Biomedical subjects

Michael Weiss

Publications and source records attributed to Michael Weiss.

At least 19 recordsLinked to original sources

PubMed2007

Circulatory transport and capillary-tissue exchange as determinants of the distribution kinetics of inulin and antipyrine in dog.

A pharmacokinetic model was developed to estimate physiologically meaningful parameters of distribution kinetics from plasma concentration-time data. The model is based on simultaneously measured disposition curves of drug and vascular marker. Employing residence time distribution theory, a recirculatory model with two subsystems, the pulmonary and systemic circulation, was constructed. In addition to intravascular mixing, the axially distributed model of the systemic circulation accounts for transcapillary transport of solutes, quantified by permeability-surface area product (PS) and diffusional equilibration time. Parameters of ICG, inulin, and antipyrine were estimated from disposition data obtained in awake dogs under control conditions and during an isoproterenol infusion or moderate hypovolemia. Results suggest that distribution kinetics is (1) governed by extravascular diffusion and (2) its dependency on cardiac output decreases with increasing diffusional resistance. Hemorrhage decreased the effective PS of inulin. In conclusion, this novel mechanistic model effectively described both the permeability-limited distribution of inulin into interstitial fluid and the flow-limited distribution of antipyrine into total body water and might be useful for other drugs.

Animals↗

PubMed2006

Mechanistic modeling of digoxin distribution kinetics incorporating slow tissue binding.

This study aims to develop a mechanistic pharmacokinetic model that accounts for the kinetics of tissue binding in order to evaluate the effect of slow binding of digoxin to skeletal muscular Na(+)/K(+)-ATPase in humans. The approach is based on a minimal circulatory model with a systemic transit time density function that accounts for vascular mixing, transcapillary permeation and extravascular binding of the drug. The model parameters were estimated using previously published disposition data of digoxin in healthy volunteers and physiological distribution volumes taken from the literature. A time constant of the binding process of 34min was estimated indicating that receptor binding and not permeation clearance is the rate-limiting step of the distribution process. Model simulations suggest that up- or downregulation of sodium pumps, typically observed under physiological or pathophysiological conditions, could be detected with this method. The model allows a quantitative prediction of the effect of changes in skeletal muscular sodium pump activity on plasma levels of digoxin.

Adult↗

PubMed2006

The root endophytic fungus Piriformospora indica requires host cell death for proliferation during mutualistic symbiosis with barley.

Fungi of the recently defined order Sebacinales (Basidiomycota) are involved in a wide spectrum of mutualistic symbioses (including mycorrhizae) with various plants, thereby exhibiting a unique potential for biocontrol strategies. The axenically cultivable root endophyte Piriformospora indica is a model organism of this fungal order. It is able to increase biomass and grain yield of crop plants. In barley, the endophyte induces local and systemic resistance to fungal diseases and to abiotic stress. To elucidate the lifestyle of P. indica, we analyzed its symbiotic interaction and endophytic development in barley roots. We found that fungal colonization increases with root tissue maturation. The root tip meristem showed no colonization, and the elongation zone showed mainly intercellular colonization. In contrast, the differentiation zone was heavily infested by inter- and intracellular hyphae and intracellular chlamydospores. The majority of hyphae were present in dead rhizodermal and cortical cells that became completely filled with chlamydospores. In some cases, hyphae penetrated cells and built a meshwork around plasmolyzed protoplasts, suggesting that the fungus either actively kills cells or senses cells undergoing endogenous programmed cell death. Seven days after inoculation, expression of barley BAX inhibitor-1 (HvBI-1), a gene capable of inhibiting plant cell death, was attenuated. Consistently, fungal proliferation was strongly inhibited in transgenic barley overexpressing GFP-tagged HvBI-1, which shows that P. indica requires host cell death for proliferation in differentiated barley roots. We suggest that the endophyte interferes with the host cell death program to form a mutualistic interaction with plants.

Apoptosis↗

PubMed2006

Diverse tulasnelloid fungi form mycorrhizas with epiphytic orchids in an Andean cloud forest.

The mycorrhizal state of epiphytic orchids has been controversially discussed, and the state and mycobionts of the pleurothallid orchids, occurring abundantly and with a high number of species on stems of trees in the Andean cloud forest, were unknown. Root samples of 77 adult individuals of the epiphytic orchids Stelis hallii, S. superbiens, S. concinna and Pleurothallis lilijae were collected in a tropical mountain rainforest of southern Ecuador. Ultrastructural evidence of symbiotic interaction was combined with molecular sequencing of fungi directly from the mycorrhizas and isolation of mycobionts. Ultrastructural analyses displayed vital orchid mycorrhizas formed by fungi with an imperforate parenthesome and cell wall slime bodies typical for the genus Tulasnella. Three different Tulasnella isolates were obtained in pure culture. Phylogenetic analysis of nuclear rDNA sequences from coding regions of the ribosomal large subunit (nucLSU) and the 5.8S subunit, including parts of the internal transcribed spacers, obtained directly from the roots and from the fungal isolates, yielded seven distinct Tulasnella clades. Tulasnella mycobionts in Stelis concinna were restricted to two Tulasnella sequence types while the other orchids were associated with up to six Tulasnella sequence types. All Tulasnella sequences are new to science and distinct from known sequences of mycobionts of terrestrial orchids. The results indicate that tulasnelloid fungi, adapted to the conditions on tree stems, might be important for orchid growth and maintenance in the Andean cloud forest.

Ecuador↗

PubMed2006

Ectomycorrhiza-mediated repression of the high-affinity ammonium importer gene AmAMT2 in Amanita muscaria.

A main function of ectomycorrhizas, a symbiosis between certain soil fungi and fine roots of woody plants, is the exchange of plant-derived carbohydrates for fungus-derived nutrients. As it is required in large amounts, nitrogen is of special interest. A gene (AmAMT2) coding for a putative fungal ammonium importer was identified in an EST project of functional Amanita muscaria/poplar ectomycorrhizas. Heterologous expression of the entire AmAMT2 coding region in yeast revealed the corresponding protein to be a high-affinity ammonium importer. In axenically grown Amanita hyphae AmAMT2 expression was strongly repressed by nitrogen, independent of whether the offered nitrogen source was transported by AmAMT2 or not. In functional ectomycorrhizas the AmAMT2 transcript level was further decreased in both hyphal networks (sheath and Hartig net), while extraradical hyphae revealed strong gene expression. Together our data suggest that (1) AmAMT2 expression is regulated by the endogenous nitrogen content of hyphae and (2) fungal hyphae in ectomycorrhizas are well supported with nitrogen even when the extraradical mycelium is nitrogen limited. As a consequence of AmAMT2 repression in mycorrhizas, ammonium can be suggested as a potential nitrogen source delivered by fungal hyphae in symbiosis.

Amanita↗

PubMed2006

Modeling cardiac uptake and negative inotropic response of verapamil in rat heart: effect of amiodarone.

PURPOSE: To determine the effect of the P-glycoprotein (Pgp) modulator amiodarone on the pharmacokinetics and pharmacodynamics (PK/PD) of Pgp substrate verapamil in the perfused rat heart. METHODS: In Langendorff-perfused rat hearts, the outflow concentration-time curve and inotropic response data were measured after a 1.5 nmol dose of [3H]-verapamil (infused within 1 min) in the absence and presence of the amiodarone (1 microM) in perfusate, as well as using a double dosing regimen (0.75 nmol in a 10 min interval). These data were analyzed by a PK/PD model. RESULTS: Amiodarone failed to influence the rapid uptake and equilibrium partitioning of verapamil into the heart. The time course of the negative inotropic effect of verapamil, including the 'rebound' above the original baseline after the infusion of verapamil was stopped, could be described by a PK/PD tolerance model. Tolerance development (mean delay time, 12 min) led to a reduction in predicted steady-state effect (16%). The EC50 and Emax values as estimated in single dose experiments were 16.4+/-4.1 nM and 50.5+/-18.9 mmHg, respectively. CONCLUSIONS: The result does not support the hypothesis that Pgp inhibition by amiodarone increases cardiac uptake of the Pgp substrate verapamil.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2006

Phylogenetic analysis of nuclear small subunit rDNA sequences suggests that the endangered African Pencil Cedar, Juniperus procera, is associated with distinct members of Glomeraceae.

The endangered indigenous tree species Juniperus procera, commonly known as African Pencil Cedar, is an important component of the dry Afromontane vegetation of Ethiopia and was shown to be AM in earlier studies. Here we describe the composition of AM fungi in colonized roots of J. procera from two dry Afromontane forests of Ethiopia. The nuSSU rDNA gene was amplified from colonized roots, cloned and sequenced using AM fungal specific primers that were partly developed for this study. Molecular phylogenetic analysis revealed that all the glomeralean sequences obtained belonged exclusively to the genus Glomus (Glomeraceae). Seven distinct Glomus sequence types were identified that all are new to science. The composition of the AM fungal communities between the sampled trees, and between the two study sites in general, differed significantly. Isolation and utilization of the indigenous AM fungal taxa from the respective sites might be required for successful enrichment plantation of this threatened Juniperus species.

DNA, Fungal↗

PubMed2006

Kinetic analysis of myocardial uptake and negative inotropic effect of amiodarone in rat heart.

The distribution kinetics of the highly lipophilic antiarrhythmic agent amiodarone is not well understood. The purpose of the present investigation was to develop a pharmacokinetic-pharmacodynamic (PK/PD) model to describe cardiac uptake and the negative inotropic effect of amiodarone in the isolated perfused rat heart. Amiodarone (10 microM) was infused for 15 min to 6 hearts. The time course of outflow concentration and left ventricular developed pressure were measured and analyzed by the model. The uptake of amiodarone by the heart was flow limited and characterized by an extremely high partition coefficient with a predicted tissue washout half-live of 17 h. Only 36.8% of input amount to heart recovered within 45 min after start of the 15 min infusion. The negative inotropic effect was delayed with a time constant of 11 min and the maximal decrease in left ventricular developed pressure was described by a sigmoid E(max) model with an E(max) of 37.7% and an EC(50) of 0.53 microM. Our results suggest a rapid tissue uptake and a moderate negative inotropic effect of amiodarone after intravenous injection.

Amiodarone↗

PubMed2006

Favorable response to high-dose infliximab for refractory childhood uveitis.

OBJECTIVE: Uveitis in children most commonly is associated with juvenile idiopathic arthritis. In addition to topical glucocorticoids, treatment may include systemic immunosuppressive agents. Tumor necrosis factor alpha (TNF-alpha) has been implicated in the pathogenesis of uveitis; therefore, TNF-alpha blockade seems to be a reasonable therapeutic option to investigate. We report successful treatment of children with uveitis using infliximab. STUDY DESIGN: A retrospective study of our complete experience using infliximab for the treatment of childhood uveitis was conducted. PARTICIPANTS: Seventeen children (14 females, 3 males) with chronic uveitis were administered high-dose infliximab (10-20 mg/kg/dose). MAIN OUTCOME MEASURES: Our main outcome measure was the ability to eliminate all signs of intraocular inflammation. RESULTS: All 17 patients demonstrated a dramatic, rapid response, with no observed inflammation in 13 patients after the second infusion, and 4 patients requiring 3 to 7 infusions to achieve disease quiescence. Additional immunosuppressives and topical glucocorticoids were tapered when patients achieved no intraocular inflammation. CONCLUSIONS: In this series, high-dose infliximab was a rapidly effective, well-tolerated therapeutic agent for the treatment of chronic, medically refractory, noninfectious uveitis.

Adolescent↗

PubMed2006

Transit time dispersion in pulmonary and systemic circulation: effects of cardiac output and solute diffusivity.

We present an in vivo method for analyzing the distribution kinetics of physiological markers into their respective distribution volumes utilizing information provided by the relative dispersion of transit times. Arterial concentration-time curves of markers of the vascular space [indocyanine green (ICG)], extracellular fluid (inulin), and total body water (antipyrine) measured in awake dogs under control conditions and during phenylephrine or isoproterenol infusion were analyzed by a recirculatory model to estimate the relative dispersions of transit times across the systemic and pulmonary circulation. The transit time dispersion in the systemic circulation was used to calculate the whole body distribution clearance, and an interpretation is given in terms of a lumped organ model of blood-tissue exchange. As predicted by theory, this relative dispersion increased linearly with cardiac output, with a slope that was inversely related to solute diffusivity. The relative dispersion of the flow-limited indicator antipyrine exceeded that of ICG (as a measure of intravascular mixing) only slightly and was consistent with a diffusional equilibration time in the extravascular space of approximately 10 min, except during phenylephrine infusion, which led to an anomalously high relative dispersion. A change in cardiac output did not alter the heterogeneity of capillary transit times of ICG. The results support the view that the relative dispersions of transit times in the systemic and pulmonary circulation estimated from solute disposition data in vivo are useful measures of whole body distribution kinetics of indicators and endogenous substances. This is the first model that explains the effect of flow and capillary permeability on whole body distribution of solutes without assuming well-mixed compartments.

Adrenergic beta-Agonists↗

PubMed2006

An unusual presacral mass: extramedullary hematopoiesis.

Presacral masses are a rare finding in the adult patient, confronting the physician with diagnostic and therapeutic challenges. We present an unusual case of a symptomatic presacral mass caused by extramedullary hematopoietic tissue in a thalassemic patient and review the unique aspects of this entity.

Comorbidity↗

PubMed2006

Effects of idarubicin and idarubicinol on rat coronary resistance and vasoconstrictor responsiveness of isolated aorta and mesentery.

It has been hypothesized that coronary vasoconstriction is involved in the cardiotoxic action of anthracyclines. The purpose of this study was to determine whether an increase in coronary resistance induced by idarubicin (IDA) or its primary circulating metabolite idarubicinol (IDOL) is correlated with a decrease in vascular sensitivity to vasoconstrictor agonists. Coronary vasoconstriction was studied in single-pass perfused rat hearts after a 10-min infusion of 0.5 mg IDA or IDOL. In the endothelium-intact rat thoracic aorta and mesentery we measured the inhibition of phenylephrine (PE)- and KCl-induced contraction in the presence of IDA and IDOL, respectively. The increase in coronary vascular resistance evoked by IDOL (121%) exceeded that of IDA (75%). IDA (10-100 micromol/l) concentration-dependently diminished vascular sensitivity to PE and KCl due to a reduction in maximal contractile response (Emax), i.e. the antagonism by IDA of PE- or KCl-induced vasoconstriction was non-competitive, indicating a post-receptor cellular mechanism. These reductions of PE or KCl efficacy elicited by IDOL were significantly larger than those elicited by the corresponding doses of IDA. The decrease in efficacy of PE in the presence of IDA and IDOL was characterized by IC50 estimates of 44.3 and 30.7 mumol/l, respectively. With a 10-fold lower IC50, IDA inhibited the reactivity of small mesenteric arteries to noradrenaline with 10-fold higher potency. The correlation between the increase in coronary resistance and the decrease in vasoconstrictor responsiveness may suggest that these anthracyclines act through a common cellular mechanism.

Animals↗

PubMed2006

Sebacinales form ectendomycorrhizas with Cavendishia nobilis, a member of the Andean clade of Ericaceae, in the mountain rain forest of southern Ecuador.

Cavendishia nobilis var. capitata is an endemic member of the Ericaceae growing as a hemiepiphyte in the tropical mountain rain forest of southern Ecuador. Mycorrhizas were collected from 20 individuals along an altitudinal gradient between 1850 and 2300 m. Transmission electron microscopy was used to study the symbiotic association in detail, and phylogenetic analyses based on nuclear rDNA coding for the ribosomal large subunit (nucLSU) were carried out to identify the associated mycorrhizal fungi. Microscopic and ultrastructural investigations showed the formation of a hyphal sheath, intercellular penetration of fine hyphae and colonization of the cortical cells by swollen hyphae of the same fungus. These structures were formed by hymenomycetes and ascomycetes. Molecular phylogenetic analysis detected seven groups of mycorrhizal fungi belonging to the Sebacinales. This is the first study to obtain evidence of ectendomycorrhizas in the Vaccinioideae. The ascomycetous nucLSU sequences belonged to members of the Leotiomycetes. The ectendomycorrhiza of C. nobilis with Sebacinales is discussed as a specific, hitherto undescribed mycorrhizal subcategory of ectomycorrhizas. We propose the term 'cavendishioid mycorrhiza'. This subcategory is most likely specific for the Andean clade of Ericaceae.

Ecosystem↗

PubMed2006

Phylogenomics reveal a robust fungal tree of life.

Our understanding of the tree of life (TOL) is still fragmentary. Until recently, molecular phylogeneticists have built trees based on ribosomal RNA sequences and selected protein sequences, which, however, usually suffered from lack of support for the deeper branches and inconsistencies probably due to limited subsampling of the entire genome. Now, phylogenetic hypotheses can be based on the analysis of full genomes. We used available complete genome data as well as the eukaryote orthologous group (KOG) proteins to reconstruct with confidence basal branches of the fungal TOL. Phylogenetic analysis of a core of 531 KOGs shared among 21 fungal genomes, three animal genomes and one plant genome showed a single tree with high support resulting from four different methods of phylogenetic reconstruction. The single tree that we inferred from our dataset showed excellent nodal support for each branch, suggesting that it reflects the true phylogenetic relationships of the species involved.

Evolution, Molecular↗

PubMed2006

Safe intestinal decompression in fresh postoperative gastric bypass.

BACKGROUND: Dilatation of the Roux-limb is sometimes found following Roux-en-Y gastric bypass (RYGBP) procedures. This could be the result of a transient episode due to ileus, or a partial or complete obstruction. The risk of this complication is an increase in intraluminal pressure with the potential for leak. Blind insertion of a nasogastric tube for decompression could be risky due to possible perforation at the stapled or sutured edges. METHODS AND RESULTS: The diagnosis was made with routine extended upper gastrointestinal x-rays 24 hours after surgery. To determine the relationship of the intestinal dilatation, increase in intraluminal pressures and leaks, measurements were taken in porcine models duplicating a RYGBP. Pressures obtained at the anastomoses were higher than pressures in the jejunum between the anastomoses, and related directly to the production of leaks. Elevations of intraluminal intestinal pressures have also been observed in patients who required decompression. The angles of a freshly constructed pouch and the recent stapled or sutured edges may be easily perforated with a nasogastric tube, especially a hard one. We use a soft flexible tube. An angled-end 0.035" wire is introduced into the intestines with fluoroscopic assistance. The tube tip is perforated with a needle, and through this opening, the wire is passed into the tube. The tube is then fed over the wire for safe decompression. CONCLUSION: Decreasing the intestinal pressure by safe decompression may avoid one of the causes of leaks.

Decompression, Surgical↗

PubMed2005

Aquaporins in poplar: what a difference a symbiont makes!

The formation of ectomycorrhizas, a tight association between fine roots of trees and certain soil fungi, improves plant nutrition in a nutrient-limited environment and may increase plant survival under water stress conditions. To investigate the impact of mycorrhiza formation on plant water uptake, seven genes coding for putative water channel proteins (aquaporins) were isolated from a poplar ectomycorrhizal cDNA library. Four out of the seven genes were preferentially expressed in roots. Mycorrhiza formation resulted in an increased transcript level for three of these genes, two of which are the most prominently expressed aquaporins in roots. When expressed in Xenopus laevis oocytes, the corresponding proteins of both genes were able to transport water. Together, these data indicate, that the water transport capacity of the plasma membrane of root cells is strongly increased in mycorrhized plants. Measurements of the hydraulic conductance of intact root systems revealed an increased water transport capacity of mycorrhized poplar roots. These data, however, also indicate that changes in the properties of the plasma membrane as well as those of the apoplast are responsible for the increased root hydraulic conductance in ectomycorrhizal symbiosis.

Amino Acid Sequence↗

PubMed2005

Mechanism-based modeling of reduced inotropic responsiveness to digoxin in endotoxemic rat hearts.

The mechanisms by which endotoxemia affects myocardial contractility and responsiveness to inotropic drugs are not well understood. We examined the positive inotropic effect of digoxin in single-pass Langendorff-perfused hearts from rats after in vivo pretreatment with lipopolysaccharide (LPS, 4 mg/kg, i.p., 4 h before heart isolation). Using a mathematical modeling approach that allows differentiation between effects elicited at the receptor and postreceptor level, we studied uptake, receptor binding and effectuation kinetics after three consecutive digoxin doses (15, 30, and 45 microg) in the absence and presence of the reverse mode Na(+)/Ca(2+) exchange (NCX) inhibitor KB-R7943 (0.1 microM) in perfusate. LPS significantly depressed baseline contractility and the inotropic response to digoxin without affecting its uptake mechanism. Compared with the control group, the slope of the functional receptor occupancy (stimulus)-to-response relationship was reduced by 44% in the LPS group. Model analysis revealed a significant correlation between changes in digoxin action and LPS-induced febrile response: digoxin receptor affinity increased and the response/stimulus ratio decreased with rise in body temperature, respectively. In contrast, the diminished responsiveness to digoxin observed after NCX inhibition in the control group was not further attenuated in the LPS group. These results support the hypothesis that postreceptor events may be responsible for the diminished contractile response to digoxin during endotoxemia.

Animals↗

PubMed2005

Down-regulation of Na+ pump alpha 2 isoform in isoprenaline-induced cardiac hypertrophy in rat: evidence for increased receptor binding affinity but reduced inotropic potency of digoxin.

Cardiac hypertrophy in rats induces a down-regulation of Na(+),K(+)-ATPase alpha(2) isoform, although its functional consequences are poorly understood. Using a mathematical modeling approach that allows differentiation between effects elicited at the receptor and postreceptor level, we studied uptake, receptor binding kinetics, and positive inotropism of digoxin in single-pass Langendorff-perfused hearts of vehicle- and isoprenaline-pretreated rats (2.4 mg/kg per day over 4 days). Digoxin outflow concentration and left ventricular developed pressure data were measured for three consecutive doses (15, 30, and 45 microg) in the absence and presence of the reverse mode Na(+)/Ca(2+) exchange inhibitor 2-[2-[4-(4-nitrobenzyloxyl-)phenyl]ethyl isothiourea methansulfonate] (KB-R7943) (0.1 microM) in perfusate. In hypertrophied hearts, 1) the amount of alpha(2) receptors was reduced to 52% of control levels; 2) the digoxin binding affinity was increased 12-fold due to a decrease in dissociation rate constants of alpha(1) and alpha(2) receptors, and 3) inotropic responsiveness to digoxin the was attenuated on the stimulus-response level, where the coupling ratio of stimulus to response was reduced to 38% of control values. Only in the lowest dose level (15 microg) was this decrease in inotropic potency counterbalanced by the increase in receptor affinity. The Na(+),K(+)-ATPase isoform shift was not responsible for the diminished inotropic effect of digoxin. Coadministration of KB-R7943 significantly reduced cellular response generation at higher digoxin doses to the same limiting stimulus-response relationship in both the vehicle and isoprenaline group.

Animals↗