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To The Editor: We appreciate Dr. Fowler's positive comments on our study ("Arthroscopic Lavage or Debridement Did Not Reduce Pain More Than Placebo Did in Patients with Osteoarthritis" [ N Engl J Med. 2002;347:81-8]) in Evidence-Based Orthopaedics ( J Bone Joint Surg Am. 2002;84:387) regarding the internal validity of the study, and we wish to address his concerns regarding its external validity. We believe that all of his concerns are due to our inability to include all of our data in the article because of the limitations placed on its length by The New England Journal of Medicine . Dr. Fowler argued that, although our results were valid in the spectrum of patients whom we studied, these results might not apply more generally. First, we used the system of Kellgren and Lawrence 1 to classify each patient's study knee according to the severity of osteoarthritis. Our study cohort included thirty patients whose study …

n the early 199os, the National Institutes of Health (NIH) adopted a policy for the management of conflicts of interest on the part of clinical investigators (45 CFR 50.6045). This policy emphasized disclosure of potential or actual conflicts to institutional officials who would then develop strategies for managing them. The policy was adopted as an alternative to an earlier proposal that had emphasized mandated standards and mandated external disclosures.' Recent studies of the actual operation of conflict of interest policies cast doubt on the adequacy of the approach adopted by the NIH.',3 They indicate that as a result of the discretion allowed to institutional officials, there currently exist few uniform standards and very little accountability. These studies have suggested that to increase accountability, the scope of disclosure should be widened.

An important determinant of patient outcomes is illness severity, which must be classified to guide clinical decision making and evaluate the effectiveness of diagnostic and therapeutic interventions. Currently, no widely accepted framework for grading illness severity in human immunodeficiency virus—infected patients exists. The best known classification systems for human immunodeficiency virus infection (Centers for Disease Control and Prevention; Walter Reed) are not based on illness severity, and provide stages that are not all inclusive so that a large number of persons cannot be classified (Walter Reed). Although much previous research has focused on individual prognostic factors (oral thrush, CD4 cell count, serum β2-microglobulin), little attention has been given to incorporating these factors into illness severity scales that are easy to use in clinical settings. In addition, despite the progressive functional disability of human immunodeficiency virus—infected individuals, few of the existing approaches to illness severity classification have examined the contribution of functional status. We urge investigators to develop clinically sensible severity scales that are easy to use. Such scales will considerably improve existing approaches that tend to rely solely on the CD4 cell count and do not take into account the known prognostic effects of other variables. (Arch Intern Med. 1993;153:2749-2755)

In this study, the authors determined how residents in internal medicine allotted their time during patient management rounds (work rounds). Fourteen house staff teams were observed for four days each, and the time spent on all activities was recorded. Of the 56 days studied, work rounds were not conducted on nine days. On the 47 days during which work rounds occurred, only 502 (76.4 percent) of a possible 657 visits to patients were made. Daily time spent on work rounds by each team averaged 49.4 minutes (range: 23.9 to 73.1), or 4.6 minutes (range: 2.3 to 6.6) per patient evaluated. Some part of a physical examination was performed on only 44 percent of the patients. For those patients examined, the average time of an examination was approximately one minute per patient. Vital signs sheets and medication sheets were reviewed infrequently. This study suggests that medical educators should be concerned about the thoroughness of house staff work rounds.

Aryl hydrocarbon hydroxylase was measured in cultured human lymphocytes induced with benzathracene and in pulmonary alveolar macrophages induced in situ in cigarette smokers. Considered separately, neither lymphocyte AHH nor macrophage AHH levels were distinctly different in either noncancer or lung cancer patients. Considered simultaneously, lymphocyte and macrophage AHH levels are quite different in noncancer and lung cancer patients. The lung cancer patient group was seen to contain a significantly higher percentage of persons with high levels of AHH than did an age-matched group of noncancer patients, (P less than 0.001), when more than one tissue was assayed to determine the individual's enzyme levels.

• A case of Legionella pneumophila infection complicated by thrombotic thrombocytopenic purpura (TTP) was confirmed at autopsy by the demonstration of the organism in lung tissue, and by the finding of widespread intravascular and subendothelial thrombi associated with microinfarctions in all major organs examined. In addition to the typical hematologic abnormalities of TTP, the patient was found to have a low serum C3 level and elevated levels of immune complexes as measured by the liquid phase C1q binding assay. We suggest that the L pneumophila infection caused endothelial damage and/or platelet aggregation, perhaps as a consequence of complement activation, thus initiating the sequence of events leading to extensive microvascular thromboses.

A component capable of binding benzo(a)pyrene was measured in plasma from cigarette smokers and nonsmokers. This plasma fraction was found to have a high specificity of binding to benzo(a)pyrene, bound benzanthracene competitively with benzo(a)pyrene, and was positively correlated (r = 0.861, p less than 0.001) with the capacity of the individual subject's lymphocytes to be induced for AHH activity in culture. An inverse correlation (r = -0.957, p less than 0.001) between the presence of the plasma component in lung cancer patients and the capacity of lung cancer patients' lymphocytes to be induced in culture is unexplained at this time. A benzo(a)pyrene-binding fraction was not found in induced or uninduced cultured lymphocytes from smokers or nonsmokers, or in homogenates of lung excisional tissue from smokers with or without primary lung cancer.

Free alveolar macrophages (FAMs) obtained by bronchoalveolar lavage from healthy nonsmoking volunteers were incubated with varying concentrations (0–300 μg/ml) of Mt. Saint Helens volcanic ash obtained from either Portland, Oregon, or Pullman, Washington, to assess the cytotoxic effects of the ash on human lung cells. Trypan dye exclusion techniques were employed for assessment of cell viability. Following the initial 24 hour culture with the Portland ash samples, decreased viability was observed at all ash concentrations (P < 0.001 in all instances), and further decreases in viability were noted at 48 and 72 hours for all concentrations of ash tested (P < 0.001 in all instances). When the Pullman, Washington, ash sample was evaluated, a decrease in cell viability was noted for the 300 μg/ml concentration (P < 0.017) after the initial 24 hours in culture. Further decreases in cell viability were noted only when cells were cultured for longer time intervals (48 and 72 hours) (P < 0.05 in all instances). Differences in cellular response to the 2 ash samples were further investigated by exposing FAMs from a single individual to the 2 different types of ash. These studies demonstrated similar cytotoxic effects of the 2 ash samples at all concentrations and times tested (P < 0.30 in all instances) with the exception of the 100 μg/ml concentrations at 72 hours (P < 0.020). These data suggest that the differences observed between the 2 types of ash in the independent studies are probably related to interindividual variation in FAM response to the ash rather than to differences in the cytotoxicities of the 2 ash samples. Cytotoxicity of the volcanic ash was also compared with other environmentally relevant airborne particulates, such as amosite and chrysotile asbestos, as well as amorphous and crystalline silica. These results demonstrated an intermediate cytotoxic effect of the ash between innocuous amorphous silica and the very cytotoxic chrysotile asbestos. The affinity for volcanic ash to adsorb tritiated benzo(a)pyrene (3H-BaP) was also compared with that of amorphous silica and amosite asbestos. These studies demonstrate that volcanic ash has intermediate adsorption qualities (4.3 ± 0.1; pmoles 3H-BaP adsorbed/μg particulate ± SD) between those of amorphous silica (1.9 ± 1.0) and amosite asbestos (7.8 ± 1.2) (P < 0.05 in all instances). These data suggest volcanic ash exhibits moderate biological properties compared with those of other environmentally important airborne particulates. Whether in vitro studies reflect in vivo response of human lung cells to the ash cannot be determined at this time, and follow-up of assessment of individuals exposed to the ash will be required to assess its long-term effects on pulmonary tissue.

Human mitogen-stimulated lymphocytes, cultured in the presence of amosite asbestos (AS), demonstrated a slight increase in aryl hydrocarbon hydroxylase (AHH) activity compared with non-induced (control) cultures (P = 0.005). A much greater increase in enzyme activity occurred following addition of the inducers benzanthracene (BA) or cigarette tars (CT) to cell cultures (P less than 0.001 in both instances). Significant enzyme induction also occurred when AS fibers were first preincubated with CT or BA, washed with acetone, then added to lymphocyte cultures (P less than 0.003 in all instances). This increase in AHH activity was not as great, however, as the induction observed when BA or CT was added to cell cultures. No further increase in enzyme activity was noted when AS and CT or AS and BA were simultaneously added to culture lymphocytes (P greater than 0.070 in all instances). The results demonstrate that polycyclic aromatic hydrocarbons (PAH), such as BA and other components of CT, are adsorbed and transported by amosite AS particles. These AS-PAH complexes are capable of inducing AHH in cultured human lymphocytes.

Pulmonary alveolar macrophages (PAMs) obtained by bronchopulmonary lavage from 6 normal non-smoking volunteers were incubated with [3H]-benzo[alpha]pyrene to ascertain the normal metabolism and conjugation of polycyclic aromatic hydrocarbons. Through the use of a crude glucuronidase preparation, both glucuronic acid and sulfate conjugates were examined. Phenols and quinones were identified by high-pressure liquid chromatography as the principal free metabolites formed during 1 h incubation with benzanthracene induced PAMs. In addition, phenols and quinones were major substrates utilized by these cells for conjugation during the incubation period. The ranges of benzo[alpha]pyrene metabolites produced by PAMs from non-smokers were compiled and the variation in production as well as detoxification of proximate carcinogenic benzo[alpha]pyrene metabolites are presented.

A patient presenting with apparent pulmonary edema in whom transient, large increases in systemic arterial, pulmonary arterial, and pulmonary capillary wedge pressures occurred and spontaneously resolved within a few minutes is presented. This appears to lend support to the pressure and volume overload theory of the pathogenesis of neurogenic pulmonary edema that previously has not been demonstrated in humans.

In a 25 year old man shock and pulmonary edema developed following the intravenous administration of meglumine diatrizoate for an intravenous pyelogram. A pulmonary-capillary wedge pressure of 3 torr and a high protein content in the pulmonary edema effluent confirmed the diagnosis of noncardiogenic pulmonary edema. We suggest that the basis of the increased capillary permeability in this patient may be related to an immunologic reaction to intravenous pyelogram dye.

The use of reversed-phase thin-layer chromatography for the separation of benzo[a]pyrene metabolites has been investigated. Two systems are described for the separation of the major metabolites of benzo[a]pyrene, including sulfate and glucuronide conjugates.

Human pulmonary alveolar macrophages (PAMs) were cultured for 24--72 h with varying concentrations (0--300 microgram/ml) of amosite asbestos (AS). At lower AS concentrations, (less than 100 microgram/ml) no decrease in cell viability occurred during the first 24 h of culture. Significant cytotoxicity (P less than 0.005 in all instances) was observed, however, following incubation for 24 h with higher AS concentrations (greater than 100 microgram/ml). Even following incubation with lower concentrations of AS, significant cytotoxicity (P less than 0.006 in all instances) was observed after 48 or 72 h of culture. Scanning electron microscopy (SEM) clearly illustrates the various stages of AS phagocytosis by PAMs. SEM also documented morphological changes in PAMs following AS exposure. These included increased zeiosis and the appearance of a fibrous-like material on the surface of AS fibers following initial contact with the PAM cytoplasmic membrane. Further study of the biological interactions between AS and human cells, such as PAMs, might provide valuable information regarding the etiology of AS-related lung disorders.

Aryl hydrocarbon hydroxylase (AHH) activity was measured in pulmonary alveolar macrophages (PAMs) and peripheral blood lymphocytes from cigarette smokers with and without primary lung cancer. Frequency distribution analysis of AHH induction ratios for the two groups revealed an increased number of individuals in the lung cancer patient group with high lymphocyte induction values (P less than 0.05). A similar increase was not shown for high-PAM AHH values in lung cancer patients (P greater than 0.2). When individual PAM and lymphocyte AHH values were compared between noncancer and lung cancer patients, a positive correlation was observed for noncancer patients (r=0.195, P less than 0.001), but no correlation of these values was noted for lung cancer patients. The lung cancer patients were divided into three subgroups of patients showing (I) high PAM and low lymphocyte AHH levels, (II) low PAM and low lymphocyte AHH levels, and (III) low PAM and high lymphocyte AHH levels. When the incidence of family history of cancer was compared for these subgroups, no family cancer history was recorded for persons in subgroup II; however, individuals in subgroups I and III presented family cancer history incidence of 9.5% and 39.3%, respectively. Patients in group III averaged 6 years younger than those in group I. These data suggest that familial factors may be identified among lung cancer patients and that these factors appear to associate as either a cause of an effect with the capacity of pulmonary alveolar macrophages and lymphocytes to be induced for AHH. The data support the hypothesis that high AHH values may be characteristic of lung cancer patients but show that enzyme values determined from a single tissue, either PAMs or lymphocytes, may not be appropriate for showing whether high AHH inducibility is correlated with lung cancer.

Many of the polycyclic aromatic hydrocarbons (e.g., benzo[a]pyrene (B[a]P), benzanthracene (BA), 3-methylcholanthrene (3-MC)) are not only carcinogenic, but also induce AHH in human tissues. Recently, chrysene has been implicated as an etiologic determinant of chemical carcinogenesis. Here we describe the ability of chrysene to induce AHH in cultured human lymphocytes. Lymphocytes were obtained from 9 healthy subjects, divided into 2 sets, and cultured in duplicate, triplicate, or quadruplicate for 48 h. Chrysene (25 microM final concentration) in acetone was then added to the induced culture set and the control set received acetone alone. Lymphocytes were then cultured an additional 24 h before harvesting. AHH was quantitated by a fluorometric analysis of the phenolic metabolites produced by incubating the lymphocytes with B[a]P for 35 min. A significant increase in enzyme induction occurred in the chrysene-induced cultures compared with control (non-induced) cells (one-tailed student t-test; P less than 0.001). It was also observed that the interindividual variation in AHH inducibility seen with other PAHs is also observed with chrysene.

We performed a prospective study of 250 men undergoing transurethral resection of the prostate to determine the incidence of perioperative myocardial infarction. The prevalence of coronary artery disease in the study group was 27%. Patients had measurement of total creatine kinase and its MB isoenzyme and electrocardiography preoperatively and on the first three postoperative days. Only one myocardial infarction was diagnosed, an incidence rate of 0.4%. The overall rate of serious post-operative complications was 3.6%. No deaths occurred during the operative hospitalization. We conclude that with transurethral resection perioperative myocardial infarction is a rare event despite the high prevalence of coronary artery disease in this surgical population. Routine postoperative surveillance with electrocardiograms and creatine kinase determinations in asymptomatic patients is not warranted.

A significant portion of internal medicine residency training in the United States today occurs in general medicine sections of Veterans Administration hospitals. The authors studied the demographic, diagnostic, and prognostic characteristics of the patients treated by house staff members rotating through the general medical wards of the Houston, Texas, Veterans Administration (VA) Medical Center. In 2,131 admissions over 13 months, the most frequent primary causes of admissions included congestive heart failure, pneumonia, exacerbation of chronic obstructive lung disease, and malignancy. In 85 percent of the admissions, two or more chronic diseases were present. In 53 percent of admissions, the patients were deemed to be moderately or severely ill on admission. The data indicate that the residents' experience is representative of problems encountered by practicing internists and that VA hospitals make a significant contribution to internal medicine training and thus to the provision of health care for the nation.

• We performed an observational study to determine the prevalence of severe dementia in a general medicine unit, the categories of acute medical care provided to these patients, the process by which treatment decisions are made, and their cost implications. The prevalence of severe dementia was 4.4%. The patients from whom some form of acute medical care was withheld (26 [45.6%] of 57) were more severely ill at admission and had a mortality rate five times higher than those who received full care. Physicians cited family wishes in 75.9% of the decisions to limit care but in only 10.9% of the decisions to give full care. The only differences in charges incurred were due to differential mortality rates in individuals from whom care was withheld. We recommend that hospitals develop and implement protocols for decision making in the care of the severely demented to promote open discussions among providers and families and to increase family contributions to decision making. We believe that the extension of this consultative approach to decisions involving severely demented patients may have the virtue of combining more humane care with more cost-effective care. ( Arch Intern Med 1988;148:1980-1984)

A significant number of errors in physical examination can be detected when house staff are observed by attending physicians. In this study, observation of residents and interns showed a total error of 13.1% and 15.6%, respectively, with incorrect findings of 3.3% and 4.9% and omitted findings of 9.8% and 10.7%, respectively. Approximately two thirds of all patients examined had at least one error noted. A method was instituted for detecting and correcting these errors that can be integrated into daily attending rounds. Using this method, a statistically significant decrease in the number of errors was shown. The method used emphasizes the physical examination pertinent to the patient's main problem, consumes very little rounding time, and is well received by both attending physicians and house officers. ( JAMA 1983;249:1035-1037)