Biomedical subjects
S J Anderson
Publications and source records attributed to S J Anderson.
Epstein-Barr virus LMP2A drives B cell development and survival in the absence of normal B cell receptor signals.
Epstein-Barr virus (EBV) establishes a persistent latent infection in peripheral B lymphocytes in humans and is associated with a variety of malignancies and proliferative disorders. Latent membrane protein 2A (LMP2A) is one of only two viral proteins expressed in latently infected B lymphocytes in vivo. LMP2A blocks B cell receptor (BCR) signal transduction in vitro by binding the Syk and Lyn protein tyrosine kinases. To analyze the significance of LMP2A expression in vivo, transgenic mice with B cell lineage expression of LMP2A were generated. LMP2A expression results in the bypass of normal B lymphocyte developmental checkpoints allowing immunoglobulin-negative cells to colonize peripheral lymphoid organs, indicating that LMP2A possesses a constitutive signaling activity in nontransformed cells.
A comparison of behavioral techniques to teach functional independent-living skills to individuals with severe and profound mental retardation.
The efficacy of two treatment approaches was compared for functional skill acquisition in individuals with severe and profound mental retardation. Participants included 22 residents from a large developmental center (Pinecrest) in central Louisiana. Treatment including staff training, feedback, and edible reinforcement in addition to prompting, modeling, and physical guidance was more effective than prompting, modeling, and physical guidance alone. Additionally, daily documentation of teaching did not enhance treatment effectiveness. Implications of the findings are discussed.
Bcl-2 counters apoptosis by Bax heterodimerization-dependent and -independent mechanisms in the T-cell lineage.
The effect of the cell death inhibitor Bcl-2 in relation to its capacity to dimerize with apoptosis promoter Bax or its homologs at their physiological expression levels was explored in the T-cell lineage. Transgenic mice expressing a BH1 mutant Bcl-2 (Bcl-2 mI-3), which fails to heterodimerize with proapoptotic members of the Bcl-2 family, such as Bax, were generated. Bcl-2 mI-3 protected immature CD4+8- thymocytes from spontaneous, glucocorticoid and anti-CD3-induced apoptosis and altered T cell maturation, resulting in increased percentages of CD3(hi) and CD4-8+ thymocytes. In contrast, apoptosis of peripheral T-cells was unaffected by transgene expression. This correlated with their high Bax expression level and insensitivity to the caspase inhibitor, zVAD-fmk, a functional hallmark of Bax-like activity. Thus, within the T-cell lineage Bcl-2 can inhibit apoptosis independent of its association with Bax or its homologs; yet, above a threshold level of their physiologic proapoptotic activity, the capacity of Bcl-2 to heterodimerize with Bax or its homologs appears essential for it to counter cell death.
The Syk and ZAP-70 SH2-containing tyrosine kinases are implicated in pre-T cell receptor signaling.
An early stage in thymocyte development, after rearrangement of the beta chain genes of the T cell receptor (TCR), involves expression of the pre-TCR complex and accompanying differentiation of CD4(-)CD8(-) double negative (DN) cells to CD4(+)CD8(+) double positive (DP) cells. The ZAP-70 and Syk tyrosine kinases each contain two N-terminal SH2 domains that bind phosphorylated motifs in antigen receptor subunits and are implicated in pre-T receptor signaling. However, mice deficient in either ZAP-70 or Syk have no defect in the formation of DP thymocytes. Here we show that, in mice lacking both Syk and ZAP-70, DN thymocytes undergo beta chain gene rearrangement but fail to initiate clonal expansion and are incapable of differentiating into DP cells after expression of the pre-TCR. These data suggest that the ZAP-70 and Syk tyrosine kinases have crucial but overlapping functions in signaling from the pre-TCR and hence in early thymocyte development.
Magnetoencephalographic investigation of human cortical area V1 using color stimuli.
The aim of this study was to determine the response properties of the human visual cortex to chromatic stimuli using magnetoencephalography (MEG). Evoked responses were recorded to isoluminant red/green sinusoidal gratings for a wide range of spatial and temporal frequencies. For each condition the response was dominated by a single major component which was well modeled by an equivalent current dipole. Coregistration of MEG and MRI data provided evidence that the principal evoked cortical activity originated from visual area V1. To investigate the chromatic response properties of this area, the maximum global field power of the evoked response was plotted as a function of stimulus spatial and temporal frequency. The spatial-frequency tuning was lowpass and the temporal-frequency tuning was multimodal, with peaks at 0 and 4 Hz. The results demonstrate the use of MEG as a technique for investigating activity from discrete regions of cortex.
The epidemiology of quantitative ultrasound: a review of the relationships with bone mass, osteoporosis and fracture risk.
Quantitative ultrasound (QUS) is a simple, inexpensive and non-invasive measure of bone which has been used in research settings for the prediction of osteoporosis. This review summarizes the current status of the epidemiology of QUS analysis, including its relationship with bone mineral density (BMD), risk of osteoporotic fracture and risk factors for osteoporosis. Although only moderately correlated with BMD, QUS appears to be as strong a predictor of osteoporotic fracture as BMD and may predict fracture independent of BMD. Risk factors for low QUS, including age, menopause, body composition and physical inactivity, seem to parallel those of low BMD. More longitudinal research is needed to confirm the clinical utility of QUS and more experimental and population-based studies are needed to determine whether the etiology of low QUS values is different from that of low bone mass.
Magnetoencephalographic evidence for non-geniculostriate visual input to human cortical area V5.
The aim of this study was to establish whether there is non-geniculostriate input to the extrastriate motion-sensitive area V5 in humans. Responses were measured with a SQUID neuro-magnetometer to motion stimuli presented within the blind hemifield of GY, a well-documented subject with a complete absence of the left primary visual cortical area V1. The motion stimulus was a 0.5c/deg, rapidly drifting (16Hz) achromatic sinusoidal grating. With this stimulus, the magnetic responses recorded over the temporo-parieto-occipital region in normals are well modelled by localized current sources in areas V1 and V5 (Anderson, S. J. et al., Proceedings of the Royal Society, London, Series B, 1996, 263, 423-431). As a control, evoked responses were measured to a 1.0 c/deg, stationary, photometrically isoluminant red/green sinusoidal grating. With the chromatic stimulus, the principal component of the magnetic responses recorded over the occipital pole in normals is well modelled by a current source in area V1 (Fylan, F. et al., Investigative Ophthalmology and Visual Science, 1995, 36, s1053). Both stimuli subtended 4 deg vertically by 6 deg horizontally, positioned such that the stimulus extended beyond the area of macular sparing into the lower field quadrant of the blind (or sighted) hemifield. Chromatic stimuli failed to evoked responses from GY's blind (contralateral) hemifield, consistent with there being no V1 activity in his left cortical hemisphere. However, motion stimuli did evoke responses from GY's blind hemifield, originating from a location consistent with activity in area V5. We further observed that both colour and motion stimuli evoked responses from GY's sighted (ipsilateral) hemifield. We conclude that there is non-geniculostriate input to extrastriate motion-sensitive areas in the human visual system, and that this pathway subserves the residual visual sensitivity to motion in the blind hemifield that has been demonstrated psychophysically in observer GY.
Changes in memory awareness during learning: the acquisition of knowledge by psychology undergraduates.
First-year psychology students took multiple-choice examinations following each of 4 lecture courses and 3 laboratory research methods courses. One lecture course was later retested. Students indicated state of memory awareness accompanying each answer: recollective experience (remember), "just know" (know), feeling of familiarity (familiarity), or guess. On the lecture courses, higher performing students differed from other students because they had more remember responses. On research methods, higher performing students differed because they knew more, and in the delayed retest, higher performing students differed because they now knew rather than remembered more. These findings demonstrate a shift from remembering to knowing, dependent upon level attained, type of course, and retention interval, and suggest an underlying shift in knowledge representation from episodic to semantic memory. The authors discuss theoretical and educational implications of the findings.
A longitudinal study of visual evoked responses to tritan stimuli in human infants.
The principal goal of this study was to assess the development of the S-cone pathway in human infants. For comparison, development of the L-M opponent pathway was also assessed. Visual evoked responses were measured to chromatic (tritan and red-green) and luminance-modulated (yellow-black) sinusoidal gratings of 0.2 cpd, viewed binocularly at a distance of 40 cm. For each type of chromatic stimulus, responses were recorded at a range of color ratios around the adult isoluminant point, as determined using standard flicker photometry criteria. Presentation was by abrupt pattern-onset with a stimulus duration of 100 ms and an interstimulus interval of 400 ms. Responses were recorded from Oz, referred to Cz, by averaging 30 sweeps. Infants were examined between the ages of 4 weeks and 3 months. Reliable visual evoked responses were recorded to isoluminant tritan stimuli from as early as 4 weeks of age, and to red-green stimuli from 6 weeks. Responses to the luminance-modulated stimuli were evident in all infants at 4 weeks of age (the earliest age examined). Our results provide evidence that the rate of development for pathways mediating information about tritan stimuli, red-green stimuli, and luminance-modulated stimuli is similar.
Localization and functional analysis of human cortical area V5 using magneto-encephalography.
Using a multi-channel SQUID-based neuromagnetometer, we have determined the location, temporal dynamics and functional response properties of the human homologue of the primate cortical area V5 (MT). We provide evidence that area V5 in humans is located near the occipito-temporal border in a minor sulcus immediately below the superior temporal sulcus. this area is selective for low spatial frequencies ( < or = 4.0 c/deg), responds to a wide range of temporal frequencies ( < or = 35 Hz) and shows response saturation for stimulus contrasts greater than 10%. In addition, we find that this area is not responsive to purely chromatic patterns but is responsive to motion-contrast stimuli. Our results are consistent with the hypothesis that area V5 in humans represents a stage of processing within the magnocellular pathway. We discuss our results in relation to the widespread belief that area V5 in humans is specifically concerned with motion perception.
Inhibition of Nef- and phorbol ester-induced CD4 degradation by macrolide antibiotics.
Human immunodeficiency virus type 1 (HIV-1) is the causative agent of AIDS. The simian immunodeficiency virus (SIV) causes a similar syndrome in macaques. The product of the nef gene of SIV has been shown to be important for virus replication and disease progression in vivo. In vitro, both SIV and HIV Nef downregulate surface expression of CD4 and accelerate total CD4 turnover. The mechanism by which Nef downregulates CD4 has not been established. A current model suggests that Nef enhances cell surface CD4 endocytosis and degradation in lysosomes. However, this was recently challenged when CD4 was found to accumulate in early endosomes of cells expressing Nef. Because inhibition of Nef function might halt virus replication and disease progression, we tested two macrolide antibiotics for their ability to inhibit Nef function. Concanamycin B (ConB) and bafilomycin A1 (BFLA1) are specific inhibitors of acidification of cell endosomes and lysosomes and, unlike other inhibitors, do not affect transport. Although ConB (25 nM) and BFLA1 (100 nM) blocked phorbol myristate acetate- and Nef-induced CD4 degradation in human monocyte U937 cells, CD4 surface expression was not recovered. Instead, CD4 accumulated in lysosomes. To determine if Nef is directly responsible for CD4 degradation or if they bind to each other in a manner similar to Vpu, transcripts of human CD4 and HIV-1 nef were cotranslated in vitro. Our results indicate that under our experimental conditions, Nef does not affect CD4 stability and does not associate with CD4 in this in vitro system. Our data suggest that (i) CD4 downregulation by Nef results in degradation of CD4 in lysosomes, (ii) inhibition of CD4 degradation by macrolide antibiotics does not restore surface expression, and (iii) the inhibition of CD4 expression by Nef appears to be indirect and is likely to involve cellular factors.
Comments on Scott and Ponsoda's (1996) positive and negative flashbulb memories.
Most of the events studied in flashbulb memory research are negative. Scott and Ponsoda (1996) are thoroughly commended for examining differences between positive and negative flashbulbs. Here we address three points. First, we note that other applicable research on autobiographical memory exists and stress that research on flashbulb memories should be prevented from becoming an isolated topic. Second, we identify some areas wherein flashbulb research has been applied, which help explain why there has been an imbalance towards negative events. Finally, we discuss some of the methodological difficulties matching positive and negative events.
Evaluation and treatment of ankle sprains.
Explore the source record for details and available documents.
Sample size determination for comparing more than two survival distributions.
We examine the asymptotic properties of the Tarone and Ware and Harrington and Fleming classes of test statistics under alternative hypotheses when there are comparisons between more than two survival distributions in the presence of arbitrary right censoring. When we assume equal censoring distributions across treatment groups and proportional hazards, we derive the sample size formula for testing the equality of k > or = 2 survival distributions using the logrank test. This work extends Schoenfeld's derivation for comparing two survival distributions and also generalizes the results of Makuch and Simon. We also derive the sample size formula for testing monotone dose-response using Tarone's trend test. We then investigate the practicality of the formula in various situations by presenting empirical power with use of Monte Carlo simulations. In addition, with stratification present, we derive the sample size formula for the stratified logrank test, which is an extension of Palta and Amini.
Breast cancer trials on trial: a case of conflicting ethical interests.
Explore the source record for details and available documents.
Methods for bounding the marginal survival distribution.
For time to event data with many potential failure types, one cannot uniquely determine the distribution of time to a specific event type, or marginal survival distribution, in the case where event types are mutually exclusive. In this paper we discuss several methods for estimating functions that bound the non-identifiable marginal survival distribution in the competing risks problem. We compute and compare bounds for data simulated from two bivariate survival distributions. Results show that the methods provide a suitable estimate of the marginal survival probability when one has specified dependence correctly. Data from a large clinical trial for breast cancer illustrate the methods.
V(D)J recombination and allelic exclusion of a TCR beta-chain minilocus occurs in the absence of a functional promoter.
Transcriptional activation of rearranging Ag receptor gene segments has been hypothesized to regulate their accessibility to V(D)J recombination. We analyzed the role of a functional promoter in the rearrangement of the murine TCR beta-chain locus using two transgenic minilocus constructs. These miniloci each contain an unrearranged V beta 8.3 gene. One has a wild-type V beta 8.3 gene, but the other has a V beta 8.3 gene with a promoter mutation that was previously shown to abrogate transcription in tissue culture. FACS analysis of thymus and lymph node cells from transgenic mouse lines showed that only the lines with the wild-type V beta 8.3 gene promoter express an 8.3 TCR beta-chain. Consistent with the protein expression data, V beta 8.3 gene transcripts were found only in the transgenic lines with the wild-type promoter. Using a quantitative PCR-based assay, it was shown that both types of transgenic lines recombine the V beta 8.3 gene at similar levels. Rearrangement of the transgenes was normal with respect to thymic development and junctional reading frame. Interestingly, both types of miniloci also underwent allelic exclusion in that recombination was blocked by the expression of a rearranged TCR beta-chain transgene. We conclude that a functional V beta gene promoter is not necessary for proper V(D)J recombination to occur.