Invasive micropapillary carcinoma of the breast is associated with chromosome 8 abnormalities detected by comparative genomic hybridization

Invasive micropapillary carcinoma (IMC) of the breast is a rare variant of invasive ductal carcinoma (IDC) characterized by unique histology and an extremely high incidence of lymph node metastases (approximately 95%). Comparative genomic hybridization (CGH) was used to characterize DNA extracted from 16 archival IMC cases to identify clonal genetic changes associated with this unique and highly metastatic cancer subtype. The average number of chromosomal alterations per IMC tumor was 7.4 +/-2.9 (3.4 gains and 3.9 losses), fewer than the number that we have observed in IDCs not otherwise specified (9.5 +/-6.6), IDCs with erbB-2 gene amplification (12.6 +/-5.9), and invasive lobular carcinomas (8.2 +/-5.5). The mean number of changes in IMC was significantly higher than we have observed in the rarely metastasizing tubular subtype of IDC (3.9 +/-2.3, P = 0.001), but less than the more aggressive subset of erbB-2-amplified IDC (P = 0.02). Remarkably, 100% of IMCs demonstrated loss involving the short arm of chromosome 8 (8p). Six cases showed loss of the entire 8p arm, whereas in 10 cases the loss was limited to the distal portion (8p21-pter) with localized gain of proximal 8p (8p11-p12). A reciprocal gain of 8q was detected in 14 cases (88%). Other common alterations included loss of 17p in 50% of tumors and loss of 16q in 50% of IMC cases. Gains of 17q (38%), 1q (31%), and 16p (25%) were also commonly detected. In comparison, IDCs (not otherwise specified), IDCs of the tubular subtype, and invasive lobular carcinomas showed only modest 8p loss (33%, 28%, and 13%, respectively). This region of chromosome 8 may contain 1 or more genes whose loss leads to this particular histology and/or the lymphotrophic phenotype associated with this histopathologic pattern.     

Performance of the hypertrophied left ventricle in spontaneously hypertensive rats. Effects of adrenergic stimulation

The performance of isolated hearts from adult male spontaneously hypertensive rats (SHR) and matched normotensive controls (NCR) was investigated in an antegrade perfusion system, where preload and afterload could be varied independently. During electrical pacing of the heart to constant heart rate, increases in afterload, but not in preload, considerably raised cardiac contractility, measured as left ventricular max dP/dt. At afterloads equalling their respective in vivo ones, max dP/dt was similar in SHR and NCR. This indicates that the SHR hearts by myocardial hypertrophy are so well adapted to their raised afterload that an increased inotropic state of the heart is not required. Upon adrenaline addition, SHR and NCR did not differ concerning either "chronotropic sensitivity", i.e. per cent increase in heart rate of the spontaneously beating heart or in "inotropic sensitivity", measured as increase in max dP/dt. However, in this in vitro situation adrenaline increased stroke volume only when the hearts worked at reduced inotropism, induced by lowered temperature (30 degrees C). At maximal inotropic stimulation by adrenaline and occluded outflow, the SHR hearts produced higher systolic pressures than the NCR ones. This reveals an increased maximal contractile capacity of the hypertrophied SHR left ventricle, rather than a reduced one as sometimes suggested.     

Central haemodynamics during morphine abstinence in anaesthetized rats

Central haemodynamics were studied in one group of morphine-dependent rats, and in a non-dependent control group, before and after administration of repeated bolus doses of naloxone. Dependence was induced by s.c. morphine pellet implantations. Mean arterial pressure (MAP), heart rate (HR), cardiac output (CO) and mean transit time (MTT) were measured in the conscious state, after induction of chloralose anaesthesia and after the administration of naloxone (0.005, 0.05, 0.5 and 5 mg kg-1 i.v.). Total peripheral resistance (TPR), stroke volume (SV) and central blood volume (CBV) were subsequently calculated. The haemodynamic variables did not differ significantly in the conscious state, except for a lower SV, when compared with the non-dependent control group. However, in response to anaesthesia the dependent rats exhibited a greater fall in MAP, mainly due to a TPR decrease. Naloxone elicited a marked increase in MAP in the morphine-dependent group, which was mainly caused by an increase in TPR. Naloxone induced no significant change compared with the control group in CO and CBV, while SV increased concomitantly with a lowered HR after naloxone in the morphine-dependent group. These results suggest that the withdrawal hypertension during morphine abstinence was mainly explained by an increase in TPR, reflecting an augmented tone of the resistance vessels. The minor changes in CBV indicate that the tone of the venous capacitance vessels was largely unaffected by naloxone-induced morphine abstinence.     

Cardiac receptors with non-medullated vagal afferents in the rat.

The characteristics of 22 atrial receptors in 15 normotensive adult male Wistar rats were investigated. All the receptor afferents were included in the C-fibre group with conduction velocities from 0.4 to 1.2 m/sec. No atrial medullated receptors or ventricular C-fibre endings were found. Two receptors were located in right atrium and 2 receptors throughout left atrium. Upon elevation of the left atrial pressure the receptor discharge was markedly elevated with thresholds from 2.5 to 9 mmHg in mean left atrial pressure. Ten of the atrial receptors displayed a clear cardiac rhythmicity upon activation and the discharge correlated with the v-wave, indicating distension as the cause of receptor activation. The maximal firing rate in most receptors was very high (up to 70 Hz), but 8 receptors had maximal firing rates below 25 Hz. These low frequency receptors had higher threshold and showed a more irregular firing. Thus, there is a substantial population of atrial receptors with vagal non-medullated afferents in the rat heart and the thresholds for many of these receptors are so low that they are likely to be active during normal conditions.     

Renal sympathetic nerve activation in relation to reserpine-induced depletion of neuropeptide Y in the kidney of the rat

The effect of reserpine treatment on renal sympathetic nerve activity and tissue levels of neuropeptide Y (NPY)-like immunoreactivity (LI) and noradrenaline (NA) were studied in rats. Injection of reserpine (1 mg kg-1 i.v.) caused a clear-cut (about 50%) increase in rectified activity of the post-ganglionic sympathetic nerves to the kidney within 15 min in chloralose-anaesthetized rats compared to a saline-treated control group. This increase in nerve activity was still maintained 120 min after the reserpine injection. The renal nerve activation was accompanied by a progressive fall in mean arterial blood pressure and an initial tachycardia. In a separate group of conscious rats, the levels of NPY-LI (1.3 +/- 0.06 pmol g-1) and NA (1.6 +/- 0.07 nmol g-1) in the kidney were significantly reduced (by 74 and 83%, respectively) 24 h after reserpine treatment (1 mg kg-1 i.v.). The reserpine-induced depletion of NPY-LI, but not that of NA, was inhibited by pretreatment with the ganglionic blocking agent chlorisondamine or the alpha 2-adrenoceptor agonist clonidine, both of which are known to decrease renal sympathetic nerve activity. The tissue content of NPY-LI in the right atrium (16.3 +/- 0.7 pmol g-1) was not reduced by reserpine. Arterial plasma NPY-LI in the rat was high (222 +/- 5 pmol l-1), and this value did not change after pretreatment with reserpine, chlorisondamine or clonidine, indicating that, in the rat, circulating NPY-LI is not a good indicator of sympatho-adrenal activity.(ABSTRACT TRUNCATED AT 250 WORDS)     

Cytotoxic T-lymphocyte clones, established by stimulation with the HLA-A2 binding p5365-73 wild type peptide loaded on dendritic cells In vitro, specifically recognize and lyse HLA-A2 tumour cells overexpressing the p53 protein

Mutations in the tumour suppressor gene p53 are among the most frequent genetic alterations in human malignancies, often associated with an accumulation of the p53 protein in the cytoplasm. We have generated a number of cytotoxic T lymphocyte (CTL) clones that specifically recognize the HLA-A*0201 p53 wild type peptide RMPEAAPPV [65-73], designated R9V, by the in vitro stimulation of CD8 enriched peripheral blood lymphocytes from a healthy HLA-A*0201 donor using peptide loaded autologous dendritic cells. A total of 22 CTL clones were generated from the same bulk culture and demonstrated to carry identical T-cell receptors. The CTL clone, 2D9, was shown to specifically lyse the HLA-A*0201+ squamous carcinoma cell line SCC9 and the breast cancer cell line MDA-MB-468. Our data demonstrate that human peripheral blood lymphocytes from normal healthy individuals comprise T cells capable of recognizing p53 derived wild type (self) peptides. Furthermore, the capacity of R9V specific T cell clones to exert HLA restricted cytotoxicity, argues that the R9V peptide is naturally presented on certain cancer cells. This supports the view that p53 derived wild type peptides might serve as candidate target antigens for the immunotherapeutic treatment of cancer.     

Cerebral function during hypotensive haemorrhage in spontaneously hypertensive rats and Wistar Kyoto rats

Studies on cerebral function during cerebral ischaemia are usually performed on conscious animals after ligation of a major vessel supplying the brain. In this work, we studied somatosensory evoked potentials (SEP) in chloralose-anaesthetized Wistar Kyoto (WKY) and spontaneously hypertensive rats (SHR) during hypotensive haemorrhage, with the main emphasis on the SHR which are more vulnerable. The main purpose was to see whether haemorrhaged SHR could be used for studies of cerebral function during relative cerebral ischaemia in anaesthetized rats. The mean arterial pressure (MAP) was rapidly lowered to 45-50 mm Hg and maintained at that level by adjustments of bleeding and transfusion. This resulted in pronounced sympathetic inhibition and bradycardia in all rats. In SHR, this sympatho-inhibitory response was usually reversed after about 20 min. In one group of hypertensive rats (SHRt, n = 24), MAP was raised to 75 mm Hg by partial re-transfusion, when heart rate (HR) had returned to the pre-bleeding level and MAP was maintained at that level for the rest of the experiment. All the other rats (SHR, n = 12; WKY, n = 11) were kept at 45-50 mm Hg for 32 min, after which WKY were bled further to a MAP of 30 mm Hg for 8 min. SEP amplitudes decreased after haemorrhage in all groups but more so in SHR. In the WKY group, SEP were only modestly attenuated during the first 32 min, but after further bleeding to 30 mm Hg the amplitudes were reduced to the same extent as in SHR. Some SHR showed flat SEP immediately upon haemorrhage and were excluded from the SHRt group.(ABSTRACT TRUNCATED AT 250 WORDS)     

The use of blood components in surgical transfusion therapy

Blood components can be prepared either by separation of ordinary whole blood units or, selectively, by apheresis techniques. In recent years, new methods for improvement of quality and length of storage have been developed. The additive solution approach is now being applied increasingly. Its advantages and the difference between some available systems are described. Blood component therapy must be integrated into the patients' water/electrolyte balance and nutrition schedule. An outline is given of the role of blood components in the treatment of shock. The question of excessive bleeding, the possibilities of making the diagnosis of its cause(s) in the individual case, and the use of blood components is described. Coronary pulmonary bypass is used as an example of a complicated situation that can be handled effectively by a limited number of diagnostic and therapeutic tools.

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Resumen Los componentes sanguíneos pueden ser preparados bien por separación de unidades ordinarias de sangre total o, selectivamente, por técnicas de aferesis. Estas últimas tienen la ventaja de permitir la selección de donantes particularmente apropiados en relación a compatibilidad inmunológica o a la ausencia de agentes infecciosos transmisibles, así como a la posibilidad de que un mismo donante pueda ser usado en forma repetida dentro de un período de tiempo corto. Nuevos métodos de mejoramiento y prolongación del período de almacenamiento han sido desarrollados. El enfoque de las soluciones aditivas es empleado con creciente frecuencia; se describen sus ventajas y las diferencias con otros métodos disponibles en la actualidad.La terapia con componentes sanguíneos debe ser parte integral del manejo del equilibrio de agua y electrolitos y del programa de soporte nutricional. Se provee una guía sobre el uso de componentes sanguíneos en el tratamiento del shock.Se describe el problema del sangrado excesivo, la posibilidad de establecer el diagnóstico de su causa en cada caso individual, y el uso de los componentes sanguíneos. El bypass coronario es presentado como ejemplo de una situación compleja que puede ser manejada en forma efectiva por medio de un número limitado de métodos de diagnóstico y tratamiento.

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Résumé Les constituants du sang peuvent être isolés soit par séparation des unités de sang total ordinaire, soit sélectivement par techniques d'apharèse. Au cours des récentes années des méthodes pour améliorer la qualité et la durée du stockage ont été mises au point. Pour ce faire, l'emploi d'additifs est largement répandu. Les avantages et les différences entre quelques méthodes disponibles sont décrits par les auteurs. Le traitement par constituants du sang doit être associé à l'équilibre hydroélectrolytique et nutritif. Le rôle des différentes parties constituantes du sang dans le traitement du choc est souligné. La question de l'hémorragie excessive, les possibilités de faire le diagnostic de ses causes dans les cas individuels et l'emploi des parties constituantes adéquates du sang sont décrits. A titre d'exemple le By pass pulmo-coronarien, situation particulièrement délicate, peut être contrôlé efficacement par un nombre limité de méthodes diagnostiques et thérapeutiques.

     

Tumor-associated glycoprotein (TAG-72) detected in adenocarcinomas and benign lesions of the stomach

Murine monoclonal antibody (MAb) B72.3, prepared against a membrane-enriched extract of metastatic carcinoma and reactive with a high-molecular-weight determinant, designated tumor-associated glycoprotein (TAG)-72, was shown to be reactive immunohistochemically with 97% of a variety of primary adenocarcinomas of the stomach (n = 40). All "early" gastric carcinomas were reactive with MAb B72.3, although the average percentage cellular reactivity was lower than in "advanced" carcinomas. TAG-72 antigen was detected in benign lesions (i.e. adenomatous polyps and hyperplastic polyps) with intestinal metaplasia. Dysplastic lesions characterized by cellular atypia, abnormal differentiation, and disorganized mucosal architecture demonstrated higher TAG-72 expression than non-dysplastic epithelia. In contrast, normal gastric mucosa was generally non-reactive with MAb B72.3. Assays using serial sections of normal, benign and malignant gastric tissues with two MAbs (B1.1 and COL-6) directed against distinct epitopes of carcinoembryonic antigen (CEA) demonstrated differential reactivity, confirming that TAG-72 and CEA are distinct, non-coordinately expressed antigens. Our results suggest that TAG-72 antigen may be expressed in malignant and dysplastic epithelial cells, as well as in intestinalized epithelium of the stomach which has been closely related to subsequent carcinoma development. Hence, MAb B72.3 may be a useful immunohistochemical adjunct for detecting early foci of adenocarcinomas and premalignant lesions of the stomach.     

APOE ε4 and late-life cognition: mediation by structural brain imaging markers

European Journal of Epidemiology - The apolipoprotein E allele 4 (APOE-ε4) is established as a major genetic risk factor for cognitive decline and late-onset Alzheimer’s disease....