Biomedical subjects
Publications and source records attributed to S M Wolff.
The orbital lesions in six patients with Wegener's granulomatosis were studied by computer assisted tomography (CAT). Four patients had active orbital disease and proptosis, and each was found to have orbital masses accompanied by varying degrees of bone and sinus destruction. Two additional patients with histories of proptosis had no orbital lesions at the time of CAT study.
Secondary amyloidosis is a complication of diseases characterized by recurrent acute inflammation. In this study, a standardized stimulus which induced fever and inflammation was given to six normal subjects (19-24 yr old) to follow the fluctuation in concentration of serum amyloid A (SAA), the precursor of the secondary amyloid fibril protein. After a single intramuscular injection of etiocholanolone (0.3 mg/kg), blood samples were drawn twice a day for 12 days for determination of SAA by solid phase radioimmunoassay. From a base line of <100 mug/ml, the SAA concentration began rising within 12 h to a maximum value at about 48 h of 1,350-1,800 mug/ml in three males and 380-900 mug/ml in three females and returned to base line by 4-5 days. The SAA response showed a similar time response to C-reactive protein (CRP), a well-documented acute phase protein which was assayed semiquantitatively by capillary tube precipitin reaction. CRP, but not SAA, showed a quantitative correlation with the amount of fever induced by etiocholanolone. One subject exhibited a second rise in SAA and CRP concentrations after acute over-indulgence with alcohol, suggesting that acute liver damage may have caused an acute phase reaction. Thus, a controlled episode of fever and inflammation produced a prompt and prolonged elevation of SAA and CRP concentrations. Unlike SAA, CRP has not been implicated in the pathogenesis of amyloidosis, although its relationship to the P component of amyloid has recently been established.
Histiocytic medullary reticulosis represents a proliferation of malignant histiocytes which produce pancytopenia through marrow involvement and the phagocytosis of granulocytes, leukocytes and platelets. The disease is typically characterized by a fulminant febrile course which results in death from a variety of complications due to pancytopenia or intercurrent infections. Its diagnosis is based on bone marrow aspiration or tissue section in which large histiocytes can be demonstrated phagocytizing red or white blood cells and platelets. Therapy has included irradiation, steroids, antibiotics, antimetabolites, and the like, but with poor results. Two patients with head and neck manifestations of histiocytic medullary reticulosis are described in detail. It is felt that refinements in diagnosis must still be made,, since any patient survival may well be predicated by the early initiation of aggressive cytotoxic therapy.
The classical radiologic manifestations of Wegener's granulomatosis are paranasal sinus disease and pulmonary nodules. A review of 31 clinicopathologically proven cases of Wegener's granulomatosis was undertaken to delineate some of the atypical radiologic presentations in this disorder. In 16 of the 31 patients a total of 18 atypical radiographic findings were demonstrated. These included lesions of the airways, parenchyma, pleura, and kidneys. We feel the "typical radiologic findings" of Wegener's granulomatosis should be expanded to include (1) endobronchial disease resulting in atelectasis of either a lobe or a complete lung, and (2) pleural disease with thickening or effusion which may be massive. While some of the rarer presentations are still not included, such a redefinition would cover more than 75% of our 31 cases.
Previous studies of patients with the hypereosinophilic syndrome have found very significant morbidity and a high mortality of 77% at 3 years. Our study analyzes the therapy and prognosis of 26 patients with the hypereosinophilic syndrome. Five patients showed no evidence of progressive organ-system dysfunction and were given no therapy; all have done well. Sixteen patients with progressive organ dysfunction were treated with corticosteroids; six of the 16 had a good response and needed no further therapy. Five patients were treated with various chemotherapeutic agents that proved to be ineffective. In eight patients who were unresponsive to corticosteroid therapy, hydroxyurea produced excellent responses in six and partial responses in two. With the above regimen, our 26 patients (including 12 with poor prognostic indicators) have had a marked increase in survival (3-year mortality of 4%) when compared with the historical control group.
We report the histopathologic and dermatologic manifestations of eight patients with hypereosinophilic syndrome (HES). Skin lesions occurred in eight patients (53%) in a group of 15 patients with HES, and were generally of two types: (1) erythematous pruritic papules and nodules, or (2) urticaria and angioedema. As HES was treated with appropriate therapy, the skin lesions improved. Skin eruption may be the only manifestation of disease in otherwise asymptomatic patients with HES.
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Early idiopathic hemochromatosis was diagnosed in a 52-year-old woman during the course of a hospitalization for another disorder. Quantitative studies revealed massive hepatic parenchymal siderosis and absent stainable marrow iron. Additionally, intestinal absorption and hepatic sequestration of radiolabeled iron were elevated. These studies in a patient with very early hemochromatosis, before organ damage, complement observations previously made in patients with advanced disease and provide further support for the concept that this disorder may result from impaired reticuloendothelial handling of iron.
Ten patients with bone-marrow failure from myelofibrosis, aplastic anaemia, paroxysmal nocturnal haemoglobinuria, and "hairy cell" leukaemia, who had failed to respond to androgens and/or glucocorticosteroids, were treated with a combination of aetiocholanolone and prednisolone. All patients except one with aplastic anaemia responded with an increase in reticulocytes, haematocrit, red blood cell mass, and blood neutrophils and platelets. These data suggest that aetiocholanolone, and similar 5beta-hydroxy steroids, may be valuable in treating certain patients with chronic marrow failure.
Human leukocytes stimulated in vitro release leukocytic pyrogen (LP), a protein which is the mediator of fever. In order to study human leukocytic pyrogen, we attempted to purify this molecule from the large quantity and variety of proteins which are present in leukocyte supernates. Human peripheral leukocytes were stimulated in vitro by phagocytosis of killed staphylococci, and several methods were used to isolate the pyrogen protein. First, using isoelectric focusing, it was found that crude leukocyte supernates contained two molecular species of LP which were separable by precipitation in cold alcohol. Isoelectric focusing, although used for confirmation of the molecular homogeneity of LP, could not be employed as a preparative purification technique. Following alcohol precipitation, human LP was chromatographed on ion-exchange materials at various pH with modest recovery of initial activity but marked increase in specific activity. Gel-filtration was also employed and yielded partially purified LP. When alcohol precipitation was combined with ion exchange at alkaline pH and followed by gel-filtration, resulting LP preparations contained 5 or 6 contaminating proteins. These results demonstrate that human LP can be partially purified from the large quantity and variety of proteins present in crude leukocyte supernates and during purification procedures, the pyrogen did not change in either molecular weight or isoelectric point. This work provides reliable techniques for initial purification of human LP.
Ocular manifestations of Wegener's granulomatosis may occur secondary to contiguous granulomatous sinusitis or as a result of focal vasculitis. Contiguous granulomatous sinus disease causes nasolacrimal duct obstruction, proptosis and ocular muscle or optic nerve involvement. Focal vasculitis unrelated to contiguous upper respiratory tract disease is manifested by conjunctivitis, episcleritis, scleritis, corneoscleral ulceration, uveitis, and granulomatous vasculitis of the retina and optic nerve. A review of 29 cases of Wegener's granulomatosis and three cases of lymphomatoid granulomatosis studied over the past 15 years at the National Institute of Allergy and Infectious Diseases (NIAID) disclosed single or multiple ocular manifestations of disease in 15 patients (47 per cent). The pattern of ocular disease, its relationship to systemic involvement, diagnostic methods and the response to therapy are discussed.
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Leukocytic pyrogen is a small endogenous protein that mediates fever. Because of the limitations of bioassays, circulating leukocytic pyrogen has not been demonstrated during fever in humans. The pyrogen was produced in vitro after phagocytosis of staphylococci by blood monocytes. Antibody against the pyrogen was obtained from rabbits immunized with leukocytic pyrogen and the antiserum was purified by solid-phase immunoadsorbants. Purified antibody to the pyrogen was attached to activated Sepharose 4B and used in conjunction with gel filtration to purify the pyrogen. The pyrogen was labeled with 125I and further purified by gel filtration and ion-exchange chromatography. The final preparation of 125I-labeled pyrogen demonstrated a homogeneous band during isoelectric focusing and other separation procedures. With antibody to pyrogen attached to Sepharose, less than 0.1 of a rabbit pyrogenic dose of human leukocytic pyrogen inhibited the binding of 125I-labeled pyrogen to this immunoadsorbant, and this inhibition was not affected by the presence of human serum. Thus, a radioimmunoassay for human leukocytic pyrogen has been developed that may be used to detect circulating pyrogen during fever in humans.
Human peripheral blood leukocytes were stimulated with killed staphylococci in vitro to release leukocytic pyrogen (LP). Supernates from these stimulated leukocytes were concentrated, emulsified in Freund's complete adjuvant, and injected intradermally into rabbits. After seven monthly booster injections, rabbit antiserum destroyed the pyrogenic activity of human LP, and the titer of this neutralizing ability increased in the subsequent 7 mo. The pyrogen-neutralizing capacity of the rabbit antiserum was recovered in the globulin fraction, the IgG and IgM peaks of Sephadex G-200, and the acid-eluted fraction of a goat anti-rabbit IgG immunoadsorbant. The neutralizing antibody was specific for human LP inasmuch as it had no effect on rabbit, guinea pig, or monkey LP. When coupled to Sepharose, this antibody bound human LP; after acid elution from this immunoadsorbant, LP was recovered without loss of biologic or chemical characteristics. The antiserum was also absorbed with stimulated leukocyte supernates which did not contain LP, and this had no effect on the titer of anti-LP. Crude human LP, eluted from immunoadsorbant columns prepared from absorbed antiserum, contained significantly reduced contaminating protein when evaluated by polyacrylamide gel electrophoresis. These studies have established that specific antibody to human leukocytic pyrogen can be produced. This antibody is useful in the further study and purification of leukocytic pyrogen and its role in the pathogenesis of human fever.
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Nine patients with familial Mediterranean fever (FMF) were admitted to a controlled, double-blind trial to determine if there are patients with this disease who are able to abort their acute episodes of pain and fever with short courses of colchicine taken at the onset of attacks. Five patients completed their treatment assignments, and colchicine was significantly effective in aborting the attacks of three but was ineffective in two. The remaining four patients could not be assessed because of insufficient numbers of courses. During the 10 months of the trial, 28 courses of colchicine and 31 of placebo were taken during the early stages of FMF attacks. Twenty-one (75%) colchicine courses were followed by attacks considered to have been aborted, compared to only three (10%) placebo courses. This trial shows that patients can recognize the prodrome of their FMF attacks and that some patients can consistently abort their attacks with short courses of colchicine taken at the very onset of symptoms.
The Hypereosinophilic Syndrome (HES) is a disease of unknown etiology and pathogenesis characterized by blood and bone marrow eosinophilia associated with infiltration of eosinophils into tissues and multi-system organ dysfunction. Patients with HES historically have very significant morbidity and a high mortality of 77% at 3 years. This study is a prospective (9 years) and retrospective (24 years) analysis of the therapy and prognosis of 26 patients with HES. Five patients (19%) showed no evidence of progressive organ system dysfunction and were given no therapy; all have done well. Sixteen patients with progressive organ dysfunction were treated with corticosteroids; 6 of the 16 (38%) had a good response and required no further therapy. Six of 8 patients who were corticosteroid unresponsive and had serious prognostic signs had excellent responses to hydroxyurea therapy, while 2 patients showed partial responses. Employing the above regimen, we have demonstrated that our 26 patients (including 12 with poor prognostic indicators) have a marked increase in survival (3 year mortality 4%) when compared with the historical control.