Magnetic resonance spectroscopy and tissue protein concentrations together suggest lower glutamate signaling in dentate gyrus in schizophrenia.

Hippocampal dysfunction in schizophrenia is widely acknowledged, yet the mechanism of such dysfunction remains debated. In this study we investigate the excitatory and inhibitory hippocampal neurotransmission using two complementary methodologies, proton magnetic resonance spectroscopy (MRS) and tissue biochemistry, sampling individuals with schizophrenia in vivo and postmortem hippocampal tissue in vitro. The results show significantly lower glutamate concentrations in hippocampus in schizophrenia, an in vivo finding mirrored by lower GluN1 protein levels selectively in the dentate gyrus (DG) in vitro. In a mouse model with a DG knockout of the GRIN1 gene, we further confirmed that a selective decrease in DG GluN1 is sufficient to decrease the glutamate concentrations in the whole hippocampus. Gamma-aminobutyric acid (GABA) concentrations and GAD67 protein were not significantly different in hippocampus in schizophrenia. Similarly, GABA concentrations in the hippocampi of mice with a DG knockout of the GRIN1 gene were not significantly different from wild type. These findings provide strong evidence implicating the excitatory system within hippocampus in the pathophysiology of schizophrenia, particularly indicating the DG as a site of pathology.

Kv3.1-containing K(+) channels are reduced in untreated schizophrenia and normalized with antipsychotic drugs.

Neuronal firing is a fundamental element of cerebral function; and, voltage-gated potassium (K(+)) channels regulate that firing through the repolarization of action potentials. Kv3-type channels (Kv3.1-Kv3.4) represent a family of voltage-gated K(+) channels that have fast-spiking properties. Kv3.1 channel subunits are predominantly localized to cortical parvalbumin (PV)-positive, inhibitory interneurons. The firing properties of these interneurons participate in establishing the normal gamma oscillations and synchrony of cortical neuronal populations, thought to be the signature of higher information processing in human brain. Schizophrenia (SZ) is associated with abnormalities in cortical gamma synchrony and in information processing, particularly with dysfunction in working memory and executive function. Here, we report the distribution of Kv3.1b and Kv3.2 protein in normal human brain, showing that Kv3.1b is limited to neocortical areas, whereas Kv3.2 is abundantly represented in neo- and subcortical regions. In SZ cases, levels of Kv3.1b protein are decreased in the neocortex, but only in cases without antipsychotic drug (APD) treatment; Kv3.1 levels are normal in antipsychotic-treated cases. Kv3.2 is not different in distribution or in level between normal and SZ cases, nor influenced by APD, in any region tested. The apparent increase in Kv3.1b protein levels by APDs in SZ neocortex was confirmed in laboratory rodents treated with chronic APDs. These findings show a decrease in Kv3.1b channel protein in SZ neocortex, a deficit that is restored by APDs. This alteration could be fundamentally involved in the cortical manifestations of SZ and in the therapeutic response to APDs.

An important role for cholecystokinin, a CLOCK target gene, in the development and treatment of manic-like behaviors.

Mice with a mutation in the Clock gene (ClockΔ19) have been identified as a model of mania; however, the mechanisms that underlie this phenotype, and the changes in the brain that are necessary for lithium's effectiveness on these mice remain unclear. Here, we find that cholecystokinin (Cck) is a direct transcriptional target of CLOCK and levels of Cck are reduced in the ventral tegmental area (VTA) of ClockΔ19 mice. Selective knockdown of Cck expression via RNA interference in the VTA of wild-type mice produces a manic-like phenotype. Moreover, chronic treatment with lithium restores Cck expression to near wild-type and this increase is necessary for the therapeutic actions of lithium. The decrease in Cck expression in the ClockΔ19 mice appears to be due to a lack of interaction with the histone methyltransferase, MLL1, resulting in decreased histone H3K4me3 and gene transcription, an effect reversed by lithium. Human postmortem tissue from bipolar subjects reveals a similar increase in Cck expression in the VTA with mood stabilizer treatment. These studies identify a key role for Cck in the development and treatment of mania, and describe some of the molecular mechanisms by which lithium may act as an effective antimanic agent.

Quantum signatures of chaos in a kicked top.

Chaotic behaviour is ubiquitous and plays an important part in most fields of science. In classical physics, chaos is characterized by hypersensitivity of the time evolution of a system to initial conditions. Quantum mechanics does not permit a similar definition owing in part to the uncertainty principle, and in part to the Schrödinger equation, which preserves the overlap between quantum states. This fundamental disconnect poses a challenge to quantum-classical correspondence, and has motivated a long-standing search for quantum signatures of classical chaos. Here we present the experimental realization of a common paradigm for quantum chaos-the quantum kicked top- and the observation directly in quantum phase space of dynamics that have a chaotic classical counterpart. Our system is based on the combined electronic and nuclear spin of a single atom and is therefore deep in the quantum regime; nevertheless, we find good correspondence between the quantum dynamics and classical phase space structures. Because chaos is inherently a dynamical phenomenon, special significance attaches to dynamical signatures such as sensitivity to perturbation or the generation of entropy and entanglement, for which only indirect evidence has been available. We observe clear differences in the sensitivity to perturbation in chaotic versus regular, non-chaotic regimes, and present experimental evidence for dynamical entanglement as a signature of chaos.

An ex vivo model using human osteoarthritic cartilage demonstrates the release of bioactive insulin-like growth factor-1 from a collagen-glycosaminoglycan scaffold.

Biomimetic scaffolds hold great promise for therapeutic repair of cartilage, but although most scaffolds are tested with cells in vitro, there are very few ex vivo models (EVMs) where adult cartilage and scaffolds are co-cultured to optimize their interaction prior to in vivo studies. This study describes a simple, non-compressive method that is applicable to mammalian or human cartilage and provides a reasonable throughput of samples. Rings of full-depth articular cartilage slices were derived from human donors undergoing knee replacement for osteoarthritis and a 3 mm core of a collagen/glycosaminoglycan biomimetic scaffold (Tigenix, UK) inserted to create the EVM. Adult osteoarthritis chondrocytes were seeded into the scaffold and cultures maintained for up to 30 days. Ex vivo models were stable throughout experiments, and cells remained viable. Chondrocytes seeded into the EVM attached throughout the scaffold and in contact with the cartilage explants. Cell migration and deposition of extracellular matrix proteins in the scaffold was enhanced by growth factors particularly if the scaffold was preloaded with growth factors. This study demonstrates that the EVM represents a suitable model that has potential for testing a range of therapeutic parameters such as numbers/types of cell, growth factors or therapeutic drugs before progressing to costly pre-clinical trials.

Digital Subtraction Angiography is Superior to Magnetic Resonance Angiography in Diagnosis of Cerebral Arteriovenous Malformation.

This study was carried out to compare MRA and DSA in diagnosis of cerebral AVM. It was a retrospective observational study conducted in the Department of Neurology Dhaka Medical College Hospital (DMCH), Dhaka during the period of January 2010 to December 2010. Thirty patients with haemorrhagic stroke age ranging from 13 to 65 years were selected on the basis of inclusion and exclusion criteria as the study sample. MRA and DSA were done in all the selected patients. The mean age of the patients of haemorrhagic stroke was 30.3 ± 14.3 years and male female ratio was 2.7:1. Regarding the venous drainage of AVM 13 and 12 were superficial and deep respectively, and evaluated 100% by MRA. In the diagnosis of cerebral AVM nidus size S1: <3 and S2: 3-6 cm sensitivity was 100% but accuracy was 100% and 73.3% respectively. DSA was 100% sensitive in the diagnosis of superficial and deep venous drainage AVM. Regarding the eloquence of brain area 15 had no eloquence by both MRA and DSA and identification of eloquence of brain area sensitivity was 73.3% and accuracy was 86.7%. The main feeding vessels was found (22, 73.3%) in both DSA and MRA findings. Distal vessels was seen (8, 26.7%) in DSA but not seen in MRA findings. Intranidal aneurysm and Angiopathic AVM were seen in 3(10.0%) and 4(13.3%) respectively in DSA. This study was carried out to diagnose the patients presented with cerebral AVM by MRA and DSA. MRA could not be evaluated flow status of AVM, distal feeding arteries, intranidal aneurysm and angiopathic AVM which could be detected by DSA. So, DSA is superior to MRA in diagnosis of cerebral AVM.

Epigenetic inactivation of the E-cadherin gene in eyelid sebaceous gland carcinoma.

BACKGROUND: E-cadherin and ß-catenin are crucial components of the cell-cell adhesion complex. Their loss has often been associated with tumour metastasis and poor clinical outcome. Both loss of E-cadherin at the cell membrane and a stabilizing mutation in CTNNB1 (ß-catenin gene) have been associated with ovarian, colorectal, hepatocellular and nonmelanoma skin cancer, such as squamous and basal cell carcinomas. Absence of E-cadherin may be caused by promoter hypermethylation of the E-cadherin gene (CDH1). OBJECTIVES: To determine the role of E-cadherin promoter hypermethylation and CTNNB1 gene mutation in the aggressive behaviour of sebaceous gland carcinoma of the eyelid. METHODS: Thirty-six cases of sebaceous gland carcinoma were subjected to E-cadherin methylation-specific polymerase chain reaction and mutational analysis for the CTNNB1 gene. E-cadherin and ß-catenin staining was evaluated by immunohistochemistry. Results were correlated with the clinicopathological features of sebaceous gland carcinoma. RESULTS: nMethylation of the E-cadherin promoter region was detected in 72% of eyelid sebaceous gland carcinoma cases and loss of E-cadherin immunostaining in 83%. E-cadherin promoter hypermethylation showed a significant association with the loss of membranous E-cadherin (P = 0·038) and it was of borderline significance with reduced disease-free survival (P = 0·05). It was also found to be associated with advanced age (73%), tumour size ≥ 2 cm (77%), orbital invasion (83%), lymph node metastasis (60%), tumour recurrence (60%) and poor histological differentiation (90%). DNA sequencing revealed no stabilizing ß-catenin gene mutation in sebaceous gland carcinoma. Loss of membranous ß-catenin was observed in 61% cases, which associated significantly with both E-cadherin promoter methylation (P = 0·0262) and loss of E-cadherin membranous localization (P=0·0015). CONCLUSION: Epigenetic inactivation of the E-cadherin gene causes loss of membrane-bound E-cadherin and could contribute to the reduced disease-free survival in eyelid sebaceous gland carcinoma. Mutations in the ß-catenin gene do not seem to be involved in the pathogenesis of eyelid sebaceous gland carcinoma.

Evaluation of calcium dobesilate for its anti-cataract potential in experimental animal models.

The present study evaluated the protective action of calcium dobesilate (CDO) in various experimental models of cataract. CDO was studied in hydrocortisone-induced cataract in developing chick embryos and selenite-induced cataract in pups. CDO anti-cataract activity was also evaluated after oral and topical application as eye drops in galactose (30%) fed rats. This study was further extended to evaluate the intraocular penetration of a single dose of 1% CDO (50 microL) in rabbits. CDO exhibited significant protection against cataract in experimental models and considerable penetration after single topical application. Anti-cataract activity may be due to its antioxidant as well as aldose reductase inhibitor properties. Further studies are in progress to evaluate its clinical efficacy in diabetic cataract.

Ordering of V2+, Mn2+, and Fe3+ Ions in Zoisite, Ca2Al3Si3O12(OH).

The presence of very small amounts of Mn(2+), V(2+), and Fe(3+) ions in zoisite can be easily detected by the electron paramagnetic resonance technique at room temperature. The Mn(2+) and Fe(3+) ions are completely ordered and are probably located in the Ca(1)- and Al(II)-sites, respectively, whereas the V(2+) ions probably occupy both Ca(1)- and Ca(2)-sites, with a preference for the Ca(1)-site.

Dynamics of a Second-Order Phase Transition: P macr; to I1 Phase Transition in Anorthite, CaAl2Si2O8.

Electron microscopic study of the reversible P1 to I1 phase transition in anorthite (transition temperature T(c) = 516 Kelvin) shows that the antiphase boundaries (APBs) with the displacement vector R = 1/2[111] become unstable at T(c), and numerous small APB loops are formed. These interfaces are highly mobile, and their vibration frequency increases strongly with temperature. These observations suggest that close to T(c), breathing-motion-type lattice vibrations of the framework cause the two different configurations around the calcium atoms, which are related by a translation of R approximately 1/2[111], to interchange dynamically through an intermediate I1 configuration. The high-temperature I1 structure is interpreted as a statistical-dynamic average of highly mobile antiphase domains of primitive anorthite.

Core Binding Energy Difference between Bridging and Nonbridging Oxygen Atoms in a Silicate Chain.

The x-ray photoelectron spectra of the oxygen 1s level of olivines contain a single component whereas those of pyroxenes contain two components with an intensity ratio of 2:1 and an energy separation of about 1 electron volt. We interpret these two components to be the result of the binding energy differences between nonbridging and bridging oxygen atoms within a silicate chain in the pyroxene structure.

Phonon Density of States and Specific Heat of Forsterite, Mg2SiO4.

The phonon density of states of the geophysically important mineral forsterite has been calculated with a rigid-ion model, which gives good agreement with an experimental measurement by inelastic neutron scattering. The density of states has been used to calculate the specific heat as a function of temperature, the results of which are in excellent agreement with calorimetrically measured values. The rigid-ion model takes account of the interatomic interactions and normal modes of vibration on a detailed microscopic basis, and is therefore more realistic than the Debye and other empirical models used previously.

An apparatus and method for directly measuring the depth-dependent gain and spatial resolution of turbid scintillators.

PURPOSE: Turbid (powder or columnar-structured) scintillators are widely used in indirect flat panel detectors (I-FPDs) for scientific, industrial, and medical radiography. Light diffusion and absorption within these scintillators is expected to cause depth-dependent variations in their x ray conversion gain and spatial blur. These variations degrade the detective quantum efficiency of I-FPDs at all spatial frequencies. Despite their importance, there are currently no established methods for directly measuring scintillator depth effects. This work develops the instrumentation and methods to achieve this capability. METHODS: An ultra-high-sensitivity camera was assembled for imaging single x ray interactions in two commercial Gd2 O2 S:Tb (GOS) screens (Lanex Regular and Fast Back, Eastman Kodak Company). X ray interactions were localized to known depths in the screens using a slit beam of parallel synchrotron radiation (32 keV), with beam width (~20 µm) much narrower than the screen thickness. Depth-localized x ray interaction images were acquired in 30 µm depth-intervals, and analyzed to measure each scintillator's depth-dependent average gain g ¯ ( z ) and modulation transfer function MTF(z,f). These measurements were used to calculate each screen's expected MTF(f) in an energy-integrating detector (e.g., I-FPD). Calculations were compared to presampling MTF measurements made by coupling each screen to a high-resolution CMOS image sensor (48 µm pixel) and using the slanted-edge method. RESULTS: Both g ¯ ( z ) and MTF(z,f) continuously increased as interactions occurred closer to each screen's sensor-coupled surface. The Regular yielded 1351 ± 66 and 2117 ± 54 photons per absorbed x ray (42-66 keV-1 ) in interactions occurring furthest from and nearest to the image sensor, while the Fast Back yielded 833 ± 22 and 1910 ± 39 photons (26-60 keV-1 ). At f = 1 mm-1 , MTF(z,f) varied between 0.63 and 0.78 in the Regular and 0.30-0.76 in the Fast Back. Calculations of presampling MTF(f) using g ¯ ( z ) and MTF(z,f) showed excellent agreement with slanted-edge measurements. CONCLUSIONS: The developed instrument and method enable direct measurements of the depth-dependent gain and spatial resolution of turbid scintillators. This knowledge can be used to predict, understand, and potentially improve I-FPD imaging performance.

Squeezing dynamics of a nanowire system with spin-orbit interaction.

We analyze the dynamics of squeezing in a ballistic quantum wire with Rashba spin-orbit interaction in the presence of both strong and weak magnetic fields and for different initial states of the system. Compared to the more standard measure of squeezing based on variances, we show that entropy squeezing is a more sensitive measure. Our results show that there is a strong relationship between the spin-orbit interaction and the strength of entropy squeezing. Furthermore, there is a relationship between the initial state and the number of squeezed components. This allows new knobs to control the strength and the component of entropy squeezing in a nanowire system.

Ocular hazards of the colors used during the festival-of-colors (Holi) in India--malachite green toxicity.

The objective of this study was to evaluate the nature of the colors used and their toxicity to the eye upon exposure to them during celebration of Holi (our festival-of-colors). Color powders and formulations were procured at random in and around Delhi during the festival. The green/bluish-green colors reported with the higher incidence of ocular toxicity were subjected for further evaluation. Eyewash fluid collected from the patients exposed to the colors was also subjected for analysis. This study was further extended to evaluate the corneal penetration of malachite green using goat cornea in perfusion chamber. In 16/18 color samples collected, malachite green or 4-[(4-dimethylaminophenyl)-phenyl-methyl]-N,N-dimethyl-aniline was detected at different concentrations. In the eyewash fluid of four patients, HPLC estimation confirmed the presence of malachite green at concentrations of 1.3, 0.18, 3.5 and 5.4 microg in 250 ml which was responsible for its reported toxicity. The in vitrotrans-corneal penetration studies did not show any detectable amount of malachite green in effluent fluid-in vitro tissue retention studies revealed that increasing the contact time increases tissue concentration. After 2 min of exposure, the tissue concentration was significantly higher. To conclude, malachite green was extensively used in our festival of Holi and has caused severe ocular irritation with epithelial defect upon exposure, though it did not penetrate through the cornea-further in vitro and in vivo studies are required on colors used in Holi.

Large Thermal Motion in Halide Perovskites.

Solar cells based on hybrid perovskites have shown high efficiency while possessing simple processing methods. To gain a fundamental understanding of their properties on an atomic level, we investigate single crystals of CH3NH3PbI3 with a narrow transition (~5 K) near 327 K. Temperature dependent structural measurements reveal a persistent tetragonal structure with smooth changes in the atomic displacement parameters (ADPs) on crossing T*. We show that the ADPs for I ions yield extended flat regions in the potential wells consistent with the measured large thermal expansion parameter. Molecular dynamics simulations reveal that this material exhibits significant asymmetries in the Pb-I pair distribution functions. We also show that the intrinsically enhanced freedom of motion of the iodine atoms enables large deformations. This flexibility (softness) of the atomic structure results in highly localized atomic relaxation about defects and hence accounts for both the high carrier mobility as well as the structural instability.

Radiotherapy dose-distribution to the perirectal fat space (PRS) is related to gastrointestinal control-related complications.

Traditionally rectal symptoms following pelvic/prostate radiotherapy are correlated to the dosimetry of the anorectum or a substructure of this. It has been suggested that the perirectal fat space (PRS) surrounding the rectum may also be relevant. This study considers the delineation and dosimetry of the PRS related to both rectal bleeding and control-related toxicity. Initially, a case-control cohort of 100 patients from the RADAR study were chosen based on presence/absence of rectal control-related toxicity. Automated contouring was developed to delineate the PRS. 79 of the 100 auto-segmentations were considered successful. Balanced case-control cohorts were defined from these cases. Atlas of Complication Incidence (ACI) were generated to relate the DVH of the PRS with specific rectal symptoms; rectal bleeding and control-related symptoms (LENT/SOM). ACI demonstrated that control-related symptoms were related to the dose distribution to the PRS which was confirmed with Wilcoxon rank sum test (p < 0.05). To the authors knowledge this is the first study implicating the dose distribution to the PRS to the incidence of control-related symptoms of rectal toxicity.