Neurometric subgroups in attentional and affective disorders and their association with pharmacotherapeutic outcome.

To determine if quantitative electrophysiologic measures correlate with pharmacotherapeutic response, we conducted a retrospective analysis of treatment outcomes in sequential patients with attention deficit disorder and affective disorders. One hundred medication-free patients meeting DSM-III-R criteria for attentional and affective disorders underwent pretreatment EEG, quantitative Neurometric EEG, and physical/laboratory examinations. Attention-disordered patients were first treated with a stimulant, secondarily with an antidepressant, and tertially with an anticonvulsant. Affectively disordered patients were treated initially with antidepressant, and secondarily augmented with anticonvulsant or lithium. Tertiary treatment was a stimulant. Patients were assessed up to 6 months. A Clinical Global Improvement score was assigned. Similar Neurometric subgroups were identified within both the attentional and the affectively disordered patients. Subgroups were relative alpha frequency excess, relative theta frequency excess, and/or inter-hemispheric hypercoherence. Without regard to DSM-III-R diagnosis, there were robust correlations between Neurometric subgroup membership, responsivity to selected pharmacologic agent class(es), and clinical outcome. The frontal alpha excess subgroup was 87% responsive to antidepressants. The frontal theta excess subgroup was 100% responsive to stimulants. The frontal alpha excess/hypercoherent subgroup was 85% or more responsive to anticonvulsants/lithium. The frontal theta excess/hypercoherent subgroup was 80% responsive to anticonvulsants. Patients with similar Neurometric features responded to the same class(es) of psychopharmacologic agent(s) despite their DSM-III-R classification.

Prognosis of moderate dysplasia. Predictive value of selected markers in routinely prepared cervical smears.

Digital image analysis was used to extract features from 1,123 abnormal cells in 23 routinely prepared, Papanicolaou-stained cervical smears. All slides examined had a cytologic diagnosis of moderate dysplasia. Seven slides came from patients who eventually progressed to either a severe dysplasia or carcinoma in situ; the other 16 slides came from patients whose dysplasias regressed without evidence of more serious disease. Linear discriminant analysis correctly classified approximately 73% of the cells from the regression group and 66% of the cells from the progression group. Cell features contributing to the majority of variance in the model were the mean optical density of the nucleus, an autocorrelation measure, the mean optical density of the cytoplasm and the nuclear-cytoplasmic ratio. At the patient level, 13 (81.2%) of the 16 slides from the regression group and 6 (85.7%) of the 7 slides from the progression group were correctly classified. These figures yield a sensitivity of 66.7%, a specificity of 92.9%, a predictive value of a progression prognosis of 85.9% and a predictive value of a regression prognosis of 81.2%. The overall efficiency of the model was 82.6%. These preliminary results should encourage further studies for the identification of markers to indicate which patients are at high risk for progression of their cervical dysplasias.

Prediction of cervical neoplasia diagnosis groups. Discriminant analysis on digitized cell images.

The purpose of this study was to develop discriminant analysis models for predicting cervical dysplasia/neoplasia case diagnoses using cytometric features derived from the digital image analysis of cell monolayers. The data base consisted of 925 cells from 27 cases diagnosed either as moderate dysplasia (n = 10), severe dysplasia (n = 5), carcinoma in situ (n = 8) or invasive carcinoma (n = 4) on both tissue biopsy and monolayer preparations. Cell features examined were cell diameter, nuclear diameter, nuclear mean optical density (OD), nuclear integrated OD (IOD), nuclear OD standard deviation, normalized IOD, nuclear texture and nuclear-cytoplasmic ratio. Features derived from cells visually classified as moderate dysplasia correctly predicted the case diagnosis of moderate dysplasia versus more severe disease for 85% of the cells. Prediction models using summary measures (mean and variance) derived from all visually classified abnormal cells within each case correctly separated all cases into their respective diagnostic categories. These findings suggest that dysplastic cells in a cytologic sample have features that collectively reflect the tissue diagnosis, regardless of the visual differences among the cells. Such information has potential use for diagnosis and possibly for prognosis.

Respiratory syncytial viral infection in children with compromised immune function.

For 10 winters, 608 children five years old or younger who were hospitalized with respiratory syncytial virus (RSV) infection were prospectively studied to evaluate the relation between their immune status and the severity of their infection. Forty-seven had been immunocompromised by chemotherapy, steroid therapy, or a primary immunodeficiency disorder. Among the immunocompromised children, those receiving chemotherapy for cancer and those with immunodeficiency disease had more severe RSV disease, with pneumonia occurring at all ages, and a higher mortality rate. Children receiving long-term steroid therapy did not appear to have more severe clinical manifestations than normal children. Viral shedding, however, was significantly greater and more prolonged in the children receiving steroid therapy, and particularly in those receiving chemotherapy or with an immunodeficiency disease. Giant-cell pneumonia was documented in one child with leukemia. Over half the immunocompromised children acquired the RSV infection nosocomially. These findings indicate that children receiving chemotherapy for cancer and those with immunodeficiency disease are at risk for complicated or fatal infections from RSV and should be considered for antiviral and other therapies as they become available. Efforts should also be made to protect compromised children if hospitalization cannot be avoided.

Cytomorphometric differences among individual "moderate dysplasia" cells derived from cervical intraepithelial neoplasia.

Individual abnormal cervical epithelial cells can be categorized either by the lesion from which they are derived or by their unique cytologic characteristics. In building a data base for image analysis of cervical epithelial cells, categories of cells were defined according to distinct cytomorphologic characteristics, without knowledge of the lesion of origin. The three individual scorers, two cytopathologists and one senior cytotechnologist, most frequently agreed upon the cells classified as "moderate dysplasia." The measurements of digitized cells in this category had the smallest confidence intervals of any of the abnormal cell categories. For these two reasons, as well as the ubiquitous nature of "moderate dysplasia" cells in smears obtained from all patients with cervical epithelial neoplasia, cells in this category were studied in greater detail. Significant differences were noted in cell measurements among cells in this class when the cells came from patients with different grades of cervical neoplasia. The findings indicate that visually similar "moderate dysplasia" cells can be separated by digitized measurements into clusters dependent upon the parent lesion. The biologic implications are not yet clear, but such findings suggest that each disease is perhaps a committed lesion from inception. Therefore, predictability of ultimate outcome could be based on image analysis of cells derived from early cervical lesions, which would allow therapy to be performed on a more logical basis.

Evidence for both respiratory syncytial virus and measles virus antigens in the osteoclasts of patients with Paget's disease of bone.

Recent ultrastructural and immunohistochemical evidence supports the hypothesis that Paget's disease of bone is a slow viral infection of the Paramyxoviridae family. Conflicting evidence for the presence of respiratory syncytial virus (RSV), a pneumovirus, or measles, a morbillivirus, has been reported. By the indirect fluorescent antibody assay, four RSV antisera were compared with four measles antisera on serial sections of pagetic bone or replicate coverslips of cells from pagetic bone grown in culture from 30 patients. Results produced positive immunofluorescence for RSV in 28 of 29 patients and positive immunofluorescence for measles in 11 of 22 patients. Of the 20 patients from whom comparable samples could be tested for antigens, 11 were found to harbor both antigens. These studies support the hypothesis that Paget's disease of bone is a slow viral infection of the Paramyxoviridae family more closely related to the pneumoviruses than the morbilliviruses.

Immunoglobulin classes of Aleutian disease virus antibody.

Aleutian disease virus (ADV) persistently infects mink and causes marked hypergammaglobulinemia. Immunoglobulin class-specific antisera were used to define the total immunoglobulin of each class by radial immunodiffusion and the immunoglobulin class of ADV-specific antibody by immunofluorescence in experimentally and naturally infected mink. Electrophoretic gamma globulin closely reflects the immunoglobulin G (IgG) level in mink, and the majority of the increased immunoglobulin and ADV antibody in infected mink is IgG. IgM becomes elevated within 6 days after infection, reaches peak levels by 15 to 18 days, and returns to normal by 60 days after infection. The first ADV antibody demonstrable is IgM, and most mink have virus-specific IgM antibody for at least 85 days postinfection. Serum IgA levels in normal mink are not normally distributed, and ADV infection causes a marked elevation of IgA. Low levels of ADV-specific IgA antibody can be shown throughout the course of infection. Failure of large amounts of virus-specific IgG antibody to inhibit the reaction of virus-specific IgM and IgA antibodies suggests that the various classes of antibodies are directed against spatially different antigenic determinants. The IgM and IgA were shown not to be rheumatoid factors.

The effect of filtration on the loss of abnormal cervical cells in specimen preparation for automated cytology.

The UCLA monolayer procedure is used to produce a preparation of cervical epithelial cells for automated cytology. We investigated the nylon mesh filtration step of the procedure to determine if it altered the proportion of abnormal epithelial cells in the specimen. The proportion of such cells was found to be significantly lower (P less than 0.05) in the final specimen retained by a 10 micron nylon mesh filter than in the filtrate, which has been routinely discarded in our studies. The filtrate specimen is contaminated by large numbers of polymorphonuclear leukocytes, however, making it unusable for automated cytology at present. The implications of our findings for the cost effectiveness of classifier performance are considered, and the implications of the results for further improvements in specimen preparation are discussed.

Granulomatous pleuritis caused by Francisella tularensis: possible confusion with tuberculous pleuritis.

Granulomatous pleuritis, diagnosed by pleural biopsy, is rarely caused by disease processes other than tuberculosis. We present a case of granulomatous pleuritis caused by Francisella tularensis that occurred in a 55-yr-old male sheep shearer with an exudative, lymphocytic, pleural effusion. Confirmation of the diagnosis was made by elevated serum agglutination titers against F. tularensis and detection of the organism in a pleural biopsy specimen by the glucose oxidase immunoenzyme technique. We conclude that F. tularensis, not previously described as a cause of granulomatous pleuritis, must be considered in the differential diagnosis of granulomas found in pleural biopsy specimens.

Parenteral immunization with live respiratory syncytial virus is blocked in seropositive cotton rats.

Seropositive cotton rats cannot be immunized by intramuscular inoculation of live respiratory syncytial virus. Passively administered antiserum was shown to effect the immunosuppression. By contrast, the presence of serum antibody did not block immunization by the intranasal route.

Respiratory syncytial viral infection in infants with congenital heart disease.

Occasional reports have suggested that infants with congenital heart disease may have an increased risk of severe illness from respiratory syncytial virus (RSV) infection. We prospectively studied 699 infants hospitalized during the winters of 1976 through 1980, when RSV was prevalent in the community; 229 of these infants had proved RSV infections acquired either before admission or during hospitalization; 27 had both congenital heart disease and RSV infection, and 46 had congenital heart disease without RSV infection. Infected infants with congenital heart disease had significantly more severe illness than those without congenital heart disease, as judged by the requirement for intensive care and assisted ventilation and by the mortality rate (37 per cent vs. 1.5 per cent, P less than 0.01). The infection was acquired nosocomially by 21 per cent of infected infants; the mortality rate from nosocomial infection was also higher in infants with congenital heart disease (44 per cent vs. 5 per cent, P less than 0.01). Pulmonary hypertension was the one condition particularly associated with severe RSV illness. Eight of the 11 infants (73 per cent) with congenital heart disease and pulmonary hypertension died during their RSV illness. The courses in infants with congenital heart disease with and without RSV infection were also compared. Their ages, types of cardiac lesions, and incidence of pulmonary hypertension were similar, but the infants with RSV infection had a higher mortality rate (37 per cent vs. 6.5 per cent, P less than 0.1).

Respiratory syncytial virus infection in cyclophosphamide-treated cotton rats.

Cotton rats infected intranasally with respiratory syncytial virus and immunosuppressed with cyclophosphamide shed virus for at least 7 weeks. Dissemination of virus beyond the respiratory tract was observed. In contrast, virus was recovered from infected, non-immunosuppressed rats for only 1 week, and only from the respiratory tract.

In vivo inhibition of respiratory syncytial virus by ribavirin.

Ribavirin reduced the amount of respiratory syncytial virus in nasal turbinates and lung tissues of experimentally infected cotton rats by over 90%. An effect was seen when the drug was given either intraperitoneally or by aerosol; however, the antiviral effect was achieved at much lower doses when delivered by the aerosol route. No animal deaths due to the drug were seen.

Glucose oxidase immunoenzyme methodology as a substitute for fluorescence microscopy in the clinical laboratory.

Enzymes as markers for antigens or antibodies in immunohistochemical procedures have several advantages over commonly used fluorochrome labels. These include use of a regular light microscope and the ability to get permanently stable slide preparations. Glucose oxidase (EC 1.1.2.3.4), being absent in mammalian tissue, provides no background staining, such as that seen with the commonly used horseradish peroxidase (EC 1.11.1.7) owing to peroxidase-like activity in tissues. A glucose oxidase histochemical method is detailed that is useful for detection of human antibodies; it can be easily used in clinical laboratories as a substitute for fluorescent techniques.

Quantitative histologic effects on mouse thymus of controlled dietary restriction.

Specific volume fractions (VF) of cellular populations of 6-month-old mouse thymus are altered in animals dietarily restricted since weaning. The VF ratios of cortex:medulla are 2:1 for restricted animals and 1:1 for controls. Thymic cortex of restricted mice exhibits a greater VF of lymphoid cells. Dietary restriction did not alter the VF of medullary lymphoid cells. The VF of non-lymphoid cellular elements tended to decrease throughout the thymus with dietary restriction. No dietary effect on the VF of thymic vascular and connective tissues was observed. VF ratios of cortical lymphoid cells:medullary lymphoid cells show a tendency to increase in restricted mice as does the VF ratio of cortical lymphoid cells:cortical non-lymphoid cells. The VF ratio of thymic medullary lymphoid cells:medullary non-lymphoid cells also increases in restricted mice. VF ratios of cortical non-lymphoid cells:medullary non-lymphoid cells were not altered by diet.

Legionella pneumophila: identification in tissue sections by a new immunoenzymatic procedure.

A modified glucose oxidase immunoenzyme technique was shown to be highly sensitive and specific for detection of serogroup 1 Legionella pneumophila in 4% formaldehyde solution-fixed, paraffin-embedded tissue sections. There was complete concordance between infection with L pneumophila and detection of the organisms in tissue sections by glucose oxidase immunoenzyme staining. The L pneumophila organisms stained blue-black and were found within phagocytic cells as well as in the extracellular space. A cloud of blue-black pigment, probably representing diffusable antigen, was present in the extracellular spaces in the area of L pneumophila localization. No false-positive or false-negative reactions were found. This technique requires no specialized equipment, may be applicable to retrospective diagnostic problems, and can be adapted to routine diagnostic practice.

Respiratory syncytial virus infection in owl monkeys: viral shedding, immunological response, and associated illness caused by wild-type virus and two temperature-sensitive mutants.

Intranasal inoculation of owl monkeys with wild-type respiratory syncytial virus induced upper respiratory tract disease in each of seven animals. The response of owl monkeys to two highly defective, temperature-sensitive, multiple-lesion mutants was then compared to the pattern seen with wild-type respiratory syncytial virus. These mutants, ts-1 NG-1 and ts-1 NG-16, were derived from the ts-1 mutant that had been remutagenized with nitrosoguanidine (NG). Previously the ts-1 NG-1 and ts-1 NG-16 mutants had been shown to be more temperature sensitive and more stable genetically than their ts-1 parent. Both ts-1 NG-1 and ts-1 NG-16 produced infection that was delayed in onsent compared to wild-type virus infection. However, the mutants were shed from the upper respiratory tract for the same period of time and at the same titer as wild-type virus. The serum neutralizing antibody response to infection with the mutants was nearly equivalent to that elicited by wild-type virus. However, the extent of disease induced by the mutants was significantly less than that seen with wild-type virus. These observations suggest that the mutants are potential vaccine condidates and should be subjected to additional in vivo testing in primates and, ultimately, humans.

Respiratory syncytial virus infection in inbred mice.

Respiratory syncytial virus infected the nose and lungs of each of 20 strains of inbred mice, with viral titers varying 100-fold from least permissive to most permissive strains. Viral titers appeared to be under genetic control, but did not correlate with the H-2 haplotype.