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Biomedical subjects

C Koch

Publications and source records attributed to C Koch.

At least 307 records · Page 17Linked to original sources
PubMed1992

Immunoglobulin allotypes and IgG subclass antibody response to Pseudomonas aeruginosa antigens in chronically infected cystic fibrosis patients.

Chronic Pseudomonas aeruginosa lung infection is the leading cause of death in patients with cystic fibrosis (CF). Poor prognosis correlates with a high number of anti-pseudomonas precipitins and with high levels of IgG2 and IgG3 anti-pseudomonas antibodies. Reports of several highly significant associations between certain Gm (genetic markers of IgG on human chromosome 14) and Km (k-type light chain determinants on chromosome 2) phenotypes and immune responsiveness to various antigens suggest that allotype-linked immune response genes do exist in man. Furthermore correlation between Gm types and IgG subclass levels has been reported. A group of 143 CF patients were investigated (31 non-infected and 112 chronic infected). The IgG subclass antibodies to three different P. aeruginosa antigens (P. aeruginosa standard antigen (St-Ag), alginate and LPS) were determined. Immunoglobulin allotypes were determined by haemagglutination inhibition. Samples were typed for G1m(1,2,3, and 17), G2m(23), G3m(5,21), and Km(1,3). Statistical analysis of our data demonstrate that IgG3 anti-pseudomonas antibody levels and Gm markers are related. IgG3 antibody levels to all investigated P. aeruginosa antigens are significantly higher in sera homozygous for Gm(3;5), somewhat lower in heterozygous sera, and significantly lower in sera homozygous for Gm(1,2,17;21). We suggest that genetic differences between the patients may explain the present differences in subclass patterns.

Antibodies, Bacterial↗
PubMed1991

Synaptic background activity influences spatiotemporal integration in single pyramidal cells.

The standard one-dimensional Rall cable model assumes that the electrotonic structure of neurons does not change in response to synaptic input. This model is used in a great number of both theoretical and anatomical-physiological structure-function studies. In particular, the membrane time constant, tau m, the somatic input resistance, Rin, and the electrotonic length are used to characterize single cells. However, these studies do not take into account that neurons are embedded in a network of spontaneously active cells. Synapses from these cells will contribute significantly to the membrane conductance, especially if recent evidence of very high specific membrane resistance, Rm = 100 k omega.cm2, is taken into account. We numerically simulated the electrical behavior of an anatomically reconstructed layer V cortical pyramidal cell receiving input from 4000 excitatory and 1000 inhibitory cells firing spontaneously at 0-7 Hz. We found that, over this range of synaptic background activity, tau m and Rin change by a factor of 10 (80-7 msec, 110-14 M omega) and the electrotonic length of the cell changes by a factor of 3. We show that this significantly changes the response of the cell to temporal desynchronized versus temporal synchronized synaptic input distributed throughout the neuron. Thus, the global activity of the network can control how individual cells perform spatial and temporal integration.

Action Potentials↗
PubMed1991

The N-terminal part of the E.coli DNA binding protein FIS is essential for stimulating site-specific DNA inversion but is not required for specific DNA binding.

FIS protein is involved in several different cellular processes stimulating site-specific recombination in phages Mu and lambda as well as transcription of stable RNA operons in E.coli. We have performed a mutational analysis of fis and provide genetic and biochemical evidence that a truncated version of FIS lacking the N-terminal region is sufficient for specific DNA binding and for stimulating lambda excision. These mutants also retain their ability to autoregulate fis gene expression. Such mutant proteins, however, cannot stimulate the enhancer dependent DNA inversion reaction.

Amino Acid Sequence↗
PubMed1991

Prevention of chronic Pseudomonas aeruginosa colonisation in cystic fibrosis by early treatment.

To assess whether chronic pulmonary colonisation with Pseudomonas aeruginosa in cystic fibrosis is preventable, 26 patients who had never received anti-pseudomonas chemotherapy were randomly allocated to groups receiving either no anti-pseudomonas chemotherapy or oral ciprofloxacin and aerosol inhalations of colistin twice daily for 3 weeks, whenever Ps aeruginosa was isolated from routine sputum cultures. During the 27 months of the trial, infection with Ps aeruginosa became chronic in significantly fewer treated than untreated subjects (2 [14%] vs 7 [58%]; p less than 0.05) and there were significantly fewer Ps aeruginosa isolates in routine sputum cultures in the treated group (49/214 [23%] vs 64/158 [41%]; p = 0.0006). Thus, chronic colonisation with Ps aeruginosa can be prevented in cystic fibrosis by early institution of anti-pseudomonas chemotherapy.

Child↗
PubMed1991

Characterization of the functional domains of the natriuretic peptide receptor/guanylate cyclase by radiation inactivation.

Radiation inactivation has been used to evaluate the molecular size of domains responsible for atrial natriuretic peptide (ANP)-binding and cyclase functions of the ANP receptor/guanylate cyclase. Two types of inactivation curves were observed for cyclase function in both adrenal cortex and aortic smooth muscle cells: 1) biphasic with enhanced guanylate cyclase activity after exposure to low radiation doses and 2) linear after preincubation of membrane proteins with 0.5 microM ANP or solubilization with Triton X-100. The existence of an inhibitory component was the simplest model that best explained the types of radiation curves obtained. Activation of guanylate cyclase by ANP or Triton X-100 could occur via the dissociation of this inhibitory component from the catalytic domain. On the other hand, the loss of ANP-binding activity was linear with increasing radiation exposures under basal, ANP treatment, and Triton X-100 solubilization conditions. Radiation inactivation sizes of about 30 kDa for cyclase function, 20 kDa for ANP-binding function, and 90 kDa for inhibitory function were calculated. These studies suggest that the ANP receptor/guanylate cyclase behaves as a multidomain protein. The results obtained by radiation inactivation of the various biological functions of this receptor are compatible with the hypothesis of an intramolecular inhibitory domain repressing the guanylate cyclase catalytic domain within its membrane environment.

Adrenal Glands↗
PubMed1991

Severity of cystic fibrosis in patients homozygous and heterozygous for delta F508 mutation.

To assess the relation between genotype and severity of disease in cystic fibrosis (CF) the frequencies and extent of several features of its phenotypic expression were investigated in the 235 patients who attend the Danish CF Centre. 14 patients who attend irregularly and 3 who do not carry the delta F508 mutation at all were excluded. The case-reports of the remaining 218 patients (aged 4 months to 41 years) were carefully evaluated, and they were all analysed for the delta F508 mutation. 172 (79%) were homozygous for delta F508 and 46 (20%) were heterozygous. The mutation therefore occurs on 89% of the chromosomes analysed. There were no significant differences between the homozygous and heterozygous groups in the proportions with meconium ileus at birth, liver involvement, or chronic Pseudomonas aeruginosa infection. However, significantly more of the homozygous patients had onset of symptoms before the age of 6 months (p less than 0.025); they were significantly younger at diagnosis (p = 0.013) and centre referral (p = 0.006); they required greater pancreatic enzyme substitution (p = 0.0002) and had poorer lung function; and the calculated yearly incidence of chronic Ps aeruginosa infection and yearly mortality rates were greater than in heterozygous patients (p = 0.0001).

Adolescent↗
PubMed1991

Three-dimensional structure of the E. coli DNA-binding protein FIS.

The factor for inversion stimulation, FIS, is involved in several cellular processes, including site-specific recombination and transcriptional activation. In the reactions catalysed by the DNA invertases Gin, Hin and Cin, FIS stimulates recombination by binding to an enhancer sequence. Within the enhancer, two FIS dimers (each 2 x 98 amino acids) bind to two 15-base-pair consensus sequences and induce bending of the DNA. Current models propose that the enhancer-FIS complex organizes a specific synapse, either through direct interactions with Gin, or by modelling the substrate into a configuration suitable for recombination. Using X-ray analysis at 2.0 A resolution, we now show that FIS is composed of four alpha helices tightly intertwined to form a globular dimer with two protruding helix-turn-helix motifs. The 24 N-terminal amino acids are so poorly defined in the electron density map as to make interpretation doubtful, indicating that they might act as 'feelers' suitable for DNA or protein (invertase) recognition. We infer from model building that DNA has to bend for tight binding to FIS.

Amino Acid Sequence↗
PubMed1991

An assay for complement factor B in species at different levels of evolution.

The alternative complement pathway is regarded as the evolutionary ancestral complement system. It is therefore of interest to analyze and characterize factor B of the alternative complement pathway in animals at different levels of evolution. We describe a functional assay which is based on the interaction of factor B from various animal species with Cobra Venom Factor, the snake C3b-analog. The signal system in the assay is C3-conversion in factor B-depleted chicken serum. The results show that a functional C3-convertase can be created with factor B from mammals, aves, and amphibians.

Animals↗
PubMed1991

Does anesthesia cause loss of consciousness?

Although about 30 million operations carried out under general anesthetic are routinely performed each year in the USA alone, it is not possible to determine reliably whether or not a given anesthetized patient is conscious during surgery. As a result, some patients may be either partially aware during the operation or may be able to recall some aspects of it afterwards. It is therefore crucial to develop some experimental means to evaluate the state of consciousness of the anesthetized patient. Recent developments suggest that 40 Hz neuronal oscillations might help to solve this problem.

Anesthesia↗
PubMed1991

Effect of geometrical irregularities on propagation delay in axonal trees.

Multiple successive geometrical inhomogeneities, such as extensive arborization and terminal varicosities, are usual characteristics of axons. Near such regions the velocity of the action potential (AP) changes. This study uses AXONTREE, a modeling tool developed in the companion paper for two purposes: (a) to gain insights into the consequence of these irregularities for the propagation delay along axons, and (b) to simulate the propagation of APs along a reconstructed axon from a cortical cell, taking into account information concerning the distribution of boutons (release sites) along such axons to estimate the distribution of arrival times of APs to the axons release sites. We used Hodgkin and Huxley (1952) like membrane properties at 20 degrees C. Focusing on the propagation delay which results from geometrical changes along the axon (and not from the actual diameters or length of the axon), the main results are: (a) the propagation delay at a region of a single geometrical change (a step change in axon diameter or a branch point) is in the order of a few tenths of a millisecond. This delay critically depends on the kinetics and the density of the excitable channels; (b) as a general rule, the lag imposed on the AP propagation at a region with a geometrical ratio GR greater than 1 is larger than the lead obtained at a region with a reciprocal of that GR value; (c) when the electronic distance between two successive geometrical changes (Xdis) is small, the delay is not the sum of the individual delays at each geometrical change, when isolated. When both geometrical changes are with GR greater than 1 or both with GR less than 1, this delay is supralinear (larger than the sum of individual delays). The two other combinations yield a sublinear delay; and (d) in a varicose axon, where the diameter changes frequently from thin to thick and back to thin, the propagation velocity may be slower than the velocity along a uniform axon with the thin diameter. Finally, we computed propagation delays along a morphologically characterized axon from layer V of the somatosensory cortex of the cat. This axon projects mainly to area 4 but also sends collaterals to areas 3b and 3a. The model predicts that, for this axon, areas 3a, 3b, and the proximal part of area 4 are activated approximately 2 ms before the activation of the distal part of area 4.

Action Potentials↗
PubMed1991

Monoclonal antibody treatment (anti-CD4 and anti-interleukin-2 receptor) combined with cyclosporin A has a positive but not simple dose-dependent effect on rat renal allograft survival.

The use of monoclonal antibodies (MoAbs) in experimental and clinical organ transplantation is of increasing interest since this treatment seems to offer an opportunity for specific immunomodulation. In a rat kidney allograft model, Cyclosporin A (CyA) treatment (12.5 mg/kg/d, day 0-14) was combined with murine anti-rat CD4 (MRC OX-38) and murine anti-rat IL-2R (MRC OX-39) MoAbs at doses of 100 or 300 micrograms/kg/d (day 0-7) and plasma concentrations of the murine MoAb were determined. In both groups receiving combined treatment with CyA and MoAb, graft survival was prolonged to an average of 65 days, compared to a graft survival of 9-10 days in non-treated recipients. Further, the data showed a beneficial effect of CyA + MoAb treatment versus CyA alone (graft survival 32 days). The threefold increased MoAb dose did not seem to improve graft survival or function. Treatment with OX-38 + OX-39 at a dose of 100 micrograms/kg/d each resulted in plasma levels of 280 ng/ml 14 days after transplantation. Corresponding values after the administration of 300 micrograms/kg/d were 1800 ng/ml in graft recipients as well as controls. These findings indicate that the effect of MoAbs in complex organ transplantation models is not simply dose dependent and that in vitro assays are of limited value in predicting the effect of a given MoAb when used in vivo. The determination of MoAb plasma levels, however, may be a useful tool in defining optimal MoAb administration and to monitor therapeutically effective plasma levels.

Animals↗
PubMed1991

Endocrine and exocrine pancreatic function and the delta F508 mutation in cystic fibrosis.

The relationship between the cystic fibrosis (CF) genotype and endocrine and exocrine pancreatic function was studied in 215 CF patients. In the 211 patients with the delta F508 mutation, endocrine pancreatic function (oral glucose tolerance; WHO criteria) was normal in 72.5%, impaired in 12.3%, and diabetic in 15.2% of the patients, with no difference between CF patients homozygous (N = 163, median age 15 years, range 2-40) or heterozygous (N = 48, 18 years, 3-40; age difference not significant) for the delta F508 mutation. Exocrine pancreatic sufficiency (no need for pancreatic enzyme substitution) was found in 0.6% of the patients homozygous for the delta F508 mutation and in 10.4% of the heterozygotes (p less than 0.01). Homozygous patients with pancreatic insufficiency took more pancreatic enzyme capsules (median 42 per day, range 0-192) than the heterozygotes (29 per day, 0-300; p less than 0.001). The four patients (1.9%) without the delta F508 mutation had normal glucose tolerance but exocrine pancreatic insufficiency. In conclusion, the major mutation genotype in CF (delta F508) affects the severity of the exocrine pancreatic insufficiency, whereas endocrine pancreatic function is unrelated to this genotype.

Adolescent↗
PubMed1991

Glucose tolerance in cystic fibrosis.

Glucose tolerance was evaluated in 356 living and dead patients with cystic fibrosis who were recorded at the Danish Cystic Fibrosis Centre. Twenty two patients (6%) were treated elsewhere, 25 (7%) were unable, unwilling or too young (age less than 2 years) to participate; 309 patients (87%) were therefore eligible for the study of whom 99 (32%) were dead and 210 (68%) were alive. Of the dead patients, 13 also had diabetes mellitus (13%). Of the living patients (median age 14 years, range 2-40), nine (4%) were known to have diabetes and all were being treated with insulin. In the remaining 201 patients an oral glucose tolerance test (1.75 g/kg body weight, maximum 75 g) was carried out. A total of 155 patients (74%) had normal glucose tolerance, 31 (15%) had impaired glucose tolerance, and 15 (7%) had diabetes mellitus according to the WHO criteria. The percentage of glycated haemoglobin (HbA1c) (reference range 4.1-6.4%) increased significantly as glucose tolerance decreased: when glucose tolerance was normal the median was 5.2%; when it was impaired the figure was 5.5%; in patients whose diabetes was diagnosed by the oral glucose tolerance test it was 5.9%; and in patients already known to have diabetes mellitus it was 8.6%. The incidence and prevalence of impaired glucose tolerance and diabetes mellitus increased with age. From the age of 15 to 30 years the decrease in the prevalence of normal glucose tolerance was almost linear. Within this age span the proportion of patients with cystic fibrosis with normal glucose tolerance was reduced by roughly 5%/year. Only 35% (95% confidence interval (CI) 22 to 48%) of the patients with cystic fibrosis who were alive at the age of 25 years had normal glucose tolerance; 32% (95% CI 14 to 49%) were diabetic. The prevalence of glucose intolerance in cystic fibrosis is rapidly increasing with age; its potentially harmful effect on the prognosis of cystic fibrosis is of increasing importance as the length of survival of these patients increases.

Adolescent↗
PubMed1991

Isotropic connections generate functional asymmetrical behavior in visual cortical cells.

1. We study the relationship between structure and function in inhibitory long-range interactions in visual cortex. The sharpening of orientation tuning with "cross-orientation inhibition" is used as an example to discuss anisotropies that are generated by long-range connections. 2. In this study, as opposed to the detailed cortex model described in a previous report, a model of the cortical orientation column structure is proposed in which cortical cells are described only by their orientation preference. 3. We present results using different geometric arrangements of orientation columns. In the simplest case, straight parallel orientation columns were used. We also utilized more realistic, curved columns generated by a simple algorithm. The results were confirmed by the study of a patch of real column structure, determined experimentally by Swindale et al. 4. A given cell receives functionally defined cross-orientation inhibition if the cell receives inhibitory input that is strongest along its nonpreferred orientation. On the other hand, a cell is said to receive structurally defined cross-orientation inhibition if the inhibition arises from source cells with an orientation preference orthogonal to that of the target cell. Even though those definitions seem to describe similar situations, we show that, in the general case, structurally defined cross-orientation inhibition does not efficiently sharpen orientation selectivity. In particular, for straight and parallel columns, structurally defined cross-orientation inhibition results in unequal amounts of inhibition for whole cell populations with different preferred orientations. 5. In more realistic column structures, we studied the question of whether structural cross-orientation inhibition could be implemented in a more efficient way. However, for the majority of cells, it is demonstrated that their nonpreferred stimulus will not preferably excite "cross-oriented" cells. Thus structural cross-orientation inhibition is not efficient in real cortical columns. 6. We propose a new mechanism called circular inhibition. In this connection scheme, a target cell receives inhibitory input from source cells that are located at a given distance (the same for all cells) from the target cell. Circular inhibition can be regarded as two-dimensional long-range lateral inhibition. As opposed to structural cross-orientation inhibition, this mechanism does not introduce unwanted anisotropies in the orientation tuning of the target cells. It is also conceptually much simpler and developmentally advantageous. It is shown that this connection scheme results in a net functional cross-orientation inhibition in all realistic column geometries. The inhibitory tuning strength obtained with circular inhibition is weak and similar to that measured in reality.(ABSTRACT TRUNCATED AT 400 WORDS)

Algorithms↗
PubMed1991

[Results of surgical therapy of esophageal carcinoma].

In esophageal cancer radical resection of the affected segment is the therapy of choice for tumours confined to the wall. Palliative resection at advanced tumour stages does not improve survival and markedly increases mortality. Neither chemotherapy nor radiation influence the survival rates. Tumours of the middle third are resected by the thoracic approach, while tumours of the lower third may be resected by blunt dissection. The best reconstruction is achieved by interposition of the stomach. The jejunum or colon may be interposed in the case of a previous gastric resection. In our department, postoperative mortality was 8.8%, corresponding to 137 operations with stomach interposition. The 5 year survival rate was 39.9% in stage I and II and 10.6% in stage III and IV. Complications and mortality were markedly increased in advanced tumour stages. The thoracic approach was not correlated with higher postoperative lethality.

Adult↗