The effect of combined treatment with total lymphoid irradiation, cyclosporin A, and anti-CD4 monoclonal antibodies in a hamster-to-rat heart transplantation model.
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Animals↗
Biomedical subjects
C Koch
Publications and source records attributed to C Koch.
A detailed model of the primary visual pathway in the cat: comparison of afferent excitatory and intracortical inhibitory connection schemes for orientation selectivity.
In order to arrive at a quantitative understanding of the dynamics of cortical neuronal networks, we simulated a detailed model of the primary visual pathway of the adult cat. This computer model comprises a 5 degrees x 5 degrees patch of the visual field at a retinal eccentricity of 4.5 degrees and includes 2048 ON- and OFF-center retinal beta-ganglion cells, 8192 geniculate X-cells, and 4096 simple cells in layer IV in area 17. The neurons are implemented as improved integrate-and-fire units. Cortical receptive fields are determined by the pattern of afferent convergence and by inhibitory intracortical connections. Orientation columns are implemented continuously with a realistic receptive field scatter and jitter in the preferred orientations. We first show that realistic ON-OFF-responses, orientation selectivity, velocity low-pass behaviour, null response, and responses to spot stimuli can be obtained with an appropriate alignment of geniculate neurons converging onto the cortical simple cell (Hubel and Wiesel, 1962) and in the absence of intracortical connections. However, the average receptive field elongation (length to width) required to obtain realistic orientation tuning is 4.0, much higher than the average observed elongation. This strongly argues for additional intracortical mechanisms sharpening orientation selectivity. In the second stage, we simulated five different inhibitory intracortical connection patterns (random, local, sparse-local, circular, and cross-orientation) in order to investigate the connection specificity necessary to achieve orientation tuning. Inhibitory connection schemes were superimposed onto Hubel and Wiesel-type receptive fields with an elongation of 1.78. Cross-orientation inhibition gave rise to different horizontal and vertical orientation tuning curves, something not observed experimentally. A combination of two inhibitory schemes, local and circular inhibition (a weak form of cross-orientation inhibition), is in good agreement with observed receptive field properties. The specificity required to establish these connections during development is low. We propose that orientation selectivity is caused by at least three different mechanisms ("eclectic" model): a weak afferent geniculate bias, broadly tuned cross-orientation inhibition, and some iso-orientation inhibition. The most surprising finding is that an isotropic connection scheme, circular inhibition, in which a cell inhibits all of its postsynaptic target cells at a distance of approximately 500 microns, enhances orientation tuning and leads to a significant directional bias. This is caused by the embedding of cortical cells within a columnar structure and does not depend on our specific assumptions.(ABSTRACT TRUNCATED AT 400 WORDS)
Animals↗
Molecular basis of polymorphisms of human complement component C3.
C3 exhibits two common allotypic variants that may be separated by gel electrophoresis and are called C3 fast (C3 F) and C3 slow (C3 S). C3 F, the less common variant, occurs at appreciable frequencies only in Caucasoid populations (gene frequency = 0.20). An increased prevalence of the C3 F allele has been reported in patients with partial lipodystrophy, IgA nephropathy, and Indian childhood hepatic cirrhosis. Studies of the genomic organization of the human C3 gene led to the identification of a single change (C to G) between C3 S and C3 F at nucleotide 364 in exon 3. This leads, at the translation level, to the substitution of an arginine residue (positively charged) in C3 S for a glycine residue (neutral) in C3 F. This substitution results in a polymorphic restriction site for the enzyme HhaI. The resulting restriction fragment length polymorphism (RFLP) was investigated using genomic DNA, amplified using the polymerase chain reaction; there was absolute concordance between the genomic polymorphism and the distribution of C3 S and C3 F in 50 normal subjects. The molecular basis of a second structural polymorphism, defined by the monoclonal antibody HAV 4-1, was also characterized. The polymorphic determinant was identified at codon 314 in the exon 9 of the beta chain where a leucine residue (HAV 4-1+) is substituted for a proline residue (HAV 4-1-). Identification of the amino acid sequences of these polymorphic variants will facilitate characterization of possible functional differences between different allotypes of C3. Three RFLPs (BamHI, EcoRI, and SstI) were located to introns in the C3 gene. There was no allelic association between these three RFLPs, or between the RFLPs and the C3 F/S polymorphic site. Genetic equilibration of these polymorphisms has occurred within a gene of 41 kb.
Antibodies, Monoclonal↗
A two-dimensional analog VLSI circuit for detecting discontinuities in early vision.
A large number of computer vision algorithms for finding intensity edges, computing motion, depth, and color, and recovering the three-dimensional shape of objects have been developed within the framework of minimizing an associated "energy" or "cost" functional. Particularly successful has been the introduction of binary variables coding for discontinuities in intensity, optical flow field, depth, and other variables, allowing image segmentation to occur in these modalities. The associated nonconvex variational functionals can be mapped onto analog, resistive networks, such that the stationary voltage distribution in the network corresponds to a minimum of the functional. The performance of an experimental analog very-large-scale integration (VLSI) circuit implementing the nonlinear resistive network for the problem of two-dimensional surface interpolation in the presence of discontinuities is demonstrated; this circuit is implemented in complementary metal oxide semiconductor technology.
Algorithms↗
Treatment with total lymphoid irradiation, cyclosporin A and a monoclonal anti-T-cell antibody in a hamster-to-rat heart transplantation model: graft survival and morphological analysis.
Treatment with preoperative total lymphoid irradiation and post-transplant cyclosporin A has been shown to have a synergistic effect on graft survival in allo- and xenotransplantation. Specific monoclonal antibodies against T cells and T cell subpopulations could offer new ways of preventing graft rejection in xenotransplantation. Graft survival and histology were examined after total lymphoid irradiation plus cyclosporin A treatment versus cyclosporin A plus a monoclonal antibody in a concordant, heterotopic, hamster-to-rat heart transplantation model. Preoperative total lymphoid irradiation was given at a dose of 1.25 Gy, 12 times over a period of 3 weeks. Cyclosporin A at a dose of 12.5 mg/kg per day was administered perorally and OX-19, a pan T cell monoclonal antibody, was given as intraperitoneal injections at doses of 100 micrograms or 500 micrograms/kg per day from day 0 until graft rejection. While total lymphoid irradiation alone prolonged graft survival to 9.4 days, total lymphoid irradiation plus cyclosporin A extended graft survival to a mean of 22 days. Cyclosporin alone or combined with the monoclonal antibody could not increase graft survival significantly when compared to untreated animals, which rejected their grafts within 3.7 days. Vascular rejection was the characteristic morphological finding, even after some weeks of excellent graft function. In conclusion, total lymphoid irradiation and cyclosporin A had a synergistic effect on graft survival in this concordant xenotransplantation model, although recent impressive results from other groups could not be reproduced. Total lymphoid irradiation combined with cyclosporin A appears to delay a primary humoral graft rejection, while the mechanism of rejection, judged by histology, stays the same.
Analysis of Variance↗
Frequency of the delta F508 mutation on cystic fibrosis chromosomes in Denmark.
We have investigated the frequency of the delta F508 mutation on cystic fibrosis (CF) chromosomes in Denmark. Of 304 chromosome tested, 86.8% have the delta F508 mutation. The majority of the chromosomes with this mutation are found on chromosomes with the XV2c/KM19 haplotype B (97.3%), whereas 15/16 chromosomes with haplotype C have another mutation, confirming that only very few mutations will account for the majority of CF genes in the Danish population.
Cystic Fibrosis↗
Biophysical model of a Hebbian synapse.
We present a biophysical model of electrical and Ca(2+) dynamics following activation of N-methyl-D-aspartate (NMDA) receptors located on a dendritic spine. The model accounts for much of the phenomenology of the induction of long-term potentiation at a Hebbian synapse in hippocampal region CA1. Computer simulations suggested four important functions of spines in this Ca(2+)-dependent synaptic modification: (i) compartmentalizing transient changes in [Ca(2+)] to just those synapses that satisfy the conjunctive requirement for synaptic modification; (ii) isolating the spine head from changes in the [Ca(2+)] at the dendritic shaft; (iii) amplifying the concentration changes at those synapses; and (iv) increasing the voltage dependence of the processes underlying long term potentiation induction. This proposed role of spines in the regulation of Ca(2+) dynamics contrasts with traditional approaches to spine function that have stressed electronic properties. This model can be used to explore the computational implications of Hebbian synapses.
Animals↗
Clinical experiences with fusidic acid in cystic fibrosis patients.
A survey of Staphylococcus aureus lung infection in 243 patients with cystic fibrosis (CF) was conducted between 1986 and 1988. A total of 217 patients (89%) received 1605 courses of anti-staphylococcal therapy given during this period. The majority of courses comprised combined therapy with two anti-staphylococcal drugs. The combination of dicloxacillin and fusidic acid was employed most frequently. Some patients were given other anti-staphylococcal regimens, because of penicillin allergy (14 cases) or dyspeptic side effects with fusidic acid (21 patients). A small but significant increase in precipitins against S. aureus was observed during the study period. Bacterial resistance to the anti-staphylococcal drugs used remained at a low level (strains resistant to methicillin less than 0.1%, strains resistant to fusidic acid 1.2%). When the isolates were compared with 56,140 strains of S. aureus isolated from non-CF patients hospitalized in Denmark over the same period, no differences in phagetypes or in antibiotic resistance were seen, indicating that selection of strains and cross infection do not seem to be a major problem in CF patients.
Bacteriophage Typing↗
Some reflections on visual awareness.
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Animals↗
IgG subclass antibodies to Pseudomonas aeruginosa in sera from patients with chronic Ps. aeruginosa infection investigated by ELISA.
ELISAs using subclass-specific monoclonal antibodies were developed for the quantification of human IgG1, IgG2, IgG3 and IgG4 antibodies to Ps. aeruginosa. We investigated the pattern of IgG subclass antibodies against Ps. aeruginosa in serum from patients with cystic fibrosis (CF), other patients with chronic Ps. aeruginosa infection, and healthy controls. Healthy controls and patients with CF but without Ps. aeruginosa infection showed no or very low titres of antibodies against Ps. aeruginosa. In the early stage of chronic Ps. aeruginosa infection, antibody titres in all four subclasses were significantly higher than either normals or CF patients without infection. Other patients with Ps. aeruginosa infection showed the same increased level of IgG subclass antibodies as CF patients in an early stage of infection. Sixteen patients (eight in good and eight in poor clinical condition) have been followed for an average of 13 years with multiple serum samples covering the pre-infection, early and late stages of chronic infection. Patients in a poor clinical condition showed significantly higher levels of IgG3 antibodies in the first year of infection and 2 years later also had significantly higher IgG2 antibody levels. We conclude that elevated levels of IgG2 and IgG3 antibodies to Ps. aeruginosa are a sign of poor prognosis in CF.
Adolescent↗
Bacteria and endotoxin enhance basophil histamine release and potentiation is abolished by carbohydrates.
Histamine release caused by anti-IgE, specific antigens and calcium ionophore A23187 was examined in leukocyte suspensions from healthy individuals and patients allergic to house dust mite and birch pollen. Staphylococcus aureus and LPS from Salmonella typhimurium were found to cause a synergistic enhancement of the release. The potentiation of mediator release by the bacteria and the endotoxin depends on a binding to the basophilocyte, followed by a non-transient event, since the potentiating effect persists after preincubation of the cells with the LPS followed by washout and leaving the cells for 30 min at 37 degrees C before stimulation with anti-IgE. The potentiation was abolished or reduced by galactose (10(-7) and 10(-6) M) and N-acetylglucosamine (10(-6) and 10(-5) M), acting by a binding to the basophil cell membrane, demonstrated by the persistence of effect after preincubation and washout of unbound sugar.
Adult↗
Cystic fibrosis. 1. Pseudomonas aeruginosa infection in cystic fibrosis and its management.
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Anti-Bacterial Agents↗
Complement and immunoglobulin studies in 15 cases of chronic meningococcemia: properdin deficiency and hypoimmunoglobulinemia.
The purpose of this study was to investigate whether patients with chronic meningococcemia have abnormalities in their humoral immune system. The alternative and classical complement system, the levels of IgA, IgG and IgM, as well as IgG subclasses were studied in 15 individuals who had recovered from chronic meningococcemia. We found one individual with complete deficiency of properdin, a component of the alternative complement pathway. In the other patients, the complement system was normal. The mean plasma IgG concentration was significantly below normal in the patient group, while the mean values of IgA, IgM and the IgG subclasses were normal. Two individuals, however, had low IgG2 and IgG4 levels. We conclude that properdin deficiency and reduced plasma IgG levels may predispose to chronic meningococcal disease, but that the majority of patients with chronic meningococcemia have a normal humoral immune system.
Adolescent↗
Hope for successful xenografting by immunosuppression with monoclonal antibody against CD4, total lymphoid irradiation and cyclosporine. Six months' survival of hamster heart transplanted into rat.
Hamster hearts were transplanted to rats, and the effects of combinations of total lymphoid irradiation (TLI), cyclophosphamide, cyclosporine A (CyA) and monoclonal antibodies (MAB) were investigated. Controls not immunosuppressed rejected their xenograft in 3 to 5 days, while combination immunosuppression including MABs against CD4 or IL-2-receptors extended graft survival significantly. In one case, the graft was still functioning 180 days after transplantation, which is the longest survival seen in this model. The use of specific MABs may open a new era for both xeno- and allo-transplantation.
Animals↗
Quality control of perfusion: monitoring venous blood oxygen tension to prevent hypoxic acidosis.
The long-held belief that venous oxygen tension mirrored tissue oxygen tension became suspect in the 1960s when new instrumentation consistently showed that tissue oxygen tension was 10 to 30 torr less than venous oxygen tension. Moreover, a countercurrent of oxygen exchange between terminal arteries and veins was shown to exist. Despite this conflict in scientific theory, however, monitoring venous oxygen tension as a means to control hypothermic cardiopulmonary bypass has been repeatedly urged, since myocardial acidosis is clearly extremely detrimental. This study of the relationship between venous oxygen tension during hypothermic bypass and a concurrent increment in lactacidemia yields strong objective evidence to support the use of on-line venous oxygen tension monitoring to guide perfusion. In a random series of 36 patients, venous blood samples were drawn at five preselected intervals during operation and were analyzed for pH, carbon dioxide tension, oxygen tension, lactic acid, hematocrit, and base excess. Analysis of the data revealed that venous pH and base excess showed no correlation to venous oxygen tension. However, lactic acid showed a strong correlation with venous oxygen tension, with a correlation coefficient of 0.4338 at a confidence level of p less than 0.0001. If the patients were divided into three clinically pertinent groups based on the lowest venous oxygen tension recorded, a strong relationship between venous oxygen tension and lactic acid emerged. If the lowest measurement of venous oxygen tension was greater than 35 mm Hg (group A), the mean rise in lactic acid was only 0.12 microns/ml. If the lowest measurement was between 30 and 34 mm Hg (group B), the mean rise was 0.64 microns/ml. Whereas, if any venous oxygen tension value fell below 30 mm Hg (group C), the mean rise in lactic acid was 2.56 microns/ml. Analysis of variance showed that group C values were significantly different from groups A and B values (p less than 0.0002). A scientific hypothesis relating venous oxygen tension to adequate tissue oxygenation is proposed. Use of venous oxygen tension monitoring with the goal to maintain the level above 35 mm Hg is strongly supported by this study.
Acidosis, Lactic↗
Graft survival in a hamster-to-rat heart transplantation model after treatment with total lymphoid irradiation, cyclosporine A, and a monoclonal anti-T-cell antibody.
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Animals↗
Visibility of synaptically induced conductance changes: theory and simulations of anatomically characterized cortical pyramidal cells.
A recent report has provided evidence that there are no significant increases in the neuronal input conductance during the response of cortical cells in cat visual cortex to non-preferred visual stimuli (Douglas et al., 1988). A criticism of experiments of this kind is that changes in the membrane conductance occurring in the dendritic tree may not be visible from electrodes that impale the soma. Our paper describes theoretical and numerical results concerning the visibility of synaptically induced conductance changes from intracellular electrodes, in both ideal and anatomically well-characterized cortical neurons. Based on earlier work by Rall (1967), we here derive theoretical expressions for the change in input conductance at any location in a passive dendritic tree resulting from activation of a single synapse and obtain bounds for the effects of multiple synapses. We find that the conductance change measured at the cell body is always less than the sum of the synaptic conductance changes and that this observed conductance change does not depend on the synaptic reversal potential. For the case of an infinite dendritic cylinder, the change in input resistance due to a single synaptic input decays exponentially with distance of the synapse from the recording site. Numerical simulations of synaptic inputs that change approximately as fast as the membrane time-constant produce an increase in input conductance that is only slightly less visible than that of a constant input. We also compute the changes in somatic input conductance of 2 morphologically identified pyramidal cells from cat visual cortex during activity of a single inhibitory basket cell with known synaptic input locations. We find that the increase in conductance due to the activity of the inhibitory basket cells is clearly visible from the cell body of the pyramidal cells and that a 70% reduction in the amplitude of excitation is associated with at least a 30% increase in somatic input conductance, which would be visible in intracellular recordings. Taken together with the negative experimental evidence of Douglas et al. (1988), our results cast doubt on a large class of models of direction selectivity that rely on synaptically mediated inhibitory conductance increases to veto or block excitatory conductances increases.
Animals↗
Crystallization of the DNA-binding Escherichia coli protein FIS.
The specific DNA-binding protein FIS (factor for inversion stimulation), which stimulates site-specific DNA inversion by interaction with an enhancer sequence, was purified from an Escherichia coli strain overproducing the protein. FIS was crystallized at room temperature by microdialysis against 1.2 to 1.5 M-sodium/potassium phosphate containing 10 mM-Tris.HCl, 0.5 to 1 M-NaCl and 1 mM-NaN3 at pH 8.0 to 8.2. The crystals are stout prisms and suitable for X-ray diffraction study beyond 2.5 A resolution. They belong to the orthorhombic space group P2(1)2(1)2(1). The unit cell has dimensions a = 47.57(4) A, b = 51.13(4) A, c = 79.83(6) A and contains one FIS dimer in the asymmetric unit.
Bacterial Proteins↗