Acute regulation of IGF-I by alterations in post-exercise macronutrients.

This investigation sought to examine the contributions of exercise and nutrient replenishment on in vivo regulation of the insulin-like growth factor-I (IGF-I) axis components. Eight college-aged males completed three high-intensity interval training (HIIT) protocols followed by three post-exercise nutritional protocols: (1) placebo (EX); (2) carbohydrate only (CHO); and (3) essential amino acid/carbohydrate (EAA/CHO). Samples were analyzed for growth hormone (GH), free IGF-I, IGFBP-1, IGFBP-2, insulin, hematocrit, hemoglobin, serum leucine, matrix metalloproteinase-9 (MMP-9) proteolytic activity, and presence of IGFBP-3 protease activity. No evidence for IGFBP-3 proteolysis was observed. Significant increases in [free IGF-I] and [leucine] were observed in the EAA/CHO group only. Significant differences were noted in [IGFBP-1] and [IGFBP-2] across conditions. Significant increases in [GH] and MMP-9 activity were observed in all groups. These results indicate that post-exercise macronutrient ratio is a determinant of [free IGF-I], [IGFBP-1 and -2] and may play a role in modulating the IGF-I axis in vivo.

Levels of analysis in psychiatric research.

Most of the major psychiatric disorders have been analyzed at each of several different levels. For example, at the broadest level, epidemiological studies have served to establish the incidence of disorders like schizophrenia and major depression in a number of different populations. Family and twin studies have been important in determining the heritability of certain mental illnesses, and chromosomal and linkage analyses have identified a number of discrete loci that appear to be implicated in disease susceptibility or, even directly, in the pathogenesis of some disorders. In a few cases, specific genes have been found to be mutated or polymorphic and proteins they encode are currently being analyzed. This article reviews how these different levels contribute to our understanding of a number of psychiatric disorders, including drug addiction, which has been the focus of much of our own work.

The human genome project and its impact on psychiatry.

There has been substantial evidence for more than three decades that the major psychiatric illnesses such as schizophrenia, bipolar disorder, autism, and alcoholism have a strong genetic basis. During the past 15 years considerable effort has been expended in trying to establish the genetic loci associated with susceptibility to these and other mental disorders using principally linkage analysis. Despite this, only a handful of specific genes have been identified, and it is now generally recognized that further advances along these lines will require the analysis of literally hundreds of affected individuals and their families. Fortunately, the emergence in the past three years of a number of new approaches and more effective tools has given new hope to those engaged in the search for the underlying genetic and environmental factors involved in causing these illnesses, which collectively are among the most serious in all societies. Chief among these new tools is the availability of the entire human genome sequence and the prospect that within the next several years the entire complement of human genes will be known and the functions of most of their protein products elucidated. In the meantime the search for susceptibility loci is being facilitated by the availability of single nucleotide polymorphisms (SNPs) and by the beginning of haplotype mapping, which tracks the distribution of clusters of SNPs that segregate as a group. Together with high throughput DNA sequencing, microarrays for whole genome scanning, advances in proteomics, and the development of more sophisticated computer programs for analyzing sequence and association data, these advances hold promise of greatly accelerating the search for the genetic basis of most mental illnesses while, at the same time, providing molecular targets for the development of new and more effective therapies.

Viktor Hamburger and Rita Levi-Montalcini: the path to the discovery of nerve growth factor.

The announcement in October 1986 that the Nobel Prize for physiology or medicine was to be awarded to Rita Levi-Montalcini and Stanley Cohen for the discoveries of NGF and EGF, respectively, caused many to wonder why Viktor Hamburger (in whose laboratory the initial work was done) had not been included in the award. Now that the dust has settled, the time seems opportune to reconsider the antecedent studies on the relation of the developing nervous system to the peripheral structures it innervates. The studies undertaken primarily to investigate this issue culminated in the late 1950s in the discovery that certain tissues produce a nerve growth-promoting factor that is essential for the survival and maintenance of spinal (sensory) ganglion cells and sympathetic neurons. In this review, the many contributions that Viktor and Rita made to this problem, both independently and jointly, are reexamined by considering chronologically each of the relevant research publications together with some of the retrospective memoirs they have published in the years since the discovery of NGF was first reported.

Prospects for neurology and psychiatry.

Neurological and psychiatric illnesses are among the most common and most serious health problems in developed societies. The most promising advances in neurological and psychiatric diseases will require advances in neuroscience for their elucidation, prevention, and treatment. Technical advances have improved methods for identifying brain regions involved during various types of cognitive activity, for tracing connections between parts of the brain, for visualizing individual neurons in living brain preparations, for recording the activities of neurons, and for studying the activity of single-ion channels and the receptors for various neurotransmitters. The most significant advances in the past 20 years have come from the application to the nervous system of molecular genetics and molecular cell biology. Discovery of the monogenic disorder responsible for Huntington disease and understanding its pathogenesis can serve as a paradigm for unraveling the much more complex, polygenic disorders responsible for such psychiatric diseases as schizophrenia, manic depressive illness, and borderline personality disorder. Thus, a new degree of cooperation between neurology and psychiatry is likely to result, especially for the treatment of patients with illnesses such as autism, mental retardation, cognitive disorders associated with Alzheimer and Parkinson disease that overlap between the 2 disciplines.

Enzyme application development.

The range of enzyme applications has grown considerably in the last 10 years and new techniques are required to discover and evaluate the future areas of use. A number of different aspects of enzyme application are evaluated and consideration given as to how we may develop these new areas.

Interactions between search mechanisms in conjunction search.

We report the results of a technique designed to measure interactions between different visual search processes. We interrupted pop-out search before it produced a detection response, by adding extra distractors to the display so that a target initially defined by a single feature difference (e.g., a yellow horizontal line among yellow vertical lines) could then only be found on the basis of the conjunction of two features (a yellow horizontal line among yellow vertical lines and pink horizontal lines; difficult search). This technique has been used to measure the duration of the perceptual components of pop-out search, independent of over-all response time, for targets presented among different sets of distractors. In addition, when pop-out failed because it was interrupted, past work has shown that it nevertheless provided useful information to the processes responsible for difficult search. That is, partial pop-out assisted difficult search, when extra distractors made search difficult because the target was between the two types of distractors in the relevant feature space (Olds, Cowan, & Jolicoeur, 2000a,b,c). The present results demonstrate that partial pop-out also assists difficult search when difficult search is a conjunction search, and therefore these interactions may occur at a stage where information from different feature dimensions is combined.

Tracking visual search over space and time.

Visual perception consists of early preattentive processing and subsequent attention-demanding processing. Most researchers implicitly treat preattentive processing as a domain-dependent, indivisible stage. We show, however, by interrupting preattentive visual processing of color before its completion, that it can be dissected both temporally and spatially. The experiment depends on changing easy (preattentive) selection into difficult (attention-demanding) selection. We show that although the mechanism subserving preattentive selection completes processing as early as 200 msec after stimulus onset, partial selection information is available well before completion. Furthermore, partial selection occurs first at locations near fixation, spreading radially outward as processing proceeds.

The emergence of modern neuroscience: some implications for neurology and psychiatry.

One of the most significant developments in biology in the past half century was the emergence, in the late 1950s and early 1960s, of neuroscience as a distinct discipline. We review here factors that led to the convergence into a common discipline of the traditional fields of neurophysiology, neuroanatomy, neurochemistry, and behavior, and we emphasize the seminal roles played by David McKenzie Rioch, Francis O Schmitt, and especially Stephen W Kuffler in creating neuroscience as we now know it. The application of the techniques of molecular and cellular biology to the study of the nervous system has greatly accelerated our understanding of the mechanisms involved in neuronal signaling, neural development, and the function of the major sensory and motor systems of the brain. The elucidation of the underlying causes of most neurological and psychiatric disorders has proved to be more difficult; but striking progress is now being made in determining the genetic basis of such disorders as Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, and a number of ion channel and mitochondrial disorders, and a significant start has been made in identifying genetic factors in the etiology of such disorders as manic depressive illness and schizophrenia. These developments presage the emergence in the coming decades of a new nosology, certainly in neurology and perhaps also in psychiatry, based not on symptomatology but on the dysfunction of specific genes, molecules, neuronal organelles and particular neural systems.

A study of interval breast cancer within the NHS breast screening programme.

AIM: To define the biological nature and malignant potential of interval cancers presenting to a breast unit within the NHS breast screening programme. METHODS: 112 interval cancers were compared with matched, screen detected and symptomatic cancers in terms of their radiographic, histopathological, and immunohistochemical features. RESULTS: Interval cancers, strictly defined, showed no characteristic radiographic pattern. In terms of size, vascular invasion, lymph node status, and prognosis they were intermediate between screen detected and symptomatic cancers. Within the interval cancers there was an excess of grade 1 and grade 3 tumours, and lesions with a high Ki67 index but immunohistochemistry otherwise failed to discriminate between the three groups. Inclusion of data from false negative "interval cancers" did not significantly alter the results. CONCLUSIONS: Interval cancers are more aggressive than screen detected cancers but in general less aggressive than symptomatic cancers. However, within a heterogeneous group, occasional interval cancers are exceptionally malignant.

The time-course of pop-out search.

Olds, Cowan and Jolicoeur [2000. Tracking visual search over space and time. Psychonomic Bulletin & Review (in press)] interrupted pop-out search by adding distractors to a display after a delay. They analyzed the response time distributions from conditions with different delays for interruption and showed that when pop-out search fails, its partially completed computations can be used to assist other, slower search processes. This paper demonstrates that expectancies, numbers of items and colors in the display, and color onsets do not explain those results. Finally, an experiment in which the target was moved mid-trial demonstrates that partial pop-out assists difficult search by indicating something about where the target is, or where the target is not.

Partial orientation pop-out helps difficult search for orientation.

We interrupted pop-out search before it produced a detection response by adding extra distractors to the search display. We show that when pop-out for an orientation target fails because of this interruption, it nevertheless provides useful information to the processes responsible for difficult search. That is, partial pop-out assists difficult search. This interaction has also been found for color stimuli (Olds, Cowan, & Jolicoeur, 2000a, 2000b). These results indicate that interactions and/or overlap between the mechanisms responsible for pop-out and the mechanisms responsible for difficult search may be quite general in early visual selection.

The effect of denervation on leukocyte function in soft tissue infection.

BACKGROUND: The present study was undertaken to investigate the effect of denervation on leukocyte function in soft-tissue infection in an isolated in vivo ovine flap model. METHODS: Fifteen adult ewes were divided into three groups. An island pedicle flap was raised on the right buttock. In group I (no denervation), the cutaneous nerve remained intact, whereas in group II (acute denervation) the nerve was divided acutely. In group III (prolonged denervation) the nerve was divided 7 days before flap elevation. All flaps received intradermal inoculation of 10(7) Staphylococcus aureus, and the animals were observed for 96 hours. RESULTS: In both groups II and III, the leukocyte chemiluminescence and chemotaxis were significantly decreased when compared with group I. Furthermore, there was profound impairment of leukocyte functions in group III compared with group II. Group III also had significantly higher bacterial counts, larger septic foci, lower viable leukocyte ratios, and decreased bacterial killing compared with group I. CONCLUSIONS: Denervation, particularly over a period of time, results in increased bacterial growth of soft-tissue septic foci. This appears to be due to decreased leukocyte function resulting in diminished bacterial killing.

Convex hull test of the linear separability hypothesis in visual search.

Visual search for a colour target in distractors of two other colours is dramatically affected by the configuration of the colours in CIE (x, y) space. To a first approximation, search is difficult when a target's chromaticity falls directly between (i.e. is not linearly separable from) two distractor chromaticities, otherwise search is easy (D'Zmura [1991, Vision Research, 31, 951-966]; Bauer, Jolicoeur, & Cowan [1996a, Vision Research, 36, 1439-1466]; Bauer, Jolicoeur, & Cowan [1996b, Perception, 25, 1282-1294]). In this paper, we demonstrate that the linear separability effect transcends the two distractor case. Placing a target colour inside the convex hull defined by a set of distractors hindered search performance compared with a target placed outside the convex hull. This is true whether the target was linearly separable in chromaticity only (Experiments 1 and 2), or in a combination of luminance and chromaticity (Experiments 3 and 4).

Stimulus-determined discrimination mechanisms for color search.

Visual attention can be goal driven, stimulus driven, or a combination of the two. Here we report evidence for an unexpectedly stimulus-driven component of visual search for a target defined by color. Observers demonstrated a surprisingly cost-free ability to incorporate multiple classifiers in search for a target of one color from among distractors of other colors. A target color was presented among distractors that could change from trial to trial (intermixed presentation) or that remained constant across all trials in a block (blocked presentation). For blocked presentation, a single search classifier (a mechanism that segregates the target from distractors in color space) could be adopted, whereas for intermixed presentation different classifiers had to be used when the distractor colors changed. The benefit of blocked presentation was very small, suggesting that the appropriate classifier was determined very quickly in trials for which the classifier changed. The results suggest that the stimulus-driven activation of an appropriate stimulus classifier can be very efficient.

The linear separability effect in color visual search: ruling out the additive color hypothesis.

Bauer, Jolicoeur, and Cowan (1996b, 1996c) demonstrated difficult visual search for color targets that were not linearly separable (in color space) from two distractor colors and easier search for linearly separable targets. This suggested that search is mediated by a chromatically linear discrimination mechanism (see D'Zmura, 1991). However, in those experiments, the targets that were not linearly separable fell midway between the distractor colors and thus corresponded to the admix of the distractor colors. An alternate interpretation of the results of Bauer et al. is that search was more difficult when the target corresponded to the distractor admix than when it did not. We tested this hypothesis in three experiments by contrasting conditions in which a target that was not linearly separable did or did not correspond to the admix of the distractor colors. In all cases, a target that was not linearly separable produced difficult search, demonstrating that linear separability determines search performance.

Aberration-correction results from a segmented microelectromechanical deformable mirror and a refractive lenslet array.

Quadratic aberration is successfully corrected with a segmented microelectromechanical deformable mirror in conjunction with a refractive lenslet array. Use of the lenslet array greatly improves the effective fill factor of the correcting element. Experimental results show correction approaching the diffraction limit for an extreme spherical aberration.

The pathological and biological nature of screen-detected breast carcinomas: a morphological and immunohistochemical study.

Traditional and immunohistochemical markers of prognosis were examined in 455 mammary carcinomas derived from breast cancer screening and compared with those of 277 carcinomas presenting symptomatically over the same period. Tumours detected by population screening under the U.K. National Health Service Programme do not differ from those detected by other screening projects, but compared with symptomatic cancers, screen-detected cancers are more likely to be in situ and if invasive, to be smaller, of lower grade, and to have invaded vessels, perineural spaces, and lymph nodes less frequently. Tubular and cribriform types are more often represented in screened patients. Immunohistochemical markers which have been proposed as being related to likely tumour behaviour (epidermal growth factor receptor, c-erbB-2 protein, oestrogen and progesterone receptors, cathepsin D, p53, and retinoblastoma protein) do not distinguish screen-detected from 'clinical' cancers. It is concluded that cancers diagnosed at screening do not differ biologically from those presenting clinically, but are the same lesions detected at an earlier stage of their natural history.