Anatomy of a meta-analysis: a critical review of "exercise echocardiography or exercise SPECT imaging? A meta-analysis of diagnostic test performance".

BACKGROUND: Accurate diagnosis of coronary heart disease has the potential to contribute substantially to cost-effective delivery of health services. Recent work by Fleischmann et al (JAMA 1998;280:913-20) represents an effort to summarize the accuracy of exercise echocardiography and exercise single photon emission computed tomography (SPECT). METHODS AND RESULTS: A critique of the previous work was constructed, obtaining the 44 articles used. These articles were reviewed and summarized with established techniques for meta-analysis. The studies summarized by Fleischmann et al were found to be significantly heterogeneous (echocardiography and SPECT, both P<.001). In the SPECT cohort, combination of different radioisotopes and reading techniques, and inclusion of reports using experimental techniques, were sources of heterogeneity. In the echocardiography cohort, experimental techniques and an individual series were identified. When the sample was stratified for sources of heterogeneity, it was found that there was no significant difference in diagnostic accuracy between the echocardiography and SPECT techniques used in current clinical practice. Meta-regression with summary receiver operating characteristic curve techniques, after adjustment of the model for multicolinearity and outliers, revealed that there were no significant differences between SPECT as used in current clinical practice and echocardiography. CONCLUSION: The report by Fleischmann et al contains serious flaws that limit its validity and generalizability.

Accumulation of 3,4-dihydroxyphenylglycolaldehyde, the neurotoxic monoamine oxidase A metabolite of norepinephrine, in locus ceruleus cell bodies in Alzheimer's disease: mechanism of neuron death.

3,4-Dihydroxyphenylglycolaldehyde (DOPEGAL) is the neurotoxic monoamine oxidase A (MAO-A) metabolite of norepinephrine (NE). NE neurons in the locus ceruleus (LC) die in Alzheimer's disease (AD). To determine if DOPEGAL could contribute to NE neuron death in AD we measured levels of DOPEGAL, NE and their synthesizing enzymes in LC from AD and matched controls. We found 2.8- and 3.6-fold increases in DOPEGAL and MAO-A in AD LC neuronal cell bodies compared to controls. NE and dopamine beta-hydroxylase were increased by 3.8- and 10.7-fold, respectively. Implications for the mechanism of neuron death in AD are discussed.

Missouri's Take a Seat, Please! and program evaluation.

In Missouri, injuries from motor vehicle crashes are the leading cause of death to children aged one to four. In 1984, the state legislature enacted child passenger safety legislation, but by 1992, compliance with the law was still disappointingly low. The Missouri Department of Health implemented a program called Take a Seat, Please! in which concerned citizens reported motorists who transported children under age four in a way not compliant with the state law. Two years later, a telephone survey and a pre- and postobservation study at child care centers did not show that the intervention had any effect. The program was discontinued in September 1995.

Evidence for acute renal cortical vasoconstriction after uninephrectomy.

The rate of progression of chronic renal failure (CRF) is similar for many diseases, suggesting a common, perhaps intrinsic, renal signal for its progression. The remnant nephron hypothesis of Bricker suggests that CRF may be the result of persistent compensatory renal growth (CRG). Normally, CRG after unilateral nephrectomy (uniNx) ceases within 1 week. Knowledge of the signals that initiate CRG may therefore shed light on the signals responsible for ongoing CRF. The signals responsible for the initiation of compensatory renal growth after uniNx are unknown. Hemodynamic changes in the remaining renal artery have been observed, but there are as yet no data for the main renal compartment which undergoes hypertrophy, the superficial renal cortex. The noninvasive technique of laser-Doppler flowmetry allows the continuous and independent monitoring of blood velocity and blood volume. The product of the two signals is proportional to tissue blood flow per unit volume of the tissue observed. Under controlled conditions in adult male Sprague-Dawley rats, renal cortical blood velocity increased by 22% within 5 min after uniNx and remained elevated at this level for 60 min. Renal cortical blood volume decreased throughout the experiment. Their product, renal cortical blood flow, increased briefly by 14% 5 min after uniNx but decreased over the time of observation in parallel with renal cortical blood volume. The simultaneous increase in blood velocity and decrease in blood volume in the superficial renal cortex acutely after uniNx suggest that vasoconstriction is an early event in compensatory renal growth.

Prognostic value of noninvasive risk stratification in younger and older patients referred for evaluation of suspected coronary artery disease.

OBJECTIVES: The purpose of this investigation is to explore the relationship of patient gender and age on coronary artery disease diagnostic evaluation and to assess the impact of noninvasive testing results on coronary revascularization rates and cardiac event-free survival. STUDY DESIGN: Retrospective observational cohort. PARTICIPANTS: From a series of 5322 consecutively tested patients from a Midwestern university tertiary medical center, a hospital cohort of 1345 patients with clinically suspected coronary artery disease was enrolled from 1988 through 1989. MEASUREMENTS AND RESULTS: Cardiac risk factor and symptom profiles were worse in women, whereas rates of positive test results were similar in both sexes. Multivariable-adjusted risk for follow-up diagnostic testing was 1.8 and 1.9 times greater, respectively, for men < or = and > 65 years of age than for women (P < .01). Younger women were 4.9 times (P = .001) more likely to experience a cardiac event than younger men, with no differences between younger and older women (relative risk = 1.1; P > .20). Overall cardiac event rates were 2.3, 7.4, 16.7, and 20.2% for young men, young women, older women, and older men, respectively. Initial screening was delayed 2 to 7 times longer for older and younger women compared with men (P < .001); the greatest delays were observed for younger women. Diagnostic follow-up and subsequent cost of total care from initial evaluation through 2 years of follow-up were higher for men than for women (P < .0001), with older women having the lowest rate of subsequent diagnostic and interventional follow-up. In the highest risk patients, subsequent utilization rates were 40 and 20% higher for younger and older men than for similarly aged women. In particular, diabetics were less likely to undergo follow-up diagnostic testing and revascularization (67% younger women). CONCLUSIONS: Age appears to significantly and differently influence decisions regarding noninvasive and invasive medical service utilization in men and women and may partially account for variable outcomes in this and previous gender-based comparisons.

Norepinephrine transmitter metabolite is a selective cell death messenger in differentiated rat pheochromocytoma cells.

3,4-Dihydroxyphenylglycolaldehyde (DOPEGAL) is the monoamine oxidase A (MAO-A) metabolite of norepinephrine (NE) and epinephrine (Epi). Oxidative metabolites of amines are predicted toxins. In this study we determine the toxicity of DOPEGAL, its tautomer 2',3,4-trihydroxyacetophenone (THAP) as well as NE, Epi and their oxidative and methylated metabolites in cultures of differentiated PC-12 cells. At 59.5 microM DOPEGAL, THAP and Epi, but not NE or other NE or Epi metabolites decreased PC-12 cells by 43.8%, 26.7% and 16.8% respectively. DOPEGAL toxicity was concentration and time dependent. Possible implications for degenerative diseases are discussed.

Post-treatment management options for patients with lung cancer.

OBJECTIVES: The first objective was to identify variations in patient management practice patterns after potentially curative lung cancer surgery. Patient management practice patterns were expected to range from intensive follow-up to no active surveillance. The second objective was to measure whether intensity of follow-up was related to patient outcomes. METHODS: An 18-month retrospective analysis was conducted of 182 patients with low TNM stage (< or = IIIA) lung cancer who were surgically treated with curative intent over the 11-year period from 1982 through 1992 at the St. Louis Department of Veterans Affairs Medical Center. RESULTS: Patients were followed for a mean of 3.3 years, until death or the end of the study. Analyses of diagnostic test and outpatient visit frequency distributions and cluster analyses facilitated the identification of 62 nonintensively followed patients and 120 intensively followed patients. Both groups were comparable at baseline, and there were no significant differences in patient outcomes attributable to intensity of follow-up. Intensively followed patients did, however, live an average of 192 days longer than nonintensively followed patients. CONCLUSIONS: Significant variations in follow-up practice patterns can exist within a single health care facility. In this analysis, variations in test and visit frequency did not result in statistically significant differences in patient outcomes, though the survival difference between groups suggests that some benefit might exist. Only well-designed prospective trials are likely to answer the question of what constitutes optimal follow-up after potentially curative lung cancer treatment.

A gender-specific hazard-based clinical and noninvasive coronary risk scoring system for patients with suspected coronary artery disease.

OBJECTIVE: An outpatient-based scoring system was developed for at-risk patients with coronary artery disease based on data derived from the clinical history and noninvasive testing results for the prediction of an adverse event, the development of risk subsets, and the evaluation of the appropriateness of utilization patterns in an ambulatory care patient population. METHOD: This was a hospital-based cohort study. From a population of 3,795 consecutively tested patients, 872 with suspected coronary artery disease were enrolled from a midwestern university tertiary medical center from 1988 to 1989. RESULTS: Multivariable Cox modeling was used to develop scoring weights with scores ranging from -1.6 to 8.5 points. Significant multivariable disease predictors of cardiac death or myocardial infarction were use of nitroglycerin or insulin, ST-T wave changes, female gender, left ventricular hypertrophy, and a reversible thallium 201 defect. Receiver operating characteristics curves by use of the hazard score were comparable by gender. A probability threshold of .30 for cardiac death or myocardial infarction yielded a cut point of acceptable sensitivity and specificity for prompting medical management decisions. Below this threshold, the rate of follow-up diagnostic testing was 16.9% for women and 57.8% for men (p=.00001). Above this threshold, the rate of follow-up diagnostic testing was 40.6% for women and 64.3% for men (p= .04). CONCLUSION: Use of cardiac diagnostic services and cardiac event-free survival varies by gender in patients screened by noninvasive testing. For men at low risk of cardiac death or myocardial infarction, a statistically greater use of follow-up diagnostic testing was reported, thus reflecting more aggressive treatment and overuse of services for men as compared with women.

Degenerative changes in epinephrine tonic vasomotor neurons in Alzheimer's disease.

The C-1 region in the rostral ventral lateral medulla contains mainly epinephrine (Epi) neurons. These neurons are the tonic vasomotor center of the brain. We previously demonstrated changes in the enzymatic activity of phenylethanolamine N-methyltransferase (PNMT) in axon terminals and cell bodies of Epi neurons from the medulla of Alzheimer's disease (AD) brains. In this study, we investigated the perikarya of C-1 neurons for the morphometric, immunohistochemical and histochemical changes that are seen in severely affected regions of Alzheimer brain. The mean areas and size distributions of C-1 neurons from 6 AD and 6 neurologically normal patients were compared using the Wilcoxon rank sum test and Kolmogorov-Smirnov z tests respectively. Additional brain sections from the C-1 region of AD and control individuals were stained with cresyl violet or immunostained with antibodies to the lysosomal hydrolase cathepsin D, Tau-2, Alz-50 and beta-amyloid protein. The average area of C-1 neurons in AD brains was decreased 18.3% (P < 0.001) compared to the areas of the same cell population in age-matched control brains. A shift toward smaller sized C-1 neurons was seen in the AD cases. Nissl stain demonstrated a central chromatolytic appearance in 3.7% of AD neurons sampled. No beta-amyloid deposits were detected histologically or immunocytochemically in the C-1 region of AD brains. Both Tau-2 and Alz-50 immunoreactivity was observed in occasional (1%) C-1 neurons from AD brains but not in controls. A small proportion (30%) of the C-1 neurons showing atrophy displayed increased cathepsin D immunoreactivity.(ABSTRACT TRUNCATED AT 250 WORDS)

MR imaging diagnosis of central precocious puberty: importance of changes in the shape and size of the pituitary gland.

OBJECTIVE: Central precocious puberty occurs as a result of premature pituitary stimulation and increased secretion of gonadotropins. The aims of this study were to analyze MR imaging findings in the pituitary glands of children with central precocious puberty compared with matched control subjects, to define MR imaging-derived variables useful in the diagnosis of central precocious puberty, and to correlate MR imaging-derived variables with the hormonal profile and other imaging and clinical findings. MATERIALS AND METHODS: Twenty-six children with central precocious puberty (two boys and 24 girls) were divided into two subgroups according to MR imaging findings: idiopathic (21 patients) and nonidiopathic (five patients: three hypothalamic hamartomas, one pineal tumor, one empty sella syndrome). The control group consisted of 17 normal age- and sex-matched children (two boys, 15 girls). Analyzed parameters included pituitary height, length, width, midsagittal cross-sectional area, calculated volume, and shape. The shape was assessed by a pituitary grading system and two other shape indexes (length-to-height and length-to-width ratios). Pituitary grade was defined by the concavity of the upper pituitary surface (grade 1 = marked concavity, grade 2 = mild concavity, grade 3 = flat, grade 4 = mild convexity, grade 5 = marked convexity). RESULTS: Pituitary grade showed a highly significant difference among groups (p < .001). Area, height, and length-to-height ratio were significantly different (p < .05), whereas length, width, length-to-width ratio, and volume were not. There was no significant difference in any of the variables compared between idiopathic and nonidiopathic groups. When selected variables (pituitary grade, area, height, length) in the central precocious puberty group were stratified by bone age and findings on pelvic sonograms, patients with advanced bone age had a significantly higher pituitary grade (p < .01) and had a tendency toward a greater pituitary length. Pituitary size and shape correlated with the hormonal profile. CONCLUSION: Change in pituitary grade is the most helpful variable for the diagnosis of central precocious puberty in a prepubertal child. A high pituitary grade (4 or above) is highly predictive of central precocious puberty, with the highest specificity and positive predictive value, but with low sensitivity. The use of combinations of high pituitary grade with two other positive findings (height and area greater than 1 SD from the respective means in the control group) improves the sensitivity, specificity, and predictive value of MR imaging in the diagnosis of central precocious puberty.

Effects of 'stroke-belt' residence, screening blood pressure and personal history risk factors on all-cause mortality among hypertensive veterans.

OBJECTIVES: To seek regional differences within the USA in the 'all-cause mortality' of hypertensive men during the 14 years following institution of antihypertensive treatment, and to determine how other pretreatment data can be related to that all-cause mortality. DESIGN: In the mid-1970s pretreatment clinical data were collected and computerized for 5698 hypertensive veterans. Deaths during the subsequent 14 years were obtained from the Veterans Administration Beneficiary Identification and Record Location System and the National Death Index. Relationships between pretreatment data and death were sought using chi 2- and z-tests for bivariate comparisons and logistic regression for multivariate analyses. PATIENTS: Half of the 5698 previously untreated male hypertensive military veterans were Black. Their mean age was 52.3 years and mean pretreatment blood pressure was 160/104 mmHg. Additional pretreatment data included body mass index, cigarette and alcohol usage, age and self-reported comorbidities. These patients began antihypertensive treatment during 1974-1975 in 28 special Veterans Administration outpatient clinics throughout the USA. RESULTS: During the 14 years after treatment began, 2283 of these patients (40%) died. Those from the southeastern USA, i.e. in the 'Stroke Belt', were 1.32-fold more likely to die than patients living elsewhere. Other pretreatment characteristics positively related to all-cause mortality included age, systolic blood pressure, cigarette and alcohol usage, and self-reported comorbidities. Race was unrelated to mortality. CONCLUSION: All-cause mortality was increased among hypertensive subjects from the southeastern USA. The reasons for this excess mortality remain unclear. Other pretreatment characteristics were also related to mortality, but race was not.

Occurrence of cancer in Alzheimer and elderly control patients: an epidemiologic necropsy study.

Epidemiologic necropsy provides an accurate measure of the occurrence rates of diseases. To determine the occurrence of cancer in Alzheimer patients as well as in non-Alzheimer elderly controls, we examined autopsy reports of 575 control and 71 Alzheimer cases aged 50-100 years for histologic evidence of cancer. We compared expected rates of cancers calculated from the National Cancer Institute's Surveillance, Epidemiology and End Result (SEER) Program data to rates observed at autopsy using a chi-squared test. To determine whether there was an association between the occurrence of cancer and Alzheimer disease, we compared rates for all cancer and three specific cancers in Alzheimer and control patients using an odds ratio test. We found from fourfold to 98-fold more cancer in Alzheimer patients and controls than that expected from SEER data. There was no statistical difference in the autopsy incidence of total, lung, or prostate cancer between Alzheimer patients and controls. However, the occurrence of pancreatic cancer was 6.7-fold higher in Alzheimer patients than in control subjects. Controlling for multiple comparisons, the odds ratio for pancreatic cancer in Alzheimer's disease was significantly higher than in controls (p < 0.001). Our results indicate that cancer occurs more frequently than expected in both Alzheimer patients and control subjects. In addition, there may be an association between the occurrence of certain cancers and Alzheimer's disease.

Effect of epidermal growth factor in the rat 5/6 renal ablation model.

Acute administration of epidermal growth factor (EGF) has been shown to promote recovery from ischemic and nephrotoxic acute renal failure in vivo. The question of whether chronic subcutaneous administration of EGF (19.1 micrograms/day for 3 or 6 wk) could alter the course of chronic renal failure in rats subjected to 5/6 nephrectomy was studied. By week 6, there was no difference in renal function, as assessed by animal survival, BUN, urea and inulin clearances, proteinuria, renal morphometry, or renal size, between EGF- and vehicle-treated rats. This suggests that chronic renal insufficiency differs from acute tubular injury in its sensitivity to exogenous EGF. Unexpectedly, EGF significantly attenuated the rise in systolic blood pressure that occurred by the fourth week after 5/6 nephrectomy. The antihypertensive effect of EGF was still evident at week 5. Urinary flow rate, free water clearance, and excretion of total solutes, Na+, and K+, however, were not significantly altered by EGF at weeks 2, 4, 5, or 6, suggesting a mechanism other than increased natriuresis or diuresis for this antihypertensive effect.

Intraoperative autologous blood salvage with cardiac surgery: an analysis of five years' experience in more than 3,000 patients.

STUDY OBJECTIVE: To analyze intraoperative autologous salvage of shed mediastinal blood and subsequent transfusion in cardiac surgery. DESIGN: Retrospective statistical analysis. SETTING: University hospital. PATIENTS: Three thousand twenty two patients undergoing cardiac surgery from 1984 to 1988. INTERVENTIONS: A review of anesthesia and transfusion records of all patients who underwent intraoperative salvage of shed blood and autologous transfusion using the Sorenson Receptal Auto Transfusion System (ATS) with saline wash prior to reinfusion in cardiac surgery. MEASUREMENTS AND MAIN RESULTS: The salvaged blood volume ranged from 36 to 2,795 ml, with a mean of 321 +/- 222 ml (SD). Eighteen percent of patients did not receive any homologous blood products during their hospitalization. Patients who received only salvaged autologous transfusion were younger, had higher preoperative hemoglobin and hematocrit values, had a larger body surface area, and had shorter surgeries compared with patients who received only homologous blood or both autologous and homologous blood. More blood products were given to patients who received salvaged autologous blood compared with those who did not. Patients who underwent normovolemic hemodilution prior to extracorporeal circulation with subsequent reinfusion received significantly fewer blood products. Ten preoperative and four intraoperative variables significantly influenced the salvaged volume. Previous cardiac surgery was the most significant preoperative variable, and repair of ventricular septal defect produced by myocardial ischemia was the most significant intraoperative variable. CONCLUSION: Considering the average salvaged volume and its current autologous transfusion-related expense, autologous blood salvage is potentially an economic benefit. Perioperative blood conservation requires a considerable commitment from surgeons, anesthesiologists, perfusionists, and intensive care physicians to be effective.

The effects of residency training programs on the financial performance of Veterans Affairs medical centers.

This study examines financial performance and physician productivity in Veterans Affairs teaching hospitals following the elimination of a separate payment for the indirect costs of medical education. Financial performance of teaching hospitals in the VA system was no worse than nonteaching peers even without a teaching subsidy. Residents were found to provide patient care but this contribution to output was offset by indirect teaching costs of resident training. Physicians were less productive in teaching hospitals, possibly reflecting the time spent in training and supervising residents, while nurses were more productive. Finally, as staff size increases, the indirect costs of medical education decrease. Future downsizing of residency programs would financially benefit smaller-staffed VAMCs; larger-staffed facilities would lose.

Evidence for decreased transport of PNMT protein in advanced Alzheimer's disease.

Phenylethanolamine N-methyltransferase (PNMT) is the rate-limiting enzyme in the synthesis of epinephrine and a specific marker for adrenergic neurons. PNMT protein is decreased in axon terminals in brains from patients with Alzheimer's disease due to retrograde degeneration of epinephrine neurons. To determine the subcellular mechanism underlying retrograde degeneration, the distribution of PNMT between axon terminal and cell body was calculated in early and advanced Alzheimer cases compared with age-matched controls. In early Alzheimer's disease there is a decrease in PNMT in axon terminals and in total PNMT in epinephrine cell bodies and terminals compared with control values. There is no difference in the ratio of PNMT in cell body/axon terminal compared with controls. In contrast, in advanced Alzheimer's disease, PNMT activity increases by 124% in epinephrine neuronal cell bodies compared with controls. Immunochemical titration shows that this increased enzyme activity is due to an increase in PNMT protein. The cell body/axon terminal ratio of PNMT is increased 2.5-fold in advanced Alzheimer's disease compared with controls. These findings are consistent with the hypothesis that in early Alzheimer's disease there is a decreased synthesis or increased degradation of PNMT. However, in advanced Alzheimer's disease we propose that the accumulation of this enzyme in the perikarya results from a diminished transport of PNMT to axon terminals. We further postulate that epinephrine, the product of PNMT, and its further metabolites are endogenous neurotoxins. Therefore, the accumulation of PNMT in epinephrine cell bodies may contribute to the degeneration of these neurons in Alzheimer's disease.

A comparison of in-house and regionalized computerized tomography scanning: clinical impact and cost.

Over a two-year interval, computerized tomography (CT) scans at an urban, 400-bed Department of Veterans Affairs medical center (VAMC) were obtained in three ways. First, an in-house low-efficiency machine was used. Then, scans were done at another area hospital, in effect duplicating some aspects of regionalizing services. Finally, a high-efficiency in-house machine was used. Clinical outcomes and costs of diagnosing 181 bronchogenic cancer patients were compared across the three time periods to identify any differences associated with regionalization of CT services. Patient groups were homogeneous with respect to sociodemographic characteristics, clinical presentation, and severity of disease. The first part of the analysis investigated whether the site of CT scanning affected clinical outcomes. Diagnostic procedures, surgical results, mortality, and length of stay were compared using one-way analysis of variance. Significant differences were found only for conventional tomography and CT utilization rates. While conventional tomography declined across the periods, CT utilization increased, exceeding national trends. The second part of the analysis examined the costs of CT scanning. During the regionalized period, the hospital paid a fixed fee of $519 per scan. Estimated costs of in-house scans were $285 in the low-efficiency and $141 in the high-efficiency periods. Charge-based payments made to the external facility and differences in the volumes of patients scanned internally account for the cost differences. The analysis showed that while regionalized CT scanning did not compromise the quality of care for these VA patients, it was more costly. Results suggest that VA hospital administrators should carefully consider ownership and payment arrangements when comparing regionalized and in-house provision of services.

Practice pattern variation between two medical schools.

This study examined physician test-ordering behavior at a large urban Veterans Administration Medical Center staffed by two medical schools. Patients are assigned randomly to the two schools' wards, which operate independently of each other. The medical records of 119 patients, admitted during a 5-month period, were abstracted for data on the process and outcomes of medical care. Only one statistically significant difference in diagnostic testing practices was revealed by the observation that 12% of patients on one service received another abdominal film, while no patients on the other service did. The implications of studies such as this for small-area analysis are discussed. If variation in the utilization of health services is observed in a geographic region, then a study of physician behavior at a single facility may help to identify the reason for the variation.