Relationship between bronchial responsiveness to hyperventilation with cold and methacholine in asthma

Twenty-seven subjects with asthma and normal baseline lung function were challenged with aerosols of methacholine (M) and by isocapnic hyperventilation with cold air (HV). Stimulus-effect relationships were determined for each provocational technique on separate days and were expressed as the dose required to produce a 20% fall in forced expired volume in 1 sec (FEV₁) obtained by linear interpolation from log stimulus vs. response curves (PD₂₀). Each stimulus was applied with a sufficient intensity to produce a 20% or greater fall in FEV₁ in each subject. The PD₂₀ for M correlated significantly with the PD₂₀ for HV (p < 0.001) when the latter was expressed in liters per minute. The correlation between cumulative M PD₂₀ and HV PD₂₀ expressed as a percent of maximal voluntary ventilation was significant but less strong. We conclude that the airway response to HV reflects nonspecific bronchial hyperresponsiveness and that the dose of HV is best determined as the absolute level of ventilation.     

Exercise-induced anaphylaxis: a serious form of physical allergy associated with mast cell degranulation

Exercise-induced anaphylaxis (EIA) is a unique and an increasingly recognized syndrome consisting of premonitory symptoms and signs of generalized body warmth, pruritus, and erythema, which progresses on continued exertion to confluent urticaria, laryngeal edema with stridor or hoarseness, and gastrointestinal colic and frequently culminates in vascular collapse. Previous studies of five individuals with this condition have demonstrated significant elevations of serum histamine concurrent with the early clinical manifestations after experimental exercise. To assess relevant morphologic alterations in the skin of these patients, cutaneous mast cells were examined by light and transmission electron microscopy before and during the initial erythema elicited by exertion. The marked alterations observed in mast cells immediately after exercise consisted of (1) loss of electron density and internal substructure of granules, (2) fusion of granule membranes with those of adjacent granules and with mast cell membranes creating conduits to the extracellular space, and (3) an apparent decrease in the number of intact granules per cell. Biopsy specimens obtained before exercise from patients with EIA and from two normal individuals who served as control subjects were identical, and the control subjects had normal mast cell morphology after exercise. Serum histamine levels were significantly elevated in patients with EIA after exercise at the time of biopsy, whereas control subjects had normal levels. These observations provide evidence that EIA is a distinct form of physical allergy associated with mast cell degranulation similar in morphology to that of human pulmonary mast cell IgE-Fc-dependent activation secretion. Characterization of this disorder is important because its prevalence may be underestimated, and its clinical consequences, which may include some morbidity, are not fully known.     

Magnitude and site of airway response to exercise in asthmatics in relation to arterial histamine levels

In order to determine if there is a relationship among arterial histamine levels, state of disease activity, and the magnitude and site of obstruction in exercise-induced asthma, we recorded airway resistance, lung volumes, spirometry, and density dependence of maximum expiratory flow before and after an exercise challenge in 17 asymptomatic individuals. These observations were then related to the concentration of histamine in systemic arterial blood. This study demonstrates that those individuals whose disease process was the most active at the time of investigation had more depressed lung function and higher baseline histamine levels, and responded to the challenge with severe obstruction that involved the airways in the periphery of the lung. In contrast, those subjects whose underlying disease was more quiescent had lower histamine values and the response to provocation was less severe and predominated in the larger airways. In neither group did the postchallenge values for histamine increase. It is suggested that the factor that determines these patterns of response is the state of inflammation of the airways, for which histamine may serve as a marker.     

Rheumatoid arthritis: psychiatric aspects and use of psychotropics

Many of the psychiatric side effects—especially depression—of agents (corticosteroids, nonsteroidal anti-inflammatory drugs (NSAIDs), and hydroxychloroquine) commonly used to treat rheumatoid arthritis may be mistaken for psychological sequelae to the disease itself. By and large, psychotropics can be used safely with the usual cautions but without undue concern for drug interactions, except for the tendency of lithium clearance to be reduced by several of the NSAIDs. Most specific choices of antidepressant or neuroleptic are made to avoid the side effects most disruptive to the patient with RA.     

An ultrastructural comparison of mesotheliomas with adenocarcinomas of the lung and breast

The ultrastructural features of 15 mesotheliomas were compared with those of equal numbers of adenocarcinomas of the lung and of the breast in a double-blind study. Combined quantitative and qualitative features were evaluated to provide criteria for distinguishing among these three tumors, which may present as either primary or metastatic pleural tumors. mesotheliomas could be distinguished from adenocarcinomas of the lung by length of microvilli (mean ratios of length to diameter [LDR], 15.7 and 8.7, respectively; P less than 0.01) and content of tonofilaments. Length of microvilli was also useful in distinguishing mesotheliomas from breast adenocarcinomas (mean LDR, 15.7 and 6.9, respectively; P less than 0.001). Adenocarcinomas of the lung could be distinguished from adenocarcinomas of the breast by tonofilament content and the presence of intracytoplasmic lumina. Combined quantitative and qualitative criteria are essential for maximal ultrastructural discrimination among these tumors.     

Giant cell myocarditis after mitral valve replacement: case report and studies of the nature of giant cells

A 22-year-old man with Marfan's syndrome and a history of antinuclear antibody-positive hepatitis died 25 days after undergoing cardiac valve replacement surgery for mitral valve prolapse. Giant cell myocarditis was found at autopsy. The multinucleated giant cells were shown by immunoperoxidase techniques to contain lysozyme, but not myosin or creatine phosphokinase, suggesting that they were derived from macrophage, rather than myocyte, precursors.     

Anatomic analysis of removed prosthetic heart valves: causes of failure of 33 mechanical valves and 58 bioprostheses, 1980 to 1983

The details of heart valve prosthesis-associated problems are not widely known. This study investigated the etiologies of the failures of 91 valves, 33 mechanical prostheses and 58 bioprostheses, obtained at reoperation (83) or autopsy (eight) at the Brigham and Women's Hospital during the 42-month period from mid- 1980 through 1983, one to 264 months (mean, 72 months) after valve replacement. Analysis was by gross, histologic, radiographic, and microbiologic examination, as well as review of clinical records. Overall causes of failure included paravalvular leak (15 per cent), thrombosis (7 per cent), tissue overgrowth (8 per cent), degeneration or mechanical failure (43 per cent), and endocarditis (19 per cent). Endocarditis and paravalvular leak were equally frequent with mechanical prostheses and bioprostheses. In addition, thrombosis (18 per cent), tissue overgrowth (21 per cent), and structural failure (12 per cent) were all important failure modes for mechanical prostheses. Sterile degeneration was the overwhelming cause of failure for bioprostheses, accounting for the failure of 35 of 58 (60 per cent) of those recovered. Sterile degeneration took several forms: calcification, with or without cuspal tears (27 cases, 47 per cent of bioprostheses; mean, 77 months, range, 44 to 108 months) and cuspal defects without calcification (eight cases, 14 per cent; mean, 59 months, range, eight to 122 months). In general, calcification increased with time after implantation, but the propensity for the mineralization of bioprostheses varied widely among patients. Four torn valves that had been in place for more than six years had radiographically undetectable calcific deposits. The results of this study indicate that paravalvular leak and endocarditis are frequent causes of failure for all valve types. No clear failure mode predominates with mechanical valve prostheses, although some designs have specific inherent limitations. In contrast, degeneration, especially that related to mineralization, is the most important cause of the late failure of contemporary bioprostheses.     

Diagnosis of duodenal and ampullary epithelial neoplasms by endoscopic biopsy: a clinicopathologic and immunohistochemical study

A series of 19 duodenal and 16 ampullary neoplasms was studied to determine their pathologic features on endoscopic biopsy, to evaluate the diagnostic accuracy of this procedure, and to assess the usefulness of immunohistochemical staining for carcinoembryonic antigen (CEA) in these neoplasms. The 11 benign neoplasms (31 per cent) were adenomas, five of which had focal hyperplastic features; the 24 malignant neoplasms (69 per cent) included ten intestinal-type carcinomas (resembling colonic carcinoma), seven anaplastic carcinomas (resembling diffuse gastric carcinoma), two adenocarcinomas in situ, and five lesions of unoriented, cytologically malignant epithelium. Malignancy was suspected endoscopically in 19 of 24 carcinomas, and the majority of the benign neoplasms were described as polyps or plaques. Resections (performed in 20 cases) demonstrated the accuracy of the biopsy diagnoses in 17 cases (85 per cent). In the three discordant cases, diagnosed by biopsy as adenoma in two cases and carcinoma in situ in one, coexistent in situ or infiltrating carcinomas were identified in the resected specimens. Carcinoembryonic antigen (20 cases) was identified mostly along glycocalyceal borders in normal and adenomatous tissues, whereas the carcinomas also showed strong cytoplasmic staining for CEA. Endoscopic biopsy is a valuable procedure in the diagnosis of duodenal and ampullary neoplasms. Correlation of the pathologic features of biopsy specimens with endoscopic appearances may result in more accurate diagnoses.     

Keratin proteins and carcinoembryonic antigen in synovial sarcomas: an immunohistochemical study of 24 cases

Twenty-four synovial sarcomas were examined for the presence of keratin proteins by an indirect immunoperoxidase method with paraffin-embedded tissues. Keratin proteins were identified in 16 of 24 cases (67 per cent). Both the pseudoglandular and spindle cell areas of all eight of the biphasic synovial sarcomas and the spindle cells of eight of the 16 monophasic synovial sarcomas contained keratin proteins. In spindle cell areas, staining was observed in single cells and small cords and clusters of cells in the absence of cleft formation or other evidence of a pseudoglandular component. The predominant cytologic staining pattern in all cases was peripheral, with localization of staining to the cell membrane or adjacent areas, but diffuse and focal cytoplasmic staining patterns were also observed. No staining for keratin proteins was seen in 101 control cases, including 52 sarcomas of various types. Carcinoembryonic antigen was also identified in four of the 24 synovial sarcomas by an indirect immunoperoxidase technique. The identification of keratin proteins may be helpful in the pathologic diagnosis of synovial sarcoma, particularly the spindle cell monophasic variant.     

The prevalence of carcinoma in situ in normal and cancer-associated breasts

Two hundred ninety-two human breasts were examined in toto by a subgross sampling technique with histologic confirmation. The samples consisted of 185 breasts from random autopsies, 63 cancer-containing breasts, and 44 breasts contralateral to cancer-containing breasts. The method permits the identification and enumeration of essentially all of the dysplastic, hyperplastic, and neoplastic lesions present in each breast. Emphasis was on the prevalence within each sample category of ductal carcinoma in situ (DCIS), lobular carcinoma in situ (LCIS), and epithelial proliferative lesions with severe atypia, previously termed ALA 4 and ALB 4, which correspond to the clinicopathologic entities atypical ductal hyperplasia and atypical lobular hyperplasia, respectively. Additional primary foci of DCIS (unrelated to invasive breast carcinoma, if present) were found in 52.5 per cent of cancer-containing breasts, and were seen in 47.7 per cent of contralateral and 5.9 per cent of the breasts from random autopsies. Lobular carcinoma in situ was generally seen only in association with infiltrating carcinoma, usually of the ductal type. No LCIS was seen in the breasts from random autopsies. These trends are the same if the proliferative lesions with severe atypia are included with carcinoma in situ. The numbers of lesions were also markedly greater in affected cancer-associated breasts than in affected breasts obtained from autopsies. These findings suggest that LCIS, although a rare lesion in the general population, may be a significant marker for clinical carcinoma. They support previous studies showing a small percentage of women with undetected DCIS of uncertain clinical and biological potential. The multicentric nature of preinvasive breast carcinoma is further substantiated. Finally, when the prevalence and number of lesions are considered in association with the ages of the patients, the lower prevalence of such lesions in the older patients in each sample suggests that at least some DCIS and LCIS may be dependent on a premenopausal hormonal milieu for their continuing existence.     

Cytotoxic T lymphocytes and phenotypically abnormal epidermal dendritic cells in fixed cutaneous eruptions

Fixed cutaneous eruptions are erythematous plaques or bullae that recur, often after drug ingestion, at precisely the same cutaneous sites. The study of this condition may provide insight into the mechanisms responsible for regionally localized, immunologically mediated dermatoses. Biopsy specimens from both advancing borders and established centers of fixed eruptions were studied by immunofluorescence microscopy, light microscopy (1-micron sections), and transmission electron microscopy, and with a panel of monoclonal antibodies to Langerhans cells and subsets of T lymphocytes. The dermal inflammatory infiltrates of the advancing edges of the lesions were composed predominantly of OKT4/Leu-3a-positive lymphoid cells in perivascular array. In more established regions (the centers of the lesions), the majority of mononuclear cells were OKT8-positive lymphocytes disposed along the dermal-epidermal junction and migrating into the epidermis through focal defects in the basement membrane. In these areas, keratinocyte reactivity for anti-HLA-DR antibody and the apposition of intraepidermal lymphocytes to degenerating keratinocytes were observed. T6-positive epidermal dendritic cells were observed in normal numbers in the epidermis, although extensive study failed to reveal characteristic Langerhans cell granules within these cells. It is concluded that fixed cutaneous eruptions are characterized by an early vascular phase involving lymphocytes with helper/inducer phenotypes, and a later epidermal phase involving cytotoxic/suppressor cells. Potential effector cells with the phenotypic characteristics of cytotoxic T cells appear to represent important mediators of the epidermal damage characteristic of fixed cutaneous eruptions. Morphologically abnormal epidermal dendritic cells may contribute to regionally altered antigen presentation and may thus be relevant to the recurrence of lesions at identical cutaneous sites.     

Pulmonary vascular disease and hypertension after valve surgery for mitral stenosis

The reduction of pulmonary hypertension that occurs within 24 hours of valve replacement for mitral stenosis is well documented, but patients who die after surgery have not been adequately studied. Clinical and autopsy data for 16 patients who died following mitral valve replacement were reviewed. The emphasis was on preoperative and postoperative pulmonary arterial pressure and pulmonary vascular disease, including arterial, venous, and capillary changes. Morphologic features were graded and summed to obtain an additive histologic assessment (AHA). Patients were divided into three groups: 1) those who had uneventful operations and early postoperative periods but died prior to discharge; 2) those who had postoperative difficulty, with identifiable acute anatomic causes of death; and 3) those who had postoperative difficulty, with no apparent acute anatomic cause of death. In group 1 (n = 4) the preoperative pulmonary arterial pressure was 43 +/- 17 mm Hg, and AHA ranged from 0 to 4; in group 2 (n = 5) the preoperative pulmonary arterial pressure was 60 +/- 15 mm Hg, but AHA ranged only from 2 to 5. In group 3 (n = 7) the preoperative pulmonary arterial pressure was 59 +/- 12 mm Hg; AHA ranged from 6 to 9, significantly higher than that of the other groups (P less than 0.005). Three patients from group 3 had elevated pulmonary arterial pressure (60, 52, and 50 mm Hg three, six, and 15 days after surgery, respectively). Two additional patients had right heart failure with normally contracting left ventricles terminally. It is concluded that some patients with mitral stenosis who die after surgery with persistently elevated pulmonary arterial pressure have sufficiently severe pulmonary vascular disease to account for their persistent pulmonary hypertension and death.