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Biomedical subjects

K Lange

Publications and source records attributed to K Lange.

At least 37 records · Page 2Linked to original sources
PubMed2001

Relevance of two-stage total hepatectomy and liver transplantation in acute liver failure and severe liver trauma.

Emergency liver transplantation frequently is the only life-saving procedure in cases of acute liver failure. It remains unclear whether emergency hepatectomy with portocaval shunt followed by liver transplantation as a two-stage procedure should be performed in cases in which a donor organ is not yet available. It has been stated that "toxic liver syndrome" could be treated by means of this strategy. From 1990 to 1995 we performed emergency hepatectomies in eight cases of acute liver failure or traumatic liver rupture with exsanguinating bleeding. In six cases we were able to perform a subsequent liver transplantation. Five of the six patients who underwent an emergency hepatectomy died. Emergency hepatectomy led to a significant increase in epinephrine dosage until the transplantation was performed. Only after transplantation did the need for epinephrine therapy decrease. The need for oxygen support did not change during the entire observation period. Plasmatic coagulation was stabilized by substitution, showing significantly higher values at 24 h after transplantation than at 48 h before transplantation. Fibrinogen increased significantly after transplantation in this group of patients. The experiences gathered at our clinic, however, do not show advantages that would allow a recommendation of emergency hepatectomy and subsequent liver transplantation as a two-stage procedure except for situations of severe and uncontrollable hepatic bleeding. Considering the progressive destabilization of our patients, fast procurement of donor organs seems to be of imminent importance for the outcome.

Acute Disease↗
PubMed2001

SNPs and snails and puppy dogs' tails: analysis of SNP haplotype data using the gamete competition model.

The gamete competition model is a likelihood version of the transmission disequilibrium test (TDT) that is inspired by conditional logistic regression and the Bradley-Terry ranking procedure. In family-based association studies, both the TDT and the gamete competition model apply directly to data on a single nucleotide polymorphism (SNP). Because any given SNP has limited polymorphism, it is tempting to collect several SNPs within a gene into a single super marker whose alleles are haplotypes. Unfortunately, this tactic wreaks havoc with the traditional TDT, which requires codominant markers (Spielman et al. 1993; Terwilliger & Ott, 1992). Eliminating phase ambiguities by assigning haplotypes to individuals before conducting the TDT may give misleading results because only the most probable haplotypes are then considered. Because pedigree implementations of the gamete competition model can accommodate dominant as well as codominant markers, they circumvent the phase problem by including all possible phases weighted by their estimated frequencies.

Germ Cells↗
PubMed2001

Evidence for the aetiology of injuries in Australian football.

OBJECTIVES: To determine in Australian football (a) the influence of ground hardness and playing grade (level) on game speed and structure, and (b) player movement patterns throughout the game and across levels. METHODS: The design consisted of several studies. Seventeen games played on grounds of different hardness in 2000 were used to determine game speed and structure. Four first grade and four second grade grand final games (1994, 1996, 1997, 1999) were used to determine the game speed and structure on the same ground but at different levels. Fifty one players (44 first grade and seven second grade) were used to measure movement patterns within games and across levels during the 2000 season. RESULTS: There was a significant relation between ground hardness and game speed, which could lead to higher injury rates when the ground is harder. There was a 6.7% difference in game speed between the first and second grade levels reflecting differences in injury incidence. The first grade games were also characterised by a greater number of shorter, high intensity play periods and longer stop periods than the second grade games. Midfield players in the first grade games covered about 24% greater distance than their second grade counterparts, and there was a significant difference in their playing speeds. CONCLUSIONS: Over the past 40 years, the game speed in the top level of Australian football has approximately doubled. Over the same time, the number of collisions and the estimated injury incidence have also doubled. This study provides additional support to the suggestion that these variables are strongly linked. Factors such as ground hardness, playing level, and time during the game influence game speed and are therefore important in injury development in Australian football.

Athletic Injuries↗
PubMed2001

Microvillar cell surface as a natural defense system against xenobiotics: a new interpretation of multidrug resistance.

The phenomenon of multidrug resistance (MDR) is reinterpreted on the basis of the recently proposed concept of microvillar signaling. According to this notion, substrate and ion fluxes across the surface of differentiated cells occur via transporters and ion channels that reside in membrane domains at the tips of microvilli (MV). The flux rates are regulated by the actin-based cytoskeletal core structure of MV, acting as a diffusion barrier between the microvillar tip compartment and the cytoplasm. The expression of this diffusion barrier system is a novel aspect of cell differentiation and represents a functional component of the natural defense system of epithelial cells against environmental hazardous ions and lipophilic compounds. Because of the specific organization of epithelial Ca(2+) signaling and the secretion, lipophilic compounds associated with the plasma membrane are transferred from the basal to the apical cell surface by a lipid flow mechanism. Drug release from the apical pole occurs by either direct secretion from the cell surface or metabolization by the microvillar cytochrome P-450 system and efflux of the metabolites and conjugation products through the large multifunctional anion channels localized in apical MV. The natural microvillar defense system also provides a mechanistic basis of acquired MDR in tumor cells. The microvillar surface organization is lost in rapidly growing cells such as tumor or embryonic cells but is restored during exposure of tumor cells to cytotoxins by induction of a prolonged G(0)/G(1) resting phase.

Animals↗
PubMed2001

Determination of concentrations of sex steroids in blood plasma and semen of male dogs treated with delmadinone acetate or finasteride.

The concentrations of testosterone, 5 alpha-dihydrotestosterone, oestradiol and oestrone were determined in peripheral blood plasma and semen of male dogs. In an experimental study, three Beagles were treated once with delmadinone acetate (1 mg kg-1 body weight, i.m.) and three were submitted to oral applications of finasteride (1 mg kg-1 body weight) once a day for 3 weeks. In a clinical study, 51 dogs of different breeds were divided into four groups according to the total number of spermatozoa in ejaculates (normospermia, slight oligozoospermia, severe oligozoospermia and azoospermia). The testosterone concentrations were significantly lower in sperm-rich ejaculate fractions and prostatic secretions compared with blood plasma (P < 0.05). The lowest concentration of testosterone was found in prostatic fluid. Concentrations of 5 alpha-dihydrotestosterone were similar in blood plasma and sperm-rich fractions, and significantly lower in prostatic secretions (P < 0.05). The concentrations of oestradiol and oestrone did not differ between blood plasma and either ejaculate fraction. Significantly higher 5 alpha-dihydrotestosterone concentrations and significantly lower concentrations of oestradiol and oestrone were found in prostatic secretions from azoospermic ejaculates compared with prostatic secretions of normospermic and oligozoospermic ejaculates. Delmadinone acetate and finasteride caused reversible suppression of the secretory activity of the prostate gland. The application of delmadinone acetate led to a temporary alteration of maturation of epididymal spermatozoa.

5-alpha Reductase Inhibitors↗
PubMed2000

Mutation takes no vacation: can structured treatment interruptions increase the risk of drug-resistant HIV-1?

We use a mathematical model to study the dynamics of HIV-1 replication during structured treatment interruptions (STIs) in infected patients. The model predicts rapid viral rebound, restoration of a latently infected cell pool, and critically, partially resistant mutant rebound that may be missed because of high levels of wild type virus. Because partially resistant viruses are capable of mutating to full resistance, a substantial increase in their numbers represents a threat to therapeutic response durability. Compared with continued treatment, STIs may increase the chance of mutation to full resistance by several thousandfold.

Anti-HIV Agents↗
PubMed2000

Microvillar ion channels: cytoskeletal modulation of ion fluxes.

The recently presented theory of microvillar Ca(2+)signaling [Lange, K. (1999) J. Cell. Physiol.180, 19-35], combined with Manning's theory of "condensed counterions" in linear polyelectrolytes [Manning, G. S. (1969). J. Chem. Phys.51, 924-931] and the finding of cable-like ion conductance in actin filaments [Lin, E. C. & Cantiello, H. F. (1993). Biophys. J.65, 1371-1378], allows a systematic interpretation of the role of the actin cytoskeleton in ion channel regulation. Ion conduction through actin filament bundles of microvilli exhibits unique nonlinear transmission properties some of which closely resemble that of electronic semiconductors: (1) bundles of microfilaments display significant resistance to cation conduction and (2) this resistance is decreased by supply of additional energy either as thermal, mechanical or electromagnetic field energy. Other transmission properties, however, are unique for ionic conduction in polyelectrolytes. (1) Current pulses injected into the filaments were transformed into oscillating currents or even into several discrete charge pulses closely resembling that of single-channel recordings. Discontinuous transmission is due to the existence of counterion clouds along the fixed anionic charge centers of the polymer, each acting as an "ionic capacitor". (2) The conductivity of linear polyelectrolytes strongly decreases with the charge number of the counterions; thus, Ca(2+)and Mg(2+)are effective modulator of charge transfer through linear polyelectrolytes. Field-dependent formation of divalent cation plugs on either side of the microvillar conduction line may generate the characteristic gating behavior of cation channels. (3) Mechanical movement of actin filament bundles, e.g. bending of hair cell microvilli, generates charge translocations along the filament structure (mechano-electrical coupling). (4) Energy of external fields, by inducing molecular dipoles within the polyelectrolyte matrix, can be transformed into mechanical movement of the system (electro-mechanical coupling). Because ionic transmission through linear polyelectrolytes is very slow compared with electronic conduction, only low-frequency electromagnetic fields can interact with the condensed counterion systems of linear polyelectrolytes. The delineated characteristics of microvillar ion conduction are strongly supported by the phenomenon of electro-mechanical coupling (reverse transduction) in microvilli of the audioreceptor (hair) cells and the recently reported dynamics of Ca(2+)signaling in microvilli of audio- and photoreceptor cells. Due to the cell-specific expression of different types and combinations of ion channels and transporters in the microvillar tip membrane of differentiated cells, the functional properties of this cell surface organelle are highly variable serving a multitude of different cellular functions including receptor-mediated effects such as Ca(2+)signaling, regulation of glucose and amino acid transport, as well as modulation of membrane potential. Even mechanical channel activation involved in cell volume regulation can be deduced from the systematic properties of the microvillar channel concept. In addition, the specific ion conduction properties of microfilaments combined with their proposed role in Ca(2+)signaling make microvilli the most likely cellular site for the interaction with external electric and magnetic fields.

Actins↗
PubMed2000

A multipoint method for detecting genotyping errors and mutations in sibling-pair linkage data.

The identification of genes contributing to complex diseases and quantitative traits requires genetic data of high fidelity, because undetected errors and mutations can profoundly affect linkage information. The recent emphasis on the use of the sibling-pair design eliminates or decreases the likelihood of detection of genotyping errors and marker mutations through apparent Mendelian incompatibilities or close double recombinants. In this article, we describe a hidden Markov method for detecting genotyping errors and mutations in multilocus linkage data. Specifically, we calculate the posterior probability of genotyping error or mutation for each sibling-pair-marker combination, conditional on all marker data and an assumed genotype-error rate. The method is designed for use with sibling-pair data when parental genotypes are unavailable. Through Monte Carlo simulation, we explore the effects of map density, marker-allele frequencies, marker position, and genotype-error rate on the accuracy of our error-detection method. In addition, we examine the impact of genotyping errors and error detection and correction on multipoint linkage information. We illustrate that even moderate error rates can result in substantial loss of linkage information, given efforts to fine-map a putative disease locus. Although simulations suggest that our method detects </=50% of genotyping errors, it generally flags those errors that have the largest impact on linkage results. For high-resolution genetic maps, removal of the errors identified by our method restores most or nearly all the lost linkage information and can be accomplished without generating false evidence for linkage by removing incorrectly identified errors.

Alleles↗
PubMed2000

Regulation of cell volume via microvillar ion channels.

A novel mechanism of cellular volume regulation is presented, which ensues from the recently introduced concept of transport and ion channel regulation via microvillar structures (Lange K, 1999, J Cell Physiol 180:19-35). According to this notion, the activity of ion channels and transporter proteins located on microvilli of differentiated cells is regulated by changes in the structural organization of the bundle of actin filaments in the microvillar shaft region. Cells with microvillar surfaces represent two-compartment systems consisting of the cytoplasm on the one side and the sum of the microvillar tip (or, entrance) compartments on the other side. The two compartments are separated by the microvillar actin filament bundle acting as diffusion barrier ions and other solutes. The specific organization of ion and water channels on the surface of microvillar cell types enables this two-compartment system to respond to hypo- and hyperosmotic conditions by activation of ionic fluxes along electrochemical gradients. Hypotonic exposure results in swelling of the cytoplasmic compartment accompanied by a corresponding reduction in the length of the microvillar diffusion barrier, allowing osmolyte efflux and regulatory volume decrease (RVD). Hypertonic conditions, which cause shortening of the diffusion barrier via swelling of the entrance compartment, allow osmolyte influx for regulatory volume increase (RVI). Swelling of either the cytoplasmic or the entrance compartment, by using membrane portions of the microvillar shafts for surface enlargement, activates ion fluxes between the cytoplasm and the entrance compartment by shortening of microvilli. The pool of available membrane lipids used for cell swelling, which is proportional to length and number of microvilli per cell, represents the sensor system that directly translates surface enlargements into activation of ion channels. Thus, the use of additional membrane components for osmotic swelling or other types of surface-expanding shape changes (such as the volume-invariant cell spreading or stretching) directly regulates influx and efflux activities of microvillar ion channels. The proposed mechanism of ion flux regulation also applies to the physiological main functions of epithelial cells and the auxiliary action of swelling-induced ATP release. Furthermore, the microvillar entrance compartment, as a finely dispersed ion-accessible peripheral space, represents a cellular sensor for environmental ionic/osmotic conditions able to detect concentration gradients with high lateral resolution. Volume regulation via microvillar surfaces is only one special aspect of the general property of mechanosensitivity of microvillar ionic pathways.

Animals↗
PubMed2000

Use of population isolates for mapping complex traits.

Geneticists have repeatedly turned to population isolates for mapping and cloning Mendelian disease genes. Population isolates possess many advantages in this regard. Foremost among these is the tendency for affected individuals to share ancestral haplotypes derived from a handful of founders. These haplotype signatures have guided scientists in the fine mapping of scores of rare disease genes. The past successes with Mendelian disorders using population isolates have prompted unprecedented interest among medical researchers in both the public and private sectors. Despite the obvious genetic and environmental complications, geneticists have targeted several population isolates for mapping genes for complex diseases.

Animals↗
PubMed2000

An animal model for anaplastic large cell lymphoma in the immunocompetent syngeneic C57Bl/6 mouse.

We report on the analysis of a murine anaplastic lymphoid cell line TS1G6, established recently by interleukin (IL)-9 transfection. TS1G6 revealed a highly characteristic pattern of large anaplastic cells with mononuclear, binuclear, or multinuclear cells resembling Hodgkin (H) or Sternberg-Reed (SR) cells. This cell line is tumorigenous after injection of as few as 10(4) lymphoma cells into nude or immunocompetent C57Bl/6 mice and leads to death from progressive disease of all treated animals within a few weeks. The histological analysis of these tumors revealed a diffuse large cell malignant lymphoma that is morphologically almost identical to human anaplastic large cell lymphoma (ALCL). The lymphoma cells did not show overexpression of the anaplastic lymphoma kinase (ALK) gene, which is found in about 50% of the cases of human ALCL. Thus, this model may be an animal model for an important subset of human ALCL. The cytokine profile, which is of the T helper 2 type, showed strong parallels to the human lymphoma counterpart. Mice suffering from such lymphomas could not be cured with a regimen using high dose cyclophosphamide similar to many ALCL patients. Such an animal model for ALCL has not yet been recognized, but may provide the basis for investigating new antitumor immunotherapies in a fully immunocompetent host.

Anaplastic Lymphoma Kinase↗
PubMed2000

Gamete-competition models.

The gamete-competition model is an application of the Bradley-Terry model for ranking of sports teams. If allele i of a marker locus is assigned parameter taui>0, then the probability that a parent with heterozygous genotype i/j transmits allele i is Pr(i/j-->)=tau(i)/(tau(i) + tau(j). Mendelian segregation corresponds to the choice tau(i)=1 for all i. To test whether Mendelian segregation is true, one can estimate the tau(i) from pedigree data and perform a likelihood-ratio test under the constraint that one tau(i) equals 1. Although this procedure generates an interesting method for performance of segregation analysis with a marker locus, its real promise lies in generalization of the transmission/disequilibrium test. Quantitative as well as qualitative outcomes can be considered. The gamete-competition model uses full pedigree data and gives an estimate of the strength of transmission distortion to affected children for each allele. Covariates are incorporated by rewriting of tau(i)=exp(beta(t)x(k)), where beta is a parameter vector and xk is a covariate vector for the kth transmitted gamete. Examples of covariates include disease-severity indicators for the child, sex of the child, or repeat number for tandem-repeat alleles.

ATP-Binding Cassette Transporters↗
PubMed2000

[Investigations of the effect of artificial and natural light on the development of sex organs and fertility of female rabbits].

234 female fattening rabbits with slaughtering on day 84 of age (6 rounds) and 62 does (11 rounds) kept under three light regimes: a) natural light (NL) with an intensity of 27 Lux on average, b) artificial light (AL 8) with 8 hours light a day and c) artificial light (AL 16) with 16 hours light a day (both AL with a mean light intensity of 60 Lux) were included in investigations. Weight of ovaries and uteri was measured and percentage of females with follicular development (follicles with diameter of > 1 mm, Corpora lutea, Corpora hemorrhagica) was verified after slaughter in fattening rabbits. Data of fertility (rate of conception, litter size and litter weight at birth and at weaning) were recorded in does to calculate on this basis pup index. Weight of ovaries was not influenced by light regime. Female rabbits kept under AL 8 had significantly lowest mean weight of uterus and lowest percentage of animals with follicular development (39.7% compared with 53.1% in AL 16 and 56.3% in NL). Against this, highest rate of conception (69.3%) and highest pup index alive born and weaned pups (593, 547 pups per 100 inseminated does resp.) were found in does kept under AL 8. Corresponding values were 65.9% rate of conception, 565 alive born and 539 weaned pups/100 does in AL 16 and 65.7%, 524, 505 pups resp. in NL.

Animals↗
PubMed2000

The polymorphic exon 1 androgen receptor CAG repeat in men with a potential inherited predisposition to prostate cancer.

Recent studies have provided epidemiological evidence in support of a possible prostate cancer susceptibility locus on the X chromosome. The androgen receptor (AR) gene, located at Xq11-12, has been implicated as a risk factor for the development of prostate cancer. To examine the potential role of the AR locus in prostate cancer susceptibility, the AR CAG repeat length was measured in 270 Caucasian men with prostate cancer from 133 unrelated families. Each of these families has two or more confirmed cases of prostate cancer occurring in first- and/or second-degree relatives. No evidence for linkage of the AR gene to prostate cancer was observed. We tested for the previously reported association of short CAG alleles with prostate cancer using t tests, Pearson's chi2 tests, and logistic regression; analyses were subsequently repeated to incorporate only men with moderate- to high-grade prostate cancer. No association between AR CAG allele length and prostate cancer was detected when either a subset of unrelated patients or a subset of unrelated patients with moderate- to high-grade cancer was compared with a set of unrelated controls. We failed to detect an association between short AR CAG alleles and early age of prostate cancer diagnosis. Once specific hereditary prostate cancer genes have been identified, future studies can more carefully delineate the potential role of this AR polymorphism as a modifier locus in high-risk families.

Adult↗
PubMed1999

Neuroendocrine response to antipsychotics: effects of drug type and gender.

BACKGROUND: To study the influences of drug type and gender on the neuroendocrine response to neuroleptic treatment, we compared the endocrine actions of two neuroleptics with different receptor affinity profiles--a substituted benzamide, amisulpride, a selective D2-like dopamine antagonist; and a thioxanthene, flupenthixol, a mixed D1/D2-like antagonist also blocking serotonin, H1, and D1 receptors--on anterior pituitary hormone secretion in schizophrenic patients (DSM-III-R). METHODS: Blood was withdrawn at 15-min intervals to assess basal secretion of prolactin, growth hormone (GH), and thyroid-stimulating hormone (TSH). Four hundred micrograms of thyrotropin-releasing hormone (TRH) was injected i.v. to investigate drug effects on TRH-stimulated secretion of prolactin, TSH, and GH. RESULTS: Prolactin plasma levels were markedly elevated in both treatment groups. In female, but not in male patients, this elevation was significantly more pronounced under amisulpride than under flupenthixol. The prolactin response to TRH was significantly blunted by amisulpride only in male subjects. While basal TSH secretion was significantly increased by both compounds, TRH-stimulated TSH secretion was elevated only in patients treated with amisulpride. Low basal prolactin levels predicted improvement of negative symptoms in patients treated with amisulpride. CONCLUSIONS: Amisulpride's more pronounced endocrine effects may be a reflection of its distinguished pharmacology and pharmacokinetics.

Adult↗
PubMed1999

Microvillar Ca++ signaling: a new view of an old problem.

Proceeding from the recent finding that the main components of the Ca++ signal pathway are located in small membrane protrusions on the surface of differentiated cells, called microvilli, a novel concept of cellular Ca++ signaling was developed. The main features of this concept can be summarized as follows: Microvilli are formed on the cell surface of differentiating or resting cells from exocytic membrane domains, growing out from the cell surface by elongation of an internal bundle of actin filaments. The microvillar tip membranes contain all functional important proteins synthesized such as ion channels and transporters for energy-providing substrates and structural components, which are, in rapidly growing undifferentiated cells, distributed over the whole cell surface by lateral diffusion. The microvillar shaft structure, a bundle of actin filaments, forms a dense cytoskeletal matrix tightly covered by the microvillar lipid membrane and represents an effective diffusion barrier separating the microvillar tip compartment (entrance compartment) from the cytoplasm. This diffusion barrier prevents the passage of low molecular components such as Ca++ glucose and other relevant substrates from the entrance compartment into the cytoplasm. The effectiveness of the actin-based diffusion barrier is modulated by various signal pathways and effectors, most importantly, by the actin-depolymerizing/reorganizing activity of the phospholipase C (PLC)-coupled Ca++ signaling. Moreover, the microvillar bundle of actin filaments plays a dual role in Ca++ signaling. It combines the function of a diffusion barrier, preventing Ca++ influx into the resting cell, with that of a high-affinity, ATP-dependent, and IP3-sensitive Ca++ store. Activation of Ca++ signaling via PLC-coupled receptors simultaneously empties Ca++ stores and activates the influx of external Ca++. The presented concept of Ca++ signaling is compatible with all established data on Ca++ signaling. Properties of Ca++ signaling, that could not be reconciled with the basic principles of the current hypothesis, are intrinsic properties of the new concept. Quantal Ca++ release, Ca(++)-induced Ca++ release (CICR), the coupling phenomen between the filling state of the Ca++ store and the activity of the Ca++ influx pathway, as well as the various yet unexplained complex kinetics of Ca++ uptake and release can be explained on a common mechanistic basis.

Animals↗
PubMed1999

The pravastatin-induced decrease of biliary cholesterol secretion is not directly related to an inhibition of cholesterol synthesis in humans.

3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors have been reported to suppress biliary cholesterol secretion and saturation. It remains unproven whether this is mediated by inhibition of cholesterol synthesis. Therefore, the effect of a long-term administration of pravastatin on cholesterogenesis and on biliary lipid secretion was investigated in seven healthy volunteers. Placebo or 40 mg of pravastatin were taken daily at bedtime for 5 weeks using a double-blind crossover design. During the last week, 12 hours after the last drug intake 0.04 mmol [1-13C]acetate/kg. h and 0.5 g polyethylene glycol 4,000/h were infused intraduodenally for 15 hours. Plasma and duodenal bile samples were collected hourly. Thereafter, the decay of [13C]labeled plasma cholesterol was measured during the following 3 days. The fractional and absolute syntheses of plasma and biliary cholesterol were determined by gas chromatography mass spectrometry using mass isotopomer distribution analysis. At the end of the pravastatin period plasma total and low-density lipoprotein (LDL) cholesterol had decreased by 20% and 24%, respectively. Similarly, pravastatin suppressed biliary secretion rates of cholesterol, total bile acids and phospholipids (P <.05) by 46%, 36%, and 51%. As a consequence, cholesterol saturation index remained unchanged. However, fractional syntheses of cholesterol were comparable (P >.05) on placebo compared with pravastatin with 3.1% versus 4.0% in plasma and 4.3% versus 5.2% in bile after 15 hours, respectively. The mean absolute synthesis rates amounted to 0.3 mg/kg/h on placebo versus 0.4 on pravastatin (P >. 05). In conclusion, the pravastatin-induced reduction of biliary cholesterol secretion is not directly related to an inhibition of cholesterol synthesis.

Acetates↗