Biomedical subjects

S A Klein

Publications and source records attributed to S A Klein.

At least 37 records · Page 2Linked to original sources

PubMed2000

Vernier and contrast discrimination in central and peripheral vision.

The present paper asks whether Vernier offset discrimination is limited by the observer's sensitivity to local contrast change in both central and peripheral vision. To answer this question we compared Vernier discrimination and contrast discrimination thresholds (specified in the same units) for a pair of narrow ribbons of cosine gratings. Because the ribbons are narrow, both the offset information (for Vernier discrimination) and the contrast information (for contrast discrimination) are highly localized. We found that when the stimuli are narrow ribbons, the local contrast cue is the limiting factor in Vernier discrimination. However, our results also show that integration of information along the length of the gratings (the ribbon width) is: (i) different for Vernier and contrast discrimination, and (ii) for Vernier discrimination the integration of information along the length of the gratings differs qualitatively in central and peripheral vision. For narrow ribbons, the peripheral 'template' for ribbon Vernier acuity is not as well matched to the stimulus (in two-dimensional spatial frequency space) as the foveal 'template'.

Contrast Sensitivity↗

PubMed2000

An analysis of signal detection and threshold models of source memory.

The authors analyzed source memory performance with an unequal-variance signal detection theory model and compared the findings with extant threshold (multinomial and dual-process) models. In 3 experiments, receiver operating characteristic (ROC) analyses of source discrimination revealed curvilinear functions, supporting the relative superiority of a continuous signal detection model when compared with a threshold model. This result has implications for both multinomial and dual-process models, both of which assume linear ROCs in their description of source memory performance.

Adolescent↗

PubMed2000

Undercounting features and missing features: evidence for a high-level deficit in strabismic amblyopia.

Abnormal visual development in strabismic amblyopia drastically affects visual perception and properties of neurons in primary visual cortex (V1). To test the notion that amblyopia also has consequences for higher visual areas, we asked humans with amblyopia to count briefly presented features. Using the amblyopic eye, strabismic amblyopes counted inaccurately, markedly underestimating the number of features. This inaccuracy was not due to low-level considerations (blur, visibility, crowding, undersampling or topographical jitter), as they also underestimated the number of features missing from a uniform grid. Rather, counting deficits in strabismic amblyopes reflected a higher-level limitation in the number of features the amblyopic visual system can individuate.

Adult↗

PubMed2000

Retrovirally expressed anti-HIV ribozymes confer a selective survival advantage on CD4+ T cells in vitro.

To date, a selective advantage of cells expressing anti-HIV ribozymes has not been shown. This study was undertaken to determine whether such a selective advantage can be demonstrated in vitro. A retroviral vector coding for a hairpin ribozyme targeting the HIV 5'LTR and for the low affinity nerve growth factor receptor (LNGF-RDelta) was designed. Since we demonstrated by RT-PCR that the amount of ribozyme transcripts was highly correlated with the level of surface LNGF-RDelta expression, the vector was utilized to assess ribozyme expression by flow cytometry. Transduced Hut78 and primary CD4+ T cells were purified and subsequently mixed with unmodified cells. After HIV challenge the percentage of ribozyme expressing cells in the cell mixture was monitored by flow cytometry. Twenty-one days after HIV infection the proportion of ribozyme expressing CD4+ T cells was 2.6 times higher in comparison to cells with the control vector. CD4+ T cells with a strong ribozyme expression conferred a 7.4-fold selective advantage at day 21 and a 11.7-fold at day 28. For Hut78 cells a selective advantage was detected exclusively for strongly ribozyme expressing cells. As a mechanism underlying the selective advantage an inhibition of HIV induced apoptosis was shown. These results demonstrate that anti-HIV ribozymes are able to confer a selective survival advantage and indicate that the protective effect is dependent on the amount of ribozyme expression. Gene Therapy (2000) 7, 408-416.

Apoptosis↗

PubMed2000

Interleukin-18 stimulates HIV-1 replication in a T-cell line.

Interleukin-18 (IL-18) is a recently identified proinflammatory cytokine. Its ability to induce interferon-g suggests a potential virustatic effect. On the other hand, it stimulates NFkB - an activator of HIV replication. Recently, stimulation of HIV-1 in monocytic cells has been demonstrated. In the present study, the influence of IL-18 on HIV-1 replication in lymphatic cells was investigated. Hut78 cells were infected with HIV-1 in the presence of recombinant human IL-18 expressed either in E. coli or eucaryotically by baculovirus in Sf9 cells. HIV-1 replication was monitored by p24 ELISA and endpoint titration of culture supernatants on C8166 cells. The addition of IL-18 led to a 3- to 15-fold enhancement of HIV replication in Hut78 cells. By addition of neutralising monoclonal anti-IL-18 antibodies, this effect of IL-18 was reduced by 75%. Exposure of Hut78 to IL-18 prior to HIV infection could exclude the possibility that IL-18 promotes infection of cells. Taken together, these data provide direct evidence for an IL-18-mediated enhancement of HIV-1 replication in lymphatic cells.

Animals↗

PubMed1999

Quantification of human interleukin 18 mRNA expression by competitive reverse transcriptase polymerase chain reaction.

Interleukin 18 (IL-18) is a recently identified cytokine, originally called interferon gamma inducing factor, due to its capacity to induce interferon gamma production in Th1 type cells. IL-18 is expressed by a wide variety of cell types including mononuclear phagocytes, osteoblasts, keratinocytes and adrenal cortex cells. To quantify human IL-18 mRNA expression in small-scale cell samples the authors developed a competitive reverse transcriptase polymerase chain reaction using a competitive template as an internal standard. This assay was demonstrated as a valid, sensitive and precise tool to quantify human IL-18 mRNA expression. IL-18 mRNA expression of primary peripheral blood monocytes, CD4(+)T cells, CD8(+)T cells, B cells and NK cells was assessed by competitive RT-PCR. Basal IL-18 expression could be detected in all types of peripheral blood mononuclear cells (PBMC). The kinetics of IL-18 mRNA expression in PBMC from healthy donors was defined in vitro after monocyte-specific (lipopolysaccharide LPS), T-cell-specific (anti-CD3) and polyclonal-unspecific stimulation (phytohaemagglutinin PHA). Only LPS led to a strong increase of IL-18 mRNA expression peaking after 2 h. These results indicate that IL-18 is expressed constitutionally by all major PBMC subtypes. However, only monocyte specific stimulation resulted in a significant induction of IL-18 mRNA expression suggesting activated monocytes e.g. in inflammation as the main source of IL-18 expression.

Binding, Competitive↗

PubMed1999

Angiogenesis inhibitor TNP-470 inhibits murine cutaneous wound healing.

BACKGROUND: TNP-470 (AGM-1470) is a potent inhibitor of angiogenesis with potential therapeutic applications in neoplastic and angio-proliferative diseases. This study evaluated its effect on cutaneous wound healing in a murine dorsal excisional wound model. MATERIALS AND METHODS: Full-thickness wounds (1.60 cm2) were created on the dorsum of homozygous/hairless mice (7 to 9 weeks). Wound areas were measured on alternate days for 16 days. Experimental groups consisted of (1) TNP-470 administered in doses of 0.05, 0.5, and 5.0 mg/kg on Days 0, 2, and 4 or Days 0 through 6; (2) TNP-470 (5.0 mg/kg) coadministered with minocycline (4.0 and 10 mg/kg) on Days 0, 2, and 4; and (3) TNP-470 (5.0 mg/kg on Days 0, 2, and 4) coadministered with topical basic fibroblast growth factor (bFGF) 1. 0 microg/wound on Days 0, 1, and 2. Hematoxylin and eosin staining was used to compare experimental and control wounds. RESULTS: TNP-470 administration significantly decreased wound healing in a dose-dependent manner versus controls (P <.05). The 5.0 mg/kg concentration yielded the greatest effect by maintaining an average wound area 20.4% greater than controls and a marked delay in wound healing on H&E staining. Alternate-day dosing was as effective as consecutive day administration. Minocycline did not augment the wound healing inhibition of TNP-470. Coadministration of TNP-470 and bFGF eliminated any rate-altering effect of TNP-470 upon wound healing and resulted in wound areas similar to controls. CONCLUSION: Therapy with TNP-470 induces a significant delay in murine cutaneous wound healing. This effect may be exploited for use in situations where wound healing is excessive and debilitating. Topical application of bFGF can overcome TNP-470-induced wound healing inhibition.

Angiogenesis Inhibitors↗

PubMed1999

Maternal magnesium sulfate and the development of neonatal periventricular leucomalacia and intraventricular hemorrhage.

OBJECTIVE: Neonatal periventricular leucomalacia and intraventricular hemorrhage are strong correlates of cerebral palsy. Our objective was to evaluate the effect of maternal magnesium sulfate exposure on the incidence and severity of periventricular leucomalacia and intraventricular hemorrhage in preterm neonates. METHODS: Nine hundred eighteen consecutive inborn neonates with birth weights from 500 to 1750 g were divided primarily into two groups on the basis of maternal exposure to magnesium sulfate. The groups were divided secondarily into two clinical groups, a physician-initiated group, which consisted of neonates delivered for maternal or fetal indications, and a preterm delivery group, which included neonates delivered as a result of preterm labor or preterm premature rupture of membranes. These clinical groups were stratified further into magnesium sulfate-exposed and -unexposed subgroups. Neonatal neurosonograms were performed on days 3 and 7 of life and described as normal or abnormal. Abnormal sonograms included any periventricular leucomalacia or intraventricular hemorrhage. Severe lesions included periventricular leucomalacia, periventricular leucomalacia with intraventricular hemorrhage, or grades 3 or 4 intraventricular hemorrhage. The magnesium sulfate groups and the clinical groups with their magnesium sulfate strata were compared for the incidence and severity of abnormal sonograms. They also were compared for maternal and neonatal characteristics. RESULTS: Maternal magnesium sulfate exposure was not associated with reduction in the incidence of abnormal sonograms when compared with the unexposed group (27% compared with 33%, P = .06). However, fewer severe lesions were observed in the exposed group (14% compared with 21%, P = .004). When clinical groups were examined, magnesium sulfate was not associated with a decrease in abnormal sonograms (adjusted odds ratio [OR] 1.09, 95% confidence interval [CI] 0.78, 1.52, P = .40) or severe lesions (adjusted OR 1.11, 95% CI 0.73, 1.68, P = .42). Logistic regression analyses of magnesium sulfate exposure within clinical groups controlling for the confounding effects of maternal and neonatal characteristics revealed no protective effect of magnesium sulfate exposure on the incidence of abnormal sonograms (adjusted OR 1.01, 95% CI 0.70, 1.44, P = .97) or severe lesions (adjusted OR 1.01, 95% CI 0.70, 1.74, P = .69). Within clinical groups, the preterm delivery group exhibited an increased risk for abnormal sonograms (adjusted OR 1.63, 95% CI 1.01, 2.67, P = .05) and severe lesions (adjusted OR 9.79, 95% CI 3.27, 29.29, P = .001) when compared with the physician-initiated delivery group, independent of maternal magnesium sulfate exposure. CONCLUSION: Maternal magnesium sulfate exposure had no protective effect on the incidence or severity of periventricular leucomalacia and intraventricular hemorrhage in preterm neonates. The prevalence of these lesions was correlated better with the clinical group of origin and indication for its use.

Anticonvulsants↗

PubMed1999

Optimal spatial localization is limited by contrast sensitivity.

Bisection is one of several spatial localization tasks that achieve hyperacuity performance levels. We find that optimal bisection thresholds, and hyperacuity tasks in general, are no better than might be expected from simple contrast detection and discrimination performance. The three-line bisection task can be described in terms of the test-pedestal paradigm where the test pattern is a horizontal dipole and the pedestal is a horizontal three-line pattern with equal spacing between the lines. When the dipole test is added to the center line, the line shifts up or down, depending on the test polarity. For low contrast pedestal lines at the optimal separation, the bisection threshold falls between the observer's own dipole contrast detection threshold and the bottom of the dipole contrast discrimination dipper function. At higher pedestal strengths performance degrades with a slope of about 0.5-0.7, similar to that found in contrast discrimination tasks. Therefore, bisection performance is compatible with expectations based on contrast discrimination data. At large pedestal line separations (> 10 min) bisection thresholds in min are about 1/60 the separation and relatively independent of pedestal strength. These findings are consistent with the idea that two processes are involved in limiting bisection performance; the first limit is based on contrast sensitivity of the system and the second limit to performance is based on a local sign or position tag processing. Finally, when bisection is compared with Vernier acuity and blur resolution tasks, where the test is also a dipole, bisection performance falls roughly midway, better than Vernier acuity but worse than blur resolution.

Contrast Sensitivity↗

PubMed1999

Position jitter and undersampling in pattern perception.

The present paper addresses whether topographical jitter or undersampling might limit pattern perception in foveal, peripheral and strabismic amblyopic vision. In the first experiment, we measured contrast thresholds for detecting and identifying the orientation (up, down, left, right) of E-like patterns comprised of Gabor samples. We found that detection and identification thresholds were both degraded in peripheral and amblyopic vision; however, the orientation identification/detection threshold ratio was approximately the same in foveal, peripheral and amblyopic vision. This result is somewhat surprising, because we anticipated that a high degree of uncalibrated topographical jitter in peripheral and amblyopic vision would have affected orientation identification to a greater extent than detection. In the second experiment, we investigated the tolerance of human and model observers to perturbation of the positions of the samples defining the pattern when its contrast was suprathreshold, by measuring a 'jitter threshold' (the amount of jitter required to reduce performance from near perfect to 62.5% correct). The results and modeling of our jitter experiments suggest that pattern identification is highly robust to positional jitter. The positional tolerance of foveal, peripheral and amblyopic vision is equal to about half the separation of the features and the close similarity between the three visual systems argues against extreme topographical jitter. The effects of jitter on human performance are consistent with the predictions of a 'template' model. In the third experiment we determined what fraction of the 17 Gabor samples are needed to reliably identify the orientation of the E-patterns by measuring a 'sample threshold' (the proportion of samples required for 62.5% correct performance). In foveal vision, human observers are highly efficient requiring only about half the samples for reliable pattern identification. Relative to an ideal observer model, humans perform this task with 85% efficiency. In contrast, in both peripheral vision and strabismic amblyopia more samples are required. The increased number of features required in peripheral vision and strabismic amblyopia suggests that in these visual systems, the stimulus is underrepresented at the stage of feature integration.

Adult↗

PubMed1999

Using multi-stimulus VEP source localization to obtain a retinotopic map of human primary visual cortex.

OBJECTIVE: The goal of this study was to acquire a detailed spatial and temporal map of primary visual cortex using a novel VEP stimulus and analysis technique. METHODS: A multi-stimulus array spanning the central 18 degrees of the visual field was used where each of 60 checkerboard stimulus 'patches' was simultaneously modulated with an independent binary m-sequence (Sutter, 1992). VEPs corresponding to each patch were recorded from 3 subjects using a dense posterior electrode array. For each stimulus patch, single dipole source localization was conducted to determine the location, magnitude, and time-function of the underlying neural activation. To reduce ambiguity in the solution, a common time-function was assumed for stimulus patches at the same visual eccentricity (defining an annulus). The analysis was conducted independently for each annulus composed of 4-12 patches. RESULTS: The loci of the dipole solutions followed a smooth retinotopic pattern across annuli consistent with the classical organization of primary visual cortex. Specifically, each dipole was found contralateral to the corresponding stimulus patch and field inversion was observed for all subjects. CONCLUSIONS: Using this technique, the most detailed spatial and temporal retinotopic map of primary visual cortex to date has been obtained.

Adult↗

PubMed1999

Posttraumatic thoracic splenosis and chronic aortic pseudoaneurysm.

Thoracic splenosis is the autotransplantation of splenic tissue into the pleural cavity, usually following traumatic injury that simultaneously involves the spleen and diaphragm. Intrathoracic splenosis is an uncommonly reported phenomenon. We present a case of intrathoracic splenosis in a patient with a chronic aortic pseudoaneurysm, both detected, incidentally, three decades after the traumatic event. The diagnosis of thoracic splenosis can be confirmed noninvasively, using 99mTc sulfur colloid nuclear scintigraphy.

Aneurysm, False↗

PubMed1998

Quantitation of apolipoprotein epsilon gene expression by competitive polymerase chain reaction in a patient with familial apolipoprotein E deficiency.

A simple method of obtaining semiquantitative and reliable data on apolipoprotein (apo) sigma gene expression is described. We detected apo sigma specific sequences by reverse transcription (rT)-PCR. For quantitative measurement, an apo sigma DNA standard was produced allowing the development of a competitive PCR-method. The efficiency of RNA extraction and cDNA synthesis was controlled by quantitation of a housekeeping gene (glyceraldehyde-3-phosphatedehydrogenase, G3PDH) in separate reactions. To imitate a defined induction of apo sigma gene expression, serial twofold dilutions of total RNA were reversely transcribed and the respective cDNAs used to perform a competitive apo sigma and G3PDH PCR. The change in apo sigma cDNA and G3PDH cDNA was 1.7-2.3-fold with an expected value of 2.0-fold. Standard deviations in three independently performed experiments were within a range of < 15% of the mean, indicating low intra-assay variation and high reproducibility. To illustrate this method, apo sigma gene expression was measured in a patient with complete lack of functional active apo E in comparison to healthy controls. The method presented here might be valuable in assessment of apo sigma gene expression in human disease.

Adolescent↗

PubMed1998

Mechanism of gamma sigma T-cell-mediated inhibition of stem cell differentiation in vitro: possible relevance for myelosuppression in HIV-infected individuals.

We investigated whether gamma delta T cells contribute to the suppression of myelopoiesis in HIV infection. Freshly isolated gamma delta T cells from HIV seropositive patients suppressed CFU-GM growth in vitro. Preactivation of gamma delta T cells with IL-2 and/or IL-15 further reduced the number of CFU-GM. Natural killer cells and to a lower extent CD4+ and CD8+ cells also inhibited CFU-GM growth. In contrast to gamma delta T cells, this effect was not dependent on IL-15 or IL-2 preactivation. Moreover, no enhanced inhibitory effect of CD56+ and CD4+ cells was observed in HIV+ subjects compared to HIV- donors. The myelosuppressive effect of supernatants of gamma delta T cells could be inhibited by antibodies against IFN-gamma or TNF-alpha. Accordingly, we found increased numbers of TNF-alpha or IFN-gamma-secreting CD8+ gamma delta T cells in HIV+ patients. We conclude that the increased fraction of activated gamma delta T cells producing myelosuppressive cytokines might contribute to the dyshematopoiesis frequently observed in HIV-infected individuals.

Cell Differentiation↗

PubMed1998

Differential expression of bcl-2 and susceptibility to programmed cell death in lymphocytes of HIV-1-infected individuals.

The bcl-2 protooncogene encodes an inner mitochondrial membrane protein that blocks programmed cell death. There is now increasing evidence that regulation of bcl-2 expression is a determinant of life or death in normal lymphocytes. In this study, we examined bcl-2 expression in lymphocytes from human immunodeficiency virus type 1 (HIV-1)-infected and healthy subjects by flow cytometry. bcl-2 expression was detected in more than 97% of peripheral blood lymphocytes in both healthy and HIV-infected individuals. It was consistently observed that CD4+ lymphocytes from HIV-1-infected individuals with less than 200 CD4+ cells/microliter expressed significantly less bcl-2 than healthy controls. In contrast, bcl-2 expression in CD8+ lymphocytes of these patients was significantly enhanced. No significant alteration of bcl-2 expression was found when lymphocytes of healthy individuals were polyclonally activated in the presence of various regulatory cytokines. Cells undergoing apoptosis showed significantly lower bcl-2 expression than viable cells. Staining of apoptotic cells revealed that lymphocytes from HIV-1-infected subjects were characterized by an increased susceptibility to programmed cell death which was not restricted to a particular lymphocyte subset. Despite significantly different bcl-2 expression in CD4+ and CD8+ lymphocytes of HIV-1-infected individuals with less than 200 CD4+ cells/microliter, no difference could be observed concerning their susceptibility to undergo apoptosis. Therefore, we conclude that sensitivity or resistance to in vitro induction of apoptosis does not directly correlate with bcl-2 expression.

Adult↗

PubMed1998

Quantification of the morphological features of a full microvascular network.

Investigations into the changes that occur in microvasculature following the surgical procedure called delay have brought about the need for a computer system capable of quantifying the morphological features of a full microvascular network in terms of average vessel length, diameter, and tortuosity. Both the formulaic conventions that have been developed to measure these quantities as well as their implementation in the form of a HP-9000/UNIX based computer software system that we developed specifically for this purpose are discussed. Reliability studies performed using the final system to measure the microcirculatory network of a mouse latissmus dorsi muscle (LDM) showed 95% confidence intervals within 5% of means and coefficients of variability within 7% of means for all quantities measured in large (150-300 microns), medium (50-150 microns), and small (< 50 microns) diameter vessels. These variations were significantly smaller than the changes that were observed in a preliminary study comparing these microvascular network parameters before and after delay in the hairless mouse LDM, showing the proposed quantification methods to be well suited to the study of the microvascular changes following delay. It is hoped that the formulaic conventions, implementation process and reliability data will provide a useful comparison for other researchers interested in measuring similar features of microcirculatory networks.

Animals↗

PubMed1998

Spatial uncertainty and sampling efficiency in amblyopic position acuity.

Spatial uncertainty and undersampling are two of the major hypotheses for the losses of amblyopic spatial vision. To test these two hypotheses, equivalent spatial uncertainty and spatial integration efficiency in spatial position judgments were quantified with a spatial perturbation paradigm. Specifically, three-line bisection thresholds were measured for the amblyopic eyes of two strabismic and two anisometropic amblyopes, and for normal controls. The horizontal stimulus lines comprised discrete dark dots distributed randomly around the mean line position according to a gaussian function. Line separation, the number of dots on each line (N), stimulus contrast (C), and the vertical standard deviation (sigma e) of the dot distribution were varied. An ideal observer analysis quantified the magnitude of equivalent spatial uncertainty (sigma s), the effective number of dots used (k), and spatial integration efficiency (k/N). At the optimal separation, equivalent spatial uncertainty (sigma s) is approximately ten-fold higher in both types of amblyopic visual systems than in control observers, even when stimulus visibility is accounted for. This apparent increase in sigma s is largely due to a shift in spatial scale of analysis in the amblyopic eye. Integration efficiency (k/N) increases in proportion to stimulus contrast or visibility (in units of detection threshold). Unlike sigma s, k/N is different between the two types of amblyopia. For the anisometropic observers, k/N is quantitatively similar to that of control observers. For the strabismic observers, on the other hand, k/N is reduced even after taking stimulus visibility into account. The decreased spatial integration efficiency in the strabismic visual system suggests that spatial undersampling may occur at a secondary stage of visual processing, beyond the detection stage.

Adult↗

PubMed1998

Increase in Vdelta1+ gammadelta T cells in the peripheral blood and bone marrow as a selective feature of HIV-1 but not other virus infections.

Dysregulation of T-cell receptor (TCR) alphabeta bearing lymphocytes and an increase in Vdelta1+ gammadelta T cells are typical features of HIV-1 infection. However, the role of gammadelta T cells remains unclear. Therefore, peripheral blood mononuclear cells (PBMC) of 103 HIV-1-infected patients were investigated with respect to expression of Vdelta1. These results were compared to the Vdelta1 expression of bone marrow mononuclear cells (BMMC). In contrast to healthy controls, Vdelta1+ cells dominated among both PBMC and BMMC in HIV-1-infected patients. Analysis of the coexpression of CD25, CD8, HLA-DR and CD45RO revealed a high prevalence of Vdelta1/CD45RO and Vdelta1/HLA-DR double-positive PBMC only in HIV-1-infected patients but not in healthy donors. Furthermore, analysis of the gammadelta TCR repertoire in patients infected with hepatitis B virus, hepatitis C virus, herpes simplex virus (HSV)-1 and HSV-2 showed that the selective enhancement of Vdelta1+ cells was restricted to HIV infection and not observed in other virus diseases. Our data provide further support for the involvement of gammadelta T cells in immunosuppression and progression of HIV infection.

Adult↗