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Relaxor ferroelectrics are important in technological applications due to strong electromechanical response, energy storage capacity, electrocaloric effect, and pyroelectric energy conversion properties. Current efforts to discover and design materials in this class generally rely on substitutional doping as slight changes to local compositional order can significantly affect the Curie temperature, morphotropic phase boundary, and electromechanical responses. In this work, we demonstrate that moving to the strong limit of compositional complexity in an ABO3perovskite allows stabilization of relaxor responses that do not rely on a single narrow phase transition region. Entropy-assisted synthesis approaches are utilized to synthesize single-crystal Ba(Ti0.2Sn0.2Zr0.2Hf0.2Nb0.2)O3[Ba(5B)O] films. The high levels of configurational disorder present in this system are found to influence dielectric relaxation, phase transitions, nanopolar domain formation, and Curie temperature. Temperature-dependent dielectric, Raman spectroscopy, and second-harmonic generation measurements reveal multiple phase transitions, a high Curie temperature of 570 K, and the relaxor ferroelectric nature of Ba(5B)O films. The first-principles theory calculations are used to predict possible combinations of cations to design relaxor ferroelectrics and quantify the relative feasibility of synthesizing these highly disordered single-phase perovskite systems. The ability to stabilize single-phase perovskites with various cations on the B-sites offers possibilities for designing high-performance relaxor ferroelectric materials for piezoelectric, pyroelectric, and electrocaloric applications.

High-entropy oxides (HEOs) have attracted great interest in diverse fields because of their inherent opportunities to tailor and combine materials functionalities. The control of local order/disorder in the class is by extension a grand challenge toward realizing their vast potential. Here we report the first examples of pyrochlore HEOs with five M-site cations, for Nd2M2O7, in which the local structure has been investigated by neutron diffraction and pair distribution function (PDF) analysis. The average structure of the pyrochlores is found to be orthorhombic Imma, in agreement with radius-ratio rules governing the structural archetype. The computed PDFs from density functional theory relaxed special quasirandom structure models are compared with real space PDFs in this work to evaluate M-site order/disorder. Reverse Monte Carlo combined with ab initiomolecular dynamics and Metropolis Monte Carlo simulations demonstrates that Nd2(Ta0.2Sc0.2Sn0.2Hf0.2Zr0.2)2O7is synthesized with its M-site local to nanoscale order highly randomized/disordered, while Nd2(Ti0.2Nb0.2Sn0.2Hf0.2Zr0.2)2O7+xexhibits a strong distortion of the TiO6octahedron and small degree of Ti chemical short-range order (SRO) on the subnanometer scale. Calculations suggest that this may be intrinsic, energetically favored SRO rather than due to sample processing. These results offer an important demonstration that the engineered variation of participating ions in HEOs, even among those with very similar radii, provides richly diverse opportunities to control local order/disorder motifs—and therefore materials properties for future designs. This work also hints at the exquisite level of detail that may be needed in computational and experimental data analysis to guide structure–property tuning in the emerging HEO materials class.

The van der Waals interaction is of foundational importance for a wide variety of physical systems. In particular, van der Waals forces lie at the heart of potential device technologies that may be realized from the functional organization of layered two-dimensional (2D) nanomaterials. For intermediate to large-scale applications modeling, van der Waals density functionals have become the de factochoice for first-principles calculations. In particular, the vdW-DF family of functionals have provided a systematic approach to this theoretically challenging problem. While much progress has been made, there remains room for improvement in the microscopic description of vdW forces from these density functionals. In this work, we compute benchmark results for the binding energy and the electronic density response to binding in TiS2via accurate diffusion quantum Monte Carlo calculations. We compare these benchmark data to results obtained from local, semilocal, and van der Waals functionals. In particular, we gauge the quality of the original vdW-DF/vdW-DF2 functionals, as well as updated variants such as vdW-DF-C09, vdW-DF-optB88, vdW-DF-optB86b, and vdW-DF2-B86R. We find a close relationship between the accuracy of predicted interlayer separation distances and binding energies for TiS2, with the vdW-DF-optB88 functional performing very well in terms of both quantities. In general, the more recently developed functionals are systematic improvements over older ones. However, when considering the response of the electron density to binding, we find that local-density approximation (LDA) and PBEsol generally outperform the vdW-DF functionals in describing the interlayer charge accumulation with vdW-DF-C09 variants performing the best overall.

A generic method to estimate the relative feasibility of formation of high-entropy compounds in a single phase, directly from first principles, is developed. As a first step, the relative formation abilities of 56 multicomponent, AO, oxides were evaluated. These were constructed from five cation combinations chosen from A = {Ca, Co, Cu, Fe, Mg, Mn, Ni, Zn}. Candidates for multicomponent oxides are predicted from descriptors related to the enthalpy and configurational entropy obtained from the mixing enthalpies of two-component oxides. The utility of this approach is evaluated by comparing the predicted combinations with the experimentally realized entropy-stabilized oxide, (MgCoCuNiZn)O. In the second step, Monte Carlo simulations are utilized to investigate the phase composition and local ionic segregation as a function of temperature. This approach allows for the evaluation of potential secondary phases, thereby making realistic predictions of novel multicomponent compounds that can be synthesized.

Cleavable metallic antiferromagnets may be of use for low-dissipation spintronic devices; however, few are currently known. Here we present orthorhombic MnRhBi3as one such compound and present a thorough study of its physical properties. Exfoliation is demonstrated experimentally, and the cleavage energy and electronic structure are examined by density functional theory calculations. It is concluded that MnRhBi3is a van der Waals-layered material that cleaves easily between neighboring Bi layers and that the Bi atoms have lone pairs extending into the van der Waals gaps. A series of four phase transitions are observed below room temperature, and neutron diffraction shows that at least two of the transitions involve the formation of antiferromagnetic order. Anomalous thermal expansion points to a crystallographic phase transition and/or strong magnetoelastic coupling. This work reveals a complex phase evolution in MnRhBi3and establishes this cleavable antiferromagnetic metal as an interesting material for studying the interplay of structure, magnetism, and transport in the bulk and ultrathin limits, as well as the role of lone pair electrons in interface chemistry and proximity effects in van der Waals heterostructures.

We describe a continuum model of gas uptake for inhomogeneous fluids (CMGIF) and use it to predict fluid adsorption in porous materials directly from gas-substrate interaction energies determined by first-principlescalculations or accurate effective force fields. The method uses a perturbation approach to correct bulk fluid interactions for local inhomogeneities caused by gas–substrate interactions, and predicts local pressure and density of the adsorbed gas. The accuracy and limitations of the model are tested by comparison with the results of grand canonical Monte Carlo simulations of hydrogen uptake in metal–organic frameworks (MOFs). We show that the approach provides accurate predictions at room temperature and at low temperatures for less strongly interacting materials. The speed of the CMGIF method makes it a promising candidate for high-throughput materials discovery in connection with existing databases of nanoporous materials.

Several neuropsychiatric and neurodegenerative disorders share stress as a risk factor and are more prevalent in women than in men. Corticotropin-releasing factor (CRF) orchestrates the stress response, and excessive CRF is thought to contribute to the pathophysiology of these diseases. We previously found that the CRF1receptor (CRF1) is sex biased whereby coupling to its GTP-binding protein, Gs, is greater in females, whereas β-arrestin-2 coupling is greater in males. This study used a phosphoproteomic approach in CRF-overexpressing (CRF-OE) mice to test the proof of principle that when CRF is in excess, sex-biased CRF1coupling translates into divergent cell signaling that is expressed as different brain phosphoprotein profiles. Cortical phosphopeptides that distinguished female and male CRF-OE mice were overrepresented in unique pathways that were consistent with Gs-dependent signaling in females and β-arrestin-2 signaling in males. Notably, phosphopeptides that were more abundant in female CRF-OE mice were overrepresented in an Alzheimer’s disease (AD) pathway. Phosphoproteomic results were validated by demonstrating that CRF overexpression in females was associated with increased tau phosphorylation and, in a mouse model of AD pathology, phosphorylation of β-secretase, the enzyme involved in the formation of amyloid β. These females exhibited increased formation of amyloid β plaques and cognitive impairments relative to males. Collectively, the findings are consistent with a mechanism whereby the excess CRF that characterizes stress-related diseases initiates distinct cellular processes in male and female brains, as a result of sex-biased CRF1signaling. Promotion of AD-related signaling pathways through this mechanism may contribute to female vulnerability to AD.

Atomically disordered oxides have attracted significant attention in recent years due to the possibility of enhanced ionic conductivity. However, the correlation between atomic disorder, corresponding electronic structure, and the resulting oxygen diffusivity is not well understood. The disordered variants of the ordered pyrochlore structure in gadolinium titanate (Gd2Ti2O7) are seen as a particularly interesting prospect due to intrinsic presence of a vacant oxygen site in the unit atomic structure, which could provide a channel for fast oxygen conduction. In the present work, we provide insights into the subangstrom scale on the disordering-induced variations in the local atomic environment and its effect on the electronic structure in high-energy ion irradiation-induced disordered nanochannels, which can be utilized as pathways for fast oxygen ion transport. With the help of an atomic plane-by-plane-resolved analyses, the work shows how the presence of various types of TiOxpolyhedral that exist in the amorphous and disordered crystalline phase modify the electronic structures relative to the ordered pyrochlore phase in Gd2Ti2O7. The correlated molecular dynamics simulations on the disordered structures show a remarkable enhancement in oxygen diffusivity as compared with ordered pyrochlore lattice and make that a suitable candidate for applications requiring fast oxygen conduction.

α-Sb2O4(cervantite) and β-Sb2O4(clinocervantite) are mixed valence compounds with equal proportions of SbIIIand SbVas represented in the formula SbIIISbVO4. Their structure and properties can be difficult to calculate owing to the SbIIIlone-pair electrons. Here, we present a study of the lattice dynamics and vibrational properties using a combination of inelastic neutron scattering, Mössbauer spectroscopy, nuclear inelastic scattering, and density functional theory (DFT) calculations. DFT calculations that account for lone-pair electrons match the experimental densities of phonon states. Mössbauer spectroscopy reveals the β phase to be significantly harder than the α phase. Calculations with O vacancies reveal the possibility for nonstoichiometric proportions of SbIIIand SbVin both phases. An open question is what drives the stability of the α phase over the β phase, as the latter shows pronounced kinetic stability and lower symmetry despite being in the high-temperature phase. Since the vibrational entropy difference is small, it is unlikely to stabilize the α phase. Our results suggest that the α phase is more stable only because the material is not fully stoichiometric.

In the last decades, many reports have focused the attention on deleterious effects of novel environmental chemical compounds, including bisphenol A (BPA), on human health. BPA, a common and widely chemical contaminant acting as endocrine disruptor, accumulates in adipose tissue and may affect adipocyte metabolic and inflammatory functions. BPA, at low chronic doses, is now considered as an obesogen compound, and might contribute to the rise of metabolic syndrome, visceral adiposity and diabetes epidemics. The BPA worldwide presence in the environment is responsible for chronic exposure during vulnerable periods, such as foetal and neonatal life. The BPA source of contamination can occur via food, beverage, wastewater, air, dust and soil. BPA, as lipophilic compound, may accumulate into the adipose tissue already during foetal life and may affect adulthood health, through adverse effects on the growth and development of organs and tissues. Thus, based on several studies, it would be crucial to consider further actions aimed to refine risk assessment at least in vulnerable population, such as foetuses, infants and young children, to prevent metabolic diseases and obesity.

The isolation of graphene in 2004 from graphite was a defining moment for the “birth” of a field: two-dimensional (2D) materials. In recent years, there has been a rapidly increasing number of papers focusing on non-graphene layered materials, including transition-metal dichalcogenides (TMDs), because of the new properties and applications that emerge upon 2D confinement. Here, we review significant recent advances and important new developments in 2D materials “beyond graphene”. We provide insight into the theoretical modeling and understanding of the van der Waals (vdW) forces that hold together the 2D layers in bulk solids, as well as their excitonic properties and growth morphologies. Additionally, we highlight recent breakthroughs in TMD synthesis and characterization and discuss the newest families of 2D materials, including monoelement 2D materials (i.e., silicene, phosphorene, etc.) and transition metal carbide- and carbon nitride-based MXenes. We then discuss the doping and functionalization of 2D materials beyond graphene that enable device applications, followed by advances in electronic, optoelectronic, and magnetic devices and theory. Finally, we provide perspectives on the future of 2D materials beyond graphene.

The chemical bonding of adsorbate molecules on transition-metal surfaces is strongly influenced by the hybridization between the molecular orbitals and the metal d-band. The strength of this interaction is often correlated with the location of the metal d-band center relative to the Fermi level. Here, we exploit finite size effects in the electronic structure of ultrathin Pd(111) films grown on Ru(0001) to tune their reactivity by changing the film thickness one atom layer at a time, while keeping all other variables unchanged. Interestingly, while bulk Pd(111) is reactive toward oxygen, Pd(111) films below five monolayers are surprisingly inert. This observation is fully in line with the d-band model prediction when applied to the orbitals involved in the bonding. The shift of the d-band center with film thickness is primarily attributed to shifts in the partial density of states associated with the 4dxzand 4dyzorbitals. This study gives an in-depth look into the orbital specific contributions to the surface chemical reactivity, providing new insights that could be useful in surface catalysis.

The spatial volume occupied by an atom depends on its electronic density. Although this density can only be evaluated exactly for hydrogen-like atoms, there are many excellent algorithms and packages to calculate it numerically for other materials. Three-dimensional visualization of charge density is challenging, especially when several molecular/atomic levels are intertwined in space. In this paper, we explore several approaches to this, including the extension of an anaglyphic stereo visualization application based on the AViz package for hydrogen atoms and simple molecules to larger structures such as nanotubes. We will describe motivations and potential applications of these tools for answering interesting physical questions about nanotube properties. [ABSTRACT FROM AUTHOR]

Li2MnO3is believed to be a critical component of the high capacity Li-rich–manganese-rich oxide materials; however, the mechanism of its electrochemical activity remains controversial. Here, Raman spectroscopy and mapping are used to follow the chemical and structural changes that occur in Li2MnO3during electrochemical cycling. Conventional composite electrodes cast from a slurry and thin films are studied as a function of the state of charge (voltage) and cycle number. Thin films have similar electrochemical properties as electrodes prepared from slurries but enable spectroscopy of uniform samples without carbon additives and binder. First-principles density functional theory is used to calculate the phonon spectra and identify the Raman-active modes. On the basis of the calculations of phonon spectra for pristine Li2MnO3and structures with Li vacancies, we discuss the origin of Raman-active peaks observed during the electrochemical cycling. The spectral changes correlate well with the electrochemical behavior and support a mechanism whereby capacity is lost upon extended cycling due to the formation of new manganese oxide phases.

Defects and surface reconstructions are thought to be crucial for the long-term stability of high-voltage lithium–manganese-rich cathodes. Unfortunately, many of these defects arise only after electrochemical cycling which occurs under harsh conditions, making it difficult to fully comprehend the role they play in degrading material performance. Recently, it has been observed that defects are present even in the pristine material. This study, therefore, focuses on examining the nature of the disorder observed in pristine Li1.2Ni0.175Mn0.525Co0.1O2(LNMCO) particles. Using atomic-resolution Z-contrast imaging and electron energy loss spectroscopy measurements, we show that there is indeed a significant amount of antisite defects present in this material, with transition metals substituting on Li metal sites. Furthermore, we find a strong segregation tendency of these types of defects toward open facets (surfaces perpendicular to the layered arrangement of atoms) rather than closed facets (surfaces parallel to the layered arrangement of atoms). First-principles calculations identify antisite defect pairs of Ni swapping with Li ions as the predominant defect in the material. Furthermore, energetically favorable swapping of Ni on the Mn sites was observed to lead to Mn depletion at open facets. Relatively, low Ni migration barriers also support the notion that Ni is the predominant cause of disorder. These insights suggest that certain facets of the LNMCO particles may be more useful for inhibiting surface reconstruction and improving the stability of these materials through careful consideration of the exposed surface.

We present a framework for rapidly predicting gas adsorption properties based on van der Waals density functional calculations and thermodynamic modeling. Utilizing this model and experimentally determined pore size distributions, we are able to accurately predict uptakes in five activated carbon materials without empirical potentials or lengthy simulations. Our results demonstrate that materials with smaller pores and higher heats of adsorption can still have poor adsorption characteristics due to relatively low densities of highly adsorbent pores.

Polycystic Ovary Syndrome (PCOS) is characterized by an extreme variety of phenotypes and controversial metabolic implications. Hepatic Steatosis (HS) and low-grade chronic inflammation (LGCI) might be common findings in PCOS. We conducted a cross-sectional study to evaluate the LGCI and HS in young women with PCOS according to their Body Mass index (BMI), Insulin Resistance (IR), and PCOS phenotypes. Sixty young premenopausal PCOS women and 20 age-matched controls participated. Primary outcome measures were the presence/severity of HS; LGCI index evaluated as spleen longitudinal diameter (SLD) by UltraSound, C-Reactive Protein (CRP) and Interleukin (IL)-6 levels; BMI and the Homeostasis Model Assessment (HoMA) of IR. The second outcome measures were testosterone, Sex Hormone-Binding Globulin (SHBG) levels, and Free Androgen Index (FAI). The presence of HS and LGCI was not significantly different between NW and O/O patients, while there were significant differences particularly when the PCOS-women were grouped according to IR or to PCOS phenotypes. At multiple regression adjusted for BMI, HoMA-IR and the spleen size were the major determinants of the severity of HS (ß= 0.36, p=0.007, and ß= 0.28, p=0.034, respectively). At multiple regression SLD represented the unique predictor of FAI (ß=0.32; p=0.018). In young women with PCOS, HS was detected independently from obesity and was well predicted not only by IR but also by spleen size, with variable expression of the liver-spleen axis across the different PCOS subtypes. A possible role of the spleen in determining LGCI also in women with PCOS is emphasized.

Background: The cellular abundance of the phosphoprotein enriched in diabetes (PED/PEA-15), a 15 kDa protein related to insulin resistance (IR), is increased in women with polycystic ovary syndrome (PCOS). Aim: To investigate whether metformin (MET) has additive effects on PED/PEA-15 protein levels. Material/subjects and methods: This is an open label, prospective clinical study over 6 months. Ten hyperandrogenic obese PCOS women [age: 24.6±1.6 yr; body mass index (BMI): 30.7±1.2 kg/m2] were treated with MET (1250 mg/day). Ten age- and BMI-matched normo-androgenic women were used as controls. Outcome measures are: PED/PEA-15 protein levels, fasting plasma glucose and insulin (FPI), reciprocal index of homeostasis model assessment of insulin resistance (1/HOMA-IR); quantitative insulin sensitivity check index (QUICKI); whole-body insulin sensitivity index (ISI); SHBG; total testosterone; free androgen index (FAI). Results: At baseline FPI and PED/PEA-15 protein levels were higher, while 1/HOMA-IR, QUICKI, and ISI were lower (p<0.001) in MET group than in controls. After treatment, independently of body weight and hyperandrogenism, FPI, and PED/PEA-15 protein levels decreased (p=0.001 and 0.004, respectively), while, 1/HOMA-IR, QUICKI, and ISI increased (p<0.001). PED/PEA-15 protein levels correlated significantly with ISI either before (r=0.636; p=0.048), and after treatment (r=0.758; p=0.011). Conclusions: PED/PEA-15 protein levels reduced after a short course of treatment with MET in a group hyperandrogenic obese PCOS women. This effect was independent of body weight and hyperandrogenism, and correlated with ISI, thus adding a further benefit to obese PCOS women.

High entropy ceramics provide enhanced flexibility for tailoring a wide range of physical properties, emerging from the diverse chemical and configurational degrees of freedom. Expanding upon the endeavors of recently synthesized high entropy ceramics in rock salt, fluorite, spinel, and perovskite structures, we explore the relative feasibility of formation of high entropy pyrochlore oxides, A2B2O7, with multication occupancy of the B-site, estimated from first-principles-based thermodynamic descriptors. Subsequently, we used Monte Carlo simulations to estimate the phase composition, oxygen vacancy concentration, and local ionic segregation as a function of temperature and oxygen partial pressure. In synergy with the theoretical calculations, we have investigated the synthesis of several multicomponent oxides with a pyrochlore composition, related to our computational investigations, resulting in four phase pure and one 97.4% pure high entropy pyrochlore oxides. Ultimately, our approach allows us to evaluate potential impurity phases, ionic disorder, and oxygen vacancy concentration in response to the experimental variables, thereby making realistic predictions that can direct and accelerate experimental synthesis of novel multicomponent ceramics.

The aim of this study was to investigate the direct involvement of hyperinsulinaemia, DHEA and DHEA-S [DHEA(S)] in severe obesity in early carotid atherosclerosis, measured as intima-media thickness (IMT). Seventeen normotensive premenopausal women with very high BMI (43.5±1.6 kg/m2) were recruited for the study. Six women were also evaluated 12 months after laparoscopic adjustable silicone gastric banding (LASGB). Dietary intake, fasting plasma lipid profile, glycemic and insulinemic response to the OGTT, adrenal secretion, at baseline and after ACTH stimulation test, were measured. IMT, common carotid diameter (CD) and left ventricular mass index (LVMi) were measured by B-mode echotomography. All obese subjects showed higher fasting and stimulated insulin levels, but lower DHEA(S) levels than controls, showing a negative correlation between both fasting and stimulated insulin and DHEA(S), either at baseline or after ACTH testing. IMT was higher (p<0.05) than controls, with a positive correlation with stimulated insulin (p<0.05) and a strong negative correlation with DHEA(S) (p<0.001). In a multiple linear regression analysis, insulin response to OGTT maintained an association with DHEA(S) independent of fasting insulin, while DHEA maintained the association with IMT independent of stimulated insulin (p<0.0001). In the six patients evaluated 12 months after LASGB, fasting insulin levels decreased, while DHEA(S) levels increased (p<0.05). In conclusion, an early cardiovascular involvement was detected in this group of severe obese with hyperinsulinaemia and low DHEA(S), even in the absence of other well known CVD risk factors.

OBJECTIVE: Coeliac disease (CD) is associated with autoimmune thyroid disease. Gluten sensitivity represents a spectrum, with at one end cases with severe gluten-dependent enteropathy, and at the other subjects with minor signs of deranged mucosal immune response. The aim of this paper was to look for signs of minor small bowel injury and immunohistochemical markers of gluten sensitivity in a group of patients with Hashimoto's disease. SUBJECTS AND METHODS: Fourteen patients with Hashimoto's thyroiditis without serological evidence of CD underwent immunohistochemical analysis of jejunal biopsies. RESULTS: In 6/14 cases (43%) an increased density of gammadelta T cell receptor bearing intra-epithelial lymphocytes was found. In 6/14 (43%) signs of mucosal T cell activation (presence of interleukin 2 (IL2) receptor (CD25) on lamina propria T cells and/or expression of human lymphocyte antigen (HLA)-DR molecules on crypt epithelial cells) were noted. In 4 out of 6 such cases, HLA haplotypes were described in association with CD. CONCLUSION: A significant proportion of patients with Hashimoto's thyroiditis present signs of 'potential' CD and of activated mucosal T cell immunity. The gluten dependence of such findings remains to be ascertained.

The etiologic diagnosis of hirsutism is often difficult. Previous studies have reported normal basal androgen and SHBG concentrations in 33–50% of hirsute women, suggesting the presence of an “idiopathic” form of hirsutism as the most frequent cause of this problem. The recent use of GnRH-analogues together with the corticotropin stimulation test allows better understanding of whether the cause of hirsutism is androgen excess and, if so, whether the origin of the latter is ovarian, adrenal or both. The present study evaluated adrenal and ovarian function in 48 young hirsute women as well as in 78 normal women matched for body mass index and age, who acted as control group. To determine ovarian function, a single 100-μg dose of GnRH analogue triptorelin was injected sc; thereafter, gonadotropins, 17-hydroxyprogesterone (17-OHP), Δ4-androstenedione (Δ4), total testosterone (T) and estradiol were determined. To better understand the adrenal function, 250 μg of 1,24 ACTH were administrated as iv infusion for 5 h, and plasma cortisol (F), 17-OHP, Δ4, DHEAS, T, 11-desossicortisol were measured. The combined use of these two stimulation tests was able to detect mild to moderate abnormalities in the steroidogenesis of ovaries alone (23%), adrenals alone (16.6%), or both (35.4%) in most hirsute women (75%) with otherwise normal baseline androgen concentrations. In particular, patients showed significantly increased responses of 17-OHP, Δ4, total T, 11-desossicorti-sol, and F to 1,24-ACTH administration. Moreover, they also had significantly higher 17-OHP and T responses to triptorelin. In conclusion, milder forms of functional ovarian and/or adrenal hyperandrogenism, similar to those found in clearly hyperandrogenic women, were observed and could be an underlying mechanism of idiopathic hirsutism.

Corticotropin-releasing factor (CRF) acts as a putative neurotransmitter in the locus ceruleus (LC) to mediate its activation by certain stressors. In this study, we quantified LC sensitivity to CRF 24 h after swim stress, at a time when behavioral depression that is sensitive to antidepressants is apparent. Rats were placed in a tank with 30 cm (swim stress) or 4 cm water and 24 h later, either behavior was monitored in a forced swim test or LC discharge was recorded. Swim stress rats were more immobile than control animals in the swim test. LC neurons of swim stress rats were sensitized to low doses of CRF (0.1-0.3 microgram i.c.v.) that were ineffective in control animals and were desensitized to higher doses. Swim stress selectively altered LC sensitivity to CRF because neither LC spontaneous discharge nor responses to other agents (e.g., carbachol, vasoactive intestinal peptide) were altered. Finally, the mechanism for sensitization was localized to the LC because neuronal activation by low doses of CRF was prevented by the intracerulear administration of a CRF antagonist. CRF dose-response curves were consistent with a two-site model with similar dissociation constants under control conditions but divergent dissociation constants after swim stress. The results suggest that swim stress (and perhaps other stressors) functionally alters CRF receptors that have an impact on LC activity. Stress-induced regulation of LC sensitivity to CRF may underlie behavioral aspects of stress-related psychiatric disorders.

The pituitary-thyroid axis and neurohumoral activation indexes were simultaneously investigated in 16 in-patients hospitalized for cardiac heart failure (CHF), New York Heart Association (NYHA), class II-IV, and Killip clinical scale, class II-III, to evaluate their relationship with CHF morbidity and the relative prognostic value. At entry the patients were divided into two subgroups (A and B), according to the severity of CHF. Patients were further classified into two subgroups, according to the subsequent clinical course (C, poor outcome and D, improved clinical course). Blood samples were obtained every day for the radioimmunoassay measurement of plasma a-atrial natriuretic peptide (aANP), arginine vasopressin (AVP), and thyroid hormones, and the results were compared with those of 12 control subjects. At admission, aANP and 3,3',5'-triiodothyronine (rT3) values were higher, while 3,3',5-triiodothyronine (T3) to rT3 (T3/rT3) ratio was lower in subgroups A and B than in controls (p<0.001), respectively, and in C than in D (p<0.001), respectively, according to the prognosis. Conversely, no differences in other thyroid indexes, nor a significant correlation between aANP and either rT3 or T3/rT3 ratio were present in any of the subgroups. AVP plasma levels in subgroup A were not statistically different from those of controls, whereas they were significantly decreased in subgroups B and C (p<0.05) and D (p<0.001). In conclusion, these results indicate that in CHF the pituitary-thyroid axis is not altered, that aANP and T3/rT3 ratio are non-invasive and reliable predictors of severity and prognosis, while AVP might be affected by the different pathological processes leading to CHF or by the concomitant use of drugs.

The coexistence of autoimmune endocrine diseases, particularly autoimmune thyroid disease and celiac disease (CD), has recently been reported. We here present a 23-year-old woman with a diagnosis of hypothyroidism due to Hashimoto’s thyroiditis, autoimmune Addison’s disease, and kariotypically normal spontaneous premature ovarian failure. Considering the close association between autoimmune diseases and CD, we decided to search for IgA anti-endomysium antibodies (EmA) in the serum. The positivity of EmA and the presence of total villous atrophy at jejunal biopsy allowed the diagnosis of CD. On a gluten-free diet the patient showed a marked clinical improvement accompanied, over a 3-month period, by a progressive decrease in the need for thyroid and adrenal replacement therapies. After 6 months, serum EmA became negative and after 12 months a new jejunal biopsy showed complete mucosal recovery. After 18 months on gluten-free diet, the anti-thyroid antibodies titre decreased significantly, and we could discontinue thyroid substitutive therapy. This case emphasizes the association between autoimmune polyglandular disease and CD; the precocious identification of these cases is clinically relevant not only for the high risk of complications (e.g. Iymphoma) inherent to untreated CD, but also because CD is one of the causes for the failure of substitute hormonal therapy in patients with autoimmune thyroid disease.

Because the physiological characteristics of noradrenergic locus ceruleus (LC) neurons differ in anesthetized and unanesthetized rats, the effects of morphine on LC activity recorded in both conditions were compared. Intracerebroventricular administration of morphine inhibited spontaneous LC discharge of both anesthetized and unanesthetized rats but morphine was at least 10 times more potent in anesthetized rats. In anesthetized rats LC discharge evoked by sciatic nerve stimulation was insensitive to doses of morphine (0.03 or 0.1 microgram) that inhibited LC spontaneous activity. Only the highest dose of morphine (0.3 microgram) which inhibited completely tonic activity decreased significantly evoked discharge. In parallel experiments in unanesthetized rats, the presentation of auditory stimuli evoked a pattern of LC discharge similar to that evoked by sciatic nerve stimulation in anesthetized rats. Morphine (1.0 and 3.0 micrograms) decreased both spontaneous and evoked activity in these rats; however, spontaneous LC discharge was more sensitive to morphine, as was observed with anesthetized rats. Quantitative analyses of these effects indicated that morphine tends to alter the pattern of LC discharge to sensory stimuli such that the signal-to-noise ratio (ratio of evoked/tonic activity during stimulus presentation) is increased. Morphine effects were reversed by naltrexone (1.0 mg/kg s.c.) in anesthetized rats and 1.0 microgram i.c.v. in unanesthetized rats. The present results indicate that the degree of arousal and the availability of environmental stimuli are important determinants of opiate effects on LC activity.

A neonatal screening for both 21-hydroxylase and 11-β-hydroxylase deficiencies, responsible for congenital adrenal hyperplasia (CAH), has been conducted in Campania Region, Southern Italy. In 4380 neonates, aged 2–10 days, capillary blood from a heel prick was collected on microfilter paper, and 17-α-hydroxyprogesterone (17OHP) measured by radioimmunoassay (RIA) using a highly specific antibody (Ab A). In addition, in 295 of these samples, both 17OHP and 11-deoxycortisol (S) were measured using an anti-deoxycortisol antibody (Ab B) cross-reacting with 17OHP 100%. All results were compared with plasma 17OHP and S levels in 21 patients with diagnosed 21-hydroxylase deficiency and in 5 healthy volunteers on metyrapone test used for blocking the 11-β-hydroxylase activity. CAH due to 21-hydroxylase deficiency was diagnosed in a female newborn. The assay, based on the antibody reacting with both 17OHP and S, is particularly suitable for wide-scale screening programs enabling the simultaneous detection of two congenital enzyme defects.

Antithyroid hormone autoantibodies (THBA), described in both humans and animals, result in variable interference when thyroid hormone plasma levels are measured by immunoassays. We previously described a quick chromatographic method to detect circulating THBA in humans. In the present experience, we applied the method on canine sera (10 normal dogs and 3 dogs affected by hypothyroidism) to detect the THBA presence in a dog (no. 13) with clinical evidence of hypothyroidism, in spite of apparently extremely high values of thyroid hormone. After a short incubation of samples with 125I-T3 and 125I-T4 in presence of 8-anilino-1-naphtalenesulfonic acid, samples were eluted and radioactivity values counted. Eluate radioactivity values >10% and >30% were considered positive for THBA presence for antiT3 and antiT4 detection, respectively. High radioactivity values were detected in dog serun no. 13 and, therefore, it was considered positive for THBA presence. The Scatchard plot analysis revealed the presence of a monoclonal autoantibody with the highest affinity for T3 and an additional tenfold lower affinity for T4. In conclusion, our chromatographic method allows the detection and the characterization of THBA in species different from humans, with species specific differences in thyroid hormone metabolism; thus, taking into account the rarely availability of canine serum TSH and anti-thyroglobulin antibody immunoassay detection methods, it was possible to correctly diagnose the hypothyroidism in a dog with apparently extremely high values of thyroid hormones due to THBA interference.

The catalytic activity of a chabazite tuff in the partial oxidation of H2S to sulfur has been determined. The effects of temperature, feed concentration and chemical composition of the tuff on H2S conversion and selectivity to sulfur have been investigated. Encouraging results in view of a possible use in H2S removal processes have been obtained.

The effects of corticotropin-releasing factor (CRF), a benzodiazepine inverse agonist (methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate; DMCM) and electric foot-shock on rat conflict behavior were characterized and compared. Rats were trained to lever press under a multiple fixed-ratio schedule (FR 20) of food reinforcement in which responses during the first component were not punished, and the first response of each FR during the second component produced electric shock of an intensity sufficient to suppress responding by 10% to 15%. Intracerebroventricular injection of CRF (0.1-5.6 micrograms) caused a dose-dependent decrease in the rate of responding in both components of the schedule. However, CRF was more potent in decreasing rates of punished responding (proconflict effect). DMCM (10-100 micrograms; i.c.v.) also decreased rates of punished and nonpunished responding and was more potent during the punishment component. The suppression of punished and nonpunished responding by CRF and DMCM was mimicked by increasing the shock intensity (delta = 0.1 to 0.6 mA) during the punishment component. To determine whether CRF, DMCM and electric shock shared common mechanisms for these effects, rats were pretreated with i.c.v. injections of either a CRF antagonist (alpha helical CRF9-41, 50 micrograms), a benzodiazepine agonist (chlordiazepoxide, 10 micrograms) or a benzodiazepine antagonist (flumazenil, 10 micrograms) before the administration of equieffective doses of CRF or DMCM or an increase in shock intensity. Chlordiazepoxide attenuated the effects of all three stimuli. Flumazenil antagonized DMCM and CRF, but not shock, implicating a pharmacologic interaction between CRF and benzodiazepine systems.(ABSTRACT TRUNCATED AT 250 WORDS)

To study the involvement of gonadotropin-releasing hormone (GnRH) in glycosylation of circulating gonadotropin isoforms in anorexia nervosa (AN), 14 amenorrhoic patients with AN, 14 age-matched volunteers in early follicular phase, and five normal-weight re-fed patients with AN were investigated under baseline conditions and after acute administration of GnRH. Plasma gonadotropins were assayed using IRMA before and after concanavalin A affinity chromatography. Baseline plasma gonadotropin levels were lower for both AN and re-fed AN patients than in controls (P<0.005). The increase in FSH and LH after GnRH administration was lower than in controls for AN (P<0.005) and re-fed AN (P<0.005 and P<0.05 respectively) patients. Percentages of total gonadotropin not bound to concanavalin A (complex carbohydrate chains) under baseline conditions were higher in patients with AN than in controls (P<0.005) but decreased after GnRH administration (P<0.001). In re-fed AN patients, the percentage of unbound FSH was higher than in controls (P<0.05), and decreased after GnRH administration (P<0.001), whereas the percentages of unbound LH were not significantly different from controls either before or after GnRH administration. These data suggest that: (a) the acute administration of GnRH induces quantitative and qualitative changes in circulating gonadotropin isoforms in both normal controls and AN patients; (b) during recovery the LH response in re-fed AN patients is associated with a glycosylation pattern that is the same as that for controls.

We have studied a young untreated patient with low-renin hypertension. All the clinical tests were in normal range, except plasma renin activity, which was low. Also all traditional tests evaluating the adrenal function were normal. A test of supraphysiological ACTH stimulation revealed a partial enzymatic defect of adrenal 11-hydroxylase. The patient has been treated with dexamethasone (0.75 mg once daily), during 4 weeks. At the end of the treatment blood pressure reached normal values. The traditional adrenal function tests are not sufficient to exclude enzymatic abnormalities and their possible involvement in the pathogenesis of hypertension.

The aim of this study was to evaluate the feasibility of a chromatographic method to easily detect circulating anti-thyroid hormone autoantibodies (THBA), to calculate their affinity constant and the total thyroid hormone (TH) levels in presence of THBA. This method was applied to sera from 4 subject with suspected THBA and 20 controls (10 normal subjects and 10 patients with thyroid dysfunctions). After a short incubation with 125I-T3 or T4 tracer solution containing 8-anilino-1-naphthalenesulfonic acid as inhibitor of the binding of TH to plasma proteins without affecting THBA binding, the samples were chromatographied on prepacked Sephadex LH 20 columns and eluted with TRIS buffer to separate free TH from THBA-bound TH. Samples were considered THBA positive when radioactivity values in TRIS eluates were higher than in controls. THBA-bound TH were subsequently eluted with methanol and used to calculate the total TH present in patients with THBA. After a validation test using two standardized methods, we propose this method to quickly detect THBA in samples with suspected spuriously high values of free and total TH.

Corticotropin-releasing factor (CRF) administered intracerebroventricularly (i.c.v.) activates noradrenergic locus coeruleus (LC) neurons of halothane-anesthetized and unanesthetized rats. This study used a technique for microinfusing CRF into the LC from calibrated micropipettes to characterize and quantify the effects of locally administered CRF on LC discharge in halothane-anesthetized rats. CRF (3-100 ng) microinfusion into the LC increased discharge rate in a dose-dependent manner from 28 +/- 8 to 105 +/- 26% above preinfusion discharge rates. The CRF dose-response curve generated by local microinfusion was parallel to, and shifted approximately 200-fold to the left, of that generated by i.c.v. administration. Intracoerulear microinfusion of the CRF antagonist, [DPhe12,Nle(21,38),CalphaMeLeu37]r/hCRF(12-41), greatly attenuated LC activation produced by a maximally effective dose of i.c.v. administered CRF, suggesting that these effects are primarily due to actions within the LC. In rats in which both LC discharge rate and norepinephrine levels in prefrontal cortex were measured by in vivo microdialysis, CRF microinfused into the LC increased both endpoints. Finally, LC activation produced by CRF (60 ng) microinfusion into the LC was associated with cortical electroencephalographic activation. Taken together with previous anatomical and electrophysiological evidence for endogenous CRF interactions in the LC, our results support the hypothesis that CRF serves as an excitatory neurotransmitter in the LC, and suggest that its actions on LC neurons are translated to enhanced norepinephrine release and an impact on cortical targets.

The present study compared the effects of two analogs of corticotropin-releasing factor (CRF), [D-Phe12,Nle21,38, C alpha MeLeu37]CRF12-41 (D-PheCRF12-41) and alpha helical CRF9-41, as antagonists of CRF in in vivo and in vitro assays. In halothane-anesthetized rats, intracerebroventricular (i.c.v.) administration of both analogs inhibited the activation of locus coeruleus (LC) neuronal discharge produced by CRF (3.0 micrograms, i.c.v.). LC activation by hypotensive stress elicited by intravenous (i.v.) infusion of nitroprusside was antagonized by the same doses of the CRF antagonists that were effective in antagonizing CRF, suggesting that the receptors involved in LC activation by CRF and by hypotensive stress are similar. However, D-PheCRF12-41 was approximately 100 times more potent than alpha helical CRF9-41 when administered i.c.v. The IC50 values for D-PheCRF12-41 as an antagonist of CRF and of nitroprusside were 0.16 and 0.14 microgram, i.c.v., respectively. The IC50 values for alpha helical CRF9-41 as an antagonist of CRF and of nitroprusside were 18 and 27 micrograms, i.c.v., respectively. In contrast, D-PheCRF12-41 was only slightly more potent than alpha helical CRF9-41 in antagonizing CRF-stimulated cyclic AMP production in rat brain homogenates, with IC50s of 78 +/- 15 and 260 +/- 30 nM for D-PheCRF12-41 and alpha helical CRF9-41, respectively. Moreover, the antagonists had similar affinities for CRF binding sites in rat brain homogenates, with Kis of 15.5 +/- 4 nM and 10.3 +/- 6 nM for D-PheCRF12-41 and alpha helical CRF9-41, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

The potencies of several opiates and opioid peptides for potentiating the synaptic activation of CA1 pyramidal cells were compared in the rat hippocampal slice preparation. Morphine and the opioid peptides [D-Ala2, D-Leu5]-enkephalin (DADL), beta-endorphin and Tyr-D-Ser-Gly-Phe-Leu-Thr (a delta agonist) caused a concentration-dependent shift to the left in the input-output curve constructed by plotting population spike amplitude (a measure of evoked firing) as a function of the dendritic field excitatory postsynaptic potential. The concentration-response curves for DADL and morphine had similar slopes and maxima, although the curve for morphine was biphasic due to the addition of a nonopiate effect that became apparent at higher concentrations (greater than or equal to 20 microM). The EC50 values were 68 nM for DADL and 3000 nM for morphine. The IC50 values of naloxone against equieffective concentrations of DADL and morphine were not significantly different. Perfusion of slices with a combination of nearly maximally effective concentrations of DADL and morphine resulted in an effect that was no greater than the maximum effect obtained by either drug alone. The results suggest that these opioids produce their actions through a common pathway. The rank order of potency to produce identical effects was DADL greater than Tyr-D-Ser-Gly-Phe-Leu-Thr greater than beta-endorphin greater than morphine. The kappa agonist ethylketocyclazocine was inactive at concentrations up to 10 microM. The data suggest that delta opioid receptors play a key role in the epileptiform action of these opiates in the CA1 region of the rat hippocampus. However, this opioid response may be different from those characterized in peripheral preparations because ethylketocyclazocine appears to be inactive in the hippocampal CA1 region.

Corticotropin-releasing factor (CRF), the hormone responsible for adrenocorticotropin release during stress, is thought to be hypersecreted in depression. Because recent studies suggest that CRF may serve as a neurotransmitter in the major noradrenergic nucleus, locus coeruleus (LC), it was hypothesized that antidepressants interfere with the putative neurotransmitter role of CRF in the LC by either: 1) decreasing release of CRF; 2) pharmacologically antagonizing CRF; or 3) functionally antagonizing CRF by producing effects on LC cells that oppose these of CRF. In order to test this hypothesis, the effects of acute and chronic administration of two antidepressants, a norepinephrine re-uptake inhibitor (desmethylimipramine, DMI) and a serotonin re-uptake inhibitor (sertraline, SER), on LC spontaneous discharge, LC sensory evoked discharge, LC activation by a stressor and LC activation by CRF, were compared in halothane-anesthetized rats. Acute i.v. administration of DMI decreased both LC spontaneous discharge and discharge evoked by repeated sciatic nerve stimulation. In contrast, acute i.v. SER administration decreased only evoked LC discharge rate. Chronic DMI administration (10.0 mg/kg/day, i.p., 21 days) resulted in tolerance to its effects on spontaneous and sensory-evoked LC discharge. However, chronic DMI administration attenuated LC activation by hemodynamic stress, which is thought to require CRF release. LC activation by intracerebroventricular CRF was not altered in the chronic DMI rats. In contrast to DMI, chronic SER (10 mg/kg/day, i.p., 21 days) did not alter LC activation by either stress of CRF. However, the response of LC cells to repeated sciatic nerve stimulation was somewhat enhanced in chronic SER rats. This is an effect that is opposite that produced by CRF.(ABSTRACT TRUNCATED AT 250 WORDS)