In utero surgery rescues neurological function at birth in sheep with spina bifida.

We hypothesize that the neurologic deficit associated with open spina bifida is not directly caused by the primary defect but rather is due to chronic mechanical and chemical trauma since the unprotected neural tissue is exposed to the intrauterine environment. We report here that exposure of the normal spinal cord to the amniotic cavity in midgestational sheep fetuses leads to a human-like open spina bifida with paraplegia at birth, indicating that the exposed neural tissue is progressively destroyed during pregnancy. When open spina bifida was repaired in utero at an intermediate stage, the animals had near-normal neurologic function. The spinal cord was deformed but largely preserved. These findings suggest that secondary neural tissue destruction during pregnancy is primarily responsible for the functional loss and that timely in utero repair of open spina bifida might rescue neurologic function.

Tissue content of dihydrotestosterone in human prostatic hyperplasis is not supranormal.

The dihydrotestosterone content of normal peripheral and benign hyperplastic prostates was measured in tissue obtained at open surgical procedures on 29 men of ages 36 to 82 yr. The dihydrotestosterone content in normal prostates (mean +/- SE, 5.1 +/- 0.4 ng/g tissue) and in benign hyperplastic prostates (5.0 +/- 0.4) was similar. In 11 patients in whom both normal and hyperplastic prostatic tissue was harvested simultaneously at the same operation, there was no significant difference in the content of dihydrotestosterone in the two types of tissue. These findings fail to confirm the widespread belief that dihydrotestosterone content is elevated in benign hyperplastic prostates. Our data differ from the reported literature in one major respect: the dihydrotestosterone content of normal peripheral prostate in this study is three to four times higher than previously reported. This difference between the present and earlier studies was resolved by experiments performed on cadavers, which were the source of normal prostatic tissue used by other investigators. Dihydrotestosterone content was measured in seven cadavers ranging in age from 19 to 82 yr of age. The results of this experiment indicate that the dihydrotestosterone content of prostatic tissue removed at autopsy is factitiously low (0.7-1.0 ng/g tissue). This finding was confirmed by in vitro incubations of fresh prostatic tissue at 37 degrees C that demonstrated reduction of dihydrotestosterone content to low levels within 2 h. When taken together, these results indicate that when prostatic tissue is harvested appropriately, the dihydrotestosterone content of normal peripheral and hyperplastic tissues is the same. This finding should influence future research into the etiology of benign prostatic hyperplasia.

Beta 2-microglobulin expression in human embryonal neuroblastoma reflects its developmental regulation.

Class I major histocompatibility complex (MHC) antigen expression in neuroblastoma may play a role in the oncogenicity of this embryonal tumor of childhood. Since N-myc amplification in neuroblastoma tumors is associated with rapid tumor progression (33) and N-myc decreases Class I MHC antigen expression in rat neuroblastoma cells (21), we quantitated levels of N-myc mRNA and Class I MHC cell surface antigens in a panel of 24 human neuroblastoma cell lines. We found that N-myc expression is not invariably associated with low levels of beta 2-microglobulin (B2M) and Class I MHC antigen expression. As we considered that Class I MHC antigens may be regulated in association with the differentiation stage of the neuroblastoma tumor, we examined the expression of B2M during development of the human adrenal medulla, the tissue of origin of most neuroblastomas. We found that B2M is a marker of differentiated adrenal medullary cells, expressed late during the third trimester of development. Moreover, using morphological and immunological criteria, we found that B2M is expressed in differentiated tumor cells. These data suggest that the expression of B2M in neuroblastoma is associated with the stage of differentiation of the tumor cell and not N-myc expression. Furthermore, these findings suggest that neuroblastomas may correspond to the arrested differentiation of adrenal neuroblasts at different stages of development.

Patterned distribution of metastases from malignant melanoma in humans.

Malignant melanoma has an unpredictable clinical course in terms of metastatic behavior, and further understanding might lead to improved therapeutic intervention with immune agents or antagonists. To determine whether metastases show patterns or are randomly distributed, we analyzed the distributions of metastases in the 56 patients with metastatic malignant melanoma, subjected to complete autopsy at The Johns Hopkins Hospital, using parametric statistics and cluster analysis. Variables examined included age, race, sex, location of primary tumor, length of survival, mode of therapy, histology of tumor, location of metastases, and extent of tumor infiltration at each metastatic site. The results indicate that the distributions of metastases from malignant melanoma are patterned such that significant positive correlations (p less than 0.05 or better) were observed among various tissues and organs. We identified several aggregations with respect to the distributions of metastases: (a) central nervous system; (b) mesodermal; (c) endocrine; (d) reticuloendothelial; and (e) foregut. Organs and tissues comprising each aggregation were interrelated by their similar developmental origins or functions. A very highly significant negative correlation between central nervous system and hepatic metastases (p less than 0.001) was also demonstrated by cluster analysis. We concluded that the distributions of metastases from malignant melanoma are not random; the patterns of metastases may be related to the embryological derivation of tissues involved.

Altered glucose metabolism in adriamycin-induced heart failure.

Spontaneously hypertensive rats received 1 mg/kg of Adriamycin intravenously once a week for up to 12 weeks; their hearts were excised and perfused with buffer containing 5 mM [1-13C]glucose. Histological evidence of Adriamycin cardiotoxicity was evident after 8 and 12 weeks of treatment and was accompanied by a significant decrease in cardiac function. There were only minor changes in the 31P-NMR spectra in hearts following treatment; however, 13C-NMR spectra revealed decreased incorporation of label into the lactate, alanine and glutamate pools in hearts with severe tissue damage compared to hearts from untreated animals.

Focal myocardial ischemic necroses associated with unstable angina pectoris.

OBJECTIVES: We sought to determine whether myocardial lesions develop in association with unstable angina pectoris. BACKGROUND: We observed a patient with unstable angina pectoris who developed foci of ischemic necroses in the distribution of a single coronary artery. The artery had an atherosclerotic plaque that had undergone ulceration of its fibrous cap. This case prompted us to study the occurrence of focal myocardial ischemic necroses in other patients with unstable angina pectoris. METHODS: Focal ischemic injuries of an age consistent with the duration of the episode of unstable angina pectoris were observed in 6 of 21 patients who died after hospital admission. The 21 patients had not undergone any invasive coronary procedures or thrombolysis, and the heart had been examined after postmortem arteriography and fixation in distension. RESULTS: Of the six patients with focal ischemic lesions, three had foci of contraction band necrosis and three had focal areas of ischemic necrosis in a state of early repair. Three had a recent myocardial infarct of an age less than the duration of unstable angina pectoris. In each of the six patients, the histologic age of the focal myocardial lesions correlated with the time frame of unstable angina. CONCLUSIONS: We conclude that the focal ischemic injuries observed in the myocardium were due to ischemic episodes that also produced the clinical manifestations of unstable angina pectoris.

Infarct expansion: pathologic analysis of 204 patients with a single myocardial infarct.

The reasons for the marked variability in expansion of myocardial infarcts are unknown. To examine this question, the hearts in 204 patients with a single myocardial infarct, autopsied at The Johns Hopkins Hospital and studied after coronary arteriography and fixation in distension, were reviewed. There were 58 (28%) hearts with marked infarct expansion, 34 (17%) with moderate expansion and 112 (55%) with no or minimal expansion. The degree of expansion was greater in larger, more transmural infarcts (p less than 0.001). Infarcts with greater expansion had significantly more endocardial thrombus (p less than 0.001) and endocardial fibroelastosis (p less than 0.01). Larger heart weight and degree of left ventricular hypertrophy had a significant negative correlation with infarct expansion (p less than 0.05). A markedly greater degree of expansion was noted in the 101 infarcts (50%) caused by lesions in the distribution of the left anterior descending coronary artery as compared with the 57 infarcts (28%) secondary to right coronary lesions and the 46 infarcts (23%) in the distribution of the left circumflex coronary artery (p less than 0.001). The results show that expansion is associated with large infarcts but is less marked in hearts with ventricular hypertrophy. Expansion occurs predominantly in infarcts in the left anterior descending coronary artery distribution, that is, regions of the left ventricular myocardium with the greatest curvature. These results suggest that the degree to which an infarct expands may be influenced by the preinfarction thickness of the ventricular wall.

Clinicopathologic description of myocarditis.

Histologic evidence of myocarditis was demonstrated in 35 of 348 patients submitted to endomyocardial biopsy over 5 years. Analysis of the histologic findings and clinical course of these patients resulted in a new clinicopathologic classification of myocarditis in which four distinct subgroups are identified. Patients with fulminant myocarditis become acutely ill after a distinct viral prodrome, have severe cardiovascular compromise, multiple foci of active myocarditis by histologic study and ventricular dysfunction that either resolves spontaneously or results in death. Patients with acute, chronic active and chronic persistent myocarditis have a less distinct onset of illness. Patients with acute myocarditis present with established ventricular dysfunction and may respond to immunosuppressive therapy or their condition may progress to dilated cardiomyopathy. Those with chronic active myocarditis initially respond to immunosuppressive therapy, but they have clinical and histologic relapses and develop ventricular dysfunction associated with chronic inflammatory changes including giant cells on histologic study. Chronic persistent myocarditis is characterized by a persistent histologic infiltrate, often with foci of myocyte necrosis but without ventricular dysfunction despite other cardiovascular symptoms such as chest pain or palpitation.

Echocardiographic findings in fulminant and acute myocarditis.

OBJECTIVES: We sought to use echocardiography to assess the presentation and potential for recovery of left ventricular (LV) function of patients with fulminant myocarditis compared with those with acute myocarditis. BACKGROUND: The clinical course of patients with myocarditis remains poorly defined. We have previously proposed a classification that provides prognostic information in myocarditis patients. Fulminant myocarditis causes a distinct onset of illness and severe hemodynamic compromise, whereas acute myocarditis has an indistinct presentation, less severe hemodynamic compromise and a greater likelihood of progression to dilated cardiomyopathy. METHODS: Echocardiography was performed at presentation and at six months to test the hypothesis that fulminant (n = 11) or acute (n = 43) myocarditis could be distinguished morphologically. RESULTS: Patients with both fulminant (fractional shortening 19 +/- 4%) and acute myocarditis (17 +/- 7%) had LV systolic dysfunction. Patients with fulminant myocarditis had near normal LV diastolic dimensions (5.3 +/- 0.9 cm) but increased septal thickness (1.2 +/- 0.2 cm) at presentation, while those with acute myocarditis had increased diastolic dimensions (6.1 +/- 0.8 cm, p < 0.01 vs. fulminant) but normal septal thickness (1.0 +/- 0.1 cm, p = 0.01 vs. fulminant). At six months, patients with fulminant myocarditis had dramatic improvement in fractional shortening (30 +/- 8%) compared with no improvement in patients with acute myocarditis (19 +/- 7%, p < 0.01 for interaction between time and type of myocarditis). CONCLUSIONS: Fulminant myocarditis is distinguishable from acute myocarditis by echocardiography. Patients with fulminant myocarditis exhibit a substantial improvement in ventricular function at six months compared with those with acute myocarditis. Echocardiography has value in classifying patients with myocarditis and may provide prognostic information.

Ischemic cardiomyopathy: endomyocardial biopsy and ventriculographic evaluation of patients with congestive heart failure, dilated cardiomyopathy and coronary artery disease.

OBJECTIVES: This study was designed to define clinical and pathophysiologic similarities and differences between patients with ischemic and idiopathic dilated cardiomyopathy. BACKGROUND: Significant coronary artery disease in patients with new onset congestive heart failure due to dilated cardiomyopathy has important prognostic and therapeutic implications. METHODS: Clinical, histologic, ventriculographic and hemodynamic features of patients with dilated cardiomyopathy who underwent coronary angiography were reviewed. RESULTS: Patients with ischemic cardiomyopathy (n = 21) compared with those with idiopathic cardiomyopathy (n = 40) had similar presenting symptoms, durations of illness, and coronary risk factor profiles, with the exception of a greater prevalence of cigarette smoking (71% vs. 39%, p = 0.028) and male gender (100% vs. 70%, p = 0.014). Endomyocardial biopsy specimens from patients with ischemic cardiomyopathy demonstrated a greater prevalence of replacement fibrosis (48% vs. 8%, p = 0.001) and a lesser degree of histologically assessed myocyte hypertrophy (mean grade 0.5 +/- 0.7 vs. 1.3 +/- 1.3, p = 0.015). Although ventriculographically determined regional dyskinesia was present in both groups, there was a higher prevalence of two or more adjacent segments in the ischemic cardiomyopathy group (50% vs. 10%, p = 0.03). This ischemic group had hemodynamic variables associated with a worse prognosis: higher pulmonary artery wedge pressure (23 +/- 10 vs. 15 +/- 9 mm Hg, p = 0.006) and lower cardiac index (2.0 +/- 0.5 vs. 2.3 +/- 0.5 liters/min per m2, p = 0.044). Also, in this group, patients had a mean of 2.6 +/- 0.7 diseased vessels; 15 (71%) of 21 patients had triple-vessel disease and 18 (86%) of 21 had at least one occluded or suboccluded artery. CONCLUSIONS: 1) Patients with ischemic and idiopathic cardiomyopathy may be clinically indistinguishable unless coronary angiography is performed. 2) A greater prevalence of replacement fibrosis and a lesser degree of myocardial hypertrophy in patients with ischemic cardiomyopathy may account for the greater extent of hemodynamic decompensation observed at presentation.

Postmortem and intraoperative balloon valvuloplasty of calcific aortic stenosis in elderly patients: mechanisms of successful dilation.

Percutaneous balloon dilation of the aortic valve has recently been proposed as a palliative procedure for treating nonsurgical candidates with calcific aortic stenosis. To assess the safety, efficacy and mechanisms of successful balloon valvuloplasty, postmortem (n = 33) and intraoperative (n = 6) balloon aortic valvuloplasty was performed in the hearts of 39 elderly patients with calcific aortic stenosis. The cause of aortic stenosis was degenerative nodular calcification in 28 cases, calcific bicuspid aortic stenosis in 8 cases and rheumatic heart disease in 3 cases. Balloon dilation was performed with 15 to 25 mm balloons in the postmortem specimens, and with 18 to 20 mm balloons in the operating room immediately before aortic valve replacement. After balloon dilation, valve orifice dimensions and leaflet mobility increased in all patients. The mechanisms of successful dilation included fracture of calcified nodules in 16 aortic valves, separation of fused commissures in 5 valves, both in 6 valves and grossly inapparent microfractures in 12 valves. Valve leaflet avulsion occurred in one heart after inflation with a clearly oversized balloon. Liberation of calcific debris, valve ring disruption or midleaflet tears did not occur in any heart. In conclusion, there are at least three mechanisms of successful aortic valvuloplasty, depending on the origin of valvular stenosis. Embolic phenomena and acute valvular regurgitation do not appear to be likely events associated with this procedure.

The causes of dilated cardiomyopathy: a clinicopathologic review of 673 consecutive patients.

OBJECTIVES: The purpose of this study was to document the various causes of dilated cardiomyopathy in a large group of adult patients with congestive heart failure. BACKGROUND: Previous reports of the causes of dilated cardiomyopathy have usually been case reports of a single specific etiology or review articles. The frequency of any single specific heart muscle disease is largely unknown. METHODS: We evaluated 673 patients referred for congestive heart failure due to dilated cardiomyopathy. The evaluation included medical history, physical examination, routine blood chemistry and hematologic measurements, electrocardiography and echocardiography. Thyroid function tests, antinuclear antibody tests and urinary vanillylmandelic acid and metanephrine levels were also obtained. Endomyocardial biopsy with right heart catheterization was performed in every patient. Coronary arteriography was performed in patients who had at least two standard cardiovascular risk factors or a history suggestive of myocardial ischemia. The cases were retrospectively reviewed, and a final cause for dilated cardiomyopathy was listed for each patient. RESULTS: The most common causes of dilated cardiomyopathy were idiopathic origin (47%), idiopathic myocarditis (12%) and coronary artery disease (11%). The other identifiable causes of dilated cardiomyopathy made up 31% of the total cases. CONCLUSIONS: Idiopathic dilated cardiomyopathy is a common cause of congestive heart failure. Specific heart muscle diseases occur with much less frequency.

Pathologic findings related to the lead system and repeated defibrillations in patients with the automatic implantable cardioverter-defibrillator.

The purpose of the present study was to examine at autopsy the effect of multiple defibrillations on the myocardium and the pathologic consequences of short- and long-term placement of the intravascular and interpericardial leads of the automatic implantable cardioverter-defibrillator. Twenty-five patients were examined at autopsy; 8 of them underwent lead implantation only and 17 received both leads and the automatic implantable cardioverter-defibrillator. Twelve patients (48%) died of ventricular tachycardia or ventricular fibrillation; seven (28%) died of other causes. Acute pericarditis occurred in all patients, resulting in a localized, progressive fibrosis around the apical patch lead without giving rise to pericardial restriction. Thrombus formation was associated with the superior vena cava spring electrode in four patients (17%) and the right ventricular rate-sensing electrode in one patient (4%). Asymptomatic pulmonary emboli occurred in two patients (8%). In one patient who underwent defibrillation 59 times, superior vena cava changes consisted of vein wall destruction, fibrosis and thrombus formation. Pathologic changes under the apical patch related to defibrillation were observed in seven patients; two of these had fewer than 5 defibrillations, one had 8 defibrillations and four had 21 to 74 defibrillations. These changes consisted of contraction band necrosis in four patients, vacuolar cytoplasmic clearing and loss of myocytes confined to the myocardium under the patch electrode in five patients who had multiple defibrillations. The observed pathologic changes were estimated to affect less than 2% of the total myocardial mass. Thus, the automatic implantable cardioverter-defibrillator lead system and multiple defibrillations result in localized myocardial injury confined to the tissue under the patch electrode.(ABSTRACT TRUNCATED AT 250 WORDS)

Left atrial leiomyosarcoma: manifestation as unexplained pulmonary vascular disease.

Primary, left-sided cardiac tumors are a rare cause of unexplained pulmonary hypertension. We describe herein two patients with leiomyosarcoma of the left atrium, who were initially seen with symptoms suggestive of primary pulmonary hypertension, venoocclusive disease, or multiple, small thromboemboli. Postmortem examination showed extension of the leiomyosarcoma into the pulmonary veins, which resulted in pulmonary venous hypertension. Although unusual, the occurrence of left-sided cardiac neoplasms should be included in the differential diagnosis of patients who are initially seen with unexplained pulmonary hypertension. An open lung biopsy should be considered and may indicate a venous origin for the hypertension.

Problems with proper completion and accuracy of the cause-of-death statement.

BACKGROUND: Mortality statistics are largely based on death certificates, so it is important that the data on the death certificate is accurate. At our institution, clinicians complete cause-of-death statements (CODs) prior to autopsy. Since May 1995, separate CODs have been included in autopsy face sheets. METHODS: Clinical and autopsy-based CODs filled out separately on 494 cases between June 1995 and February 1997 were compared for proper reporting and accuracy using the published guidelines and definitions of immediate, intermediate, and underlying causes of death put forth by the College of American Pathologists and the National Center for Health Statistics. RESULTS: Of the 494 death certificates, 204 (41%) contained improperly completed CODs. Of these, 49 (24%) contained major discrepancies between clinicians' and pathologists' CODs. Of the 494 death certificates, 290 (59%) had properly completed CODs. Of the 290 properly completed CODs, 141 (49%) contained disagreements: 73 (52%) on underlying CODs; 44 (31%) on immediate CODs; and 47 (33%) on other significant conditions (part II). CONCLUSIONS: The reliability and accuracy of CODs remain a significant problem. Despite its limitations, the autopsy remains the best standard against which to judge premortem diagnoses. The CODs of the death certificate may be improved if death certificates are completed in conjunction with the postmortem examination and amended when the autopsy findings show a discrepancy.

Collateral blood flow after coronary occlusion: influence of barbiturate anaesthesia and thoracotomy.

A study was undertaken to determine whether barbiturate anaesthesia, with or without thoracotomy, adversely affects collateral blood flow during acute coronary artery occlusion. Twelve dogs were instrumented with an electromagnetic flow probe and pneumatic occluder on the left circumflex artery; seven days later, in the conscious state, complete coronary artery occlusion was induced for 8 min. Heart rate, mean aortic pressure, and subendocardial and subepicardial blood flow in the ischaemic zone were measured by radioactive microspheres before and 5 min into coronary artery occlusion. Measurements were repeated after pentobarbital 30 mg.kg-1 (n = 7) and after pentobarbital plus thoracotomy (n = 12). Compared with the conscious state, pentobarbital and thoracotomy produced a decrease in endocardial blood flow in the ischaemic zone (0.21(0.04) to 0.15(0.03) ml.min-1.g-1) and a modest redistribution from endocardium to epicardium (ratio of endocardial to epicardial flow 0.55(0.06) to 0.49(0.07) ml.min-1.g-1), coincident with an increase in heart rate from 127 to 178 beats.min-1 but no change in mean arterial pressure. Directionally similar, but smaller, changes occurred during anaesthesia without thoracotomy. To determine the role of tachycardia five of the animals were studied in the conscious state during a 50% increase in heart rate induced by atrial pacing. A similar decrease occurred in coronary blood flows as with anaesthesia. The results indicate that barbiturate anaesthesia and thoracotomy produce a diminution in collateral flow to ischaemic myocardium, together with an accentuation of its transmural maldistribution, and suggest that anaesthetic induced tachycardia is primarily responsible for these flow alterations.

Lack of evidence for an association between neurofibromatosis type I and intracranial aneurysms: autopsy study and review of the literature.

BACKGROUND AND PURPOSE: Neurofibromatosis type I (NF1) is an autosomal dominant, hereditary, neurocutaneous syndrome purported to be associated with intracranial aneurysms. To study the relationship between NF1 and intracranial aneurysms, we have analyzed all intracranial autopsies of NF1 patients performed at our institution from 1889 to 1999 and analyzed all intracranial aneurysm cases at our institution from 1990 to 1999 in an attempt to identify patients with NF1. In addition, we have reviewed published clinical series of NF1 patients. METHODS: The autopsy database at our institution, which contains 50 000 cases from 1889 to 1999, was searched to identify NF1 patients, and the results of these autopsies were reviewed. The prevalence of intracranial aneurysms in these NF1 patients was compared with the prevalence of intracranial aneurysms in our hospital's autopsy population and with the published prevalence of intracranial aneurysms in the general population. To identify patients with intracranial aneurysms and NF1, our institution's intracranial aneurysm database was searched for patients with clinical manifestations of NF1. Published clinical series of NF1 patients were identified through searches of the literature. RESULTS: None of the 25 autopsy patients with NF1 had an intracranial aneurysm. None of the 925 patients treated for intracranial aneurysms were affected by NF1. A review of the literature identified 8 comprehensive clinical studies, all of which failed to document any relationship between NF1 and intracranial aneurysms. CONCLUSIONS: The autopsy prevalence of no NF1 patients with intracranial aneurysms out of 25 is not different from the prevalence of intracranial aneurysms in the general autopsy population. In addition, no patients treated for intracranial aneurysms at this institution had NF1. These findings are supported by the observation that an association between NF1 and intracranial aneurysms has never been identified in 8 large clinical studies of NF1 patients. We conclude that there is a lack of evidence for any association between NF1 and intracranial aneurysms.

Correlation between wall shear and intimal thickness at a coronary artery branch.

Pulsatile velocities were measured by laser Doppler anemometry at fourteen sites near the walls of a cast of a minimally diseased human left coronary artery bifurcation. The flow wave used in the experiments was physiologically realistic. The sites selected for hemodynamic measurement were at the outer walls of the left main artery and its anterior descending and circumflex branches, and along the flow divider. The intimal and medial thicknesses at corresponding sites in the original branch were also measured. Wall shear rates were derived from the velocity data. The correlations between time-average or maximum instantaneous wall shear rate and intimal thickness had negative slopes (P less than 0.005); that is, the intima was generally thicker at sites exposed to lower shears. These results are consistent with those obtained earlier using other human arterial bifurcations.

Correlation between intimal thickness and fluid shear in human arteries.

A realistic pulsatile flow was passed through a cast of the aortic bifurcation of a 63-year-old male with mild atherosclerosis, and a laser Doppler anemometer was used to measure fluid velocities in the cast at 15 selected sites near the lateral and medial walls. Intimal, medial and adventitial thickness were measured, and sudanophilia was scored, at corresponding sites in the vessel from which the cast had been made. A negative correlation was found between intimal thickness (IT) and wall shear rate (i.e., the velocity gradient at the blood-artery interface). The strongest negative correlation (P less than 0.005) was between IT and "pulse shear rate" (PSR), defined by analogy with pulse pressure. Sudanophilia also correlated negatively with PSR (P less than 0.01). These results suggest that large excursions of interfacial shear, at levels too low to cause damage, may inhibit intimal thickening.

Shear-dependent thickening of the human arterial intima.

Hemodynamic data were obtained by laser Doppler anemometry at 163 sites in 10 flow-through casts of minimally diseased human aortic bifurcations, and the intimal thickness at each of these sites in the original vessels was measured (mean = 208 micron, range = 10-967 micron). Analysis of the results suggests that the intimal thickness at sites exposed to high shear stresses increases quickly to a modest value, growing slowly thereafter, while the thickness at sites exposed to low shears rises more slowly but, after time, reaches higher values. Thus the intima of younger vessels is thicker where shear is high, and that of older vessels is thicker where shear is low. This behavior is rationalized by a parsimonious model in which a substance from the lumen enters the wall and is catabolized or otherwise removed. The intimal permeability and removal rate both increase as the shear stress is raised. Intimal thickness is related to the amount of the substance in the wall. This model fits the experimental data with an overall standard error of estimate of 105 micron. Although the model is an extreme simplification of the actual thickening process, it shows that the observed results can be the consequence of competing shear-dependent processes.