Conformational nature of the Borrelia burgdorferi decorin binding protein A epitopes that elicit protective antibodies.

Decorin binding protein A (DbpA) has been shown by several laboratories to be a protective antigen for the prevention of experimental Borrelia burgdorferi infection in the mouse model of Lyme borreliosis. However, different recombinant forms of the antigen having either lipidated amino termini, approximating the natural secretion and posttranslational processing, or nonprocessed cytosolic forms have elicited disparate levels of protection in the mouse model. We have now used the unique functional properties of this molecule to investigate the structural requirements needed to elicit a protective immune response. Genetic and physicochemical alterations to DbpA showed that the ability to bind to the ligand decorin is indicative of a potent immunogen but is not conclusive. By mutating the two carboxy-terminal nonconserved cysteines of DbpA from B. burgdorferi strain N40, we have determined that the stability afforded by the putative disulfide bond is essential for the generation of protective antibodies. This mutated protein was more sensitive to thermal denaturation and proteolysis, suggesting that it is in a less ordered state. Immunization with DbpA that was thermally denatured and functionally inactivated stimulated an immune response that was not protective and lacked bactericidal antibodies. Antibodies against conformationally altered forms of DbpA also failed to kill heterologous B. garinii and B. afzelii strains. Additionally, nonsecreted recombinant forms of DbpA(N40) were found to be inferior to secreted lipoprotein DbpA(N40) in terms of functional activity and antigenic potency. These data suggest that elicitation of a bactericidal and protective immune response to DbpA requires a properly folded conformation for the production of functional antibodies.

Neoplasms involving the heart, their simulators, and adverse consequences of their therapy.

Primary cardiac tumors involving the heart may be either benign or malignant. Most of the benign tumors are myxomas, which are most commonly located in the left atrium. Primary malignant neoplasms usually involve the myocardium and the interior of the cardiac cavities, whereas neoplasms metastatic to the heart most commonly involve pericardium, and pericardial effusion and constriction are the most common consequences. Computed tomography and magnetic resonance imaging are becoming the most useful instruments of precision for the diagnosis of cardiac tumors. Pericardial cysts, teratomas, lipomatous hypertrophy of the atrial septum, papillary fibroelastomas, thrombi, and sarcoid are frequently mistaken for cardiac neoplasms. There are a number of cardiac consequences of malignancy, including radiation heart disease, cardiac hemorrhages, cardiac infection, cardiac adiposity or the corticosteroid-treated heart, cardiac hemosiderosis, and toxicity due to anthracycline chemotherapy.

Comparison of modes of death and cardiac necropsy findings in fatal acute myocardial infarction in men and women >75 years of age.

In comparing the cause of death and other cardiac morphologic findings among 60 women and 40 men aged >75 years who died of acute myocardial infarction, we found that women died more often from mechanical complications than left ventricular pump failure. Women had cardiomegaly, nonanterior location of acute myocardial infarction, healed myocardial infarcts, and dilated left ventricular cavity less often than men.

Morphology and significance of the left ventricular collagen network in young patients with hypertrophic cardiomyopathy and sudden cardiac death.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is a primary cardiac disease with a diverse clinical spectrum, in which many of the abnormal structural and pathophysiologic features are consequences of inappropriate left ventricular hypertrophy. METHODS: We analyzed the amount, distribution and structure of the cardiac collagen network in transmural sections of the ventricular septum (thickness 17 to 40 mm, mean 25 mm) in 16 previously asymptomatic children and young adults with HCM (11 to 31 years of age, mean 20 years) who died suddenly. The morphologic appearance and volume fractions of interstitial (matrix) and perivascular (adventitial) collagen were analyzed with polarization microscopy and computerized videodensitometry in picrosirius red-stained sections. Findings were compared with 16 structurally normal hearts, 5 with systemic hypertension and 6 infants who died of HCM. RESULTS: Adults and young children with HCM had an eightfold greater amount of matrix collagen compared with normal controls (14.1 +/- 8.8% vs. 1.8 +/- 1% of the tissue section; p < 0.0001), and a threefold increase compared with patients with systemic hypertension (4.5 +/- 1.3%; p < 0.001) and infants with HCM (4.0 +/- 2.4%; p < 0.001). Compared with normal controls and hypertensives, adults and young children (and infants) with HCM showed increased numbers and thickness of each collagen fiber component of the matrix (perimysial coils, pericellular weaves and struts), which were often arranged in disorganized patterns. In HCM patients, the amount of collagen was not a consequence of other clinical, demographic and morphologic disease variables. CONCLUSIONS: Left ventricular collagen matrix in young, previously asymptomatic patients with HCM who died suddenly is morphologically abnormal and substantially increased in size. The enlarged matrix collagen compartment is present in HCM at an early age, further expands during growth, is partially responsible for increased ventricular septal thickness and likely represents a primary morphologic abnormality in this disease. These findings support the view that the complex HCM disease process is not confined to sarcomere protein abnormalities, but also involves connective tissue elements.