Neuroimaging Auditory Hallucinations in Schizophrenia: From Neuroanatomy to Neurochemistry and Beyond

Despite more than 2 decades of neuroimaging investigations, there is currently insufficient evidence to fully understand the neurobiological substrate of auditory hallucinations (AH). However, some progress has been made with imaging studies in patients with AH consistently reporting altered structure and function in speech and language, sensory, and nonsensory regions. This report provides an update of neuroimaging studies of AH with a particular emphasis on more recent anatomical, physiological, and neurochemical imaging studies. Specifically, we provide (1) a review of findings in schizophrenia and nonschizophrenia voice hearers, (2) a discussion regarding key issues that have interfered with progress, and (3) practical recommendations for future studies.

Effects Of The Flash Welding Process On Mechanical And Microstructural Properties Of Structural Steel Joints Assessed Using Dest

ASTM A529 carbon¿manganese steel angle specimens were joined by flash butt welding and the effects of varying process parameter settings on the resulting welds were investigated. The weld metal and heat affected zones were examined and tested using tensile testing, ultrasonic scanning, Rockwell hardness testing, optical microscopy, and scanning electron microscopy with energy dispersive spectroscopy in order to quantify the effect of process variables on weld quality. Statistical analysis of experimental tensile and ultrasonic scanning data highlighted the sensitivity of weld strength and the presence of weld zone inclusions and interfacial defects to the process factors of upset current, flashing time duration, and upset dimension. Subsequent microstructural analysis revealed various phases within the weld and heat affected zone, including acicular ferrite, Widmanstätten or side-plate ferrite, and grain boundary ferrite. Inspection of the fracture surfaces of multiple tensile specimens, with scanning electron microscopy, displayed evidence of brittle cleavage fracture within the weld zone for certain factor combinations. Test results also indicated that hardness was increased in the weld zone for all specimens, which can be attributed to the extensive deformation of the upset operation. The significance of weld process factor levels on microstructure, fracture characteristics, and weld zone strength was analyzed. The relationships between significant flash welding process variables and weld quality metrics as applied to ASTM A529-Grade 50 steel angle were formalized in empirical process models.

Bulk Metallic Glasses Deform via Slip Avalanches

For the first time in metallic glasses, we extract both the exponents and scaling functions that describe the nature, statistics, and dynamics of slip events during slow deformation, according to a simple mean field model. We model the slips as avalanches of rearrangements of atoms in coupled shear transformation zones (STZs). Using high temporal resolution measurements, we find the predicted, different statistics and dynamics for small and large slips thereby excluding self-organized criticality. The agreement between model and data across numerous independent measures provides evidence for slip avalanches of STZs as the elementary mechanism of inhomogeneous deformation in metallic glasses.

Shear bands in metallic glasses are not necessarily hot

We have used the fusible tin coating method to detect shear band heating in amorphous Zr57Ti5Cu20Ni8Al10 loaded under quasi-static uniaxial compression. High-rate load data allowed a precise determination of the duration of shearing events and final fracture. When loading was halted prior to fracture we saw no evidence of melted tin despite the presence of shear offsets up to 6μm on some shear bands. Samples loaded to fracture showed evidence of tin melting near the fracture surface. We attribute the difference to the duration of the events, which is much longer for shear banding (milliseconds) than for fracture (microseconds).

NADPH-cytochrome P450 oxidoreductase: roles in physiology, pharmacology, and toxicology

This is a report on a symposium sponsored by the American Society for Pharmacology and Experimental Therapeutics and held at the Experimental Biology 2012 meeting in San Diego, California, on April 25, 2012. The symposium speakers summarized and critically evaluated our current understanding of the physiologic, pharmacological, and toxicological roles of NADPH-cytochrome P450 oxidoreductase (POR), a flavoprotein involved in electron transfer to microsomal cytochromes P450 (P450), cytochrome b(5), squalene mono-oxygenase, and heme oxygenase. Considerable insight has been derived from the development and characterization of mouse models with conditional Por deletion in particular tissues or partial suppression of POR expression in all tissues. Additional mouse models with global or conditional hepatic deletion of cytochrome b(5) are helping to clarify the P450 isoform- and substrate-specific influences of cytochrome b(5) on P450 electron transfer and catalytic function. This symposium also considered studies using siRNA to suppress POR expression in a hepatoma cell-culture model to explore the basis of the hepatic lipidosis phenotype observed in mice with conditional deletion of Por in liver. The symposium concluded with a strong translational perspective, relating the basic science of human POR structure and function to the impacts of POR genetic variation on human drug and steroid metabolism.

Anthracyclines during induction therapy in acute myeloid leukaemia: a systematic review and meta-analysis

This systematic review and meta-analysis compared the efficacy of different anthracyclines and anthracycline dosing schedules for induction therapy in acute myeloid leukaemia in children and adults younger than 60 years of age. Twenty-nine randomized controlled trials were eligible for inclusion in the review. Idarubicin (IDA), in comparison to daunorubicin (DNR), reduced remission failure rates (risk ratio (RR) 0·81; 95% confidence interval (CI), 0·66-0·99; P = 0·04), but did not alter rates of early death or overall mortality. Superiority of IDA for remission induction was limited to studies with a DNR/IDA dose ratio <5 (ratio <5: RR 0·65; 95% CI, 0·51-0·81; P < 0·001; ratio ≥5: RR 1·03; 95% CI, 0·91-1·16; P = 0·63). Higher-dose DNR, compared to lower-dose DNR, was associated with reduced rates for remission failure (RR 0·75; 95% CI, 0·60-0·94; P = 0·003) and overall mortality (RR 0·83; 95% CI, 0·75-0·93; P < 0·001), but not for early death. Comparisons of several other anthracycline derivates did not reveal significant differences in outcomes. Survival estimates in adults suggest that both high-dose DNR (90 mg/m(2) daily × 3 or 50 mg/m(2) daily × 5) and IDA (12 mg/m(2) daily × 3) can achieve 5-year survival rates of between 40 and 50 percent.

Effects of glenoid component version on humeral head displacement and joint reaction forces: an experimental study

The purpose of this study was to determine whether changes in glenoid version are associated with humeral head displacement and changes in the joint reaction forces, as these might contribute to instability or loosening in total shoulder replacement. A total shoulder prosthesis was implanted in neutral version in 6 cadaveric shoulders. Glenoid version was then changed in steps of 4 degrees toward more anteversion and retroversion. An increase in anteversion resulted in anterior translation of the humeral head and in eccentric loading of the anterior part of the glenoid. Retroversion was associated with posterior displacement and posterior loading of the glenoid. A change in rotation of the humeral component did not compensate for altered version of the glenoid component. These results suggest that both instability and glenoid component loosening may be related to the version of the glenoid component. Therefore, assessment of loosening and instability justifies precise assessment of glenoid component version.

Capsule genes of Streptococcus pneumoniae influence growth in vitro

Recently, we showed that the in vitro lag phase correlates with the pneumococcal serotype. This study investigated the role of capsule genes in bacterial growth using strain D39. Deletion of the entire capsule operon induced a significantly prolonged lag phase in Todd Hewitt broth (P=0.0002). However, partial deletions showed a different influence on the lag phase. Supplementation of media with 5% fetal bovine serum restored normal growth, at least partially, in mutants with a prolonged lag phase. Therefore, pneumococcal capsule gene products influence bacterial growth in vitro in strain D39.

Design, expression, and processing of epitomized hepatitis C virus-encoded CTL epitopes

Hepatitis C virus (HCV) vaccine efficacy may crucially depend on immunogen length and coverage of viral sequence diversity. However, covering a considerable proportion of the circulating viral sequence variants would likely require long immunogens, which for the conserved portions of the viral genome, would contain unnecessarily redundant sequence information. In this study, we present the design and in vitro performance analysis of a novel "epitome" approach that compresses frequent immune targets of the cellular immune response against HCV into a shorter immunogen sequence. Compression of immunological information is achieved by partial overlapping shared sequence motifs between individual epitopes. At the same time, sequence diversity coverage is provided by taking advantage of emerging cross-reactivity patterns among epitope variants so that epitope variants associated with the broadest variant cross-recognition are preferentially included. The processing and presentation analysis of specific epitopes included in such a compressed, in vitro-expressed HCV epitome indicated effective processing of a majority of tested epitopes, although re-presentation of some epitopes may require refined sequence design. Together, the present study establishes the epitome approach as a potential powerful tool for vaccine immunogen design, especially suitable for the induction of cellular immune responses against highly variable pathogens.

Increased cytotoxic T-lymphocyte epitope variant cross-recognition and functional avidity are associated with hepatitis C virus clearance

Hepatitis C virus (HCV) clearance has been associated with reduced viral evolution in targeted cytotoxic T-lymphocyte (CTL) epitopes, suggesting that HCV clearers may mount CTL responses with a superior ability to recognize epitope variants and prevent viral immune escape. Here, 40 HCV-infected subjects were tested with 406 10-mer peptides covering the vast majority of the sequence diversity spanning a 197-residue region of the NS3 protein. HCV clearers mounted significantly broader CTL responses of higher functional avidity and with wider variant cross-recognition capacity than nonclearers. These observations have important implications for vaccine approaches that may need to induce high-avidity responses in vivo.

Motesanib diphosphate in progressive differentiated thyroid cancer

BACKGROUND: The expression of vascular endothelial growth factor (VEGF) is characteristic of differentiated thyroid cancer and is associated with aggressive tumor behavior and a poor clinical outcome. Motesanib diphosphate (AMG 706) is a novel oral inhibitor of VEGF receptors, platelet-derived growth-factor receptor, and KIT. METHODS: In an open-label, single-group, phase 2 study, we treated 93 patients who had progressive, locally advanced or metastatic, radioiodine-resistant differentiated thyroid cancer with 125 mg of motesanib diphosphate, administered orally once daily. The primary end point was an objective response as assessed by an independent radiographic review. Additional end points included the duration of the response, progression-free survival, safety, and changes in serum thyroglobulin concentration. RESULTS: Of the 93 patients, 57 (61%) had papillary thyroid carcinoma. The objective response rate was 14%. Stable disease was achieved in 67% of the patients, and stable disease was maintained for 24 weeks or longer in 35%; 8% had progressive disease as the best response. The Kaplan-Meier estimate of the median duration of the response was 32 weeks (the lower limit of the 95% confidence interval [CI] was 24; the upper limit could not be estimated because of an insufficient number of events); the estimate of median progression-free survival was 40 weeks (95% CI, 32 to 50). Among the 75 patients in whom thyroglobulin analysis was performed, 81% had decreased serum thyroglobulin concentrations during treatment, as compared with baseline levels. The most common treatment-related adverse events were diarrhea (in 59% of the patients), hypertension (56%), fatigue (46%), and weight loss (40%). CONCLUSIONS: Motesanib diphosphate can induce partial responses in patients with advanced or metastatic differentiated thyroid cancer that is progressive. (ClinicalTrials.gov number, NCT00121628.)

Prostate carcinoma: diffusion-weighted imaging as potential alternative to conventional MR and 11C-choline PET/CT for detection of bone metastases

In a technical development study approved by the institutional ethics committee, the feasibility of fast diffusion-weighted imaging as a replacement for conventional magnetic resonance (MR) imaging sequences (short inversion time inversion recovery [STIR] and T1-weighted spin echo [SE]) and positron emission tomography (PET)/computed tomography (CT) in the detection of skeletal metastases from prostate cancer was evaluated. MR imaging and carbon 11 ((11)C) choline PET/CT data from 11 consecutive prostate cancer patients with bone metastases were analyzed. Diffusion-weighted imaging appears to be equal, if not superior, to STIR and T1-weighted SE sequences and equally as effective as (11)C-choline PET/CT in detection of bone metastases in these patients. Diffusion-weighted imaging should be considered for further evaluation and comparisons with PET/CT for comprehensive whole-body staging and restaging in prostate and other cancers.

Accelerated hypertrophic chondrocyte kinetics in GDF-7 deficient murine tibial growth plates

The Growth/Differentiation Factors (GDFs) are a subgroup of the Bone Morphogenetic Proteins (BMPs) well known for their role in joint formation and chondrogenesis. Mice deficient in one of these signaling molecules, GDF-5, have recently been shown to exhibit a decreased rate of endochondral bone growth in the proximal tibia due to a significantly longer hypertrophic phase duration. GDF-7 is a related family member, which exhibits a high degree of sequence identity with GDF-5. The purpose of the present study was to determine whether GDF-7 deficiency also alters the endochondral bone growth rate in mice and, if so, how this is achieved. Stereologic and cell kinetic parameters in proximal tibial growth plates from 5-week-old female GDF-7 -/- mice and wild type control littermates were examined. GDF-7 deficiency resulted in a statistically significant increase in growth rate (+26%; p = 0.0084) and rate of cell loss at the chondrosseous junction (+25%; p = 0.0217). Cells from GDF-7 deficient mice also exhibited a significantly shorter hypertrophic phase duration compared to wild type controls (-27%; p = 0.0326). These data demonstrate that, in the absence of GDF-7, the rate of endochondral bone growth is affected through the modulation of hypertrophic phase duration in growth plate chondrocytes. These findings further support a growing body of evidence implicating the GDFs in the formation, maturation, and maintenance of healthy cartilage.

The Rate of Precipitation of Copper Aluminide in the Silver Rich Silver-Copper-Aluminum Alloys

In order to determine the best annealing temperature at which to age-harden the alloys, hardness tests on speci­men annealed for different lengths of time at different temperatures were made.