Myocardial function and perfusion in the CREST syndrome variant of progressive systemic sclerosis. Exercise radionuclide evaluation and comparison with diffuse scleroderma

Myocardial function and perfusion were evaluated in 22 patients with progressive systemic sclerosis with the CREST syndrome using exercise and radionuclide techniques, pulmonary function testing, and chest roentgenography. The results were compared with a similar study of 26 patients with progressive systemic sclerosis with diffuse scleroderma. The prevalence of thallium perfusion abnormalities was similar in the groups with CREST syndrome and diffuse scleroderma, (64 percent versus 77 percent), but the defects were significantly smaller in the CREST syndrome (p less than 0.01). Reperfusion thallium defects in the absence of extramural coronary artery disease were seen in 38 percent of patients with diffuse scleroderma. This finding was not seen in any of the patients with the CREST syndrome. In diffuse scleroderma, abnormalities of both right and left ventricular function were related to larger thallium perfusion defects. In the CREST syndrome, abnormalities of left ventricular function were minor, were seen only during exercise, and were unrelated to thallium perfusion defects. Abnormal resting right ventricular function was seen in 36 percent of the patients with the CREST syndrome and was associated with an isolated decrease in diffusing capacity of carbon monoxide. It is concluded that the cardiac manifestations of the CREST syndrome are distinct from those found in diffuse scleroderma. Unlike diffuse scleroderma, abnormalities of left ventricular function in the CREST syndrome are minor and are unrelated to abnormalities of coronary perfusion. Right ventricular dysfunction in the CREST syndrome appears to be primarily related to pulmonary vascular disease.     

Influence of clofibrate on thyroid hormone and muscle protein turnover

Clofibrate, a hypolipidemic agent, has been shown to increase muscle protein degradation. The possible role of thyroid hormones in this phenomena was examined. Clofibrate treatment of rats for 2 weeks resulted in a significant decrease in total thyroxine and triiodothyronine levels in serum. Reverse T3 and resin uptake values remained unchanged. When exogenous thyroxine was co-administered with clofibrate, serum TSH levels were suppressed, but the increased muscle protein degradation was not reversed. Equilibrium dialysis and Scatchard analysis of the binding of 125I-thyroxine to serum proteins indicated that clofibrate competitively inhibits the binding of thyroid hormone to serum proteins by decreasing its apparent binding affinity. In the presence of lower total thyroid hormone concentrations and an elevated free thyroxine fraction, the total free hormone levels are estimated to be in the normal range in the serum of clofibrate treated rats. Clofibrate seems to act like thyroid hormone since it binds to and displaces T4 from plasma proteins. Because free thyroid hormone levels are in the normal range, the thyroid hormone-like effects of clofibrate on the cell may be additive to the T4 effects, and are probably responsible for the hypermetabolic state seen in the muscle of clofibrate-treated animals. Our data suggest that the effects of clofibrate in muscle are complex. In addition to competitively altering the binding of thyroxine to serum proteins, this substance may also exert a hitherto unrecognized thyroid-hormone-like subcellular effect resulting in increased muscle protein degradation, and in augmented ouabain-sensitive ATPase activities.     

Cardiac conduction abnormalities in Reiter's syndrome

Reiter's syndrome was found in three men who presented with cardiac conduction disturbances. In two patients, Reiter's syndrome had been present for more than 30 years and had been previously unrecognized. These patients included a 67 year old man with complete heart block of 13 years' duration, and his son, who had left bundle branch block and chronic generalized cardiomyopathy. A chart review of 19 other patients with Reiter's syndrome who were seen at this institution disclosed five patients with conduction abnormalities. Transient first-degree heart block was the most common disturbance detected and was usually associated with active Reiter's syndrome. Some conduction abnormalities appeared after a long latent period at a time when other manifestations of Reiter's syndrome were inactive. An association with this disorder was therefore not obvious. In all five patients with Reiter's syndrome and conduction disturbances, testing for B27 antigen gave positive results. Both clinical and histopathologic changes in the heart in Reiter's syndrome are analogous to those in ankylosing spondylitis, also associated with B27 antigen. We suggest that the heart, like the joints and iris, may be a target organ for B27-associated disease by a mechanism that remains to be defined.     

Amyopathic dermatomyositis

Amyopathic dermatomyositis is a •ariant of dermatomyositis that is characterized by the typical skin rash but without the muscle abnormalities. It has been proposed that the amyopathic and myopathic forms of dermatomyositis exist on a continuum, a concept that is supported by family and genetic studies and the obser•ation that a small proportion of amyopathic patients transform to a frankly myopathic state. The amyopathic state is defined by a lack of muscle weakness and through diagnostic tests, including serum muscle enzymes, electromyogram studies, and muscle biopsies, that are usually normal or show only minimal abnormalities. Despite the lack of weakness, many patients complain of debilitating fatigue. More sensiti•e measures of muscle function, such as P-31 magnetic resonance spectroscopy, suggest that muscle metabolism is abnormal in amyopathic patients. The amyopathic form is more commonly seen in adults than in children, although ju•enile cases are reported. Some early series suggested no association with underlying malignancies, but recent reports indicate that malignancies occur. Determining whether a patient has amyopathic rather than myopathic disease may ha•e prognostic implications.     

Electrocardiographic and vectorcardiographic abnormalities in Fabry's disease.

Fabry's disease has been reported to be associated with ECG abnormalities. Thirty-two patients with this disease followed in the University of Minnesota had ECG's and 15 had VCG's. An abonrmal rhythm was observed in two patients on initial examination and four more developed abnormal rhythm on follow-up examinations. A short PR interval (120 msec. or less) was seen in five patients. Thirteen others had a PR interval that was less than 140 msec. Conduction abnormalities involving the A-V node or His bundle or its branches were present in 22 per cent of the patients, most frequently the intraventricular conduction defects progressing to the right bundle branch block. Atrial or ventricular enlargement was seen in 60 per cent of the patients, left ventricular hypertrophy being the most common. ST-T changes with or without chamber enlargement were seen in 10 patients. One patient had an anterior myocardial infarction pattern on his ECG. Hemizygosity was found to be associated with significantly more abnormalities than heterozygosity. The severity of conduction defects also increased with the duration of the disease process. Vectorcardiography in this study did not provide significant additional information other than that observed on the ECG alone. Since the pathology usually reveals myocardial fibers, conduction system, and blood vessels infiltrated with glycosphingolipid, it is believed that lipid infiltration is responsible for conduction defects, chanber enlargement, and other abnormalities. Although Fabry's disease is rate, it may be amenable to therapy; therefore, recognition of cardiac involvement is important.     

Liver disease in rheumatoid arthritis and Sj?gren's syndrome. Prospective study using biochemical and serological markers of hepatic dysfunction.

Inter-relationships of biochemical and immunological tests of liver function have been studied in a prospective study of 216 patients with rheumatoid arthritis (RA), 32 patients with Sjogren's syndrome, and 27 patients with the sicca syndrome, and these results have been compared with those obtained 289 patients with osteoarthrosis or with a form of seronegative polyarthropathy. In general the prevalence of abnormalities in serum alkaline phosphatase, bromsulphthalein excretion, smooth muscle antibody, and mitochondrial antibody in the former three groups was higher than in patients with osteoarthrosis. Patients with Sjogren's syndrome with RA had a higher prevalence of abnormalities of bromsulphthalein excretion, salivary duct antibody than patients with the sicca syndrome. Patients with RA had a higher pervalence of rheumatoid factor than those with the sicca syndrome. Patients with a positive smooth muscle or mitochondrial antibody were found to have a higher prevalence of hepatomegaly and splenomegaly, of abnormal liver function tests, of other autoantibodies, and of histological abnromalitis of liver than those in whom these tests were negative.     

Clofibrate does not alter cyclic nucleotide metabolism in muscle

Clofibrate is a hypolipidemic agent that causes muscle protein breakdown in rats, and an acute muscular syndrome in man. It also inhibits adenylate cyclase in fat tissue. Muscle protein metabolism has been shown to be regulated by cyclic nucleotides. In the present experiments were measured several parameters of cyclic nucleotide metabolism to determine the role that cyclic nucleotides play in clofibrate-induced muscle protein degradation. It was found that clofibrate treatment did not alter cyclic nucleotide levels, nor did it change the activities of basal or hormone-stimulated adenylate cyclase, or cyclic nucleotide phosphodiesterase in muscle. Our results suggest that muscle protein breakdown in clofibrate-treated rats is not regulated by cyclic nucleotides.     

Multiple forms of acid phosphatase activity in Gaucher's disease.

Although the primary genetic defect in all individuals with Gaucher's disease is a deficiency in glucocerebrosidase activity, the finding of marked elevations in splenic and serum acid phosphatase activity is almost as consistent a finding. Gaucher spleen and serum contain at least two forms of acid phosphatase that can be readily separated by chromatography on columns containing the cation exchange resin Sulphopropyl Sephadex. The major species of acid phosphatase (designated SP-I) contained in Triton X-100 (1% v/v) extracts of Gaucher spleen accounts for 65%--95% of the total activity and has the following properties: (1) it does not bind to the cation exchange column; (2) it exhibitis a pH optimum of 4.5--5.0; (3) it is inhibited by sodium fluoride (15 mM), L(+)-tartaric acid (20 mM), and beta-mercaptoethanol (2.1 M), and (4) it is resistant to inhibition by sodium dithionite (10 mM). The minor acid phosphatase activity (designated SP-II) present in extracts of Gaucher spleen has properties similar to those of the major species of acid phosphatase activity contained in serum from patients with Gaucher's disease: (1) it binds firmly to cation exchange columns (eluted by 0.5 M sodium chloride); (2) it exhibits a pH optimum of 5.0--6.0; (3) it is inhibited by sodium fluoride and sodium dithionite; and (4) it is resistant to inhibition by beta-mercaptoethanol (2.1 M) and L(+)-tartaric acid (20 mM). In addition, a second form of acid phosphatase that is tartrate resistant was found to be elevated in Gaucher serum. This form of serum acid phosphatase did not bind to Sulphopropyl Sephadex, was found to be significantly resistant to beta-mercaptoethanol (2.1 M), and was only partially inhibited by sodium dithionite (10 mM). The findings reported here indicate that at least three distinct forms of acid phosphatase activity are elevated in Gaucher's disease. Furthermore, the minor acid phosphatase activity contained in spleen homogenates has properties very similar to those of the major acid phosphatase activity observed to be present in serum of patients with Gaucher's disease. These data indicate that simple spleen spillage cannot account for the increased levels of serum acid phosphatase in patients with Gaucher's disease.     

Thyroid function tests in adults with Down's syndrome.

Thyroid status was studied in 24 patients above the age of 40 years with Down's syndrome. Three patients had thyroid function tests indicating hypothyroidism. Eight patients had thyroid autoantibodies in serum and 8 patients had a higher than normal level of thyroid stimulating hormone in serum. None of the patients had figures indicating thyrotoxicosis. None of the patients showed any of the clinical signs usually seen in patients with hypothyroidism. It is concluded that biochemical tests indicating hypothyroidism are much more often seen in patients with Down's syndrome than in normal subjects and that thyroid status should be assessed in old patients with this disease.     

Steroid myopathy in connective tissue disease

In eight women with polymyositis (three patients), systemic lupus erythematosus (SLE) (three patients), rheumatoid arthritis (one patient) and shoulder-hand syndrome (one patient), weakness developed during high dose prednisone therapy. These women were studied using serial functional and manual muscle tests, determination of serum glutamic oxaloacetic transaminase (SGOT), creatinine phosphokinase (CPK) and serum aldolase levels, and urinary excretion of creatine. Insidious onset of weakness was characteristic. Myalgias were seen in five patients and unusual sudden weakness in two. Weakness was always most severe in the pelvic girdle muscles; there was a lesser involvement of shoulder girdle and distal muscles.Serum muscle enzyme levels were normal in all cases, but urinary creatine excretion was invariably increased and proved to be the most sensitive laboratory indicator for clinical diagnosis and for monitoring patient improvement. Serial urinary creatine excretion and serum enzyme studies were of value in differenting steroid myopathy from a flare of myositis in patients with connective tissue disease. Diagnosis and effective management were achieved by the use of readily available laboratory and clinical procedures without resorting to muscle biopsy.     

Life-threatening arrhythmias in the mitral valve prolapse syndrome

This study describes seven patients with the mitral valve prolapse or click-murmur syndrome who have survived one or more episodes of life-threatening ventricular arrhythmias. These arrhythmias include cardiac arrest due to ventricular fibrillation, recurrent ventricular tachycardia causing syncope or sustained ventricular tachycardia requiring electroversion. These patients were seen over a two-year period in a single medical center. Five of the seven had repolarization abnormalities in the resting electrocardiogram. Premature ventricular contractions were present in the routine resting electrocardiograms of six of the seven patients and were frequent during treadmill testing and ambulatory electrocardiographic monitoring in all six tested. There were electrolyte abnormalities or changes in medications known to affect myocardial repolarization during the week before the episode in three of the four patients with cardiac arrest. The diagnosis of mitral valve prolapse click-murmur syndrome was made prior to the episode of life-threatening arrhythmia in only two of the seven patients. Varying forms of antiarrhythmic therapy were given to these patients during follow-up periods of five to 26 months. Although the incidence of fatal arrhythmias in the mitral prolapse syndrome is probably small, we suggest that such arrhythmias may not be extremely rare, particularly among those patients who have repolarization abnormalities in the resting electrocardiogram and frequent premature beats. Patients with unexplained ventricular arrhythmias should be screened for mitral valve prolapse.     

Clinical pathologic conference

A study was made of the incidence of CAVO, as it occurs by itself and as it is associated with other complexes, and the association of these complexes with Down's syndrome, and splenic abnormalities. It was found that the complete complicated type (associated with other abnormalities) is more common than the complete simple type where there are no splenic abnormalities. All types, complete and incomplete, had balanced, dominant right and dominant left forms, which is important surgically. The simple type, in situs solitus, does not show severe abnormalities of the spleen, but the complicated type does. Incomplete types are rarely associated with severe abnormalities of the spleen.The complete complicated type without splenic abnormalities is less often associated with Down's syndrome than is the complete simple, and the incomplete less often than the complete type. There is an inverse relationship between Down's syndrome and CAVO associated with splenic abnormalities.The association of patent ductus arteriosus with CAVO is favorable, and the association with fetal coarctation or splenic abnormalities is unfavorable for longevity.     

Fluoride as a possible aetiological factor in non-ulcer dyspepsia

A prospective case controlled study was conducted to evaluate the role of fluoride as a possible aetiological factor for non-ulcer dyspepsia (NUD). Twenty patients with NUD and 10 age and sex matched healthy controls were subjected to clinical evaluation, upper gastrointestinal endoscopy and biopsies from the gastric antrum and duodenum. The antral and duodenal mucosa was subjected to a rapid urease test for Helicobacter pylori and histological and electron microscopic examinations. Fluoride levels in the drinking water, serum and urine were estimated using a ION 85 ion-analyser. These levels were significantly higher in patients with NUD than in controls (P less than 0.05). Histological abnormalities in the antral and duodenal mucosa were seen in 14 patients (70%) with NUD and 1 control subject (10%) (P less than 0.05). Electron microscopic abnormalities in the mucosal cells were seen in all patients with NUD but in none of the controls (P less than 0.01). The fluoride levels in serum and urine correlated with the symptoms, histological and electron microscopic abnormalities (P less than 0.05). It was concluded that chronic exposure to fluoride may result in NUD and should be considered in patients where other known cause of dyspepsia have been excluded.     

Demonstration of a deficiency of β-xylosidase activity in various forms of Gaucher's disease

Gaucher's disease is a lipid storage disease caused by a deficiency in the activity of a lysosomal enzyme, glucocerebrosidase. We have recently described a patient with subacute neuropathic (type 3) Gaucher's disease whose tissues were deficient in β-xylosidase, as well as glucocerebrosidase activity (Chiao et al²¹). In an effort to determine if a deficiency of β-xylosidase activity is a general feature of Gaucher's disease, tissues from individuals with all three clinical forms of Gaucher's disease were analyzed for β-xylosidase activity. Spleen, fibroblasts, and leukocytes were all found to be deficient in β-xylosidase activity. In addition, preliminary experiments suggest that patients with the most severe forms of disease may display the lowest levels of residual β-xylosidase activity. It has been our experience that patients with the lowest levels of residual glucocerebrosidase activity do not always display the most severe clinical manifestations of Gaucher's disease. The possibility should be entertained, therefore, that certain biochemical abnormalities in addition to the deficiency of glucocerebrosidase activity, such as a deficiency of β-xylosidase activity, might produce more severe disease in some individuals with this disease. Also, possible chemical and biochemical relationships between glucocerebrosidase and β-xylosidase should be explored.     

Interaction of "supplementary" scintigraphic indicators of ischemia and stress electrocardiography in the diagnosis of multivessel coronary disease

Lung uptake, ventricular cavitary dilation and basal myocardial uptake represent abnormalities that have been associated with myocardial ischemia on stress thallium-201 images, but that are supplementary to the conventional assessment of perfusion distribution. These "supplementary" indicators of ischemia were related to the coronary distribution of perfusion abnormalities, the results of electrocardiographic stress testing and to the findings on coronary angiography in 73 patients. Forty patients had multivessel coronary disease; 19 of these had three vessel disease. Perfusion abnormalities were seen in 39 of these 40 patients but were indicative of multivessel coronary disease in only 28 and of three vessel disease in only 6. However, supplementary indicators were present in 33 of 40 patients with multivessel disease and in 15 of 19 with three vessel disease. Furthermore, they were seen in 16 of 22 patients with multivessel disease in whom conventional perfusion abnormalities underestimated the extent of disease, but in only 4 of 12 patients in whom the extent of disease was overestimated. The presence of either perfusion abnormalities in a multivessel distribution or supplementary indicators identified 38 (95%) of 40 patients with multivessel disease. A markedly positive electrocardiographic treadmill test was a less sensitive indicator of multivessel disease, appearing in only 15 of 40 patients. However, it was present in only 4 of 33 patients without multivessel coronary disease and was more specific for that diagnosis than were supplementary scintigraphic indicators (88 versus 67%, p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Current concepts in the pathogenesis of the obesity-hypoventilation syndrome. Mechanical and circulatory factors

The pathogenesis of carbon dioxide retention associated with obesity, the obesity hypoventilation syndrome (OHS), remains obscure. In an attempt to Identify factors which might Initiate or contribute to this syndrome, we reviewed respiratory and circulatory function in two groups of obese subjects: those who were not hypercapnic (simple obesity) and those who were (OHS).Obese subjects in both groups display reduction of lung and chest wall compliance, normal airway resistance, closure of peripheral lung units and increased energy cost of breathing. These abnormalities are more severe in those who hypoventilate, especially the reduction In compliance. Respiratory muscle efficiency is reduced in both groups. Inspiratory muscle strength of patients with OHS is 60 to 70 per cent of normal. In OHS arterial carbon dioxide tension (PaCO₂), vital capacity and maximum voluntary ventilation improve significantly with weight toss, whereas in simple obesity there Is little change in these factors with weight loss.In both groups the major circulatory findings are increased total and pulmonary blood volume, with preservation of a normal ratio between the two; and good perfusion but marked underventilation of dependent regions of the lung. These changes are more pronounced In OHS. Left ventricular end diastolic pressure is elevated in some patients, but the rise is not confined to those with OHS. In OHS alveolar hypoxia and acidemia produce pulmonary arterial vasoconstriction and pulmonary arterial hypertension. As a consequence pulmonary artery pressure exceeds left ventricular pressure at the end of diastole.We suggest that excessive reduction of chest wall compliance and inspiratory muscle weakness interact with the circulatory abnormalities already present in simple obesity to generate carbon dioxide retention. The contribution of altered central nervous system function to this process remains controversial.     

The heart in the Hurler syndrome: Gross,histologic and ultrastructural observations in five necropsy cases

Clinical and morphologic features of the cardiovascular system are described in five necropsy patients with the Hurler syndrome. In all five patients the coronary arteries, four cardiac valves, mural endocardium of all four chambers, myocardial walls and aorta were affected in a characteristic manner. All of these sites contained large clear cells known as Hurler cells (readily visible by light microscopy). In addition, granular cells were observed in semi-thin (1 μ) sections and by electron microscopy in the coronary arteries, atrioventricular (A-V) valves and in myocardial interstitlum. These latter cells appear to produce collagen in an abnormal way and are probably responsible for the heavy deposits of collagen in the cardiovascular system of patients with the Hurler syndrome. In the cardiac muscle cells, in smooth muscle cells of the coronary arteries and in fibroblasts, wherever located, deposits of acid mucopolysaccharides and glycolipids usually were also observed. The acid mucopolysaccharide deposits were observed easily with light microscopy except in the cardiac muscle cells where they were seen only with electron microscopy. The glycolipid deposits, observed only on examination of 1 μ thick sections or with electron microscopy, have not previously been observed in coronary arteries or in myocardial cells.The infiltration into the heart by these cells and deposits in all five patients resulted in severe narrowing of the extramural coronary arteries, considerable thickening of the cardiac valves (the left-sided more than the right-sided valves), generalized thickening of mural endocardium and “stiffening” of the myocardial walls. Thus, the cardiovascular lesions in the Hurler syndrome are specific and life-threatenlng.     

The hematologic disorders of alcoholism

Alcoholism is associated with abnormalities of the red cells, platelets and white cells. These hematologic disorders of alcoholism are considered herein. The section on red cells deals with abnormalities of folate and iron metabolism; marrow erythroid disorders, including the ring sideroblasts seen in alcoholic patients; and the hemolytic anemias associated with stomatocytosis, acanthocytosis and Zieve's syndrome. The section on platelets reviews the literature on the incidence and pathogenesis of thrombocytopenia in alcoholic patients. Finally, the section on white cells considers the alcohol-related disorders of leukocyte kinetics and function.     

A new syndrome: ascites, hyperbilirubinemia, and hypoalbuminemia after biochemical modulation of fluorouracil with N-phosphonacetyl-L-aspartate (PALA)

OBJECTIVE: To report a new syndrome of ascites, hyperbilirubinemia, and hypoalbuminemia after treatment with N-phosphonacetyl-L-aspartate (PALA) and fluorouracil for metastatic colorectal cancer. DESIGN: Retrospective analysis. SETTING: Regional cancer treatment center. PATIENTS: Forty-four previously untreated patients with metastatic colorectal cancer in a phase I-II trial of PALA-fluorouracil. MEASUREMENTS AND MAIN RESULTS: One or more transient hepatic abnormalities frequently occurred in 15 of the 17 responding patients. Within the first 10 weeks of treatment, 5 patients developed ascites, 12 had a decrease in the serum albumin level, 6 developed bilirubin elevations, and 7 had transaminase elevations, all in the presence of a complete or partial tumor response. Prolongations of the prothrombin time and elevations of serum glucose levels were also seen. CONCLUSIONS: An unusual syndrome of ascites, hyperbilirubinemia, and hypoalbuminemia is associated with a PALA-fluorouracil regimen. These abnormalities, which may be related to decreased hepatic protein synthesis, occurred more often in patients whose tumor was responding to chemotherapy. Clinicians must recognize that in patients undergoing chemotherapy with these agents, ascites and elevated liver function tests may be secondary to drug administration and are not necessarily due to disease progression.     

Chronic graft versus host disease: a syndrome of disordered immunity.

A chronic, debilitating syndrome related to graft-versus-host disease (GVHD) has been recognized in long-term survivors following allogeneic bone marrow transplantation. In six of 20 marrow graft recipients who survived for more than one year after receiving a transplant, this complication developed; they were studied to better define the syndrome. There was no association between the sex of either donor or recipient, HLA type, blood group, conditioning regimen or marrow cell dose and subsequent development of chronic GVHD. All six patients had mild to moderate manifestations of acute GVHD following prompt engraftment. Chronic GVHD was characterized in each patient by progression to scleroderma-like skin involvement with hyperkeratosis, reticular hyperpigmentation, atrophy with ulceration and fibrosis with limitation of joint movement. A sicca syndrome was prominent in five patients. Four patients had idiopathic interstitial pneumonitis. Infectious complications were frequent, and DNA viral infections were prominent. Autoimmune hemolytic anemia was present in three patients, and one patient had antinuclear antibody (ANA). A spectrum of immune abnormalities was observed including hypergammaglobulinemia, immunoglobulin M (IgM) paraprotein, elevated circulating immune complexes, plasma cell hyperplasia, lymphocytotoxic antibodies and autoantibodies to autologous or donor lymphocytes. Despite clinical similarity to collagen vascular diseases, none of these patients had anti-DNA antibodies or antibodies to smooth muscle, thyroid or extractable nuclear antigens. In one patient, a skin graft from the marrow donor remained healthy despite progressive involvement in recipient skin, whereas unrelated skin grafts were rejected. Immunosuppressive therapy and plasmapheresis have not been effective. Four patients have died (median survival 458 days from transplantation). Chronic GVHD appears to be a syndrome of disordered immune regulation features of immunodeficiency and autoimmunity.