A reassessment of the risk of multiple sclerosis developing in patients with optic neuritis after extended follow-up.

One hundred and one of 146 patients presenting with isolated idiopathic optic neuritis, previously reviewed in 1978, were reassessed clinically, and retyped for HLA antigens and Factor B alleles, after a mean follow-up of 11.6 years. Fifty eight patients (57%) had developed multiple sclerosis at the time of reassessment in the present study, of whom 51 (88%) had clinically definite disease. This compared with 40% of the original group, in 1978, of whom 62% then had clinically definite multiple sclerosis. When the life-table method of analysis was used, the probability of developing multiple sclerosis was 75%, 15 years after the initial episode of optic neuritis. The frequencies of HLA-DR2 and the recently defined D-region antigen, DQw1, were significantly increased in patients with isolated optic neuritis and those who subsequently developed multiple sclerosis compared with normal controls, but neither allele appears to influence progression from optic neuritis to multiple sclerosis. Patients with optic neuritis who were HLA-DR3 positive had an increased risk for the development of multiple sclerosis (RR = 2.8) and this risk was further enhanced when DR3 occurred in combination with DR2 (RR = 6.7). The overall increased risk of developing multiple sclerosis for patients with this combination was 26 times that for the normal population. When the patients' original tissue-typing was considered BT 101 no longer influenced conversion of optic neuritis to multiple sclerosis. This may partly be explained by improved methods of tissue-typing, since not all BT 101 patients were subsequently found to be positive for HLA-DR2 or HLA-DQw1 and vice versa and by extended follow-up as multiple sclerosis conversion in HLA-DR2 negative individuals increased with time. All 101 patients were typed for Factor B alleles. No significant differences in frequencies were found between individuals with isolated optic neuritis or those who progressed to multiple sclerosis compared with the control population. Recurrent episodes of optic neuritis were associated with an increased risk for the development of multiple sclerosis in this study.     

Substance P-immunoreactive sensory axons in the rat respiratory tract: a quantitative study of their distribution and role in neurogenic inflammation.

Substance P is one of the peptides released from sensory nerves that mediate "neurogenic inflammation." Although substance P-immunoreactive (SP-IR) axons are known to be present within the mucosa of the respiratory tract, the relative extent of the innervation of various components of the mucosa is not known. Therefore, we determined the distribution and number of SP-IR axons in the rat trachea and bronchi, by using immunohistochemistry on tissue whole mounts. Specifically, we sought to learn whether these axons directly innervate the postcapillary venules involved in neurogenic plasma extravasation, the arterioles involved in neurogenic vasodilatation, and the airway smooth muscle involved in bronchoconstriction in pathogen-free, adult male F344 rats. We found that 90% of the SP-IR axons were single axons, usually having varicosities. Eighty-five percent of these were in the epithelium, 6% innervated arterioles, and the remainder elsewhere in the lamina propria. Only 10% of the mediator-sensitive postcapillary venules (i.e., venules labeled with Monastral blue pigment after challenge with capsaicin or substance P) were within 10 microns of SP-IR axons. SP-IR axons were more than 10 times as frequent in the smooth muscle of the distal bronchi as in the trachea. Capsaicin pretreatment (168 mg/kg over 7 days) reduced the number of SP-IR axons in the trachea by 96%, which is consistent with their being sensory. Unilateral vagotomy reduced the number of SP-IR axons bilaterally in the trachea and ipsilaterally in the main stem bronchus. Using an antibody to Protein Gene Product 9.5 as a nonspecific marker for all nerves in the trachea, we determined that SP-IR axons constituted 90% of the axons in the epithelium, 32% of the axons on arterioles, and only 4% of the axons in the smooth muscle. We conclude that most SP-IR nerves in the trachea are sensory axons and most of these axons end in the epithelium. SP-IR axons innervate mucosal arterioles, but few innervate postcapillary venules. Therefore, the mechanism by which sensory axons evoke plasma extravasation from these venules is likely to involve the diffusion of the peptide or a secondary mediator from the epithelium or from the arterioles upstream.     

Anticytoplasmic autoantibodies in the diagnosis and follow-up of Wegener's granulomatosis

Sixty-five patients with biopsy-proven Wegener's granulomatosis (WG), 54 with systemic vasculitis, 22 with relapsing polychondritis, 20 with sarcoidosis, 20 with malignant pulmonary lesions, and 15 with other conditions underwent determination of anticytoplasmic autoantibodies (ACPA) by the indirect immunofluorescence technique on neutrophil cytospin preparations to assess the specificity of ACPA for WG, their sensitivity in relationship to the extent and activity of the disease, and their value for follow-up of WG. Of these 65 patients with WG, 38 were ACPA positive. Two patients in the vasculitis group, best categorized as having microscopic polyarteritis, were ACPA positive. We obtained 125 serum samples from the 65 patients with WG and assigned them to one of two categories (limited or generalized), based on the extent of disease. Each of these categories was then subdivided into "active" or "in remission." Median ACPA titers were significantly different between active disease and remission in each category, as well as between active limited and active generalized disease. All patients whose disease changed from active to in remission had reductions in ACPA titer levels; those who experienced flares had titer increases. Patients with intercurrent illnesses or complications of treatment, mimicking WG flares, did not have titer increases. We conclude that ACPA determined by the indirect immunofluorescence technique is highly specific for WG. The sensitivity is dependent on the extent and activity of WG, and serial titer determinations are valuable in monitoring disease activity.     

Second malignant tumors in patients with laryngeal carcinoma: diagnosis, treatment, and prevention

Although the survival rates reported for patients with larynx carcinoma are quite good, there is a risk of developing second malignant tumors (SMT) in this population. The prognosis for SMT is poor, particularly with tumors of the lung and esophagus. The Rochester series was analyzed for larynx stage and specific SMT sites, possible common etiologic factors, and survival of the population as a whole, as well as for the SMT group. From a total of 235 patients with larynx carcinoma and a median follow-up of 10 years, 50 patients with 61 SMT were identified. The overall incidence of developing a SMT was 21%, with 44% of the SMT in the lung. The median survival from SMT diagnosis was 8.74 months and the 2-year survival was only 26%. More than twice as many SMT were observed than would be expected in the population at risk, with an observed-to-expected ratio (OER) for lung SMT of 5.3, and 8 times as many head and neck SMT occurring in our population. These SMT are not treatment related but are most likely caused by a combination of exposure to a common carcinogen, that is, tobacco smoke and alcohol, and to inherent factors, notably "condemned mucosa syndrome." Follow-up procedures, from the perspective of SMT development in larynx cancer patients, are addressed in an attempt to improve survival. The focus of this study is the high incidence of lung primaries that could be mistaken for metastatic disease, which is relatively uncommon in early larynx cancer patients.     

Metabolic depression and myocardial potassium

Summary The action potential duration (APD) of guinea pig atrial muscle responded qualitatively to metabolic depression and altered glucose concentration as shown previously for papillary muscle. Both preparations lost potassium and gained sodium during 8 h anoxic incubations and these changes were partially prevented by 50 mM glucose. Experiments with potassium⁴² indicated that anoxia-induced loss of potassium was not primarily due to an increased efflux but to a decreased influx. Stimulation did not increase potassium⁴² efflux from atria but caused some increase in potassium loss. The ATP content of atria and ventricular muscle decreased rapidly during anoxic incubation but was maintained at a significantly higher level in the presence of 50 mM glucose. Since muscle potassium levels following 8 h of anoxic incubation were incompatible with observed resting potentials, the results support the concept of either an electrogenic sodium pump or the intracellular compartmentalization of potassium. In addition, the anoxia-induced reduction of action potential duration does not appear to be associated with an increase in potassium⁴² efflux.This work was supported by grants from the Medical Research Council of Canada and the Canadian Heart Foundation.     

In vitro parasite-monocyte interactions in human leishmaniasis: possible role of fibronectin in parasite attachment.

Leishmania spp. must attach to mononuclear phagocyte surfaces before entering this host cell. We investigated the potential role of fibronectin in facilitating parasite attachment. Human plasma fibronectin bound to axenically cultured promastigotes, and promastigotes and amastigotes preferentially bound to fibronectin-coated cover slips. Promastigotes grown in the absence of fibronectin were strikingly deficient in their ability to attach to human monocytes compared with promastigotes grown in the presence of fibronectin. Rabbit anti-human plasma fibronectin antiserum decreased promastigote and amastigote attachment to monocytes. Immunoglobulin G F(ab')2 and Fab fragments also reduced the ability of amastigotes to bind to monocytes. Antiserum pretreatment of amastigotes followed by washing resulted in reduced parasite binding, whereas antibody pretreatment of monocytes did not. Addition of exogenous fibronectin did not enhance parasite attachment to monocytes. These findings suggest that Leishmania spp. can bind fibronectin and may utilize this glycoprotein to facilitate attachment to the mononuclear phagocytes that they infect.     

Morphometry of right ventricular hypertrophy induced by myocardial infarction in the rat.

The growth response of the right ventricle was studied in rats following ligation of the left coronary artery, which produced infarcts comprising approximately 40% of the left ventricle. A month after surgery the weight of the right ventricle was increased 30%, and this hypertrophic change was characterized by a 17% wall thickening, consistent with the 13% greater diameter of myocytes. Myocardial hypertrophy was accompanied by an inadequate growth of the microvasculature that supports tissue oxygenation. This was seen by relative decreases in capillary luminal volume density (-27%) and capillary luminal surface density (-21%) and by an increase in the average maximum distance from the capillary wall to the mitochondria of myocytes (19%). In contrast, measurements of the mean myocyte volume per nucleus showed a proportional enlargement of these cells (32%), from 16,300 cu mu in control animals to 21,500 cu mu in experimental rats. Quantitative analysis of the right coronary artery revealed a 33% increase in its luminal area, commensurate with the magnitude of ventricular hypertrophy.     

Functional Analysis of B-L (Ia-Like) Antigen-Bearing Chicken Peripheral Blood Cells

The functional of B-L (Ia-equivalent)-positive (B-L+) adn -negative (B-L-) chicken peripheral blood lymphocytes (PBL) was studied in vitro and in vivo. The PBL were first stained in direct immunofluorescence tests with a fluorescein isothiocyanate-labelled anti-B-L alloantiserum and then separated by means of a fluorescence-activated cell sorter. In agreement with our previous findings, B-L- cells showed functional properties of T lymphocytes, responding to concanavalin A and phytohaemagglutinin-P in vitro and inducing a graft-versus-host (GVH) reaction when injected into allogeneic embryos. Sorted B-L+ gave no responses in any of these assays. Neither B-L+ nor B-L- cells, when tested alone, responded significantly to pokeweed mitogen, but mixtures of the two restored the responsiveness to that of the original unsorted suspension. Of the B-L+ PBL, 10% were T cells, which may account for the low GVH reactivity given by this population.     

Neutrophils Injure Bronchial Epithelium after Ozone Exposure

Neutrophil (PMN) influx is an early, prominent finding in the airways of humans after experimental inhalation of ozone (O3), however the potential for PMN to contribute to epithelial injury in this setting is unknown. Bronchial epithelial cells of the human BEAS 2B R1.4 cell line or primary human bronchial epithelial cells underwent DNA labeling by incubation with BrdU. Monolayers were exposed to O3 (0.05 to 1 ppm) or filtered air for 60 min., and subsequently incubated with PMN for 2 h. Epithelial cell cytolysis was significant only in BEAS exposed to O3 and co-cultured with PMN. Apoptosis was maximal in BEAS exposed to O3 + PMN. Primary bronchial epithelial cells were resistant to injury; no cytolysis was detected, and apoptosis was detected only after treatment with 10 mM H₂O₂. Neutrophils may increase damage to the respiratory epithelium after O3 exposure, but primary bronchial epithelial cells are resistant to PMN and ozone induced injury.