The effect of anti-inflammatory agents and inflammation on granulocyte adherence: Evidence for regulation by plasma factors

Significant inhibition of granulocyte adherence to nylon fiber columns followed the administration of alcohol, aspirin, sodium salicylate, acetaminophen, indomethacin, phenylbutazone, colchicine or prednisone to normal subjects. The addition of salicylates and glucocorticoids to blood in vitro had no effect on adherence, but plasma from volunteer subjects treated with either drug contained a factor which inhibited the adherence of normal granulocytes. The factor is heat stable, nondialyzable and not present in serum; it produces a linear dose response in normal cells. When mixed with the adherence-increasing factor found in inflammatory diseases, it neutralizes the augmenting effect and normal granulocyte adherence results.The effect of anti-inflammatory therapy on inflammatory disease was studied in aspirin-treated patients with rheumatoid arthritis. Their granulocyte adherence fell into two categories based on the clinical control of their disease: patients in good control had only slightly increased granulocyte adherence, but those in poor control had an average adherence more than twice normal. Mean blood aspirin levels were equivalent for the two groups ($\text{11.0}\text{mg}\text{100}\text{ml}$ for the well controlled and $\text{13.4}\text{mg}\text{100}\text{ml}$ for those poorly controlled). Thus, clinical response to anti-inflammatory therapy correlates well with granulocyte adherence, not with aspirin levels. The potential pathogenetic role of adherence-modifying factors in inflammatory diseases remains to be determined.     

Discoid lupus erythematosus with macroglobulinemia. Correlations between autoimmunity and B cell malignancy with hyperimmunoglobulinemia

A 44 year old woman presented with discoid lupus erythematosus and then chronic lymphocytic leukemia of the B cell type with macroglobulinemia developed. Immunologic studies revealed suppressed thymus-dependent cell function, increased bone marrow-dependent cells of the immunoglobulin M (IgM) class and increased null cells.The pathogenesis and relation of lupus erythematosus to B cell malignancy with hyperimmunoglobulinemia are discussed.     

Energy utilization by the lung

Lung tissue requires oxidative metabolism in order to sustain essential functions. Evidence for the aerobic nature of lung tissue has been obtained previously from measurements of tissue oxygen utilization, analysis of the effect of hypoxia on the tissue adenosine triphosphate (ATP) level, and study of substrate utilization and ultrastructure of lung mitochondria. This study was designed to investigate two energy utilizing systems of the lung. An isolated perfused lung preparation was developed and used to evaluate energy requirements for serotonin uptake and de novo lipid synthesis. Lungs removed serotonin from the pulmonary capillaries and metabolized it to 5-hydroxyindole acetic acid (5-HIAA). Metabolic inhibitors including ouabain, anoxia and potassium cyanide significantly depressed the rate of serotonin uptake. De novo synthesis of lung lipids was studied by adding glucose uniformly labelled with radioactive carbon (¹⁴C-glucose) to the perfusate. In the presence of severe hypoxia, incorporation of radioactivity into lung lipids was significantly decreased. These studies suggest two important lung metabolic activities that depend for maximal rate on energy produced during aerobic metabolism and indicate that anaerobic pathways alone cannot maintain normal energy status of the lung. Interference with pathways of energy generation in lung tissue may be important in the pathophysiology of lung damage due to oxidant injury and may also lead to tissue changes with local hypoxia.     

A year's experience with tuberculosis in a private urban teaching hospital in the postsanatorium era

Because brief general hospital admission and extended ambulatory management have replaced sanatorium care for tuberculosis, we reviewed 41 cases admitted to a private urban hospital during 1971–1972 to assess the spectrum of disease and the problems created by the closing of sanatoriums. Almost half the cases were misdiagnosed, exposing an average of 35 hospital personnel to unisolated patients with positive smears. Clinical manifestations often were subtle. Of those with pulmonary involvement, 14 per cent denied having symptoms and less than half had positive sputum smears. Transfer to ambulatory care for half the patients was complicated by having different physicians manage their hospital and outpatient care, with poor communication between the two. Outpatient physicians were sent discharge summaries for fewer than two thirds of their patients, and then only after an average $\text{2}\text{1}\text{2}$ month delay. Similarly, slowness in case reporting impaired contact investigation. Only three contacts were identified per patient, and only 71 per cent of these were investigated. Improved diagnostic ability, better communication with public health workers, and attention to details of transfer to ambulatory care are necessary for effectively integrating the present components of tuberculosis management.     

1,25(OH)2D3 is not the only D metabolite involved in the pathogenesis of osteomalacia

Three patients are described in whom there was no simple correlation between plasma 1,25(OH)2D3 concentration and the occurrence of osteomalacia. One patient had severe osteomalacia with high plasma 1,25(OH)2D3 and normal mineral ion product; the second had a normal mineral ion product and no evidence of osteomalacia even though plasma 1,25(OH)2D3 was undetectable; and the third had osteomalacia, low plasma 1,25(OH)2D3 and a reduced mineral ion product. In considering these data in the light of presently available information, it is concluded that osteomalacia can occur as a consequence of a lack of a vitamin D metabolite other than 1,25(OH)2D3, or a consequence of a reduced mineral ion product, but not as a consequence of 1,25(OH)2D3 lack if the mineral ion product is normally maintained and other D metabolites are present. However, a deficiency of 1,25(OH)2D3 normally leads to a reduction in the mineral ion product hence 1,25(OH)2D3 deficiency may play a role in the development of certain forms of osteomalacia.     

Cutaneous signs of cryoparaproteinemia: Control with burst alkeran and prednisone

A patient is described whose primary manifestations of a circulating immunoglobulin G_k (IgG_k) cryoparaprotein were incapacitating edema, vascular obstruction and necrotic ulcerations of the lower extremities. Although the fundamental cause for the deleterious, anomalous immunoglobulin remains undefined, the cyclic, predictable and periodic recurrence of clinical and laboratory abnormalities were and remain successfully controlled using high-dose, short-course, combined chemotherapy with phenylalanine mustard (Alkeran®) and prednisone. This treatment, used only when the skin lesions become overtly manifest, produces no immediate untoward side effects, is tolerated with impunity and forms the basis for judicious outpatient management of this and analogous paraproteinemias.     

Relapsing polychondritis with insulin resistance and antibodies to cartilage

Described here is a patient with typical relapsing polychondritis in whom insulin-resistant diabetes mellitus was associated with high titers of insulin antibody. Widespread immunologic dysfunction was demonstrated including the presence of antinuclear antibody and a probably biologic false-positive fluorescent treponemal antibody absorbed (FTA-ABS) test. In addition, anticartilage antibody activity was found by indirect immunofluorescence. The substructure and antigenicity of cartilage in animal models and in our patient are discussed.     

Persistent Lymphocytosis with Chromosomal Evidence of Malignancy

An inappropriate, sustained and absolute lymphocytosis in a young man was investigated using technics which attempted to define the more detailed features of these cells and their T and B subpopulations. The results of the tests for lymphocyte RFC (E) and complement (EAC) rosette formation, immunofluorescence, in vitro phytohemagglutlnin (PHA) stimulation and ¹⁴C-cyclophosphamide binding assays, when evaluated in a combined and interrelated fashion, indicated that the lymphocytosis was mainly but not solely, due to an absolute elevation in circulating T lymphocytes. Moreover, an aneuploid cell line with 47 chromosomes, presumably T cells, also was detected in PHA-stimulated cultures. These data, associated with the patient's anemia, lymphocyte-infiltrated bone marrow, hepatosplenomegaly, pharyngeal lymphold tumor and the clonal proliferation of lymphocytes bearing an abnormal karyotype, furnish evidence that the lymphocytosis is more than an unremitting leukemoid reaction and is potentially neoplastic. The detection of the chromosomal abnormality at this patient's age and point in disease may make him especially unique in that he could be a clinical prototype for other patients with lymphoreticular tumors which remain undetected at their onset.     

Disseminated listeriosis presenting as acute hepatitis: Case reports and review of hepatic involvement in listeriosis

We report three cases of disseminated listeriosls that presented as acute hepatitis characterized by striking increase of liver function test values and fever. Peak serum transaminases (SGOT) for each of three patients were 5,380, 2,350, and 443 mu/ml respectlvely. The correct diagnosis was not suspected in any of the patients until blood and cerebrospinal fluid cultures obtained routinely in the course of evaluation for fever grew Listeria monocytogenes. When antibiotic therapy was instituted, serum transaminase values plummeted in two patients; these two were eventually cured of their infection. The third patient succumbed to his infection; postmortem examination showed miliary abscesses of the liver which revealed L. monocytogenes. Review of the literature for previous reports of hepatic involvement in adult patients with Ilsterioris shows that hepatitis is an unusual mode of presentation. However, since we observed these three cases over a one-year period, we suspect this may not be an uncommon occurrence.     

Post-marketing studies of drug efficacy: How?

This report reviews the 100 most recently approved drugs in order to quantify the frequency with which post-marketing studies of drug efficacy can be performed experimentally and non-experimentally. These drugs represent 131 potential drug uses. Of them, the absolute efficacy of 89 (68 percent) could be evaluated from clinical observations. Of the remaining 42, six (14 percent) could be studied experimentally or non-experimentally, six (14 percent) only experimentally, one (2 percent) only non-experimentally, and 29 (69 percent) by neither technique. Answers to all questions of relative efficacy required formal research. Of these, 94 (72 percent) could be studied using either experimental or non-experimental techniques. The remaining 37 (28 percent) could be studied experimentally only. Thus, clinical observations and non-experimental research can contribute a large proportion of the information about drug efficacy still needed after marketing.     

Osteomalacia and osteitis fibrosa in a man ingesting aluminum hydroxide antacid

A 53-year-old man with a history of long-term aluminum hydroxide antacid ingestion reported diffuse bone pain and multiple stress fractures over a two-year period. An undecalcified transiliac bone biopsy specimen revealed osteomalacia with osteitis fibrosa; plasma parathyroid hormone and cyclic AMP levels were normal. Following withdrawal of antacids and treatment with calcium and phosphorus, an initially elevated plasma, 1,25-dihydroxyvitamin D level fell to within the normal range, accompanied by decreased bone pain, healed stress fractures, and increased axial bone mineral content as determined by computed tomography of lumbar trabecular bone. Phosphate deprivation and 1,25-dihydroxyvitamin D excess may contribute to the poor mineralization and exaggerated resorption of bone observed in this syndrome. The clinical, biochemical, radiologic, and histologic features of previously reported cases are reviewed. Early recognition of this syndrome is important, since appropriate therapy promotes skeletal remineralization and prevents morbidity.     

Erythroid aplasia in systemic lupus erythematosus

A patient with systemic lupus erythematosus presented with red cell aplasia. Her anemia responded to prednisone therapy. The occurrence of red cell aplasia in association with a variety of immune phenomena lends support to the concept that in systemic lupus erythematosus also, erythroid aplasia may be of immune etiology.     

Vigorous supplementation of a hypocaloric diet prevents cardiac arrhythmias and mineral depletion

We have previously demonstrated that a hypocaloric, nutritionally deficient, liquid protein diet is associated with potentially lifethreatening cardiac arrhythmias, which increased in frequency and complexity over the duration of the study. The present investigation was designed to evaluate the metabolic and cardiac changes associated with a hypocaloric, but otherwise nutritionally complete, diet. Six healthy, obese females from 154 to 182 percent of ideal body weight were evaluated in a metabolic ward for 48 days. The subjects ingested a weight maintenance diet during an eight-day period, which was followed by 40 days of an experimental diet containing 472 kcal of a mixture of protein (60 percent of calories), carbohydrate (25 percent), and fat (15 percent). This diet equaled or exceeded the recommended daily allowances for minerals, trace elements, vitamins, and essential fatty acids. The subjects were monitored for balances of nitrogen and minerals, as well as for the appearance of cardiac arrhythmias by 24-hour electrocardiographic recordings. Nitrogen balance was positive, and the previously demonstrated negative balances for potassium, sodium, calcium, magnesium, and phosphorus were either reversed or markedly decreased. In contrast to our previous study, no arrhythmias were observed in subjects ingesting the present experimental diet, and no significant change in cardiac rhythm was found in 13 obese, but otherwise healthy, outpatients. The data, based on a limited number of subjects, suggest that a hypocaloric diet vigorously supplemented with essential elements, micronutrients, and vitamins appears to be safer than the once popular, incomplete liquid protein preparation.     

Influence of the kidney upon urate homeostasis in health and disease

The role of the kidney in the maintenance of urate homeostasis is reviewed, with particular emphasis upon the major contributions of Dr. Alexander B. Gutman to our understanding in this area. Data in support of various models of renal urate transport are presented, in conjunction with a discussion of the pyrazinamide suppression test and its limitations as a means of characterizing urate transport. It is proposed that postsecretory reabsorption of urate, as well as the rate of urate secretion, controls and modulates the final rate of urate excretion in man.The renal basis for some of the disturbances of urate homeostasis encountered clinically is also considered. The role of the kidney in the pathogenesis of the hyperuricemia observed in hypertension, toxemia of pregnancy, gout and renal failure is discussed, as well as three apparently distinct defects in tubular reabsorption of urate which lead to hypouricemia. It is emphasized that the mechanisms of renal urate handling in health, and the pathogenesis of the disordered states of renal urate homeostasis which are discussed, remain partially within the realm of speculation. A clearer understanding of the pathophysiologic mechanisms underlying disordered urate balance awaits more complete knowledge of normal physiology.     

Unusual electrocardiographic finding—Bifascicular block due to hyperkalemia

A unique case in which the patient had bifascicular block consisting of right bundle branch block and left posterior hemiblock as a result of marked hyperkalemia is presented. To our knowledge, this is the first reported case in which such unusual electrocardiographic abnormalities due to hyperkalemia were demonstrated. The electrocardiographic abnormalities produced by hyperkalemia in this case disappeared promptly by hemodialysis, as the serum potassium level returned to normal. It has been stressed that hyperkalemia should be considered as an important etiologic factor in the differential diagnosis of bundle branch block, hemiblocks and bifascicular block, particularly when these intraventricular blocks are produced suddenly.     

Behçet's syndrome: Report of a case associated with pericardial effusion and cryoglobulinemia treated with indomethacin

A patient with Behçet's syndrome manifested by optic atrophy, purulent conjunctivitis and orogenital ulcerations presented with a high fever and pericardial effusion. A mixed cryoglobulinemia (immunoglobulin A (IgA)-immunoglobulin G (IgG)) was observed. Treatment with indomethacin resulted in rapid defervescence, resolution of the pericardial effusion and the orogenital ulcerations, and disappearance of the cryoglobulinemia. Discontinuation of indomethacin therapy was followed by a recurrence of the oral and genital ulcerations that responded promptly to the reinstitution of indomethacin treatment.