Physical anhedonia in the acute phase of schizophrenia

BACKGROUND: The aim of the current study is to investigate the relationship between physical anhedonia and psychopathological parameters, pharmacological parameters or motor side-effects in a sample of inpatients with schizophrenia in an acute episode of their illness. METHOD: Eighty one patients with schizophrenia, consecutively admitted, with an acute episode of their illness, at the Eginition Hospital, Department of Psychiatry, University of Athens, during a one-year period were investigated regarding possible relationships between physical anhedonia, social-demographic data and clinical parameters as well as motor side-effects, induced by antipsychotic agents. All patients were assessed using the Chapman Revised Physical Anhedonia Scale (RPAS), the Positive and Negative Syndrome Scale (PANSS), the Rating Scale for Extrapyramidal Side-Effects (EPSE), the Barnes Akathisia Rating Scale (BARS) and the Abnormal Involuntary Movement Scale (AIMS). Simple cross tabulations were initially employed. Subsequently, multiple regression analysis was performed. RESULTS: Both positive and negative symptoms were associated with physical anhedonia. A positive association between physical anhedonia and the non-paranoid sub-category of schizophrenia was also proved. CONCLUSION: According to these results, it seems that in the acute phase of schizophrenia, physical anhedonia may be a contributing factor to patient's psychopathology

Candidate pathways and genes for prostate cancer: a meta-analysis of gene expression data

<p>Abstract</p> <p>Backgound</p> <p>The genetic mechanisms of prostate tumorigenesis remain poorly understood, but with the advent of gene expression array capabilities, we can now produce a large amount of data that can be used to explore the molecular and genetic mechanisms of prostate tumorigenesis.</p> <p>Methods</p> <p>We conducted a meta-analysis of gene expression data from 18 gene array datasets targeting transition from normal to localized prostate cancer and from localized to metastatic prostate cancer. We functionally annotated the top 500 differentially expressed genes and identified several candidate pathways associated with prostate tumorigeneses.</p> <p>Results</p> <p>We found the top differentially expressed genes to be clustered in pathways involving integrin-based cell adhesion: integrin signaling, the actin cytoskeleton, cell death, and cell motility pathways. We also found integrins themselves to be downregulated in the transition from normal prostate tissue to primary localized prostate cancer. Based on the results of this study, we developed a collagen hypothesis of prostate tumorigenesis. According to this hypothesis, the initiating event in prostate tumorigenesis is the age-related decrease in the expression of collagen genes and other genes encoding integrin ligands. This concomitant depletion of integrin ligands leads to the accumulation of ligandless integrin and activation of integrin-associated cell death. To escape integrin-associated death, cells suppress the expression of integrins, which in turn alters the actin cytoskeleton, elevates cell motility and proliferation, and disorganizes prostate histology, contributing to the histologic progression of prostate cancer and its increased metastasizing potential.</p> <p>Conclusion</p> <p>The results of this study suggest that prostate tumor progression is associated with the suppression of integrin-based cell adhesion. Suppression of integrin expression driven by integrin-mediated cell death leads to increased cell proliferation and motility and increased tumor malignancy.</p

Chronic p53-independent p21 expression causes genomic instability by deregulating replication licensing

The cyclin-dependent kinase inhibitor p21WAF1/CIP1 (p21) is a cell-cycle checkpoint effector and inducer of senescence, regulated by p53. Yet, evidence suggests that p21 could also be oncogenic, through a mechanism that has so far remained obscure. We report that a subset of atypical cancerous cells strongly expressing p21 showed proliferation features. This occurred predominantly in p53-mutant human cancers, suggesting p53-independent upregulation of p21 selectively in more aggressive tumour cells. Multifaceted phenotypic and genomic analyses of p21-inducible, p53-null, cancerous and near-normal cellular models showed that after an initial senescence-like phase, a subpopulation of p21-expressing proliferating cells emerged, featuring increased genomic instability, aggressiveness and chemoresistance. Mechanistically, sustained p21 accumulation inhibited mainly the CRL4–CDT2 ubiquitin ligase, leading to deregulated origin licensing and replication stress. Collectively, our data reveal the tumour-promoting ability of p21 through deregulation of DNA replication licensing machinery—an unorthodox role to be considered in cancer treatment, since p21 responds to various stimuli including some chemotherapy drugs

Significance of abnormal 53BP1 expression as a novel molecular pathologic parameter of follicular-shaped B-cell lymphoid lesions in human digestive tract

The digestive tract is a common site of extranodal malignant lymphomas (MLs) and benign lymphoid lesions (BLs). TP53-binding protein 1 (53BP1) expression has been widely investigated in class switch recombination but rarely in human lymphoid tissues with respect to tumorigenesis. We previously reported that immunofluorescence (IF) analysis of 53BP1 nuclear foci (NF), reflecting DNA double strand breaks, is useful for estimating genomic instability in different tumor types. In this study, we evaluated the potential of IF-based analysis of 53BP1 expression in differentiating MLs from BLs. We examined 231 biopsied tissue samples of primary MLs and BLs in the digestive tract. The 53BP1 immunoreactivity pattern was determined by multicolor IF. Compared to BLs, MLs showed a high frequency of abnormal 53BP1 expression (p < 0.0001). Statistically, abnormal 53BP1 expression is an effective test for distinguishing follicular lymphomas from BLs (specificity 98.6%, sensitivity 86.8%) and for distinguishing small B-cell lymphomas from BLs (specificity 98.3%, sensitivity 77.6%). Furthermore, a high frequency of abnormal 53BP1 expression was associated with “high-risk” MALT lymphomas, which exhibited t(11;18)(q21;21) (p = 0.0145). Collectively, these results suggest that IF-based analysis of 53BP1 expression in biopsy samples is a promising technique for diagnosing MLs in the digestive system

Bupivacaine-induced regeneration of rat soleus muscle: Ultrastructural and immunohistochemical aspects

The regeneration of soleus muscle injury induced by the bupivacaine model was studied ultrastructurally and immunohistochemically. Twenty-one young (age range 3-3.5 months) male Wistar rats were subjected to a single intramuscular injection of 1 mL of 0.5% Marcaine. The muscles were examined on biopsy days 1, 2, 3, 5, 7, 14, and 21. By day 1, mononuclear inflammatory cells had invaded the necrotic sarcoplasm. Degenerative morphological findings counted mainly for the hypercontracted fibers, dilation of sarcoplasmic reticulum, plasma membrane defects, mitochondrial alterations, and myofibril discontinuities. By day 2 proliferating myoblasts were seen with variety in shape, which fused on the day 3. Myotubes with multiple central nuclei and euchromatic nucleoli were formed by day 5. Asynchronous repair events were seen with bundles of myofilaments toward the core of the fibers, in contrast to the least mature distal growth cones, which had free myoblasts in proximity and formatted pseudopods. Chronologically asynchronous regeneration stages possibly suggested successive satellite cell activation profiles or heterogeneity in satellite cell population. In parallel with the electron microscopy, in light microscope immunocytochemistry, desmin- and vimentin-positive mononuclear cells were observed within the first 3 biopsy days, but as regeneration proceeded, desmin predominated over vimentin. Merosin immunoreactivity revealed preservation of the basal lamina, which is crucial for the stability and survival of myotubes. By day 21, fibers restored the overall control architecture. Copyright © Informa Healthcare

Ultrastructural identification of protein bodies, cellular markers of human catecholamine neurons, in a temporal lobe ganglioglioma

A temporal lobe ganglioglioma, surgically removed from an 8-year-old body, and a human brainstem at the level of locus coeruleus (LC) were processed for light microscopy (LM), with formalin fixation and paraffin embedding, and for electron microscopy (EM) with glutaraldehyde fixation, potassium permanganate postfixation, phosphotungstic acid-hematoxylin block-staining, and epoxy - resin embedding. The paraffin sections were stained with toluidine blue O/rhodamine B and observed under epi-fluorescence. The thin sections for EM were viewed directly without further staining. The neuronal neoplastic cells of ganglioglioma and the neurons of LC are known to produce catecholamines. Both also contain spherical protein bodies (pb), cellular markers that identify catecholamine neurons in humans. The ultrastructural characteristics of the pb in LC were compared with those of the pb in neoplastic ganglion cells. These bodies had an identical ultrastructure, in both tissues, consisting of electron-lucent core surrounded by an electron-dense thin rim. The rhodamine B-stained sections also emphasized the identical morphology of the pb in ganglioglioma and LC. Based on the EM comparison, these brightly fluorescing spherical bodies are ideal markers for identifying in LM, the clusters of large neoplastic cells, representing neurons, which are the most important clue to the correct diagnosis of gangliogliomas

The bright and dark side of skin senescence. Could skin rejuvenation anti-senescence interventions become a “bright” new strategy for the prevention of age-related skin pathologies?

The number of senescent cells in the skin is increasing with age. Numerous studies have attempted to elucidate the role of these cells in normal aging of the skin as well as in age-related skin conditions. In recent years, attempts have also been made to find treatments that aim either to cleanse the skin tissues of senescent cells or to neutralize their effects (referred to as senolytics and senomorphics respectively) and thus prevent the consequences, particularly on the skin&apos;s appearance in advanced age. Through this review, we have tried to gather data on the role of senescent cells in the skin, in treatments aimed at removing them, and we are asking a reasonable question as to whether anti-senescence treatments may contribute to the protection against age-related skin pathologies, including skin cancer, such as non-melanoma skin cancer, in addition to their involvement in skin rejuvenation. © 2020 Elsevier B.V

Noradrenaline storage function of species-specific protein bodies, markers of monoamine neurons in human locus coeruleus demonstrated by dopamine-β-hydroxylase immunogold localization

Our histochemical and ultrastructural studies have identified, in human catecholamine locus coeruleus (LC) neurons, abundant and large spherical protein bodies (PB), containing histone-like, arginine-rich proteins, which originate as dense bodies in mitochondria. This species-specific phenotype in the neurons of man is highly intriguing. In the electron microscope PB are disrupted in LC neurons in depressed individuals, where noradrenaline is known to be reduced. This coincidence of ultrastructure and neurochemistry raises the question whether these bodies could qualify as noradrenaline-storing organelles in the human LC. Our rationale was to examine, in known model tissues that contain catecholamines - sympathetic ganglia and tumors of the autonomic nervous system - if vesicles show the same fine structure and histochemistry as the PB of the human LC. Hence, we selected biopsy tissues of five ganglioneuromas and postmortem tissues of LC from 25 control subjects. Since dopamine-β- hydroxylase (DBH) is a hallmark of noradrenaline identity and present in dense core vesicles, the investigation of DBH localization with the immunogold method constituted the experiment of choice for this study. Histochemical determinations of arginine with Carmoisine L, and of lipids with Rhodamine B complemented the study of similarities between the PB of the human LC and ganglioneuromas. Our results showed, with the colloidal gold method, that DBH immunogold labeling was localized in the core and in the double membranes of the PB, and also in the adjacent mitochondria. These results indicate that protein bodies (a) are unequivocal storage vesicles of noradrenaline, and (b) derive from regular mitochondria and represent a new phenotype in man, which is probably an evolutionary adaptation of amine-storing organelles. © 2004 Elsevier Inc. All rights reserved

mTORC1-dependent protein synthesis and autophagy uncouple in the regulation of Apolipoprotein A-I expression

Background: Apolipoprotein A-I (ApoA-I) is involved in reverse cholesterol transport as a major component of HDL, but also conveys anti-thrombotic, anti-oxidative, anti-inflammatory and immune-regulatory properties that are pertinent to its protective roles in cardiovascular, inflammatory and malignant pathologies. Despite the pleiotropy in ApoA-I functions, the regulation of intracellular ApoA-I levels remains poorly explored. Methods: HepG2 hepatoma cells and primary mouse hepatocytes were used as in vitro models to study the impact of genetic and chemical inhibitors of autophagy and the proteasome on ApoA-I by immunoblot, immunofluorescence and electron microscopy. Different growth conditions were implemented in conjunction with mTORC inhibitors to model the influence of nutrient scarcity versus sufficiency on ApoA-I regulation. Hepatic ApoA-I expression was also evaluated in high fat diet-fed mice displaying blockade in autophagy. Results: Under nutrient-rich conditions, basal ApoA-I levels in liver cells are sustained by the balancing act of autophagy and of mTORC1-dependent de novo protein synthesis. ApoA-I proteolysis occurs through a canonical autophagic pathway involving Beclin1 and ULK1 and the receptor protein p62/SQSTM1 that targets ApoA-I to autophagosomes. However, upon aminoacid insufficiency, suppression of ApoA-I synthesis prevails, rendering mTORC1 inactivation dispensable for autophagy-mediated ApoA-I proteolysis. Conclusion: These data underscore the major contribution of post-transcriptional mechanisms to ApoA-I levels which differentially involve mTORC1-dependent signaling to protein synthesis and autophagy, depending on nutrient availability. Given the established role of ApoA-I in HDL-mediated reverse cholesterol transport, this mode of ApoA-I regulation may reflect a hepatocellular response to the organismal requirement for maintenance of cholesterol and lipid reserves under conditions of nutrient scarcity. © 2020 Elsevier Inc