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Biomedical subjects

H J Müller

Publications and source records attributed to H J Müller.

At least 37 records · Page 2Linked to original sources
PubMed2000

Enhanced GABA(A) inhibition enhances synchrony coding in human perception.

The benzodiazepine, lorazepam enhances the efficiency of local, inhibitory GABA(A) synapses in the cortex, which stabilize postsynaptic, excitatory activity by synchronizing their own discharges at around 40 Hz. Treatment with lorazepam has also been shown to adversely influence detection performance in perceptual tasks, suggesting a role for GABA(A)-mediated synchronization during visuo-perceptual organization. Consistent with these findings we report that reaction times to target stimuli were slower following lorazepam treatment. However, when targets followed presentation of a synchronized prime, presented within a flickering 40-Hz display matrix, the effects of priming were amplified relative to baseline and control conditions. We conclude that enhanced GABA(A)-induced inhibition enhances stimulus-evoked synchronization with differential effects upon mechanisms of perceptual segmentation and grouping.

Adult↗
PubMed2000

Regression of left ventricular hypertrophy by AT1 receptor blockade in renal transplant recipients.

AT1 receptor antagonists control blood pressure (BP) effectively and reduce left ventricular hypertrophy in patients with essential hypertension. Because left ventricular hypertrophy is very common in renal transplant recipients, we examined the cardiovascular effects and the safety profile of the AT1 receptor antagonist losartan in hypertensive renal transplant recipients. In 20 renal transplant recipients with stable renal graft function 50 mg of losartan was added to the preexisting antihypertensive treatment (no angiotensin-converting enzyme inhibitors) at least 6 months after renal transplantation. Twenty-four-hour ambulatory BP, two-dimensional-guided M-mode echocardiography, and duplex sonography, as well as renal function, red blood cell count, cyclosporine A and FK 506 levels, erythropoetin, and angiotensin II concentration were determined at baseline and after 6 months of therapy. With 24-h ambulatory BP measurement, systolic blood pressure (SBP) was reduced by 7.5 +/- 2.4 mm Hg and diastolic blood pressure (DBP) by 4.5 +/- 1.8 mm Hg (P < .01 and P < .05, respectively). Posterior, septal, and relative wall thickness decreased by 0.95 +/- 0.2 mm, 0.91 +/- 0.2 mm and 0.04 +/- 0.01 mm, respectively (all P < .001). Left ventricular mass index decreased by 18.1 +/- 4.7 g/m2 (P < .01). Ejection fraction and midwall fractional fiber shortening as systolic parameters and the relation of passive-to-active diastolic filling of the left ventricle were unaltered. Serum creatinine and cyclosporine A concentration remained stable in all patients. Hemoglobin and hematocrit decreased by 1.0 +/- 0.3 g/dL and 3.6% +/- 0.9%, respectively (P < .002 and P < .001) without a change in serum erythropoetin level. In renal transplant recipients the AT1 receptor antagonist losartan reduces left ventricular hypertrophy without altering systolic or diastolic function. It is safe with regard to renal function and immunosuppression, but slightly decreases hemoglobin level.

Adult↗
PubMed2000

Dimension-based visual attention modulates dual-judgment accuracy in Duncan's (1984) one- versus two-object report paradigm.

Four experiments, adapting the object-judgment paradigm developed by J. Duncan (1984), examined the relationship between object-based and domain-based mechanisms of visual attention. The experiments demonstrated a cross-domain cost, in terms of accuracy, when observers made dual color-form judgments to one or two overlapping objects presented briefly, relative to within-domain, dual-color and dual-form judgments. This domain-based selection effect was additive to an object-based effect, a cost of making dual judgments to separate objects, as reported by J. Duncan (1984). The pattern of object- and domain-based effects points to a capacity limitation in how multidimensional features are bound into a coherent object representation, consistent with the dimension-weighting account of H. J. Miller, D. Heller, and J. Ziegler (1995), which postulates that there is a limit to the total selection weight available to be allocated to an object's dimensions.

Adolescent↗
PubMed2000

Probing distractor inhibition in visual search: inhibition of return.

The role of inhibition of return (IOR) in serial visual search was reinvestigated using R. Klein's (1988) paradigm of a search task followed by a probe-detection task. Probes were presented at either the location of a potentially inhibited search distractor or an empty location. No evidence of IOR was obtained when the search objects were removed after the search-task response. But when the search objects remained on, a pattern of effects similar to Klein's results emerged. However, when just the search-critical object parts were removed or when participants received immediate error feedback to prevent rechecking of the search objects, IOR effects were observed only when probes appeared equally likely at search array and empty locations. These results support the operation of object-based IOR in serial visual search, with IOR demonstrable only when rechecking is prevented (facilitating task switching) and monitoring for probes is not biased toward search objects.

Adolescent↗
PubMed2000

Evidence for 40-Hz oscillatory short-term visual memory revealed by human reaction-time measurements.

Four experiments show that presentation of a synchronous premask frame within a 40-Hz, flickering premask matrix primes subsequent detection of a Kanizsa-type square by generation of a 40-Hz prime. Reaction time (RT) priming effects indicated a 150-200-ms prime duration following premask display. RTs were also found to be sensitive to the phase relationship between offset of the premask display relative to the onset time of the target: Priming effects were maximal when the target was presented out of phase with premask presentation (i.e., at interstimulus intervals displaced by 180 degrees relative to the 40-Hz rhythm of premask-frame presentation). Taken together, these results demonstrate the existence of a very short-term visual memory that oscillates at 40 Hz. The findings are discussed in the context of complementary psychological and neurophysiological findings related to visual-object coding and the role of gamma-band activity in the brain.

Adult↗
PubMed2000

Asparagine synthetase activity in paediatric acute leukaemias: AML-M5 subtype shows lowest activity.

Lack of sufficient cellular activity of asparagine synthetase (AS) in blast cells compared with normal tissue is thought to be the basis of the antileukaemic effect of L-asparaginase in acute lymphoblastic leukaemia (ALL). Although L-asparaginase is routinely used in ALL, its role and value in the treatment of acute myelogenous leukaemia (AML) is still being discussed. To evaluate the pharmacological basis for L-asparaginase treatment, we established pretreatment monitoring of the intracellular AS activity in blast cells of patients with AML and ALL. There was no general difference in AS activity between ALL and AML samples. Significantly lower AS activity, however, was found in the B-lineage ALL subgroups as well as AML-M5.

Adolescent↗
PubMed2000

Pegylated asparaginase (Oncaspar) in children with ALL: drug monitoring in reinduction according to the ALL/NHL-BFM 95 protocols.

Hypersensitivity reactions are relevant adverse effects of asparaginase therapy. Therefore, children treated with native Escherichia coli asparaginase in induction therapy of acute lymphoblastic leukaemia (ALL) or non-Hodgkin's lymphoma (NHL) were switched to the pegylated enzyme for reinduction under drug monitoring. Seventy children, including four patients with allergic reactions during induction, were given one dose of Oncaspar 1,000 U/m2 intravenously. Activity was determined every third or fourth day until it dropped below the limit of quantification. In current reinduction protocols [ALL/NHL-Berlin-Frankfurt-Münster (BFM) 95 trials], four doses of 10,000 U/m2 E. coli asparaginase deplete asparagine for about 2-3 weeks, therefore activities of >/= 100 U/l up to day 14 and >/= 50 U/l up to day 21 were targeted. In 66 patients without an allergic reaction during induction, the mean activity was 606 +/- 313 U/l, 232 +/- 211 U/l and 44 +/- 50 U/l after 1, 2 and 3 weeks respectively. In 44/66 patients, activity was >/= 100 U/l after 14 d. A rapid decline in activity was seen in the remaining 22 patients, including 8/22 patients who showed no activity after 1 week. Toxicity was low and comparable to the native enzymes but, in contrast to about 30% of hypersensitivity reactions with conventional reinduction therapy, no allergic reaction was seen. Substituting 4 x 10,000 U/m2 asparaginase medac for one dose of 1,000 U/m2 Oncaspar was safe and well tolerated. Comparable pharmacokinetic treatment intensity was achieved in about two-thirds of patients.

Adolescent↗
PubMed2000

A fronto-posterior network involved in visual dimension changes.

Objects characterized by a unique visual feature may pop out of their environment. When participants have to search for such "odd-one-out" targets, detection is facilitated when targets are consistently defined within the same feature dimension (e.g., color) compared with when the target dimension is uncertain (e.g., color or motion). Further, with dimensional uncertainty, there is a cost when a given target is defined in a different dimension to the preceding target, relative to when the critical dimension remains the same. Behavioral evidence suggests that a target dimension change involves a shift of attention to the new dimension. The present fMRI study revealed increased activation in the left frontopolar cortex, as well as in posterior visual areas of the dorsal and ventral streams, specific to changes in the target dimension. In contrast, activation in the striate cortex was decreased. This pattern suggests control of cross-dimensional attention shifts by the frontopolar cortex, modulating visual cortical processing by increased activation in higher-tier visual areas and suppression of activation in lower-tier areas.

Adolescent↗
PubMed2000

Perceptual integration of motion and form information: evidence of parallel-continuous processing.

In three visual search experiments, the processes involved in the efficient detection of motion-form conjunction targets were investigated. Experiment 1 was designed to estimate the relative contributions of stationary and moving nontargets to the search rate. Search rates were primarily determined by the number of moving nontargets; stationary nontargets sharing the target form also exerted a significant effect, but this was only about half as strong as that of moving nontargets; stationary nontargets not sharing the target form had little influence. In Experiments 2 and 3, the effects of display factors influencing the visual (form) quality of moving items (movement speed and item size) were examined. Increasing the speed of the moving items (> 1.5 degrees/sec) facilitated target detection when the task required segregation of the moving from the stationary items. When no segregation was necessary, increasing the movement speed impaired performance: With large display items, motion speed had little effect on target detection, but with small items, search efficiency declined when items moved faster than 1.5 degrees/sec. This pattern indicates that moving nontargets exert a strong effect on the search rate (Experiment 1) because of the loss of visual quality for moving items above a certain movement speed. A parallel-continuous processing account of motion-form conjunction search is proposed, which combines aspects of Guided Search (Wolfe, 1994) and attentional engagement theory (Duncan & Humphreys, 1989).

Adolescent↗
PubMed2000

Object-based selection operates on a grouped array of locations.

In two experiments, space- and object-based selection effects were investigated, using variants of the ring-cuing paradigm of Egly and Homa (1984). The results revealed significant cuing modulation for nonring configurations of target locations spanning a range of retinal eccentricities, with the cuing effects independent of eccentricity and confined to the configuration of locations (rather than extending to locations within the space enclosed by the cued configuration). These results are consistent with object-based selection operating on a grouped spatial array (Vecera & Farah, 1994). Object selection may be based on a supradimensional saliency map representation of the field, modulated by feature-specific segmentation mechanisms (e.g., an object may be made salient on the basis of its color). Complex objects may be represented by grouped saliency signals. In this way, a two-dimensional spatial (saliency) representation may provide the common format for object-based selection, prior to full object definition.

Adult↗
PubMed1999

Pharmacokinetic dose adjustment of Erwinia asparaginase in protocol II of the paediatric ALL/NHL-BFM treatment protocols.

Native forms of asparaginase stem from different biological sources. Previously reported data from children treated with Erwinase showed significantly lower trough levels and pharmacokinetic dose intensity than after E. coli-derived preparations. Hence, schedule optimization was initiated to achieve relevant serum activities. 21 children on reinduction therapy received Erwinase on Mondays, Wednesdays and Fridays for 3 weeks (9 x 20000 IU/m2 i.v.) instead of 4x 10 000IU/m2 of E. coli asparaginase (twice weekly for 2 weeks). Asparaginase trough activities were measured as the primary parameter, targeting 100-200 IU/I after 2 d and >50 IU/l after 3 d. Concurrently, asparagine trough concentrations were monitored. The mean trough activity was 156+/-99 IU/l, with 2/108 samples showing no detectable activity. Regarding trough levels per individual (three or more measurements/patient), means ranged from 52+/-29 to 276+/-114 IU/l (20 patients, 106 samples), with nine, six, and five children inside, below, and above the target range, respectively. The mean 3 d trough activity was 50+/-39 IU/l (20 patients, 51 samples). In 11 of these samples no activity was measurable. Mean trough activities calculated per individual ranged from < 20-84+/-30 IU/l (14 patients, 42 samples) with seven children below the target limit of 50 IU/l and asparagine concentrations <0.2 - 1.5microM. We concluded that an increased dose of 9x20000 IU/m2 of Erwinia asparaginase within 3 weeks resulted in a pharmacokinetic dose intensity comparable to former observations made with 4 x 10 000IU/m2 of the E. coli product Crasnitin which is no longer marketed. High interindividual variability and the phenomenon of 'silent' inactivation necessitate monitoring wherever possible.

Antineoplastic Agents↗
PubMed1999

Searching for impossible objects: processing form and attributes in early vision.

In five experiments, we investigated the extent to which form (shape) and metric attributes (three-dimensional, 3-D, orientation), both defined by relations between line elements, are processed in early vision. Search for a target defined by an abstract property of form (i.e., impossibility) was slow and serial. In contrast, search for a 3-D orientation target was considerably easier. Subsequent experiments suggest that this difference reflects the fact that 3-D orientation is derivable from localized sets of lines, whereas impossibility is an idiosyncratic property of the complete set of relations between lines. We conclude that only "gross" aspects of form are available in early vision as the complete set of line relations is not processed preattentively. However, localized processing of line relations is sufficient to derive 3-D orientation.

Analysis of Variance↗
PubMed1999

Attentional localization prior to simple and directed manual responses.

The relationship between attention and the programming of motor responses was investigated, using a paradigm in which the onsets of targets for movements were preceded by peripheral attentional cues. Simple (button release) and reaching manual responses were compared under conditions in which the subjects either made saccades toward the target location or refrained from making eye movements. The timing of the movement onset was used as the dependent measure for both simple and reaching manual responses. Eye movement latencies were also measured. A follow-up experiment measured the effect of the same peripheral cuing procedure on purely visual processes, using signal detection measures of visual sensitivity and response bias. The results of the first experiment showed that reaction time (RT) increased with the distance between the cued and the target locations. Stronger distance effects were observed when goal-directed responses were required, which suggests enhanced attentional localization of target positions under these conditions. The requirement to generate an eye movement response was found to delay simple manual RTs. However, mean reaching RTs were unaffected by the eye movement condition. Distance gradients on eye movement latencies were relatively shallow, as compared with those on goal-directed manual responses. The second experiment showed that the peripheral cue had only a very small effect on visual detection sensitivity in the absence of directed motor responses. It is concluded that cue-target distance effects with peripheral cues are modulated by the motor-programming requirements of the task. The effect of the peripheral cue on eye movement latencies was qualitatively different from that observed on manual RTs, indicating the existence of separate neural representations underlying both response types. At the same time, the interactions between response modalities are consistent with a supramodal representation of attentional space, within which different motor programs may interact.

Adult↗
PubMed1999

Transgenic mice expressing a human apolipoprotein[a] allele.

The most important determinant of plasma levels of Lp[a] are sequence differences at the highly polymorphic apolipoprotein[a] (apo[a]) locus. To define the sequences that mediate the regulation of apo[a] expression, we cloned a 370 kb DNA fragment that included a 130 kb apo[a] gene, and 40 kb 5'- and 200 kb 3'-flanking region from an individual with high plasma levels of Lp[a] using a YAC vector. This genomic clone was used to generate transgenic mice. In the YAC-apo[a] transgenic mouse, apo[a] was only expressed in the liver, as it is in humans. The mean serum level of apo[a] in 4-week-old YAC-apo[a] transgenic mice was 20 mg/dl. In the female mice the levels of apo[a] varied over a 1.5-fold range during the 4-day estrus cycle and the levels correlated directly with serum progesterone levels. The serum levels of apo[a] decreased to almost undetectable level in male mice after puberty and this decrease was reversed by castration. Ingestion of a high-fat diet resulted in a approximately 100-fold fall in hepatic apo[a] mRNA levels and >60-fold decrease in serum apo[a] levels. To delimit the control elements that mediate tissue-specific and sex hormone-responsive apo[a] transcription, we derived a reporter YAC in which 40 kb of 5' flanking sequences from the cloned apo[a] allele were linked to a luciferase reporter gene. Analysis of four independent transgenic lines revealed no hepatic luciferase expression, suggesting that important cis -acting elements located outside the apo[a] 5'-flanking region are necessary for in vivo expression of apo[a].

Alleles↗
PubMed1998

Drosophila morphogenesis: orchestrating cell rearrangements.

Changes in shape of individual cells need to be coordinated to generate the movements of cell groups and sheets that are so important in morphogenesis. Recent results have shown that, during Drosophila gastrulation, multiple signalling pathways act to orchestrate the complex cell rearrangements.

Animals↗
PubMed1998

Intracellular metabolism of human apolipoprotein(a) in stably transfected Hep G2 cells.

Lipoprotein(a) [Lp(a)] consists of LDL and the glycoprotein apolipoprotein(a) [apo(a)], which are covalently linked via a single disulfide bridge. The formation of Lp(a) occurs extracellularly, but an intracellular assembly in human liver cells has also been claimed. The human apo(a) gene locus is highly polymorphic due to a variable number of tandemly arranged kringle IV repeats. The size of apo(a) isoforms correlates inversely with Lp(a) plasma concentrations, which is believed to reflect different synthesis rates. To examine this association at the cellular level, we analyzed the subcellular localization and fate of apo(a) in stably transfected HepG2 cells. Our results demonstrate that apo(a) is synthesized as a precursor with a lower molecular mass which is processed into the mature, secreted form. The retention times of the precursor in the ER positively correlated with the sizes of apo(a) isoforms. The mature form was observed intracellularly at low levels and only in the Golgi apparatus. No apo(a) was found to be associated with the plasma membrane. Under temperature-blocking conditions, we did not detect any apo(a)/apoB-100 complexes within cells. This finding was confirmed in HepG2 cells transiently expressing KDEL-tagged apo(a). The precursor and the mature forms of apo(a) were found in the ER and Golgi fractions, respectively, also in human liver tissue. From our data, we conclude that in HepG2 cells the apo(a) precursor, dependent on the apo(a) isoform, is retained in the ER for a prolonged period of time, possibly due to an extensive maturation process of this large protein. The assembly of Lp(a) takes place exclusively extracellularly following the separate secretion of apo(a) and apoB.

Apolipoproteins A↗
PubMed1998

Use of L-asparaginase in childhood ALL.

Owing to the high efficacy of L-asparaginase in the treatment of acute lymphatic leukaemia the enzyme was introduced into the chemotherapy schedules for remission induction of this disease shortly after results of large-scale clinical trials had become available. Since asparaginase monotherapy was associated with a high response rate but short remission duration, the enzyme is currently employed within the framework of combination chemotherapy schedules which achieve treatment response in about 90% and long-term remissions in the majority of patients. Recently initiated clinical trials have still confirmed the eminent value of asparaginase in the combination chemotherapy of acute lymphatic leukaemia and of some subtypes of non-Hodgkin lymphoma, and its important role as an essential component of multimodal treatment protocols. Despite the unique mechanism of action of this cytotoxic substance which shows relative selectivity with regard to the metabolism of malignant cells, some patients experience toxic effects during asparaginase therapy. Immunological reactions toward the foreign protein include enzyme inactivation without any clinical manifestations as well as anaphylactic shock. Severe functional disorders of organ systems result from the impaired homeostasis of the amino acids asparagine and glutamine. The changes affecting the proteins of the coagulation system have considerable clinical impact as they may induce bleeding as well as thromboembolic events and may be associated with life-threatening complications when the central nervous system is involved. Risk factors predisposing to thromboembolic complications are hereditary resistance against activated protein C and any other hereditary thrombophilia. Other organ systems potentially affected by relevant functional disorders are the central nervous system, the liver, and the pancreas, with patients who have a history of pancreatic disorders carrying an especially high risk of developing pancreatitis. Studies on the mechanisms of action and the occurrence of resistance phenomena have shown that a treatment response may only be expected if the malignant cells are unable to increase their asparagine synthetase activity to an extent providing enough asparagine to the cell; one may thus conclude that the enzyme-induced asparagine depletion of the serum constitutes the decisive cytotoxic mechanism. Independent of the asparagine depletion related cytotoxicity however, there are other mechanisms of clinical relevance like induction of apoptosis. Besides this, further influences on signal transduction cannot be excluded. Only few publications have dealt with the question of minimum trough activities to be ensured before each subsequent asparaginase dose in order to maintain uninterrupted asparagine depletion under treatment, and answers to this problem are not definitive. Clinical studies using enzymes from E. coli strains indicate that a trough activity of 100 U/l will suffice for complete asparagine depletion of the fluid body compartments with the preparations studied. These findings have been transferred to enzymes from other E. coli strains as well as those isolated from Erwinia chrysanthemi and to the PEG-conjugated E. coli asparaginases. It might be desirable to countercheck the results for confirmation or correction. The dosage and administration schedule of the various enzyme preparations required for complete asparagine depletion over a period of time have been insufficiently defined. While pharmacokinetic studies showed clinically relevant differences in biological activity and activity half-lives for enzymes from different biological sources, the findings of recently published clinical trials indicate that the therapeutic efficacy is affected when different asparaginase preparations are given by identical therapy schedules. (ABSTRACT TRUNCATED)

Antineoplastic Agents↗