Absence of default mode downregulation in response to a mild psychological stressor marks stress-vulnerability across diverse psychiatric disorders.

Clinically, it is well-established that vulnerability to stress is a common feature across a broad spectrum of psychiatric disorders. However, this link has been mechanistically studied almost exclusively in patients with so-called stress-related disorders such as depression and anxiety. To probe transdiagnostic mechanisms, we set out to study the acute stress response across a broader range of psychiatric disorders taking a large-scale brain network perspective. We investigated the brain's response to a mild, experimentally well-controlled psychological stressor in the form of an aversive movie. We studied 168 patients with stress-related and/or neurodevelopmental disorders (including comorbidity) and 46 control subjects. We focused on three networks that have a central role in the brain's stress response and are affected in a wide range of psychiatric disorders: the salience network (SN), default mode network (DMN) and frontoparietal network (FPN). Our results support an increased vulnerability to stress across all patients, indicated by a higher subjective stress level at baseline and follow-up compared to matched controls. At the brain systems level, the stress response was characterized by a relatively decreased FPN connectivity and an absence of a decrease in the within DMN connectivity across all disorders compared to controls. At the neurocognitive level, these findings may reflect a diminished top-down control and a tendency to more pronounced (negative) self-referential processing. Besides these shared aspects of the maladaptive stress response, we also discuss indications for disorder-specific aspects. Taken together, our results emphasize the importance of investigating the mechanistic underpinnings of psychiatric disorders transdiagnostically as recently done in neurogenetics.

How the brain connects in response to acute stress: A review at the human brain systems level.

The brain's response to stress is a matter of extensive neurocognitive research in an attempt to unravel the mechanistic underpinnings of neural adaptation. In line with the broadly defined concept of acute stress, a wide variety of induction procedures are used to mimic stress experimentally. We set out to review commonalities and diversities of the stress-related functional activity and connectivity changes of functional brain networks in healthy adults across procedures. The acute stress response is consistently associated with both increased activity and connectivity in the salience network (SN) and surprisingly also with increased activity in the default mode network (DMN), while most studies show no changes in the central executive network. These results confirm earlier findings of an essential, coordinating role of the SN in the acute stress response and indicate a dynamic role of the DMN whose function is less clear. Moreover, paradigm specific brain responses have to be taken into account when investigating the role and the within and between network connectivity of these three networks.

Comparison between interphase and metaphase cytogenetics in detecting chromosome 7 defects in hematological neoplasias.

Monosomy 7 (-7) is one of the most common chromosomal abnormalities found in the leukemic cells of patients with acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS). Because patients with -7 have a poor prognosis, their identification is important for treatment planning. Conventionally, -7 is detected by the G-banding technique. This study examines the use of fluorescent in situ hybridization (FISH) methodology to detect -7 cells in interphase nuclei and metaphase chromosomes. Fifteen AML or MDS patients whose leukemic cells were found to have -7 by G-banding at disease presentation were studied. In 13 of these patients, -7 could be detected in interphase by FISH using a chromosome 7-specific centromeric DNA probe. The two patients whose leukemic cells were not detectable by interphase FISH had -7 and t(1q;7p), which were detectable by FISH in metaphase using a chromosome 7-specific painting probe. Metaphase FISH was particularly useful in further defining chromosome 7 defects in cells that contained aberrant or marker chromosomes. For example, in 6 patients, chromosome 7 sequences were detectable in aberrant or marker chromosomes by metaphase FISH, but not by G-banding. These results suggest that metaphase FISH is an important adjunct to conventional cytogenetic methods for defining chromosome 7 abnormalities in AML and MDS patients. Furthermore, interphase FISH is useful for follow-up studies in patients who are found informative for the FISH study at presentation.

Detection of residual proliferating leukemic cells by fluorescence in situ hybridization in CML patients in complete remission after interferon treatment.

Interferon-alpha produces a complete hematologic and cytogenetic remission in approximately 20% of patients with chronic myelogenous leukemia (CML). In this study, we applied fluorescent in situ hybridization (FISH) methodology to examine the possibility that a low level of proliferating Philadelphia-chromosome-positive (Ph+) cells may be present in interferon-treated CML patients who have achieved complete cytogenetic remission (as defined by the absence of Ph chromosome in 20-25 metaphases analyzed). Ten such patients in remission for 6-35 months were studied by this technique, in which a chromosome-22-specific DNA painting probe was used to detect leukemic cells with the characteristic 9;22 chromosomal translocation. In six of the 10 patients (60%), 3-9% Ph+ metaphases were detected. No Ph+ cells were observed in nine control individuals. Thus, this study demonstrates that FISH technology is more sensitive than conventional cytogenetic analysis for the detection of minimal residual disease in CML.

Classification of routinely processed anaplastic large cell tumours with a small panel of antibodies. An immunohistochemical study with clinical follow-up.

A proportion of anaplastic large cell tumours is difficult to classify on sections of routinely processed, paraffin-embedded tissue. Differentiation into large cell lymphoma, carcinoma, melanoma or sarcoma is important in order to assess prognosis and proper treatment. Although the use of immunohistochemistry has been reported in the differentiation between some of these types of neoplasms, no antibody panel, which can directly differentiate all of them, has been described. In the present study we evaluated the value of a panel of 5 antibodies for the classification of 29 anaplastic large cell tumours, which could not be classified by experienced pathologists using conventional histological and histochemical techniques. The panel, which can be used on routinely fixed paraffin-embedded tissue, consisted of 5 different antibodies directed against keratin, vimentin, the human milk-fat globule membrane antigen MAM-6, a melanoma associated antigen and common leucocyte antigen. The use of this panel directly resulted in a definite diagnosis in 95% of the cases and provided valuable information for the diagnosis in the remaining cases. The diagnosis was confirmed by additional marker studies and electron microscopy. Moreover, clinical follow-up, including treatment data, was in accordance with the diagnosis based on the panel.

Theoretical aspects of diagnostic histopathology and their relation to morphometry.

The theoretical aspects of diagnostic histopathology are discussed and their relationship to morphometry is examined. In diagnostic pathology, one tends to look at certain structural features, overlooking other details regarded as unimportant. In fact, the pathologist is continuously reducing the images under observation into a new simplified reality, based on a theoretical model (concept). The model is composed of features in a structural interrelation that is thought to be specific for the pathologic diagnosis being considered. The pathologist also selects appropriate regions for study in order to enhance the possible successful application of the appropriate criteria for the given diagnosis; the diversity of different tissues within, between and at different levels requires a vast experience in order to select the appropriate criteria in a specific situation. Analytical histopathology and morphometry require a more conscious construction of a model comprising the concept of the pathologic process and the criteria for its diagnosis. The theoretical background subconsciously used in the pathologist's daily practice is thus the essential knowledge for the application of morphometry in diagnostic histopathology, the basis on which elements for measurement or counting and on which compartments for calculation are selected.

The involvement of dendritic cells in the handling of the immune stimulant C. parvum. A morphological investigation using immunoperoxidase techniques.

In earlier experiments we showed that locally administered Corynebacterium parvum (C. parvum) stimulated the T-cell system and had a beneficial effect on the recurrence rate of surgically resected cancers of the uterine cervix. In this paper we report the use of an immunoperoxidase technique to trace C. parvum antigen in the draining lymph nodes. In a guinea pig model the popliteal lymph node was studied after the injection of 70 micrograms of C. parvum in the hind footpad. At 6 h, intact bacteria were detected in sinus histiocytes. A transient granuloma formation was apparent between days 2 and 6, originating in the subcapsular and interfollicular areas. Three antigen-positive cell types were observed in these granulomas: a) cytophagocytic macrophages which were weakly positive, the antigen being distributed in clumps; b) dendritic cells with a strong, fine-granular positivity and c) some epithelioid cells with a small positive cytoplasmic rim. The majority of epithelioid cells was negative. Antigen-positive dendritic cells were also observed just beyond the granulomas in the T-dependent paracortical area. These cells are known as interdigitating cells (IDC) and present antigen to T-cells. Ten days following C. parvum injection the lymph node follicles became positive and the antigen could be detected in the long cellular protrusions of the dendritic reticulum cells (DRC). DRC probably play a part in immunological memory by trapping antigen in the form of immune complexes.(ABSTRACT TRUNCATED AT 250 WORDS)

Quantitative morphology. A study of the trophoblast.

It is difficult to predict the possible development of a malignant trophoblastic tumor after the evacuation of a hydatidiform mole. In order to help resolve this difficulty, a morphometric study has been carried out. The mean nuclear area of the trophoblast in a group of hydatidiform moles, followed by a trophoblastic malignancy, was found to be statistically significantly larger than that of the trophoblast in a group of hydatidiform moles which were not followed by malignant trophoblastic disease. However, the mean trophoblast/nontrophoblast ratio in villi demonstrated no statistically significant difference between those 2 groups of hydatidiform moles. Therefore it is not advisable to grade hydatidiform moles on the basis of trophoblastic proliferation alone. It is suggested that the trophoblastic lining of hydropic villi in the placental tissue of hydatidiform moles has malignant features already, but these are more pronounced in those hydatidiform moles which are subsequently followed by a choriocarcinoma.

Morphology of draining lymph nodes after local immune stimulation with C. parvum: comparison of pelvic nodes in carcinoma of cervix and popliteal and inguinal nodes of guinea-pig.

Morphological changes are described in pelvic lymph nodes excised 10 days after C. parvum (CP) treatment of patients with cervical carcinoma. Guinea-pig popliteal and inguinal lymph nodes were investigated from Days 1 to 10 after an injection of 70 micrograms CP into the footpad. Eosinophils were detected from the first few hours after stimulation, initially in the marginal sinus, then in the medullary sinuses and subsequently in the efferent lymphatics. From Day 2 to Day 6, histiocyte accumulations with the appearance of epithelioid cells were found mainly in subcapsular and interfollicular areas, and small granulomas were also seen in the paracortex. The granuloma formation in the lymph node was considered as an indication of the activation of histiocytes. Besides small granulomas in the paracortex, activated interdigitating cells, surrounded by scattered lymphoblasts and eosinophils, were also present. We considered this lymphoblastic response and eosinophilic accumulation as likely to be due to blastogenic factor and eosinophil stimulation promotor. Eight to 10 days after CP stimulation, the macrophage lymphoblast eosinophil response was replaced by a B-cell reaction: germinal-centre activation and medullary plasma cells. Such a B-cell reaction was also found in the human pelvic nodes removed at operation, but this reaction could not be attributed to CP treatment alone, since cervical-carcinoma patients not treated with CP also showed such reactions. In contrast, pelvic lymph nodes removed at necropsy from females killed in traffic accidents showed no predominance of either B- or T-cell stimulation.

Lower relapse rates after neighbourhood injection of Corynebacterium parvum in operable cervix carcinoma.

The effect of adjuvant immunotherapy with a single neighbourhood injection of 2 mg C. parvum (CP) was investigated in a randomized study involving 43 patients with carcinoma of the cervix uteri, all of whom were treated by radical surgery. All patients had carcinoma confined to the cervix, the upper part of the vagina or the parametrial region. When the malignancy had spread to the parametrial region, additional postoperative radiotherapy was given. 22 patients received immunotherapy 10 days before surgery, whereas the remaining 21 control patients received no immune stimulation. Only minor side effects of CP were encountered. Follow-up shows a relapse rate of 5% in the CP treated group and of 29% in the controls (P less than 0.05). A further 15 patients with more advanced malignancies were added to our studies. In these, CP stimulation had no effect on relapse rates, but the relapse-free intervals were longer after immune stimulation: control 3.5 months (mean) +/- 1.5 (s.d.), CP 13.0 months +/- 7.0 (P less than 0.05). The number of peripheral T cells and the ability to become sensitized to DNCB were increased after CP stimulation. A decrease was found in the number of blood monocytes and the number of monocytes capable of transforming into active macrophages, indicating a possible sequestration of these cells in the tissues.

A quantitative structural model of the testis of fertile males with normal sperm counts.

The morphology of testicular biopsies of 8 healthy fertile men with proven normal sperm counts was studied using stereological techniques. Quantitative estimations were made of different cellular compartments in the testicular biopsies. The experimental errors of observation, homogeneity of the section, accuracy of the measurements and errors caused during the preparation of the sections were studied. A stereological model of the human testis comprising all compartments was designed. The present observations on the stereological parameters were compared with the results in literature; generally a good agreement was found. This stereological model enabled the authors to establish the quantitative correlations that exist between the separate compartments of the human testis. The tubular length density was positively correlated with the tubular surface density. The tubular surface density showed a negative correlation with the volume density of the germinal cell nuclei. The tubular volume density showed a negative correlation with the volume density of the Leydig cells. The intra-tubular volume density correlated negatively with the volume density of the Leydig cells and with the volume density of the remaining extra-tubular tissue. The intra-tubular tissue density correlated negatively with the volume density of the intra-tubular space.

A direct competitive binding radioimmunoassay for carcinoembryonic antigen.

We have incorporated commercially available CEA standard and antiserum into the triple isotope double antibody radioimmunoassay and we have evaluated this assay for the routine determination of CEA. The competitive protein binding (CPB) assay for CEA can be performed directly on serum or plasma without perchloric acid extraction. The assay sensitivity was 0.98 ng/ml, and the day-to-day precision as defined by the coefficient of variation was 12.5% and 13.3% for mean values of 7.6 and 23.9 ng CEA/ml, respectively. The normal range (X +/- 2 S.D.) for CEA determined with the direct CPB method was 3.2--6.2 ng CEA/ml for non-smokers. The upper limit of normal for smokers was 10.0 ng/ml. A method comparison study (Roche perchloric acid extraction vs. direct CPB) showed excellent agreement between the methods for plasma samples containing less than 20.0 ng CEA/ml. The least square analysis parameters were: N = 116, slope = 1.01, y-intercept = 3.5 ng/ml, Sy/x -2.05 ng/ml, and the correlation coefficient was 0.79. Recovery and dilution studies showed no demonstrable non-specific interference due to serum proteins in the direct CPB assay. The clinical significance of the direct CPB assay for CEA was assessed by correlating serial CEA values with the clinical status of patients with breast and colorectal cancer. Increasing CEA values correlated with progressive or recurrent neoplastic disease, and decreasing CEA values correlated with response of the patient to therapy. No false positive direct CPB values for CEA were observed in the clinical study or in the method comparison study. Our laboratory and clinical evaluation demonstrate that the direct CPB method is an accurate and reliable method for the quantitation of CEA. In addition, the method permits high volume analysis and eliminates the hazards to safety that are associated with perchloric acid.

Quantitative morphology of the placenta. III. The growth of the placenta and its relationship to birth weight.

The relationship of placental components to birth weight was investigated by stereology. 37 placentas from nonpathological pregnancies delivered after a period of 224-303 days of amenorrhea were examined. The umbilical cord was clamped immediately after birth. The ratios of the volume, the surface, the length of the villous vessels and the surface of the villi with birth weight showed a decrease after 277 days of amenorrhea. In contrast to this decrease, the ratio of the volume of the trophoblast with birth weight seems to increase. No difference could be found for the ratios of the placental volume (placental index), the volume of the villous tissue, the volume of the intervillous space and the volume of the nonfunctional tissue with birth weight. These ratios reveal a quantitative morphological base for the clinical experience that postmature fetuses are at a higher risk through deterioration of the placenta.

Quantitative morphology of the placenta. II. The growth of the placenta and the problem of postmaturity.

The morphological changes in the placenta concomitant with the transition from maturity to postmaturity were investigated by stereology under early clamping of the umbilical cord. 37 placentas from nonpathological pregnancies delivered after a period of 224-303 days of amenorrhea were examined. It appeared that after 267-288 days of amenorrhea, 8 out of 9 placental components showed no further growth and even showed regression. Only the volume of the trophoblast continued to grow in postmaturity. It is suggested that during postmaturity the villous capacity to produce steroids is continuing at a normal rate (as judged by the increase of the volume of the trophoblast), whereas the capability to transfer is deteriorating (as testified by the decreasing surface of the trophoblast).

Histopathology of acute and chronic inflammation.

Inflammation, defined as local reaction to injury, is basically a homeostatic process-loop system with morphological and biochemical components. If this homeostatic loop is uncomplicated a normal situation is reached soon after injury. Morphologically different patterns of inflammation can appear, depending on the character and intensity of the injury. Furthermore, the contributions made by hyperaemia, exudation of fluid, infiltrates carrying inflammatory cells, and cell proliferation not only vary with the type of injury but also depend on the time after injury. Some of the histopathological changes can be seen as essential for the restoration of the normal situation, whereas others damage the tissue more than seems desirable. The morphological aspects of different types of inflammation are discussed in relation to the homeostatic nature of the inflammatory process.