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PubMed2001

Infant exposure to chemicals in breast milk in the United States: what we need to learn from a breast milk monitoring program.

The presence of environmental chemicals in breast milk has gained increased attention from regulatory agencies and groups advocating women's and children's health. As the published literature on chemicals in breast milk has grown, there remains a paucity of data on parameters related to infant exposure via breast-feeding, particularly those with a time-dependent nature. This information is necessary for performing exposure assessments without heavy reliance on default assumptions. Although most experts agree that, except in unusual situations, breast-feeding is the preferred nutrition, a better understanding of an infant's level of exposure to environmental chemicals is essential, particularly in the United States where information is sparse. In this paper, we review extant data on two parameters needed to conduct realistic exposure assessments for breast-fed infants: a) levels of chemicals in human milk in the United States (and trends for dioxins/furans); and b) elimination kinetics (depuration) of chemicals from the mother during breast-feeding. The limitations of the existing data restrict our ability to predict infant body burdens of these chemicals from breast-feeding. Although the data indicate a decrease in breast milk dioxin toxic equivalents over time for several countries, the results for the United States are ambiguous. Whereas available information supports the inclusion of depuration when estimating exposures from breast-feeding, the data do not support selection of a specific rate of depuration. A program of breast milk monitoring would serve to provide the information needed to assess infant exposures during breast-feeding and develop scientifically sound information on benefits and risks of breast-feeding in the United States.

Adult↗
PubMed2003

Human visual object categorization can be described by models with low memory capacity.

Studies of high-level models of visual object categorization have left unresolved issues of neurobiological relevance, including how features are extracted from the image and the role played by memory capacity in categorization performance. We compared the ability of a comprehensive set of models to match the categorization performance of human observers while explicitly accounting for the models' numbers of free parameters. The most successful models did not require a large memory capacity, suggesting that a sparse, abstracted representation of category properties may underlie categorization performance. This type of representation--different from classical prototype abstraction--could also be extracted directly from two-dimensional images via a biologically plausible early-vision model, rather than relying on experimenter-imposed features.

Adolescent↗
PubMed2006

Global and local processing in adult humans (Homo sapiens), 5-year-old children (Homo sapiens), and adult cotton-top tamarins (Saguinus oedipus).

This study compared adults (Homo sapiens), young children (Homo sapiens), and adult tamarins (Saguinus oedipus) while they discriminated global and local properties of stimuli. Subjects were trained to discriminate a circle made of circle elements from a square made of square elements and were tested with circles made of squares and squares made of circles. Adult humans showed a global bias in testing that was unaffected by the density of the elements in the stimuli. Children showed a global bias with dense displays but discriminated by both local and global properties with sparse displays. Adult tamarins' biases matched those of the children. The striking similarity between the perceptual processing of adult monkeys and humans diagnosed with autism and the difference between this and normatively developing human perception is discussed.

Adolescent↗
PubMed2004

Drug treatment of poststroke aphasia.

Impairment of language function (aphasia) is one of the most common neurological symptoms after stroke. Approximately one in every three patients who have an acute stroke will suffer from aphasia. The estimated incidence and prevalence of stroke in Western Europe is 140 and 800 per 100,000 of the population. Aphasia often results in significant disability and handicap. It is a major obstacle for patients to live independently in the community. When recovery from aphasia occurs, it is usually incomplete and patients are rarely able to return to full employment and other social activities. Currently, the main treatment for aphasia is conventional speech and language therapy. However, the effectiveness of this intervention has not been conclusively demonstrated and empirical observations suggest that spontaneous biological recovery may explain most of the improvement in language function that occurs in aphasics. The generally poor prognosis of the severe forms of poststroke language impairment (Broca, Wernicke and global aphasia), coupled with the limited effectiveness of conventional speech and language therapy has stimulated the search for other treatments that may be used in conjunction with speech and language therapy, including the use of various drugs. Dopamine agonists, piracetam (Nootropil), amphetamines, and more recently donepezil (Aricept), have been used in the treatment of aphasia in both the acute and chronic phase. The justification for the use of drugs in the treatment of aphasia is based on two types of evidence. Some drugs, such as dextroamphetamine (Dexedrine), improve attention span and enhance learning and memory. Learning is an essential mechanism for the acquisition of new motor and cognitive skills, and hence, for recovery from aphasia. Second, laboratory and clinical data suggest that drug treatment may partially restore the metabolic function in the ischemic zone that surrounds the brain lesion and also has a neuroprotective effect following acute brain damage. An example of this is the nootropic agent piracetam. Extensive animal studies have demonstrated the beneficial effects of this and other drugs on neural plasticity, but data on humans are still sparse. This review provides a critical analysis of the current evidence of the effectiveness of these drugs in the treatment of acute and chronic aphasia.

Amphetamine↗
PubMed2025

A novel high-dimensional model for identifying regional DNA methylation QTLs.

Varying coefficient models offer the flexibility to learn the dynamic changes of regression coefficients. Despite their good interpretability and diverse applications, in high-dimensional settings, existing estimation methods for such models have important limitations. For example, we routinely encounter the need for variable selection when faced with a large collection of covariates with nonlinear/varying effects on outcomes, and no ideal solutions exist. One illustration of this situation could be identifying a subset of genetic variants with local influence on methylation levels in a regulatory region. To address this problem, we propose a composite sparse penalty that encourages both sparsity and smoothness for the varying coefficients. We present an efficient proximal gradient descent algorithm that scales to high-dimensional predictor spaces, providing sparse solutions for the varying coefficients. A comprehensive simulation study has been conducted to evaluate the performance of our approach in terms of estimation, prediction and selection accuracy. We show that the inclusion of smoothness control yields much better results over sparsity-only approaches. An adaptive version of the penalty offers additional performance gains. We further demonstrate the utility of our method in identifying regional mQTLs from asymptomatic samples in the CARTaGENE cohort. The methodology is implemented in the R package sparseSOMNiBUS, available on GitHub.

Humans↗
PubMed2000

Population pharmacokinetic analysis of amikacin and validation on neonates using Monte Carlo method.

AIM: To make programs for population pharmacokinetic analysis and to assess the ability of this method in pharmacokinetic parameter estimation and in the prediction of serum concentrations. METHODS: Data of amikacin as a model drug were collected from 42 neonates with 142 serum samples. A one-compartment open model was used to describe the kinetics of amikacin after the intravenous infusion. Following Sheiner's idea of population pharmacokinetics, we made the programs to evaluate population parameter and individual parameter. The target function minimality was obtained from Monte Carlo algorithm. The validation of the population analysis was performed using classic pharmacokinetic program 3p87 for antithesis. The predictability of the developed method was evaluated by computing precision and accuracy of serum concentration predicted using the parameter estimates. RESULTS: The stability of our self-made program was good. The population parameters obtained from this approach were in conformity with those from 3p87, and the interindividual variability was relatively small. For the learning sample and the validation sample, predicted and observed concentrations were all close with correlation coefficient 0.995 and 0.990, respectively. Most of predicted errors were found < +/- 1 mg/L, and RMSD and BIAS were 0.58 and -0.07 for the validation sample, respectively. The choice of blood sampling time was an important factor for the predictive performance. An early sampling time after the infusion was observed to be the best sampling time. CONCLUSION: The estimation program of population parameter and individual parameter made by us ran stably, and allowed us to use sparse data to estimate population pharmacokinetic parameters. It provided accurate estimates of these parameters and satisfactory ability of serum concentration prediction. Therefore, it can be used for the population pharmacokinetic analysis and individualization of dosage regimen.

Amikacin↗
PubMed2004

A Bayesian approach to joint feature selection and classifier design.

This paper adopts a Bayesian approach to simultaneously learn both an optimal nonlinear classifier and a subset of predictor variables (or features) that are most relevant to the classification task. The approach uses heavy-tailed priors to promote sparsity in the utilization of both basis functions and features; these priors act as regularizers for the likelihood function that rewards good classification on the training data. We derive an expectation-maximization (EM) algorithm to efficiently compute a maximum a posteriori (MAP) point estimate of the various parameters. The algorithm is an extension of recent state-of-the-art sparse Bayesian classifiers, which in turn can be seen as Bayesian counterparts of support vector machines. Experimental comparisons using kernel classifiers demonstrate both parsimonious feature selection and excellent classification accuracy on a range of synthetic and benchmark data sets.

Algorithms↗
PubMed2004

Dynamical model of birdsong maintenance and control.

The neuroethology of song learning, production, and maintenance in songbirds presents interesting similarities to human speech. We have developed a biophysical model of the manner in which song could be maintained in adult songbirds. This model may inform us about the human counterpart to these processes. In songbirds, signals generated in nucleus High Vocal center (HVc) follow a direct route along a premotor pathway to the robust nucleus of the archistriatum (RA) as well as an indirect route to RA through the anterior forebrain pathway (AFP): the neurons of RA are innervated from both sources. HVc expresses very sparse bursts of spikes having interspike intervals of about 2 ms. The expressions of these bursts arrive at the RA with a time difference DeltaT approximately equal to 50+/-10 ms between the two pathways. The observed combination of AMPA and NMDA receptors at RA projection neurons suggests that long-term potentiation and long-term depression can both be induced by spike timing plasticity through the pairing of the HVc and AFP signals. We present a dynamical model that stabilizes this synaptic plasticity through a feedback from the RA to the AFP using known connections. The stabilization occurs dynamically and is absent when the RA-->AFP connection is removed. This requires a dynamical selection of DeltaT. The model does this, and DeltaT lies within the observed range. Our model represents an illustration of a functional consequence of activity-dependent plasticity directly connected with neuroethological observations. Within the model the parameters of the AFP, and thus the magnitude of DeltaT, can also be tuned to an unstable regime. This means that destabilization might be induced by neuromodulation of the AFP.

Action Potentials↗
PubMed1992

Profile and prevalence of the brain fag syndrome: psychiatric morbidity in school populations in Africa.

The profile and prevalence of a syndrome of somaticised anxiety associated with education in Africa was explored by survey of 2040 senior secondary school students in different types of school: rural, urban, and elite. Response to two different screening methods, an open question to elicit symptoms spontaneously, and the SRQ-24, was compared. Symptom prevalence was higher in rural schools, 34%, than periurban, 22%, and elite, 6%, but the central urban school serving a shanty town was also high at 35%. Three categories of the culturally relevant symptoms were identified--somatic, cognitive and 'spiritual'--with affective symptoms sparsely represented in the cultural idiom. The SRQ-24 items screening for psychosis were associated with a range of spontaneous symptoms representing anxiety. This 'spiritual' expression of neurosis reflects the world views and beliefs of the culture. Intensification under stress could produce the picture of transient reactive psychosis.

Adolescent↗
PubMed1998

Quality development in health care in Greenland: facing unlikely odds.

Health care in Greenland is historically founded on a fully tax-based system financed in large part by the Danish state. Administratively, the system was until 1992 under the Danish health authorities, with a concomitant lack of clarity concerning lines of communication in quality issues. Because of the enormous distance and communications problems, the individual districts were and continue to be run with a great deal of autonomy; and to this time the level of centralized data sources concerning qualitative aspects of the health care sector are extremely sparse. An attempt is being made to introduce a state-of-the-art centralized data collection and analysis function, with all that that entails in terms of system and personnel development. This system is described as a project, using an analysis of the official waiting-list database as a case study. The establishment and administration of the system is described. A cross-sectional analysis of the database is presented, illustrating issues of validity and reliability, as well as specifying the areas of system and personnel development necessary to make this system functional. The author's perception of the generalized implications of the lessons learned to date is presented.

Delivery of Health Care↗
PubMed1996

Perceiving self-motion in depth: the role of stereoscopic motion and changing-size cues.

During self-motions, different patterns of optic flow are presented to the left and right eyes. Previous research has, however, focused mainly on the self-motion information contained in a single pattern of optic flow. The present experiments investigated the role that binocular disparity plays in the visual perception of self-motion, showing that the addition of stereoscopic cues to optic flow significantly improves forward linear vection in central vision. Improvements were also achieved by adding changing-size cues to sparse (but not dense) flow patterns. These findings showed that assumptions in the heading literature that stereoscopic cues facilitate self-motion only when the optic flow has ambiguous depth ordering do not apply to vection. Rather, it was concluded that both stereoscopic and changing-size cues provide additional motion-in-depth information that is used in perceiving self-motion.

Adolescent↗
PubMed1992

Connections between the retrosplenial cortex and the hippocampal formation in the rat: a review.

The retrosplenial cortex is situated at the crossroads between the hippocampal formation and many areas of the neocortex, but few studies have examined the connections between the hippocampal formation and the retrosplenial cortex in detail. Each subdivision of the retrosplenial cortex projects to a discrete terminal field in the hippocampal formation. The retrosplenial dysgranular cortex (Rdg) projects to the postsubiculum, caudal parts of parasubiculum, caudal and lateral parts of the entorhinal cortex, and the perirhinal cortex. The retrosplenial granular b cortex (Rgb) projects only to the postsubiculum, but the retrosplenial granular a cortex (Rga) projects to the postsubiculu, rostral presubiculum, parasubiculum, and caudal medial entorhinal cortex. Reciprocating projections from the hippocampal formation to Rdg originate in septal parts of CA1, postsubiculum, and caudal parts of the entorhinal cortex, but these are only sparse projections. In contrast, Rgb and Rga receive dense projections from the hippocampal formation. The hippocampal projection to Rgb originates in area CA1, dorsal (septal) subiculum, and post-subiculum. Conversely, Rga is innervated by ventral (temporal) subiculum and postsubiculum. Further, the connections between the retrosplenial cortex and the hippocampal formation are topographically organized. Rostral retrosplenial cortex is connected primarily to the septal (rostrodorsal) hippocampal formation, while caudal parts of the retrosplenial cortex are connected with temporal (caudoventral) areas of the hippocampal formation. Together, the elaborate connections between the retrosplenial cortex and the hippocampal formation suggest that this projection provides an important pathway by which the hippocampus affects learning, memory, and emotional behavior.

Afferent Pathways↗
PubMed1994

Similarity- versus rule-based categorization.

An influential study by Rips (1989) provides the strongest evidence available that categorization cannot be reduced to similarity. In Rips's study, subjects were presented a sparse description of an object that mentioned only a value on a single dimension (e.g., "an object 3 inches in diameter"), followed by two categories (e.g., pizza and quarter), where one allowed more variability on the relevant dimension than did the other (the diameter of pizzas is more variable than that of quarters). Subjects judged the described object to be more likely to be a member of the variable category (pizza), but more similar to the nonvariable category (quarter). This dissociation between categorization and similarity strongly implies that categorization was not based on similarity. In our first experiment, we used sparse descriptions like Rips's, as well as rich descriptions that contained features characteristic of the nonvariable category. We found that categorization tracked similarity with both kinds of descriptions. In a second experiment, we modified our procedure to be more like that of Rips's by requiring subjects to think aloud while making their decisions. Now, like Rips, we found a dissociation between similarity and categorization with sparse items; with rich descriptions, categorization again tracked similarity. These findings are consistent with the hypothesis that categorization can be done in two ways, by similarity and by rule. An exclusive reliance on rule-based categorization seems to occur only when the description of the to-be-categorized object does not contain any features characteristic of any relevant category.

Adult↗
PubMed1985

Distribution of serotonin-immunoreactive cell bodies and processes in the abdominal ganglion of mature Aplysia.

Sensitization of the gill withdrawal reflex in Aplysia californica is an elementary form of learning, in part resulting from presynaptic facilitation of the LE mechanoreceptor neurons of the abdominal ganglion. It has previously been established that either application of serotonin or direct stimulation of a group of facilitatory neurons, the L29 cells of the abdominal ganglion, can simulate the effect of physiological stimulation in producing presynaptic facilitation. Because the evidence that serotonin serves as a facilitatory transmitter was indirect, we examined the distribution of serotonin-immunoreactive fibers and cell bodies in the abdominal ganglion in order to answer two questions: (1) do the sensory neurons receive serotonergic innervation and (2) are the L29 cells serotonergic? We observed two distinctive patterns of serotonergic innervation within the ganglion, sparse and dense. The sparse pattern is correlated with a serotonin-stimulated increase in cAMP in identified target cells, while the dense innervation is not. We found a sparse distribution of serotonin-immunoreactive fibers with varicosities close to both cell bodies and processes of identified LE sensory cells. It therefore is likely that the sensory neurons do receive serotonergic innervation. We also mapped the population of serotonergic neuronal cell bodies in the ganglion, and found five clusters of neurons. Cells in one of these clusters, the identified RB neurons, had previously been shown to synthesize serotonin from tryptophan and to contain the neurotransmitter in high concentration. Identified L29 facilitator cells marked by injection with Lucifer Yellow do not contain serotonin immunoreactivity and therefore evidently are not a source of serotonergic input onto sensory cells.

Animals↗
PubMed2026

CROP: a feature-independent context-aware method for CRISPR-Cas9 frameshift prediction.

MOTIVATION: The CRISPR-Cas9 complex has revolutionized genome-editing technologies. By designing a 20&#x2009;nt-long guide RNA, a Cas9 nuclease can be guided to cleave almost any genomic target site (followed by NGG). The cleavage induces double-stranded DNA breaks, which are then repaired by cellular pathways. Accurate CRISPR-Cas9 repair-outcome prediction is essential for designing guide RNAs with desired genomic effects, such as gene knockout. A central challenge is quantifying the rate of frameshifts, i.e. repair-outcomes that lead to a change in the local length that is not a multiple of three. Previous methods for frameshift-rate prediction were trained on only a few experimental or cellular contexts, mostly relied on manually defined microhomology features, and were limited by sparse features and class labels. RESULTS: We developed CROP, a feature-independent context-aware repair-outcome prediction method. By aggregating specific repair outcomes as &#x394;length classes, CROP overcomes class sparsity. We designed CROP to work with variable input sequence lengths and output classes to utilize multiple datasets simultaneously. We benchmarked CROP against state-of-the-art repair-outcome prediction methods over 18 datasets, which we curated and standardized from various studies. Across all datasets, CROP outperformed all competing methods in frameshift-rate prediction. We performed cross-experiment and cross-cellular frameshift-rate predictions to investigate the generalizability of repair mechanisms. Finally, we show that CROP learned microhomology principles from raw sequences without explicit feature engineering, establishing an end-to-end architecture for CRISPR-Cas9 repair-outcome prediction that learns from multiple datasets. AVAILABILITY AND IMPLEMENTATION: CROP is available at https://github.com/OrensteinLab/CROP.

CRISPR-Cas Systems↗
PubMed1984

The cognitions questionnaire: specific thinking errors in depression.

With the development of cognitive models of depression, interest in identifying an enduring cognitive style characteristic of depression-prone individuals has increased. However, empirical evidence for cognitive vulnerability of this kind is as yet sparse. The paper describes the development of a Cognitions Questionnaire (CQ), designed not only to provide an overall measure of depressive cognitive style, but also to assess specific dimensions of negative thinking in relation to different types of hypothetical events. Results of a study investigating the CQ's association with depression and its capacity to detect residual cognitive vulnerability following an episode of depression are reported.

Adult↗
PubMed2006

Differences in mnemonic processing by neurons in the human hippocampus and parahippocampal regions.

Different structures within the medial-temporal lobe likely make distinct contributions to declarative memory. In particular, several current psychological and computational models of memory predict that the hippocampus and parahippocampal regions play different roles in the formation and retrieval of declarative memories [e.g., Norman, K. A., & O'Reilly, R. C. Modeling hippocampal and neocortical contributions to recognition memory: A complementary-learning systems approach. Psychological Review, 110, 611-646, 2003]. Here, we examined the neuronal firing patterns in these two regions during recognition memory. Recording directly from neurons in humans, we find that cells in both regions respond to novel stimuli with an increase in firing (excitation). However, already on the second presentation of a stimulus, neurons in these regions show very different firing patterns. In the parahippocampal region there is dramatic decrease in the number of cells responding to the stimuli, whereas in the hippocampus there is recruitment of a large subset of neurons showing inhibitory (decrease from baseline firing) responses. These results suggest that inhibition is a mechanism used by cells in the human hippocampus to support sparse coding in mnemonic processing. The findings also provide further evidence for the division of labor in the medial-temporal lobe with respect to declarative memory processes.

Cell Differentiation↗
PubMed2002

Electrophysiological and morphological properties of cell types in the chick neostriatum caudolaterale.

The neostriatum caudolaterale, in the chick also referred to as dorsocaudal neostriatal complex, is a polymodal associative area in the forebrain of birds that is involved in sensorimotor integration and memory processes. We have used whole-cell patch-clamp recordings in chick brain slices to characterize the principal cell types of the neostriatum caudolaterale. Electrophysiological properties distinguished four classes of neurons. The morphological characteristics of these classes were examined by intracellular injection of Lucifer Yellow. Type I neurons characteristically fired a brief burst of action potentials. Morphologically, type I neurons had large somata and thick dendrites with many spines. Type II neurons were characterized by a repetitive firing pattern with conspicuous frequency adaptation. Type II neurons also had large somata and thick dendrites with many spines. There was no clear morphological distinction between type I and type II neurons. Type III neurons showed high-frequency firing with little accommodation and a prominent time-dependent inward rectification. They had thin, sparsely spiny dendrites and extensive local axonal arborizations. Electrophysiological and morphological properties indicated them as being interneurons. Type IV neurons had a longer action potential duration, a larger input resistance, and a longer membrane time constant than the other classes. Type IV neurons had small somata and short dendrites with few spines. The long axon collaterals of neurons in all spiny cell classes (types I, II, IV) followed similar patterns, suggesting that neurons from all these types can contribute to the projections of the neostriatum caudolaterale to sensory, limbic and motor areas. The electrophysiological and anatomical characterization of the major classes of neurons in the caudal forebrain of the chick provides a framework for the investigation of sensorimotor integration and learning at the cellular level in birds.

Action Potentials↗