Use of a Pseudomonas aeruginosa vaccine in patients with acute leukemia and cystic fibrosis

A heptavalent lipopolysaccharide Pseudomonas vaccine was evaluated in 22 patients with acute leukemia and 12 patients with cystic fibrosis during an 18 month interval at the Clinical Center of the National Institutes of Health. Of the 34 patients, 32 had an excellent serum hemagglutinating (HA) antibody response to immunization. In comparison to the patients with cystic fibrosis, the patients with leukemia had a smaller HA antibody response, which lasted a shorter period of time, and also experienced greater toxicity from the vaccine. The mixing of adrenal corticosteroids with vaccine greatly decreased side reactions among the patients with leukemia without significantly inhibiting antibody production. Previous antineoplastic chemotherapy had little influence on antibody response in patients with leukemia, with the exception of methotrexate. Vaccinated patients with leukemia had 1 Pseudomonas infection of 14 bacterial or fungal infections, whereas 2 Pseudomonas infections of 5 bacterial or fungal infections occurred in a control group of 20 patients with acute leukemia. Of the 12 patients with cystic fibrosis, 4 had a Pseudomonas infection after vaccination.     

Pseudomonas pneumonia. A retrospective study of 36 cases

The clinical course in 36 cases of Pseudomonas pneumonia collected over a 15 year period (1956 to 1970) at the Clinical Center of the National Institutes of Health were reviewed to identify factors which increased the risk of infection and affected prognosis. In all cases, the patients had a serious underlying disease which predisposed to infection, and the majority had neoplastic diseases, particularly acute leukemia; cardiac or pulmonary diseases were less frequent. Pseudomonas related mortality was 81 per cent and was not influenced by type of antibiotic therapy or by the year of occurrence. Many patients were neutropenic, usually subsequent to cytotoxic chemotherapy, and frequently had been treated with steroids or antibiotics just prior to the development of pneumonia. Adequate numbers of circulating granulocytes were essential to survival. No patient with a positive blood culture survived. Possibilities for new means of prevention and treatment of Pseudomonas pneumonia are discussed.     

Alternate-day corticosteroid therapy

We treated five patients with persistent Staphylococcus aureus bacteremia and endocarditis. Surgical intervention or a “secondline” antistaphylococcal agent was required for bacteriologic cure in each. Special bacteriologic evaluation failed to demonstrate methicillin resistance or antibiotic “tolerance” among the strains of Staphylococcus tested. Cephalosporin agents were noted to be more susceptible to inoculum effect than either methicillin or nafcillin. All patients survived; the explanation for their atypical course is obscure. We present an approach to patients with persistent Staph. aureus bacteremia and endocarditis.     

Glucocorticoid binding proteins in myeloblasts of acute myelogenous leukemia

The myeloblasts of 16 patients with untreated acute myelogenous leukemia were examined for specific glucocorticoid binding proteins. In only 3 of the 16 patients were such high affinity receptors found. The presence of glucocorticoid binding protein activity was positively correlated with inhibition of macromolecular synthesis of myeloblasts in vitro whereas absence of binding protein activity was associated with lack of glucocorticoid inhibition of the cells. Since glucocorticoids appear efficacious in only a small fraction of cases of acute myelogenous leukemia, determination of glucocorticoid binding protein activity may provide assistance in planning chemotherapeutic regimens.     

Hypercalcemia with suppressed parathyroid hormone in Burkitt's lymphoma.

Two patients with Burkitt's lymphoma presented with severe hypercalcemia, a previously unreported complication of this tumor. Roentgenograms and radionuclide scans showed multiple osteolytic lesions in both patients. Plasma parathyroid hormone (PTH) was undetectable during the hypercalcemia phase. Chemotherapy was followed by rapid tumor lysis, hyperphosphatemia, phosphaturia and hypocalcemia. The hypocalcemic phase persisted for two weeks despite rapid normalization of serum phosphorus and renal function. Measurement of urinary cyclic AMP, an index of PTH action, indicated that parathyroid function had been suppressed by the hypercalcemia and remained suppressed for almost one week despite marked hypocalcemia.     

Immunohistochemical characterization of intrathyroid lymphocytes in Graves' disease: Interstitial and intraepithelial populations

The phenotypic cell surface markers of the lymphocytes present in thyroid tissue from four patients with Graves' disease were quantitatively analyzed using the avidin-biotin immunoperoxidase technique. As control specimens, normal perinodular tissues from three patients who had benign thyroid nodules resected were also studied. In contrast to normal thyroid tissue, which contained very few T cells and no B cells, thyroid tissue of all four patients with Graves' disease contained a lymphocytic infiltrate, and this could be divided into two populations of lymphocytes. The first population was located in the follicular epithelium and expressed a cytotoxic-suppressor T cell marker (Leu2a). On the average, these cells were 4.2 times as numerous in Graves' tissues as in normal tissues (p < 0.05). Most of these cells did not express Leu1, a pan-T cell marker. The second population was found in the interstitial tissues, often within lymphoid aggregates, and 70 to 83 percent of the cells expressed Leu1. The majority of these cells expressed a helperinducer T cell marker, Leu3a; $\text{Leu3a}\text{Leu2a}$ ratios within aggregates ranged from 1.9 to 2.1. The number of B cells present was small, ranging from 5.8 to 12.1 percent of the interstitial lymphocytes. These findings are consistent with the involvement of both helperinducer and suppressor-cytotoxic T cells in a localized autoimmune reaction directed, at least in part, against the thyroid follicular epithelial cells.     

Echocardiographic identification of cardiac abnormality in scleroderma and related disorders.

Although pathologic examination may readily disclose cardiac abnormality in patients with scleroderma, clinical identification of primary heart involvement can be difficult. In order to assess left ventricular systolic function, chamber size and wall thickness, and to determine whether pericardial effusion is present, echocardiograms were obtained in 11 patients with progressive systemic sclerosis (PSS) and in 13 patients with forms of scleroderma in which visceral involvement has been considered rare or absent: three with CREST syndrome, three with morphea, three with diffuse fasciitis with eosinophilia, and four with mixed connective tissue disease. Increased left ventricular wall thickness was noted in 13 of 23 (57 per cent) patients who could be evaluated, including six (46 per cent) from subgroups other than PSS. Left atrial dimension was increased in 12 patients (52 per cent) whereas the left ventricular end-diastolic dimension was increased in only three (13 per cent). Mitral valve closure velocity, an index of left ventricular compliance, was diminished in 10 (42 per cent) patients. However, left ventricular systolic contractile performance was normal in all. Pericardial effusion was detected in five patients (21 per cent), including one patient each with morphea, mixed connective tissue disease and diffuse fasciitis. Cardiac abnormalities were evident even in patients with PSS and no renal or severe pulmonary involvement. Thus, primary cardiac involvement, characterized by left ventricular wall thickening, decreased left ventricular compliance, left atrial enlargement and pericardial effusion, may be common in patients with scleroderma. These abnormalities occur in patients with PSS as well as in those with “nonsystemic” forms of scleroderma and are readily detected by echocardiography.     

Immune complex glomerulonephritis in sicca syndrome.

In three patients with the sicca syndrome (Sjögren's syndrome), who were followed for one to seven years, glomerulonephritis developed. None of these patients fulfilled the diagnostic criteria for systemic lupus erythematosus. All of these patients had circulating immune complexes as detected by the Clq binding assay.Glomerular histology by light and electron microscopy revealed changes compatible with membranoproliferative glomerulonephritis in two of the patients and membranous glomerulonephritis in the third.All patients showed rapid improvement in renal function following moderate doses of corticosteroids. In addition, the treatment decreased the level of circulating immune complexes in two patients who were followed for a sufficient period of time.     

The cardiovascular manifestations of the hypereosinophilic syndrome. Prospective study of 26 patients, with review of the literature.

The major cause of morbidity and mortality in patients with the hypereosinophilic syndrome is cardiac dysfunction. A review of 65 cases from the literature (historic series) revealed the following cardiovascular manifestations to be most common: dyspnea (60 per cent), signs of congestive heart failure (75 per cent), murmur of mitral regurgitation (49 per cent), cardiomegaly (37 per cent), T wave inversions on electrocardiogram (37 per cent) and pathologic findings of endocardial fibrosis, myocardial inflammation and mural thrombus formation (57 per cent). We have prospectively followed 26 patients with the hypereosinophilic syndrome for up to nine years (average follow-up prospectively was 3.3 years, retrospectively 5.7 years). Common cardiac findings in our 26 patients were dyspnea (42 per cent), chest pain (27 per cent), signs of congestive heart failure (38 per cent), murmur of mitral regurgitation (42 per cent), cardiomegaly (35 per cent) and T wave inversions (35 per cent). Thus, these patients demonstrated cardiovascular manifestations similar to those in the historic series, although the literature review showed a higher incidence of overt congestive heart failure.Of 22 patients having echocardiograms, 55 per cent demonstrated some clinical, roentgenographic or electrocardiographic evidence of cardiac involvement, but 82 per cent had echocardiographic abnormalities. This suggests that the echocardiogram is a sensitive and perhaps early indicator of cardiac involvement in this disease. Common echocardiographic findings included increased left ventricular wall thickness (68 per cent), left ventricular mass (73 per cent) and left atrial size (37 per cent). Prospective echocardiographic follow-up of 18 patients (for up to four and a half years) revealed that seven of eight untreated or inadequately treated patients had increases in left ventricular wall thickness, whereas all 10 adequately treated patients had decreases (eight of 10) or no change (two of 10) in left ventricular wall thickness. This suggests that adequate antihypereosinophilic therapy (with prednisone and/or hydroxyurea) may stabilize and, in some cases, reverse the cardiac manifestations of the hypereosinophilic syndrome.In previous studies, congestive heart failure due to eosinophilic cardiomyopathy has been reported to be very resistant to therapy. In our patients with congestive heart failure, treatment has been almost invariably effective when digitalis and diuretics were combined with adequate antihypereosinophilic therapy.     

The heart in systemic lupus erythematosus and the changes induced in it by corticosteroid therapy: A study of 36 necropsy patients

The natural history of the cardiovascular manifestations of systemic lupus erythematosus (SLE) have been altered by corticosteroids which exert their own cardiovascular effects. This study describes clinical and necropsy observations in 36 corticosteroid-treated patients with SLE and compares them to necropsy observations in patients with SLE reported before the use of corticosteroid therapy. The 36 patients averaged 32 years of age, and 33 were women. Systemic hypertension was present in 25 (69 per cent) and left ventricular hypertrophy in 23 (64 per cent) patients. Hypertension was twice as common in the 19 patients who received this drug for more than 12 months (average 38 months) than in the 17 patients who received this drug for less than 12 months (average 6 months), and was almost five times more common among our patients than in patients with SLE in the presteroid era. Congestive cardiac failure occurred in 15 patients (43 per cent), eight times more frequent than that reported in noncorticosteroid-treated patients with SLE. Subepicardial and myocardial fat was increased in all 36 patients.Lupus carditis was similar in frequency but differed morphologically in our patients compared to those not treated with corticosteroids. Libman-Sacks-type endocardial lesions, present in 18 (50 per cent) of our patients, were smaller, fewer in number, univalvular rather than multivalvular, and mainly left-sided. Most verrucae were either partly or completely healed, and some were calcified. Pericarditis, present in 19 (53 per cent) patients, was predominantly of the fibrous type. Myocarditis was present in three patients, each of whom also had endocarditis and pericarditis. The lumen of at least one of the three major coronary arteries was narrowed more than 50 per cent by atherosclerotic plaques in 42 per cent of the 18 patients who received corticosteroids for more than 1 year, but in none of the 17 patients who received corticosteroids for less than 1 year. Four of the eight patients with narrowed coronary arteries had myocardial infarcts.Although vital to the management of SLE, corticosteroids have an over-all deleterious effect on the heart. Systemic hypertension and left ventricular hypertrophy appear or, when present, worsen; congestive cardiac failure increases; epicardial and myocardial fat increases, and coronary atherosclerosis appears to be accelerated.     

Diffuse histiocytic lymphoma in a patient treated with cyclophosphamide for Wegener's granulomatosis

Diffuse histiocytic lymphoma developed in a 48-year-old man with Wegener's granulomatosis after nine years of therapy with cyclophosphamide. He died despite aggressive surgical and medical therapy for the lymphoma. This may be the first report of diffuse histiocytic lymphoma following treatment of Wegener's granulomatosis with cyclophosphamide. Recommendations for the approach towards extended therapy of smoldering Wegener's granulomatosis are discussed.     

Reduction of renal function by newer nonsteroidal anti-inflammatory drugs

Because aspirin and indomethacin, two structurally dissimilar anti-inflammatory agents which reduce prostaglandin synthesis, both alter renal function, we studied the effect on renal function of three new nonsteroidal anti-inflammatory drugs which also reduce prostaglandin synthesis. We have shown that ibuprofen, naproxen, and fenoprofen are able to reduce renal function in patients with systemic lupus erythematosus and that such changes are associated with reduced excretion of urinary prostaglandin E (PGE)-like compounds. The changes may attenuate despite continued drug administration. These findings emphasize that renal function must be assessed with caution in patients taking these and perhaps other drugs which inhibit prostaglandin synthesis.     

Divalent cation metabolism: Familial hypocalciuric hypercalcemia versus typical primary hyperparathyroidism

Twenty-three members of three families with a syndrome of hypercalcemia without hypercalciuria (familial hypocalciuric hypercalcemia) were compared to a group of 64 subjects with hypercalcemia due to typical primary hyperparathyroidism. Patients with familial hypocalciuric hypercalcemia had higher creatinine clearance values than those with primary hyperparathyrodism (115 ± 27 versus 87 ± 27 ml/min/1.73 m² (mean ± 1 standard deviation [SD] p < 0.0001). Although renal function was well preserved, the group with familial hypocalciuric hypercalcemia showed a mean serum magnesium concentration of 2.05 ± 0.17 meq/liter, significantly higher than that in normal subjects (1.74 ± 0.12 meq/liter, p < 0.0001) or than in the group with primary hyperparathyroidism (1.71 ± 0.21 meq/liter, p < 0.0001). In familial hypocalciuric hypercalcemia the degree of hypermagnesemia was directly proportional to the degree of hypercalcemia (R = +0.54, p < 0.01), contrasting with an inverse relation of serum calcium and magnesium concentrations in primary hyperparathyroidism (R = ?0.32, p < 0.02). Urinary excretion of both calcium (calcium:creatinine clearance ratio 0.006 ± 0.004 versus 0.024 ± 0.01, p < 0.0001) and magnesium (magnesium:creatinine clearance ratio 0.031 ± 0.0008 versus 0.047 ± 0.03, p < 0.003) was significantly lower in familial hypocalciuric hypercalcemia than in primary hyperparathyroidism. There was no evidence that abnormal protein binding of cations in serum from those with familial hypocalciuric hypercalcemia accounted for the hypercalcemia and hypermagnesemia or for the disproportionately low urinary excretion of divalent cations by rendering them resistant to glomerular filtration. After fractionation by electrophoresis on cellulose acetate, the major plasma protein components were quantitatively similar in both groups. Furthermore, ionized and ultrafiltrable calcium and ultrafiltrable magnesium showed consistent relations to total calcium and total magnesium concentrations in plasma from both groups. Therefore, in familial hypocalciuric hypercalcemia there are increased serum concentrations of the physiologically active forms of both calcium and magnesium, and the renal handling of the filtered load of these divalent cations differs in familial hypocalciuric hypercalcemia and primary hyperparathyroidism.     

Parathyroid carcinoma in familial hyperparathyroidism

We present the first reported occurrence of parathyroid carcinoma in familial parathyroid hyperplasia or multiple endocrine adenomatosis, type I. The patient's hypercalcemia persisted through 8 years even though abnormal parathyroid tissue was removed from three separate sites in the neck. The original clinical presentation and review of tissue removed initially from the left thyroid lobe suggested the possibility of parathyroid carcinoma; tissue from the second and third operations (on the right) was histologically benign, showing chief cell hyperplasia. A fourth operation then revealed implants of parathyroid carcinoma unilaterally in the left side of the neck. The patient's brother and sister also had parathyroid hyperplasia, and his mother died of a pancreatic tumor of undocumented cell type. The patient himself had no evidence of pancreatic or pituitary tumor.     

Cardiac sarcoma causing "ASH" and simulating coronary heart disease.

A patient is described in whom primary cardiac sarcoma preferentially infiltrated the ventricular septum while essentially sparing the left ventricular free wall, resulting in striking echocardiographic and morphologic asymmetry between septum and free wall (ASH). No reports have appeared previously of a patient with an intramural cardiac neoplasm demonstrated by echocardiogram. Additionally, the patient clinically had features typical of coronary heart disease, yet at necropsy the extramural coronary arteries showed insignificant (< 75 per cent) cross-sectional area luminal narrowing by atherosclerotic plaques.     

The hypertensive diseases. Evidence that systemic hypertension is a greater risk factor to the development of other cardiovascular diseases than previously suspected.

This report summarizes the clinical frequencies of systemic hypertension and necropsy evidence of cardiomegaly in various cardiovascular conditions (Table I), termed "the hypertensive diseases" because of their frequent association with systemic hypertension. Although long recognized as a major risk factor, systemic hypertension appears to be an even greater risk factor to the development of various cardiovascular conditions than previously appreciated. Hypertension by itself appears to be the sole underlying factor in most cases of nontraumatic cerebral arterial or aortic (dissection = partial rupture) rupture. In association with hyperlipidemia, hypertension clearly accelerates atherosclerosis and its devastating consequences.     

Recent studies on the chemistry of human, bovine and porcine parathyroid hormones

The amino acid sequence of the NH₂-terminal 34 residues of human parathyroid hormone (PTH) has been determined and duplicated synthetically to produce a peptide that is biologically active. In the amino acid sequences of the bovine and porcine hormones, the glutamic acid function at position 22 has been revised to glutamine. Among these initial 34 residues, human PTH differs from bovine PTH by 5 residues and from porcine PTH by 4 residues. Native human PTH and the synthetic human PTH (1–34) peptide are not rigid structures, and significant changes in conformation were observed during pH titration. In addition, at physiologic pH, native human PTH appeared to differ in structure from human PTH (1–34) in the region of the tryptophan residue (residue 23). The fluorescence spectrum of human PTH revealed a maximum at 344 nm, but the spectrum of human PTH (1–34) had a peak at 343 nm; the spectrum of human PTH (1–34) was normalized to 346 nm in 6 M guanidine hydrochloride, but there was no shift with the intact hormone. Fluorescence titration of human PTH in the alkaline region revealed no loss of tryptophanyl fluorescence in aqueous solution or in 6 M guanidine hydrochloride. The synthetic human PTH (1–34) peptide, however, showed an approximately 25 per cent loss of indole fluorescence during alkaline titration which could be normalized with denaturing reagents. These studies suggest that synthetic fragments of the native hormone may not have the same tertiary conformation as the same sequence in the intact hormone. These findings may be of major significance with regard to the biologic activity and immunologic cross reactivity of synthetic fragments and the native hormone.     

Dilatation of the mitral anulus. A rare cause of mitral regurgitation.

To confirm or deny the thesis that mitral anular dilatation is a cause of mitral regurgitation, this anulus was measured in 102 patients, 24 of whom had normal hearts and 78 of whom had dilated left ventricles, some associated with mitral regurgitation, others not. The circumference of the mitral anulus in the 24 patients with normal hearts averaged 9 cm (range 7 to 11 cm); in 24 patients with idiopathic cardiomyopathy of the ventricular dilated type, both with (12 patients) and without (12 patients) mild to moderate regurgitation, 11 cm (range 10 to 14 cm); and in 31 patients with severe mitral regurgitation, 12 cm (range 8 to 18 cm). Among the latter 31 patients with severe mitral regurgitation, the anulus was only mildly dilated in the 15 with rheumatic disease (average 11 cm) and in the six with ruptured chordae tendinease on previously normal valves (average 10 cm); in contrast, in the 10 patients with floppy mitral valves with or without the Marfan syndrome the mitral anulus was greatly dilated (average 15.5 cm). Thus, only in patients with floppy valves with or without the Marfan syndrome or both does anular dilatation by itself appear great enough to cause mitral regurgitation. It appears, therefore, that dilatation of the mitral anulus is a rare cause of mitral regurgitation and that abnormality of the fibrous skeleton of the heart is necessary for the mitral anulus to dilate enough to cause mitral regurgitation.     

Vascular complications of thorium dioxide.

Vascular complications occurring late after exposure to thorium dioxide (thorotrast) are described in two patients. One patient had both cerebral andmyocardial infarcts and died at age 25 years. Necropsy disclosed both adventitial and intimal fibrosis of the left carotid artery and greater than 75 per cent cross-sectional area luminal narrowing of both the left main and left anterior descending coronary arteries. The other patient, a 33 year old man, had no cerebral symptoms in life but total obstruction of the right carotid artery secondary to a thorotrastoma was found at necropsy. Vascular complications due to thorotrast appear to represent consequences of chronic alpha irradiation.     

Atrioventricular valve replacement in the idiopathic hypereosinophilic syndrome

Three patients with the idiopathic hypereosinophilic syndrome and the associated endocardiopathy are described who underwent atrioventricular valve replacement after intractable congestive heart failure secondary to valvular dysfunction developed. Following valve replacement, all three patients sustained striking improvement in exercise tolerance and control of congestive heart failure. Thus, atrioventricular valve replacement may be beneficial to selected patients with congestive heart failure associated with the endocardial process of the idiopathic hypereosinophilic syndrome.