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K Lange

Publications and source records attributed to K Lange.

At least 73 records · Page 4Linked to original sources
PubMed1997

Prednicarbate biotransformation in human foreskin keratinocytes and fibroblasts.

PURPOSE: Evaluation of skin layer-specific prednicarbate (PC) biotransformation, possibly explaining the improved benefit/risk ratio of this topical corticosteroid in atopic dermatitis (1,2). METHODS: Metabolism of PC in keratinocyte and fibroblast monolayers derived from human juvenile foreskin was evaluated. Drug concentration was determined by HPLC/UV-absorption. Accompanying cell viability tests (MTT-tests) were performed to exclude toxic drug effects. RESULTS: Keratinocytes hydrolyzed the double ester PC (2.5 x 10(-5) M) at position 21 to the monoester prednisolone 17-ethylcarbonate (P17EC) which nonenzymatically transformed to prednisolone 21-ethylcarbonate (P21EC). This metabolite was enzymatically cleaved to prednisolone (PD), the main biotransformation product at 24 hours. Fibroblasts, however, showed a distinctively lower enzyme activity. Both, PC and P17EC (or rather P21EC) were hydrolyzed to a minor extent only. The biotransformation pathway, however, was the same. When P17EC was added separately, it transformed to P21EC and again was cleaved by keratinocytes to a much higher extent. Despite of the rather high glucocorticoid concentration MTT-tests proved a non-disturbed cell viability and proliferation rate. CONCLUSIONS: Extrapolating our results to the in-vivo situation, topically applied PC may be metabolized by epidermal cells during skin penetration. A complex mixture of compounds reaches the dermis, whose fibroblasts are barely able to metabolize the steroids. Since skin atrophy is less pronounced with PC as compared to conventional halogenated glucocorticoids, less potent PC metabolites appear to be the dominant species in the dermis.

Administration, Topical↗
PubMed1997

Prednicarbate versus conventional topical glucocorticoids: pharmacodynamic characterization in vitro.

PURPOSE: Pharmacodynamic characterization of topical glucocorticoids as prednicarbate (PC), its metabolites prednisolone 17-ethylcarbonate (PEC) and prednisolone (PD), betamethasone 17-valerate (BMV), betamethasone (BM) and desoximetasone (DM) by evaluating their effects on epidermal and dermal cells. Synopsis of pharmacokinetic and pharmacodynamic studies, possibly explaining the improved benefit-risk ratio of prednicarbate. METHODS: Isolated foreskin keratinocytes were used to investigate the influence on epidermal inflammatory processes, dermal fibroblasts of the same origin to study antiproliferative activities of glucocorticoids. Interleukins were measured by ELISA-assay, the influence on II-1 alpha-production also on mRNA-level by RNAse protection assay. Proliferation was assessed by 3H thymidine incorporation and biodegradation by HPLC/UV-absorption. Cell viability was controlled by MTT assay. RESULTS: In keratinocytes, inflammation was induced by TNF alpha, resulting in an increased II-1 alpha synthesis. This cytokine was particularly suppressed by PC and BMV, whereas PEC, PD, DM and BM were less potent (p < or = 0.05). Since, however, the double ester PC is rapidly degraded in keratinocytes, a RNAse-protection assay of II-1 alpha mRNA was performed allowing short incubation times and thus minimizing biodegradation effects. In agreement with the previous experiment, the antiinflammatory potency of native PC was confirmed. In fibroblasts, II-1 alpha and II-6 synthesis indicate proliferation and inflammation respectively. Whereas PC inhibited II-1 alpha and II-6 production in fibroblasts to a minor extent only, it was strongly reduced by the conventional glucocorticoids and PEC (p < or = 0.05). The minor unwanted effect of PC on fibroblasts was also reflected by its low influence on cell proliferation as assayed by 3H thymidine incorporation. More pronounced antiproliferative features were observed with BM, PEC and especially BMV. CONCLUSIONS: Correlating antiphlogistic effects in keratinocytes (suppression of II-1 alpha) with antiproliferative effects in fibroblasts (suppression of II-1 alpha and II-6), the improved benefit-risk ratio of PC compared to conventional glucocorticoids does not result only from distinct drug metabolism in the skin but also from a specific influence on the cytokine network.

Administration, Topical↗
PubMed1997

An approximate model of polygenic inheritance.

The finite polygenic model approximates polygenic inheritance by postulating that a quantitative trait is determined by n independent, additive loci. The 3n possible genotypes for each person in this model limit its applicability. CANNINGS, THOMPSON, and SKOLNICK suggested a simplified, nongenetic version of the model involving only 2n + 1 genotypes per person. This article shows that this hypergeometric polygenic model also approximates polygenic inheritance well. In particular, for noninbred pedigrees, trait means, variances, covariances, and marginal distributions match those of the ordinary finite polygenic model. Furthermore as n --> infinity, the trait values within a pedigree collectively tend toward multivariate normality. The implications of these results for likelihood evaluation under the polygenic threshold and mixed models of inheritance are discussed. Finally, a simple numerical example illustrates the application of the hypergeometric polygenic model to risk prediction under the polygenic threshold model.

Female↗
PubMed1997

Grouped-coordinate ascent algorithms for penalized-likelihood transmission image reconstruction.

This paper presents a new class of algorithms for penalized-likelihood reconstruction of attenuation maps from low-count transmission scans. We derive the algorithms by applying to the transmission log-likelihood a version of the convexity technique developed by De Pierro for emission tomography. The new class includes the single-coordinate ascent (SCA) algorithm and Lange's convex algorithm for transmission tomography as special cases. The new grouped-coordinate ascent (GCA) algorithms in the class overcome several limitations associated with previous algorithms. 1) Fewer exponentiations are required than in the transmission maximum likelihood-expectation maximization (ML-EM) algorithm or in the SCA algorithm. 2) The algorithms intrinsically accommodate nonnegativity constraints, unlike many gradient-based methods. 3) The algorithms are easily parallelizable, unlike the SCA algorithm and perhaps line-search algorithms. We show that the GCA algorithms converge faster than the SCA algorithm, even on conventional workstations. An example from a low-count positron emission tomography (PET) transmission scan illustrates the method.

Algorithms↗
PubMed1997

Newly synthesized cholesterol in human bile and plasma: quantitation by mass isotopomer distribution analysis.

The purpose of this study was to quantitate the contribution of newly synthesized cholesterol to bile and plasma in humans. Eight healthy volunteers were intravenously infused with 0.125 mmol of [1-(13)C]acetate per kilogram per hour for 15 h. During continuous enteral nutrition, plasma aliquots and samples of duodenal bile were collected hourly. The trimethysilylether of unesterified cholesterol was analyzed by gas chromatography-mass spectrometry for quantitation of the mass fragments M(+0) [mass-to-charge ratio (m/z) 368], M(+1) (m/z 369), M(+2) (m/z 370), M(+3) (m/z 371), and M(+4) (m/z 372). The fractional syntheses of plasma and biliary cholesterol were determined using mass isotopomer distribution analysis. After 6 h of infusion, the 13C enrichment of the acetate pool remained constant at 12%. The fractional synthesis increased continuously during [13C]acetate infusion and reached 4.2% and 5.3% in cholesterol of plasma and bile, respectively. Both were highly correlated, but the fractional synthesis of biliary cholesterol exceeded that of plasma (P < 0.05). It may be concluded that the contribution of de novo cholesterol synthesis to bile exceeds that to plasma but is minor in humans.

Adult↗
PubMed1997

EM algorithms without missing data.

Most problems in computational statistics involve optimization of an objective function such as a loglikelihood, a sum of squares, or a log posterior function. The EM algorithm is one of the most effective algorithms for maximization because it iteratively transfers maximization from a complex function to a simple, surrogate function. This theoretical perspective clarifies the operation of the EM algorithm and suggests novel generalizations. Besides simplifying maximization, optimization transfer usually leads to highly stable algorithms with well-understood local and global convergence properties. Although convergence can be excruciatingly slow, various devices exist for accelerating it. Beginning with the EM algorithm, we review in this paper several optimization transfer algorithms of substantial utility in medical statistics.

Algorithms↗
PubMed1997

Effects of low doses of prostaglandin F2 alpha during the early luteal phase before and after implantation in beagle bitches.

Three groups of five beagle bitches were treated three times a day with natural prostaglandin F2 alpha (PGF2 alpha) at a dosage of either 20 micrograms kg-1 bodyweight (days 5-8 of metoestrus), 50 micrograms kg-1 bodyweight (days 5-11 of metoestrus) or 20 micrograms kg-1 bodyweight after detection of pregnancy (days 20-21 after ovulation) for 7 days. A dose of 20 micrograms PGF2 alpha kg-1 bodyweight administered during the early luteal stage could not induce a reliable decrease of progesterone concentrations, while injections of 50 micrograms PGF2 alpha kg-1 bodyweight beginning before implantation resulted in arrest of luteal progesterone production and prevention of nidation in all five bitches. The application of 20 micrograms PGF2 alpha kg-1 bodyweight shortly after implantation induced functional arrest of corpora lutea and led to embryonic or fetal resorption in all cases. In general, the luteolytic effect of low PGF2 alpha doses was insufficient because of the recovery of the corpora lutea seen in nearly all bitches and the prolonged process of embryonic or fetal resorption that increase the risk of uterine disease.

Abortion, Induced↗
PubMed1997

[T-plate osteosynthesis in dislocated proximal humerus fractures].

From 1988 through 1995 we operated 48 patients with dislocated humeral fractures using the T-Plate (median age 66 years [20 to 90 years], 32 male, 16 female). After a median 22 months (9 to 60 months) 33 patients were followed up clinically and radiologically. Six patients had suffered a 2-part fracture, 17 a 3-part fracture, and 10 a 4-part fracture. Judged by the Constant score 6 patients reached a very good result, 8 had a good result, 4 a satisfactory and 15 a poor result. Radiologically we saw an arthrosis in 31%, an axial deviation in 50%, and a dislocation of the fragments in 72%. The rate of necrosis of the humeral head was 39%. MRI (17 patients) provided additional relevant information about soft tissue and bone quality and is valuable in the early detection of necrosis of the humeral head. Functionally poor results correlated rather to dislocated fragments and persisting axial deviation than to the type of fracture or the necrosis of the humeral head. The T-plate osteosynthesis is one way to treat dislocated fractures of the proximal humerus, if early operation, correct reposition, and biological principles are respected.

Adult↗
PubMed1997

[Acromioclavicular joint injuries: efficient therapy from the economic viewpoint].

The results of surgical treatment with tension band wiring versus conservative therapy with bandages are described in a retrospective study. Operative therapy is associated with complications in 32.3% and two occasions of hospitalisation. The advantages of conservative therapy are obvious: it is easy and comfortable for the patient; there are no complications and low costs, and it is associated with a shorter temporary disablement. Therefore, conservative therapy is our standard, and surgery is performed only for Rockwood IV-VI lesions and in exceptional cases.

Acromioclavicular Joint↗
PubMed1996

Detection of the ATP-dependent nonmitochondrial calcium store in a cell surface-derived vesicle fraction from isolated rat hepatocytes.

In preceding studies, the IP3-sensitive Ca2+ store of the hamster insulinoma cell line, HIT, was detected in cell surface protrusions such as microvilli and related membrane structures [Lange, K., and Brandt, U. (1993) FEBS Lett. 320, 183-188; and (1993) FEBS Lett. 325, 205-209]. In this study, these experiments were extended on rat hepatocytes. We used the previously described shearing technique for isolating cell surface-derived vesicle fractions from freshly isolated and 48-h-cultured rat hepatocytes. As shown by Western blot analysis, these vesicles contained the hepatocyte-specific glucose transporter, GluT2, and actin, which are both typical microvillar components. Scanning electron microscopy revealed that a spherical vesicle population of uniform size (about 1 microm in diameter) originates from the hepatocyte microvilli. This vesicle fraction exhibited ATP-dependent and thapsigargin-sensitive Ca2+ storage activity with properties identical to those of the known microsomal systems and of HIT cell surface-derived vesicles, except that the ATP-dependent Ca2+ pool was insensitive to IP3. Like HIT surface vesicles, hepatocyte surface vesicles rapidly took up ATP via a 4,4'-diisocyanostilbene-2,2'-disulfonic acid (DIDS)-sensitive anion pathway. Inhibition of ATP influx into the vesicles by DIDS also completely inhibited ATP-dependent Ca2+ storage. Moreover, determination of efflux kinetics of Ca2+ from passively (in the absence of ATP) loaded vesicles revealed a La(3+)-sensitive but IP3-independent Ca2+ pathway which rapidly equilibrated intravesicular free Ca2+ with the external medium. Permeabilization of the vesicles with saponin (0.005%) opened an additional efflux pathway for Ca2+ which is not La(3+)-sensitive. However, saponin treatment of vesicles preloaded with Ca2+ in the presence of ATP did not affect the thapsigargin-sensitive vesicular Ca2+ store but only released a small portion (about 20%) of the vesicular Ca2+ that is not part of the thapsigargin-sensitive Ca2+ pool. Also, the size of the saponin-releasable Ca2+ pool was not affected by depletion of the thapsigargin-sensitive Ca2+ store. These findings indicate that hepatocyte surface vesicles are readily permeable for Ca2+ and ATP via cation and anion pathways. Consequently, Ca2+ storage into these vesicles does not occur by concentrative Ca2+ pumping but rather appears to be due to an internal, ATP-dependent mechanism of Ca2+ sequestration. The presented data are in accord with the previously reported colocalization of the ATP-dependent Ca2+ store and its functionally coupled, store-regulated Ca2+ influx pathway in special cell surface organelles, the microvilli.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMed1996

Calcium storage and release properties of F-actin: evidence for the involvement of F-actin in cellular calcium signaling.

Preceding studies have shown that the bulk of the ATP-dependent, inositol 1,4,5-trisphosphate (IP3)-sensitive Ca2+ store of hamster insulinoma (HIT) cells is located in microvilli on the cell surface. Similar results were obtained with isolated rat hepatocytes. Moreover, in vesicles of microvillar origin, passive fluxes of Ca2+, ATP, and IP3 occur through cation and anion channels, respectively, suggesting that Ca2+ storage is due to ATP-dependent Ca2+ binding to an intravesicular component. Here we demonstrate that F-actin may be a possible candidate for this function. ATP-actin monomers bind Ca2+ with high affinity (Kd = 2-8 nM) to their divalent cation binding sites. Polymerization of actin monomers decreases the rate constant for divalent cation exchange at this binding site by more than 3 orders of magnitude rendering bound cations nearly unavailable. F-actin-bound Ca2+ can be released by depolymerization and dissociation from Ca(2+)-ADP-actin monomers (Kd = 375 nM). We now provide additional evidence for the possible involvement of actin in Ca2+ storage. (1) Preincubation of surface-derived Ca(2+)-storing vesicles from HIT cells with the F-actin stabilizer, phalloidin, strongly inhibited ATP-dependent Ca2+ uptake, reducing the IP3-sensitive Ca2+ pool by 70%. Phalloidin, when added after the loading process, affected neither the amount of stored Ca2+ nor IP3 action on the store. (2) F-actin polymerized in the presence of Mg2+ in nominally Ca(2+)-free buffer still contained about half of the high affinity sites occupied with Ca2+ (Mg/Ca-F-actin). (3) Using the fura-2 technique, we found that in the presence of ATP, Mg/Ca-F-actin incorporated free Ca2+ at a relatively low rate. Short pulses of ultrasound (3-10 s) strongly accelerated Ca2+ uptake, decreasing free Ca2+ from 500 nM to below 100 nM. (4) In the presence of physiological levels of Mg2+ (0.5 mM), sonication liberated large amounts of Ca2+ from Mg/Ca-F-actin. (5) Ca-F-actin released bound Ca2+ at a very slow rate. Short ultrasonic pulses rapidly elevated free Ca2+ from about 50 nM up to 500 nM. (6) Small amounts of profilin, an actin-binding protein, released Ca2+ both from Ca- and Mg/Ca-F-actin and also inhibited uptake of Ca2+ into Mg/Ca-F-actin. (7) Phalloidin completely inhibited Ca-uptake into Mg/Ca-F-actin even during ultrasonic treatment. These findings suggest that Ca2+ storage may occur by addition of Ca-ATP-actin monomers to reactive ends of the polymer and emptying of this store by profilin-stimulated release of Ca-ADP-actin. Thus, receptor-operated Ca2+ signaling, initiated by phospholipase C activation, may proceed via the well-known phosphatidylinositol phosphate-regulated profilin/gelsolin pathway of actin reorganization/depolymerization. The importance of the proposed microvillar Ca2+ signaling system for living cells remains to be established.

Actins↗
PubMed1996

[Bilateral luxatio erecta of the shoulder joint--a rare injury. Management and therapy in polytrauma patients].

The case of a 36-year-old male patient is reported who fell from 20 m, sustaining injuries to the abdomen and pelvis and fractures of both arms and the left leg as well as erect dislocation of both shoulders (luxatio erecta humeri). The injury on the right was subcoracoid, that on the left subglenoid-a compound dislocation of the humerus head through the axilla. Based on this case and the pertinent literature, the pathophysiology, diagnosis and treatment of this rare injury are discussed. After immediate closed reduction, soft tissue damage, fractures or neurovascular lesions should be operated on as soon as possible.

Adult↗
PubMed1996

Descent graphs in pedigree analysis: applications to haplotyping, location scores, and marker-sharing statistics.

The introduction of stochastic methods in pedigree analysis has enabled geneticists to tackle computations intractable by standard deterministic methods. Until now these stochastic techniques have worked by running a Markov chain on the set of genetic descent states of a pedigree. Each descent state specifies the paths of gene flow in the pedigree and the founder alleles dropped down each path. The current paper follows up on a suggestion by Elizabeth Thompson that genetic descent graphs offer a more appropriate space for executing a Markov chain. A descent graph specifies the paths of gene flow but not the particular founder alleles traveling down the paths. This paper explores algorithms for implementing Thompson's suggestion for codominant markers in the context of automatic haplotyping, estimating location scores, and computing gene-clustering statistics for robust linkage analysis. Realistic numerical examples demonstrate the feasibility of the algorithms.

Alleles↗
PubMed1996

Selected locus and multiple panel models for radiation hybrid mapping.

We develop two new types of models for whole-genome radiation hybrid mapping using the general multipoint framework. The first, selected locus models, are appropriate for mapping markers in the region of a selectable locus that was used in creation of the hybrids. The models allow for strong retention of the selectable locus, with retention rates decreasing with increasing distance from the selectable locus in both directions. We illustrate the application of these models with 10 chromosome 17 sequence-tagged site (STS) markers and the thymidine kinase (TK) locus typed on a whole-genome hybrid panel in which TK was used in the selection process. The second set of models are appropriate when loci typed on two or more independent panels are to be used to build maps. Maps can be built assuming interlocus distances are independent or proportional between the panels, and the hypothesis of proportional distances can be tested. We illustrate the application of these models by using 27 chromosome 21 STS markers typed on two hybrid panels created with radiation doses of approximately 10,000 and approximately 50,000 Rads.

Chromosome Mapping↗
PubMed1996

[The effect of the albumin concentration on the relation between the concentration of ionized calcium and total calcium in the blood of dogs].

Based on the results of 367 healthy dogs of different age, it could be demonstrated that the concentration of ionized calcium corrected to the pH-value of 7.4 ([Cai (7.4)]) as well as the concentration of total calcium ([Catot]) clearly decreased with increasing age. The most obvious changes were found during the first four months. The [Cai (7.4)] was not influenced distinctly by sex or by breed. The reference range (2.5-97.5% quantil) for [Cai (7.4)] in heparinized plasma was 1.32-1.51 mmol/l in 4-months- to 1-year-old dogs and 1.22-1.46 mmol/l in dogs older than one year, corresponding to a proportion of Cai to Catot of 44.9-54.9%. A moderately close correlation existed between [Cai (7.4)] and the [Catot] (r = 0.754) (n = 393 adult dogs: 180 healthy animals and 213 unselected patients). A similar correlation coefficient was found between the concentrations of Catot and albumin (r = 0.718) or total protein (r = 0.617), respectively. The proportion of Cai to Catot decreased with an increasing concentration of albumin, whereas [Cai (7.4)] tended to increase. The correction of the [Catot] for albumin did not lead to an increased correlation coefficient for the relation with [Cai (7.4)] (r = 0.676). In addition to albumin concentration, the relation between [Cai (7.4)] and the Catot is primarily influenced by complex-forming ions. This became clear by the transient citrate-induced decrease of [Cai (7.4)] whereas [Catot] increased after infusion of fresh frozen plasma in dogs suffering from diarrhea. This investigation shows the limits of the estimation of calcium homoeostasis on the basis of the [Catot].

Aging↗
PubMed1996

Bone mineral density in premenopausal women with oestrogen deficiency and symptomatic coronary heart disease.

Serum oestrogen deficiency is one of the main causes of osteoporosis in post-menopausal women. In premenopausal women, oestrogen deficiency is rare. In 13 premenopausal women with symptomatic coronary heart disease (CHD) and significantly reduced serum oestrogen levels, bone mineral density, determined by quantitative computed tomography (QCT), was not reduce. In these women, oestrogen deficiency was probably one risk factor for the development of CHD. The level of serum oestrogen that protects women from the development of CHD might be different from the level that protects them from early loss of bone mineral density. Seven of the 13 women had a history of tubal sterilisation. This might be a possible risk factor, causing ovarial dysfunction and oestrogen deficiency.

Adult↗
PubMed1995

Applications of the Dirichlet distribution to forensic match probabilities.

The Dirichlet distribution provides a convenient conjugate prior for Bayesian analyses involving multinomial proportions. In particular, allele frequency estimation can be carried out with a Dirichlet prior. If data from several distinct populations are available, then the parameters characterizing the Dirichlet prior can be estimated by maximum likelihood and then used for allele frequency estimation in each of the separate populations. This empirical Bayes procedure tends to moderate extreme multinomial estimates based on sample proportions. The Dirichlet distribution can also be employed to model the contributions from different ancestral populations in computing forensic match probabilities. If the ancestral populations are in genetic equilibrium, then the product rule for computing match probabilities is valid conditional on the ancestral contributions to a typical person of the reference population. This fact facilitates computation of match probabilities and tight upper bounds to match probabilities.

Alleles↗