Scintillation and radioluminescence mechanism in ß-Ga2O3 semiconducting single crystals.

In this paper, we present the results of experiments on samples of ß-Ga2O3 single crystals under a project aimed at assessing and improving the scintillation performance of this material by studying scintillation and radioluminescence mechanism and its limitations. In addition to standard experiments, such as scintillation light yields and time profiles, radio-, and thermoluminescence, we developed and tested a new and promising two-beam experiment, in which a sample is excited by an X-ray beam and additionally stimulated by an IR laser diode. Fe and Mg doping compensate for the inherent n-type conductivity of ß-Ga2O3 to obtain semi-insulating single crystals for large-area substrates and wafers. At the same time, residual Fe and Ir are ubiquitous uncontrolled impurities leached from the Ir crucibles used to grow large bulk crystals by the Czochralski method. For these experiments, we selected four samples cut from the Czochralski grown 2-cm diameter ß-Ga2O3 single crystal boules; one with a reduced Fe content, two unintentionally Fe- and Ir-doped (UID) with lower and higher Fe content, and one doped with Mg. We find that steady-state radioluminescence spectra measured at temperatures between 10 and 350 K are dominated by the UV emission peaking at about 350-370 nm. Unfortunately, even for the best sample with a reduced Fe-content, the intensity of this emission drops precipitously with the temperature down to about 10 % at 300 K. From the two-beam experiments, we conclude that recombination via inadvertent Fe impurity involving three charge states (2+, 3+, and 4+) may reduce a steady-state UV emission of ß-Ga2O3 under X-ray excitation by as much as 60-70 %, one-third to one-half of which is due to the recombination (specific for Fe-doped ß-Ga2O3) involving the 4+ and 3+ charge states of Fe and the remaining 50-70 % being due to a more familiar route typical of other oxides, involving the 2+ and 3+ charge states of Fe. These losses are at higher temperatures enhanced by a thermally activated redistribution of self-trapped holes (STHs). In addition, the trapping of electrons by Fe and holes by Mg, Fe, and Ir may be responsible for scintillation light loss and reduction of the zero-time amplitude essential for the fast timing scintillation applications. Despite indirect evidence of competitive recombination in ß-Ga2O3 involving a deep Ir3+/4+ donor level, we could not quantitatively assess losses of the UV steady state radioluminescence light due to the inadvertent Ir impurity.

Transcriptomic profiling of mare endometrium at different stages of endometrosis.

In the current study, transcriptome profiles of mare endometrium, classified into categories I, IIA, and IIB according to Kenney and Doig, were compared using RNA sequencing, analyzed, and functionally annotated using in silico analysis. In the mild stage (IIA) of endometrosis compared to category I endometrium, differentially expressed genes (DEGs) were annotated to inflammation, abnormal metabolism, wound healing, and quantity of connective tissue. In the moderate stage (IIB) of endometrosis compared to category I endometrium, DEGs were annotated to inflammation, fibrosis, cellular homeostasis, mitochondrial dysfunction, and pregnancy disorders. Ingenuity pathway analysis (IPA) identified cytokines such as transforming growth factor (TGF)-ß1, interleukin (IL)-4, IL-13, and IL-17 as upstream regulators of DEGs associated with cellular homeostasis, metabolism, and fibrosis signaling pathways. In vitro studies showed the effect of these cytokines on DEGs such as ADAMTS1, -4, -5, -9, and HK2 in endometrial fibroblasts at different stages of endometrosis. The effect of cytokines on ADAMTS members' gene transcription in fibroblasts differs according to the severity of endometrosis. The identified transcriptomic changes associated with endometrosis suggest that inflammation and metabolic changes are features of mild and moderate stages of endometrosis. The changes of ADAMTS-1, -4, -5, -9, in fibrotic endometrium as well as in endometrial fibroblast in response to TGF-ß1, IL-4, IL-13, and IL-17 suggest the important role of these factors in the development of endometrosis.

Triclocarban Disrupts the Epigenetic Status of Neuronal Cells and Induces AHR/CAR-Mediated Apoptosis.

Triclocarban is a phenyl ether that has recently been classified as a contaminant of emerging concern. Evidence shows that triclocarban is present in human tissues, but little is known about the impact of triclocarban on the nervous system, particularly at early developmental stages. This study demonstrated that triclocarban that was used at environmentally relevant concentrations induced apoptosis in mouse embryonic neurons, inhibited sumoylation, and changed the epigenetic status, as evidenced by impaired activities of HDAC, sirtuins, and DNMT, global DNA hypomethylation, and alterations of methylation levels of bax, bcl2, Ahr, and Car genes. The use of selective antagonists and specific siRNAs, which was followed by the co-localization of aryl hydrocarbon receptor (AHR) and constitutive androstane receptor (CAR) in mouse neurons, points to the involvement of AHR and CAR in triclocarban-induced neurotoxicity. A 24-h treatment with triclocarban enhanced protein levels of the receptors which was paralleled by Car hypomethylation and Ahr hypermethylation. Car hypomethylation is in line with global DNA hypomethylation and explains the increased mRNA and protein levels of CAR in response to triclocarban. Ahr hypermethylation could reflect reduced Ahr mRNA expression and corresponds to lowered protein levels after 3- and 6-h exposures to triclocarban that is likely related to proteasomal degradation of activated AHR. We hypothesize that the triclocarban-induced apoptosis in mouse neurons and the disruption of epigenetic status involve both AHR- and CAR-mediated effects, which may substantiate a fetal basis of the adult onset of neurological diseases; however, the expression of the receptors is regulated in different ways.

Frequency of Pathologic Changes in the Oral Cavity in Patients Subjected to Long-term Pharmacologic Immunosuppressive Therapy After Kidney, Liver, and Hematopoietic Cell Transplantation.

INTRODUCTION: Patients subjected to long-term immunosuppressive therapy after organ and cells transplantation are more susceptible than healthy people to the development of the pathologic changes in the oral cavity, including precancerous lesions, oral cancers, lesions following viral infections (herpes simplex virus, Epstein-Barr virus, and cytomegalovirus), fungal infections mainly caused by Candida albicans, drug-induced gingival overgrowth, stomatitis, and tongue disorders. MATERIAL AND METHODS: Clinical case material included 38 patients after kidney, liver, or blood-forming cells transplantation subjected to various immunosuppressive therapy schemes. The study comprised standard case taking and physical examination of the patient, including detailed intraoral and extraoral stomatological examinations. RESULTS: Extraoral examination confirmed 1 case of multifocal basal cell carcinoma in the auricular region and one case of systemic lupus erythematosus. Intraoral examination revealed gingivitis (60.5%), gingival recession (58%), periodontitis (55.26%), macroglossia (15.8%), lingual papillary atrophy (13.16%), leukoplakia aphthae/ulcerations (10.5%), lichen planus, pallor of mucous membranes (7.9%), pathologic pigmentation of oral mucosa, geographic tongue (5.26%) and erythroplakia (2.6%). When their histories were taken, patients reported xerostomia (68.42%), halitosis (23.68%), gum bleeding while brushing teeth (18.42%), and dysgeusia (15.78%). DISCUSSION: Both the patients after organ and hematopoietic stem cells transplantations and those qualified for a transplant should undergo multispecialty treatment, particularly dental treatment, to enable the detection of pathologies at an early stage and commencement of effective therapy. Cooperation between the main doctor and the dentist is crucial in the process of treatment of this group of patients.

Dramatic photoluminescence quenching in carbon dots induced by cyclic voltammetry.

This study focuses on the structural rearrangements and the photoluminescent behavior of pyrolytically derived carbon dots when subjected to a series of cyclic voltammetry sweeps. Although the electrical signals involved are not pronounced, multiple electrochemical cycling results in a progressive suppression of the photoluminescence, so that after 42 sweeps the intensity is reduced by one order of magnitude. At the same time, the fluorescence component stemming from the organic fluorophores is blue-shifted, while the contribution of the carbogenic cores is red-shifted. XPS and FTIR spectra reveal that the voltammetric field induces an extensive formation of C-O and C[double bond, length as m-dash]O at the expense of the C[double bond, length as m-dash]C bonds. Our findings indicate a close relationship between the electrochemical response and the structure of C-dots and, thus, have direct implications on the development of C-dot based electroluminescent materials, electrochemical sensors and solar cells.

Impact of smoking on multiple primary cancers survival: a retrospective analysis.

According to available literature, active tobacco smoking enhances the risks of recurrence and development of new primary malignancies. Smoking also shortens the survival period for patients with a diagnosed neoplastic disease. Medical records of 1622 patients hospitalized at the Center for Pulmonary Diseases from January 2013 till March 2017 were retrospectively analyzed, out of which 741 cases with a diagnosis of at least one primary cancer were selected, including 111 patients with multiple primary malignancies. Survival time, the impact of smoking on cancer development and the influence of smoking cessation on the prognosis of the development of new malignancies were analyzed. The incidence of multiple primary malignancies in the population of cancer patients amounted to 14.98%. In the group of smokers, those who ceased smoking developed the second primary malignancy later as compared to those who did not: the period between the first and the new cancer was 11.55 years (SD 7.24) for those who quit smoking, whereas for those who continued to smoke after their first cancer diagnosis it was 6.10 years (SD 8.62) (p = 0.005). It was revealed that patients who had never smoked lived longer than those who had continued to smoke (p = 0.004) and that those who had ceased smoking had a longer survival time than those who had not (p = 0.027). Ceasing smoking after the first cancer diagnosis prolongs the time before a new malignancy develops and is diagnosed, as well as the total survival time after the first cancer diagnosis.

The Crucial Involvement of Retinoid X Receptors in DDE Neurotoxicity.

Dichlorodiphenyldichloroethylene (DDE) is a primary environmental and metabolic degradation product of the pesticide dichlorodiphenyltrichloroethane (DDT). It is one of the most toxic compounds belonging to organochlorines. DDE has never been commercially produced; however, the parent pesticide DDT is still used in some developing countries for disease-vector control of malaria. DDT and DDE remain in the environment because these chemicals are resistant to degradation and bioaccumulate in the food chain. Little is known, however, about DDE toxicity during the early stages of neural development. The results of the present study demonstrate that DDE induced a caspase-3-dependent apoptosis and caused the global DNA hypomethylation in mouse embryonic neuronal cells. This study also provided evidence for DDE-isomer-non-specific alterations of retinoid X receptor α (RXRα)- and retinoid X receptor ß (RXRß)-mediated intracellular signaling, including changes in the levels of the receptor mRNAs and changes in the protein levels of the receptors. DDE-induced stimulation of RXRα and RXRß was verified using selective antagonist and specific siRNAs. Co-localization of RXRα and RXRß was demonstrated using confocal microscopy. The apoptotic action of DDE was supported at the cellular level through Hoechst 33342 and calcein AM staining experiments. In conclusion, the results of the present study demonstrated that the stimulation of RXRα- and RXRß-mediated intracellular signaling plays an important role in the propagation of DDE-induced apoptosis during early stages of neural development.

Pathological gamma oscillations, impaired dopamine release, synapse loss and reduced dynamic range of unitary glutamatergic synaptic transmission in the striatum of hypokinetic Q175 Huntington mice.

Huntington's disease (HD) is a severe genetically inherited neurodegenerative disorder. Patients present with three principal phenotypes of motor symptoms: choreatic, hypokinetic-rigid and mixed. The Q175 mouse model of disease offers an opportunity to investigate the cellular basis of the hypokinetic-rigid form of HD. At the age of 1 year homozygote Q175 mice exhibited the following signs of hypokinesia: Reduced frequency of spontaneous movements on a precision balance at daytime (-55%), increased total time spent without movement in an open field (+42%), failures in the execution of unconditioned avoidance reactions (+32%), reduced ability for conditioned avoidance (-96%) and increased reaction times (+65%) in a shuttle box. Local field potential recordings revealed low-frequency gamma oscillations in the striatum as a characteristic feature of HD mice at rest. There was no significant loss of DARPP-32 immunolabeled striatal projection neurons (SPNs) although the level of DARPP-32 immunoreactivity was lower in HD. As a potential cause of hypokinesia, HD mice revealed a strong reduction in striatal KCl-induced dopamine release, accompanied by a decrease in the number of tyrosine hydroxylase-(TH)- and VMAT2-positive synaptic varicosities. The presynaptic TH fluorescence level was also reduced. Patch-clamp experiments were performed in slices from 1-year-old mice to record unitary EPSCs (uEPSCs) of presumed cortical origin in the absence of G-protein-mediated modulation. In HD mice, the maximal amplitudes of uEPSCs amounted to 69% of the WT level which matches the loss of VGluT1+/SYP+ synaptic terminals in immunostained sections. These results identify impairment of cortico-striatal synaptic transmission and dopamine release as a potential basis of hypokinesia in HD.

Dexketoprofen/tramadol: randomised double-blind trial and confirmation of empirical theory of combination analgesics in acute pain.

BACKGROUND: Combination analgesics are effective in acute pain, and a theoretical framework predicts efficacy for combinations. The combination of dexketoprofen and tramadol is untested, but predicted to be highly effective. METHODS: This was a randomised, double-blind, double-dummy, parallel-group, placebo-controlled, single-dose trial in patients with moderate or severe pain following third molar extraction. There were ten treatment arms, including dexketoprofen trometamol (12.5 mg and 25 mg) and tramadol hydrochloride (37.5 mg and 75 mg), given as four different fixed combinations and single components, with ibuprofen 400 mg as active control as well as a placebo control. The study objective was to evaluate the superior analgesic efficacy and safety of each combination and each single agent versus placebo. The primary outcome was the proportion of patients with at least 50 % max TOTPAR over six hours. RESULTS: 606 patients were randomised and provided at least one post-dose assessment. All combinations were significantly better than placebo. The highest percentage of responders (72%) was achieved in the dexketoprofen trometamol 25 mg plus tramadol hydrochloride 75 mg group (NNT 1.6, 95% confidence interval 1.3 to 2.1). Addition of tramadol to dexketoprofen resulted in greater peak pain relief and greater pain relief over the longer term, particularly at times longer than six hours (median duration of 8.1 h). Adverse events were unremarkable. CONCLUSIONS: Dexketoprofen trometamol 25 mg combined with tramadol hydrochloride 75 mg provided good analgesia with rapid onset and long duration in a model of moderate to severe pain. The results of the dose finding study are consistent with pre-trial calculations based on empirical formulae. TRIAL REGISTRATION: EudraCT (2010-022798-32); Clinicaltrials.gov (NCT01307020).

Triclosan induces Fas receptor-dependent apoptosis in mouse neocortical neurons in vitro.

Triclosan (TCS) is a commonly used antimicrobial agent in personal care and sanitizing products, as well as in household items. Numerous studies have demonstrated the presence of TCS in various human tissues. Several studies have reported the accumulation of TCS in fish and human brain tissue. The aim of the present study was to investigate the effect of TCS on apoptosis in mouse neocortical neurons after 7 days of culture in vitro following 3, 6 and 24 h of exposure. To explore the mechanism underlying the effects of TCS in neurons, we studied the activation and protein expression of the Fas receptor (FasR) and caspase-8, caspase-9 and caspase-3, as well as DNA fragmentation in TCS-treated cells. Cultures of neocortical neurons were prepared from Swiss mouse embryos on day 15/16 of gestation. The cells were cultured in phenol red-free Neurobasal medium with B27 and glutamine. The cultures were treated with concentrations of TCS ranging from 1 nM to 100 µM for 3, 6 and 24 h. The level of lactate dehydrogenase (LDH) was measured in the culture medium to exclude the cytotoxic concentrations. The cytotoxic effects were only observed when the highest concentrations of TCS were used (50 and 100 µM). To study apoptosis, the activities of caspase-8, caspase-9 and caspase-3 were measured, and DNA fragmentation was evaluated. Our results are the first time to demonstrate that TCS can induce an apoptotic process in neocortical neurons in vitro. The data demonstrated that TCS caused caspase-3 activation, DNA fragmentation and apoptotic body formation. Non-cytotoxic concentrations of TCS activated the extrinsic apoptotic signaling pathway, which is dependent on FasR and caspase-8 activation. However, it is also possible that TCS may activate the intrinsic apoptotic pathway after long-term exposure. Therefore, further studies on the mechanism underlying the effects of TCS on the nervous system are needed.

Incidence of bone formation by whole bone marrow cell suspensions and by its stromal cell cultures injected into kidney parenchyma of Balb/c mice.

The evaluation of incidence of bone formation by whole syngeneic bone marrow cell suspension and by bone marrow stromal cell cultured in vitro injection into kidney parenchyma was done. Bone tissue was found in 26 kidneys out of 100 injected with whole bone marrow cells suspension. Cultured stromal bone marrow cells grafted into kidney parenchyma produced ossicles in only 4 out of 101 injected kidneys. Such low incidence of bone forming ability of the marrow stromal cell cultures grafted into kidney indicate their useless for study on bone histogenesis in the kidney by murine marrow stromal cell cultures.

Autologous osteoblast transplantation, an innovative method of bone defect treatment: role of a tissue and cell bank in the process.

BACKGROUND: The idea of cell treatment of various diseases and medical conditions has become very popular. Some procedures are well established, as is autologous chondrocyte implantation, whereas others are still in the process of early development, laboratory experiments, and some clinical trials. METHODS: This report is devoted to an example of an emerging cell treatment: bone augmentation with the use of autologous cells and its legal and technical background. Various requirements set by law must be met by tissue banks performing cell seeding of grafts. In Europe, the requirements are described in directives 2004/23/EC, 2006/17/EC, 2006/86/EC, and in the regulation 2007/1394/EC. RESULTS: Revitalization of biostatic allografts gives new, promising tools for creation of functional parts of organs; brings the methodology used in tissue banks closer to tissue engineering; places the enterprise in the mainstream of advanced biotechnology; allows the full potential of tissue allografts; and opens a new, large area for clinical and laboratory research. Cell and tissue processing also have a financial impact on the treatment: it produces additional expenditures. CONCLUSIONS: Clinical effectiveness will be the most decisive factor of whether this innovative treatment will be applied in a particular type of medical condition. From a tissue establishment perspective, the most important issue is to develop a procedure that ensures safety for the patient in graft quality terms.

Isomer-nonspecific action of dichlorodiphenyltrichloroethane on aryl hydrocarbon receptor and G-protein-coupled receptor 30 intracellular signaling in apoptotic neuronal cells.

Extended residual persistence of the pesticide dichlorodiphenyltrichloroethane (DDT) raises concerns about its long-term neurotoxic effects. Little is known, however, about DDT toxicity during the early stages of neural development. This study demonstrated that DDT-induced apoptosis of mouse embryonic neuronal cells is a caspase-9-, caspase-3-, and GSK-3ß-dependent process, which involves p,p'-DDT-specific impairment of classical ERs. It also provided evidence for DDT-isomer-nonspecific alterations of AhR- and GPR30-mediated intracellular signaling, including changes in the levels of the receptor and receptor-regulated mRNAs, and also changes in the protein levels of the receptors. DDT-induced stimulation of AhR-signaling and reduction of GPR30-signaling were verified using selective ligands and specific siRNAs. Co-localization of the receptors was demonstrated with confocal microscopy, and the presence of functional GPR30 was detected by electrophysiology. This study demonstrates that stimulation of AhR-signaling and impairment of GPR30-signaling play important roles in the propagation of DDT-induced apoptosis during the early stages of neural development.

Estimation of inbreeding and effective population size of full-blood Wagyu cattle registered with the American Wagyu Cattle Association.

The objective of this research was to examine the population structure of full-blood (100%) Wagyu cattle registered in the United States with the American Wagyu Association, with the aim of estimating and comparing the levels of inbreeding from both pedigree and genotypic data. A total of 4132 full-blood Wagyu cattle pedigrees were assessed and used to compute the inbreeding coefficients (FIT and FST ) and the effective population size (Ne ) from pedigree data for the period 1994 to 2011. In addition to pedigree analysis, 47 full-blood Wagyu cattle representing eight prominent sire lines in the American Wagyu cattle population were genotyped using the Illumina BovineSNP50 BeadChip. Genotypic data were then used to estimate genomic inbreeding coefficients (FROH ) by calculating runs of homozygosity. The mean inbreeding coefficient based on the pedigree data was estimated at 4.80%. The effective population size averaged 17 between the years 1994 and 2011 with an increase of 42.9 in 2000 and a drop of 1.8 in 2011. Examination of the runs of homozygosity revealed that the 47 Wagyu cattle from the eight prominent sire lines had a mean genomic inbreeding coefficient (FROH ) estimated at 9.08% compared to a mean inbreeding coefficient based on pedigree data of 4.8%. These data suggest that the mean genotype inbreeding coefficient of full-blood Wagyu cattle exceeds the inbreeding coefficient identified by pedigree. Inbreeding has increased slowly at a rate of 0.03% per year over the past 17 years. Wagyu breeders should continue to utilize many sires from divergent lines and consider outcrossing to other breeds to enhance genetic diversity and minimize the adverse effects of inbreeding in Wagyu.

The key involvement of estrogen receptor ß and G-protein-coupled receptor 30 in the neuroprotective action of daidzein.

Phytoestrogens have received considerable attention because they provide an array of beneficial effects, such as neuroprotection. To better understand the molecular and functional link between phytoestrogens and classical as well as membrane estrogen receptors (ERs), we investigated the effect of daidzein on the glutamate-mediated apoptotic pathway. Our study demonstrated that daidzein (0.1-10µM) inhibited the pro-apoptotic and neurotoxic effects caused by glutamate treatment. Hippocampal, neocortical and cerebellar tissues responded to the inhibitory action of daidzein on glutamate-activated caspase-3 and lactate dehydrogenase (LDH) release in a similar manner. Biochemical data were supported at the cellular level by Hoechst 33342 and calcein AM staining. The sensitivity of neuronal cells to daidzein-mediated protection was most prominent in hippocampal cultures at an early stage of development 7th day in vitro. A selective estrogen receptor ß (ERß) antagonist, 4-[2-phenyl-5,7-bis(trifluoromethyl)pyrazolo[1,5,-a]pyrimidin-3-yl]phenol (PHTPP), and a selective G-protein-coupled receptor 30 (GPR30) antagonist, 3aS(∗),4R(∗),9bR(∗))-4-(6-Bromo-1,3-benzodioxol-5-yl)-3a,4,5,9b-3H-cyclopenta[c]quinoline (G15), reversed the daidzein-mediated inhibition of glutamate-induced loss of membrane mitochondrial potential, caspase-3 activity, and LDH release. A selective ERα antagonist, methyl-piperidino-pyrazole (MPP), did not influence any anti-apoptotic effect of daidzein. However, a high-affinity estrogen receptor antagonist, 7α,17ß-[9-[(4,4,5,5,5-pentafluoropentyl)sulfinyl]nonyl]estra-1,3,5(10)-triene-3,17-diol (ICI) 182,780, and a selective GPR30 agonist, (±)-1-[(3aR(∗),4S(∗),9bS(∗))-4-(6-bromo-1,3-benzodioxol-5-yl)-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinolin-8-yl]-ethanone (G1), intensified the protective action of daidzein against glutamate-induced loss of membrane mitochondrial potential and LDH release. In siRNA ERß- and siRNA GPR30-transfected cells, daidzein did not inhibit the glutamate-induced effects. Twenty-four hour exposure to glutamate did not affect the cellular distribution of ERß and GPR30, but caused greater than 100% increase in the levels of the receptors. Co-treatment with daidzein decreased the level of ERß without significant changing of the GPR30 protein level. Here, we elucidated neuroprotective effects of daidzein at low micromolar concentrations and demonstrated that the phytoestrogens may exert their effects through novel extranuclear GPR30 and the classical transcriptionally acting ERß. These studies uncover key roles of the ERß and GPR30 intracellular signaling pathways in mediating the anti-apoptotic action of daidzein and may provide insight into new strategies to treat or prevent neural degeneration.

Seasonal changes in the interactions among leptin, ghrelin, and orexin in sheep.

The adaptation of the physiology of an animal to changing conditions of light and food availability is evident at the behavioral and hormonal levels. Melatonin, leptin, ghrelin, and orexin, which exhibit rhythmic secretion profiles under ad libitum feeding conditions, are sensitive to changes in daylength, forming a tight web of interrelationships in the regulation of energy balance. The aim of this study was to determine the effects of central injections of leptin, ghrelin, and orexin on the reciprocal interactions among these hormones and the influence of photoperiod on these responses. Twenty-four ovariectomized and estradiol-implanted ewes were used in a replicated switchback design. The ewes were assigned randomly to 1 of 6 treatment groups, and the treatments were infused into their third ventricles 3 times at 0, 1, and 2 h, with 0 h being at dusk. The treatments were as follows: 1) control, Ringer-Locke buffer; 2) leptin, 0.5 µg/kg BW; 3) ghrelin, 2.5 µg/kg BW; 4) orexin B, 0.3 µg/kg BW; 5) leptin antagonist, 50 µg/kg BW, then ghrelin, 2.5 µg/kg BW; and 6) leptin antagonist, 50 µg/kg BW, then orexin B, 0.3 µg/kg BW. Blood samples (5 mL) were collected at 15-min intervals for 6 h. The administration of leptin increased (P < 0.05) plasma concentrations of melatonin during short-day (ShD) photoperiods and decreased (P < 0.05) them during long-day (LD) photoperiods, whereas ghrelin decreased (P < 0.05) melatonin concentrations during ShD photoperiod, and orexin had no effect (P > 0.1). Leptin attenuated (P < 0.05) ghrelin concentrations relative to the concentration in controls during ShD. The plasma concentrations of orexin were reduced (P < 0.05) after leptin infusions during LD and ShD photoperiods; however, ghrelin had the opposite effect (P < 0.05) on orexin concentration. Orexin increased (P < 0.05) ghrelin concentrations during LD. Ghrelin and orexin concentrations were increased (P < 0.05) after leptin antagonist infusions. Our data provide evidence that the secretion of leptin, ghrelin, and orexin are seasonally dependent, with relationships that are subject to photoperiodic regulation, and that leptin is an important factor that regulates ghrelin and orexin releases in sheep.

Endocrine disrupters: a review of some sources, effects, and mechanisms of actions on behaviour and neuroendocrine systems.

Some environmental contaminants interact with hormones and may exert adverse consequences as a result of their actions as endocrine disrupting chemicals (EDCs). Exposure in people is typically a result of contamination of the food chain, inhalation of contaminated house dust or occupational exposure. EDCs include pesticides and herbicides (such as dichlorodiphenyl trichloroethane or its metabolites), methoxychlor, biocides, heat stabilisers and chemical catalysts (such as tributyltin), plastic contaminants (e.g. bisphenol A), pharmaceuticals (i.e. diethylstilbestrol; 17α-ethinylestradiol) or dietary components (such as phytoestrogens). The goal of this review is to address the sources, effects and actions of EDCs, with an emphasis on topics discussed at the International Congress on Steroids and the Nervous System. EDCs may alter reproductively-relevant or nonreproductive, sexually-dimorphic behaviours. In addition, EDCs may have significant effects on neurodevelopmental processes, influencing the morphology of sexually-dimorphic cerebral circuits. Exposure to EDCs is more dangerous if it occurs during specific 'critical periods' of life, such as intrauterine, perinatal, juvenile or puberty periods, when organisms are more sensitive to hormonal disruption, compared to other periods. However, exposure to EDCs in adulthood can also alter physiology. Several EDCs are xenoestrogens, which can alter serum lipid concentrations or metabolism enzymes that are necessary for converting cholesterol to steroid hormones. This can ultimately alter the production of oestradiol and/or other steroids. Finally, many EDCs may have actions via (or independent of) classic actions at cognate steroid receptors. EDCs may have effects through numerous other substrates, such as the aryl hydrocarbon receptor, the peroxisome proliferator-activated receptor and the retinoid X receptor, signal transduction pathways, calcium influx and/or neurotransmitter receptors. Thus, EDCs, from varied sources, may have organisational effects during development and/or activational effects in adulthood that influence sexually-dimorphic, reproductively-relevant processes or other functions, by mimicking, antagonising or altering steroidal actions.

Effects of orexigenic peptides and leptin on melatonin secretion during different photoperiods in seasonal breeding ewes: an in vitro study.

The pineal gland (PG) acts as a neuroendocrine transducer of daily and seasonal time through the nocturnal release of melatonin. Here, we examined the interaction of season, orexin, ghrelin, and leptin on melatonin secretion by pineal explants in short-term culture. Glands were collected after sunset from 12 ewes during long days (LD; April and May) and from an additional 12 ewes during short days (SD; October and November). Glands were transected sagittally into strips, with each equilibrated in 2.5 mL of Dulbecco's modified Eagle's medium for 60 min, followed by a 2-h incubation in control medium or medium containing orexin B (10 and 100 ng/mL), ghrelin (10 and 100 ng/mL), or 50 ng/mL of leptin. After a 3-h incubation, some PG explants treated previously with lower doses of orexin or ghrelin were challenged with 50 ng/mL of leptin and those treated with both doses of orexin were challenged with 300 nM of the ß-agonist isoproterenol. One milliliter of medium was harvested and replaced from each well every 30 min. Treatment with the low dose of orexin during LD increased melatonin secretion about 110% (P<0.01); treatment with a high dose increased melatonin secretion about 47% (P<0.001). During the SD period, leptin stimulated (P < 0.05) melatonin secretion slightly compared with mean melatonin concentration in controls. However, together, orexin and leptin depressed (P<0.01) melatonin secretion. Both doses of ghrelin reduced (P < 0.01) melatonin concentration during the SD season compared with control culture. Addition of ghrelin and leptin to culture medium increased (P<0.01) melatonin concentration compared with ghrelin-treated culture and decreased melatonin concentration (P<0.01) compared with leptin-treated culture during SD. Isoproterenol stimulated (P<0.01) melatonin secretion compared with values observed during the pretreatment period. We conclude that orexigenic peptides (orexin B and ghrelin) and an anorectic peptide (leptin) affect PG directly. The responses of PG to those hormones depend on day length. Moreover, secretion of melatonin from the ovine PG is under an adrenergic regulation.

Beta-adrenergic receptor activation induces long-lasting potentiation in burst-spiking but not regular-spiking cells at CA1-subiculum synapses.

The hippocampus plays a central role in memory formation in the mammalian brain. The subiculum is the principal target of CA1 pyramidal cells and thus serves as the major relay station for the outgoing hippocampal information. Pyramidal cells in the subiculum have been classified as burst-spiking (BS) and regular-spiking (RS) cells. In this study we demonstrate that application of the ß-adrenergic agonist isoproterenol (2 µM) induces a chemical form of long-term potentiation (LTP) of responses to alvear stimulation in (BS) but not in (RS) cells. This effect is prevented by the ß-adrenergic receptor antagonist propranolol (2 µM). The isoproterenol-induced LTP in (BS) cells does not depend on postsynaptic Ca(2+)-signaling, as 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA) does not prevent its induction. Furthermore, paired-pulse facilitation (PPF) and coefficient of variation (CV) analysis indicate the site of the LTP expression to be presynaptic. Our findings show that activation of ß-adrenergic receptors (ß-ARs) at CA1-subiculum synapses induces a cell-type-specific form of chemical LTP in subicular (BS) cells that may allow a target-specific trafficking of hippocampal output.

C-type natriuretic peptide modulates bidirectional plasticity in hippocampal area CA1 in vitro.

C-type natriuretic peptide (CNP) and the natriuretic peptide receptor B (NPR-B) are expressed throughout the hippocampus. We tested whether CNP affected long-term potentiation (LTP) or long-term depression (LTD) in area CA1. Field potentials (FP) were simultaneously recorded in stratum pyramidale (SP) and stratum radiatum (SR) of area CA1 in rat hippocampal slices. To induce LTD and LTP stimulation was applied to SR in area CA1 at 1 and 5 Hz and 30-100 Hz, respectively. CNP (100 nM) increased LTD magnitude while LTP induction was impeded. Thus, in the presence of CNP the threshold for LTP induction was shifted to higher stimulus frequencies, a modulation that showed layer-specific differences in area CA1. Effects of CNP were prevented by the NPR-B antagonist HS-142-1. In the presence of the GABA(A) receptor blocker bicuculline (BMI, 5 microM), CNP-mediated effects were attenuated in SP and SR. Intracellular recordings under this condition revealed that CNP significantly reduced number of action potentials generated during depolarizing current steps. The input resistance of CA1 cells and amplitude of isolated excitatory postsynaptic potential (EPSPs) were significantly increased by CNP whereas these changes were not observed in the absence of BMI. 100 Hz stimulation induced stable potentiation of the EPSP amplitude in CA1 pyramidal cells while this effect was strongly attenuated by CNP. This effect was prevented by BMI. Immunohistochemistry indicated that the peptide binds to receptors expressed on pyramidal cells and GAD(65/67)-immunopositive interneurons. 20 Hz stimulation, applied for 30 s, induced LTP in SR and SP. CNP attenuated LTP in SP and reversed LTP into LTD in SR. These effects were mimicked by low-dose dl-2-amino-5-phosphonopentanoic acid (dl-APV) (10 microM) suggesting partial N-methyl d-aspartate (NMDA) receptor dependency of CNP-mediated effects. Together, our data suggest that CNP is involved in the regulation of bidirectional plasticity in area CA1 potentially by modulating GABA(A)-mediated inhibition and NMDA receptors.