HLA-B27-associated heart disease. Clinicopathologic study of three cases

The histologic features of the cardiac lesions in HLA-B27-associated heart disease were examined in three cases that illustrate different nuances of the clinical spectrum of this disorder. One of these cases constitutes an important link between the previously established concept of cardiac manifestations in ankylosing spondylitis and Reiter's disease and the recently introduced, wider concept of HLA-B27-associated cardiac manifestations. A correlation between the invasive electrophysiologic results and the autopsy findings is demonstrated in another case.     

Premature death and associated risk factors in urban middle-aged men

The full range of premature mortality and associated risk factors was analyzed for a follow-up period of three and a half to eight years in a uniform group of 7,935 middle-aged males (46 to 48 years old at screening) participating between the years 1975 and 1979 in the preventive population program in Malmö (participation rate 76.7 percent). Of the 218 deaths that occurred, necropsy was performed in 181 (83.0 percent). Three major causes of death were established: cancer (61/218), alcohol-related deaths (55/218), and coronary heart disease (50/218). In these three main categories of male premature mortality, significant and distinctly differential risk factor patterns were found. In coronary heart disease, smoking (p = 0.0062), serum cholesterol level (p = 0.00014), serum triglyceride level (p = 0.00013), systolic blood pressure (p = 0.000012), and diastolic blood pressure (p = 0.0021) were the strongest single determinants, but the independent role of the diastolic blood pressure disappeared in a multivariate analysis whereas all the others could be combined in a highly predictive logistic model. In the alcohol-related group, equal or stronger risk factor associations were present for serum gamma-glutamyltransferase level (p < 0.0001), questionnaire alcoholism screening response (p < 0.0001) and, inversely, serum cholesterol level (p = 0.0046) and serum creatinine level (p < 0.0001), all of which were independent and could be combined in an even more predictive logistic model than in the coronary heart disease group. In the cancer deaths, significant associations were found for serum urate level (p = 0.023) and, inversely, serum cholesterol level (p = 0.056 ? 0.031). Malignant and alcohol-related diseases constituted at least equally prominent groups as the cardiovascular disorders of the total premature deaths that occurred during middle age in these cohorts of Malmö males. All of these conditions are potentially avoidable and seem to be associated with significant and distinctive risk factor patterns. It seems possible that these factors may be applied, in current alcohol-related disorders and in future malignant diseases, both as indicators of the respective risks and as signals and instruments for directed preventive measures like the previously well established and tested methods for the regulation of blood pressure, serum lipids levels, and so on.     

The nephropathy of the nail-patella syndrome: Clinicopathologic analysis of 11 kindred

Seventy-two members of 11 kindred with the nail-patella syndrome were studied. Twelve patients who had electron microscopic examinations of renal tissue had abnormalities of the glomerular basement membrane. An unaffected family member did not. This lesion consisted of irregular basement membrane thickening, epithelial foot process fusion and the presence of fibrillar collagen-like material within the substance of the membrane. Many patients also showed areas of increased lucency giving the membrane a “moth-eaten” appearance. The presence of the ultrastructural lesion bore no relation to the presence or absence of abnormalities by light or immunofluorescent microscopy and also no relation to demonstrable alterations of renal function. The determinants of clinically significant nephropathy are unknown but in most patients the prognosis is favorable.     

Sporothrix schenckii meningitis in a farmer with Hodgkin's disease

A fatal case of chronic meningeal sporotrichosis occurring as an opportunistic infection in a patient with Hodgkin's disease is presented. A pulmonary source of infection was identified at autopsy. The diagnostic importance of the isolation of Sporothrix schenckii from cerebrospinal fluid, even if only from a single specimen, is stressed.     

Reappearance of beriberi heart disease in Japan: A study of 23 cases

Twenty-three Japanese patients with beriberi heart disease, 17 of them teenagers, were studied. The recent tendency for teenagers to take excessive sweet carbonated soft drinks, instant noodles and powermill-polished rice readily induces relative thiamine deficiency. A sudden increase in thiamine requirements due to strenuous exercise can result in overt beriberi heart disease. Alcohol had nothing to do with the development of the disease.Characteristic features commonly seen in teenage patients include peripheral edema, low peripheral vascular resistance, increased venous pressure, enlarged heart, T wave abnormalities, hyperkinetic circulatory state and increased circulating blood volume. Thiamine deficiency was confirmed by a decrease in blood thiamine concentration, a decrease in erythrocyte transketolase activity and an increase in thiamine pyrophosphate (TPP) effect. Improvement was rapidly achieved with thiamine administration, balanced nutrition and rest, especially in the teenage patients.Increased circulating blood volume was useful in differentiating beriberi heart disease from hyperthyroidism.     

Ankylosing spondylitis: An important cause of severe disturbances of the cardiac conduction system: Prevalence among 223 pacemaker-treated men

The cause of severe disturbances of the cardiac conduction system is seldom possible to establish clinically at pacemaker implantation, apart from cases of acute myocardial infarction or digitalis intoxication and in relatively rare cases of inflammatory disorders such as sarcoidosis and systemic sclerosis. Since cardiac manifestations, mainly conduction disturbances, occur in patients with ankylosing spondylitis, the prevalence of this disease was determined using radiologie screening for sacroillitis in a population of 223 men who had permanently implanted pacemakers. Sacroillitis was found in 19 men (8.5 percent), 15 of whom fulfilled the diagnostic criteria for ankylosing spondylitis. In six patients, sacroillitis was asymptomatic and two of the patients were completely free of symptoms other than those originating from their heart manifestations. In seven of the 15 patients with ankylosing spondylitis and in the four patients with sacroillitis without clinical criteria of ankylosing spondylitis, the diagnosis was previously unknown. Uveltis and aortic regurgitation occurred in five patients each, while peripheral arthritis was twice as common. The prevalence of sacroillitis and ankylosing spondylitis of 8.5 and 6.7 percent, respectively, differ significantly (p < 0.01) from the frequencies found in general Caucasian populations of 1 to 2 and 0.1 to 0.5 percent, respectively. HLA B27 was present in more than 80 percent of the patients with sacrolilltis and/or ankylosing spondylitis, compared with 8 to 10 percent in the general population. This strong association is in accordance with previous studies of patients with symptomatic sacroillitis and/or ankylosing spondylitis. Thus sacroillitis, diagnosed by x-ray, can be considered a marker for this relatively common rheumatic cause of severe disturbances of the cardiac conduction system.     

Mixed cryoglobulinemia: Clinical aspects and long-term follow-up of 40 patients

The clinical course of 40 patients with significant quantities of mixed cryoglobulins, but without lymphoproliferative, collagen-vascular or chronic infectious diseases, is presented. These cases comprise 51.3 percent of all mixed and 31.7 percent of all types of cryoglobulins evaluated by us over the period 1960–1978. A characteristic clinical syndrome, consisting of recurrent palpable purpura (100 percent), polyarthralgias (72.5 percent) and renal disease (55 percent), was seen. Biopsy specimens of skin lesions showed cutaneous vasculitis, and half had immune reactants in vessel walls. Seventy percent of patients had evidence of hepatic dysfunction, often subclinical, and more than 60 percent of those tested had serologic evidence of prior infection with hepatitis B virus. Hepatic lesions ranged from minimal triaditis to chronic active hepatitis and/or cirrhosis. All 22 patients in whom clinical renal disease developed had significant proteinuria; 63.6 percent had diastolic hypertension, 77.3 percent edema, 45.5 percent renal failure and 22.7 percent were nephrotic. Glomerular disease associated with deposition of immunoglobulin G, immunoglobulin M and complement, often with coexistent renal arteritis, was confirmed pathlologically in 15 cases.All cryoglobulins had rheumatoid factor activity and consisted of IgM and polyclonal IgG; five also contained IgA. Thirteen had a monoclonal IgM kappa component. Serum protein electrophoresis was unremarkable or showed diffuse hyperglobulinemia. Striking depression of early complement components was noted but did not correlate well with the cryoprotein concentration, renal involvement or clinical course.Follow-up for periods up to 21 years from onset of symptoms revealed that renal involvement has a deleterious effect on prognosis. Postmortem examinations of nine patients demonstrated widespread vasculitis in addition to renal involvement. Preterminal infection was found in eight.     

Cellular immune findings in Lyme disease. Correlation with serum IgM and disease activity

Cellular immune findings were studied in 48 patients with various stages of Lyme disease. At each stage, some patients, particularly those with neuritis or carditis, had elevated serum IgM levels and lymphopenia. During early disease, mononuclear cells tended to respond normally to phytohemagglutinin, and spontaneous suppressor cell activity was greater than normal. Later, during active neuritis, carditis, or arthritis, the trend was toward heightened phytohemagglutinin responsiveness and less suppression than normal. By multiple regression analysis, serum IgM levels correlated directly with disease activity (p = 0.025) and inversely with the number of T cells (p = 0.02); during acute disease only, elevated IgM levels correlated with increased phytohemagglutinin responsiveness (p = 0.004) and decreased suppressor cell activity (p = 0.03). Decreased suppression, observed later in the disease, may permit damage to host tissues because of either autoimmune phenomena or a heightened response to the Lyme spirochete.     

Prazosin and congestive heart failure: Short- and long-term therapy

Reviewed here are the data from 34 patients given prazosin for chronic intractable heart failure. In 13 patients in whom hemodynamics were measured after the fifth 3 mg dose of prazosin was given, no attenuation was found. The cardiac index increased from 1.77 ± 0.13 to 2.5 ± 0.13 liters/min/m² (p < 0.001), and the pulmonary capillary wedge pressure decreased from 31.46 ± 1.56 to 23.54 ± 1.11 mg Hg (p < 0.001).During long-term follow-up (15.9 ± 1.5 months) the administration of spironolactone proved to be very useful. Within three months of starting prazosin therapy, none of the 15 patients discharged on a regimen of spironolactone needed readmission for edema, but 11 of the 13 patients discharged without a spironolactone regimen did. The addition of spironolactone or an increase in furosemide to the therapeutic regimen was helpful but a change to hydralazine was not.We conclude that prazosin causes short-term hemodynamic and long-term clinical improvement in patients with intractable heart failure; that spironolactone helps to prevent clinical attenuation but that more detailed studies are required to better characterize the attenuation to vasodilators seen in patients with congestive heart failure.     

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.     

Pericardial disease in rheumatoid arthritis.

Six patients with rheumatoid constrictive pericarditis, five seen in a two and one half year period, are described. All patients were male, all had rheumatoid factor, and all had active arthritis. Diagnosis was suspected from careful physical examination and confirmed in five patients by cardiac catheterization. Pericardiectomy was successful in all five patients on whom it was performed. Rheumatoid constrictive pericarditis should be suspected in any patient with rheumatoid arthritis and unexplained signs of right heart failure.     

Response of Paget's disease to porcine and salmon calcitonins: effects of long-term treatment

Multiple clinical, biochemical and immunologic variables were measured in 49 patients with Paget's disease during 4 to 41 months (mean, 25 months) of treatment with porcine (PCT) or synthetic salmon calcitonin (SCT) or both. Mild nausea and dermal reactions occurred in 20 per cent of the patients and were generally transient. Skeletal and radicular pain, and overt neurologic deficits were moderately to dramatically relieved in 75 per cent of the patients. Maximal clinical benefits were achieved during the first 6 to 12 months of treatment, with only one fifth of the patients experiencing intermittent exacerbations of pain during the 2nd and 3rd years of treatment. Three examples of dramatic roentgenologic improvement were observed. SCT doses of 50 MRC units three times a week generally were as effective as 100 MRC units three times a week or daily. Dissociation among the clinical effects, the decrease in serum alkaline phosphatase and the decrease in urinary hydroxyproline were common.Binding antibodies developed in 60 per cent of the patients treated with PCT and in 30 per cent of those treated with SCT; however, SCT-binding antibodies usually were present in higher titer and with a greater frequency of SCT neutralization activity. No correlations were present between the development of antibodies and the incidence of biochemical rebounds or the failure of increased doses of SCT to renew biochemical effects. No evidence of increased secretory activity of the parathyroid glands was observed in 10 patients with biochemical rebounds.These data demonstrate the feasibility and efficacy of continuous long-term therapy with calcitonin on an outpatient basis, and SCT may be the treatment of choice for Paget's disease.     

Chest pain with angiographically insignificant coronary arterial obstruction: Clinical presentation and long-term follow-up

Among 3,242 coronary angiograms performed from November 1972 through October 1975 at the Massachusetts General Hospital, 175 patients had normal coronary arteries or luminal narrowings of less than 30 per cent. All patients were studied for chest pain, and none had experienced prior myocardial infarction. Subsequent information was available in 159 patients over a mean follow-up period of 42.7 months. There were no deaths, and only one myocardial infarction occurred during this period. However, among the patients followed, continued chest pain with episodes occurring at least once monthly was present in 54 per cent. In addition, 17 per cent of all patients required subsequent hospitalization and 44 per cent continued to receive antianginal medication. Nearly half of the group (46 per cent) suffered some limitation of activity, and 22 per cent stated that they had either changed jobs or stopped work because of chest pain. Continuing chest pain was significantly more common in women and in patients who had experienced chest pain for more than one year before angiography. However, typicality of chest pain for angina or the occurrence of electrocardiographic changes of ischemia prior to angiography did not predict continued chest pain during the follow-up period. Thus, although mortality and morbidity are low in this group of patients, the syndrome of chest pain with angiographically insignificant coronary artery obstruction has an important impact on the lives of a majority of those affected.     

Efficacy of new inotropic drugs in clinical coronary heart failure

The cardiovascular effects of dobutamine, 2.5 to 10 μg/kg/min, were studied nonlnvasively using a phonocardiographic method in seven patients with aortic ball valve prostheses. Increases in left ventricular ejection rate were produced which were similiar to those achieved after the administration of Isoproterenol, 0.02–0.08 μg/kg/min, but the increase in heart rate was only minimal with dobutamine. In 10 patients with coronary disease the same concentrations of dobutamine increased cardiac output and rate of increase in left ventricular pressure (dp/dt) without changing heart rate; separation of inotropic from chronotropic effects was thereby produced with dobutamine. Further, continuous infusion of the agent in three patients with advanced coronary failure showed enhanced contractility by noninvasive systolic time intervals with parallel improvement in clinical status. Thus, dobutamine has therapeutic value in acute and chronic coronary heart failure.UK 14,275, a phosphodiesterase inhibitor, was shown to possess positive inotropic activity by noninvasive systolic time intervals in 10 normal subjects. This inotropic effect produced by 16 to 128 μg/kg/min of the new agent was abolished by prior treatment with propranolol. Inotropic activity of UK 14,275 was also demonstrated hemodynamically in eight patients with coronary disease: 128 and 256 μg/kg/min substantially increased left ventricular dp/dt and cardiac output without chronotropic change. Since preliminary clinical studies have also demonstrated cardtotonic activity with oral UK 14,275, this compound has potential value in the ambulatory therapy of chronic heart failure. Since Q-T interval prolongation occurs with UK 14,275, potential arrhythmogenlcity of the agent requires evaluation.     

Chronic neutropenia in childhood: Analysis of 16 cases and a review of the literature

We analyzed the clinical histories and hematologic information concerning 16 persons in whom chronic neutropenia was discovered early in life. Only two of them, those with the lowest mean neutrophil counts, had frequent and severe pyogenic infections. Almost all the infections were caused by Staphylococcus aureus or by enteric microorganisms and involved the skin, respiratory tract or gastrointestinal system. The prognosis in our subjects or in patients described in the literature could not be predicted from the bone marrow morphology, presence or absence of blood monocytosis, pattern of genetic transmission or results of special tests of neutrophil function.We propose that the complex nomenclature associated with chronic neutropenic states be discarded until a better basis for classification becomes available.     

The physiologic significance of plasma transport of vitamin D and metabolites

Vitamin D and its metabolites do not circulate free but are bound to specific plasma transport proteins that solubilize them and protect them from oxidative inactivation. A specific vitamin D transport protein has been demonstrated in man, rat and chick; it preferentially binds 25-hydroxyvitamin D (25-(OH)D), the major active form of the vitamin in the circulation. The binding of vitamin D and its analogs by the D/25-(OH)D transport protein from rat plasma involves recognition of structural properties and steric configuration of both the single ring and the side chain. The C-25 hydroxyl group plus the vitamin D₃ configuration of both the side chain and the single ring maximize the binding. Although the binding of vitamin D₂ and its analogs by human and rat D/25-(OH)D transport protein is roughly equivalent to that of vitamin D₃ and its analogs, abnormal plasma binding of vitamin D₂ and 25-(OH)D₂ by the D/25-(OH)D transport protein in chick plasma may play an important role in the increased metabolic inactivation of these compounds and the resultant decreased antirachitic potency of vitamin D₂ in the chick. Preliminary studies suggest that 1,25-(OH)₂D is carried by the D/25-(OH)D transport protein in rat plasma but that a specific dihydroxy transport protein also exists in human plasma. These studies suggest that transport proteins play an important role in the facilitation of vitamin D transport and normal vitamin D metabolism.