Cost-effectiveness analysis of a randomized clinical trial of early versus deferred endovenous ablation of superficial venous reflux in patients with venous ulceration.

BACKGROUND: Treatment of superficial venous reflux in addition to compression therapy accelerates venous leg ulcer healing and reduces ulcer recurrence. The aim of this study was to evaluate the costs and cost-effectiveness of early versus delayed endovenous treatment of patients with venous leg ulcers. METHODS: This was a within-trial cost-utility analysis with a 1-year time horizon using data from the EVRA (Early Venous Reflux Ablation) trial. The study compared early versus deferred endovenous ablation for superficial venous truncal reflux in patients with a venous leg ulcer. The outcome measure was the cost per quality-adjusted life-year (QALY) over 1 year. Sensitivity analyses were conducted with alternative methods of handling missing data, alternative preference weights for health-related quality of life, and per protocol. RESULTS: After early intervention, the mean(s.e.m.) cost was higher (difference in cost per patient £163(318) (€184(358))) and early intervention was associated with more QALYs at 1 year (mean(s.e.m.) difference 0·041(0·017)). The incremental cost-effectiveness ratio (ICER) was £3976 (€4482) per QALY. There was an 89 per cent probability that early venous intervention is cost-effective at a threshold of £20 000 (€22 546)/QALY. Sensitivity analyses produced similar results, confirming that early treatment of superficial reflux is highly likely to be cost-effective. CONCLUSION: Early treatment of superficial reflux is highly likely to be cost-effective in patients with venous leg ulcers over 1 year. Registration number: ISRCTN02335796 (http://www.isrctn.com).

Cost-effectiveness of traditional and endovenous treatments for varicose veins.

BACKGROUND: The aim of this study was to evaluate the cost-effectiveness of traditional and endovenous treatments for patients with primary great saphenous varicose veins. METHODS: A Markov model was constructed to compare costs and quality-adjusted life years (QALYs) for great saphenous vein (GSV) reflux. Eight popular treatment strategies were compared up to 5 years. Estimates for the effectiveness of treatments were obtained from published randomized studies and cost values were obtained from published National Health Service (NHS) healthcare resource group tariffs and device manufacturers. Parameter uncertainty was tested using sensitivity analysis and Monte Carlo simulation. RESULTS: Ultrasound-guided foam sclerotherapy (UGFS) had the lowest initial cost, but a higher requirement for further interventions. Day-case surgery (with concomitant treatment of varicosities), endovenous laser ablation (EVLA) and radiofrequency ablation (RFA) performed in an outpatient or office setting (with staged treatment of varicosities) were likely to be cost-effective treatment strategies. The incremental cost-effectiveness ratio (ICER) for UGFS (versus conservative care), EVLA (versus UGFS) and RFA (versus EVLA) were £1366, £5799 and £17 350 per QALY respectively. The ICER for traditional surgery (performed on a day-case basis) was £19 012 compared with RFA. Other strategies were not cost-effective using the NHS threshold of £20 000 per QALY. CONCLUSION: Day-case surgery or endovenous ablation using EVLA or RFA performed as an outpatient are likely to be cost-effective treatment strategies for patients with primary unilateral GSV reflux requiring treatment.

Modelling the long-term cost-effectiveness of endovascular or open repair for abdominal aortic aneurysm.

BACKGROUND: Recent randomized trials have shown that endovascular abdominal aortic aneurysm repair (EVAR) has a 3 per cent aneurysm-related survival benefit in patients fit for open surgery, but it also has uncertain long-term outcomes and higher costs. This study assessed the cost-effectiveness of EVAR. METHODS: A decision model was constructed to estimate the lifetime costs and quality-adjusted life years (QALYs) with EVAR and open repair in men aged 74 years. The model includes the risks of death from aneurysm, other cardiovascular and non-cardiovascular causes, secondary reinterventions and non-fatal cardiovascular events. Data were taken largely from the EVAR trial 1 and supplemented from other sources. RESULTS: Under the base-case (primary) assumptions, EVAR cost 3800 pounds sterling (95 per cent confidence interval (c.i.) 2400 pounds sterling to 5200 pounds sterling) more per patient than open repair but produced fewer lifetime QALYs (mean -0.020 (95 per cent c.i. -0.189 to 0.165)). These results were sensitive to alternative model assumptions. CONCLUSION: EVAR is unlikely to be cost-effective on the basis of existing devices, costs and evidence, but there remains considerable uncertainty.

[A comparison of costs and survival in colorectal cancer patients undergoing surgery according to different organizational models]. / Comparación de costes y supervivencia en pacientes intervenidos quirúrgicamente de cáncer colorrectal según diferentes modelos organizativos.

OBJECTIVE: To determine the effectiveness and costs of different organizational models in caring for colorectal cancer patients through either clinical management functional units or traditional clinical services. METHOD: Post-operative and long-term (after 30 days and 5 years) mortality was analyzed according to number of patients undergoing surgery because of colorectal cancer. Mortality was adjusted for patient-related confounding factors. With that purpose a thorough review of the literature was conducted; information obtained was used in a meta-analysis of randomized effects. Concerning costs, a literature search was run to describe differences in number of patients per year between hospitals. RESULTS: Surgery costs were found to be smaller, and mean hospital stay shorter, in big-sized hospitals. The meta-analysis showed that the risk of death at 30 days and 5 years was lower in big hospitals versus smaller ones (OR: 1.112; 95% CI 0.986-1.255, and OR: 1.114; 95% CI 1.105-1.183, respectively). CONCLUSIONS: Short- and long-term postoperative mortality is lower in hospitals with a high number of cases per year.

A versatile computer simulation of the left ventricle.

A versatile mathematical simulation of a beating left ventricle, as seen in a gated cardiac blood-pool study, is described. The basic model consists of a fifth-degree polynomial rotated about its long axis. Motion is mimicked by sinusoidally varying the lengths of the long and short axes. The quality of clinical images is simulated through addition of Poisson noise and camera blur, determined from the measured line-spread function for Tc-99m. To achieve added realism, the modeled ventricle can be inserted in place of the patient's actual ventricle in clinical images. The dimensions, activity, and ejection fraction can all be adjusted. In addition, regional wall-motion abnormalities can be generated in any of the walls. To illustrate applications of the model in testing and evaluating cardiac computer programs, the performances of two ejection-fraction programs are compared, and use of the model in evaluating digital filtering algorithms is discussed.

Tuberculous pleural effusions.

While a number of recent reports have documented the changing clinical and radiographic spectrum of parenchymal tuberculosis, relatively little attention has been paid to changes in the patterns of pleural tuberculosis. We therefore reviewed the clinical, laboratory, and radiographic characteristics of 26 adult patients with tuberculous pleural effusions. We found that pleural tuberculosis has become a disease of older adults (median age, 56 years) and that 19 percent (5/26) of the cases were due to postprimary (reactivation) disease. This shift in age led to problems in diagnosis, since many of these older patients had underlying or coexisting disease that could have caused a pleural effusion. Both specimens of pleural fluid and pleural biopsy were useful in establishing the diagnosis. Examination of sputum was less helpful. All patients who were not anergic had positive cutaneous reactions to first-strength purified protein derivative of tuberculin. Lymphocytosis of the pleural fluid was not a uniform finding; only 62 percent of our patients had greater than 50 percent lymphocytes on their initial examinations of pleural fluid, and four patients had greater than 90 percent polymorphonuclear cells. All of the effusions were exudates, and four had glucose levels in the pleural fluid that were less than 30 mg/dl. Pleural tuberculosis is an important diagnostic consideration in adult or elderly patients with exudative pleural effusions.

Prognosis of pulmonary scar carcinoma.

Eighty-one patients with resectable primary peripheral lung carcinomas were studied to determine the effect of associated scarring on prognosis. Twelve tumors (15%) originated from bronchi. 24 (30%) were associated with scars, and 45 (55%) were not associated with either bronchus or scar (non-scar). Scar carcinomas differed significantly in cell type from bronchogenic and non-scar tumors in that 21 (88%) scar carcinomas were either adenocarcinomas or bronchioloalveolar carcinomas (p less than 0.001). Origin (bronchogenic, scar, non-scar) independent of cell type and tumor stage did not significantly influence survival. Stage of disease independent of cell type or origin affected survival (p less than 0.0001), as did cell type independent of tumor stage or origin (p less than 0.0001). Stage I disease and bronchioloalveolar carcinoma were associated with longer survival, while Stage II or III disease, small cell anaplastic carcinoma, and adenocarcinoma were associated with reduced survival. We conclude that associated scar influences cell type of peripheral lung carcinoma but does not influence patient survival, even among patients with similar cell type and stage of disease.

Selective injection of magnetization by slow chemical exchange in NMR.

In a system in slow dynamic equilibrium two NMR methods are shown to be suitable for injecting magnetization from one resonance to another by means of slow chemical exchange. The combined outputs of the methods may be employed to measure the value of the off-rate constant kappa(off) in the complex. The methods are implemented experimentally using the complex of molecules composed of the enzyme Escherichia coli dihydrofolate reductase (DHFR) and the ligand folate. In an equilibrium solution with DHFR, folate is known to undergo chemical exchange between a free state and a bound state. The modified synchronous nutation method is applied to a spin of the folate molecule in the free and bound states; magnetization transfer occurs between the two sites due to the underlying exchange process. As a preliminary step for the application of the synchronous nutation method, a new one-dimensional 1H NMR technique is proposed which facilitates the assignment of the resonance of a spin in the bound state, provided the resonance of its exchange partner in the free state is known. This experiment is also used to obtain quantitative estimates of the transverse relaxation rate constant of the bound resonance. The numerical procedure necessary to analyze the experimental results of the synchronous nutation experiment is presented.

The role of radiologic screening in lung cancer.

The present available data do not support the routine utilization of chest radiography or sputum cytology for the early detection of lung cancer. While on an individual basis, as part of a general health maintenance consideration, some high risk individuals may benefit from radiologic or cytologic screening, there has been no overall decrease in cancer mortality associated with these screening procedures. The early cases picked up by screening while asymptomatic and often detected by sputum cytology have lead-time bias to account for prolonged survival. Furthermore, many of these asymptomatic lesions are so indolent that they may never come to the patient's attention during his or her lifetime and the patient may die of other causes. There are other cancers, which may be of the same histology, that develop in the interval between even closely applied screening examinations. Patients with these cancers are often symptomatic and the biologic behavior of these lung cancers is so aggressive that, regardless of intervention, the prognosis is miserable. The cooperative studies also show a fairly high miss rate for the diagnosis of lung cancer even in patients who are being heavily screened. The miss rate for the early detection of lung cancer with chest radiography is probably on the order of 30% or more. That is, in at least 30% of cases, the tumor can be identified retrospectively on earlier examination. Nevertheless, in spite of the significant miss rate, those tumors with an indolent biologic behavior can be present for 2, 3, or more years and still remain localized, have a high resectability rate, and carry a prolonged survival prognosis.(ABSTRACT TRUNCATED AT 250 WORDS)

Pulmonary lymphoproliferative disorders.

Nonlymphomatous pulmonary lymphoproliferative disorders include plasma cell granuloma, Castleman's disease, pseudolymphoma, lymphocytic interstitial pneumonitis, angioimmunoblastic lymphadenopathy, and lymphomatoid granulomatosis. They are thought to represent a hyperplasia of the pulmonary immune system in response to chronic antigenic stimulation. A description of the variable clinical, radiographic, and pathologic features of each entity is presented.

Bronchioloalveolar carcinoma.

It is helpful to consider BAC as two distinct clinical entities. The solitary or focal form presents as a well circumscribed pulmonary nodule, tends to remain localized with slow growth, and has an excellent prognosis following resection. While it may progress to diffuse disease, this is distinctly unusual and is only supported by Hill's study in the literature. It may metastasize to regional lymph nodes or to distant sites not unlike other carcinomas of the lung, although the incidence of metastatic disease is quite low. The diffuse form of BAC, recognizable as multiple nodules or consolidation, represents an aggressive malignancy with limited survival regardless of intervention.

Legal implications of managed care arrangements.

Prior to the 1980s, managed care was virtually nonexistent as a force in health care. Presently, 64 percent of employees in America are covered by managed care plans, including health maintenance organizations (20 percent) and preferred provider organizations (44 percent). In contrast, only 29 percent of employees were enrolled in managed care plans in 1988 and only 47 percent in 1991. To date, the primary reason for this incredible growth in managed care has been economic-market pressure to reduce health care costs. For the foreseeable future, political pressures are likely to fuel this growth, as managed care is at the center of President Clinton's national health care plan. Although there are numerous legal issues surrounding managed care, this article focuses primarily on antitrust implications when forming managed care entities. In addition, the corporate practice of medicine doctrine, certain tax issues, and the fraud and abuse laws are discussed.

Clinical and economic evaluation of laparoscopic surgery compared with medical management for gastro-oesophageal reflux disease: 5-year follow-up of multicentre randomised trial (the REFLUX trial).

BACKGROUND: Despite promising evidence that laparoscopic fundoplication provides better short-term relief of gastro-oesophageal reflux disease (GORD) than continued medical management, uncertainty remains about whether benefits are sustained and outweigh risks. OBJECTIVE: To evaluate the long-term clinical effectiveness, cost-effectiveness and safety of laparoscopic surgery among people with GORD requiring long-term medication and suitable for both surgical and medical management. DESIGN: Five-year follow-up of a randomised trial (with parallel non-randomised preference groups) comparing a laparoscopic surgery-based policy with a continued medical management policy. Cost-effectiveness was assessed alongside the trial using a NHS perspective for costs and expressing health outcomes in terms of quality-adjusted life-years (QALYs). SETTING: Follow-up was by annual postal questionnaire and selective hospital case notes review; initial recruitment in 21 UK hospitals. PARTICIPANTS: Questionnaire responders among the 810 original participants. At entry, all had documented evidence of GORD and symptoms for > 12 months. Questionnaire response rates (years 1-5) were from 89.5% to 68.9%. INTERVENTIONS: Three hundred and fifty-seven participants were recruited to the randomised comparison (178 randomised to surgical management and 179 randomised to continued medical management) and 453 to the preference groups (261 surgical management and 192 medical management). The surgeon chose the type of fundoplication. MAIN OUTCOME MEASURES: Primary: disease-specific outcome measure (the REFLUX questionnaire); secondary: Short Form questionnaire-36 items (SF-36), European Quality of Life-5 Dimensions (EQ-5D), NHS resource use, reflux medication, complications. RESULTS: The randomised groups were well balanced. By 5 years, 63% in the randomised surgical group and 13% in the randomised medical management group had received a total or partial wrap fundoplication (85% and 3% in the preference groups), with few perioperative complications and no associated deaths. At 1 year (and 5 years) after surgery, 36% (41%) in the randomised surgical group - 15% (26%) of those who had surgery - were taking proton pump inhibitor medication compared with 87% (82%) in the randomised medical group. At each year, differences in the REFLUX score significantly favoured the randomised surgical group (a third of a SD; p< 0.01 at 5 years). SF-36 and EQ-5D scores also favoured surgery, but differences attenuated over time and were generally not statistically significant at 5 years. The worse the symptoms at trial entry, the larger the benefit observed after surgery. Those randomised to medical management who subsequently had surgery had low baseline scores that markedly improved after surgery. Following fundoplication, 3% had surgical treatment for a complication and 4% had subsequent reflux-related operations - most often revision of the wrap. Dysphagia, flatulence and inability to vomit were similar in the two randomised groups. The economic analysis indicated that surgery was the more cost-effective option for this patient group. The incremental cost-effectiveness ratio for surgery in the base case was £7028 per additional QALY; these findings were robust to changes in approaches and assumptions. The probability of surgery being cost-effective at a threshold of £20,000 per additional QALY was > 0.80 for all analyses. CONCLUSIONS: After 5 years, laparoscopic fundoplication continues to provide better relief of GORD symptoms with associated improved health-related quality of life. Complications of surgery were uncommon. Despite being initially more costly, a surgical policy is highly likely to be cost-effective. TRIAL REGISTRATION: Current Controlled Trials ISRCTN15517081. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 17, No. 22. See the HTA programme website for further project information.

The UK EndoVascular Aneurysm Repair (EVAR) trials: randomised trials of EVAR versus standard therapy.

OBJECTIVE: To assess the efficacy of endovascular aneurysm repair (EVAR) against standard alternative management in patients with large abdominal aortic aneurysm (AAA). DESIGN: Two national, multicentre randomised trials - EVAR trials 1 and 2. SETTING: Patients were recruited from 38 out of 41 eligible UK hospitals. PARTICIPANTS: Men and women aged at least 60 years, with an AAA measuring at least 5.5 cm on a computerised tomography scan that was regarded as anatomically suitable for EVAR, were assessed for fitness for open repair. Patients considered fit were randomised to EVAR or open repair in EVAR trial 1 and patients considered unfit were randomised to EVAR or no intervention in EVAR trial 2. INTERVENTIONS: EVAR, open repair or no intervention. MAIN OUTCOME MEASURES: The primary outcome was mortality (operative, all-cause and AAA related). Patients were flagged at the UK Office for National Statistics with centrally coded death certificates assessed by an Endpoints Committee. Power calculations based upon mortality indicated that 900 and 280 patients were required for EVAR trials 1 and 2, respectively. Secondary outcomes were graft-related complications and reinterventions, adverse events, renal function, health-related quality of life and costs. Cost-effectiveness analyses were performed for both trials. RESULTS: Recruitment occurred between 1 September 1999 and 31 August 2004, with targets exceeded in both trials: 1252 randomised into EVAR trial 1 (626 to EVAR) and 404 randomised into EVAR trial 2 (197 to EVAR). Follow-up closed in December 2009 with very little loss to follow-up (1%). In EVAR trial 1, 30-day operative mortalities were 1.8% and 4.3% in the EVAR and open-repair groups, respectively: adjusted odds ratio 0.39 [95% confidence interval (CI) 0.18 to 0.87], p = 0.02. During a total of 6904 person-years of follow-up, 524 deaths occurred (76 AAA related). Overall, there was no significant difference between the groups in terms of all-cause mortality: adjusted hazard ratio (HR) 1.03 (95% CI 0.86 to 1.23), p = 0.72. The EVAR group did demonstrate an early advantage in terms of AAA-related mortality, which was sustained for the first few years, but lost by the end of the study, primarily due to fatal endograft ruptures: adjusted HR 0.92 (95% CI 0.57 to 1.49), p = 0.73. The EVAR procedure was more expensive than open repair (mean difference £1177) and not found to be cost-effective, but the model was sensitive to alternative assumptions. In EVAR trial 2, during a total of 1413 person-years of follow-up, a total of 305 deaths occurred (78 AAA related). The 30-day operative mortality was 7.3% in the EVAR group. However, this group later demonstrated a significant advantage in terms of AAA-related mortality, but this became apparent only after 4 years: overall adjusted HR 0.53 (95% CI 0.32 to 0.89), p = 0.02. Sadly, this advantage did not result in any benefit in terms of all-cause mortality: adjusted HR 0.99 (95% CI 0.78 to 1.27), p = 0.97. Overall, EVAR was more expensive than no intervention (mean difference £10,222) and not found to be cost-effective. CONCLUSIONS: EVAR offers a clear operative mortality benefit over open repair in patients fit for both procedures, but this early benefit is not translated into a long-term survival advantage. Among patients unfit for open repair, EVAR is associated with a significant long-term reduction in AAA-related mortality but this does not appear to influence all-cause mortality. TRIAL REGISTRATION: Current Controlled Trials ISRCTN 55703451. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 16, No. 9. See the HTA programme website for further project information.

The cost-effectiveness of an early interventional strategy in non-ST-elevation acute coronary syndrome based on the RITA 3 trial.

BACKGROUND: Evidence suggests that an early interventional strategy for patients with non-ST-elevation acute coronary syndrome (NSTE-ACS) can improve health outcomes but also increase costs when compared with a conservative strategy. OBJECTIVE: The aim of this study was to assess the cost-effectiveness of an early interventional strategy in different risk groups from a UK health-service perspective. DESIGN: Decision-analytic model based on randomised clinical trial data. MAIN OUTCOME MEASURES: Costs in UK Sterling at 2003/2004 prices and quality-adjusted life years (QALYs) combined into an incremental cost-effectiveness ratio. METHODS: Data from the third Randomised Intervention Trial of unstable Angina (RITA 3) was employed to estimate rates of cardiovascular death and myocardial infarction, costs and health-related quality of life. Cost-effectiveness was estimated over patients' lifetimes within the decision-analytic model. RESULTS: The mean incremental cost per QALY gained for an early interventional strategy was approximately 55,000 pounds sterling, 22,000 pounds sterling and 12,000 pounds sterling for patients at low, intermediate and high risk, respectively. The early interventional strategy is approximately 1%, 35% and 95% likely to be cost-effective for patients at low, intermediate and high risk, respectively, at a threshold of 20,000 pounds sterling per QALY. The cost-effectiveness of early intervention in low-risk patients is sensitive to assumptions about the duration of the treatment effect. CONCLUSION: An early interventional strategy in patients presenting with NSTE-ACS is likely to be considered cost-effective for patients at high and intermediate risk, but this is less likely to be the case for patients at low risk.

The alpha-lytic protease gene of Lysobacter enzymogenes. The nucleotide sequence predicts a large prepro-peptide with homology to pro-peptides of other chymotrypsin-like enzymes.

alpha-Lytic protease is a 19.8-kDa protein secreted from the Gram-negative bacterium Lysobacter enzymogenes. We have cloned and sequenced the gene for this serine protease. The nucleotide sequence contains an open reading frame which codes for the 198-residue mature enzyme and a potential prepro-peptide, also of 198 residues. The COOH-terminal 49 residues of the pro-peptide are significantly homologous to the propeptides of Streptomyces griseus proteases A and B. We suggest that this pro-peptide region facilitates formation of the active enzyme. A region bridging the NH2-terminal pre- and pro-peptides is homologous to a maize inhibitor of serine proteases. We speculate that this region inhibits enzymatic activity of the prepro-enzyme.

Lung cancer in childhood.

A 16-year-old boy had unresolving right lower lobe consolidation due to primary adenocarcinoma of the lung. Lung cancer is rare in children, is usually adenocarcinoma or undifferentiated histology, and frequently presents with advanced disease. It may be confused with atelectasis attributable to a foreign body or bronchial adenoma, plasma cell granuloma, pulmonary sequestration, or chronic infection. We review the clinical features of pediatric lung cancer and differences in lung cancer between children and adults.

Role of serine 214 and tyrosine 171, components of the S2 subsite of alpha-lytic protease, in catalysis.

The function of a hydrogen bond network, comprised of the hydroxyl groups of Tyr 171 and Ser 214, in the hydrophobic S2 subsite of alpha-lytic protease, was investigated by mutagenesis and the kinetics of a substrate analog series. To study the catalytic role of the Tyr 171 and Ser 214 hydroxyl groups, Tyr 171 was converted to phenylalanine (Y171F) and Ser 214 to alanine (S214A). The double mutant (Y171F: S214A) also was generated. The single S214A and double Y171F:S214A mutations cause differential effects on catalysis and proenzyme processing. For S214A, kcat/Km is (4.9 x 10(3))-fold lower than that of wild type and proenzyme processing is blocked. For the double mutant (Y171F:S214A), kcat/Km is 82-fold lower than that of wild type and proenzyme processing occurs. In Y171F, kcat/Km is 34-fold lower than that of wild type, and the proenzyme is processed. The data indicate that Ser 214, although conserved among serine proteases and hydrogen bonded to the catalytic triad [Brayer, G. D., Delbaere, L. T. J., & James, M. N. G. (1979) J. Mol. Biol. 131, 743], is not essential for catalytic function in alpha-lytic protease. A substrate series (in which peptide length is varied) established that the mutations (Y171F and Y171F:S214A) do not alter enzyme-substrate interactions in subsites other than S2. The pH dependence of kcat/Km for Y171F and Y171F:S214A has changed less than 0.5 unit from that of wild type; this suggests the catalytic triad is unperturbed. In wild type, hydrophobic interactions at S2 increase kcat/Km by up to (1.2 x 10(3))-fold with no effect on Km.(ABSTRACT TRUNCATED AT 250 WORDS)

Radiographic evaluation of asbestos-related chest disorders.

This paper reviews the radiographic, clinical, pathologic, and epidemiological features of pleural and pulmonary parenchymal disorders which have been related to asbestos exposure. In particular, the following are discussed: (1) pleural plaques--radiographic detection by plain films and computed tomography, normal and abnormal densities which may mimic plaques, the 1980 ILO U/C classification, recent epidemiological data on plaques including their relationship to carcinoma and mesothelioma; (2) diffuse pleural thickening; (3) benign asbestos pleural effusions; (4) mesothelioma--emphasizing recent advances in diagnosis, staging, therapy, and prognosis; (5) parenchymal fibrosis--pathogenesis, relationship to fiber exposure, plaques, and carcinoma; (6) bronchogenic carcinoma; (7) rounded atelectasis--recent observations on its association with pleural thickening. A role of radiology in medicolegal aspects of asbestos-related disease is briefly examined.

Dynamics of the dihydrofolate reductase-folate complex: catalytic sites and regions known to undergo conformational change exhibit diverse dynamical features.

Backbone and tryptophan side-chain dynamics of uniformly 15N-labeled Escherichia coli dihydrofolate reductase were determined for the binary folate complex. The 15N T1 and T2 relaxation times and [1H]-15N heteronuclear NOEs were measured for 118 protonated backbone nitrogen atoms. The generalized order parameter (S2), the effective correlation time for internal motions (tau e), and the contribution to spin-spin relaxation through 15N exchange broadening (Rex) were determined for each residue by model-free analysis. Back-calculation of the relaxation rates for each resonance showed that the calculated dynamical parameters accurately predict the experimental data. Diverse dynamical features were evident in the DHFR backbone. Six sites exhibited order parameters significantly below the weighted mean S2 value (for the complex) of 0.81 +/- 0.002: residues G67 and D69 of the adenosine binding domain, and "hinge" residues K38 and V88, exhibited low S2 (0.29 < or = S2 < or = 0.6) and high tau e values (700 ps < or = tau e < or = 2 ns), as did sites within the beta A-alpha B loop and the beta F-beta G loop. Thus, large amplitude backbone motions, on the picosecond and nanosecond time scales, occurred at regions implicated in transition-state stabilization and in ligand-dependent conformational change. Significant Rex values (> or = 1 s-1) were determined for 45% of assigned resonances, many of which arise from residues surrounding the folate binding site. The mean S2 values of the occupied folate binding site and the unoccupied NADPH binding site were similar, indicating the backbone of the latter is at least as conformationally restricted as that of the occupied folate site. We conclude that the observed time-dependent structural fluctuations of the binary complex are in fact associated with catalytic properties of the molecule.