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Biomedical subjects

B Fischer

Publications and source records attributed to B Fischer.

At least 55 records · Page 3Linked to original sources
PubMed2000

Acidic pH inhibits non-MHC-restricted killer cell functions.

Immunotherapeutic strategies in advanced stages of solid tumors have generally met with little success. Various mechanisms have been discussed permitting the escape of tumor cells from an effective antitumoral immune response. Solid tumors are known to develop regions with acidic interstitial pH. In a recent study performed in the human system, we were able to demonstrate that non-MHC-restricted cytotoxicity is inhibited by an acidic microenvironment. To get more insight into the mechanisms leading to this reduced cytotoxic activity, we have now investigated the influence of an acidic extracellular pH (pH(e)) on the killing process in detail. Unstimulated PBMC and LAK cells were used as effector cells. Both populations are able to kill tumor cells in a MHC-independent manner via perforin/granzymes or TNFalpha, whereas only IL-2-activated cells can use the killing pathway via Fas/FasL. We studied the influence of a declining pH(e) on the different killing pathways against TNFalpha-sensitive and -resistant, as well as Fas-positive and -negative, target cells. Experiments in the absence of extracellular Ca(2+) were used to discriminate the Ca(2+)-dependent perforin-mediated killing. Here we show that the release of perforin/granzyme-containing granules, the secretion of TNFalpha, and also the cytotoxic action of Fas/FasL interaction or of membrane-bound TNFalpha were considerably inhibited by declining pH(e). Furthermore, the secretion of the activating cytokine IFNgamma, as well as the release of the down-regulating cytokines IL-10 and TGF-beta(1), was strictly influenced by surrounding pH. As a pH(e) of 5.8 resulted in a nearly complete loss of cytotoxic effector cell functions without affecting their viability, we investigated the influence of pH(e) on basic cellular functions, e.g. , mitochondrial activity and regulation of intracellular pH. We found an increasing inhibition of both functions with declining pH(e). Therefore, an acidic pH(e) obviously impairs fundamental cellular regulation, which finally prevents the killing process. In summary, our data show a strict pH(e) dependence of various killer cell functions. Thus, an acidic microenvironment within solid tumors may contribute to the observed immunosuppression in vivo, compromising antitumoral defense and immunotherapy in general, respectively.

Acids↗
PubMed2000

Social costs of untreated opioid dependence.

Using cost-of-illness methodology applied to a comprehensive survey of 114 daily opiate users not currently in or seeking treatment for their addiction, we estimated the 1996 social costs of untreated opioid dependence in Toronto (Ontario, Canada). The survey collected data on social and demographic characteristics, drug use history, physical and mental health status, the use of health care and substance treatment services, drug use modality and sex-related risks of infectious diseases, sources of income, as well as criminality and involvement with the law enforcement system. The annual social cost generated by this sample, calculated at Canadian $5.086 million, is explained mostly by crime victimization (44.6%) and law enforcement (42.4%), followed by productivity losses (7.0%) and the utilization of health care (6.1%). Applying the $13,100 cost to the estimated 8,000 to 13,000 users and 2.456 million residents living in Toronto yields a range of social cost between $43 and $69 per capita.

Cost of Illness↗
PubMed2000

Optomotor and neuropsychological performance in old age.

While a delayed initiation of visually guided saccades with increasing age has been documented in a number of studies, little research has been done on the control of antisaccades. The present study investigates aging effects on the control of visually guided saccades (prosaccades) and antisaccades as well as a selection of neuropsychological functions by the cross-sectional comparison of 14, 22, and 16 participants aged 20-35 years, 59-73 years, and 74-88 years, respectively. The geriatric and neurological status of the elder participants (including evidence from computed tomography, electroencephalography, and neurological soft signs) was assessed. In four task blocks of 200 trials each, pro- and antisaccades were elicited under the 200-ms-gap and overlap conditions. Left- and right-sided stimuli were presented in random order at 4 degrees, and the order of the task blocks was varied within each age group. In addition, the Wisconsin card-sorting test (WCST) and working memory, go-nogo discrimination, alertness, and stimulus-response incompatibility tests were administered. Participants aged 59-73 years exhibited widespread reductions of optomotor and neuropsychological performance, with greatest effect sizes of age differences in the optomotor parameters and the WCST measures. A further decay after the age of 73 years was discernible in those optomotor functions reflecting saccade disinhibition (in particular, directional errors during the antisaccade task and premature responses) and the performance in some neuropsychological tests. In line with previously published reports, variance in optomotor performance could be explained by two factors, accounting for a total of 76% of the age variance. Our results suggest that the investigation of saccade control may be a highly sensitive tool for neurodevelopmental aging research.

Adult↗
PubMed2000

Expression of proto-oncogenes in bovine preimplantation blastocysts.

Proto-oncogenes are involved in the regulation of gene expression, for example after ligand binding to growth factor receptors. Expression of the proto-oncogenes c-fos, c-jun, c-ha-ras and c-myc was studied in in vivo grown and in vitro cultured bovine preimplantation blastocysts employing RT-PCR, ribonuclease protection assay and immunohistochemistry. Thirteen- and 14- day-old preimplantation blastocysts, i.e. stages before and during trophoblast elongation, were used. In in vivo-grown blastocysts c-fos, c-jun and c-ha-ras transcripts as well as c-Fos, c-Jun and c-Myc proteins were detected in all stages studied. Cultured blastocysts were treated with 10 nM epidermal growth factor and 10 nM transforming growth factor-alpha simultaneously. Epidermal growth factor and transforming growth factor-alpha treatment induced c-fos mRNA and c-Myc protein expression. The induction of downstream targets of the epidermal growth factor receptor by epidermal growth factor and transforming growth factor-alpha indicates a functional epidermal growth factor signal transduction pathway in elongating bovine blastocysts.

Animals↗
PubMed2000

Ultrasonic characterization of liquids using resonance antireflection

This paper presents an ultrasonic method for measuring the density of liquids with a solid layer separating a reference fluid and a test fluid. By adjusting the frequency of the exciting signal according to the thickness of the layer, it is possible to generate destructive interference of the waves reflected at the first and at the second boundary of the layer. Thus, the layer appears to vanish for the incident waves. The resulting echo signal depends only on the acoustic impedances of the reference fluid and the test fluid and the density which is of interest can be extracted. Short and long-term drifts of the electronics and the ultrasonic transducer implied are eliminated by using the well-known pulse-echo technique with additional frontwave detection.

Journal Article↗
PubMed2000

On the production and correction of involuntary prosaccades in a gap antisaccade task.

In an antisaccade task, where saccades in the direction opposite of a suddenly presented stimulus are required, certain numbers of prosaccades can occur. The hypothesis is put forward that poor fixation and poor voluntary saccade control constitute two independent sources for the errors. This possibility is investigated by including the corrections of the errors in the analysis. First, the eye movements of 346 normal subjects (group N) performing a gap antisaccade and an overlap prosaccade task were measured. For each subject the proportion of express saccades in the overlap prosaccade task and the proportion of prosaccades in the gap antisaccade task were determined. The data of 150 subjects with more than 20% proerrors were divided into two groups: group A with relatively many, group B with relatively few express saccades in the overlap prosaccade task. Group A subjects produced their errors after significantly shorter reaction times and they corrected their errors significantly faster and more often than group B subjects. Second, we analysed the data of three groups of subjects: the complete normal group N, a group D of dyslexic subjects (n=343), and a group T containing all subjects irrespective of their cognitive achievements (n=780). A highly significant negative correlation exists between the correction rates and the error rates. A factor analysis of the variables performed for each group separately results in only two factors, one describing prosaccade the other antisaccade control. Only the error rate contributes significantly to both factors indicating that high errors may have two independent reasons.

Adolescent↗
PubMed2000

Generation of antibodies directed against the low-immunogenic peptide-toxins microcystin-LR/RR and nodularin.

The preparation of antibodies against the liver toxin microcystin, as described here, is of major importance for its detection and purification in food and water, and for a therapeutic approach to neutralize the toxin by passive immunization. Microcystin-LR (MLR) and microcystin-RR (MRR) were purified from cyanobacterial cell materials by extraction, Sephadex LH-20-, ODS silica gel-, ionic exchange and RP-HPLC-chromatography. In order to reduce the toxicity for parenteral administration, microcystins were coupled by the carbodiimide method to poly-L-lysine (PLL(50.000)). Mice and rabbits were immunized with the conjugates in the presence of two lipopeptide immunoadjuvants (P(3)CSK(4) and P(3)CS-T(h)). High MLR-specific antibody levels were observed after parenteral coadministration of antigen and lipopeptides, whereas no anti-MLR antibodies were obtained with free microcystin or the microcystin-PLL(50.000)-conjugate in the absence of lipopeptide. In oral immunization, coadministration of antigen and adjuvants resulted in an accelerated development of anti MLR-specific antibodies and high antibody levels. Using the antisera, we could detect different microcystins and nodularin down to a concentration range of 10-50 ng/ml by a competitive inhibition ELISA; detection of microcystins in crude cell preparations was also possible. Furthermore, microcystins from different sources could be detected and discriminated from cyclic cyanopeptolines.

Administration, Oral↗
PubMed2000

T cell activation by recombinant FcepsilonRI gamma-chain immune receptors: an extracellular spacer domain impairs antigen-dependent T cell activation but not antigen recognition.

T cells can be endowed with antigen specificity by grafting with a chimeric receptor consisting of an extracellular antigen binding moiety (scFv) derived from an antibody and an intracellular signaling domain. Conflicting data exist on the impact of an extracellular spacer domain between the antigen binding and the signaling domain with respect to cellular activation. Here, we recorded conjugate formation and antigen-driven cellular activation of T cells grafted with receptor molecules that contain the same antigen binding site (anti-CD30 HRS3-scFv) and signaling domain (FcepsilonRI gamma-chain), however, with and without an IgG1 CH2CH3 (Fc) spacer domain between the scFv and transmembrane moiety. Receptors of both configurations mediate equally efficient conjugate formation between receptor grafted T cells and antigen-positive target cells. Specific signaling by the spacer containing receptor, however, is blocked by five- to 10-fold lower concentrations of soluble antigen than by the spacer-less receptor indicating a higher avidity of the spacer containing receptor to soluble antigen. In contrast, cellular activation upon binding to antigen-positive cells is mediated more efficiently by the spacer-less receptor. This demonstrates that the extracellular spacer domain impairs antigen-dependent cellular activation by the chimeric immune receptor, but not intercellular conjugate formation.

Animals↗
PubMed2000

An acidic microenvironment impairs the generation of non-major histocompatibility complex-restricted killer cells.

The microenvironment within solid tumours has often been shown to exhibit an acidic local pH. In recent studies we could demonstrate that an acidic extracellular pH (pHe) inhibits the non-major histocompatibility complex (MHC) -restricted cytotoxicity of immunocompetent effector cells. However, within tumours the activation of cytotoxic cells may already be impaired by low pHe. Therefore, we investigated the influence of acidic conditions on the generation of active killer cells. The cytotoxic activity of natural killer (NK) as well as lymphokine-activated killer (LAK) cells against K562, Daudi and Raji cells was analysed after an activation period of 3 days at pHe 7.2-6.5. A minor reduction of pHe from 7.2 to 7.0 during the culture period resulted in a strong inhibition of the natural cytotoxicity of NK cells. Furthermore, acidic pHe below 7.2 prevented the generation of activated LAK cells by interleukin-2 (IL-2). The cytotoxic capacity could not be reconstituted if cells cultured at a pHe of 6.5 were returned to physiological pH for another 24 hr. Analysis of the cellular subtypes within the various cultures did not reveal differences regarding the frequencies of NK cells, CD8+ T cells, or CD4+ T cells. However, an acidic pHe clearly inhibited the activation-induced increase of relevant adhesion molecules. The production of cytokines which are involved in the regulation of the cytotoxic process (tumour necrosis factor-alpha, interferon-gamma, IL-10, IL-12 and transforming growth factor-beta1) was also affected by pHe, as their release was strongly inhibited at pHe 7.0. Furthermore, we observed a considerable decrease in the metabolic activity of effector cells at acidic pHe. In summary, our findings suggest that an acidic microenvironment impairs the induction of an anti-tumoral immune response within solid tumours.

CD4-Positive T-Lymphocytes↗
PubMed2000

Receptor-mediated effects of chlorinated hydrocarbons.

This short review summarizes some recent findings on arylhydrocarbon (dioxin) receptor expression during early pregnancy in mammals. The arylhydrocarbon receptor is a ligand-activated transcription factor and was originally described as a mediator of the toxic effects of dioxins and other chlorinated hydrocarbons such as polychlorinated biphenyls. Orally administered polychlorinated biphenyls accumulate in uterine secretions, in the pre-implantation blastocyst, in the foetus and in the placenta. Coplanar polychlorinated biphenyls are known ligands of the arylhydrocarbon receptor. Deletion experiments indicate physiological roles of the arylhydrocarbon receptor during development and for the function of various organs. During early pregnancy, the arylhydrocarbon receptor is specifically expressed in pre-implantation embryos, during blastocyst differentiation and implantation, in the endometrial epithelium and in the decidua cells of the placenta. Coplanar polychlorinated biphenyls were found to be embryotoxic in low doses, i.e. in doses found in tissues of not specifically exposed individuals originating from xenobiotic environmental background contamination. In initial experiments, low-dose exposure of rabbit blastocysts to coplanar polychlorinated biphenyls in vitro did not induce transcriptional changes of the so-called arylhydrocarbon receptor gene battery. The embryological and toxicological implications of the findings are discussed.

Animals↗
PubMed2000

Voluntary saccadic control in dyslexia.

The role of eye-movement control in dyslexia is still unclear. Recent studies, however, confirmed that dyslexics show poor saccadic control in single and sequential target tasks. In the present study we investigated whether dyslexic subjects are impaired on an antisaccade task requiring saccades against the direction of a stimulus. Altogether, 620 subjects between the ages of 7 and 17 years were classified as dyslexics (N = 506) or control subjects (N = 114) on the grounds of the discrepancy between their intellectual abilities and reading/spelling achievements. All subjects performed an overlap prosaccade and a gap antisaccade task with 100 trials to each side of stimulation in random order. Variables analysed were the overall saccadic reaction time of both tasks; and from the antisaccade task the number of errors (prosaccades), the number of corrected errors, and the number of trials in which the subjects still failed to reach the side opposite the stimulus even after two saccades. An analysis of variance was carried out taking into account the development of saccadic behaviour with age and the differences between the groups. The results confirm development of saccade control with age, especially in the voluntary component (a frontal-lobe function) for both groups, but indicate that the antisaccade task performance, as measured by the error and the correction rate, is significantly worse in the dyslexic group at ages above 8 years. Up to 50% of the dyslexics performed the antisaccade task 1.5 standard deviations below the mean of the controls.

Adolescent↗
PubMed2000

Dynamic visual perception of dyslexic children.

This study describes the capacity of children to detect fast changes of a small visual pattern. Three visual detection tasks for a group of normally reading (N = 140) and another group of dyslexic children (N = 366) in the age range of 7 to 16 years have been used. All three tasks require the detection of the fast changing orientation of a small pattern before it disappears. In one task, stationary fixation was required, because the orientation changes took place always at the same location. In the saccade condition, the pattern was displaced suddenly to one or the other side and a saccade was required to detect the orientation. In a third condition, a distractor was presented at one side shortly before the oriented pattern appeared at the opposite side. In this case, an antisaccade with respect to the distractor was required. In all three conditions, the dyslexic group as a whole performed significantly below the level of the control group. The performance improved with age in both groups. The differences between the test and control group were largest in the distractor condition. When compared with eye-movement performance in an antisaccade task, a parallel development of the performance of both tasks was observed in both groups. The study shows that a certain percentage of dyslexic children has difficulties in the perception of fast changing stimuli, a task presumably challenging the magnocellular system.

Adolescent↗
PubMed2000

Effects of visual training on saccade control in dyslexia.

This study reports the effects of daily practice of three visual tasks on the saccadic performance of 85 dyslexic children in the age range of 8 to 15 years. The children were selected from among other dyslexics because they showed deficits in their eye-movement control, especially in fixation stability and/or voluntary saccade control. Their eye movements were measured in an overlap prosaccade and a gap antisaccade task before and after the training. The three tasks used for the training included a fixation, a saccade, and a distractor condition. In any of these tasks, the subject had to detect the last orientation of a small pattern which rapidly changed its orientation between up, down, right, and left, before it disappeared after some time. The task was to press one of four keys corresponding to the last orientation. The visual pattern was presented on an LCD display of a small hand-held instrument given to the children for daily use at home. The results indicate that daily practice improved not only the perceptual capacity, but also the voluntary saccade control, within 3 to 8 weeks. After the training, the group of dyslexics was no longer statistically different from the control group.

Adolescent↗
PubMed2000

Delayed and blunted induction of mRNA for tissue plasminogen activator in the brain of old rats following pentylenetetrazole-induced seizure activity.

The ability of the rodent brain to support plasticity-related phenomena declines with increasing age. Here we investigated the extent to which old rats retain the capacity to initiate transcription for immediate early genes, particularly as it relates to brain plasticity, in response to a strong stimulus. The intraperitoneal administration of pentylenetetrazole (PTZ) to rats of various ages evoked tonic-clonic seizures. Using an RNA gel-blot and in situ hybridization analysis, we found that 1 hour after the onset of seizure, messenger RNA (mRNA) for tissue plasminogen activator (TPA) was increased approximately 3.7-fold in the hippocampi of 3-month-old rats. The levels of TPA mRNA in the hippocampi and cortices of 3-month-old rats returned to control levels by 3 hours after PTZ administration. The levels of TPA mRNA increased 2.5-fold in the hippocampi of 18-month-old rats and 1.8-fold in the brains of the 28-month-old-rats at 3 hours and returned to basal levels by 15 hours following PTZ treatment. Quantitatively similar increases were calculated for the cortex. At peak induction the transcripts were localized throughout the cortical layers of the 3-month-old rats, whereas the TPA mRNA expression was restricted to cortical layer V of the older rats. Our results suggest that although the aging brain retains the capacity to respond to chemically induced seizures, the induction of TPA mRNA is temporarily delayed and the levels are diminished with increasing age. Because TPA has been implicated in neuronal plasticity, this finding suggests that immediate early genes are important factors in the limited plasticity of the aging brain.

Aging↗
PubMed2000

Oxygen stress increases prolyl cis/trans isomerase activity and expression of cyclophilin 18 in rabbit blastocysts.

The peptidyl-prolyl cis/trans isomerase (PPIase) activity and the expression of cyclophilins were studied in 6-day-old rabbit preimplantation embryos cultured under physiological and increased oxygen concentrations of 5% and 20% O(2), respectively. The PPIase activity was completely inhibited by cyclosporin A (CsA). The inhibitor of FK506-binding proteins, rapamycin, had no effect on the PPIase activity, indicating that the PPIase activity in rabbit blastocysts originates from cyclophilins. Using CsA affinity chromatography, only one cyclophilin with a molecular mass of about 17.8 kDa was separated. The cDNA of rabbit cyclophilin was cloned and sequenced. Analysis of the 682-base pair cDNA revealed an open reading frame coding for a polypeptide of 164 amino acid residues with a molecular weight of 17.83 kDa. Homologies of 90% and 96% for the cDNA and amino acid sequence, respectively, to the human CyP18 were found, suggesting that the novel rabbit cyclophilin is a member of the CyP18 family (rabCyP18). The transcription level of rabCyP18 mRNA was 8.3 +/- 0.6 pg in 100 ng total RNA in noncultured blastocysts. In vitro culture with moderate oxygen stress (20% O(2)) resulted in a 1.5-fold increase in rabCyP18 transcription and an increased PPIase activity compared to that of blastocysts cultured with 5% O(2). Increase in transcription rate and PPIase activity by oxygen stress suggests an involvement of CyP18 in oxygen defense in rabbit preimplantation embryos.

Amino Acid Sequence↗
PubMed2000

Ruminant relaxin in the pregnant one-humped camel (Camelus dromedarius).

We have determined the cDNA sequence of preprorelaxin in the pregnant one-humped camel by employing reverse transcription- and rapid amplification of cDNA ends-polymerase chain reaction. Camel preprorelaxin consisted of 600 base pairs (bp) encoding a protein of 199 amino acids (aa) with a signal peptide of 25 aa (75 bp), a B domain of 28 aa (84 bp), a C domain of 121 aa (366 bp), and an A domain of 24 aa (72 bp). The N terminus of the C domain of camel prorelaxin contained the unique proline-rich repetitive sequence (-RPAP)(3)-(-K/RPAL-)(2), and within the B domain the classical -GRELVR- receptor binding motif was found. Camel preprorelaxin showed highest homology with porcine (74.6%) and equine (65.4%) relaxin. The ovary and the uteroplacental unit were a dual source of relaxin in the pregnant dromedary. Within the ovary, weak expression of relaxin was detected in large luteal cells of the mature corpus luteum. In the ovarian follicles, immunoreactive relaxin, but not relaxin mRNA, was detected in the granulosa and theca interna cell layer. Beginning at around Day 93 of gestation and coinciding with increasing interdigitation of the fetal villus with the underlying maternal endometrium, uterine luminal epithelial cells in the uteroplacental tissue expressed relaxin. Weak expression of immunoreactive relaxin, but not relaxin mRNA, was observed in villous trophoblast cells. Pseudostratified trophoblast cells at the base of the placental villi and multinucleate giant cells did not express relaxin.

Amino Acid Sequence↗
PubMed2000

Experimental observation of localization in the spatial frequency domain of a kicked optical system

An experimental realization of an optical "kicked" system is presented. It exhibits localization analogous to that of the quantum "kicked-rotor." In the experiment, free space propagating light is periodically kicked by thin sinusoidal phase gratings, which produce high order diffractions and tend to increase the spatial frequency band. The wave property suppresses this diffusive spread. The localization is realized in a regime near anti-resonance of the system, which is also studied theoretically. The behavior in this regime is similar to that of electronic motion in incommensurate potentials. A crucial part of the experimental system is the grating in-phase positioning, which is done by using the Talbot effect.

Journal Article↗