Contribution of large scale biases in decoding of direction-of-motion from high-resolution fMRI data in human early visual cortex.

Previous studies have demonstrated that the perceived direction of motion of a visual stimulus can be decoded from the pattern of functional magnetic resonance imaging (fMRI) responses in occipital cortex using multivariate analysis methods (Kamitani and Tong, 2006). One possible mechanism for this is a difference in the sampling of direction selective cortical columns between voxels, implying that information at a level smaller than the voxel size might be accessible with fMRI. Alternatively, multivariate analysis methods might be driven by the organization of neurons into clusters or even orderly maps at a much larger scale. To assess the possible sources of the direction selectivity observed in fMRI data, we tested how classification accuracy varied across different visual areas and subsets of voxels for classification of motion-direction. To enable high spatial resolution functional MRI measurements (1.5mm isotropic voxels), data were collected at 7T. To test whether information about the direction of motion is represented at the scale of retinotopic maps, we looked at classification performance after combining data across different voxels within visual areas (V1-3 and MT+/V5) before training the multivariate classifier. A recent study has shown that orientation biases in V1 are both necessary and sufficient to explain classification of stimulus orientation (Freeman et al., 2011). Here, we combined voxels with similar visual field preference as determined in separate retinotopy measurements and observed that classification accuracy was preserved when averaging in this 'retinotopically restricted' way, compared to random averaging of voxels. This insensitivity to averaging of voxels (with similar visual angle preference) across substantial distances in cortical space suggests that there are large-scale biases at the level of retinotopic maps underlying our ability to classify direction of motion.

Quantitative genetics of age-related retinal degeneration: a second F1 intercross between the A/J and C57BL/6 strains.

PURPOSE: Previously, several quantitative trait loci (QTL) that influence age-related retinal degeneration (ageRD) were demonstrated in a cross between the C57BL/6J-c(2J) and BALB/cByJ strains (B x C). In this study, as a complementary approach to ongoing recombinant progeny testing for the purpose of identifying candidate quantitative trait genes (QTG), a second test cross using the A/J and the pigmented C57BL/6J strains (A x B) was carried out. The albino A/J strain was selected because it had the most amount of ageRD among several inbred strains tested, and the pigmented C57BL/6J strain was selected because along with its coisogenic counterpart C57BL/6J-c(2J) it had the least amount of ageRD. Thus, the effect of pigment on ageRD could be tested at the same time that the C57BL/6 genetic background was kept in common between the crosses from the two studies for the purpose of comparison. METHODS: A non-reciprocal F1 intercross between the A/J and C57BL/6J strains produced 170 F2 progeny. At 8 months of age after being maintained in relatively dim light, F2 mice, control mice and mice of other strains were evaluated for retinal degeneration by measurement of the thickness of the outer nuclear layer of the retina. The F2 mice were genotyped with dinucleotide repeat markers spanning the genome. Correlation of genotype with phenotype was made with Map Manager QTX software. RESULTS: Comparison of several strains of mice including the pigmented strains 129S1/SvImJ and C57BL/6J and the albino strains A/J, NZW/LacJ, BALB/cByJ and C57BL/6J-c(2J), showed significant differences in ageRD. The greatest difference was between the albino A/J strain and the pigmented C57BL/6J strain. However, there was no significant difference between the pigmented C57BL/6J and its albino coisogenic counterpart C57BL/6J-c(2J). Neither was there significant difference between the pigmented and albino F2 mice from the A x B cross. On the other hand, F2 males had a small but significantly lower amount of ageRD than females. Several QTL were identified in the A x B cross but surprisingly none of the 3 major QTL present in the original B x C cross (Chrs 6, 10, and 16) was present. There were minor QTL on proximal Chr 12 and proximal Chr 14 in common between the two crosses, and the proximal Chr 12 QTL was present in a previous light damage study involving the B and C strains. At least one sex-limited QTL was present on the X chromosome with a peak in a different location from that of a sex-limited QTL in the previous B x C study. In addition, the protective X allele was from the BALB/cByJ strain in the B x C cross and from C57BL/6J in the A x B cross. In both crosses, the C57BL/6J X-chromosome allele was recessive. CONCLUSIONS: Significant differences were observed in ageRD among several inbred strains of mice maintained in relatively dim light. AgeRD was not influenced by pigment but was influenced by gender, albeit to a small degree. The presence of the same QTL in one light-induced and two ageRD studies suggests at least partial commonality in retinal degeneration pathways of different primary cause. However, the three main QTL present in the B x C cross were absent from the A x B cross. This suggests that the genetic determinants responsible for the greater sensitivity to ageRD of BALB/cByJ and A/J relative to C57BL/6J are not the same. This is supported by the presence of sex-limited X-chromosome QTL in the two crosses in which the C57BL/6J allele is protective relative to the A allele and sensitive relative to the C allele. The findings in the two studies of differing allelic relationships of QTG, and differing QTL aid the identification of candidate genes mapping to critical QTL. Identifying natural modifying genes that influence retinal degeneration resulting from any causal pathway, especially those QTG that are protective, will open avenues of study that may lead to broad based therapies for people suffering retinal degenerative diseases.

Selective mechanisms for complex visual patterns revealed by adaptation.

A great deal is known about the initial steps of visual processing. We know that humans have neural mechanisms selectively tuned to simple patterns of particular spatial frequencies and orientations. We also know that much later in the visual pathway, in inferotemporal cortex, cells respond to extremely complex visual patterns such as images of faces. Very little is known about intermediate levels of visual processing, where early visual signals are presumably combined to represent increasingly complex visual features. Here we show the existence of visual mechanisms in humans, tuned and selective to particular combinations of simple sinusoidal patterns, using a novel method of compound adaptation.

Barriers to the dissemination of research findings of decision modeling in the management of cardiovascular disease.

The discussion and general conclusions of a working group convened during the Regenstrief Conference are presented. The group was formed to consider issues involved in the dissemination of research findings relative to decision modeling in the management of cardiovascular disease.

The effectiveness of implementing the weight-based heparin nomogram as a practice guideline.

OBJECTIVE: To determine the effectiveness of the nomogram in a community hospital that implemented it as a practice guideline. DESIGN: A nonexperimental, retrospective time series. SETTING: A 600-bed community teaching hospital and regional referral center in Phoenix, Ariz. PATIENTS: The study population included 591 consecutive patients with venous thromboembolism, treated over a 5-year study period. METHODS: During this period, the weight-based heparin nomogram was adapted into a preprinted order sheet and distributed to the hospital wards. The main outcome variables were the time to achieve a therapeutic activated partial thromboplastin time and the rate of bleeding complications. RESULTS: Voluntary implementation of the nomogram steadily increased, reaching 94%. Comparison of the periods before and after 50% implementation demonstrated an increase in initial heparin dose (1185 vs 1420 U/h, P < .001), a decrease in time to achieve therapeutic activated partial thromboplastin time (19.6 vs 11.8 hours), a decrease in the variance of this parameter (25 vs 4 hours, P < .001), and no change in bleeding rates. The proportion of patients achieving a therapeutic activated partial thromboplastin time within 24 hours decreased from 97% to 86% when the results from our previous randomized controlled trial (efficacy) are compared with the present results (effectiveness). CONCLUSIONS: The weight-based heparin nomogram was well accepted by clinicians at our institution and led to more aggressive heparin dosing and improvements in intermediate outcomes, without increasing bleeding. Mitigation of benefit is likely to occur when practice guidelines are moved from the realm of efficacy research into clinical practice. Therefore, the effectiveness of such measures requires monitoring.

Genetic architecture of the mouse hippocampus: identification of gene loci with selective regional effects.

We recently mapped two quantitative trait loci that have widespread effects on hippocampal architecture in mouse: Hipp1a and Hipp5a. We also noted remarkable strain differences in the relative sizes of different hippocampal regions. Estimated heritable variation for these differences was 42% in hippocampus proper, 40% in dentate gyrus, 31% in granule cell layer and 18% in pyramidal cell layer. Region size varied at least 50% from largest to smallest measurement. Here we have utilized these differences to identify loci with effects on the dentate gyrus, granule cell layer, hippocampus proper and pyramidal cell layer. Our sample consists of C57BL/6J and DBA/2J and 32 BXD recombinant inbred strains. Volumetric data were corrected for shrinkage and for differences in brain weight. We identified significant loci on chromosomes (Chr) 6, 13 and 15, and a significant interaction locus on proximal Chr 11. A suggestive distal Chr 1 locus overlaps with Hipp1a. HipV13a (Chr 13, 42-78Mb) has an additive effect of 0.56 mm3 (12.1%) on dentate gyrus volume, while GrV6a (Chr 6, 29-65 Mb) has additive effects of 0.14 mm3 (16.0%) on the volume of the granule cell layer. HipV13a also interacts with DGVi11a, a locus on proximal Chr 11 that operates exclusively through its epistatic effect on HipV13a and has no independent main effect HipV15a (Chr 15, 0-51 Mb) has an additive effect of 1.76 mm3 (9.0%) on the volume of the hippocampus proper. We used WebOTL, a recently described web-based tool, to examine genetic correlation of gene expression with hippocampal volume. We identified a number of genes that map within the OTL intervals and have highly correlated expression patterns. Using WebQTL's extensive database of published BXD phenotypes, we also detected a strong and potentially biologically meaningful correlation between hippocampal volume and the acoustic startle response.

Configurational coding, familiarity and the right hemisphere advantage for face recognition in sheep.

This study examined characteristics of visual recognition of familiar and unfamiliar faces in sheep using a 2-way discrimination task. Of particular interest were effects of lateralisation and the differential use of internal (configurational) vs external features of the stimuli. Animals were trained in a Y-maze to identify target faces from pairs, both of which were familiar (same flock as the subjects) or both of which were unfamiliar (different flock). Having been trained to identify the rewarded face a series of stimuli were presented to the sheep, designed to test for the use of each visual hemifield in the discriminations and the use of internal and external facial cues. The first experiment showed that there was a left visual hemifield (LVF) advantage in the identification of 'hemifaces', and 'mirrored hemifaces' and 'chimeric' faces and that this effect was strongest with familiar faces. This represents the first evidence for visual field bias outside the primate literature. Results from the second experiment showed that, whilst both familiar and unfamiliar faces could be identified by the external features alone, only the familiar faces could be recognised by the internal features alone. Overall the results suggest separate recognition methods for socially familiar and unfamiliar faces, with the former being coded more by internal, configurational cues and showing a lateral bias to the left visual field.

Integrating stratum-specific likelihood ratios with the analysis of ROC curves.

Data used to construct receiver operating characteristic (ROC) curves and to calculate the area under the curve (ROC AUC) can be used to derive stratum-specific likelihood ratios (SSLRs) with their 95% confidence intervals (95% CIs). The purpose of this study was to determine whether useful information can be obtained by adding SSLRs to the analysis of ROC curves. The authors analyzed four previously reported sets of data: 1) serum creatine kinase (SCK) for diagnosing acute myocardial infarction (AMI) in the coronary care unit (CCU); 2) SCK in the evaluation of chest pain in the emergency center (EC); 3) four predictor variables in the diagnosis of strep throat; and 4) the ordinal assessment of computed tomographic (CT) images. Use of SCK in the CCU produced four strata that had posttest probabilities that were highly discriminating, whereas SCK in the EC resulted in only two strata with limited discriminating ability. In either study the cutpoint at which the SSLR changed from less than to greater than 1.0 was higher than the reported upper normal for the test, thereby quantitating spectrum bias. The maximum number of strata of predictor signs and symptoms for strep throat was three rather than the five used in previous studies. With a larger sample size or pooling, four strata could probably be developed. With CT images, "definitely normal," "probably normal," and "questionable" were collapsed to one negative stratum. "Probably abnormal" became the true "questionable" stratum and "definitely abnormal" was the only positive stratum. The authors conclude that additional useful information is obtained by deriving stratum-specific likelihood ratios as part of the analysis of an ROC curve.

Perceptual masking of the chlordiazepoxide discriminative cue by both caffeine and buspirone.

Twelve male Sprague-Dawley rats were trained to discriminate between the interoceptive stimulus attributes of 5 mg/kg chlordiazepoxide (CDP) and saline in a two-lever operant task under a fixed-ratio 10 (FR-10) schedule of food reinforcement. Caffeine, buspirone, and Ro 15-1788 failed to engender complete generalization when tested in combination with saline. In drug interaction test sessions caffeine (56 mg/kg) blocked the discriminative stimulus properties of the training dose of CDP and shifted the CDP discriminative dose-response function to the right. This rightward shift in CDP discriminative function was paralleled by a concomitant downward shift in the rate-of-responding dose-response function. Drug interaction test sessions conducted with 3.2 mg/kg of buspirone in combination with various doses of CDP engendered a downward shift in both the discriminative and rate-of-responding dose-response functions. Because 3.2 mg/kg buspirone in combination with the training dose of CDP resulted in complete response rate suppression, additional combination tests were conducted with 3 mg/kg CDP, a dose which reliably engendered > 90% CDP-appropriate responding, and various doses of buspirone. Similar to the CDP-caffeine interactions, buspirone blocked the cueing properties of 3 mg/kg CDP with a parallel reduction in response rates. Interaction test sessions conducted with Ro 15-1788 and CDP resulted in rightward shifts in both the discriminative and rate functions of CDP. We suggest that the interactions between CDP and both caffeine and buspirone resulted from the perceptual masking of the interoceptive (subjective) effects of CDP, whereas the interaction between Ro 15-1788 and CDP reflect pharmacological antagonism.

Consumption of biogenic nitric oxide in hydrated soil.

An experimental study was conducted in order to determine the relationship of nitric oxide (NO) consumption to water-filled pore space in soil. A test system that included the capability to blend gases, test soil samples, and analyze off-gases was used to conduct the study. The experimental set consisted of three replicates at five different levels of soil water content and three different levels of soil nitrogen in a sandy loam soil: unamended soil, soil fertilized at 56.2 kg N per ha (50 lb N acre(-1)), and soil fertilized at 112.3 kg N per ha (100 lb N acre(-1)). The average NO consumption rates were 7.1x10(-13) g-NO cm(-3) soil, 3.5x10(-11) g-NO cm(-3) soil, and 1.5x10(-10) g-NO cm(-3) soil, respectively.

Hurricane-loaded soil: effects on nitric oxide emissions from soil.

The nitric oxide (NO) flux from eastern North Carolina soils subjected to flooding from hurricanes were studied in laboratory experiments. Three sites along the Neuse River basin in eastern North Carolina that sustained different intensities of flooding in September 1999 from Hurricane Floyd were examined. Hurricane Floyd impacted the Neuse River basin by inducing flooding that damaged and disabled hog (Sus scrofa) lagoons and municipal wastewater treatment plants. Between approximately 53 and 325 million liters (14 and 86 million gallons) of untreated hog waste and between approximately 5.7 and 34.4 billion liters (1.5 and 9.1 billion gallons) of untreated municipal wastewater are projected to have entered the Neuse River basin, increasing the concentrations of nitrogen (N), phosphorus (P), and total solids. Phosphorus and total solids are projected to have increased 3.2 and 199.2 mg/L, respectively. Total N was projected to have increased by 9.8 mg/L, which is posited to have increased the NO flux from flooded soils for months after the hurricane. Nitric oxide emissions from soil can adversely affect ozone levels in the lower troposphere. Minimization of NO flux from soil is advantageous, protecting air quality as well as conserving valued nitrogen fertilizers. Hurricane-loaded soils were found to produce more than 30 times greater NO emissions than nonflooded soils with NO fluxes ranging from 0.1 to 102.5 ng N/(m2 s).

The paradox of physicians and administrators in health care organizations.

Rapidly changing times in health care challenge both physicians and health care administrators to manage the paradox of providing orderly, high quality, and efficient care while bringing forth innovations to address present unmet problems and surprises that emerge. Health care has grown throughout the past several centuries through differentiation and integration, becoming a highly complex biological system with the hospital as the central attractive force--or "strange attractor"--during this century. The theoretical model of complex adaptive systems promises more effective strategic direction in addressing these chaotic times where the new strange attractor moves beyond the hospital.

A major influence of sex-specific loci on alcohol preference in C57Bl/6 and DBA/2 inbred mice.

C57Bl/6 mice reproducibly prefer to ingest more 10% ethanol in a two-bottle choice paradigm than do DBA/2J mice. In this paper we report the identification of two new sex-specific alcohol preference (Alcp) loci. Melo and associates (1996) identified two loci: Alcp1, a male-specific locus on Chromosome (Chr) 2, and Alcp2, a female- and cross-specific locus on Chr 11. We have additionally identified Alcp3, a male-specific locus on Chr 3, and Alcp4, a female-specific locus on Chr 1. We have also performed a statistical analysis to exclude the possibility of undiscovered major alcohol preference loci that are not sex-specific in our backcross paradigm. Our results indicate that alcohol preference in C57BL/6 mice, as measured in our backcross, is largely controlled in a sex-specific manner.

Using the free-to-total prostate-specific antigen ratio to detect prostate cancer in men with nonspecific elevations of prostate-specific antigen levels.

BACKGROUND: Prostate-specific antigen (PSA) levels between 4.0 to 10.0 ng/ml have poor specificity in prostate cancer screening, leading to unnecessary biopsies. OBJECTIVE: To determine whether the free-to-total PSA ratio (F/T PSA) improved the diagnostic accuracy of these nonspecific PSA levels. MEASUREMENTS AND MAIN RESULTS: MEDLINE searchedwas from 1986 to 1997. Additional studies were identified from article bibliographies and by searching urology journals. Two investigators independently identified English-language studies providing F/T PSA ratio test-operating characteristics data on > or = 10 cancer patients with PSA values between 2.0 and 10.0 ng/ml. Twenty-one of 90 retrieved studies met selection criteria. Two investigators independently extracted data on methodology and diagnostic performance. Investigator-selected cut points for the optimal F/T PSA ratio had a median likelihood ratio of 1.76 (interquartile range, 1.40 to 2.11) for a positive test and 0.27 (0.20 to 0.40) for a negative test. Assuming a 25% pretest probability of cancer, the posttest probabilities were 37% following a positive test and 8% following a negative test. The summary receiver operating characteristic curve showed that maintaining test sensitivity above 90% was associated with false positive rates of 60% to 90%. Methodologic problems limited the validity and generalizability of the literature. CONCLUSIONS: A negative test reduced the posttest probability of cancer to approximately 10%. However, patients may find that this probability is not low enough to avoid undergoing prostate biopsy. The optimal F/T PSA ratio cut point and precise estimates for test specificity still need to be determined.

Human face recognition in sheep: lack of configurational coding and right hemisphere advantage.

Face recognition in sheep is qualitatively similar to that in humans in terms of its left visual field bias, and the effects of expertise and configural coding. The current study was designed to determine whether such effects are species specific by investigating the case of sheep recognising humans. It was found that the sheep could identify human faces and while they showed a small inversion-induced decline in discriminatory performance, this was significantly less than seen with sheep faces. In other aspects, there were qualitative differences with human face recognition compared with conspecific recognition. In contrast with sheep faces there was no left visual field advantage in the recognition of human faces and the internal features were not used at all as visual cues. The data suggest that these sheep, whilst being extensively exposed to interactions with humans, were unable to identify them with all the same 'expert' methods as were used to discriminate other sheep. This suggests that different neural systems may, to some extent, be used for recognition of sheep as opposed to human faces. The relative contribution to differential neural processing of the faces of the different species and the role of expertise are discussed.

Dexamethasone potentiates IGF-I actions in porcine granulosa cells.

To understand better interactions between glucocorticoids and insulin-like growth factor I (IGF-I) in the ovary, we studied the effects of dexamethasone on IGF-I stimulation of P-450 cholesterol side-chain cleavage enzyme (P-450scc) mRNA concentrations in porcine granulosa cells. Dexamethasone potentiated IGF-I-stimulated P-450scc mRNA concentrations and progesterone production in granulosa cell cultures. Time-course and dose-response studies showed that maximal enhancement occurred at a 1-microM dexamethasone concentration after 48 h of treatment. This potentiation was prevented by the glucocorticoid receptor antagonist RU-38486, 17 beta-hydroxy-11 beta-[-4-dimethyl-aminophenyl]estra-4,9,-dien-3-one (RU-486). We investigated mechanisms for this potentiation by performing IGF-I binding studies in porcine granulosa cells. Dexamethasone increased IGF-I binding, and Scatchard analysis showed this enhanced binding was caused by an increase in receptor concentration. Northern blot hybridization using a rat type I IGF-I receptor gene riboprobe showed that although dexamethasone alone did not increase IGF-I receptor mRNA concentrations, it did prevent a decrease in receptor mRNA concentrations caused by IGF-I. In addition, we used synthetic primers from conserved regions of the rat type I IGF-I receptor gene with total RNA from porcine granulosa cells and polymerase chain reaction to isolate a 615-base pair porcine type I IGF-I receptor cDNA clone. Ribonuclease protection assay results were similar to those found with the rat IGF-I receptor riboprobe. We conclude that dexamethasone potentiates IGF-I actions on steroidogenesis in the porcine ovary.

Apparently changing patterns of inheritance in Alport's hereditary nephritis: genetic heterogeneity versus altered diagnostic criteria.

With the use of more stringent diagnostic criteria, it has recently been shown that some large pedigrees of Alport's and non-Alport's hereditary nephritis fit sex-linked dominant inheritance (O'Neill et al. 1978). We have used similar diagnostic criteria and have studied a number of Michigan pedigrees in order to see if this hypothesis would be confirmed. We found one small pedigree which definitely shows male-to-male transmission, while one large pedigree is tentatively compatible with sex-linked dominant inheritance. Many of the other pedigrees suggested male-to-male transmission. This Michigan experience is compared to other published reports and found to be consistent, although a trend of fewer reports of male-to-male transmission is seen. We conclude that genetic heterogeneity of Alport's hereditary nephritis is likely.

Fine-needle aspiration biopsy of abdominal lesions: diagnostic yield for different needle tip configurations.

Four fine-needle aspiration biopsy needles with different tip configurations were used in 133 patients with abdominal lesions. The 20-gauge needles were used in random sequence by several physicians. The specimen from each of the 522 needle passes was evaluated by two cytopathologists for adequacy to render a diagnosis and for the presence of cell block material. The Franseen needle produced a 16% and 9% better yield for diagnostic material than did the cut biopsy and spinal needles (P less than .05), respectively. The Westcott needle was better than the cut biopsy needle by 13%, and the spinal needle produced an 11% better yield than did the cut biopsy needle. Differences did not exist in liver biopsies but were present in pancreatic biopsies. The spinal needle was the least successful in yielding cell block material. Use of the cut biopsy needle resulted in the largest proportion of inadequate specimens, except its yield in cell blocks in the liver was 25% higher than that of the Westcott needle. The authors conclude that not all unusual designs for 20-gauge needle tips render results superior to those of the simple spinal needle.