Vasoconstrictive effects of endothelin-1, endothelin-3, and urotensin II in isolated perfused human lungs and isolated human pulmonary arteries.

BACKGROUND: Urotensin II (UII) has been identified as a ligand for the orphan receptor GPR14 through which it elicits potent vasoconstriction in humans and non-human primates. The pulmonary vasculature is particularly sensitive; human UII (hUII) exhibits a potency 28 times that of endothelin (ET)-1 in isolated pulmonary arteries obtained from cynomolgus monkeys. However, hUII induced vasoconstriction in isolated human intralobar pulmonary arteries is variable, possibly as a result of location dependent differences in receptor density or because it is only uncovered by disease dependent endothelial dysfunction. METHODS: The vasoactivity of both hUII and gobi UII (gUII) in comparison with ET-1 and ET-3 was studied in isolated perfused lung preparations (n = 14) and isolated intralobar pulmonary arteries (n = 40, mean diameter 548 (27) microm) obtained from 17 men of mean (SE) age 67 (2) years and eight women of mean (SE) age 65 (3) years with a variety of vascular diseases. RESULTS: ET-1 (10 pM-100 nM) and ET-3 (10 pM-30 nM) elicited vasoconstriction in the lung preparations, inducing comparable increases in pulmonary arterial pressure of 24.8 (4.5) mm Hg and 14.5 (4.9) mm Hg, respectively, at 30 nM (p = 0.13). Similarly, ET-1 (10 pM-300 nM) and ET-3 (10 pM-100 nM) caused marked vasoconstriction in isolated pulmonary arteries, inducing maximal changes in tension of 4.36 (0.26) mN/mm and 1.54 (0.44) mN/mm, respectively, generating -logEC(50) values of 7.67 (0.04) M and 8.08 (0.07) M, respectively (both p<0.05). However, neither hUII nor gUII (both 10 pM-1 micro M) had any vasoactive effect in either preparation. CONCLUSION: UII does not induce vasoconstriction in isolated human pulmonary arterial or lung preparations and is therefore unlikely to be involved in the control of pulmonary vascular tone.

Chromosomal analysis of non-small-cell lung cancer by multicolour fluorescent in situ hybridisation.

The cytogenetic abnormalities in non-small-cell lung cancer remain elusive due primarily to the difficulty in obtaining metaphase spreads from solid tumours. We have used the molecular cytogenetic techniques of multicolour fluorescent in situ hybridisation (M-FISH) and comparative genomic hybridisation (CGH) to analyse four primary non-small-cell lung cancer samples and two established cell lines (COR-L23 and COR-L105) in order to identify common chromosomal aberrations. CGH revealed regions on 5p, 3q, 8q, 11q, 2q, 12p and 12q to be commonly over-represented and regions on 9p, 3p, 6q, 17p, 22q, 8p, 10p, 10q and 19p to be commonly under-represented. M-FISH revealed numerous complex chromosomal rearrangements. Translocations between chromosomes 5 and 14, 5 and 11 and 1 and 6 were observed in three of the six samples, with a further 14 translocations being observed in two samples each. Loss of the Y chromosome and gains of chromosomes 20 and 5p were also frequent. Chromosomes 4, 5, 8, 11, 12 and 19 were most frequently involved in interchromosomal translocations. Further investigation of the recurrent aberrations will be necessary to identify the specific breakpoints involved and any role they may have in the aetiology, diagnosis and prognosis of non-small-cell lung cancer.

Chromosomal alterations in small cell lung cancer revealed by multicolour fluorescence in situ hybridization.

Small cell lung cancer (SCLC) is a major cause of cancer related morbidity and mortality. Karyotypic studies have revealed numerous chromosomal aberrations in most SCLC however, classical G-banding analysis is unable to fully characterise complex marker chromosomes. Recent developments in molecular cytogenetics now allow accurate identification of the chromosomal components of complicated rearrangements. We have applied the technique of multicolour fluorescence in situ hybridization (M-FISH) in combination with comparative genomic hybridization (CGH) to the analysis of 5 SCLC cell lines and 1 primary tumour specimen to characterise the chromosomal abnormalities. CGH analysis identified many similarities between specimens, with frequent DNA copy number decreases on chromosomes 3p, 5q, 10, 16q, 17p and frequent gains on 3q, 1p, 1q and 14q. In contrast, M-FISH analysis revealed a large number of structural abnormalities, with each specimen demonstrating an individual pattern of chromosomal translocations. Forty different translocations were identified with the vast majority (39) being unbalanced. Chromosome 5 was the most frequently rearranged chromosome (9 translocations) followed by chromosomes 2, 10 and 16 (6 translocations each). Further investigation of these frequently involved chromosomes is warranted to establish whether consistent break points are involved in these translocations, causing dysregulation of specific genes that are crucial for tumour progression and secondly to identify the affected genes.

The impact of the duration of mechanical ventilation on the respiratory outcome in smokers undergoing cardiac surgery.

STUDY OBJECTIVE: To determine the impact of the duration of mechanical ventilation on the rate of pulmonary complications in smokers undergoing cardiac surgery. METHODS: Retrospective analysis of 2163 patients who underwent elective cardiac surgery between September 1993 and August 1999. Based on a 3-month preoperative smoking cessation, patients were classified as smokers, ex-smokers and non-smokers. Their postoperative pulmonary complications were compared and related to the duration of mechanical ventilation. RESULTS: Postoperative pulmonary complications were twice as common in smokers (29.5%) as non-smokers (13.6%) and ex-smokers (14.7%). Although smokers required a longer duration of mechanical ventilation, this was not statistically significant. Smokers had a higher rate of increase in postoperative pulmonary complications beyond 6 h of mechanical ventilation (P<0.002). CONCLUSION: Prolonged mechanical ventilation in active smokers undergoing cardiac surgery is associated with a significant increase in the respiratory morbidity. Surgical strategies that allow early extubation may improve the respiratory outcome in smokers.

Right ventricular needle embolus in an injecting drug user: the need for early removal.

This case report describes an unusual cardiac complication in a 22 year old, female injecting drug user. The retention of two fractured injection needles at the site of intravenous injection in the groin, and the subsequent embolisation of one to the right ventricle, predisposed to recurrent local and systemic infections, and endocarditis. Two years later, the needle was completely embedded in the wall of the right ventricle and not suitable for transvenous removal. Removal of the retained and/or embolised needle at an earlier stage would have precluded these complications.

An unusual combination of diaphragmatic hernias in a patient presenting with the clinical features of restrictive pulmonary disease: report of a case.

The combination of a Morgagni hernia and a paraesophageal hernia in adults is very rarely encountered in clinical practice. In fact, to our knowledge, only three cases of this condition, which is probably a coincidental occurrence, have been reported in the medical literature. We discuss the management of a 74-year-old man found to have combined Morgagni and paraesophageal hernia who presented with clinical features of a restrictive pulmonary disease.

Pharmaceutical cost growth under capitation: a case study.

Rising drug spending has generated concern among purchasers and policymakers. This paper compares drug cost growth in a capitated system with that in managed care systems that generally did not place physicians directly at risk for drug spending. We focus on cost growth because a substantial body of literature indicates that managed care interventions that reduce the level of costs may not influence the rate of cost growth. Drug cost growth under capitation initially was below that of other systems but still above targeted rates. Over time the capitation rates rose, the amount of risk transferred to physicians declined, and spending growth accelerated.

Assessing quality of life in men with clinically localized prostate cancer: development of a new instrument for use in multiple settings.

BACKGROUND: Quality of life in prostate cancer patients with clinically localized disease has become the focus of increasing attention over the past decade. However, few instruments have been developed and validated to assess quality of life specifically in this patient population. OBJECTIVE: The purpose of this investigation was to create a comprehensive, multi-scale quality of life instrument that can be tailored to the needs of the clinician/investigator in multiple settings. DESIGN, SUBJECTS, AND MEASURES: Patients diagnosed with clinically localized prostate cancer were mailed a questionnaire consisting of new and previously validated quality of life items and ancillary scales. Data from returned questionnaires were analyzed and used to create a multiscale instrument that assesses the effects of treatment and disease on urinary, sexual, and bowel domains, supplemented by a scale assessing anxiety over disease course/effectiveness of treatment. The instrument was then mailed to a second sample of prostate cancer patients once and then again two weeks later to assess test retest reliability. To assess feasibility in clinical settings, the instrument was self-administered to a third patient sample during a urology clinic visit. RESULTS: All scales exhibited good internal consistency and test retest reliability, convergent and discriminant validity, and significant correlations with disease specific, generic health-related, and global measures of quality of life. Men with greater physiologic impairment reported more limitations in role activities and more bother. Scales were also able to differentiate patients undergoing different therapies. All scales exhibited negligible correlations with a measure of socially desirable responding. Additionally, the instrument proved feasible when used as a self-administered questionnaire in a clinical setting. CONCLUSIONS: The current instrument possesses brief multi-item scales that can be successfully self-administered in multiple settings. The instrument is flexible, relatively quick, psychometrically reliable and valid, and permits a more comprehensive assessment of patients' quality of life.

Telephone interviews vs. workstation sessions for acquiring quality of life data.

Patient quality of life data can be acquired in a variety of ways, including over the telephone and through computerized questionnaires. However, if the method of collection produces different results, medical decisions regarding appropriate and cost-effective care may be influenced by collection method. We conducted an experiment where subjects had two quality of life measures, the time trade-off and rating scale utilities, assessed both in telephone interivews and via computer touchscreens. The order of telephone and touchscreen was randomized. We found that rating scale utilities were similar whether obtained via the telephone or via touchscreen regardless of which was done first. However, patients who had their time trade-off utilities assessed over the telephone first did not provide as consistent responses as those elicited first via touchscreen (p = 0.01). Caution is suggested when considering eliciting time trade-off over the telephone with subjects who have not had time trade-off elicited previously.

Methods for analyzing referral patterns.

OBJECTIVE: To develop a sound method to identify patient and physician characteristics that influence specialty referrals. DESIGN: A retrospective cohort analysis of medical claims data from 1996 supplemented with surveys of primary care physicians. SETTING: A 600-member independent practice association in southeastern Michigan that provided care for 90,000 members of an HMO. PATIENTS: Five cohorts, each of 2,000 to 6,000 patients with diagnoses that could be referred to cardiologists, ophthalmologists, pulmonologists, orthopedists, or general surgeons. MAIN RESULTS: The referral rates for the different cohorts ranged from 1% to 7%. The discriminatory ability of the multivariate logistic models (c-statistic) ranged from 0.66 to 0.79. The likelihood of referral was associated with the patient's diagnoses and medications and with the referring physician's age, years out of medical school, satisfaction with the specialty being referred to, and the importance of making or confirming a diagnosis. CONCLUSIONS: Because these methods were not difficult to implement and the results were credible, we believe that other organizations should be able to use them.

Serial prostate specific antigen screening for prostate cancer: a computer model evaluates competing strategies.

PURPOSE: We compare prostate specific antigen (PSA) screening strategies in terms of expected years of life saved with screening, number of screens, number of false-positive screens and rates of over diagnosis, defined as detection by PSA screening of patients who would never have been diagnosed without screening. MATERIALS AND METHODS: A computer model of disease progression, clinical diagnosis, PSA growth and PSA screening was used. Under baseline conditions, when screening is not considered, the model replicates clinical diagnosis and disease mortality rates recorded by the Surveillance, Epidemiology and End Results Program of the National Cancer Institute in the mid 1980s. RESULTS: Biannual screening with PSA greater than 4.0 ng./ml. was projected to reduce the number of screens and false-positive tests by almost 50% relative to annual screening while retaining 93% of years of life saved. With annual screening use of an age specific bound for PSA to consider a test positive instead of the standard 4.0 ng./ml. was projected to reduce false-positive screens by 27% and over diagnosis by a third while retaining almost 95% of years of life saved. Sensitivity analyses did not change the relative efficacy of biannual screening. CONCLUSIONS: Under the model assumptions biannual PSA screening is a cost-effective alternative to annual PSA screening for prostate cancer. With annual screening use of an age specific bound for PSA positivity appears to reduce false-positive results and over diagnosis rates sharply relative to a bound of 4 ng./ml. while retaining most of the survival benefits.

Preoperative predictors of cost in Medicare-age patients undergoing coronary artery bypass grafting.

BACKGROUND: Identification of preoperative factors that contribute to the cost of coronary artery bypass grafting could aid in predicting the procedure's expense. In this study, 30 sociodemographic and clinical preoperative factors were examined with "survival analysis" techniques to determine characteristics related to total hospital cost. METHODS: Characteristics of all patients age 65 or older undergoing isolated coronary artery bypass grafting from July 1993 to April 1995 (n = 757) were recorded. Software was developed within the hospital's Transitions Systems, Inc, database to calculate the outcome variable of total cost. Nonparametric methods were used for the univariate analysis of the data, and the Cox proportional hazards model was used for the multivariable analysis, censoring 25 patients who died in the hospital. RESULTS: Median hospital cost from the day of the operation until discharge was $15,198. Median length of stay after the operation was 6 days. Multivariable analysis revealed that age, preoperative renal failure, history of cerebrovascular accident, low ejection fraction, and surgical urgency were independent predictors of total cost. CONCLUSIONS: This study, using an accurate representation of true hospital cost and a modeling technique that accounts for the confounding effect of in-hospital death on cost, provides a template for analysis of cost in other patient groups.

Casemix adjustment of managed care claims data using the clinical classification for health policy research method.

OBJECTIVES: The objective of this study was to explore the use of the Clinical Classification for Health Policy Research (CCHPR) as a casemix adjustment method for examining physician practice patterns. METHODS: The data source was 2 years of administrative claims from an 86,000 member health maintenance organization in southeastern Michigan. The CCHPR version 2 algorithm, which is in the public domain, was used to assign each claim to one of 260 clinical categories. CCHPR and age-sex categories were used as explanatory variables in multiple linear regression models with approved claims payments in dollars as the outcome variable. Regressions were performed retrospectively for 1994 and 1995, and with 1994 claims' history to predict 1995 utilization. Similar regressions were performed with age-sex categories alone, and also with the ambulatory diagnostic groups. RESULTS: The adjusted R2 value of the retrospective regression models for total approved dollars was 0.42 for both study years when CCHPR categories were used. In contrast, age-sex explanatory variables alone achieved an R2 of 0.02. CONCLUSIONS: The CCHPR method appears to be a promising tool to understand variability in physician resource utilization in managed care.

The danger of applying group-level utilities in decision analyses of the treatment of localized prostate cancer in individual patients.

The optimal management strategy for men who have localized prostate cancer remains controversial. This study examines the extent to which suggested treatment based on the perspective of a group or society agrees with that derived from individual patients' preferences. A previously published decision analysis for localized prostate cancer was used to suggest the treatment that maximized quality-adjusted life expectancy. Two treatment recommendations were obtained for each patient: the first (group-level) was derived using the mean utilities of the cohort; the second (individual-level) used his own set of utilities. Group-level utilities misrepresented 25-48% of individuals' preferences depending on the grade of tumor modeled. The best kappa measure achieved between group and individual preferences was 0.11. The average quality-adjusted life years lost due to misrepresentation of preference was as high as 1.7 quality-adjusted life years. Use of aggregated utilities in a group-level decision analysis can ignore the substantial variability at the individual level. Caution is needed when applying a group-level recommendation to the treatment of localized prostate cancer in an individual patient.

Spontaneous pneumothorax in a patient with an azygos lobe.

The association between a spontaneous pneumothorax and an azygos lobe is surprisingly rare. A case is reported in which surgical management was difficult; it is suggested that thoracotomy is preferable to video-assisted thoracoscopic surgery in this situation. It is possible that the presence of an azygos lobe might protect against the subsequent development of a spontaneous pneumothorax, and the possible mechanism of this is discussed.

A decision analysis for treatment of clinically localized prostate cancer.

OBJECTIVE: To determine the preferred treatment of clinically localized prostate cancer. DESIGN: Cancer grade, patient age, and comorbidities are considered in a Markov model with Monte Carlo sensitivity analyses. Large and recent pooled analyses and patient-derived utilities are included. RESULTS: Principal findings suggest benefit for radical prostatectomy relative to watchful waiting for men under 70 years of age with low to moderate comorbidity. Men older than 70 with high comorbidity and disease of low to moderate grade do better with watchful waiting. CONCLUSIONS: Cohort-level sensitivity analyses suggest a quality-based treatment benefit for radical prostatectomy for younger men and treatment harm for older men. Tailored patient and clinician decisions remain necessary, especially for men older than 70 in good health but with aggressive cancers.

Survival estimates for patients with abnormal swallowing studies.

OBJECTIVE: To better understand the life expectancy of patients who have an abnormal videofluoroscopic swallowing study. DESIGN: Retrospective cohort study. The common starting point was the time of the severely abnormal swallowing study. Hospital charts were reviewed for clinical variables of potential prognostic significance by reviewers blinded to the outcome of interest, survival time. SETTING: A university-affiliated, community teaching hospital. PATIENTS: One hundred forty-nine hospitalized patients who were deemed nonoral feeders based on their swallowing study. Patients excluded were those with head, neck, or esophageal cancer, or those undergoing a thoracotomy procedure. MEASUREMENTS AND MAIN RESULTS: Clinical and demographic variables and time until death or censoring were measured. Overall 1-year mortality was 62%. Multivariable Cox proportional hazards analyses identified four variables that independently predicted death: advanced age, reduced serum albumin concentration, disorientation to person, and higher Charlson comorbidity score. Eighty patients (54%) subsequently underwent placement of a percutaneous endoscopic gastrostomy (PEG) tube after their swallowing study. CONCLUSIONS: Mortality is high in patients with severely abnormal swallowing studies. Common clinical variables can be used to identify groups of patients with particularly poor prognoses. This information may help guide discussions regarding possible PEG placement.

A national survey of attitudes regarding participation in prostate carcinoma testing.

BACKGROUND: The prevalence of prostate carcinoma testing is rapidly changing. Little is known about the frequency of testing in the non-Medicare population in the United States. The current study was conducted for a better understanding of who is being tested and some of the reasons why. METHODS: A randomized national telephone survey was administered to 800 men by the George H. Gallup International Institute. Questions in the survey were evaluated for their association with participation in prostate carcinoma testing reported by the men interviewed. RESULTS: Participation in prostate carcinoma testing approximated the frequency of colon carcinoma testing Eighty-six percent of the men surveyed believed that prostate carcinoma is a serious malignancy, and 78% believed that it could be cured often if detected early. Multivariate logistic regression models identified six factors that increased the likelihood of men in the survey being tested: white race, willingness to be tested, previous conversation with a physician or health professional, having had serum cholesterol tested, having been tested for colon carcinoma, and belonging to successively advanced age groups. CONCLUSIONS: Prostate carcinoma testing is commonly performed in men older than 40 years. Physician counsel and patient prevention consciousness appear to be the major influences when a patient decides to be tested. If early detection is considered beneficial, special efforts would be needed to reach the nonwhite population.

A guide for planning community-oriented health care: the health sector resource allocation model.

The objective of this study was to demonstrate the value of a planning model for the design and evaluation of community health services. The health status of Washtenaw County, Michigan was modeled. Data were obtained from the Michigan Department of Public Health, Medstat Systems, and the medical literature for 32 diseases or conditions, representing approximately 85% of causes of death and 56% of medical payments (excluding medication costs). An expanded life-table approach was used for 16 age-and sex-matched cohorts exposed to a disease attack rate, access-to-care rate, case fatality rate, morbidity, and costs. Rates can be modified to reflect changes due to treatment, secular trends, or prevention programs. Two alternative delivery methods were considered to show the potential impact of reducing cardiovascular deaths (worksite initiative), or increasing utilization of services (lay health promotion) on county health status and costs over time. Deaths, bed days, and annual medical payments were the main outcome measurements. Cardiovascular and cancer conditions are and will be the primary causes of death in this population. The most important causes of bed days are musculoskeletal conditions, chronic obstructive pulmonary disease, accidents, strokes, and depression. The major health-care payments are for angina pectoris and/or other cardiac conditions, musculoskeletal conditions, accidents, prenatal care, and/or childbirth, and depression. The two alternative scenarios illustrate how reductions in mortality are not necessarily equated with similar improvements in morbidity or costs. This model presents an overview of the current and projected health status of a community. With such a planning tool, a community can better understand the impact of potential prevention or intervention programs, and help design its health-care system within the constraints of available resources.