Anesthetic drugs modulate feeding behavior and hypothalamic expression of the POMC polypeptide precursor and the NPY neuropeptide.

BACKGROUND: Several hypnotic drugs have been previously identified as modulators of food intake, but exact mechanisms remain unknown. Feeding behavior implicates several neuronal populations in the hypothalamic arcuate nucleus including orexigenic neuropeptide Y and anorexigenic pro-opiomelanocortin producing neurons. The aim of this study was to investigate in mice the impact of different hypnotic drugs on food consumption and neuropeptide Y or pro-opiomelanocortine mRNA expression level in the hypothalamic arcuate nucleus. METHODS: Saline control, isoflurane, thiopental, midazolam or propofol were administered to C57Bl/6 mice. Feeding behavior was evaluated during 6 h. In situ hybridization of neuropeptide Y and pro-opiomelanocortine mRNAs in the hypothalamus brain region was also performed. Data were analyzed by Kruskal Wallis test and analysis of variance (p < 0.05). RESULTS: Midazolam, thiopental and propofol induced feeding behavior. Midazolam and thiopental increased neuropeptide Y mRNA level (respectively by 106 and 125%, p < 0.001) compared with control. Propofol and midazolam decreased pro-opiomelanocortine mRNA level by 31% (p < 0,01) compared with control. Isoflurane increased pro-opiomelanocortine mRNA level by 40% compared with control. CONCLUSION: In our murine model, most hypnotics induced food consumption. The hypnotic-induced regulation of neuropeptide Y and pro-opiomelanocortine hypothalamic peptides is associated with this finding. Our data suggest that administration of some hypnotic drugs may affect hypothalamic peptide precursor and neuropeptide expression and concomittantly modulate food intake. Thus, this questions the choice of anesthetics for better care management of patients undergoing major surgery or at risk of undernutrition.

The microphysics of collisionless shock waves.

Collisionless shocks, that is shocks mediated by electromagnetic processes, are customary in space physics and in astrophysics. They are to be found in a great variety of objects and environments: magnetospheric and heliospheric shocks, supernova remnants, pulsar winds and their nebulæ, active galactic nuclei, gamma-ray bursts and clusters of galaxies shock waves. Collisionless shock microphysics enters at different stages of shock formation, shock dynamics and particle energization and/or acceleration. It turns out that the shock phenomenon is a multi-scale non-linear problem in time and space. It is complexified by the impact due to high-energy cosmic rays in astrophysical environments. This review adresses the physics of shock formation, shock dynamics and particle acceleration based on a close examination of available multi-wavelength or in situ observations, analytical and numerical developments. A particular emphasis is made on the different instabilities triggered during the shock formation and in association with particle acceleration processes with regards to the properties of the background upstream medium. It appears that among the most important parameters the background magnetic field through the magnetization and its obliquity is the dominant one. The shock velocity that can reach relativistic speeds has also a strong impact over the development of the micro-instabilities and the fate of particle acceleration. Recent developments of laboratory shock experiments has started to bring some new insights in the physics of space plasma and astrophysical shock waves. A special section is dedicated to new laser plasma experiments probing shock physics.

Opinions, hopes and concerns regarding pharmacogenomics: a comparison of healthy individuals, heart failure patients and heart transplant recipients.

It is not yet known whether healthy individuals and patients with a chronic disease have similar attitudes towards pharmacogenomics. Thus we conducted a survey of 175 healthy volunteers, 175 heart failure (HF) patients and 100 heart transplant recipients to compare their opinions on this subject. Most participants (>90%) stated that they would accept pharmacogenomic testing and expressed high hopes regarding its potential applications. Overall, interest for pharmacogenomics was shared equally among the three groups. In contrast, after adjusting for age, gender, education and income, healthy individuals were more likely to voice concerns about potential employment (P=0.008 vs HF, odds ratio (OR)=2.93, confidence interval (CI)=1.33-6.47; P=0.010 vs Transplant, OR=2.46, CI=1.24-4.90) and insurance discrimination (P=0.001 vs HF, OR=5.58, CI=2.01-15.48; P<0.001 vs Transplant, OR=4.98, CI=2.03-12.21) and were possibly more worried by confidentiality issues. These findings highlight the need for strict legislation and proper educational strategies directed at the general population to facilitate the clinical implementation of pharmacogenomics.

Exploring the Potential Impact of GLP-1 Receptor Agonists on Substance Use, Compulsive Behavior, and Libido: Insights from Social Media Using a Mixed-Methods Approach.

Glucagon-like peptide-1 (GLP-1) is involved in a range of central and peripheral pathways related to appetitive behavior. Hence, this study explored the effects of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) on substance and behavioral addictions, including alcohol, caffeine, nicotine, cannabis, psychostimulants, compulsive shopping, and sex drive/libido. Data were collected from various social platforms. Keywords related to GLP-1 RAs and substance/behavioral addiction were used to extract relevant comments. The study employed a mixed-methods approach to analyze online discussions posted from December 2019 to June 2023 and collected using a specialized web application. Reddit entries were the focus here due to limited data from other platforms, such as TikTok and YouTube. A total of 5859 threads and related comments were extracted from six subreddits, which included threads about GLP-1 RAs drugs and associated brand names. To obtain relevant posts, keywords related to potential substance use and compulsive behavior were selected. Further analysis involved two main steps: (1) manually coding posts based on users' references to the potential impact of GLP-1 RAs on substance use and non-substance habits, excluding irrelevant or unclear comments; (2) performing a thematic analysis on the dataset of keywords, using AI-assisted techniques followed by the manual revision of the generated themes. Second, a thematic analysis was performed on the keyword-related dataset, using AI-assisted techniques followed by the manual revision of the generated themes. In total, 29.75% of alcohol-related; 22.22% of caffeine-related; and 23.08% of nicotine-related comments clearly stated a cessation of the intake of these substances following the start of GLP-1 RAs prescription. Conversely, mixed results were found for cannabis intake, and only limited, anecdotal data were made available for cocaine, entactogens, and dissociative drugs' misuse. Regarding behavioral addictions, 21.35% of comments reported a compulsive shopping interruption, whilst the sexual drive/libido elements reportedly increased in several users. The current mixed-methods approach appeared to be a useful tool in gaining insight into complex topics such as the effects of GLP-1 RAs on substance and non-substance addiction-related disorders; some GLP-1 RA-related mental health benefits could also be inferred from here. Overall, it appeared that GLP-1 RAs may show the potential to target both substance craving and maladaptive/addictive behaviors, although further empirical research is needed.

Is There a Risk for Semaglutide Misuse? Focus on the Food and Drug Administration's FDA Adverse Events Reporting System (FAERS) Pharmacovigilance Dataset.

Recent media reports commented about a possible issue of the misuse of antidiabetics related to molecules promoted as a weight-loss treatment in non-obese people. We evaluated here available pharmacovigilance misuse/abuse signals related to semaglutide, a glucagon-like peptide-1 (GLP-1) analogue, in comparison to other GLP-1 receptor agonists (albiglutide, dulaglutide, exenatide, liraglutide, lixisenatide, and tirzepatide) and the phentermine-topiramate combination. To acheieve that aim, we analyzed the Food and Drug Administration's FDA Adverse Events Reporting System (FAERS) dataset, performing a descriptive analysis of adverse event reports (AERs) and calculating related pharmacovigilance measures, including the reporting odds ratio (ROR) and the proportional reporting ratio (PRR). During January 2018-December 2022, a total of 31,542 AERs involving the selected molecules were submitted to FAERS; most involved dulaglutide (n = 11,858; 37.6%) and semaglutide (n = 8249; 26.1%). In comparing semaglutide vs. the remaining molecules, the respective PRR values of the AERs 'drug abuse', 'drug withdrawal syndrome', 'prescription drug used without a prescription', and 'intentional product use issue' were 4.05, 4.05, 3.60, and 1.80 (all < 0.01). The same comparisons of semaglutide vs. the phentermine-topiramate combination were not associated with any significant differences. To the best of our knowledge, this is the first study documenting the misuse/abuse potential of semaglutide in comparison with other GLP1 analogues and the phentermine-topiramate combination. The current findings will need to be confirmed by further empirical investigations to fully understand the safety profile of those molecules.

Effects of developmental exposure to mixtures of environmental contaminants on the hepatic metabolism of estradiol-17ß in immature female Sprague Dawley rats.

Exposure to environmental contaminants induces the activation of cytochrome P450s (CYP) which lead to the hydroxylation of contaminants and endogenous hormones such as estrogens. The hydroxylation of estrogens forms catecholestrogens (CEs), one of them being the mutagenic 4-hydroxyestradiol-17ß (4-OH-E2). Catecholestrogens are transformed by catechol-o-methyltransferases (COMTs) into nonreactive methoxyestrogens. To investigate the hepatic metabolism of estradiol-17ß in female offspring at postnatal day (PND) 21, pregnant rats were dosed daily from gestation day 1 until PND 21 with 2 dose levels of organochlorine pesticides (OCPs; 0.019 or 1.9 mg/kg per d), methylmercury (MeHg; 0.02 or 2 mg/kg per d), polychlorinated biphenyls (PCBs; 0.011 or 1.1 mg/kg per d), or a mixture (M; 0.05 or 5 mg/kg per d) including all 3 groups of chemicals. Concentrations of organochlorines in the mixture M were based on their proportions in serum of the Canadian Arctic population. The messenger RNA (mRNA) expressions of CYP and COMT were analyzed by quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR). High-performance thin layer chromatography and phosphor imaging were used to measure the transformation of (14)C substrates into estrogen metabolites. The low-dose treatments or the MeHg groups had no effect. The high-dose OCP, PCB, and M group increased the production of 2-OH-E2 and 6α-OH-E2, while only the PCB and M groups increased the 2-OH-CE/methoxyestrogen ratio. In all groups, the cytosolic COMT activity exceeded the microsomal production rate of 4-OH-E2. Although the M treatment included the PCB and OCP mixtures, it did not modify the estrogen metabolism more than did the PCB mixture alone. This endocrine disruption information contributes to our understanding of chemical interactions in the toxicology of chemical mixtures.

Characterization of the potential impact of retention tank emptying on wastewater primary treatment: a new element for CSO management.

Theoretical studies have shown that discharges from retention tanks could have a negative impact on the WWTP's (Wastewater Treatment Plant) effluent. Characterization of such discharges is necessary to better understand these impacts. This study aims at: (1) characterizing water quality during emptying of a tank; and (2) characterizing the temporal variation of settling velocities of the waters released to the WWTP. Two full-scale sampling campaigns (18 rain events) have been realized in Quebec City and laboratory analyses have shown a wide variability of total suspended solids (TSS) and Chemical Oxygen Demand (COD) concentrations in the water released from the tank. Suspended solids seem to settle quickly because they are only found in large amounts during the first 15 min of pumping to the WWTP. These solids are hypothesized to come from the pumping in which solids remained after a previous event. When these solids are evacuated, low TSS containing waters are pumped from the retention tank. A second concentration peak occurs at the end of the emptying period when the tank is cleaned with wash water. Finally, settling velocity studies allowed characterizing combined sewer wastewaters by separating three main fractions of pollutants which correspond to the beginning, middle and end of emptying. In most cases, it is noticed that particle settling velocities increase as the pollutant load increases.

Studies on the release of leukotrienes and histamine by human lung parenchymal and bronchial fragments upon immunologic and nonimmunologic stimulation. Effects of nordihydroguaiaretic acid, aspirin, and sodium cromoglycate.

Fragments of human lung parenchyma or bronchi were studied by high performance liquid chromatography, gas chromatography-mass spectrometry, and bioassay for the biosynthesis of 5-lipoxygenase metabolites of arachidonic acid, and by radioenzymatic assay for the release of histamine, upon immunologic and nonimmunologic stimulation. Human lung parenchyma were passively sensitized with serum from timothy-positive allergic patients (radioallergosorbent test, 30-40%) and challenged with 0.5 microgram/ml of timothy allergen. Analysis of the incubation media showed the presence of LTB4, LTC4, LTD4, LTE4, and histamine. Maximum release of LTB4 and LTD4 was observed after 15 min of challenge (92.8 +/- 21, and 67.8 +/- 14 pmol/g tissue wet weight, respectively; mean +/- SEM) whereas maximum release of LTC4 was observed after 5 min of challenge (25 +/- 7.1 pmol). In parallel to leukotriene formation, histamine was released rapidly and reached a maximum after approximately 15 min of challenge (2.85 +/- 0.76 nmol/g tissue). When fragments of human lung parenchyma were stimulated with ionophore A23187 (4 microM), we observed a profile of leukotriene and histamine release similar to that seen in response to the allergen. Ionophore A23187 stimulated the release of two- to fivefold greater amounts of leukotrienes and histamine than did the allergen. Release of LTC4 and histamine was maximal after 5 min of stimulation (83 +/- 22.2 and 5.2 +/- 0.95 nmol/g tissue, respectively), whereas LTB4 and LTD4 release reached a maximum after 15 min (438 +/- 66.6 and 205 +/- 68 nmol/g tissue, respectively). In addition, human lung parenchyma metabolized LTB4 into omega-OH-LTB4 and omega-COOH-LTB4. This tissue also released 5-hydroxy-eicosatetraenoic acid (5-Hete), 12-Hete, and 15-Hete. Fragments of human lung bronchi also released a similar profile of leukotrienes (except LTC4) and histamine when challenged with the allergen or ionophore A23187. Maximum release of LTB4 and LTD4 by allergen or ionophore stimulation was observed after approximately 15 min (40 +/- 7.5 and 21 +/- 8 pmol/g tissue, respectively, upon allergen challenge; 100 +/- 13 and 47 +/- 10.6 pmol/g tissue, respectively, upon ionophore stimulation). The maximum release of histamine by bronchi was observed after approximately 15 min of allergen challenge and 5 min of ionophore stimulation (2.25 +/- 0.65 and 3.15 +/- 0.9 nmol/g tissue, respectively). The release of leukotrienes but not of histamine by human lung parenchyma upon both allergen and ionophore challenge was inhibited by nordihydroguaiaretic acid (NDGA) (ID50, 2 X 10(-6)M).(ABSTRACT TRUNCATED AT 400 WORDS)

Autoradiographic studies of synthesis and intracellular migration of glycoproteins in the rat anterior pituitary gland.

The incorporation of [(3)H]fucose in the somatotrophic and gonadotrophic cells of the rat adenohypophysis has been studied by electron microscope autoradiography to determine the site of synthesis of glycoproteins and to follow the migration of newly synthesized glycoproteins. The pituitaries were fixed 5 min, 20 min, 1 h, and 4 h after the in vivo injection of [(3)H]fucose and autoradiographs analyzed quantitatively. At 5 min after [(3)H]fucose administration, 80-90% of the silver grains were localized over the Golgi apparatus in both somatotrophs and gonadotrophs. By 20 min, the Golgi apparatus was still labeled and some radioactivity appeared over granules. At 1 h and 4 h, silver grains were found predominantly over secretory granules. The kinetic analysis showed that in both protein-secreting cells (somatotrophs) and glycoprotein-secreting cells (gonadotrophs), the glycoproteins have their synthesis completed in the Golgi apparatus and migrate subsequently to the secretory granules. It is concluded from these in vivo studies that glycoproteins which are not hormones are utilized for the formation of the matrix and/or of the membrane of the secretory granules. The incorporation of [(3)H]fucose in gonadectomy cells (hyperstimulated gonadotrophs) was also studied in vitro after pulse labeling of pituitary fragments in medium containing [(3)H]fucose. The incorporation of [(3)H]fucose was localized in both the rough endoplasmic reticulum (ER) and the Golgi apparatus. Later, the radioactivity over granules increased while that over the Golgi apparatus decreased. The concentration of silver grains over the dilated cisternae of the rough ER was not found to be modified at the longest time intervals studied.

Localization of a 16,000-dalton fragment of the common precursor of adrenocorticotropin and beta-lipotropin in the rat and human pituitary gland.

To clearly identify cells and organelles containing the common precursor (31,000 dalton) for both adrenocorticotropin (ACTH) and beta-lipotropin (beta-LPH), an immunohistochemical localization of a fragment (16,000 dalton) of the precursor that is not common to beta-LPH and ACTH was conducted in rat and human pituitary glands. With the help of specific antibodies that do not cross-react with beta-LPH and ACTH, the 16,000-dalton fragment was localized in the cells that also produce ACTH and beta-LPH in both the pars distalis and pars intermedia of the rat pituitary. At the electron microscope level, the secretory granules that contain ACTH were also stained for 16,000-dalton fragment. In the human pituitary, the 16,000-dalton fragment was also observed in all the secretory granules of lipocorticotrophs. These results suggest that, after enzymatic cleavage, fragment(s) of the common precursor and/or the whole common precursor remain packaged within the secretory granules with peptides of known activity.

Changes of cell morphology and prolactin secretion induced by 2-Br-alpha-ergocryptine, estradiol, and thyrotropin-releasing hormone in rat anterior pituitary cells in culture.

The secretion of prolactin in cultured pituitary cells was studied in correlation with the cellular changes induced by stimulatory or inhibitory agents. The techniques used in this study were: radioimmunoassay, immunocytochemistry, scanning (SEM) as well as transmission (TEM) electron microscopy. Prolactin secretion was stimulated by 17 beta-estradiol (10 nM) as well as thyrotropin-releasing hormone (TRH) (3 nM) and inhibited by 2-Br-alpha-ergocryptine (CB-154) (1 muM). The total prolactin (release and cell content) increased between 2 and 8 d of estradiol treatment, indicating an increase of both synthesis and release of prolactin. This finding was in agreement with TEM observations because, in estradiol-treated prolactin cells, the Golgi saccules were distended and Golgi elements were increased, thus indicating increased synthetic activity of these cells. The addition of TRH over a 4-h period resulted in a significant degranulation of prolactin cells. In contrast, prolactin secretory granules became accumulated in the cells after CB-154 treatment for a period ranging from 4 to 24 h. In agreement, light microscope immunocytochemistry showed an increased reaction for prolactin after short-term (< 24 h) incubation with CB-154. Because prolactin cells represent approximately 70% of the glandular cell population as revealed by immunocytochemistry, it was then possible to observe the changes of cell surface by SEM. In most cells, estradiol and TRH led to an increase in the number and prominence of microvilli and blebs, whereas CB-154 treatment resulted in a slightly decreased number of microvilli and an increased occurrence of membrane foldings. This report thus provides morphological evidence for the stimulatory effects of estradiol and TRH, and the inhibitory effects of CB-154 on prolactin secretion in pituitary cells in primary culture. These data, moreover, show that acute changes in secretory activity of prolactin-secreting cells are accompanied by marked changes of their morphological characteristics.

Somatostatin: electron microscope immunohistochemical localization in secretory neurons of rat hypothalamus.

Somatostatin, the hypothalamic hormone which inhibits the secretion of growth hormone by the pituitary, has been localized in the rat hypothalamus by using electron microscope immunohistochemistry. Somatostatin occurs in secretory granules (80 to 110 nm in diameter) of a few neurons located in the hypothalamic periventricular nucleus. These observations establish the identity of neurosecretory neurons involved in the regulation of adenohypophyseal secretion.

Chronic administration of dehydroepiandrosterone (DHEA) to female monkey and rat has no effect on mammary gland histology.

Dehydroepiandrosterone (DHEA), the major steroid precursor of androgens and estrogens produced in peripheral tissues in primates, has been shown to exert chemopreventive effect on the development of carcinogen-induced rat mammary tumors. Since little is known on the effect of DHEA administration on mammary gland physiology and histology, we have studied the effect of long-term administration of DHEA to normal female monkey and rat on mammary gland histology as well as on serum DHEA, DHEA sulphate (DHEA-S), testosterone and estradiol levels. In monkeys, DHEA treatment (2 or 10 mg/(kg b.w.day)) induced a dose-related increase in serum DHEA and DHEA-S (above 20-fold) levels. At the highest dose of DHEA, serum testosterone levels were significantly increased (three- to fourfold), while serum estradiol concentration was not modified. DHEA treatment did not modify the histological characteristics of monkey mammary glands. In the rat, following DHEA administration (10 or 100 mg/(kg b.w.day)), a dose-related marked increase in serum DHEA and DHEA-S was observed. Serum testosterone was also increased in DHEA-treated animals, while no significant changes in serum estradiol levels were detected. As in the monkey, the histology of the female rat mammary gland remained unchanged following long-term treatment with any of the two doses of DHEA.

Expression of 17beta-hydroxysteroid dehydrogenase type 2 and type 5 in breast cancer and adjacent non-malignant tissue: a correlation to clinicopathological parameters.

Estrogens play an important role in the development and progression of breast cancer. 17beta-Hydroxysteroid dehydrogenase (17beta-HSD) type 2 and type 5 are involved in sex steroid metabolism. 17beta-HSD type 2 converts estradiol to estrone while 17beta-HSD type 5 converts androstenedione to testosterone. Using immunocytochemistry, we have studied the expression of 17beta-HSD type 2 and type 5 in 50 specimens of breast carcinoma and adjacent non-malignant tissues. The results were correlated with the estrogen receptor alpha (ERalpha) and beta (ERbeta), progesterone receptor A (PRA) and B (PRB), androgen receptor and CDC47 and with the tumor stage, tumor size, nodal status and menopausal status. 17beta-HSD type 2 was expressed in 20% and 17beta-HSD type 5 in 56% of breast cancer specimens. In adjacent normal tissues, both enzymes were highly expressed in almost all the patients. No significant association could be found between the expression of 17beta-HSD type 2 and 17beta-HSD type 5 and between the expression of each enzyme and the clinicopathological parameters studied. The decrease in 17beta-HSD type 2 and 17beta-HSD type 5 expressions in breast cancer may play a predominant role in the development and/or progression of the cancer by modifying the intratumoral levels of estrogens and androgens.

Gene expression profiling in rat cerebellum following in utero and lactational exposure to mixtures of methylmercury, polychlorinated biphenyls and organochlorine pesticides.

Although human populations are continuously exposed to complex mixtures of contaminants, the effects of such exposure on the developing brain transcriptome are poorly characterized. Rats were exposed perinatally to the northern contaminant mixture (NCM) which was designed to reflect the blood contaminant profile of Canadian arctic populations, to components of the NCM administered separately (methylmercury (MeHg), polychlorinated biphenyls (PCBs) and organochlorine pesticides (OCs)) or to the goitrogen propylthiouracyl. Post-natal day (PND) 14 cerebellum global gene expression resulting from such exposures was investigated using high-density cDNA microarrays. Fifty known genes were identified as differentially expressed between the control group and at least one other treatment group. The microarray data were validated by quantitative PCR (qPCR) on a subset of 10 genes. The differentially expressed genes are involved in a variety of processes, including nerve cell differentiation, migration, myelination and synaptic transmission. The comparison of cerebellum gene expression profiles resulting from exposure to the NCM and its individual components in male and female pups revealed that (i) gender is a crucial biological variable influencing genomic response to environmental contaminants and (ii) contaminant co-exposure significantly masks the effects of individual mixture components on cerebellum gene expression.

Liver cell adenomas and portosystemic shunt.

We report the case of a young man who developed multiple liver cell adenomas 13 years after a mesentericocaval shunt. Radiological findings did not provide diagnosis. Histological findings of two biopsied nodules were compatible with liver cell adenoma. Our patient had no known risk factors for liver cell adenomas. We discuss the hypothesis that disturbed hepatic vascularisation could promote the development of liver cell adenomas.

Localization and glucocorticoid regulation of 11beta-hydroxysteroid dehydrogenase type 1 mRNA in the male mouse forebrain.

The enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) converts the inactive 11-dehydrocorticosterone into the active glucocorticoid corticosterone. There is accumulating evidence indicating widespread expression of 11beta-HSD1 in the brain. However, there is little information about regulation of 11beta-HSD1 expression in this tissue. Using in situ hybridization involving use of 35S-labeled cRNA probe, we have studied the distribution of cells expressing 11beta-HSD1 mRNA in the male mouse forebrain as well as the effects of adrenalectomy (ADX) and acute administration of corticosterone (3 and 24 h) on 11beta-HSD1 mRNA levels. Cells expressing 11beta-HSD1 mRNA were mostly detected in the cerebral cortex, hippocampus, amygdala and medial preoptic area, with the highest expression in the cerebral cortex (retrosplenial granular area) and hippocampus (CA3 and granular layer of the gyrus dentatus). Seven days following ADX, 11beta-HSD mRNA levels were increased by 50% in the gyrus dentatus, by 100% in the CA3 area, and 105% in the cerebral cortex. Administration of corticosterone to ADX mice induced a significant decrease in mRNA, in both the hippocampus and cerebral cortex so that, at the 24 h time interval, the levels were similar to those observed in intact mice. These results clearly indicate that circulating corticosterone is downregulating the expression of 11beta-HSD1 mRNA in the two forebrain areas studied. This downregulation might contribute to maintain low intracellular corticosterone levels in central regions and then prevent the deleterious effects induced by high glucocorticoid levels.

Oestrogenic regulation of pro-opiomelanocortin, neuropeptide Y and corticotrophin-releasing hormone mRNAs in mouse hypothalamus.

It is well documented that oestrogen suppresses food intake by an action at the hypothalamic level. Using in situ hybridisation, we studied the effect of castration (CX) and short-term administration of oestradiol (E2) in CX female mice for three neuropeptides involved in feeding behaviour: two anorexigenic peptides, (i) the pro-opiomelanocortin (POMC)-derived peptide alpha-melanocyte-stimulating hormone and (ii) corticotrophin-releasing hormone (CRH), and the orexigenic peptide, (iii) neuropeptide Y (NPY). POMC-expressing neurones were mostly laterally located in the arcuate nucleus. POMC mRNA expression was decreased following CX and a single injection of E2 induced an increase in mRNA levels at 12- and 24-h time intervals. In the parvocellular area of the paraventricular nucleus, CRH mRNA levels were similarly decreased after CX and completely restored to normal levels at 12 and 24 h following E2 injection. On the other hand, the levels of NPY mRNA expressed in neurones located in the inner zone of the arcuate nucleus were increased by CX and decreased to the levels observed in intact animals by E2 injection (3-24 h). The present data suggest that oestrogen might exert an anorexigenic action by stimulating POMC and CRH mRNA expression and decreasing NPY mRNA expression in the hypothalamus.

UDP-glucuronosyltransferase UGT1A7 genetic polymorphisms in hepatocellular carcinoma: a differential impact according to seropositivity of HBV or HCV markers?

BACKGROUND: We conducted a case-control study to evaluate the role of UDP-glucuronosyltransferase 1A7 (UGT1A7) polymorphisms in the onset of hepatocellular carcinoma (HCC). METHODS: The study included 165 patients with HCC, 134 with cirrhosis and 142 controls without liver disease, matched for age and hospital. All were men younger than 75 years. HCC and cirrhosis patients were stratified according to time since cirrhosis diagnosis. RESULTS: We found a positive association between the UGT1A7*3/*3 genotype and HCC when the comparison was restricted to patients whose disease was of viral origin [OR = 3.4 (0.3-45)] but a negative association when it included only alcoholic patients [OR = 0.1 (0.02-0.6), p = 0.01]. CONCLUSION: Our study shows that UGT1A7 may play a role in hepatocellular carcinogenesis and that this role may differ according to the primary cause of the cirrhosis.