GS-9857 in patients with chronic hepatitis C virus genotype 1-4 infection: a randomized, double-blind, dose-ranging phase 1 study.

GS-9857, an inhibitor of the hepatitis C virus (HCV) nonstructural protein (NS) 3/4A, demonstrates potent activity against HCV genotypes 1-6 and improved coverage against commonly encountered NS3 resistance-associated variants (RAVs). In this study, the safety, tolerability, antiviral activity and pharmacokinetics (PK) of GS-9857 were evaluated in patients with chronic HCV genotype 1-4 infection. Patients with genotype 1-4 infection received placebo or once-daily GS-9857 at doses ranging from 50 to 300 mg for 3 days under fasting conditions. GS-9857 was well tolerated; all reported adverse events (AEs) were mild or moderate in severity. Diarrhoea and headache were the most commonly reported AEs. Grade 3 or 4 laboratory abnormalities were observed in 17% of patients receiving GS-9857; there were no Grade 3 or 4 abnormalities in alanine aminotransferase, aspartate aminotransferase or alkaline phosphatase levels. GS-9857 demonstrated potent antiviral activity in patients with chronic HCV infection, achieving mean and median maximum reductions in HCV RNA of ≥3 log10 IU/mL following administration of a 100-mg dose in patients with HCV genotype 1a, 1b, 2, 3 or 4 infection. The antiviral activity of GS-9857 was unaffected by the presence of pretreatment NS3 RAVs. In patients with genotype 1-4 infection, GS-9857 exhibited linear PK and was associated with a median half-life of 29-42 h, supporting once-daily dosing. Thus, the tolerability, efficacy and pharmacokinetic profile of GS-9857 support its further evaluation for treatment of patients with chronic HCV infection.

Does the corollary discharge of attention exist?

We discuss experimental support for the existence of a corollary discharge signal of attention movement control and its formulation in terms of the corollary discharge of attention model of attention movement (CODAM). The data is from fMRI, MEG and EEG activity observed about 200 ms after stimulus onset in various attention paradigms and in which the activity is mainly sited in parietal and extra-striate visual areas. Moreover the data arises from neural activity observed before report of a subject's experience occurs. The overall experimental support for the existence of a copy of the attention movement control signal generates, it is suggested, a viable route to explore the relation between this signal and human consciousness, as concluded in the paper.

Toward quantitative genetic analysis of host and parasite traits in the manifestations of Plasmodium falciparum malaria.

The complex human and parasite determinants that influence disease severity in Plasmodium falciparum malaria reflect thousands of years of selective pressure. Emerging genetic and genomic resources offer the prospect of unraveling interactions of these determinants.

CODAM: a neural network model of consciousness.

We present a review of the CODAM neural network control model of consciousness and develop it to arrive at a functional account of consciousness. The main feature is as a speed-up and error-correcting mechanism known, in engineering control theory, to be efficient in improving the speed of response and accuracy of any control system. We use the CODAM model to generate a set of predictions as to how such speed-up is achieved, as well as relate to previous explanations by CODAM of various attention-based phenomena.

Resolving some confusions over attention and consciousness.

There is presently an ongoing debate about the relation between attention and consciousness. Thus debate is being fuelled by results from experimental paradigms which probe various forms of the interaction between attention and consciousness, such as the attentional blink, object-substitution masking and change blindness. We present here simulations of these three paradigms which can all be produced from a single overarching control model of attention. This model helps to suggest an explanation of consciousness as created through attention, and helps to explore the complex nature of attention. It indicates how it is possible to accommodate the relevant experimental results without needing to regard consciousness and attention as independent processes.

Measuring ventilation and modelling M. tuberculosis transmission in indoor congregate settings, rural KwaZulu-Natal.

SETTING: Molecular epidemiology suggests that most Mycobacterium tuberculosis transmission in high-burden settings occurs outside the home. OBJECTIVE: To estimate the risk of M. tuberculosis transmission inside public buildings in a high TB burden community in KwaZulu-Natal, South Africa. DESIGN: Carbon dioxide (CO2) sensors were placed inside eight public buildings. Measurements were used with observations of occupancy to estimate infection risk using an adaptation of the Wells-Riley equation. Ventilation modelling using CONTAM was used to examine the impact of low-cost retrofits on transmission in a health clinic. RESULTS: Measurements indicate that infection risk in the church, classroom and clinic waiting room would be high with typical ventilation, occupancy levels and visit durations. For example, we estimated that health care workers in a clinic waiting room had a 16.9-24.5% annual risk of M. tuberculosis infection. Modelling results indicate that the simple addition of two new windows allowing for cross-ventilation, at a cost of US$330, would reduce the annual risk to health care workers by 57%. CONCLUSIONS: Results indicate that public buildings in this community have a range of ventilation and occupancy characteristics that may influence transmission risks. Simple retrofits may result in dramatic reductions in M. tuberculosis transmission, and intervention studies should therefore be considered.

Using genetic variation to study human disease.

The generation of a draft sequence of the human genome has spawned a unique opportunity to investigate the role of genetic variation in human diseases. The difference between any two human genomes has been estimated to be less than 0.1% overall, but still, this means that there are at least several million nucleotide differences per individual. The study of single nucleotide polymorphisms (SNPs), the most common type of variant, is likely to contribute substantially to deciphering genetic determinants of common and rare diseases. The effort to identify SNPs has been accelerated by three developments: the availability of sequence data from the genome project, improved informatic tools for searching the former and high-throughput genotype platforms. With these new tools in hand, dissecting the genetics of disease will rapidly move forward, although a number of formidable challenges will have to be met to see its promise realized in clinical medicine.

Emotion recognition in human-computer interaction.

In this paper, we outline the approach we have developed to construct an emotion-recognising system. It is based on guidance from psychological studies of emotion, as well as from the nature of emotion in its interaction with attention. A neural network architecture is constructed to be able to handle the fusion of different modalities (facial features, prosody and lexical content in speech). Results from the network are given and their implications discussed, as are implications for future direction for the research.

Liver injury is associated with mortality in sickle cell disease.

BACKGROUND: Increased life expectancy in sickle cell disease (SCD) has resulted in greater recognition of the consequences of repeated intravascular vaso-occlusion and chronic haemolysis to multiple organ systems. AIM: To report the long-term consequences of liver dysfunction in SCD. METHODS: A cohort of SCD patients was prospectively evaluated at the National Institutes of Health (NIH) Clinical Center. The association of mortality with liver enzymes, parameters of liver synthetic function and iron overload was evaluated using Cox regression. RESULTS: Exactly, 247 SCD patients were followed up for 30 months of whom 22 (9%) died. After controlling for predictors, increased direct bilirubin (DB), ferritin, alkaline phosphatase and decreased albumin were independently associated with mortality. In a multivariable model, only high DB and ferritin remained significant. Ferritin correlated with hepatic iron content and total blood transfusions but not haemolysis markers. Forty patients underwent liver biopsies and 11 (28%) had fibrosis. Twelve of 26 patients (48%) had portal hypertension by hepatic venous pressure gradient (HVPG) measurements. All patients with advanced liver fibrosis had iron overload; however, most patients (69%) with iron overload were without significant hepatic fibrosis. Ferritin did not correlate with left ventricular dysfunction by echocardiography. DB correlated with bile acid levels suggesting liver pathology. Platelet count and soluble CD14 correlated with HVPG indicating portal hypertension. CONCLUSIONS: Ferritin and direct bilirubin are independently associated with mortality in sickle cell disease. Ferritin likely relates to transfusional iron overload, while direct bilirubin suggests impairment of hepatic function, possibly impairing patients' ability to tolerate systemic insults.

The irreversible binding of acetylcholine mustard to muscarinic receptors in intestinal smooth muscle of the guinea-pig.

1. Acetylcholine mustard (N-2-chloroethyl-N-methyl-2-acetoxyethylamine), a potent muscarinic agonist, binds virtually irreversibly to muscarinic receptors in longitudinal muscle strips from guinea-pig small intesting, as shown by the inhibition of the binding of E13-H]-propylbenzilycholine mustard ([3-H-PrBCM), an affinity label for the muscarinin receptor. 2. A value for the apparent binding affinity of acetylcholine mustard and a value for the rate constant for the receptor alkylation reaction have been deduced from the rate of onset of the inhibition of [3-H]-PrBCM binding. 3. The kinetic constants obtained may refer largely to the interaction between acetylcholine mustard and the desensitized receptor. 4. At high concentrations acetylcholine mustard practically abolishes the contractile response to carbachol. At the concentrations acetylcholine mustard appears to have multiple actions on the tissue.

Multifocal benign chondroblastomas: report of a case.

Benign chondroblastoma is an unusual solitary bone tumor occurring usually in the second decade in a long bone. The tumor is often sited on epiphyseal cartilages. Very few examples of malignant variants have been documented, although local recurrence of benign tumors is not unusual. We wish to report a patient who developed two chondroblastomas in two distinct anatomical sites (tibia and calcaneus) over the space of seven years, with no clinical or histological features of malignant disease.

Non-linear dynamics in neural networks.

A general framework for the analysis of neurons as stochastic, three-dimensionally complex and non-linear units with a range of temporal properties is outlined, and a class of problems delineated. Some general mathematical properties of the resulting network are deduced, together with information-theoretic questions to be pursued. In particular examples of the relevance of the nonlinear, temporal and stochastic properties of neurons in effective information processing are briefly outlined.

Nitric oxide in cortical map formation.

We analyse the possible role of nitric oxide in the early development of cortical maps. A mathematical analysis shows that with the aid of the diffusing messenger NO, cortical maps can develop without the need for lateral-inhibitory interactions. We derive that the maps that NO can set up depend on the stimulus environment in a way that is similar to lateral-inhibitory models of map formation but that they also have properties that depend specifically on the parameters of the diffusion process. These dependencies have not before been extracted and can be used to test the involvement of NO in cortical map formation.

Diagnostic usefulness of antineutrophil cytoplasmic autoantibody serology. Comparative evaluation of commercial indirect fluorescent antibody kits and enzyme immunoassay kits.

Antineutrophil cytoplasmic autoantibodies (ANCAs) are increasingly used as serologic markers for pauci-immune crescentic glomerulonephritis and small vessel vasculitis. Many hospital laboratories and referral laboratories use commercial assay kits to detect ANCAs, despite inadequate documentation in the medical literature of kit performance. We evaluated the diagnostic sensitivity, specificity, and predictive value of 3 commercial indirect immunofluorescence assay (IFA) kits and 7 commercial enzyme immunoassay (EIA) kits for several ANCA subtypes. Serum samples from 396 patients with a variety of renal diseases were analyzed, including 146 patients with pauci-immune crescentic glomerulo-nephritis with or without systemic vasculitis. With 1 exception, the kits had more than 90% agreement with the reference standard and gave results similar to those of research laboratories. IFA diagnostic sensitivity ranged from 81% to 91% and EIA sensitivity from 75% to 84%. Maximum specificity was obtained with combined IFA and EIA. Diagnostic specificity was more than 70% for 2 of 3 IFA kits and at least 90% for 5 of 7 EIA kits. Predictive values varied with clinical manifestations. Most commercial IFA and EIA kits that were evaluated provide acceptably accurate analytic results.

Observation of quantization effects in human auditory cortex.

Auditory evoked magnetic fields were recorded from five human subjects using the BTi whole head system (148 channels). The stimuli were simple tone bursts with different inter-stimulus intervals (ISI). The magnetic field was also recorded from the same subjects in place without stimulation to provide baseline 'noise' measurements. Magnetic field tomography (MFT) was applied to the average data and activation curves were computed from well circumscribed regions of interest (ROI). Objective statistical measures (Kolmogorov-Smirnov test) were then used to identify latency segments with distribution significantly different from the baseline distribution. For latency segments with significant activations the dependence of the activation strength on ISI was modeled by an exponentially saturating function. In earlier studies, the characteristic time (tau) in this function was interpreted as a measure of a memory trace for auditory tones. Our analysis identified distinct levels for tau: all subjects had the same lower two levels (0.50 s and 0.69 s). Attention modulation introduced considerably higher tau values in most subjects but it did not change the two 'ground state' tau levels. To our knowledge, this is the first demonstration of quantization effects in the macro-properties of brain activity, which were universal amongst the subjects we studied.

A three stage model of awareness: formulation and initial experimental support.

The various components which together make up the complex state of consciousness require neural support involving a connected network of many brain areas at differing levels. At the lowest level is non-aware processing, of which there is not direct awareness. There are also modules involved in processing with awareness but without focussed attention. Finally there must be a set of modules involved in directing attention in a controlled manner. We expect to be able to dissociate the various components of the three-stage network by using different levels of attention. The results of an auditory experiment performed under three different levels of awareness and attention are analysed to show support for the three-stage model of awareness. The relevant auditory areas are delineated.

The motion aftereffect: more than area V5/MT? Evidence from 15O-butanol PET studies.

The motion aftereffect is a perceptual phenomenon which has been extensively investigated both psychologically and physiologically. Neuroimaging techniques have recently demonstrated that area V5/MT is activated during the perception of this illusion. The aim of this study was to test the hypothesis if a more broadly distributed network of brain regions subserves the motion aftereffect. To identify the neuronal structures involved in the perception of the motion aftereffect, regional cerebral blood flow (rCBF) measurements with positron emission tomography were performed in six normal volunteers. Data were analysed using SPM96. The motion-sensitive visual areas including area V5/MT were activated in both hemispheres. Additionally, the lateral parietal cortex bilaterally, the right dorsolateral prefrontal cortex, the anterior cingulate cortex and the left cerebellum showed significant increases in rCBF values during the experience of the waterfall illusion. In a further reference condition with identical attentional demand but no perception of a motion aftereffect elevated rCBF were found in these regions as well. In conclusion, our findings support the notion that the perceptual illusion of motion arises exclusively in the motion-sensitive visual area V5/MT. In addition, a more widespread network of brain regions including the prefrontal and parietal cortex is activated during the waterfall illusion which represents a non-motion aftereffect-specific subset of brain areas but is involved in more basic attentional processing and cognition.

Practice-based research: lessons from community pharmacist participants.

We designed this project to determine community pharmacists' opinions regarding the challenges and motivations of their recent participation in a pharmacy practice-based research study At the conclusion of a randomized, multicenter study, 87 community pharmacist-investigators were sent a questionnaire that explored four areas: motivating factors to participate, barriers to participation, communication tools used by study coordinators, and design issues for future studies. Fifty-eight (67%) completed questionnaires were returned. Key factors motivating participation in the study were desire to improve the profession and opportunity to learn. Time was the greatest barrier to participation. Pharmacy practice-based research has two distinct advantages. First, it translates clinical knowledge into direct application in the community. Second, it provides needed data to demonstrate the value of enhanced pharmacy practice. Thorough understanding of pharmacists' opinions is necessary to optimize the design of future studies.

Mathematical analysis of lead field expansions.

The solution to the bioelectromagnetic inverse problem is discussed in terms of a generalized lead field expansion, extended to weights depending polynomially on the current strength. The expansion coefficients are obtained from the resulting system of equations which relate the lead field expansion to the data. The framework supports a family of algorithms which include the class of minimum norm solutions and those of weighted minimum norm, including FOCUSS (suitably modified to conform to requirements of rotational invariance). The weighted-minimum-norm family is discussed in some detail, making explicit the dependence (or independence) of the weighting scheme on the modulus of the unknown current density vector. For all but the linear case, and with a single power in the weight, a highly nonlinear system of equations results. These are analyzed and their solution reduced to tractable problems for a finite number of degrees of freedom. In the simplest magnetic field tomography (MFT) case, this is shown to possess expected properties for localized distributed sources. A sensitivity analysis supports this conclusion.

Hard-wired models of working memory and temporal sequence storage and generation.

We develop hard-wired simulations of temporal sequence storage and generation by multi-modular networks based on the frontal lobe system (cortex, basal ganglia and thalamus). Single cell activity is shown to have been constructed so as to mimic results measured in monkeys on a similar task, indicating that a suitable form of chunking had been achieved in the models. The mathematical nature of these processes is discussed, from the viewpoint of bifurcation theory.