Validation of a suite of ERP and QEEG biomarkers in a pre-competitive, industry-led study in subjects with schizophrenia and healthy volunteers.

OBJECTIVE: Complexity and lack of standardization have mostly limited the use of event-related potentials (ERPs) and quantitative EEG (QEEG) biomarkers in drug development to small early phase trials. We present results from a clinical study on healthy volunteers (HV) and patients with schizophrenia (SZ) that assessed test-retest, group differences, variance, and correlation with functional assessments for ERP and QEEG measures collected at clinical and commercial trial sites with standardized instrumentation and methods, and analyzed through an automated data analysis pipeline. METHODS: 81 HV and 80 SZ were tested at one of four study sites. Subjects were administered two ERP/EEG testing sessions on separate visits. Sessions included a mismatch negativity paradigm, a 40 Hz auditory steady-state response paradigm, an eyes-closed resting state EEG, and an active auditory oddball paradigm. SZ subjects were also tested on the Brief Assessment of Cognition (BAC), Positive and Negative Syndrome Scale (PANSS), and Virtual Reality Functional Capacity Assessment Tool (VRFCAT). RESULTS: Standardized ERP/EEG instrumentation and methods ensured few test failures. The automated data analysis pipeline allowed for near real-time analysis with no human intervention. Test-retest reliability was fair-to-excellent for most of the outcome measures. SZ subjects showed significant deficits in ERP and QEEG measures consistent with published academic literature. A subset of ERP and QEEG measures correlated with functional assessments administered to the SZ subjects. CONCLUSIONS: With standardized instrumentation and methods, complex ERP/EEG testing sessions can be reliably performed at clinical and commercial trial sites to produce high-quality data in near real-time.

Stabilization of Liner Implosions via a Dynamic Screw Pinch.

Magnetically driven implosions are susceptible to magnetohydrodynamic instabilities, including the magneto-Rayleigh-Taylor instability (MRTI). To reduce MRTI growth in solid-metal liner implosions, the use of a dynamic screw pinch (DSP) has been proposed [P. F. Schmit et al., Phys. Rev. Lett. 117, 205001 (2016)PRLTAO0031-900710.1103/PhysRevLett.117.205001]. In a DSP configuration, a helical return-current structure surrounds the liner, resulting in a helical magnetic field that drives the implosion. Here, we present the first experimental tests of a solid-metal liner implosion driven by a DSP. Using the 1-MA, 100-200-ns COBRA pulsed-power driver, we tested three DSP cases (with peak axial magnetic fields of 2 T, 14 T, and 20 T) and a standard z-pinch (SZP) case (with a straight return-current structure and thus zero axial field). The liners had an initial radius of 3.2 mm and were made from 650-nm-thick aluminum foil. Images collected during the experiments reveal that helical MRTI modes developed in the DSP cases, while nonhelical (azimuthally symmetric) MRTI modes developed in the SZP case. Additionally, the MRTI amplitudes for the 14-T and 20-T DSP cases were smaller than in the SZP case. Specifically, when the liner had imploded to half of its initial radius, the MRTI amplitudes for the SZP case and for the 14-T and 20-T DSP cases were, respectively, 1.1±0.3 mm, 0.7±0.2 mm, and 0.3±0.1 mm. Relative to the SZP, the stabilization obtained using the DSP agrees reasonably well with theoretical estimates.

Resting regional brain activity correlates of verbal learning deficit in major depressive disorder.

Memory deficits are reported in major depressive disorder (MDD). Prefrontal cortical and mesiotemporal cortical (MTC)/subcortical regions are involved in the Buschke Selective Reminding Task (SRT), a verbal list-learning task. To determine whether depression-related changes in resting brain metabolism explain (in part) the deficits in SRT performance found in MDD, statistical correlation maps were calculated between SRT total recall score (TR) and relative regional cerebral metabolic rate for glucose (rCMRglu), measured by [18F]-flourodeoxyglucose (FDG) positron emission tomography (PET), in unmedicated, depressed MDD patients (N = 29). Subsequently, to explore hypothesized loss of top-down control in MDD, we compared the correlations between rCMRglu of SRT-relevant regions of the dorsolateral prefrontal cortex (dlPFC) and amygdala in a larger cohort of MDD (N = 60; 29 inclusive) versus healthy controls (HC) (N = 43). SRT performance of patients is on average 0.5 standard deviation below published normative mean. TR and rCMRglu positively correlate in bilateral dorsomedial PFC, dlPFC, dorsal anterior cingulate; negatively correlate in bilateral MTC/subcortical regions, and cerebellum. rCMRglu in dlPFC correlates negatively with that in amygdala in HC but not in MDD. Depression-related changes present in FDG-PET measured resting brain activity may be in part responsible for memory deficit found in MDD.

Multi-angle multi-pulse time-resolved Thomson scattering on laboratory plasma jets.

A single channel sub-nanosecond time-resolved Thomson scattering system used for pulsed power-driven high energy density plasma measurements has been upgraded to give electron temperatures at two different times and from two different angles simultaneously. This system was used to study plasma jets created from a 15 µm thick radial Al foil load on a 1 MA pulsed power machine. Two laser pulses were generated by splitting the initial 2.3 ns duration, 10 J, 526.5 nm laser beam into two pulses, each with 2.5 J, and delaying one relative to the other by between 3 and 14 ns. Time resolution within each pulse was obtained using a streak camera to record the scattered spectra from the two beams from two scattering angles. Analysis of the scattering profile showed that the electron temperature of the Al jet increased from 20 eV up to as much as 45 eV within about 2 ns by inverse bremsstrahlung for both laser pulses. The Thomson scattering results from jets formed with opposite current polarities showed different laser heating of the electrons, as well as possibly different ion temperatures. The two-angle scattering determined that the electron density of the plasma jet was at least 2 × 1018 cm-3.

Technique for insulated and non-insulated metal liner X-pinch radiography on a 1 MA pulsed power machine.

Broadband, high resolution X-pinch radiography has been demonstrated as a method to view the instability induced small scale structure that develops in near solid density regions of both insulated and non-insulated cylindrical metallic liners. In experiments carried out on a 1-1.2 MA 100-200 ns rise time pulsed power generator, µm scale features were imaged in initially 16 µm thick Al foil cylindrical liners. Better resolution and contrast were obtained using an X-ray sensitive film than with image plate detectors because of the properties of the X-pinch X-ray source. We also discuss configuration variations that were made to the simple cylindrical liner geometry that appeared to maintain validity of the small-scale structure measurements while improving measurement quality.

Biomarkers of Brain Structure and Function for Neurodegenerative Disorders: Are They Adequate for Go/No Go Decisions in Drug Development?

Given the high risk of developing drugs for neurodegenerative diseases if post-phase I decisions to go into efficacy studies were made with quantitative knowledge of an agent's action in brain, the risks should be diminished. Furthermore, if biomarkers were compelling, they could be utilized during a lengthy trial as an early measure of futility. What follows is one perspective on the adequacy of current and emerging measures to be applied to such decision making.

Intermittent Palm Cooling's Impact on Resistive Exercise Performance.

To examine palm cooling's (15 °C) impact, subjects performed 3 four-set leg press workouts in a randomized sequence. Per workout they received 1 of 3 treatments: no palm cooling, palm cooling between sets, or palm cooling between sets and post-exercise. Dependent variables were examined with three-way ANOVAs; average power underwent a three-way ANCOVA with body fat percentage as the covariate. Simple effects analysis was our post hoc and α=0.05. Left hand skin temperatures produced a two-way interaction (no palm cooling, palm cooling between sets>palm cooling between sets and post-exercise at several time points). A "high responder" subset had their data analyzed with an additional three-way ANOVA that again produced a two-way interaction (palm cooling between sets>no palm cooling>palm cooling between sets and post-exercise at multiple time points). Blood lactate results included a two-way interaction (no palm cooling>palm cooling between sets, palm cooling between sets and post-exercise at 0 min post-exercise). Average power yielded a two-way interaction (palm cooling between sets, palm cooling between sets>no palm cooling for the fourth set). Intermittent palm cooling hastened heat removal and blood lactate clearance, as well as delayed average power decrements.

Stigma experiences in bipolar patients: the impact upon functioning.

The aim of this study was to investigate the impact of self-rated stigma and functioning in patients with bipolar disorder in South Brazil. This is a cross-sectional study. Sixty participants with bipolar disorder were recruited from an outpatient Bipolar Disorder Program. Experiences with and impact of perceived stigma were evaluated using the Inventory of Stigmatizing Experiences. Functional impairment was assessed with the Functioning Assessment Short Test (FAST). Higher scores of self-perceived stigma were correlated with higher FAST scores, indicating more disability. After linear correlation analysis, current depressive symptoms, age at onset of treatment, age at diagnosis and functioning were correlated with self-perceived stigma. The study demonstrated a correlation between stigma and poor functioning in bipolar disorder. Perceived stigma is really important to individuals with bipolar disorder, both to how they experience their illness and to its results on functioning. Potential consequences of such results for mental health care professionals are discussed. Differential clinical features, sociocultural factors and the sample size limit the generalization of the present findings.

Report of the task force on designing clinical trials in early (predementia) AD.

BACKGROUND: A large number of promising candidate disease-modifying treatments for Alzheimer disease (AD) continue to advance into phase II and phase III testing. However, most completed trials have failed to demonstrate efficacy, and there is growing concern that methodologic difficulties may contribute to these clinical trial failures. The optimal time to intervene with such treatments is probably in the years prior to the onset of dementia, before the neuropathology has progressed to the advanced stage corresponding to clinical dementia. METHOD: An international task force of individuals from academia, industry, nonprofit foundations, and regulatory agencies was convened to discuss optimal trial design in early (predementia) AD. RESULTS: General consensus was reached on key principles involving the scope of the AD diagnosis, the selection of subjects for trials, outcome measures, and analytical methods. CONCLUSION: A consensus has been achieved in support of the testing of candidate treatments in the early (predementia) AD population.

Dose ranging for trials through biomarkers of drug effects.

To test the hypothesis that excess amyloid deposition is an essential step in the pathophysiology of Alzheimer's disease appropriate biomarkers are essential in selecting agents that modify amyloid formation or clearance. Cerebrospinal fluid concentrations of relevant analytes and PET measures of total brain load have been developed. These are directly applied to testing whether drugs reduce various soluble forms of amyloid as well as whether they enhance elimination of material deposited in brain parenchyma. The ideal profile of a drug that can fully test the amyloid hypothesis can be understood in terms of effects on currently available and future biomarkers. Dose selection for clinical trials should require a quantitative threshold effect on the most relevant biomarker.

Rad-by-rad (bit-by-bit): triumph of evidence over activities fostering fear of radiogenic cancers at low doses.

Large segments of Western populations hold sciences in low esteem. This trend became particularly pervasive in the field of radiation sciences in recent decades. The resulting lack of knowledge, easily filled with fear that feeds on itself, makes people susceptible to prevailing dogmas. Decades-long moratorium on nuclear power in the US, resentment of "anything nuclear", and delay/refusal to obtain medical radiation procedures are some of the societal consequences. The problem has been exacerbated by promulgation of the linear-no-threshold (LNT) dose response model by advisory bodies such as the ICRP, NCRP and others. This model assumes no safe level of radiation and implies that response is the same per unit dose regardless of the total dose. The most recent (June 2005) report from the National Research Council, BEIR VII (Biological Effects of Ionizing Radiation) continues this approach and quantifies potential cancer risks at low doses by linear extrapolation of risk values obtained from epidemiological observations of populations exposed to high doses, 0.2 Sv to 3 Sv. It minimizes the significance of a lack of evidence for adverse effects in populations exposed to low doses, and discounts documented beneficial effects of low dose exposures on the human immune system. The LNT doctrine is in direct conflict with current findings of radiobiology and important features of modern radiation oncology. Fortunately, these aspects are addressed in-depth in another major report-issued jointly in March 2005 by two French Academies, of Sciences and of Medicine. The latter report is much less publicized, and thus it is a responsibility of radiation professionals, physicists, nuclear engineers, and physicians to become familiar with its content and relevant studies, and to widely disseminate this information. To counteract biased media, we need to be creative in developing means of sharing good news about radiation with co-workers, patients, and the general public.

Clinical breakage, slippage and acceptability of a new commercial polyurethane condom: a randomized, controlled study.

Although latex remains the primary material for male condoms, a number of condoms made from synthetic materials have appeared in commercial markets in recent years. Published data on the safety and efficacy of these condoms is still limited, but nevertheless synthetic condoms do offer the user a wider choice and may encourage greater use of condoms for contraception and sexual transmitted infection prophylaxis. This paper reports on a study carried out in the Paris region of France on a new, commercial polyurethane condom marketed in Japan as Sagami Original and in Europe as Protex Original. A standard latex condom complying with the European standard for condoms (EN 600:1996) from the same manufacturer was used as the control in the study. The clinical breakage rate for the polyurethane condom was 0.6% (95% confidence interval 0.2-1.4%) compared to 1.3% (95% confidence interval 0.6-2.2%) for the latex condom. The difference was not statistically significant (chi(2) = 1.9, p = 0.168). Clinically significant slippage (complete slippage of the condom off the penis) was 1.1% (95% confidence interval 0.5-1.9%) for the polyurethane condom, compared to 0.5% (95% confidence interval 0.2-1.2%) for the latex; a difference that again was not statistically significant (chi(2) = 1.783, p = 0.182). The polyurethane condom was therefore equivalent to the latex condom in terms of clinical failure rate.

Simultaneous NO and CO(2) measurement in human breath with a single IV-VI mid-infrared laser.

A tunable diode laser absorption spectroscopy (TDLAS) system equipped with a IV-VI mid-IR laser operating near 5.2>mu;m was used to measure exhaled nitric oxide (eNO) and carbon dioxide (CO(2)) simultaneously in human breath over a single exhalation. Breath was sampled in real time, and eNO levels were measured from seven volunteers, two steroid-naive asthmatics and five nonasthmatics. Measured CO(2) levels were used as an internal standard to verify correct breath collection and calculate eNO values. Calculated eNO concentrations agreed well with reported values for asthmatic and nonasthmatic individuals.

Synthesis, photophysical properties, tumor uptake, and preliminary in vivo photosensitizing efficacy of a homologous series of 3-(1'-alkyloxy)ethyl-3-devinylpurpurin-18-N-alkylimides with variable lipophilicity.

Starting from methylpheophorbide-a, a homologous series of purpurinimides containing alkyl substituents at two different positions [as 3-(1(1)-O-alkyl) and 13(2)-N-alkyl] were synthesized. These compounds with variable lipophilicity (log P 5.32-16.44) exhibit long wavelength absorption near lambda(max)700 nm (epsilon: 45 000 in dichloromethane) with singlet oxygen ((1)O2) production in the range of 57-60%. The shifts in in vivo absorptions and tumor/skin uptake of these compounds were determined in C3H mice bearing RIF tumors by in vivo reflectance spectroscopy. The results obtained from a set of photosensitizers with similar lipophilicity (log P 10.68-10.88) indicate that besides the overall lipophilicity, the presence and position of the alkyl groups (O-alkyl vs N-alkyl) in a molecule play an important role in tumor uptake, tumor selectivity, and in vivo PDT efficacy. At present, all purpurinimide analogues are being evaluated at various doses, and experiments are underway to establish a quantitative structure-activity relationship on a limited set of compounds. The 1D and 2D NMR and mass spectrometry analyses confirmed the structures of the desired purpurinimides and the byproducts formed during various reaction conditions. The mechanisms of the formation of the unexpected 12-formyl- and 12-(hydroxymethyl)purpurinimides under certain reaction conditions are also discussed.

A simple and efficient approach for the synthesis of fluorinated and nonfluorinated octaethylporphyrin-based benzochlorins with variable lipophilicity, their in vivo tumor uptake, and the preliminary in vitro photosensitizing efficacy.

Starting from commercially available Ni(II)octaethylporphyrin (OEP), an efficient approach for the preparation of a series of fluorinated and nonfluorinated benzochlorins with variable lipophicity has been developed. Their spectroscopic properties, preliminary in vitro photosensitizing efficacy, and tumor selectivity were determined. Our methodology provides a facile approach for the preparation of the free-base and the related Zn(II) benzochlorins containing alkyl and alkyl ether side chains with variable carbon units. For the preparation of benzochlorins containing alkyl groups attached to the exocyclic phenyl ring, the Ni(II) meso-(2-formylvinyl)octaethyl porphyrin 2 was reacted with various reagents such as (trifluoromethyl)trimethylsilane (TMS-CF3) or the Grignard reagents of various fluorinated or nonfluorinated alkyl halides. The corresponding intermediates 3, 6a-6e, and 8 obtained via intramolecular cyclization under acidic conditions afforded the related benzochlorins 5, 7a-d, and 9 in good yields except for 7e which was obtained in poor yield (11.4%). The alcohol 10 obtained by reacting porphyrin 2 with ethynylmagnesium chloride did not produce the expected acetylenic benzochlorin; instead the corresponding acetyl derivative 11 was obtained as a major product, which under appropriate reaction conditions was converted into a series of alkyl ether derivatives 13a-13d. To obtain a benzochlorin bearing an ester functionality (15), porphyrin 2 was first reacted with ethyl acetate/LDA and the intermediate alcohol 14 was then cyclized with sulfuric acid. Unlike most of the natural and synthetic chlorins, the Zn(II) complexes of the benzochlorin analogues exhibited a significant bathochromic shift ( approximately 10 nm) in the electronic absorption spectra, and the long wavelength absorptions were observed in the range 671-677 nm (epsilon: 43270-50360). For investigating the in vitro efficacy of these analogues, Molt-4 cells were used. At a concentration of 2.5 microM, and a light dose of 4 J/cm2, all benzochlorins produced significant photosensitizing efficacy. The tumor (RIF) and muscle uptake in C3H mice of these photosensitizers was determined by in vivo reflectance spectroscopy. These results indicate that in this series increasing the length of the alkyl or alkyl ether carbon chains at the fused phenyl ring system produced a significant increase in tumor uptake.

The effects of ECT on brain glucose: a pilot FDG PET study.

BACKGROUND: Regional brain activity was measured before and after electroconvulsive therapy (ECT) using [18F]-fluorodeoxyglucose (FDG) positron emission tomography (PET). METHODS: 6 patients (4 females) with major depression were free of psychotropic medications for at least 2 weeks prior to baseline FDG scans. Patients were treated with bifrontotemporal ECT, and posttreatment scans were obtained after the last treatment. RESULTS: A region of interest (ROI) analysis of absolute metabolic rate showed a decrease in CMRglu after ECT in all 61 regions examined. In 17 of the 61 regions, the decrease was significant at the p < 0.05 level. In the right parietal lobe, and the right anterior and left posterior frontal lobes, the decrease in CMRglu significantly correlated with the decrease in Hamilton Depression Rating Scale (HDRS) scores (r = 0.83, 0.82, and 0.84, respectively). The analysis of CMRglu normalized to global metabolic rate showed significant increases in 8 of 61 regions, including basal ganglia, upper brainstem, and occipital lobe. DISCUSSION: The decreases in global glucose metabolism and correlation of changes in frontal metabolism with decreases in HDRS are consistent with earlier brain imaging studies of ECT. The relative increases in CMRglu observed in regions with known dopaminergic innervation (caudate and upper brainstem) have not been previously reported.

Identification and characterization of novel chromogranin B-derived peptides from porcine chromaffin granules by liquid chromatography/electrospray tandem MS.

Chromogranin B (CgB) is a regulated secretory protein that is stored in endocrine and neuroendocrine cells. It can be processed proteolytically to small peptide fragments. In the present study three proteolytic products of porcine CgB were obtained after size-exclusion, immunoaffinity, and reversed-phase chromatography, and then identified by electrospray tandem MS. One novel peptide was identified as S586-R602 (SR-17) and is phosphorylated at one or two serine residues. Another novel peptide H603-Q636 (HQ-34), with molecular mass 3815.56 Da, was found to be oxidized at the methionine residue. In addition, a secretolytin-like peptide fragment (KR-11), which is two amino acids shorter than the bovine secretolytin, was found. This is the first report that the C-terminal region of CgB, the homologue of human CCB, is proteolytically processed further into three small peptide fragments.

Measurements in radioactivity should not be recorded as less than MDA.

Sometimes the results of measurements in radioactivity are reported as less than MDA. Over the years there have been articles informing the reader that it is incorrect to express the results of measurements as less than MDA. A very brief review of past comments on expressing the results of measurements precedes a discussion of why measurements should not be reported as less than MDA.