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K Lange

Publications and source records attributed to K Lange.

At least 127 records · Page 7Linked to original sources
PubMed1990

Multilocus ordering strategies based on sperm typing.

Sperm typing is a promising new approach for fine-structure human gene mapping. We examine three-locus sperm typing and its implications for the estimation of recombination fractions and for locus ordering. In particular, we compare some sequential stopping rules for three-locus assignment and develop methods for approximating their mean stopping times and error probabilities. A stopping rule recently described by Thompson and Boehnke et al. appears to be nearly optimal. Under this rule, one stops sampling as soon as the number of sperm of the least frequent recombinant type is s fewer than the number of sperm of the next least frequent type. We develop a random-walk algorithm and some heuristic formulas for assessing the performance of this rule. Since the broader goal of linkage analysis is to order many more than three loci, we propose a trisection strategy for ordering a new locus relative to an existing ordered set of loci. The crux of the trisection strategy is to restrict attention to the smallest block of ordered loci among which the new locus can fall and to divide this block into thirds for the next comparison. This trisection strategy is optimal in the sense that it has the best worse-case performance of any strategy. When it is applied sequentially to order a collection of loci, it is only nearly optimal, as we demonstrate by specific counter-example. However, it does become asymptotically optimal as the size of the collection increases.

Chromosome Mapping↗
PubMed1990

The ataxia-telangiectasia gene (ATA) on chromosome II is distinct from the ETS-1 gene.

We have studied the segregation of an RFLP detected with a human ETS-1 genomic probe in 25 families containing members affected with ataxia-telangiectasia (AT) and in 27 families from the Centre d'Etude du Polymorphisme Humain (CEPH) panel. We have recently mapped a gene for AT to 11q22-23 by linkage to the markers THY1 and D11S144. Multipoint linkage analysis of the CEPH families indicated that ETS-1 is located on chromosome 11q approximately 19.2 centimorgans telomeric to THY1. Analysis of the segregation of ETS-1 alleles in AT families yields strongly negative LOD scores, excluding an AT gene from a region extending 15 cM to either side of ETS-1. Multipoint mapping of ETS-1, D11S144, THY1, and AT also excludes the possibility that an AT gene is telomeric to ETS-1.

Ataxia Telangiectasia↗
PubMed1990

Further mapping of an ataxia-telangiectasia locus to the chromosome 11q23 region.

We recently mapped the gene for ataxia-telangiectasia group A (ATA) to chromosome 11q22-23 by linkage analysis, using the genetic markers THY1 and pYNB3.12 (D11S144). The most likely order was cent-AT-S144-THY1. The present paper describes further mapping of the AT locus by means of a panel of 10 markers that span approximately 60 cM in the 11q22-23 region centered around S144 and THY1. Location scores indicate that three contiguous subsegments within the [S144-THY1] segment, as well as three contiguous segments telomeric to THY1, are each unlikely to contain the AT locus, while the more centromeric [STMY-S144] segment is most likely to contain the AT locus. These data, together with recent refinements in the linkage and physical maps of 11q22-23, place the AT locus at 11q23.

Alleles↗
PubMed1990

Immunologic evidence for the in situ deposition of a cytoplasmic streptococcal antigen (endostreptosin) on the glomerular basement membrane in rats.

Endostreptosin (ESS) is an antigen derived from the cytoplasm and the plasma membrane of nephritogenic group A and to a lesser extent group C and G streptococci. It is immunologically not related to streptococcal exoenzymes or the streptococcal cell wall and can be detected on the endothelial side of the glomerular basement membrane of kidney biopsies of patients with acute poststreptococcal glomerulonephritis (ASGN) during the early phase of the disease. Highest and most persistent antibody titers to this antigen are found in patients with ASGN. Immunoaffinity isolated ESS was injected i.v. into the tail vein of Wistar Furth (W/FU) rats for up to five successive days. The animals were sacrificed on days 1, 2, 3, 4, 5, 8, 9, 10, 11 and 12. Frozen sections of the rat kidneys were tested by immunofluorescence against rabbit anti-ESS-antibody and against sera from patients who had recently recovered from ASGN as well as against anti-rat-IgG and C3. The basement membranes of rat kidneys were positive for ESS deposition starting from day one on, but were negative for anti-rat IgG and C3 during the first four days. Rats sacrificed on days 8-12 showed increasing deposition of IgG and C3 with decreased staining for ESS. The sera of rats sacrificed on days 1-3 had no detectable anti-ESS antibodies; whereas animals from day 4 on had low levels of anti-ESS antibodies as determined by microcomplement fixation. Control animals showed no staining for ESS, IgG, C3 as well as no detectable anti-ESS antibodies.

Animals↗
PubMed1989

[Stomach tolerance of acetylsalicylic acid by addition of calcium carbonate. A study of a 2-treatment/3-period cross-over design].

18 male volunteers (age 24 +/- 4 years; Broca index 0.94 +/- 0.08; mean +/- SD) underwent six upper endoscopies (three control and three test investigations) in a single blind two treatments-crossover designed study which evaluated the effect of buffering on aspirin-induced (one single oral dose of 0.5 g aspirin to fasted subjects) gastroduodenal mucosal injury. All subjects had a normal endoscopy prior to applications of 0.5 g plain aspirin (group A; swallowed) or 0.5 g aspirin + 0.3 g calcium carbonate (group B; chewed before swallowing). The sequence groups were A-B-B (n = 9) or B-A-A (n = 9). In advance fo the performed tests a washout period of six days was chosen. Endoscopies were performed two hours after ingestion of the respective tablets. The appearance of corpus, antrum, and duodenum was scored. Biopsies were taken for histological examinations. 15 volunteers experienced no gastrointestinal side effects. Three complained short-lasting gastric burning (two of group A, one of group B). In both treatment groups no significant lesions of the duodenum were found. Buffering significantly (p less than 0.0005) reduced mucosal injuries which occurred mainly as submucosal hemorrhage but without histological alterations of the mucosal architecture after aspirin ingestion. These findings suggest that oral administration of calcium carbonate buffered, chewable aspirin tablets is less harmful to the gastric mucosa than plain aspirin.

Adult↗
PubMed1989

Endogenous regulation of 2-deoxyglucose uptake in C6 glioma cells correlates with cytoskeleton-mediated changes of surface morphology.

The cellular basis of the membrane-limited state of glucose utilization and the mechanism of the endogenous regulation of hexose uptake in dense monolayers of C6 glioma cells were investigated. In an earlier study, it was shown that at high rates of glucose transport and phosphorylation combined with the inhibition of glycolytic adenosine triphosphate (ATP) production by iodoacetate, an endogenous regulatory response occurred that resulted in rapid, periodic variations of the glucose uptake rates (Lange et al., 1982). Similar time-dependent periodic changes of uptake rates also occurred during incubation of C6 glioma cells with 2 mM 2-deoxyglucose (2-DG) without pretreatment of the cells with iodoacetate. These changes were accompanied by variations of the intracellular ATP content, by distinct alterations of the shape and arrangement of microvilli and lamellae (lamellipodia) on the cell surface, and by changes of the cytoskeletal F-actin content. Because the changes of 2-DG uptake rates occurred independent of the intracellular 2-DG concentration, the bulk of this 2-DG pool was assumed to be localized apart from the membranal transport sites. Downregulation of 2-DG uptake appeared to be triggered by a rapid decrease of a small pool of the cellular ATP involved in the phosphorylation of transported hexose. Scanning and transmission electron microscopic observations of cells fixed in different states of the endogenous uptake regulation supported the assumption that the interior of lamellae and microvilli may represent a small entrance compartment for transported hexoses in which occurred the observed close coupling between hexose transport and phosphorylation as well as the rapid variations of ATP content. Hexose uptake is supposed to be regulated by cytoskeleton-mediated changes of volume and diffusional accessibility of this compartment, modulating the degree of its metabolic coupling with the cytoplasmic main compartment.

Actins↗
PubMed1989

Single-sperm typing: determination of genetic distance between the G gamma-globin and parathyroid hormone loci by using the polymerase chain reaction and allele-specific oligomers.

The frequency of recombination between the G gamma-globin (HBG2) and parathyroid hormone (PTH) loci on the short arm of human chromosome 11 was estimated by typing greater than 700 single-sperm samples from two males. The sperm-typing technique employed involves the polymerase chain reaction and allele-specific oligonucleotide hybridization. Our maximum likelihood recombination fraction estimate of 0.16 (95%) confidence interval, 0.13-0.19) falls well within previous estimates based on family studies. With current technology and a sample size of 1000 sperm, recombination fractions down to approximately 0.009 can be estimated with statistical reliability; with a sample size of 5000 sperm, this value drops to about 0.004. Reasonable technological improvements could result in the detection of recombination frequencies less than 0.001.

Alleles↗
PubMed1989

Trials, tribulations, and triumphs of the EM algorithm in pedigree analysis.

The EM algorithm is an iterative method for finding maximum-likelihood estimates. Its advantages often include numerical stability, simplicity of computer implementation, and natural incorporation of parameter constraints. However, the EM algorithm must be tailored to each specific problem. Smith (1957) and Ott (1977, 1979) have accomplished this for a variety of problems in human pedigree analysis. The present paper clarifies their theory by presenting it from a modern perspective. Five practical numerical examples are also given in an attempt to assess the value of the EM algorithm in realistic genetic modelling. These examples deal with racial admixture, linkage homogeneity, classical segregation analysis, a Mendelian latent trait model for schizophrenia, and a heterozygote detection assay for Ataxia-telangiectasia. Comparison with a quasi-Newton method of optimization reveals that the EM algorithm generally converges more slowly, but also more stably.

Algorithms↗
PubMed1989

Efficient computation of lod scores: genotype elimination, genotype redefinition, and hybrid maximum likelihood algorithms.

Calculation of multilocus lod scores presents challenging problems in numerical analysis, combinatories, programming, and genetics. It is possible to accelerate these computations by exploiting the simple pedigree structure of a CEPH-type pedigree consisting of a nuclear family plus all four grandparents. Lathrop et al. (1986) have done this by introducing likelihood factorization and transformation rules and Lander & Green (1987) by the method of 'hidden Markov chains'. The present paper explores an alternative approach based on genotype redefinition in the grandparents and systematic phase elimination in all pedigree members. All three approaches accelerate the computation of a single likelihood. Equally relevant to multilocus mapping are search strategies for finding the maximum likelihood estimates of recombination fractions. Hybrid algorithms that start with the EM algorithm and switch midway to quasi-Newton algorithms show promise. These issues are investigated in the context of a simulated 10 locus example. This same example allows us to illustrate a simple strategy for determining locus order.

Algorithms↗
PubMed1989

Simulation of pedigree genotypes by random walks.

A random walk method, based on the Metropolis algorithm, is developed for simulating the distribution of trait and linkage marker genotypes in pedigrees where trait phenotypes are already known. The method complements techniques suggested by Ploughman and Boehnke and by Ott that are based on sequential sampling of genotypes within a pedigree. These methods are useful for estimating the power of linkage analysis before complete study of a pedigree is undertaken. We apply the random walk technique to a partially penetrant disease, schizophrenia, and to a recessive disease, ataxia-telangiectasia. In the first case we show that accessory phenotypes with higher penetrance than that of schizophrenia itself may be crucial for effective linkage analysis, and in the second case we show that impressionistic selection of informative pedigrees may be misleading.

Ataxia Telangiectasia↗
PubMed1989

Endostreptosin: isolation of the probable immunogen of acute post-streptococcal glomerulonephritis (PSGN).

It is now generally accepted that acute post-streptococcal glomerulonephritis (PSGN) is the consequence of the formation of antigen-antibody-complement complexes on the basement membrane of the glomerulus and that the antigen is of streptococcal origin. In cases of acute PSGN a high titre of specific antibodies to a streptococcal cytoplasmic extract can be found at the very beginning of the disease. This cytoplasmic antigen which we called endostreptosin (ESS) is probably the pathogenetic antigen of glomerulonephritis. It is deposited on the subendothelial side of the basement membrane in the first few days of the disease and is rapidly covered by newly-formed and specific antibody and complement with resultant immune injury causing signs and symptoms of symptomatic but also frequently asymptomatic acute glomerulonephritis. To further characterize and isolate ESS we used immunoaffinity chromatography and Western blotting techniques. PAGE analysis of the affinity-isolated ESS revealed the major component to have a molecular weight of approximately 45 kD. Sera from patients with PSGN or sera of rabbits immunized with affinity-isolated ESS reacted by Western blotting with at least one antigenic component with a molecular weight of approximately 45 kD. Normal human sera or the sera of non-immunized rabbits failed to demonstrate activity against this antigen. The basement membranes of the glomeruli of patients with very early PSGN stain with fluorescein-labelled gammaglobulin of patients with glomerulonephritis. This staining can be prevented when these sera are pre-absorbed with ESS but not by pre-absorption with intact cells or cytoplasmic extracts of other bacteria.

Acute Disease↗
PubMed1989

A multi-city study of drug misuse in Europe.

This paper presents a report of the results of a comparative epidemiological study of indicators of drug misuse in seven European cities. The study was carried out between 1982 and 1986 under the auspices of the Pompidou Group of the Council of Europe. The members of the expert group summarize the drug situation in the seven cities and critically examine a range of indicators that are sometimes assumed to reflect trends in the prevalence of drug misuse. They conclude that a valuable assessment of drug misuse problems can be provided by drawing together data from several indicators. It is essential that these agency-based data are complemented by surveys and other studies of drug misuse in the populations concerned. The members of the expert group suggest that a single organizational unit is needed to integrate and analyse data and epidemiological studies and discuss different models of how this can be achieved. Improvement in the consistency and quality of the data is essential if policies are to be based on a sound understanding of trends in drug misuse.

Europe↗
PubMed1988

Localization of an ataxia-telangiectasia gene to chromosome 11q22-23.

Ataxia-telangiectasia (AT) is a human autosomal recessive disorder of childhood characterized by: (1) progressive cerebellar ataxia with degeneration of Purkinje cells; (2) hypersensitivity of fibroblasts and lymphocytes to ionizing radiation; (3) a 61-fold and 184-fold increased cancer incidence in white and black patients, respectively; (4) non-random chromosomal rearrangements in lymphocytes; (5) thymic hypoplasia with cellular and humoral (IgA and IgG2) immunodeficiencies; (6) elevated serum level of alphafetoprotein; (7) premature ageing; and (8) endocrine disorders, such as insulin-resistant diabetes mellitus. A DNA processing or repair protein is the suspected common denominator in this pathology. Heterozygotes are generally healthy; however, the sensitivity of their cultured cells to ionizing radiation is intermediate between normal individuals and that of affected homozygotes. Furthermore, heterozygous females are at an increased risk of breast cancer. These findings, when coupled with an estimated carrier frequency of 0.5-5.0%, suggest that (1) as many as one in five women with breast cancer may carry the AT gene and that (2) the increased radiation sensitivity of AT heterozygotes may be causing radiation therapists to reduce the doses of radiation used for treating cancer in all patients. To identify the genetic defect responsible for this multifaceted disorder, and to provide effective carrier detection, we performed a genetic linkage analysis of 31 families with AT-affected members. This has allowed us to localize a gene for AT to chromosomal region 11q22-23.

Ataxia Telangiectasia↗
PubMed1988

Interaction of electrically charged drug molecules with phospholipid membranes.

Model membranes (egg-yolk PC liposomes) were exposed to the cationic form of amphiphilic drugs. Microelectrophoresis was used to measure the change of the electrokinetic potential as a function of the drug concentration. By use of the Gouy-Chapman theory the surface potential and surface charge density were calculated. A theoretical model postulating a simple partition equilibrium of the charged drug molecules between the membrane and the aqueous phase in the vicinity of the membrane failed to describe the experimental results. Modification of the partition law by introducing a mechanism of saturation at high drug concentrations, however, resulted in concordance of model and experiment. Some parameters of the model can be used as a means of evaluating the efficiency of neuroactive drugs.

Alprenolol↗
PubMed1988

Association of glycolytic enzymes with the cytoplasmic side of the plasma membrane of glioma cells.

A latex phagocytosis technique was used to prepare relatively pure plasma membranes with inside-out orientation. This method was adapted through a number of modifications in order to evaluate the association of glycolytic enzymes with the cytoplasmic side of the plasma membrane of C6 glial cells. As phosphorylation is strictly coupled with transport in these cells, glycolytic enzymes, especially hexokinase, could metabolize glucose in close vicinity to its transporter. Of the enzymes tested, hexokinase is present in considerable quantities on these membranes (nearly 40% of homogenate specific activity), followed by D-glyceraldehyde-3-phosphate dehydrogenase (10%), pyruvate kinase (8%), and 3-phosphoglycerate kinase (1%). Except for hexokinase, the enzyme pattern presented here is different from that published for other membrane preparations.

Cell Membrane↗
PubMed1988

A single dominant gene can account for eye tracking dysfunctions and schizophrenia in offspring of discordant twins.

Eye movement dysfunctions (EMDs), detectable during smooth pursuit, occur in a majority of schizophrenics and in 45% of their first-degree relatives. Previous data suggest that they represent a biologic marker for schizophrenia. To determine the mode of transmission of the schizophrenia-EMD complex, the eye movements of offspring of monozygotic and dizygotic twins were recorded. One group of twins was discordant for schizophrenia; the other group for manic depression or reactive psychosis. The data suggest that EMDs and at least some schizophrenias can be considered expressions of a single underlying trait that is transmitted by an autosomal dominant gene.

Affective Disorders, Psychotic↗