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Proteins and peptides present within clinical samples represent a valuable library of information regarding the ongoing processes within cells and tissues in health and disease. We have developed and validated novel technology applications that can be used to characterize the patterns of global protein expression in tissue and biofluids in either gel-based systems or by automated multidimensional nanocapillary liquid chromatography. Mass spectrophotometry platforms using MALDI MS and MS/MS or LTQ ion trap MS were capable of delivering sensitive and accurate identifications of hundreds of proteins contained in individual samples including individual forms of processing intermediates such as phospho peptides. The Systems Biology approach of integrating protein expression data with clinical data such as histopathology, clinical functional measurements, medical imaging scores, patient demographics, and clinical outcome provides a powerful tool for linking biomarker expression with biological processes that can be segmented and linked to disease presentation. Keywords: lung • proteomics • biomarkers • tissue • pathology • disease microenvironment • multidimensional liquid-phase separation • mass spectrometry • 2-D gel • Systems Biology

The lung proteome is a dynamic collection of specialized proteins related to pulmonary function. Many cells of different derivations, activation states, and levels of maturity contribute to the changing environment, which produces the lung proteome. Inflammatory cells reacting to environmental challenge, for example from allergens, produce and secrete proteins which have profound effects on both resident and nonresident cells located in airways, alveoli, and the vascular tree which provides blood cells to the parenchyma alveolar bed for gas exchange. In an experimental model of allergic airway inflammation, we have compared control and allergen challenged lung compartments to determine global protein expression patterns using 2D-gel electrophoresis and subsequent spot identification by MS/MS mass spectrometry. We have then specifically isolated the epithelial mucosal layer, which lines conducting airways, from control and allergen challenged lungs, using laser capture technology and performed proteome identification on these selected cell samples. A central component of our investigations has been to contextually relate the histological features of the dynamic pulmonary environment to the changes in protein expression observed following challenge. Our results provide new information of the complexity of the submucosa/epithelium interface and the mechanisms behind the transformation of airway epithelium from normal steady states to functionally activated states. Keywords: lung • mucosa • epithelium • laser capture microscopy • proteome • mass spectrometry • annotation identity • allergen

An analysis is presented for stress amplification in a ring caused by the dynamic instability of symmetric in-and-out breathing oscillations, which results in energy transfer to flexural modes. Stress amplification is shown to depend on a ring stability parameter p that is proportional to the unperturbed hoop strain and inversely proportional to the thickness-to-radius ratio. The analysis is a generalization of earlier work by Goodier and McIvor. They showed that, with p tacity assumed small, stress is amplified by approximately the factor 6, independent of the wave number of the flexural mode into which the breathing energy is transferred. The present analysis shows that for large p (increased instability), higher-order nonlinear terms must be included in the differential equations in order to give bounded solutions. With these terms included, stress amplification departs from 6 as p is increased, the peak compressive stress becoming larger and the peak tensile stress becoming smaller. With damping also included, the amplification approaches unity (no amplification) as p approaches zero, and passes through a maximum as p is increased. An experimental example of flexural fracture caused by such amplification is given.

In 14 patients aged 5-329 (mean 131) months a CarboMedics® valve was implanted because of congenital heart disease. The preoperative NYHA function class was III-IV in ten cases. Seven aortic and seven atrioventricular valves were replaced without early mortality. All patients were followed up, with mean observation time 27 months (total 384 months). One of the 14 patients died of heart failure 10 months postoperatively. Thrombosis occurred in four valves, three in tricuspid and one in mitral position. In all patients who received only warfarin, anticoagulation was demonstrably inadequate. Consequently we now recommend antiplatelet medication in addition to warfarin for children with atrioventricular mechanical valve replacement. In our experience the complication rate with CarboMedics prosthesis is acceptable, provided that anticoagulant therapy is adequate.

A large deflection, elastic-plastic numerical theory (SABOR/DRASTIC 6) is used to investigate dynamic buckling motion beyond strain-rate reversal in cylindrical shells under radial impulse. It is found that the mode number of the most amplified harmonic is smaller than predicted by the simple analytic tangent modulus theory because of the increased stiffness after strain-rate reversal, neglected in the simple theory. Nevertheless, the simple theory gives reasonable estimates for threshold buckling impulses. In buckling well beyond threshold (about three times the threshold impulse in a thin shell, radius-to-thickness ratio of 120) plastic deformation becomes more localized at the buckle crests, but compressive strain continues to dominate so that a simple plastic hinge postbuckling analysis would be inadequate. Accuracy of the numerical theory is confirmed by comparison with experiment (asymmetric loading below buckling threshold and symmetric loading above) and with the tangent modulus theory prior to strain-rate reversal.

The relationship between heart rate and cancer mortality was examined in 3 Chicago epidemiologic studies: 1233 white men originally age 40-59 followed 18 years from the Chicago Peoples Gas Company study; 1899 white men originally age 40-55 followed 17 years from the Chicago Western Electric Company study; 5784 white men originally age 45-64 followed 5 years from the Chicago Heart Association Detection Project in Industry. There was a significant association between heart rate and cancer mortality in both univariate and multivariate analyses in men from the Gas Company study and in men from the Chicago Heart Association study, but there was no association between heart rate and cancer mortality in men from the Western Electric study. The relationship persisted in the Gas Company study but not in the Chicago Heart Association study after eliminating deaths within the first 2 years of follow-up. With cancer deaths broken down by the site, mortality from lung and colon cancer in the Gas Company study and mortality from lung cancer in the Chicago Heart Association study were significantly associated with baseline heart rate on univariate analysis and on bivariate analysis controlling for age. Only colon cancer in the Gas Company, however, remained associated with heart rate when other variables were controlled. Thus, in 2 of the 3 studies examined, heart rate appeared to be an independent risk factor for cancer mortality in men.

The associations between heart rate and death from the cardiovascular diseases (CVD), coronary heart disease (CHD) and sudden death from CHD, along with death from all causes and non-cardiovascular causes, are examined for three groups of middle-aged white males: 1233 men aged 40-59 years followed for 15 years from the Chicago Peoples Gas Company study; 1899 men aged 40-55 years followed for 17 years from the Chicago Western Electric Company study; and 5784 men aged 45-64 years followed an average of five years from the Chicago Heart Association Detection Project in Industry. In univariate analyses, mortality from both cardiovascular and non-cardiovascular causes generally increases with increasing heart rate. In bivariate analyses, using the Cox regression model to control for age, heart rate is significantly related to mortality from all causes in each study, with the associations again due to both cardiovascular and non-cardiovascular causes. In multivariate Cox regression, controlling for age, blood pressure, serum cholesterol, cigarettes smoked per day and relative weight, heart rate is a significant risk factor for sudden CHD death and non-CVD death in two of the three studies, with the association with sudden death being U-shaped in one of the studies. Although heart rate may be an independent risk factor for sudden CHD death, the associations with other CVD death and non-sudden CHD death, in general, appear to be secondary to associations between heart rate and other cardiovascular risk factors.

Because of the widespread use of hypertonic solutions for intravenous administration in modern clinical practice we became interested in the question whether renal damage resulted from the employment of such solutions and, if so, what the nature and extent of this damage might be. In recent years the intravenous administration of hypertonic solutions of dextrose has become increasingly popular. Lately 50 per cent sucrose has gained wide vogue in the treatment of cerebral edema, glaucoma and retention of fluid resulting from a variety of causes.1 This material has been rapidly replacing the older dextrose solution for this type of therapy.Helmholz2 reported on a series of experiments on rabbits given single and multiple injections of 50 per cent solution of sucrose at various intervals and pathologic studies of the kidneys made at intervals of one to seven days after the final injection of the material. Included in his

INTRODUCTION Many clinicopathologic studies have been performed which report the presence at autopsy of myocardial infarctions unsuspected during life.2-5 From these studies the concept has evolved of painless, silent, occult, or asymptomatic myocardial infarction.In contrast to the wealth of necropsy material on painless myocardial infarction, there is a paucity of clinical reports describing totally asymptomatic myocardial infarction diagnosed during life.6 This report presents three such cases, and offers an estimate of the incidence rate of totally asymptomatic myocardial infarction in our urban, white, middle-aged male population. METHODS A comprehensive study was made of the case records of the medical department of a Chicago utility corporation for the four-year period 1954-1957.7 During this period 756 male employees (737 white, 19 nonwhite) in the age group 50-59 as of Jan. 1, 1954, underwent a voluntary yearly medical review consisting of a complete history and physical examination, 14×17 roentgenogram

Buckling of thin cylindrical shells from axial impact is studied under the assumption that initial imperfections can be approximated by “white noise.” Linear small-deflection theory is used to calculate the resulting growth of the normal modes, and a statistical analysis gives the expected values for the “preferred” axial and circumferential wave-lengths. Very high-speed photographs (240,000 frames/sec) of shells buckling under axial impact show excellent agreement with the theory and demonstrate that large-deflection buckling follows the pattern established by the early linear motion.

Stiffening by means of an elastic core is demonstrated to increase significantly the resistance of a cylindrical shell to buckling from an external impulsive pressure. Both theory and experiments show that the elastic core constrains the shell to absorb more energy by membrane plastic flow. Inclusion in the theory of a continuously changing tangent modulus of the shell material leads to a critical core modulus which depends on the hoop strain and explains the increased wave numbers observed in the experiments with stiff cores.

Experiments are presented which demonstrate the statistical nature of the buckling of thin strips under very high axial compression. Probability distributions of wavelengths determined theoretically from assumed “white-noise” perturbations in initial shape are compared favorably with the experimental distributions. In other experiments, a new optical-lever method of recording lateral motions is used to observe bending waves and buckling in an impacted strip. From these and experiments on large-strain buckling of rubber strips it is concluded that effects of axial-wave propagation do not significantly influence the wavelengths at which the buckles form.

The formation of small, flexural wrinkles in the walls of a sandwich shell under uniform radial impulse is examined. A buckling criterion based on the magnifications of initial wall imperfections is used to evaluate threshold impulses. Using a given weight of material, this criterion is used to determine the optimum ratios of the inner and outer wall thicknesses for various core thicknesses. It is shown that the optimum shell for a given weight of material and outer diameter is a single-wall shell. The loss in efficiency obtained by using typical sandwich shells is about 30 percent. These results are supported by experimental evidence.

This paper shows that when very thin cylindrical shells are subjected to an external impulsive pressure, the interaction between the radial, purely extensional mode and the flexural modes is sufficient to precipitate permanent wrinkles. The theory predicts that these wrinkles occur at a wavelength which depends on the magnitude of the pressure pulse as well as on the cylinder parameters; experiments on cylindrical shells and thin strips confirm this prediction. Framing camera photographs showing the formation of wrinkles of this type are also presented.