analysis of benefits and costs.

OBJECTIVE: To examine the economic benefits and costs of routine vaccination of children younger than 5 years of age against pneumococcal otitis media and pneumonia with the pneumococcal conjugate vaccine. STUDY DESIGN: A decision-analytic model of the cumulative numbers of cases and costs to age 10 years of acute otitis media (AOM), tympanostomy and related procedures (TRP), and community-acquired pneumonia (CAP) in children who either did or did not receive the pneumococcal conjugate vaccine. PATIENTS AND METHODS: Seven hypothetical cohorts of 1000 children, stratified by age at initial vaccination, were followed. Outcome measures include costs of vaccination, cumulative numbers of cases of AOM, TRP, and CAP to age 10 years, and related disease costs, including medical treatment and parental work loss. RESULTS: Routine vaccination of 1000 children against pneumococcal infection would cost between $57,000 and $226,000, depending on age (the recommended number of doses varies by age at initial vaccination). Acute otitis media, TRP, and CAP to age 10 years would decline by 139 to 330, 8 to 22, and 15 to 30 cases, respectively; costs of medical treatment and work loss would correspondingly decline by $56,000 to $138,000. Expected net economic benefits (benefits minus costs) of vaccination against pneumococcal otitis media and pneumonia range from -$88,000 to $15,000 for children less than 2 years of age, and from -$1,000 to $31,000 for those aged 2 to 5 years at vaccination. CONCLUSION: Routine vaccination against pneumococcal otitis media and pneumonia appears to be cost-increasing for children less than 2 years of age who require multiple doses, but cost-saving for children aged 2 to 5 years who would require only a single dose of the vaccine.

Bacterial Vaccines↗

PubMed1999

Lifetime health and economic consequences of obesity.

BACKGROUND: Obesity is an established risk factor for several chronic diseases. The lifetime health and economic consequences of obesity for individual patients have not been documented. OBJECTIVE: To estimate the lifetime health and economic consequences of obesity. METHODS: We developed a dynamic model of the relationship between body mass index and the risks and associated costs of 5 obesity-related diseases: hypertension, hypercholesterolemia, type 2 diabetes mellitus, coronary heart disease, and stroke. The model was estimated using data from the Third National Health and Nutrition Examination Survey, the Framingham Heart Study, and other secondary sources. We used this model to estimate (1) risks of hypertension, hypercholesterolemia, and type 2 diabetes mellitus at future ages; (2) lifetime risks of coronary heart disease and stroke; (3) life expectancy; and (4) expected lifetime medical care costs of these 5 diseases for men and women aged 35 to 64 years with body mass indexes of 22.5, 27.5, 32.5, and 37.5 kg/m2 (nonobese and mildly, moderately, and severely obese, respectively). RESULTS: Disease risks and costs increase substantially with increased body mass index. The risk of hypertension for moderately obese 45- to 54-year-old men, for example, is roughly 2-fold higher than for their nonobese peers (38.1% vs 17.7%), whereas the risk of type 2 diabetes mellitus is almost 3-fold higher (8.1% vs 3.0%). Lifetime risks of coronary heart disease and stroke are similarly elevated (41.8% vs 34.9% and 16.2% vs 13.9%, respectively), whereas life expectancy is reduced by 1 year (26.5 vs 27.5 years). Total discounted lifetime medical care costs for the treatment of these 5 diseases are estimated to differ by $10,000 ($29,600 vs $19,600). Similar results were obtained for women. CONCLUSIONS: The lifetime health and economic consequences of obesity are substantial and suggest that efforts to prevent or reduce this problem might yield significant benefits.

Adult↗

PubMed1999

Energy transduction in the sodium F-ATPase of Propionigenium modestum.

The F-ATPase of the bacterium Propionigenium modestum is driven by an electrochemical sodium gradient between the cell interior and its environment. Here we present a mechanochemical model for the transduction of transmembrane sodium-motive force into rotary torque. The same mechanism is likely to operate in other F-ATPases, including the proton-driven F-ATPases of Escherichia coli.

Bacterial Proteins↗

PubMed1999

ATP synthase: two motors, two fuels.

FoF1 ATPase is the universal protein responsible for ATP synthesis. The enzyme comprises two reversible rotary motors: Fo is either an ion 'turbine' or an ion pump, and F1 is either a hydrolysis motor or an ATP synthesizer. Recent biophysical and biochemical studies have helped to elucidate the operating principles for both motors.

Adenosine Triphosphate↗

PubMed1999

Cost effectiveness of carvedilol for heart failure.

In this study, we examine the cost effectiveness of carvedilol for the treatment of chronic heart failure (CHF). We use a Markov model to project life expectancy and lifetime medical care costs for a hypothetical cohort of patients with CHF who were assumed alternatively to receive carvedilol plus conventional therapy (digoxin, diuretics, and angiotensin-converting enzyme inhibitors) or conventional therapy alone. Patients on carvedilol were assumed to experience a reduced risk of death and hospitalization for CHF, which is consistent with findings from the US Carvedilol Heart Failure Trials Program. The benefits of carvedilol were projected under 2 alternative scenarios. In the first ("limited benefits"), benefits were conservatively assumed to persist for 6 months, the average duration of follow-up in these clinical trials, and then end abruptly. In the other ("extended benefits"), they were arbitrarily assumed to persist for 6 months and then decline gradually over time, vanishing by the end of 3 years. We estimated our model using data from the US Carvedilol Heart Failure Trials Program and other sources. For patients receiving conventional therapy alone, estimated life expectancy was 6.67 years; corresponding figures for those also receiving carvedilol were 6.98 and 7.62 years under the limited and extended benefits scenarios, respectively. Expected lifetime costs of CHF-related care were estimated to be $28,756 for conventional therapy, and $36,420 and $38,867 for carvedilol (limited and extended benefits, respectively). Cost per life-year saved for carvedilol was $29,477 and $12,799 under limited and extended benefits assumptions, respectively. The cost effectiveness of carvedilol for CHF compares favorably to that of other generally accepted medical interventions, even under conservative assumptions regarding the duration of therapeutic benefit.

Adrenergic beta-Antagonists↗

PubMed1999

Management of otitis media among children in a large health insurance plan.

BACKGROUND: Otitis media is one of the most common office diagnoses among children in the US and the leading reason for the use of antimicrobials in pediatric practice. We undertook this study to characterize medical and surgical management of otitis media. METHODS: Using claims data from a large New England health insurer, we identified all children <10 years of age who had one or more episodes of acute otitis media between July, 1995, and June, 1996, and examined patterns of treatment for this condition. RESULTS: Study subjects (n = 22,004) averaged 2.9 physician office visits for management of otitis media; among children <2 years of age, one-fourth had 6 or more such visits. Amoxicillin was prescribed as initial therapy in more than one-half (56.6%) of all episodes of acute otitis media, followed by cephalosporins (18.3%), trimethoprim-sulfamethoxazole (12.3%), macrolides (6.4%) and amoxicillin-clavulanate (6.0%). Over multiple episodes, however, use of amoxicillin declined by about 50%. Antimicrobial prophylaxis was received by 7.3% of all study subjects for a mean of 61.3 days; the incidence of breakthrough episodes of acute otitis media during prophylaxis varied according to the antimicrobial used (13.9, 12.3 and 19.5% for amoxicillin, trimethoprim-sulfamethoxazole and sulfisoxazole, respectively). Surgical procedures related to otitis media were performed on 3.8% of all study subjects, including 4.6% of children <2 years of age. CONCLUSIONS: The health care burden of otitis media is large, particularly in the first 2 years of life.

Acute Disease↗

PubMed1999

Epidermal growth factor receptor relocalization and kinase activity are necessary for directional migration of keratinocytes in DC electric fields.

Human keratinocytes migrate towards the negative pole in DC electric fields of physiological strength. This directional migration is promoted by epidermal growth factor (EGF). To investigate how EGF and its receptor (EGFR) regulate this directionality, we first examined the effect of protein tyrosine kinase inhibitors, including PD158780, a specific inhibitor for EGFR, on this response. At low concentrations, PD158780 inhibited keratinocyte migration directionality, but not the rate of migration; at higher concentrations, it reduced the migration rate as well. The less specific inhibitors, genistein, lavendustin A and tyrphostin B46, reduced the migration rate, but did not affect migration directionality. These data suggest that inhibition of EGFR kinase activity alone reduces directed motility, and inhibition of multiple tyrosine kinases, including EGFR, reduces the cell migration rate. EGFR redistribution also correlates with directional migration. EGFR concentrated on the cathodal face of the cell as early as 5 minutes after exposure to electric fields. PD158780 abolished EGFR localization to the cathodal face. These data suggest that EGFR kinase activity and redistribution in the plasma membrane are required for the directional migration of keratinocytes in DC electric fields. This study provides the first insights into the mechanisms of directed cell migration in electric fields.

Cell Movement↗

PubMed1999

Lifetime health and economic benefits of weight loss among obese persons.

OBJECTIVES: This study estimated the lifetime health and economic benefits of sustained modest weight loss among obese persons. METHODS: We developed a dynamic model of the relationship between body mass index (BMI) and the risks and costs of 5 obesity-related diseases: hypertension, hypercholesterolemia, type 2 diabetes, coronary heart disease (CHD), and stroke. We then calculated the lifetime health and economic benefits of a sustained 10% reduction in body weight for men and women aged 35 to 64 years with mild, moderate, and severe obesity. RESULTS: Depending on age, gender, and initial BMI, a sustained 10% weight loss would (1) reduce the expected number of years of life with hypertension, hypercholesterolemia, and type 2 diabetes by 1.2 to 2.9, 0.3 to 0.8, and 0.5 to 1.7, respectively; (2) reduce the expected lifetime incidence of CHD and stroke by 12 to 38 cases per 1000 and 1 to 13 cases per 1000, respectively; (3) increase life expectancy by 2 to 7 months; and (4) reduce expected lifetime medical care costs of these 5 diseases by $2200 to $5300. CONCLUSIONS: Sustained modest weight loss among obese persons would yield substantial health and economic benefits.

Adult↗

PubMed1999

The Risperidone Outcomes Study of Effectiveness (ROSE): a model for evaluating treatment strategies in typical psychiatric practice.

We describe the design of a multicenter, randomized clinical trial to compare clinical, quality-of-life, and economic outcomes in patients with schizophrenia or schizoaffective disorder who were treated with risperidone or any of 13 conventional antipsychotic drugs approved for use in the United States. This 1-year trial was designed to approximate conditions of typical clinical practice: protocol-mandated care was minimized, and all health services (including medication) were provided according to usual community practices. Measures of interest included changes in psychiatric symptoms, medication side effects, health-related quality of life, satisfaction with drug therapy, therapy switching, rehospitalization for the management of relapse, the use of psychiatric services of all types, and the cost of psychiatric care. We review the rationale for this type of trial and discuss the potential value of such trials in setting policy and in clinical practice.

Antipsychotic Agents↗

PubMed1999

Hospitalization for 5-FU toxicity in metastatic colorectal cancer: incidence and cost.

Although treatment with 5-fluorouracil (5-FU) plus calcium folinate has been reported to prolong survival in patients with metastatic colorectal cancer, it can also cause significant toxicity, potentially, resulting in hospitalization. The incidence and cost of these admissions have not been fully documented. The purpose of this study was to document the incidence and cost of toxicity-related admissions among patients with newly diagnosed metastatic colorectal cancer who received 5-FU.

Antimetabolites, Antineoplastic↗

PubMed1998

Energy transduction in the F1 motor of ATP synthase.

ATP synthase is the universal enzyme that manufactures ATP from ADP and phosphate by using the energy derived from a transmembrane protonmotive gradient. It can also reverse itself and hydrolyse ATP to pump protons against an electrochemical gradient. ATP synthase carries out both its synthetic and hydrolytic cycles by a rotary mechanism. This has been confirmed in the direction of hydrolysis after isolation of the soluble F1 portion of the protein and visualization of the actual rotation of the central 'shaft' of the enzyme with respect to the rest of the molecule, making ATP synthase the world's smallest rotary engine. Here we present a model for this engine that accounts for its mechanochemical behaviour in both the hydrolysing and synthesizing directions. We conclude that the F1 motor achieves its high mechanical torque and almost 100% efficiency because it converts the free energy of ATP binding into elastic strain, which is then released by a coordinated kinetic and tightly coupled conformational mechanism to create a rotary torque.

Adenosine Triphosphate↗

PubMed1998

Energy transduction in ATP synthase.

Mitochondria, bacteria and chloroplasts use the free energy stored in transmembrane ion gradients to manufacture ATP by the action of ATP synthase. This enzyme consists of two principal domains. The asymmetric membrane-spanning F0 portion contains the proton channel, and the soluble F1 portion contains three catalytic sites which cooperate in the synthetic reactions. The flow of protons through F0 is thought to generate a torque which is transmitted to F1 by an asymmetric shaft, the coiled-coil gamma-subunit. This acts as a rotating 'cam' within F1, sequentially releasing ATPs from the three active sites. The free-energy difference across the inner membrane of mitochondria and bacteria is sufficient to produce three ATPs per twelve protons passing through the motor. It has been suggested that this proton motive force biases the rotor's diffusion so that F0 constitutes a rotary motor turning the gamma shaft. Here we show that biased diffusion, augmented by electrostatic forces, does indeed generate sufficient torque to account for ATP production. Moreover, the motor's reversibility-supplying torque from ATP hydrolysis in F1 converts the motor into an efficient proton pump-can also be explained by our model.

Adenosine Triphosphate↗

PubMed1998

Curvature-mediated interactions between membrane proteins.

Membrane proteins can deform the lipid bilayer in which they are embedded. If the bilayer is treated as an elastic medium, then these deformations will generate elastic interactions between the proteins. The interaction between a single pair is repulsive. However, for three or more proteins, we show that there are nonpairwise forces whose magnitude is similar to the pairwise forces. When there are five or more proteins, we show that the nonpairwise forces permit the existence of stable protein aggregates, despite their pairwise repulsions.

Biophysical Phenomena↗