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PubMedDate not supplied

The double-way effects of naloxone and clonidine on experimental stress analgesia.

We have emitted the hypothesis that the double-way effect is possible not only due to the wide range of receptor substrates and receptor subtypes but it can manifest at the heterosynaptic and synaptic cotransmission level as a consequence of the informational unbalance which very low or very high doses of biological signals (in pathological disorders) or of drug signal (agonist or antagonist) can do on physiological balance between both two coupled synaptic systems. To verify this hypothesis we choosed as place of manifesting and observing of the phenomen the informational gearing between the endogenous opioid system as "modulator" and the catecholaminergic systems as "alarm". As drug signals we used naloxone (NALX) and clonidine (CLON). The function studied to reveal the double-way effect was stress analgesia monitored in the classical test of te "hot plate". The experimental stress was induced to the mouse by submitting to forced swimming using the "despair test". In the work are presented the dose-effect curves and inflexion points which mark the changing of the sense of the effect.

Analgesia↗

PubMed1997

Glutamatergic system and developmental lead neurotoxicity.

The excitatory amino acid receptor subtype N-Methyl-D-Aspartate (NMDA) has been the focus of intense investigation during the last decade because of its role in brain development and synaptic plasticity and in pathological conditions associated with excitotoxicity. This receptor complex has recently been identified to be a target for lead (Pb2+) effects on the developing central nervous system. This presentation is an overview of studies demonstrating the interaction of Pb2+ with the NMDA receptor and its potential effects on cellular function and cognition.

Animals↗

PubMed2003

Spindle cell carcinoma of the breast: a case series of a rare histological subtype.

AIM: Spindle cell carcinoma (SpCC) represents <0.5% of breast cancers. We report the 15-year experience of SpCC at the Nottingham Breast Unit. METHODS: Histopathology and case notes of metaplastic carcinomas with predominant spindle cell differentiation were analysed for patient demographics, tumour pathology, c-erb B-2 oestrogen (ER) and progesterone (PR) receptor status and radiology. Treatment, recurrence and survival rates were also analysed. RESULTS: Nineteen patients with SpCC were identified. The median age was 68 years (range 27-92). Large ill-defined mass was the only consistent radiological features suggesting SpCC. Mean tumour size was 53 mm, (range 16-200 mm). Fifteen tumours were grade 3 and four were grade 2. Six out of 15 patients with axillary surgery had positive lymph nodes (40%). All tumours were oestrogen (ER) and progesterone (PR) negative. One tumour was focally c-erb B-2 positive in the non-spindle cell component. Median Nottingham Prognostic Index was 5.2 (range 3.6-6.6). Primary treatment was surgical in 89%. Adjuvant chemotherapy was given in four cases. The median disease free interval was 7 (range 2-109) months. Twelve cases recurred (63.2%). The main sites of metastasis were the lungs (9 cases), bone (6) and liver (1). Eleven cases have died of breast cancer (58%). Median survival was 18 months (range 4-109). CONCLUSION: SpCC is an aggressive histological type of carcinoma of the breast. Omitting node sampling may result in significant under-staging. Negative ER, PR and c-erb B-2 status limits treatment options.

Adult↗

PubMed1993

Molecular distinction of three N-methyl-D-aspartate-receptor subtypes in situ and developmental receptor maturation demonstrated with the photoaffinity ligand 125I-labeled CGP 55802A.

Activation of N-methyl-D-aspartate (NMDA) receptors is essential for synaptic plasticity in the central nervous system and contributes to neuronal death under various pathological conditions. Although several subunits have been cloned, the structure of NMDA receptors in situ is unresolved. By using a photoreactive antagonist with nanomolar affinity to the NMDA-binding site, three types of receptors were differentiated by their pattern of photoaffinity-labeled subunits. In adult brain, a protein of 175-kDa was photoreactive that displayed a profile of ligand binding and autoradiographical distribution corresponding to NMDA receptors. In contrast, in early postnatal brain, proteins of both 175 kDa and 115 kDa were photolabeled. This labeling pattern is switched to that of adult brain around postnatal day 10, pointing to a structural maturation of NMDA receptors. A third type of receptor could be identified in cerebellar granule cell cultures, where NMDA receptors mediate trophic effects and photolabeling was exclusively targeted to a 115-kDa protein. To identify the proteins labeled in situ, recombinant receptors were subjected to photolabeling. When the NR1 subunit was coexpressed with either the NR2A, NR2B, or NR2C subunit, only the combination of NR1/NR2A was photoreactive. Both the NR1 and NR2A subunits were photolabeled, corresponding in size to the proteins labeled in situ. However, the lack of subunit-selectivity in photolabeling the NR1/NR2A combination suggests the presence of additional receptor components in situ to explain the subunit-selective photoreactivity in adult brain (175 kDa) and in cerebellar granule cells (115 kDa). The subunit combination NR1/NR2A by itself appears insufficient to describe a major population of NMDA receptors, in particular, in adult brain.

Affinity Labels↗

PubMed1985

Supravalvular aortic stenosis. Clinical and pathologic observations in six patients.

Supravalvular aortic stenosis with a mean pressure gradient of 101 mm Hg was encountered in six patients aged 1 1/2 to 12 years. Three patients had Williams syndrome. In two other patients the stenosis was familial. The angiographic/anatomic subtype of deformity was hourglass in four patients, diffuse in one, and membranous in one. Four patients are alive following successful surgical repair; the other two died without surgery. Microscopically, disorganized medial elements with fibrotic intima sometimes containing lacunae were observed in five cases; the one other had valvelike tissue only. Ultrastructurally, thick irregular elastic fibers, abundant swirling collagen, hypertrophied smooth-muscle cells, and scant ground substance characterized the medial tissue defect. Although hemodynamics during intrauterine development may predispose to localization of the stenosis to the supra-aortic valvar region, the cause for the mural dysplasia remains uncertain.

Adult↗

PubMed2002

ALK protein expression in rhabdomyosarcomas.

AIMS: The ALK p80 chimeric protein is thought to be up-regulated as a result of the t(2;5) as classically seen in anaplastic large cell lymphoma. However, rhabdomyosarcomas (in particular, the alveolar subtype) have also been noted to show expression of this protein. This study set out to examine ALK expression in a large number of rhabdomyosarcomas. METHODS AND RESULTS: Eighty-three cases of rhabdomyosarcomas and 16 cases of malignant mixed müllerian tumours with a rhabdomyosarcomatous component were retrieved from the archives of the Department of Anatomical Pathology for the period 1983-2001. The sections were stained with polyclonal ALK antibody. There were 52 male and 30 female patients. In one case, the gender of the patient was not indicated. The ages ranged from 1 week to 77 years. The most common site was the head and neck region, followed by the pelvis and extremities. Thirty-one cases were of the alveolar subtype while 40 cases were embryonal. There were four mixed embryonal/alveolar, six pleomorphic and two unclassifiable rhabdomyosarcomas. Fourteen of the 31 (45%) alveolar rhabdomyosarcomas stained positively for the ALK protein, while only six of the 40 embryonal (15%) cases showed positivity. One case each of the mixed embryonal/alveolar, pleomorphic and unclassified cases was also immunopositive. The rhabdomyosarcomatous component in the malignant mixed müllerian tumours was positive in four of the 16 cases. CONCLUSION: We conclude that a proportion of alveolar rhabdomyosarcomas (in particular) exhibit ALK protein expression. However, ALK expression is not restricted to this subtype. An extension of this study is to determine if this over-expression is as a result of the t(2;5) translocation.

Adolescent↗

PubMed2004

Increased release of excitatory amino acids by the actions of ATP and peroxynitrite on volume-regulated anion channels (VRACs) in astrocytes.

Rapid swelling of astrocytes in primary culture by exposure to hyposmotic medium (or slower swelling by exposure to high K+ medium) leads to release of the excitatory amino acids (EAAs) glutamate and aspartate. One question that arises is whether these phenomena are only relevant to pathological states such as ischemia and trauma where marked astrocytic swelling occurs or whether much smaller astrocytic volume changes, that might be encountered under physiological states, will cause such release. We have recently found that extracellular ATP strongly potentiated volume-regulated anion channels (VRACs)-mediated-excitatory amino acid release in non-swollen and osmotically swollen primary astrocyte cultures. However, ATP does not seem to directly activate but instead positively modulates VRACs and we postulate that a minor fraction of these are active under isoosmotic conditions based on the finding that in hyperosmotic media the ATP-induced increase was inhibited. Agonist and inhibitor analysis suggests that the effect of ATP is mediated by several subtypes of metabotropic P2Y receptors. Thus, the concept of volume transmission may be extended to volume-mediated transmission, whereby moderate cell swelling causes release of neurotransmitter substances. The product of the superoxide oxygen radical and nitric oxide, peroxynitrite, formed under pathological conditions such as cerebral ischemia, also potentiated the release of D-[3H]aspartate from astrocyte cultures exposed to limited or marked swelling via intracellular signaling mechanisms involving tyrosine kinases (TKs). Thus, the enhancement of cell volume-dependent release of excitatory amino acids from astrocytes can be physiological or pathological and its magnitude depends on the degree of the cell volume increase.

Adenosine Triphosphate↗

PubMed1992

Malignant melanomas of the oral cavity: heterogeneity of pathological and clinical features.

Data on 35 patients with oral malignant melanomas were pooled and the pathological features and the clinical course were examined in detail. Of these 35 cases, 27 (77.1%) showed a two-phase growth pattern, with both a vertical and a radial growth phase. Moreover, these 27 cases were classified into three subtypes according to gross features of the vertical growth phase; nodular, flat elevated and ulcerated types. Almost two-thirds of the cases were of the melanotic type. Malignant melanomas without a radial growth phase were found in 8 instances, all of which showed a nodular growth pattern, 1 being of melanotic type and 7 amelanotic. Mean latent insidious periods were evaluated for the cases with different growth phases. Cases with a radical growth phase exhibited the longest mean latent period (35.7 months), and a median survival time of 23.5 months. Cases without a radial growth phase showed a short mean latent period (2.1 months), and a median survival time of 7.5 months. The thickness of invasion ranged from 2 to 9 mm. Although 77.1% of the cases depicted similar pathological patterns to acral lentiginous melanomas of the skin, oral malignant melanomas demonstrated heterogeneity in morphological features, developmental process and biological behaviour. The histogenesis of oral melanomas is briefly discussed.

Adult↗

PubMed1988

The pathology of lung cancer--changing concepts and newer diagnostic techniques.

While the basic classification of lung cancer has not altered drastically over the course of the last several years, histologic criteria have undergone a slow, progressive evolution. Input from biological studies has aided the subtyping of some tumors, especially SCLC, and helped delineate the importance of the accurate typing of NSCLC. Newer technological advances, especially in molecular biology, and application of established immunohistochemical techniques using newly generated antibodies are beginning to impact on diagnosis and typing. The evolution and application of clinical protocols directed to specific types or subtypes of lung cancer will provide an even greater impetus to these studies.

Adenocarcinoma↗

PubMed1993

[Histopathology and molecular pathology of chronic myeloproliferative disorders].

Diagnosis of chronic myeloproliferative disorders (CMPD) can encounter difficulties due to overlaps and possible transitions between the different entities and their similarity to reactive myeloproliferations. In this study DNA analysis has been applied to improve differentiation of CMPD. All subtypes of CMPD analyzed, including chronic myeloid leukemia (CML), agnogenic myeloid metaplasia (AMM), polycythemia vera (PV), and essential thrombocythemia (ET), had in common that granulocytes and bone marrow cells were clonal in origin as shown by X-chromosome-linked DNA polymorphism in conjunction with methylation patterns. Reactive myeloproliferations, by contrast, revealed a polyclonal inactivation pattern. Clonality could not distinguish CMPD from cases of myelodysplastic syndrome (MDS) since the latter also exhibited clonal hematopoiesis. AMM belongs to the group of myeloproliferative syndromes. Up to now the cellular phase at onset of the disease (megakaryocytic myelosis) has not been analyzed for clonality of the hematopoietic cells. Granulocytes as well as bone marrow cells from the cellular phase and advanced stages of the disease revealed a monoclonal inactivation pattern of X-chromosomal genes. These results show that the cellular phase already represents a monoclonal, and hence probably a neoplastic, proliferation of a pluripotent stem cell. The monoclonality of granulocytes could also be demonstrated in patients with splenomegaly and strongly argues against a compensatory proliferation of regular hematopoiesis in this organ. Because of their clonal origin, peripheral granulocytes were used in all cases (n = 244) for the detection of bcr-gene rearrangement. Despite possible morphological overlaps between different types of CMPD, bcr-gene rearrangement proved to be specific for CML and could be applied to differentiate CML from other CMPD in cases of uncertain morphological diagnosis. It is concluded that CMPD represent clonal hemopoietic disorders that probably have specific underlying genetic defects. Thus, DNA analysis can substantially aid in the differential diagnosis of CMPD.

Base Sequence↗

PubMed2005

Myxoid malignant fibrous histiocytoma and pleomorphic liposarcoma share very similar genomic imbalances.

Malignant fibrous histiocytoma (MFH) is the most common soft tissue sarcoma. Nevertheless, the validity of this heterogeneous pathological entity has been recurrently questioned by pathologists. Recently, analyses by comparative genomic hybridization (CGH) of a large series of MFHs suggested that MFHs consist of morphologic modulation of other poorly differentiated sarcomas like leiomyosarcomas (LMS) or dedifferentiated liposarcomas (DLPS). We report here an analysis by CGH of 22 myxoid MFHs (mMFH), one of the five histological subtypes of MFH, and of nine pleomorphic liposarcomas (pLPS), a rare poorly differentiated LPS. The chromosome imbalances encountered in the series of mMFH were very similar to those observed in the series of pLPS studied in the laboratory and in the series of 14 pLPS published in the literature. The most frequent gains involved chromosome subregions: pericentromeric regions of 1, 5p, 19p, 19q and 20q. Losses found in the chromosomal arms 1q, 2q, 3p, 4q, 10q, 11q and 13q were also recurrent. The use of a clustering software did not separate the two pathological groups (mMFH and pLPS) on the basis of genomic data. Moreover, pLPS-mMFH represented, according to the clustering software results, an entity clearly distinguished from other soft tissue sarcomas, LMS in particular, with which they share common genetic aberrations. Additional studies are needed to identify genes targeted by these genomic aberrations, and implicated in the oncogenesis of these tumor subtypes. The characterization of common gene alterations in both tumor groups would suggest a closer relationship between these two types of soft tissue sarcomas.

Adult↗

PubMed1998

Specific genetic predictors of chemotherapeutic response and survival in patients with anaplastic oligodendrogliomas.

BACKGROUND/METHODS: Gliomas are common malignant neoplasms of the central nervous system. Among the major subtypes of gliomas, oligodendrogliomas are distinguished by their remarkable sensitivity to chemotherapy, with approximately two thirds of anaplastic (malignant) oligodendrogliomas responding dramatically to combination treatment with procarbazine, lomustine, and vincristine (termed PCV). Unfortunately, no clinical or pathologic feature of these tumors allows accurate prediction of their response to chemotherapy. Anaplastic oligodendrogliomas also are distinguished by a unique constellation of molecular genetic alterations, including coincident loss of chromosomal arms 1p and 19q in 50%-70% of tumors. We have hypothesized that these or other specific genetic changes might predict the response to chemotherapy and prognosis in patients with anaplastic oligodendrogliomas. Therefore, we have analyzed molecular genetic alterations involving chromosomes 1p, 10q, and 19q and the TP53 (on chromosome 17p) and CDKN2A (on chromosome 9p) genes, in addition to clinicopathologic features in 39 patients with anaplastic oligodendrogliomas for whom chemotherapeutic response and survival could be assessed. RESULTS/CONCLUSIONS: Allelic loss (or loss of heterozygosity) of chromosome 1p is a statistically significant predictor of chemosensitivity, and combined loss involving chromosomes 1p and 19q is statistically significantly associated with both chemosensitivity and longer recurrence-free survival after chemotherapy. Moreover, in both univariate and multivariate analyses, losses involving both chromosomes 1p and 19q were strongly associated with longer overall survival, whereas CDKN2A gene deletions and ring enhancement (i.e., contrast enhancement forming a rim around the tumor) on neuroimaging were associated with a significantly worse prognosis. The inverse relationship between CDKN2A gene deletions and losses of chromosomes 1p and 19q further implies that these differential clinical behaviors reflect two independent genetic subtypes of anaplastic oligodendroglioma. These results suggest that molecular genetic analysis may aid therapeutic decisions and predict outcome in patients with anaplastic oligodendrogliomas.

Adult↗

PubMed1999

Motor neuron disease-inclusion dementia presenting as cortical-basal ganglionic degeneration.

The frontotemporal dementias are a group of relatively new and evolving clinical and pathologic entities. The predominant frontal-temporal atrophy causes a variety of clinical syndromes, usually dominated by disturbances in behavior, mood, and speech. The motor neuron disease-inclusion dementia (MNDID) subtype is characterized by the accumulation of specific intraneuronal ubiquitin-immunoreactive inclusions with the complete absence of tau immunoreactivity. We present a patient with the clinical and neuroimaging characteristics of a highly asymmetric neurodegenerative condition distinguished by limb rigidity, bradykinesia, dystonia with an alien limb phenomenon, cortical sensory findings, and limb apraxia. His premorbid diagnosis was cortical-basal ganglionic degeneration but he had the typical histologic features of a frontotemporal dementia of the MNDID subtype.

Basal Ganglia Diseases↗

PubMed2001

Small-sized adenocarcinoma of the lung. Cytologic characteristics and clinical behavior.

BACKGROUND: Although the cytologic characteristics of advanced adenocarcinomas of the lung have been described, the unique cytologic features of early adenocarcinomas have not been established. METHODS: Cytologic specimens from 193 patients with small-sized lung adenocarcinoma, up to 2 cm in dimension, were reviewed. Cytologic investigations were performed on sputum, bronchial brushings or washings, or fine-needle aspirates obtained from the patients preoperatively. The cytologic characteristics of early adenocarcinoma were confirmed with Image Processor for Analytical Pathology from Sumitomo Chemical Co., Ltd. RESULTS: Nuclear size, variations in nuclear size, appearance of nucleolus, and nuclear atypia of the adenocarcinoma cells were found to differ between the various histologic subtypes of adenocarcinoma. The nuclei in small but advanced adenocarcinoma were generally larger and showed more variation in size than those in early adenocarcinoma (localized bronchioloalveolar carcinoma). CONCLUSIONS: Surgically curable, early adenocarcinomas of the lung were found to have a unique cytologic appearance, including small nuclear size and slight variation in nuclear size. Using these unique characteristics, they can be distinguished easily from advanced adenocarcinomas.

Adenocarcinoma↗

PubMed2004

Characterisation of the effects of ATPA, a GLU(K5) kainate receptor agonist, on GABAergic synaptic transmission in the CA1 region of rat hippocampal slices.

Kainate receptors are implicated in a variety of physiological and pathological processes in the CNS. Previously we demonstrated that (RS)-2-amino-3-(3-hydroxy-5-tert-butylisoxazol-4-yl)propanoic acid (ATPA), a selective agonist for the GLU(K5) subtype of kainate receptor, depresses monosynaptically evoked inhibitory postsynaptic potentials (IPSPs) in the CA1 region of the rat hippocampus. In the current study, we provide a more detailed characterisation of this effect. Firstly, our data demonstrate a rank order of potency of domoate>kainate>ATPA>alpha-amino-3-(3-hydroxy-5-methyl-4-isoxalolyl)propionic acid Secondly, we confirm that the effects of ATPA are not mediated indirectly via the activation of gamma-aminobutyric acid receptors (i.e. either GABA(A) or GABA(B)). Thirdly, we show that the small increase in conductance induced by ATPA is insufficient to account for the depression of monosynaptic inhibition. Fourthly, we show that the effects of ATPA on IPSPs are antagonised by the GLU(K5)-selective antagonist (3S, 4aR, 6S, 8aR)-6-(4-carboxyphenyl)methyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid (LY382884). However, LY382884 is less potent as an antagonist of the effects of ATPA on IPSPs compared to its depressant effect on EPSPs.

Animals↗

PubMed2005

Clinicopathologic review of malignant polyps in stage 1A carcinoma of the endometrium.

OBJECTIVES: The aims of this study were to determine the incidence of malignant polyps in stage 1A endometrial cancer, to define the pathological features of such cancers, and to assess whether clinical outcome differs from similar cancers without a malignant polyp. METHODS: We performed a retrospective pathological review of 107 cases of stage 1A endometrial cancer treated at two centers in New South Wales between January 1988 and July 2003. The presence of a malignant polyp was determined and a pathological description made of the tumor. Clinical data were collected, including prior tamoxifen usage, tumor recurrence and survival. The outcome of the malignant polyp group was compared to the same histological subtype not involving a malignant polyp. RESULTS: The incidence of malignant polyps in our series was 32%. Malignant polyps occurred in all 8 cases involving a serous subtype. Precursor lesions of endometrial cancer were identified within malignant polyps. Three out of the four recurrences occurred in high-grade tumor subtypes and all four had a large primary tumor (size > or = 4 cm). When comparing the same subtype of tumor with and without a malignant polyp, there was no significant difference in clinical outcome. CONCLUSIONS: Approximately one-third of stage 1A endometrial cancers are associated with a malignant polyp. Serous carcinoma commonly arises within an otherwise benign endometrial polyp. Malignant polyps offer an opportunity to identify precursors of endometrial carcinoma. Clinical outcome of stage 1A endometrial carcinoma was related to the histological subtype and the size of the tumor rather than the presence of a malignant polyp.

Adult↗

PubMed2003

Expression of functional PACAP/VIP receptors in human prostate cancer and healthy tissue.

Vasoactive intestinal peptide (VIP) is involved in prostate cell proliferation and function. VIP and pituitary adenylate cyclase-activating peptide (PACAP) are similarly recognized by VPAC(1)/VPAC(2) receptors whereas PACAP binds with higher affinity than VIP to PAC(1) receptor. Here we systematically studied the presence and distribution of functional PAC(1), VPAC(1) and VPAC(2) receptors in human normal and malignant prostate tissue. Functional PACAP/VIP receptors were detected in normal and malignant prostate by adenylyl cyclase stimulation with PACAP-27/38 and VIP. RT-PCR experiments showed PAC(1) (various isoforms due to alternative splicing), VPAC(1) and VPAC(2) receptor expression at the mRNA level, whereas Western blots found the three receptor protein classes in normal and pathological conditions. No conclusive differences could be established when comparing control and cancer tissue samples. Immunohistochemistry showed a weaker immunostaining in tumoral than in normal epithelial cells for the three receptor subtypes. In conclusion, we demonstrate the expression of functional PAC(1), VPAC(1) and VPAC(2) receptors in human prostate as well as its maintenance after malignant transformation.

Aged↗

PubMed2005

Drug Insight: endothelin-receptor antagonists for pulmonary arterial hypertension in systemic rheumatic diseases.

Rapid advances in the understanding of endothelin as a naturally occurring peptide with developmental and regulatory roles in normal physiology, along with a number of deleterious effects under pathologic conditions (including vasoconstriction, fibrosis, vascular hypertrophy, and inflammation) have led to the development of endothelin-receptor antagonists (ERAs). Bosentan, an antagonist with dual specificity for the endothelin-receptor subtypes A and B, has been shown to be efficacious and well tolerated in placebo-controlled clinical trials and is now approved in many countries, including the US, Canada, and Europe, for treatment of pulmonary arterial hypertension (PAH), including PAH associated with rheumatic diseases. ERAs with specificity for the endothelin-receptor subtype A, including sitaxsentan and ambrisentan, are currently undergoing investigation. This article reviews PAH associated with systemic rheumatic diseases and describes the role of ERAs in this setting.

Endothelin Receptor Antagonists↗