Coarse granularity of nuclear chromatin texture is a prominent feature of most malignant cell lines. We have chosen the abrupt transition from eu- to heterochromatic foci (high contrast gradient [CG]) as a novel parameter for coarseness. This feature was quantified using automated image analysis of single nuclei in smears stained by the May-Grünwald-Giemsa technique. The principle of this approach consists of eliminating, with the help of subtraction between two image lowpass filters, the small grey level differences among pixels, so that only high CG values are retained on the digitized image. The sum of these distinctive microareas is then taken as a fraction of the area of the peripherally eroded nucleus, and this ratio is designated as contrast gradient index (CGI) per nucleus. This method was tested on fine needle aspirates from 11 patients with benign breast disease (BBD) and 14 with mammary carcinoma (CA). For each specimen, 60 nuclei were analyzed, with a measuring time per nucleus of about 1 min. A high significant distinction between epithelial cell populations in BBD and CA, respectively, was obtained by variance analysis of all CGIs per nucleus (p = 2 x 10(-18). The median and the mean values of CGI per specimen were the next best discriminators, followed by the modes and the standard deviation of CGI per specimen. The percentage of nuclei per specimen with CGI values of greater than 12 was also significantly greater in CA than in BBD.

Adolescent↗

PubMed1991

Diffuse centrocytic and/or centroblastic malignant non-Hodgkin's lymphomas: comparison of mitotic and pyknotic (apoptotic) indices.

Mitotic indices (MIs) and pyknotic (apoptotic) indices (PIs) were assessed in diffuse centrocytic (CC, n = 10), centroblastic/centrocytic (CB/CC, n = 18) and centroblastic (CB, n = 20) malignant non-Hodgkin's lymphomas (NHL). Significant differences were observed. MIs were lowest in CC (median: 0.07%), intermediate in CB/CC (0.18%) and highest in CB (0.43%) NHLs. The PIs exhibited a similar pattern. The PIs of CC (0.11%) and CB/CC (0.17%) NHLs were significantly different from those of CB lymphoma (0.62%). The ratios MI/PI per case, as well as MIs and PIs per case, varied greatly and showed considerable overlapping, thus documenting a marked inter-case and inter-group heterogeneity. MIs tended to loosely correlate with PIs in a non-linear fashion, which raises the question of feedback mechanisms. More information is needed on mitotic time (TM) and apoptotic time (TA), in order to estimate cell doubling time from data on MIs and PIs.

Adult↗

PubMed1991

Primary immunodeficiency syndromes and their manifestations in lymph nodes.

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Animals↗

PubMed1990

Immunomodulation by intravenous immunoglobulin.

In 1980, it was observed in a child with idiopathic thrombocytopenic purpura (ITP) that intravenous administration of pooled human immunoglobulin-G (IVIG) was followed by a rapid increase of the platelet count. Prompted by this finding, a pilot study and two prospective multicenter studies on children with ITP were organized. Efficacy of this new treatment for ITP was soon confirmed worldwide. In addition to the immediate effect, long-term observations following administration of IVIG suggested the occurrence of modulation of the immune response. Also, concomitant with studies on the mechanism of action of IVIG, the use of IVIG in the treatment of patients with other immune-related disorders was explored.

Adjuvants, Immunologic↗

PubMed1990

Hodgkin's disease and CD30-positive anaplastic large cell lymphomas--a continuous spectrum of malignant disorders. A quantitative morphometric and immunohistologic study.

The authors have examined cellular areas of lymphoma tissue in 28 cases of Hodgkin's disease (HD) or anaplastic large cell lymphoma (ALCL, 'Ki-1 cell lymphoma') to evaluate the boundaries between the two entities. Methods applied included conventional histology; test point analysis; semiautomated morphometry of nuclear profile features of Reed-Sternberg and other atypical large cells (RSALCs); and immunohistochemistry of these elements on all paraffin sections and, in 15 cases, on frozen sections. Mean nuclear profile morphotypes of RSALCs per case varied independently of immunophenotype and histologic diagnosis. Conversely, immunohistochemistry demonstrated significant, although not consistent, preferential positivities of these CD30+ elements for CD15 in HD, and for epithelial membrane antigen (EMA) and CD43 in ALCLs. In the latter, RSALCs also exhibited a tendency for CD45 and CD45RO positivity and for the expression of T-cell-associated antigens. However, there were considerable overlaps. This continuous spectrum of RSALC nuclear profile morphotypes and immunophenotypes, ranging from HD over questionable cases, intermediate between HD and ALCL, to ALCLs, was paralleled by differences in the reactive component of lymphomas. Lymphocytes and granulocytes were significantly deficient in ALCLs.

Adolescent↗

PubMed1990

Heterogeneous subgroups among malignant diffuse small B cell lymphomas. A combined nucleometric and immunocytologic study.

The degree of heterogeneity among subtypes was evaluated in 39 of the most frequent malignant, diffusely growing small B cell lymphomas by a combination of morphometry, automated image analysis, and immunocytologic techniques. Cluster analysis of nuclear profile parameters, including nuclear area, circularity factor, and chromatin distribution pattern, distinguished 3 groups. Each group was characterized by the preponderance of certain nuclear profile types, i.e. (a) small, rather regular (roundish) and dark staining (typical small lymphocytic lymphomas and immunocytomas); (b) small to intermediate size, rather regular (roundish) and pale staining (small to intermediate size variant); or (c) small to intermediate size, irregular, rather pale staining (diffuse follicular small cleaved cell (centrocytic) lymphomas and, probably, polymorphous immunocytomas). Group 3 was clearly distinct from the rest, but groups 1 and 2 also differed significantly. Every case displayed a mixture of the 13 registered nuclear profile types. Lymphoid cells with similar nuclear profile features occurred in B cell zones of non-neoplastic lymph nodes. Frequency distribution of nuclear profile parameters significantly differed from one lymphoma group to another. However, there were considerable overlaps. No clear correlation was found between nuclear profile types and immunophenotypes. Cellular surface antigen patterns showed an extensive intra- and inter-case variability. The findings support the notion of a certain individuality of malignant B cell lymphomas and of a marked heterogeneity among their subtypes.

Adult↗

PubMed1989

Cellular events in alveolitis and the evolution of pulmonary fibrosis.

"Alveolitis", as opposed to "pneumonia" sensu strictiori, is a term used to denote diffuse inflammatory changes of the pulmonary parenchyma, excluding those that result from local bacterial, fungal or other extracellular microbial growth. The various types of alveolitis are classified according to their histological characteristics and range from "luminal phagocytic" or "mural lymphoplasmacellular" and "exudative" to "fibrosing" alveolitis. In this overview, various exogenous and endogenous causes of different types of alveolitis, and the cellular events in their pathogenesis are briefly discussed to illustrate the complex mechanisms involved. Particular emphasis is placed on the possible transition from diffuse exudative to fibrosing alveolitis. It appears that pulmonary fibrosis, which is usually patchy rather than truly diffuse, does not have a uniform pathogenesis. Besides the possibility of a certain degree of a diffuse fibrosis three major pathways are evident: (1) granulation tissue budding into alveolar lumina (luminal fibrosis) (2) exudate incorporation into alveolar walls (mural fibrosis) and--at least equally important--(3) so-called collapse (atelectatic) induration (obliterative-interseptal fibrosis), a process that has largely been neglected so far.

Air Pollutants↗

PubMed1989

Germinal center kinetics in lymph nodes of primed mice stimulated with complexed as opposed to free antigen.

Primed mice with low titers of circulating tetanus antitoxin (AB) were stimulated via the hind footpads with either fluid tetanus toxoid alone (AG) to create in vivo complexes in AG excess, or the same dose of toxoid complexed at equivalence with isologous antibody (AB-AG CPX), to have in vivo complexes in AB excess. All experimental animals reacted with three topically distinct consecutive waves of enhanced proliferative activity in popliteal lymph nodes, i.e., in the T-zone (peak on day 2), in the medullary area, the main site of plasmocytopoiesis (day 3), and in lymphoid follicles (day 5-6). Maximum serum AB titers following injection of AG-AB CPX were only about 25% of those found in animals boosted with AG alone. This suppressive effect was best reflected in a comparable reduction in plasmocytopoiesis, and to an lesser extent in the proliferative activity within the T-zone, and not at all in the overall magnitude of germinal center formation and/or expansion. However, the patterns of germinal center kinetics differed markedly between the two groups: a high sharp peak of development on day 5, followed by a marked drop on day 6 characterized the response in mice given AG alone, and a broad peak around day 6 that of those receiving AG-AB CPX. These differences could not adequately be accounted for by variations in centroblast/centrocyte proliferation rate vs. pycnotic indices, so that different patterns of lymphoid cell emigration from the centers may be considered. The results suggest that immune complexes, fixed on follicular dendritic cells, with different antigen-to-antibody ratios have divergent effects on the development and kinetics of germinal centers, the principal sites of memory B cell generation.

Animals↗

PubMed1989

What's new in quantitative pathology? Past developments and outlook.

The authors illustrate the need for the best possible level of objectivity and reproducibility in diagnostic pathology. Morphometry may help considerably in this attempt, in particular in basing the classification of neoplasms on a quantitative basis and in differentiating one type of neoplastic growth from another. Since anisotropic tissue or cell components are not suitable for stereological analysis and thus limit the applicability of stereological methods to pathology, planimetric morphometry remains the most important quantitative technique to be applied to tissue sections, smears and imprints. The counting process, analysis and reporting of results are helped by computer based graphic tablets; with these systems, parameters, such as profile, perimeter and various form factors, can be obtained. Flow cytometry is a widely efficient method for obtaining ploidy patterns of a given cell population, with a more acceptable reproducibility than that of static cytometry. Methods for quantifying the chromatin distribution in cell nuclei, such as digital image analysis and, even more so, laserscan microscopy, are of the greatest importance in oncological pathology. It will be essential in the near future to combine results of quantitative structural analysis with findings made with the help of immunocytochemical, cytogenetic and "in situ" hybridization techniques.

History, 20th Century↗

PubMed1989

Tetanus toxoid complexed with heterologous antibody can induce germinal centre formation and B cell memory in mice without evoking a detectable anti-toxin response.

Fluid free tetanus toxoid (FTT) alone or FTT complexed in vitro at equivalence (EQ) or in antibody excess (ABEX) with anti-toxin contained in a human gammaglobulin preparation (HGG), or HGG alone, were injected into the hind leg footpads of mice. Anti-toxin titres of mouse serum were measured and compared with proliferative reactions in popliteal lymph nodes, based on combined 3H-thymidine autoradiography and planimetry, as a function of time. FTT in complex with HGG in ABEX failed to elicit a measurable anti-toxin response but caused, of all the materials tested, the most marked numerical increase of germinal centres. This finding is in accord with results of earlier studies indicating that the same heterologous antigen-antibody complexes at EQ or in ABEX can prime the animals, usually without eliciting antibody production detectable by serum titration. The model system used in the present experiments is thus well suited for a separation of the two principal arms of the dichotomous humoral immune response, i.e. by inducing germinal centre and B cell memory development but not specific antibody formation.

Animals↗

PubMed1988

[Renal manifestations of sarcoidosis].

Renal manifestations of sarcoidosis are rare. In addition to calcium nephropathy, granulomatous interstitial nephritis and glomerulo-nephritis (GN) account for most cases. The latter two manifestations are described in 4 patients and in a detailed review of the literature. In comparison to a nonselected population of sarcoidosis patients, granulomatous interstitial nephritis is found more frequently in male patients above 40 years of age; it is associated more frequently with other extrathoracic manifestations of sarcoidosis; and it causes renal insufficiency of varying degree, which is at least partially reversible with steroid therapy. Predominant findings are silent microhematuria, sterile pyuria, mild proteinuria and a variety of tubular functional disorders. Glomerulonephritis (39 observations) has been described with increasing frequency in sarcoidosis. Because of the well known immunological abnormalities of sarcoidosis, frequent association of sarcoidosis with GN could be expected but this association has not yet been proven statistically. Sarcoidosis-associated GN includes a variety of histological forms, viz. membranous, proliferative and sclerosing GN. Glomerulonephritis may appear before sarcoidosis. Conversely, both diseases may appear simultaneously, or GN may follow all other manifestations of sarcoidosis with a latency period of many years.

Aged↗

PubMed1988

Age-related involution and terminal disorganization of the human thymus.

The terminal involution pattern of the human thymus was studied based on autopsy cases (both sexes, age range 63-91 years). Large sections through the entire thymic fat body were examined with the help of both conventional histological and immunohistochemical techniques. The findings demonstrate that thymic atrophy in old humans (a) goes far beyond the degree of involution observed in small rodents; (b) results in a system of thin, branching, in part interrupted, non-keratinizing epithelial plates containing no typical Hassall bodies; (c) concerns all components of the thymus except fat tissue which progressively replaces original thymic structures; and (d) involves various types of disorganization of individual lobules with T and B lymphocytes often located outside rather than within epithelial remnants. Effects of low-level radiation on this final regression of the human thymus are unknown.

Age Factors↗

PubMed1988

Heavy water (D2O)-induced shape changes, movements and F-actin redistribution in human neutrophil granulocytes.

Heavy water (D2O) induces characteristic shape changes and a distinct type of movement in human neutrophil granulocytes. In contrast to front-tail polarity as evoked by chemotactic peptides and microtubule-disassembling agents, D2O-based media produce non-polar neutrophils with many small or long surface projections. This phenotype is similar to that elicited by both phorbol myristate acetate and diacylglycerols, but the surface projections are smaller and more densely placed and are often associated with a single large projection. D2O-induced non-polar cells with surface projections perform continuous shape changes without front-tail polarity and without the unidirectional movement and cytoplasmic streaming seen in cells with front-tail polarity. Some of the cells show circus movements of a large projection indicating circular polarity. In neutrophils suspended in D2O, F-actin is shifted to the cell periphery, mainly into the surface projections of activated cells. The D2O-induced effects are reversed in H2O-based medium. D2O is dominant over the chemotactic peptide, N-formyl-L-methionyl-L-leucyl-L-phenylalanine (fMLP), colchicine and taxol in that the combined action of D2O with any of these agents results in the D2O-induced phenotype. In contrast, cytochalasin B alone and in combination with fMLP induces a considerable decrease of non-polar cells and an increase of spherical cells similar to non-stimulated cells in H2O-based medium. Earlier studies indicated that D2O acts on microtubules. Our results suggest that D2O may act on the microfilament system. Neutrophils suspended in D2O-based medium may represent a useful model to study the relationship between shapes, movements, and particular functions of these cells.

Actins↗

PubMed1988

Stainable bone iron in undecalcified, plastic-embedded sections. Occurrence in man related to the presence of "free" iron?

Iron demonstrable with the Prussian blue reaction at the osteoid/mineralized tissue interphase (osteoid seam) of trabecular bone was observed in only 2.3% of a total of 1536 conventionally fixed and processed, undecalcified, plastic-embedded biopsy specimens taken from the iliac crest of patients for various diagnostic purposes. In marked contrast, clearly stainable bone iron was noticed in all 4 biopsy specimens from the iliac crest and in 11 of 15 vertebral bone fragments obtained at autopsy from individuals with verified primary or secondary hemochromatosis. Findings, including results obtained in vitro, suggest that a positive Prussian blue reaction at the surface of trabecular bone signals the presence of low-molecular-weight ("free") iron, which can bind to the osteoid matrix directly, ie, without the help of osteoblasts. Stainable bone iron may thus be a useful criterion for early detection of hemochromatosis and other types of potentially toxic iron overload.

Adolescent↗